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Pyroglutamic acid: a unique chiral synthon
Tetrahedron: Asymmetry 20 (2009) 1581–1632
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Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Tetrahedron: Asymmetry Report Number 116
Pyroglutamic acid: a unique chiral synthon Sharad Kumar Panday a,*, Jagdish Prasad a, Dinesh Kumar Dikshit b a b
Department of Chemistry, Faculty of Engineering and Technology, M. J. P. Rohilkhand University, Bareilly, UP, India Medicinal Chemistry Division, Central Drug Research Institute, Lucknow, UP, India
a r t i c l e
i n f o
Article history: Received 26 March 2009 Accepted 8 June 2009 Available online 18 July 2009
a b s t r a c t jjj Ó 2009 Elsevier Ltd. All rights reserved.
Contents 1. 2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Asymmetric use of pyroglutamates with prior modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Reduction of carboxylic groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Activation of lactam carbonyl at C-5 by formation of thiolactam, imino, iminium ethers and as lactam acetals. . . . . . . . . . . . . . . . . . . Asymmetric use of pyroglutamates without prior modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Direct chain elongation reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Use of N-derivatized pyroglutamates for asymmetric synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Diels–Alder reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Radical cyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. N-Acylations/alkylations of native pyroglutamates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Functionalization at C-2, C-3, C-4, of pyroglutamates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Conversion of pyroglutamic acid into prolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Pyroglutamic acid or 5-oxo-proline has emerged as an important starting material for asymmetric synthesis of many natural products. From the first reported application of pyroglutamic acid in an asymmetric synthesis of Domoic acid 161a in 1982, the last two decades have witnessed an exponential outgrowth of publications on chemistry and asymmetric/biological uses of pyroglutamic acid.1b Derived from glutamic acid, derivatives of pyroglutamic acids are a cheap source of chirality. The advantage of pyroglutamic acid in asymmetric synthesis lies in a rigid five-membered skeleton with strong stereo-electronic influence of two different carbonyl entities in the molecule which can be differentially functionalized. These features of pyroglutamates have been extensively exploited
* Corresponding author. Tel./fax: +91 581 2529138. E-mail address: [email protected] (S.K. Panday). 0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2009.06.011
1581 1581 1581 1593 1605 1605 1611 1611 1611 1611 1616 1625 1629 1630 1630
and the present review makes an attempt to list out all the major advances in this area. Pyroglutamic acid has two differentially activated carbonyls. The asymmetric use of pyroglutamic acid has exploited their reactivity differences as such or by accentuating these by further derivatizations. The review is aimed to describe these developments and to explore further possibilities on the uses of pyroglutamic acid as a chiral synthon. In the present communication the major uses of pyroglutamic acid as a chiral synthon have been classified on the following lines. 2. Asymmetric use of pyroglutamates with prior modifications 2.1. Reduction of carboxylic groups The first use of pyroglutamates as chiral synthon in the synthesis of complex molecule was in the synthesis of ()-Domoic acid by Ofune et al.1a The N-protected pyroglutamic acid was reduced to
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the corresponding alcohol which was protected by TBS. This protected synthon has only one activated carbonyl which was a-alkylated in high enantiomeric excess. The reduction of carbonyl function and its subsequent protection by TBS not only excluded the deprotonation at C-2, that is, loss of chirality, but also influenced the a-approach of electrophile (Scheme 1). Similar reduction and protection sequence was also used2 in the synthesis of trans-4-cyclohexyl proline 24 (Scheme 2), an intermediate for the synthesis of fosinopril, a potent ACE inhibitor. In this case reaction of pyroglutaminol with benzaldehyde gave a bicyclic
system, where phenyl acquires an equatorial position. Alkylation of the lithio enolate proceeded with high facial selectivity to give 4-aproduct 24. Langlois et al. have carried out asymmetric synthesis of antihypertensive pyrrolidines3 34 by using 2-hydroxymethyl pyroglutamate 25 as a chiral synthon (Scheme 3). The protected 2hydroxymethylpyrrolidine-5-one was reduced to cyclic aminol 27 which was used in C–C-bond forming reaction at C-5. The carbonyl group in 29 was derivatized via thioketalization in the presence of TsOH followed by hydrogenation with Raney Ni to get
Boc
O
O
O 1. ClCO2Et/Et3N/THF, -10oC
N
terbutyldimethylsilyl chloride DMF/ imidazole
N
Boc
2. NaBH4/90%EtOH, -10oC HOOC 1
Boc
N
O
OH
3
2 O 1. LDA/THF/PhSeCl, -78oC to 0oC 2. O3/CH2Cl2, -78ºC, NaOAc, 0ºC
Boc
O OTMS
N
Boc
OTMS O 5
Bu
t
S
Bu
O
H O
N
BH3.DMS
Boc
HO
N
COOCH3 t
O S 6
OH O 7
Bu
S
t
Bu
O MeOH/p-TsOH, rt, 3h
O 1. Pyridinium dichromate, DMF, 40oC, 48h Boc N 2. CH2N2
HO
Boc N
OH
CHO H
Boc N
COOMe
Ph3P(Cl)CH2OCH3 / t-AmONa/ Benzene, rt
SePh CH-CHO H O3/CH2Cl2, -78oC
Boc N
COOMe
CHO 1. NBS/THF, rt 2. NaOAc COOMe
Boc N
12
COOMe MeOOC 12 CHO
Boc N COOMe MeOOC
CH=CHOMe H
Boc N MeOOC 11
MeOOC 10
PhSeCl/THF/Et3N/ H2O, rt
HO COOMe
MeOOC 9
OH 8
60%AcOH, 60oC, 24h
Bu
N
O
O
1. O3/CH2Cl2, -78oC, DMS, rt, 6h 2. CH2N2
t
S
t
H
135oC O 4
3. 2-methyl-2-ethyl-1,3dioxolane/p-TsOH, rt, 3h
Boc
S
Br- H Ph3+P
MeOOC
OH
H
Boc N
KOH
COOMe MeOOC
14
H
15
COOH
HN HOOC
16
COOH (-)-Domoic acid Scheme 1.
13 CH2OH 1. 2.5% KOH, rt 2. CF3COOH
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632 +
+
1. ROH/H O
COOH
N H 17
2. NaBH4
CH2OH
N H 18
O
N O 19
Ph
LAH,THF O
1. LDA 2. Br
PhCHO/H O
O
N O
Ph
Ph 20
CH2OH
N
Z-Cl/K2CO3
H2/Pd-C
CH2OH
N H 22
21
H2O-THF
1. Jones' oxidation 2. H2/Pd-C
CH2OH
N Z
COOH
N H
23
24 Scheme 2.
RO
Methylchloroformate RO DIBAH RO O O N N H COOCH3 R=H R=CH(CH3)OC2H5 R=CH(CH3)OC2H5 26 25 O
OH
N
Sodium enolate of 3',4'-methylenedioxy phenyl methyl ketone
COOCH3 27
O
O HO
RO TsOH
N
R=CH(CH3)OC2H5
N
N
O
COOCH3
O
O
COOCH3
O
O O
O
30
29
O
28 R'
H
R'' HO Reney Ni
HO 1. TsOH 29 2. Thioketalization
N COOCH3
OHC
O
32
Ph R''
1. PhMgBr
N COOCH3
O O
DMSO N COOCH3
O
R'=R''=S(CH2)2S 31
H
R'''
O O
N O
R'
2. KOH-MeOH heat
R'=R''=H R'''=OH R'=R'''=H R''=OH 34
33
SO3-Pyridine complex
O
Scheme 3.
compound 32. The resulting product on oxidation yielded an aldehyde 33 which was converted into the desired antihypertensive agent 34. Similarly the pyroglutamate-derived cyclic protected synthon has been used by Baldwin et al.4 for the generation of a Michael acceptor moiety which was used in one-pot Michael addition– alkylation sequence to yield stereodefined 3,4-disubstituted pyroglutamate derivative 36 (Scheme 4). Investigations reported by Hamada et al. on the asymmetric use of pyroglutamates with prior reduction of carbonyl group describe
the synthesis of the 2,3-dihydroxy-4-dimethylamino-5-methoxypentanoic acid5 46 a fragment of calyculins, starting from (S)-5(hydroxymethyl)-2-pyrrolidinones 18 (Scheme 5). Making use of pyroglutamic acid as a cheap chiral source, Langlois et al. reported the synthesis of enamidoaldehyde 49 as new common synthons for the preparation of analogs of sibiromycin and other antitumour antibiotics6 (Scheme 6). Compound 47 was converted into N-acylated derivative 48, by reaction with NaH and p-nitrobenzoyl chloride. Resultant N-acyl derivative 48 was converted into aldehyde 49 in three steps as shown in Scheme 6.
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
N
1. LDA 2. PhSeBr 3. O3
H O
H2C O
19
Ph
N
H
PhH2C
COOCH3
COOCH3
Sodium amide/ HMPA Alkylation with O benzyl bromide
O
35
Ph
COOCH3
COOCH3
N Ph
LDA Electrophile
H
O
36
E O
N
H
O
Ph 37 Scheme 4.
HO
MPMCl, NaH O DMSO, rt, 24 h
N H
1. DDQ, CH2Cl2-H2O (19:1), rt, 4 h
O
N
MPMO
2. CH3I, NaH, THF, rt, 1 h
H3CO
MPM 38
18
1. LDA, THF, −78 ºC, 30 min 2. PhSeCl, −78 ºC, 30 min 3. aq. H2O2, EtOAc, rt H3 CO
O
39
O
N
N MPM
1. OsO4, N-methylmorpholine N-oxide toluene-acetone-water, rt 2. 2,2-dimethoxypropane, p-TsOH, H2O, rt
MPM 40
O
O
O
O
O 20 min then rt
N
H3CO
N H
H3CO
MPM
O H3CO
42
41 O 1. LiOH, THF, H2O, 0 ºC, 30 min 2. PhCH2NH2, DPPA, Et3N DMF, 0 ºC, 1 h, rt
O H3CO N 45
O
O N Boc
O H N
H3CO BocHN
O
Ph
1. TMSOTf, CH2Cl2, 0 ºC, 1 h 2. aq. HCHO, AcOH, 5%Pd/C H2, MeOH, rt, 60 h 3. 2,2-dimethoxypropane, p-TsOH-H2O, rt
O
HO H N
O
43
44
H3C
O
(Boc)2O, DMAP Et3N, rt
CAN, CH3N-H2O, 0 ºC
Ph 6M aq HCl, MeOH 130 ºC, 1.5 h
COOH OH
H3CO H3C
CH3
N
CH3
46 Scheme 5.
A publication by Woo et al. has described the asymmetric synthesis of a-amino acids by reaction at C-3, C-4 and C-5, of pyroglutamate derivatives starting from (S)-pyroglutamic acid derivative 50.7 They also reported ring opening through 2-lithio-1,3-dithiane at low temperature furnishing compound 52, whereas reaction of 50 with vinyl magnesium bromide followed by reduction afforded compound 51 (Scheme 7). Total synthesis of (+)-monomorine 67, a natural attractant for Pharaoh ant workers was carried out from chiral cyclic b-enaminoester derived from (S) pyroglutamic acid in seven steps by Saliou et al.8 (Scheme 8). Pyroglutaminol 18 after tosylation was converted to o-tosyl derivative 62. Compound 62 on reaction with di-n-propyl lithium cuprate was converted to compound 63 having
n-Bu group at position 5. Compound 63 on reaction with dimethylsulfate followed by treatment with Meldrum’s acid and on subsequent reaction with sodium methoxide furnished b-enaminoester 64 which on hydrogenation in the presence of H2/Raney Ni afforded 65 with the desired stereochemistry. Compound 65 after the protection of NH with benzyloxy carbonyl chloride followed by reduction of alcohol group to aldehyde, was subjected to Witting reaction with CH3COCH@PPh3 ylid. The resultant compound on hydrogenation had undergone deprotection, reduction and cyclization to give (+)-monomorine 67. Stereoselective methylation of bicyclic lactams derived from Dpyroglutamic acid 68 has been reported by Armstrong et al.9 The bicyclic compound 70 was converted to 4-methyl pyroglutaminol,
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
N H
HO
TBDMSO
NaH, KI
O
N H
O
N
TBDMSO
NO2C6H4COCl
O O2N
47
18
48 CHO
1. DIBAL-H 2. QCS 3. DMF-POCl3
N
R O
O2N 49 Scheme 6.
S 2-lithio-1,3-dithiane
1. Vinyl MgBr, THF
HO
LDA, THF, −78 ºC O to 44 ºC, MoOPh
O
N
OSiBu Ph2
Boc 53 HO
PhSe
OH
O
O
N Boc
OSiBut Ph2
57
N
N Boc
OSiBut Ph2
OSiBut Ph2
N Boc
55
OSiBut Ph2
OSiBut Ph2
59
N Boc
1. THF/CH2Cl2 2. BH3DMS. THF
H3C
N
OSiBut Ph2
Boc
56
58
H 54
H3C
CH3 Me2CuLi, Ether O −78 ºC
N
LDA, THF, −78 ºC then MeI
H2O2, Pyridine CH2Cl2, −78 ºC
O
H3 C
O
N
OSiBut Ph2
Boc 52
OSiBut Ph2
LDA, PhSeCl THF, −78 ºC
Boc OsO4.NMO
HN O
1. MeMgBr, ether 2. (i) TFA (ii) NaOH(2M) (iii) NaCNBH3
Boc 50
t
S
THF, −78 ºC
2. NaBH4, CeCl3, MeOH, 0 ºC OSiBut Ph2
HO HN Boc 51
OSiBut Ph2
60
Scheme 7.
HO
N H
tosylate O TsO
H nBu
63
HCl, MeOH, LAH, ether
nBu
N H
COOCH3
R
65 H2, Pd-C, 10%, atm N Cbz
1. MeSO4 O 2. Meldrum's acid Ni(acac)2, CHCl3 3. MeONa, MeOH 1. ClCOOCH2Ph 2. PCC, CH2Cl2
H
H2, RaneyNi, 100bar
H N H 64
N H
N H
62
18 H nBu
nPr2CuLi O Ether-CH2Cl2nBu −30 ºC
H
3. CH3=CO-CH=PPh3, THF 4. H2, PtO2, atm
H
nBu
N H
R
H3C
66
67 Scheme 8.
(+)-monomorine
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
deprotection of hydroxyl groups with trifluoroacetic acid afforded (+)-hyacinthacine B1 80. Moeller et al. have modified carboxylic functional group of pyroglutamates with an objective to synthesize spirocyclic Lpyroglutamide building blocks12 86 (Scheme 12). Pyroglutamic acid was converted to its menthyl ester followed by deprotection at C-2 using Pt wire, n-Bu4PF6 and methanol as a solvent to afford C-2 methoxylated menthyl ester 82 which on reaction with allyltrimethylsilane and TiCl4 was converted to C-2 alkylated product 83. Compound 83 on reaction with methanolic ammonia and NaCN was converted to primary amide 84. Compound 84 on oxidation with aqueous OsO4/NaIO4 followed by reaction with triethylsilane and TFA using nitro methane as a solvent underwent hydrodehydroxylation to give 86 as building block. Magni et al. carried out the synthesis of (R)-3-[(S)-(5-oxo-2pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid (Pidotimod) 90 as an immunostimulating agent13a,b from pyroglutamic acid (Scheme 13). Here pyroglutamic acid was treated with ethyl L-thiaazolidine 4-carboxylate in the presence of DCC and CH2Cl2 to afford compound 88, which upon alkaline hydrolysis gave carboxylic acid
which on reduction afforded 2,4-dimethyl pyrrolidone 72 the chiral antipode, which was converted to N-protected cis-2,4-dimethylglutamide 73 in three steps (Scheme 9). Kohn et al.10 carried out the synthesis and characterization of chiral 1,2-diamines from pyroglutamic acid where pyroglutamic acid 17 on reaction with anhydrous chloral in the presence of toluene afforded bicyclic derivative 74 which on reaction with primary amine in toluene underwent ring opening of the oxazolidinone ring of bicyclic aminal 74 to furnish pyroglutamoyl amide derivative 75. Compound 75 on reduction of lactam carbonyl as well as amidic carbonyl group with lithium aluminium hydride furnished the desired 1,2-diamines 76 (Scheme 10). Sengoku et al.11 carried out asymmetric synthesis of pyrrolizidine alkaloids (+)-hyacinthacine B1 and (+)-B2. The representative synthesis of (+)-hyacinthacine B1 is described here (Scheme 11). Pyroglutamic acid derivative 77 on catalytic sharpless asymmetric dihydroxylation(AD) with AD-mix-a [(DHQ)2 PHAL ligand] afforded compound 78, which after protection, deprotection coupled with cyclization afforded compound 79. Deprotection of compound 79 with tetrabutyl ammonium fluoride in THF followed by
O
ROH/H
O
COOH
N H 68
1. NaBH4 COOR 2. PhCHO/H+ O
N H
Ph 70
OH
N H
t
1. CBr4/PPh3, pyridine
H
2. Bu3SnH, AIBN reflux toluene
H O
71
3. pTSA, H2O/MeOH
O
H3 C
O
N
69
H3C
1. LDA, THF, −78 ºC 2. MeI
H
H
+
H
CH3
N H
1. Boc anhydride H3C Et3N Boc N 2. AlMe3/NH3 H CH2Cl2
CH3 NH2 O 73
72 Scheme 9.
O
anhydrous chloral O toluene, 40 h
COOH
N H
RNH2, toluene reflux, 2 h
O
N
O
O
17
Cl3C
O
N H RHN 75
74
LiAlH4 reflux, 2 h
N H 76 RHN
Scheme 10.
O
O
O
O AD-mix-alpha[(DHQ)2PHAL ligand] HO OTBS t-BuOH/ H O
N
N
2
OH
Cbz
Cbz 78
77 H
O
H O
N TBSO
OH OH
i. Bu4NF, HF OTBS ii. TFA, H2O
N
OH
HO hyacinthacine B1 80
79 Scheme 11.
i. TBSCl, Et3N ii. MsCl, Et3N OTBS
iii. H2, Pd/C, EtOH
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
[O] Pt wire
Menthol, DCC/DMAP O
CH2Cl2
COOH
N H
O
COOR n-Bu4PF6/MeOH
N H
17
COOR O
82
81 SiMe3
COOR O
TiCl4, CH2Cl2
O
NaCN
H2O
N H
83
84
O
O Et3SiH/TFA
NH
O
OsO4/NaIO4
CONH2
NH3/MeOH
N H
OMe
N H
NH O
MeNO2
N H
N H
OH
86
85 Scheme 12.
S O
COOH
N H
+
HN
S DCC CH2Cl2 O
N H
COOEt 87
17
S
−
OH N
O
O
N
N H
COOEt
O
COOH
89
88 S ImzCO HX
O
N
N H
COX
O
X= -OC2H5, -NH2, -NHC2H5
89
Scheme 13.
89. The carboxylic acid was converted to its derivatives 90 by reaction with various nucleophiles. Lin et al. synthesized14 (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxasole 96 as a cholinergic channel activator with potent cognitive and anxiolytic activities from pyroglutamic acid 17 (Scheme 14). Pyroglutamic acid was converted to its methyl ester in situ and was subjected to Claisen condensation with acetone oxime dianion, thereby affording compound 93. The acetone oxime component in compound 93 in the presence of H2SO4 as a catalyst underwent cyclization to afford 94, which on reduction of lactam amide with borane, followed by N-methylation gave the desired ABT-418 derivative 96. Benoit Rigo et al. investigated15 various N- and C-protection and deprotection sequences in native pyroglutamate with an aim to develop different reaction methodologies for the synthesis of bioactive molecules (Scheme 15).
O
N H 17
COOH
Reaction of pyroglutamic acid chloride with isopropylidine malonate (Meldrum’s acid) is reported to give C-acylated Meldrum’s derivative whose methanolysis gave b-keto ester 103 (Scheme 16), however the reaction of acyl chloride with sodium salt of Meldrum’s acid (isopropylidene malonate) in pyridine could not be repeated by Rigo et al.15,16 Nagasaka et al.17 established a new approach to get two enantiomers of 5,5-disubstituted 2-pyrrolidinones 108 with specified configuration starting from pyroglutamic acid through its bicyclic lactam (2R,5S)-2-aryl-1-aza 3-oxabicyclo[3.3.0]oct-5-en-7-one 105 (Scheme 17). Bicyclic lactam 105 was deprotonated at C-5 by NaH and the resultant anion on Michael addition with methyl acrylate gave two diastereomeric Michael adducts 106 and 107, which were separated and pure compound 107 on acidic hydrolysis afforded the desired 5,5-disubstituted 2-pyrrolidinone 108.
1. MeOH, SOCl2 2. LiCH2CNOLi(Me)
O
Me N H 93
O
NOH
H2SO
O
Me N H 94
O
N
1. BH3, THF 2. (i) HCHO (ii) HCOOH
1. MeOH, SOCl2 2. NaH, MeI 3. LiCH2CNOLi(Me) 1. H2SO4 O
Me N Me 95
O
2. (i) BH3, THF (ii) CsF
NOH
Me N Me (ABT-418) 96
Scheme 14.
O
N
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
Pyroglutamic Acid HMDS
N
O
1. (CF3CO)2O
1. MeOCOCl 2. (COCl)2 O
COCl
COOMe 98
N 97
COOSiMe3
2. SOCl2
N
O
COCl
COCF3 99
SiMe3 (CF3CO)2O
COOSiMe3
N
O
(CF3CO)2O O CF3
COCF3 100
CF3
O
N
O
O
O 101
Scheme 15.
pyroglutamate derivative 110 through self-reproduction of chirality (Scheme 18). Ostendorf et al.19 established the synthesis of enantiopure hydroxyamidines 116, utilizing base-catalyzed enantioselective reactions such as Michael reaction (Scheme 19). Methyl pyroglutamate 111 was treated with PhMgBr at low temperature to afford tertiary alcohol, which was converted to silyl ether 112 with TBDMSOTf. Compound 112 on N-derivatization with acrylonitrile afforded compound 113 which on reductive amination of cyano group followed by N-Boc protection afforded compound 114. Compound 114 after a sequence of reactions furnished the desired bicyclic amidine 116. Acevedo et al.20 synthesized sterically constrained L-glutamine analogues (3S,4R)-3,4-dimethyl-L-glutamine 123 and (3S,4R)-3,4dimethyl-L-pyroglutamic acid from pyroglutamic acid (Scheme 20). Compound 117 already discussed1a on methylation with dimethyl lithium cuprate followed by reaction with MeI/Et2O afforded 118 which after a sequence of reactions was converted to the desired glutamine analogue 123. Marchalin et al. developed new methodology for the synthesis of (S)-thieno[f]indolizinedione 125 from N-alkylated (S)-pyroglutamic acid21 124 (Scheme 21). Olson et al.22a,b carried out reduction–iodination of methyl Nbenzyl pyroglutamate 126 to get iodide 127, which on reaction
O O OMe O
O
O
N
N H
HO O O
F3C 102
O
O
103 -
O O + DMF
O
O
Cl N O O
F3C
+
O
No reaction
O O
104
+ PY
O O Scheme 16.
In our studies on the asymmetric use of pyroglutamic acid we synthesized18 a-benzyl derivative through condensation of pyroglutamic acid with trimethylacetaldehyde to get a bicyclic derivative 109 as a chiral auxiliary which on deprotonation with LiHMDS followed by reaction with electrophiles gave chiral a-substituted
H O
O
N O Ar
COOMe
1. CH2=CHCOOMe N
2. NaH 3. DMSO.THF
+
COOMe O
N
O
O
Ar 105
Ar 107
106
107
AcOH.THF-H2O rt
COOMe O
N H
HO
108 Scheme 17.
H THF/Dioxane, TFA O
N H 17
COOH
trimethylacetaldehyde
O
N H O
109 Scheme 18.
O
1. LiHMDS, THF −78 ºC 2. Electrophile
R O
N
O H O R= -CH2Ph 110
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
PhMgBr O COOMe TBDMSOTf
N H
CN
Ph Ph OR
N H
O
1. Lawesson's reagent Ph S Ph 2. TBAF
N
114
BocHN
OTBDMS
113
Ph 1. MeI Ph 2. TFA OH 3. NaOH
N
OTBDMS
BocHN
, CoCl2 Ph 1. NaBH4 2. (Boc)2O Ph
N
NC
112a, R=H 112b, R=TBDMS
111
O
N
Ph Ph
N
OH 116
115
Scheme 19.
O
1. (CH3)2CuLi, Et2O, −78 ºC
OTBS
N
O
2. CH3I, Et2O, −78 ºC
2. HOAc, −78 ºC
Boc
Boc
4
118
+ O
OTBS
N
O
OTBS
N
119
1. LiHMDS, THF, −78 ºC
OTBS
N
1. CrO3, H2SO4 O
acetone, 0 ºC
N
COOH
Boc
Boc
Boc
118
119
120
Ni-Pr a. i-PrHN
OtBu 121
O
NH3, KCN O
b. BF3.OEt2 c. C6H12, CH2Cl2
COOtBu
N
NHBoc
H2N
THF
COOtBu
Boc 122
123 Scheme 20.
HOOC
N
O
1. SOCl2
O
Altman et al. carried out the synthesis of (S)-5-(aminoxymethyl)pyrrolidone 130 from (S)-5-(hydroxymethyl)pyrrolidone 18 through Mitsunobu reaction with hydrazoic acid followed by the hydrogenation of the resulting azide23 (Scheme 23). Wei et al.24 synthesized (S)-5-alkenyl-2-pyrrolinones 132 from N-Boc protected methylpyroglutamate 131. Ester group of compound 131 was reduced to the corresponding aldehyde with diisobutylaluminium hydride at 78 °C. Witting reaction followed by oxidation with pyridinium chlorochromate (PCC) afforded (S)-5alkenyl-2-pyrrolidinones (Scheme 24). Langlois25 et al. carried out stereoselective synthesis of (2S)-2hydroxymethylglutamic acid 136 starting from (S)-pyroglutaminol
H N
2. AlCl3
O
S
S 124
125 Scheme 21.
with vinyl magnesium bromide and dilithium tetrachloro cuprate gave 128, a precursor for peptide mimetic of the thyrotropinreleasing hormone (Scheme 22).
O
N
COOMe
1. NaBH4 2. TsCl, DMAP
I O
3. NaI, Me2CO
Bn 126
MgBr
N
Li2CuCl4
Bn 127
N Bn 129 Scheme 22.
N Bn 128
O
O
O
O
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
OH O
N H 18
1. HN3, DEAD, Ph3P
salt to afford 141 which on treatment with CH3I was converted to quaternary ammonium salt 142. Compound 142 on passing through alkaline Dowex-550A afforded (±)-deoxydysibetaine (Scheme 27). Villeneuve et al.28 carried out the synthesis of pyroglutamic acid fatty esters 145 through lipase-catalyzed esterification with medium chain alcohols (Scheme 28). Langlois et al.29 carried out diastereoselective synthesis of (±)deoxydysibetaine 152 which was prepared from methyl pyroglutamate through a regioselective Mannich reaction at C-2 (Scheme 29). Compound 146 on reaction with MsCl in pyridine followed by the introduction of azide group at position 2 using NaN3 was converted to 148, which on hydrogenation in the presence of H2/ Pd–C afforded 149. The resultant amine 149 on reaction with CH3I–iPr2NEt was converted to 151 and the desired product (±)deoxydysibetaine 152 was obtained from 151 according to the procedure already described in Scheme 27. Itoh et al.30 carried out asymmetric synthesis of 1-substituted 1,2,3,4-tetrahydro-b-carbolines employing pyroglutamic acid derivative as a chiral auxiliary (Scheme 30). Puschel et al. described the synthesis of pyrrolidinone PNA; novel conformationally restricted PNA analogues, for example, (3R,5R)(3S,5S)pyroglutamate-PNA monomers31 (Scheme 31). Compound 156, derived from pyroglutamic acid on reaction with MoOPh in the presence of LiHMDS and BuLi followed by the protection of OH group and deprotection of Boc group using Bomchloride and TFA was converted to 3-substituted product 158, which on reaction with NaH and BrCH2COOMe afforded N-acylated product 159. Compound 159 after deprotection gave an alcohol 160 which was converted to 162 by similar steps as described in Scheme 29. Compound 162 on hydrogenation with H2/Pd–C, followed by protection of amino group using Boc and subsequent reaction with H2 and Pd(OH)2 afforded 163 with deprotection of Bom. Further
NH2
O
N H 130
2. H2, Pd/C, EtOH Scheme 23.
O
N Boc 131
COOMe
1. DIBALH, PhMe
R
O
N
2. Ph3P=CHR 3. PCC
Boc 132
Scheme 24.
18 through a bicyclic silyloxypyrrole derived from versatile unsaturated lactam (Scheme 25). Compound 133 on reaction with SnCl4 and NaHCO3 was converted to 134 having hydroxyl group at position 5, which on reaction with Me3SiCN, SnCl4 followed by acidic hydrolysis afforded 136. Davies et al. achieved the synthesis and explored the utility of the 3,3-dimethyl-5-substituted-2-pyrrolidinone 140 using pyroglutamic acid as a chiral auxiliary26 (Scheme 26). Compound 18 on reaction with 2,2,dimethoxypropane in the presence of pTSA, followed by double alkylation at position 7 using LDA and MeI was converted to 138 which on acidic hydrolysis was changed to 4-substituted pyroglutaminol 139. Treatment of 139 with TBDMSCl in DMF afforded the desired product 140. Langlois et al. synthesized racemic and enantiopure (±)-deoxydysibetaine 143 from methyl pyroglutamate27 111. Compound 111 was deprotonated with LiHMDS and alkylated with Eschenmoser’s
Et3N/TBSOTf
OH O
O
N H 18
N
Bu
SnCl4
SiO
N
O Ph
35
Ph
OH O
t
CH2Cl2
NaHCO3 O 133 COOH
CN Me3SiCN
N
O
6M HCl
N
SnCl4
O
O
Ph
H3N Cl -
Ph 135
134
COOH OH
+
1. HCl 136
Scheme 25.
O OH O
N H
N
toluene, pTSA, heat
O
18
3. LDA, −78 ºC 4. MeI, −78 ºC
137
O
O MeOH
N
pTSA, heat O
138
1. LDA, −78 ºC 2. MeI, −78 ºC
2,2-dimethoxy propane
1. TBDMSCl, DMF.Im NH or Ph3CCl, DMAP OH NEt3, CH2Cl2 139
Scheme 26.
O NH R R= CH2OTBS R= CH2OCPh3 140
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O O
LiHMDS, THF Eschenmoser salt
COOMe
N H
O
CH3I
N
N H
111
O
OMe
THF
O
141
Dowex, 550A O
-
N+
N H
I-
142 O
OH
OMe
ON+
N H (±) 143
Scheme 27.
O
H2SO4 + C H OH 2 5 reflux, 24 h COOH
N H 17
Candida antarctica lipase
O
COOC2H5
N H 144
O
R=2-methyl-2-butanol
N H 145
COOR
Scheme 28.
R
R COOCH3 OH
O
R
MsCl-Py
COOCH3 OMs
O
N H 146
NaN3 DMF
N H 147
O
N H 148
COOCH3 H2-Pd/C N3
R
O
N H 149
MeI-iPr2NEt
HCHO H2, Pd/C
R
O
COOMe NH2
O
MeI
N H 150
R
R COOMe N+
N H 151
COOMe NMe2
Dowex, 550A OH-
I-
O
COOMe N+
N H R= H R= OH 152
Scheme 29.
N O
N
ClCOOCH2CCl3 N R
153
N
O
O
N
COOCH2CCl3
H
N H 155
Bu3Sn CH2Cl2, −40 ºC
N
NaOH, THF, -H2O
COOCH2CCl3
H
N R O 154 Scheme 30.
reaction of 163 under Mitsunobu conditions, followed by alkaline hydrolysis afforded 165. Oba et al.32 established novel stereocontrolled approach to conformationally constrained analogues of L-glutamic acid and L-proline via stereoselective cyclopropanation of 3,4-didehydro-Lpyroglutamic ABO ester. Compound 166 was subjected to 1,3-dipolar cycloaddition with CH2N2, followed by photolysis with benzophenone using Hg lamp and compound 168 thus obtained on hydrolysis with MeOH–HCl was converted to methyl ester 169 with deprotection of Boc group. N-Protected compound 170
on reduction with BH3–THF followed by acidic hydrolysis on Dowex 50-X8 afforded 172 (Scheme 32). Herdeis et al.33 carried out the synthesis of unsaturated orthopyroglutamic ABO ester 166 from pyroglutamic acid (Scheme 33). Pyroglutamic acid was converted to its alkenyl ester, which on reaction with mCPBA, followed by reaction with zirconocene catalyst and silver perchlorate afforded ABO ester 174, which was converted to N-protected compound 175. Compound 175 upon oxidation under usual conditions, followed by oxidative deselenenylation using H2O2 afforded 166.
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
OH TBDPSO
a. LiHMDS, BuLi, THF N
O
Bom-chloride, DIEA CH2Cl2
TBDPSO
Boc
156
O TFA: CH Cl , 0 ºC 2 2
N
b. MoOPh
Boc 157 OBom
OBom NaH, BrCH2COOMe
TBDPSO N H
O
Et3N.3HF
TBDPSO
THF
158 OBom
N
OBom
NaN3, DMF
MsCl MsO O Pyridine
HO
O
N
160
O
N
COOMe 162
161 AZ
OH
163
1. H2, Pd/C, (Boc)2O, AcOEt 2. H2, Pd(OH)2/C MeOH
N3
80 ºC
COOMe
COOMe
THF
COOMe
159 OBom
BocHN
O
N
1. adenine, PPh3 DEAD, dioxane BocHN O 2. N-benzyloxycarbonyl N -N'-methylimidazolium triflate CH2Cl2 COOMe
AZ LBiOH, THF BocHN
O then HCl
N 164
O
N
COOMe
165
COOH
Scheme 31.
N N CH2N2 O
ABO
N
ether
O
Boc 166 H O
N
H
H (Boc)2O, DMAP MeCN O COOMe
Boc 168 H
N
HCl-MeOH ABO 0 ºC
N
Boc 167 H
N H 169
H Hg-lamp(400W) ABO Benzophenone O MeCN, 0 ºC
H BH3-THF
COOMe
H
(*)
1M HCl H
H
Dowex 50-X8 COOMe
N
N H 172
Boc 171
Boc 170
*= ABO=5-methyl-2,7,8-trioxabicyclo[3,2,1]oct-lyl Scheme 32.
1. CH2=C(Me)CH2CH2OH O
N H
COOH
DCC, DMAP 2. mCPBA, CH2Cl2
N H 173
17 (Boc)2O, DMAP
CP2ZrCl2 AgClO4, CH2Cl2
O
O
O
N H
ABO
O
MeCN
N Boc 175
174
O NaN(SiMe3)2 ABO PhSeCl, DMPU THF, −78 ºC
PhSe 30% H2O2, THF O
N
O
ABO
Boc
N Boc 166
176 Scheme 33.
O
ABO
COOH
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
Stevens et al. reported a short and elegant synthetic pathway for the synthesis of 1,3-dioxo-hexahydropyrido[1,2-c][1,3]diazepine carboxylates, a new 1,3-diazepan-2,4-dione 181 containing bicyclic moiety, starting from pyroglutamate34 (Scheme 34). Compound 177 on reaction with LiHMDS was deprotected at C-2, resultant anion on reaction with electrophile afforded 178, where lactam carbonyl C–N bond was cleaved using NaH, RNCO to expend the ring and resulting product on reaction with electrophile in the presence of K2CO3 yielded 180. Compound 180 was subjected to cyclization with Grubb’s II generation catalyst thereby affording compound 181. Bourry et al. reported their studies on pyrrolidinones through reaction of methylene dichloride under Friedal–Crafts conditions, with an objective to synthesize a-hydroxymethyl ketone in the hexahydrobenzo[f]indolizine series35 (Scheme 35) using pyroglutamic acid as a chiral precursor. Mavromoustakos et al.36a,b reported the synthesis, binding studies and in vivo biological evaluation of antihypertensive analogues 188 using pyroglutamic acid as starting material (Scheme 36). Compound 111 on reaction with NaH, PhCH2Br, followed by reduction using LiBH4 was converted to N-benzyl methyl pyroglutaminol
186, which was converted to its o-tosyl derivative 187. Treatment of 187 with lithium imidazole afforded antihypertensive agent 188. Beal et al. described anodic oxidation/olefin metathesis strategy thereby developing a unified approach to the synthesis of bicyclic lactam peptidomimetics using pyroglutamic acid37 (Scheme 37). Pyroglutamic acid derivative 189 on acidic hydrolysis was converted to intermediate product and subsequent reaction with pyroglutamic acid, followed by amination using NH3 and MeOH afforded 190. Langlois et al. reported the tandem electrophilic and nucleophilic addition to bicyclic tert-butyl-dimethylsilyloxypyrrole derived from (S) pyroglutaminol38 (Scheme 38). 2.2. Activation of lactam carbonyl at C-5 by formation of thiolactam, imino, iminium ethers and as lactam acetals Suitably activated lactams and amides possess great synthetic utility for the construction of many of the nitrogen-containing heterocycles. Activation of the lactam is generally being carried out by conversion to thiolactam, imino, iminium ethers or as lactam ace-
R'
O
N H 177
LiHMDS, THF, −40 ºC O COOEt Electrophile R'=H, CH2Cl
Electrophile, K2CO3 acetone, reflux
N H 178
Grubb's 2nd generation catalyst, CH2Cl2, reflux R''' R'=H, H R''=Pr, Ph R'''=H, H
N
N
R'= H, H R''= Pr, Ph R'''= H, H
R''
O 180
N
NH
R'' O 179 COOEt
COOEt R' O
COOEt R'
O
R''NCO, NaH COOEt THF R'=H, H R'=Pr, ' Ph
R'
O N
N R''
R''' O 181
Scheme 34.
O
1. (CF3CO)2O 2. BF3.Et2O, CH2Cl2
COOH
N
CH2OH O
O O
+
N
1. (CF3CO)2O 2. BF3.Et2O
O
N
ClCH2CH2Cl O
O
O
O
O
O
182
184
183 Scheme 35.
1. SOCl2 O
COOH
N H
2. MeOH
NaH, THF O
COOMe PhCH2Br
N H
17
LiBH4, THF O
N 185
111
COOMe
25 ºC
Ph
+
OH O
N 186
DMAP or Et3N CH2Cl2 Ph
Li-N
TsCl
OTs O
N 187
N DMSO
Ph Scheme 36.
N O
N 188 Ph
N
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
H O
Boc N
O
COOMe 1. 3M HCl/EtOAc
N
Ph
NH
N H
O
O Ph
2. 17, EDCl, HOBt, CH2Cl2 3. NH3, MeOH
CONH2 N
190
189 Scheme 37.
t Bu
OH
1. SnCl4 SiO
O
N
N
2. NaHCO3 O 133
Ph
N O Ph
191
SnCl4
SnCl4 MeOH
SnCl4
Me3SiCN
MeOH
OMe O
O
Me3SiCH2CH=CH2
O 134
Ph
SnCl4
CN O
N
N
O
O
Ph
Ph 135
192
Scheme 38.
Fang et al. have carried out41 the annulation of diazomethylvinyl ketone with a variety of thiolactams prepared from (S)-pyroglutamic acid. Thiolactam derivative of pyroglutamic acid 209 was converted to 210 by Michael addition which was cyclized to get 211 in the presence of [Rh(OAc)2]2, W-2 and Ra-Ni. Resultant material on oxidation with OsO4 and H2S in methanol, followed by protection of OH group with TBSCl was converted to 212. Lithium enolate-derived reaction of 212 with t-butyl propionate afforded 213 which upon selective reduction of the double bond of side chain followed by deprotection afforded 214. Thus this synthetic strategy provided a novel route for dihydropyridones like ISO A58365A 214, the c-pyridone analog of the potent ACE inhibitor A58365A (Scheme 41). Rosset et al. have described42 the enantioselective synthesis of (5R)-2-(5-hexenyl)-5-nonyl-3,4-dihydro-2H-pyrrole and (2R,5R), 2-(5-hexenyl)-5-nonyl pyrrolidine, Monomorium minutum ant venum alkaloids, from (S)-pyroglutamic acid through lactam ether (Scheme 42). Both D- and L-pyroglutamic acids have been used43a,b with prior activation at C-5 for the synthesis of semicorrin metal complexes as enantioselective catalysts (Scheme 43). These semicorrins43b
tals. Among the activated lactams, lactam acetals are particularly useful as these react with both nucleophiles and electrophiles at C1 and C2, respectively, and with bifunctional reagents to form annulated products. Because of these reasons many workers have made use of pyroglutamates via the activation of the lactam carbonyl at C-5 of pyroglutamate. L-Pyroglutamic acid has been used as chiral starting material for the synthesis of anatoxin-a, a potent nerve depolarizing agent, via intermediacy of thiolactam.12 C–C bond formation at C-5 was effected by a sulfide contraction reaction39 (Scheme 39). Bachi et al. have described40 the synthesis of carbapenam-3carboxylates 207(a) and 207(b) starting from ethyl (S)-pyroglutamate which was converted to the corresponding 5-thioxo derivative for C–C bond formation at C-5 (Scheme 40). Compound 200 on reaction with ethyl-2-bromo-3-oxobutyrate, followed by hydrogenolysis with CH3COOH and TFA (20%) was converted to diastereomeric compounds 202, 203a and 203b, in which 203a on reaction with KOH and (Boc)2O afforded N-protected acid 204. Compound 204 was converted to its PNB ester 205 which after N-Boc deprotection followed by cyclization was converted to 207a and 207b using substituted carbodiimide.
Methyl bromo acetate in CH3CN tBuOOC
S
N
t BuOOC
CH2Cl2, PPh3, Et3N
COOCH3
2. LiBH4 in Et2O
N
Bu
Bu
193
194
O Ph3P+
1. Me2SO, CH2Cl2 OH
t
BuOOC
N
Oxalyl Chloride
CHO
t
BuOOC
Bu 195
N Bu 196
O t BuOOC
N
1. degassed N2, Pt/C, H2
Anatoxin A O
199
Bu 198 Scheme 39.
197
O
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
ethyl-2-bromo3-oxobutyrate O
COOH
N H 17
S
Et COOEt +
N H
N H
EtOOC
OH 202
203a
H 1M HCl Et in EtOAc HOOC
O
H Et COOEt + EtOOC
Et COOH
N
HOOC
Boc 204
201
COOEt
N H 203b
203a
H 1. KOH 2. DMAP, (Boc)2O, Et3N
COOEt
N H H3C
H
hydrogenation EtOOC Pt/C in H3C CH3COOH
EtOOC
COOEt NaHCO , CH Cl 3 2 2
N H 200
H dicyclohexylamine Et p-nitrobenzeldehyde KI, DMF HOOC
COOPNB
N Boc 205
H
H
CH2Cl2, Pyridine N H 206
COOPNB 1-(3'-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
+
N
N
O
O COOPNB
COOPNB 207b
207a Scheme 40.
N2
S O
O
X +
CH2 X=CHN2 X=OCH3 208
S
NaOH, THF
HN
1. [Rh(OAc)2]2 Benzene, reflux
N
O N
2. W-2, Ra-Ni, acetone
t
t BuOOC
COO Bu tBuOOC
211
210
209 OR
1. OsO4, Pyridine
OTBS
O
2. H2S, MeOH
N COOt Bu
R= H R= TBS 212
O
1. LiCA, THF, −78 ºC 2. t-Butylpropiolate, −78 ºC 3. AcOH, −78 ºC
t
BuOOC
N 213
COOtBu
TBSCl, NEt3, CH2Cl2
OH 1. W-2, Ra-Ni, acetone
O
2. HCOOH
N
HOOC
COOH ISO A 58365 A 214 Scheme 41.
225–228 possess several features that make them attractive ligands for enantioselective control of metal-catalyzed reactions. Singh et al. described44 a simple and efficient synthesis of 8methyl-3,8-diazabicyclo[3.2.1]octane (azatropane) and 3-substituted azatropanes using pyroglutamic acid as starting material and exploiting amide activation methodology (Scheme 44). Pyroglutamic acid was converted to N-methyl pyroglutamate which on reaction with Lawesson’s reagent was converted to the corresponding thio lactam. Treatment of thio lactam with methyl iodide in benzene, followed by reaction with nitro methane in the presence of triethylamine yielded nitroenamine 230. Nitroenamine
230 after catalytic hydrogenation over Pd–C in the presence of ammonium formate in absolute methanol afforded compound 231. Compound 231 on reduction of lactam carbonyl with LiAlH4 followed by N-alkylation under usual conditions furnished the desired compound 233. Liyanage et al. established45 the synthetic route for carbapyochelins via diastereoselective azidation of 5-(ethoxycarbonyl) methyl proline derivative (Scheme 45). Pyroglutamic acid derivative 234 on reduction of azide group, followed by EDC-mediated coupling of crude amine with O-benzyl salicylic acid afforded compound 235, which was subjected to the reduction
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
HOOC
1. MeOH, SOCl2 O 2. NaBH4, EtOH
N H
N
OAc HO
N 216
215
17 1. Lawesson's reagent 2. CH3I then MeONa-MeOH
OH 1. n-C9H19MgBr
MeS
ether-CH2Cl2
N
OH n-C9H19
N 218
217 n-C9H19
+
N X 219(a)
toluene
N X 219(b)
CBzCl NaHCO3 H2O
X= H
CBzCl NaHCO3 H2O
1. NaBH(OAc)3
OH
OH n-C9H19
Ac2O, Pyridine
OH HO
X= CBz
TsCl, Pyridine 2. [CH2=CH-(CH2)3]2CuLi
n-C9H19
X= H X= CBz
Me3Sil, CHCl3
R N CBZ
n-C9H19
R N H R= (CH2)4CH=CH2
R= (CH2)4CH=CH2 220
221
Scheme 42.
CN HOOC
H3COOC
O
N H 61
OEt
N 222
H3COOC
N H 223
CN
CN MeMgBr
222 CN
COOCH3
N H
N
N
Et2O
H H3 COOC
224
N
N H
COOCH3
H3 C CH3 H3 C OH 226 HO CH3
225
CN 225
COOtBu
CN (t-Bu)Me2SiCl, DMF
LiBH4 N
THF, 32 ºC
H HOH2C
N
imidazole, 40 ºC
H
CH2OH
227
N
N t Bu
OSi
OSi
t
Bu
228 Scheme 43.
Lawesson's reagent O
N Me
S
COOMe
COOMe
i. CH3I, PhH
O2N
ii. CH3NO2, Et3N, DMF
H
229b
229a
HCO2NH4
N Me
Pd-C, MeOH N H 231
LAH pellets O
THF
COOMe
230 Me N
Me N
N Me
RCl K2CO3 DMF
N H 232
Me N
N R 233
Scheme 44.
of ethyl ester group in the presence of lithium borohydride to give 236. Compound 236 on further hydrogenolysis followed by cyclization with Burgess reagent afforded 237. Compound 237 on deprotection of t-butyl group afforded the desired carbapyochelins 238. In a view to develop methodologies for the chirospecific synthesis of 5-butyl-2-heptyl pyrrolidines, Shiosaki et al. reported a pro-
cedure46 for the asymmetric synthesis of 5-substituted prolines from pyroglutamates, in which the key steps adopted were the thiolactam formation from lactam of pyroglutamates followed by induction of side chain at C-5 through sulfide contraction and reduction sequences (Scheme 46). Corey et al.47 have utilized C-5 centre of the pyroglutamate by reduction for the synthesis of poly functional, structurally defined
1597
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
OBn N3 N Me 234
EtOOC
COOtBu
O
i. Pd/C, H2, EtOH
LiBH4. Et2O
ii. O-Bn-salicylic acid EDC, Et3N, DMAP
HN COOtBu
N Me
EtOOC 235
OBn
HN HO 236
O
i. Pd/C,H2, EtOH ii. Burgess reagent THF t COO Bu
O
N Me
OH
O TFA/DCM anisole
COOtBu
N Me
N
237
COOH N Me. TFA
N OH 238
Scheme 45.
R1 t
Bu O O
S
N
But O
R2 R2 =SOOCF3
O
Bu
Ph3P
ButO
( )5
CH2Cl2
ButO
O
Bu
PtO2,
( )5 N O
CH3
50Psi, H2
CH3 COOBu
N Bu
240
239 Pd/charcoal cyclohexane
COOBu CH ( )5 3 S
+ N
241
But O
( )5 N O
242
CH3
But O +
N O
Bu 243
( )5 CH3
Bu 244
Scheme 46.
catalyst 252, which finds use in the enantioselective addition of dialkylzinc reagents to aldehydes (Scheme 47). Wistard et al. have reported the synthesis of 5-substituted pyrrolidines from N-acylated pyroglutamic acid48a,b (Scheme 48). Agarwal et al. established a concise asymmetric approach to the bridged bicyclic tropane alkaloid (+)-Ferreiginine using enyne ringclosing metathesis49 (Scheme 49). Pyroglutamic acid was converted to its benzyl ester, followed by reduction using LiEt3BH 1. DIBAL-H THF, -78oC 2. pTSA
H O
COOEt
N
H H3CO
H
Methanol-Formalin
H trimethylsilylcyanide, CH2Cl2
COOEt
N
Stannic chloride, -40oC
COOEt 246
COOEt 245 Red, H2, W-II Reney-Ni
and MeOH/pTSA to afford C-5 methoxylated ester 257, which was subsequently subjected to C-5 allylation to afford 258 with stereoselectivity. Compound 258 on reduction followed by acetylenic carbon insertion under modified Witting conditions and subsequent hydrolysis of the resultant product afforded 260. Treatment of 260 with Grubb’s catalyst yielded 261 which after a sequence of reactions afforded the desired product (+)-ferreiginine 263.
H
NMe2
N
H N NMe2 H 250
H
H
PhMgBr, THF, 0oC
Ph Ph 249 LiAlH4 OH
NMe2
H
H
NMe2
N Me
251
Scheme 47.
H N
COOEt
COOEt 247
COOEt
COOEt 248
H NC
Ph Ph OH
H N
Ph Ph OH
KOH, CH3OH, H2O
COOEt 249
H Et2Zn
H
Ph Me Ph Zn O Me2N Et 252 N
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
HO
HO
COOR''
N
COOR''
N
Nu Nu
COOR'
COOR' 253
COOR''
N
COOR'
254
255
Scheme 48.
1. iPr2EtN, BnBr O
COOH
N H
CH2Cl2 O 2. (Boc)2O, DMAP MeCN
COOBn
N
1. LiEt3BH, −78 ºC, THF
Boc 257 CH3COCN2PO(OEt)2
reduction COOBn
N
Boc N
Boc 260
259 Boc N
Me N 1. TFA, CH2Cl2, then K2CO3
H2O, DMF
PCy3 Ru Cl PCy Ph
N
Boc
PdCl2, CuCl2
Cl
2. CH2O, NaCNBH3 CH3CN
3
O
261
Grubb's 10 mol%
CHO K2CO3, MeOH
N
Boc 258
CH2Cl2
COOBn
N
Boc 256
17
BF3.OEt2 Allyltrimethylsilane −78 ºC, Et2O
MeO
2. MeOH, pTSA, 25 ºC
O
262
263
Scheme 49.
of this reaction is in the addition of trimethylsilane to various Nacyliminium ions bearing ester side chains. As a result the precursor 264 could be converted to its allylated derivative 265. Mandal et al. described an efficient synthesis of the constrained peptidomimetic 2-oxo-3-(N-9-fluorenyloxy carbonylamino)-1-azabicyclo[4.3.0]nonane-9-carboxylic acid from pyroglutamic acid51 (Scheme 51). N-Boc methyl pyroglutamate 131 on reaction with vinyl magnesium bromide afforded Micheal acceptor 266, which on reaction with Schiff’s base in the presence of Cs2CO3 followed by hydrogenation using Pd/C in EtOH/AcOH (9:1) coupled with cyclization, was converted to diastereomeric compounds 268a and 268b. Compound 268b was epimerized to 268C in the
Another approach for the preparation of pyrrolidine allylation products involving diastereoselective enzymatic ester hydrolysis (Scheme 50) has also been reported.50 An important application
XR3 '' R'O
N
COOR
COOR
N
Lewis acid
PG
PG
264
265 Scheme 50.
O
131
MeOOC
COOMe
vinylmagnesium bromide
COOtBu
(Ph)2=NCH2COOtBu NHBoc
o
THF, -40 C
CS2CO3, THF
NHBoc
O 266
267
H N
BocHN
O 268a
H NaHMDS
N
BocHN COOtBu
O
N O 269a
Ph
N O 268c
268b 1. TFA, Et3SiH, CH2Cl2 2. Fmoc-OSu, 10% Na2CO3 1,4-dioxane H H
FmocHN
10% Pd/C
EtOH/AcOH(9:1)
H
+ BocHN COOtBu
Ph
N
COOtBu
1. TFA, Et3SiH, CH2Cl2 2. Fmoc-OSu, 10% Na2CO3 1,4-dioxane H
+ FmocHN COOH
N
FmocHN
COOH O 269b Scheme 51.
N COOH O 269c
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
presence of NaHMDS. Treatment of each diastereoisomer of 268 under usual conditions afforded the desired stereospecific isomers of 269. Hanessian et al.52 synthesized N-acyloxyiminium ions generated from 4-substituted L-pyroglutamic esters with 4-(3-butenyl),4-(3-butynyl),4-(3-cinnamylmethyl) and 4-allenic ethers which subsequently underwent rapid Lewis acid-mediated carboxycyclization to afford stereodefined azacyclic compounds (Scheme 52). Conchon et al. described53 asymmetric synthesis of 3,5-disubstituted indolizidines by intramolecular addition of an allylsilane on an N-acyliminium ion derived from pyroglutamic acid. Compound 273 on reaction with benzylchloroformate in the presence of n-BuLi, followed by reduction was converted to 274, which on reaction with a-hydroxy b-trimethylsilyl-c-allyl derivative in the presence of SnCl4 was converted to 276 and subsequent reaction with PDC led to cyclization, thereby affording 278. Compound 278 after hydrogenation afforded isomers 279 and 280 (Scheme 53). Peng et al. reported the designing and synthesis of a 1,5-diazabicyclo[6,3,0]dodecane amino acid derivatives as novel dipeptide reverse-turn mimetics54 (Scheme 54). Pyroglutamic acid derivative 281 on reaction with TBSCl, followed by hydrogenation using Pd/C catalyst was converted to 282, which after N-acylation coupled with the deprotection of OH group afforded 283. Oxidation of side chain OH group of 283 followed by N-deprotection coupled with cyclization gave the desired compound 285. Angiolini et al. carried out55 synthesis of azabicyclo alkane amino acid scaffolds as reverse-turn inducer dipeptide mimics (Scheme 55). Compound 286 upon oxidation, followed by reaction with (±)-(Z)-a-phosphonoglycine trimethyl ester and subsequent protection of NH group afforded 287. Compound 287 on alkaline hydrolysis afforded 288, which on hydrogenolysis followed by
cyclization was converted to the desired molecules 289 and 290 as diastereomers. Ghammarti et al. described the synthesis of 1,5,6-10b-tetrahydro2H-pyrrolo[1,2-c]quinazoline-3-ones from pyroglutamic acid56 (Scheme 56). Danishefsky et al.57 described total synthesis of salinosporamide A, (Scheme 57) using pyroglutamic acid as a chiral starting material. Manzoni et al. reported the synthesis of spiroazabicycloalkane amino acid scaffolds as reverse-turn inducer dipeptide mimics58 starting from pyroglutamate (Scheme 58). Compound 303 on swern oxidation afforded aldehydic ester 304, which on witting reaction as described in Scheme 55 gave 305. Compound 305 after protection, deprotection and cyclization sequences afforded diastereomers 307a and 307b. Mulzer et al. synthesized rigid dipeptide mimetics. They have carried out stereocontrolled synthesis of all eight stereoisomers of 2-oxo-3-(N-Cbz-amino)-1-azabicyclo[4,3,0]nonane-9-carboxylic acid esters59 (Scheme 59). Compound 308 upon oxidation followed by witting reaction as described in Scheme 55 was converted to 310 and alkene component was subsequently reduced to get 311. Compound 311 after t-butyl ester hydrolysis, cyclization and conversion of carboxylic to its methyl ester afforded 312. Hussaini et al.60 reported a concise approach for the synthesis of cis-2,5-disubstituted pyrrolidines starting from pyroglutamic acid (Scheme 60). 5-Thioxo ethyl prolinate 200 was converted to 5alkylidine derivative 313 on reaction with diethyl bromomalonate in the presence of sodium bicarbonate. Compound 313 after Nbenzolylation afforded N-protected derivative 314. Compound 314 on hydrogenation in the presence of H2 (Pd–C), EtOH and CH2Cl2 gave N-benzoyl 2,5 disubstituted pyrrolidine 315. In another publication the same researchers have described a new methodology for the diastereoselective synthesis of 2,5-disubstituted pyrrolidine by the reduction of enamines derived from
H
H COOMe N
R'
H
Lewis acid
COOMe Lewis acid
R'=Me TMS
H O
X
N+ Boc
R'
H
O 271
N
COOMe
Boc 272 X= Cl, Br, aryl
270 Scheme 52.
1. SOCl2, NaBH4 HOOC
N H 61
O
2. TsCl, Et3N 3. Pr2CuLi, ether −20 ºC
Bu
O
N H 273
1. n-BuLi Benzylchloroformate 2. NaBH4, H2SO4 EtOH
H Bu Bu
OEt
N CBz 274
PDC, CH2Cl2
Bu
CBz
SiMe3 H
N
H2, Pd/C
CBz
MeOH
CBz
Bu
N+ R
275
R
OH
R
276
H
H Bu
N R 279
Bu
N
+ R Scheme 53.
280
O 277
OH R
H
N
N+
SnCl4 Bu
278
1600
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
1. TBSCl, N,N-diisoprpyl ethyl amine, CH2Cl2 TBSO
O O
COOH
N H
HO
N
2. H2, 10%, Pd/C, EtOAc
O
Bn 281
17
O
1. Boc-Dap(Z)-OH,EDC HOBT
HO
N,N-diisopropyl ethyl amine 2. TBAF, THF
CbzHN
O N H 282
O
Dess-Martin Periodinane
N O
CH2Cl2
O
O
O
N O
CbzHN
O
NHBoc 283
NHBoc 284
O
10%Pd/C,H2, MeOH
N O O
HN
NHBoc 285 Scheme 54.
Cbz 1. (COCl)2, DMSO, Et3N, CH2Cl2, −60 ºC
HO
(±)-(Z)-α−Phosphonoglycine trimethy lester
COOtBu
N
NBoc MeOOC
BuOK, CH2Cl2, −78 ºC, (Boc)2O, DMAP, THF
Ph 286
COOtBu
N
t
287
Ph
NHBoc HOOC
NaOH MeOH
287
COOtBu
N
1. H2, Pd/C, MeOH
Ph H2, Pd/C MeOH
N
N
2. Xylene, reflux BocHN
288
COOtBu +
O
COOtBu
N
BocHN
O 290
289
COOtBu COOMe NHBoc 291 Scheme 55.
O
N
O
COOH
SOCl2 O or ClCOCOCl
N
O
N N
COCl AlCl3 or SnCl4, CHCl3
O
N N
R
O R
R 292
294
293 Scheme 56.
pyroglutamic acid61 (Scheme 61). Compound 316 was converted to its N-Boc derivative which upon reduction in the presence of NaBH4 gave the desired product 318. Moloney et al. described62,144 a direct and versatile synthetic route for the reliable synthesis of trans-2,5-disubstituted pyrrolidines from pyroglutamic acid. N-Boc ethyl pyroglutamate 319 was reduced to 5-substituted product 320, which on reaction with PhSO2H gave 321 (Scheme 62).
Chan et al.63a–c described the conjugated addition of activated nitrogen nucleophiles, to a,b-unsaturated bicyclic lactams with an objective to synthesize enantiopure b-aminopyrrolidinones (Scheme 63) and a,b-diaminopyrrolidinones64 (Scheme 64), respectively, from (S)-pyroglutamic acid. Lithium enolate-derived Michael addition of 324 with di.tert-butyl azodicarboxylate afforded diamino lactam 325. This compound was transformed to the corresponding lactam 326 by deprotection with TFA which on
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
Ph N
R' β-face R
O
COOBn
296
N
O
O
Me
O
297
O
H
ZnCl2
PMB
CHO
COOBn
PhS-H
OEt
PMB t
H
COOtBu
N
O
O BnO
COO Bu
PMB
O
R add β to C2
H α-face 295
N
-
R add α to C3
O
PMB BnOH
COOtBu
N
EtO
C
N
O
COOtBu Me
OH COOtBu
THF, −78 ºC O
OBn
Me
OBn OBn
299
298
300
H 1. CAN, CH3CN-H2O
H N
O
2. Na, liq.NH3, −78 ºC 3. NaBH4, THF-H2O (2:1) HO
Me 301
H
OH 1. BCl3, CH2Cl2, 0 ºC O CH2 OOBn OH 2. BOPCl, TEA, CH2Cl2 3. Ph3PCl2, Pyridine, Cl CH CN, rt 3
H N
OH O
Me
O
302 Salinosporamide A
Scheme 57.
Ot Bu N HO
Ot Bu
(COCl2)2, DMSO
N
Et3N, CH2Cl2
O COCF3 303
304
Ot Bu
Ot Bu (Boc)2O, DMAP N MeOOC
THF
O COCF3 NHCbz
t-BuOK, CH2Cl2, −78 ºC
O H COCF3
O
(±)-Z-α-Phosphonoglycine trimethy lester
N
MeOOC
O COCF3 NBoc Cbz
305
2. NaBH4,MeOH 3. MeOH, reflux
306
OtBu
Ot Bu
+
N
1. H2, Pd-C, MeOH
N
O
O
O
O
BocHN
BocHN 307a
307b Scheme 58.
hydrogenolysis using Pd/C in glacial acetic acid afforded 3,4 diamino pyroglutaminols 327a and 327b. Hara et al.65 described remarkable endo selectivity on hydroxylation of bicyclic lactam enolates 328 with MoOPD and MoOPH to afford hydroxylated products 329a and 329b (Scheme 65) derived from pyroglutamic acid. In another approach Bailey et al. described the diastereoselectivity during alkylation of bicyclic lactams66 (Scheme 66). Compound 330 on reaction with acetophenone dimethyl acetal using
pTSA (catalytic amount) was converted to the corresponding product 331a, which after Li enolate-derived benzylation reaction at C7 was converted to 331b. Colombo et al. reported67 synthesis of new bicyclic lactam peptidomimetics through ring-closing metathesis reactions (Scheme 67). N-Boc-5-allyl-L-proline methyl ester 332 was converted to 333 by acidic hydrolysis with deprotection of Boc group, compound 333 on reaction with 2 benzyl 2 benzyloxycarbonylamine but-3-enoic acid and PyBropR in the presence of DIEA and DMAP
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
MeOOC COOtBu
N
HO
Dess-Martin-Periodinane CH2Cl2
Boc 308
P(O)(OMe)2
COOtBu
N
O
NHCbz
KOtBu, CH2Cl2, −78 ºC
Boc 309
CbzHN
Pt/C, ethylacetate
COOtBu
N
CbzHN
Boc
MeOOC
COOtBu
N
H COOMe
310
Boc
HCl-gas, CH2Cl2 then SOCl2, MeOH. DMF then MeOH, Hunig's base
311 H N
CbzHN
COOMe
O 312
Scheme 59.
O
N H
BrCH(COOEt)2
Lawesson's reagent COOEt CH2Cl2
S
N H
144
COOEt
(EtOOC)2C
NaHCO3
200 EtOOC
PhCOCl, Et3N
N
DMAP, CH2Cl2
EtOOC
COOEt
COPh
COOEt
N H 313
EtOOC
H2(5atm)
COOEt
N
Pd/C, EtOH CH2Cl2
EtOOC
314
COPh 315
Scheme 60.
(Boc)2O, Et3N EtOOC
EtOOC PhOC
COOMe
N H
N
DMAP
PhOC
316
COOMe
NaBH4
EtOOC
OH N
PhOC
Boc 317
Boc 318
Scheme 61.
O
N
COOEt
LiBEt3H, THF
X
−78 ºC
N
COOEt
Boc X=OH or MeO
Boc 319
320
PhSO2H CaCl2, DCM
PhO2S
N
COOEt
Boc 321
Scheme 62.
EtOOC
EtOOC
R
Nitrogen nucleophile (RH) O
N Ph
MeOH, rt O 322
O
N Ph
O 323
Scheme 63.
afforded dipeptide 334. Compound 334 on cyclization in the presence of Grubb’s reagent, followed by catalytic hydrogenation gave the desired peptidomimetic 336.
Hanessian et al.68 reported design and synthesis of diversified azacyclic inhibitors of endothelin converting enzyme. A series of azacyclic phosphonic acids were synthesized from L-pyroglutamic acid (Scheme 68) N-Boc methyl pyroglutamate 131 on reaction with allyl bromide in the presence of LiHMDS was converted to 4-substituted diastereomeric products 337a and 337b, where compound 337a was converted to its dimethylphosphonates 338a and 338b. Further reaction of allyl intermediate 338a with BH3THF and NaOH, followed by tosylation and induction of the naphthalamide moiety gave 339. Compound 339 after a sequence of reaction was converted to 340. Brana et al.69 developed a route for the synthesis of spiro-bis-clactam utilizing a chemoselective Michael reaction as a key step for
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
EtOOC
N(Bn)OBn
RHNRN
N(Bn)OBn
LDA, then O
O
N
N
O
O
Ph 322
Ph
324
N(Bn)OBn
H2N
NH2
H2, Pd/C O
N
O
Ph
(RHN)RN
TFA, DCM, rt
O
BocN=NBoc
H2 N OH
CH2OH HOAc
N H
O
NH2
+
OH O
N H
326
325
N H
327a
327b
Scheme 64.
R'' H O
R''
HO
N O R'
1. base, THF, −78 ºC
HO R'' H
H +
O
N
2. MoOPD or MoOPH −78 ºC
O
N
O R'
R''= allyl 328
O R'
(endo)
(exo) 329b
329a Scheme 65.
the synthesis (Scheme 69). Methyl N-(-p-methoxybenzyl) pyroglutamate on deprotonation with LiHMDS followed by reaction with electrophiles gave 2-substituted product 342, which on hydrogenation with Raney Ni afforded spirobis cyclic lactam 343. Harris et al.70 developed a route for the synthesis of seven macrocyclic analogues of the neuroprotective tripeptide glycyl-L-prolyl-L-glutanic acid (GPE) using pyroglutamic acid (Scheme 70) as
a chiral precursor. N-Protected pyroglutamate 311 on selective reduction of lactam carbonyl group with LiEt3BH followed by BF3Et2O mediated allylation with allyltributylstannane was converted to 344 which after deprotection of Boc, followed by N-acylation gave 347. Compound 347 after cyclization under normal conditions afforded 348 which on hydrolysis of ethyl ester afforded acid 349. Subsequent reaction of 349 with 350 in the presence of BOP-Cl gave olefin 351. Treatment of olefin over PtO2 followed by immediate deprotection of Boc and esters group afforded 352. Langlois et al. described71 the synthesis of new polyhydroxylated indolizidines from bicyclic silyloxy pyrrole (Scheme 71). Compound 134 upon oxidation was converted to regioselective isomers 353 and 354, where bicyclic derivative 353 after deprotection followed by protection with TBDMSCl, and subsequent sodium enolate-derived reaction with allyl bromide gave N-allylated products 356 and 357 which on treatment with Grubb’s catalyst underwent cyclization to give 358. Compound 358 on oxidation with OsO4 gave diols 359 and 360.
CH2Ph
H
H
H O
OR''
N R' R'= R''= H 330
Toluene, toluene p-sulphonic acid
O
LDA, TsCl
N
acetophenone dimethyl acetal ZnCl2
N
PhCH2Br
O R'
O
O R'
R'' 331a
R'' 331b
Scheme 66.
Ph PyBrop(R) CbzHN
HCl/MeOH N
COOMe
N H 333
Boc 332
N
Toluene, reflux
COOMe
COOH
DIEA, DMAP, CH 2Cl2
O NHCbz Ph cis 334
N
COOMe
COOMe
10%Pd/C
Grubb's reagent
O
N
O
H2, EtOH NH2 Ph
NHCbz Ph 335
336 Scheme 67.
COOMe
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
R''
R''
LiHMDS, THF O
−78 oC
COOMe allylbromide,
N
O
+ COOMe O
N
Boc
Boc
131
Boc
337a R''
337b
R''
O MeO
N
R''= allyl
+
P
N
OMe
COOMe
1.(i) BH3.THF, THF, 0 oC (ii) NaOH, H2O2
O MeO
Boc
o 337a 1. Super hydride,THF, −78 C COOMe 2. Ac2O, Et3N, DMAP, DCM 3. P(OMe)3, BF3.OEt2, DCM −78 oC
338a
P
N
OMe
Boc
338a
2. TsCl, Et3N, DMAP, DCM N-(1,8-dicarboxynaphthalimido) Na+ salt, DMF
COOMe
338b R'''
R''' 1.LiOH.H2O, THF/H2O/MeOH(5:4:1) 2. i-Pr2NEt, EDCl, HOBt, H-Phe-OtBu.HCl, DCM
O MeO
P
N
COOMe
O NaO P
3. HCl(gas) dioxane, reflux 4. TMSBr, DCM then 1 equiv of NaOH 0.05M
OH
OMe Boc 339 R'''= N-(1,8-dicarboxynaphthalimido)ethyl
H N
N H
R''''
O HOOC R''''=CH2(3-indolyl) 340
Scheme 68.
O
N
O
1. LiHMDS/THF NO2 Ph COOMe 2. CAN, H O
COOMe O
N H
2
PMB 341
H2,Ni/Ra
NO2
NH
O
MeOH
N H Ph 343
Ph 342 Scheme 69.
O
N H 17
COOH
1. EtOH, SOCl2
1. LiEt 3BH,THF, −78 oC, H2O2, 0 oC
O
N
2. DMAP, (Boc) 2O CH3CN
CF3COOH, CH2Cl2
tBuO COOEt +
N H
H
COOEt
H N
COOH
DCC, Et3N
O
345
N
2. BF3.OEt2, allyltributyl stannane H CH2Cl2, −78 oC
COOtBu 311
N
H
CH2Cl2
H
N
COOEt
CH2Cl2 then DMSO
HN
CH2Cl2, 0 oC
H
N
H N
COOtBu
1. PtO2, H2, THF COOtBu
H
N
2. CF3COOH, CH2Cl2
COOtBu .HCl COOtBu 350
H N
COOH
H O
O COOH
NH2.TFA 352 Scheme 70.
H2N
+
NHCOOtBu
COOtBu
O
NHCOOtBu 351
COOH O
349
H O
H
N
Dioxane
NHCOOtBu
348
BOP-Cl, Et3N,
1M eq NaOH, H2O
O
COOEt O
346
347
Cl2(PCy3)2Ru=CHPh
COOEt
COOtBu 344
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
TBDMSO
SnCl4, −78 ºC O NaHCO3
N
OH N
O
CF3COOH
O
+
N
O
Ph 133
353
SnCl4, −78 ºC Me3SiCH2CH=CH2
N H
353
O
O
+
N
N
O
O
OTBDMS R= H R= TBDMS
357
356
OTBDMS 356
354
Allyl bromide
RO TBDMSCl Im., DMF 355
Second Grubb's cat.
O Ph
Ph
NaH-KI
O
N
O
Ph 134
THF, -H 2O
O
OsO4.NMO
N
O
OTBDMS O +
N
CH3COCH3-H2O
OTBDMS N
OH
358
OH
OH 359
OH 360
Scheme 71.
Deyine et al. reported stereoselective synthetic route for the synthesis of enantiopure 3,4,5-trisubstituted piperidines, using (S)-pyroglutaminol as a chiral precursor72 (Scheme 72). Davies et al. reported73 the synthesis of an external b-turn, based on the GLDV motif of cell adhesion proteins. Pyroglutamates 364 was converted to thio ester 366 then to 5-substituted product 367 which upon hydrogenation followed by treatment with MeOH–TFA gave 368 as starting material for cyclization to get 370 (Scheme 73). Gedu et al. established the synthesis of new isoquinolines 372 starting with pyroglutamic acid via substituted ketones74 (Scheme 74). Olivo et al. achieved75 the synthesis of ()-stemoamide 377 in 11 steps from 5 acetoxy-N-crotyl-pyrrolidinone. A chiral N-acyl thiazolidinethione synthesized as an intermediate was employed for stereoselective addition to a cyclic N-acyl iminium ion (Scheme 75). Manzoni et al. reported76 stereoselective alkylation approaches for the synthesis of eight enantiopure, sterically constrained Catetrasubstituted azabicyclo alkane amino acids (Scheme 76). Pyroglutamate derivative when reacted with benzyl bromide in the presence of base gave alkylated derivatives 379 and 380 as diastereoisomers. Bracci et al. described stereoselective synthesis of functionalized 2-oxo-1-azabicyclo alkane through a ring-closing metathesis reaction thereby able to construct a seven-membered lactam 388, starting with pyroglutamate derivatives77 (Scheme 77). Compound 381 on reduction, followed by reaction with MeOH and PPTS was converted to 383 with methoxy group at C-5 O-silyl derivative 383 was converted to O-acetyl derivative 384 so as to
avoid O-deprotection. Compound 384 was transformed to 5-propenyl proline 385 on reaction with propenyl bromide in the presence of Li, CuBrMe2S and BF3Et2O. Compound 385 after N-Boc deprotection followed by N-acylation was converted to 387. Compound 387 was subjected to cyclization in the presence of Grubb’s catalyst and followed by reduction in the presence of nickel boride thereby affording cyclized products 388. 3. Asymmetric use of pyroglutamates without prior modifications Even though the earlier studies on the asymmetric use of pyroglutamates required prior modifications such as reduction at C-2 or activation at C-5 so as to prevent racemization, however few of the reports are available describing asymmetric use of pyroglutamates without prior modifications. 3.1. Direct chain elongation reactions Katritzky et al.78 discovered an expedient route for the synthesis of N-Z-pyroglutamoyl-amino acid derivative by direct coupling of the C-terminus activated N-protected pyroglutamate (Scheme 78). Toyooka et al. discovered enantioselective synthesis of a hydroxyindolizidine alkaloid using pyroglutamic acid as a starting material79 (Scheme 79). Methyl pyroglutamate was first subjected to N-protection using benzyloxy carbonyl chloride and subsequent reaction with n-butyl magnesium bromide in the presence of TMEDA resulted in ring opening coupled with the introduction of nbutyl group thereby furnishing 392. Compound 392 on Martin’s
Ph
Ph N
Ph +
N O heat
OH O
N H 18
HN
O
O
N
OH
LAH, THF O
heat
N
O
O
Ph
Ph
361
362 Scheme 72.
OH N Ph 363
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
H O
H
NaHMDS COOtBu PhCH2Br
N H 364
t
O
COO Bu THF
N
THF, −78 oC
t
S
COO Bu
N Ph
365
H
366
O
F3COCHN
H
MeOOC
COOtBu
N
H2/Pd/C/60-200 PSi
H H
MeOOC
MeOH-TFA
N H
H
H
H
BuMgCl/Et 2O/0 oC
H
COOtBu
N
t
H
K2CO3/MeOH heat
COOtBu
N
O H
COOtBu
368
Ph
367
COCH2Br
MeOOC
Ph3P/Et3N, CH3CN
Ph
F3COCHN
F3COCHN H
H
P4S10
O H
NHCOCF3 369
NH2 370
Scheme 73.
O
O
O
PPA
N
N
o
140 C
371
R
R
372 Scheme 74.
transformation produced 2,5-cis-disubstituted pyrrolidine 393. Treatment of 393 with DIBAL followed by the addition of vinyl Grignard reagent to resultant aldehyde provided alcohol 394 as a mixture of diastereomers. The cross-metathesis reaction of 394 with 1-hexen-3-one in the presence of Grubbs II generation catalyst afforded the homologated product 395. Exposure of 395 to hydrogenation in the presence of Pearlman’s catalyst furnished the two indolizidines 396a and 396b, which were separated to get ()-396a as a major diastereomer and 396b as a minor isomer. Li et al. reported80 first enantioselective synthesis of (D)-2-tertbutoxycarbonylamino-5,5-difluoro-5-phenyl-pentanoic acid 400 with an objective to incorporate in growth hormone secretagogues (Scheme 80). N-Boc ethyl pyroglutamate 319 on treatment with phenyl magnesium bromide, followed by reaction with 1,2-thioe-
S S
thane in the presence of BF3Et2O afforded two compounds 397a and 397b. Subsequent N-acylation with acetic anhydride in the presence of triethylamine afforded the desired acetamide 398. Treatment of acetamide 398 with NOBF4, HF/pyridine, followed by deacetylation yielded amino carboxylic ester 399b which after protection of primary amine with Boc group followed by ester hydrolysis afforded the desired compound 400. Gu et al. reported81 a concise synthesis of (2S,4S)-4-methylglutamic acid 406 (Scheme 81) starting from pyroglutamic acid. Compound 402 on reaction with LiN(SiMe3)2 in THF and MeI was converted to isomers 403 and 405, which after alkaline hydrolysis followed by N-Boc deprotection afforded 404 and 406. Dieterich et al.82 reported the synthesis of (2S,3S)-[3-2H1]-4methylglutamic acid and (2S,3R)-[2,3-2H2]-4-methyleneglutamic acid. Compound 131 was converted to 4-[N,N-dimethyl amino]methylene derivative 407. Compound 407 on hydrido deamination with DIBAL-H afforded 4-methylene pyroglutamate 408. Compound 408 on reaction with LiOMe in the presence of MeOH, followed by acidic hydrolysis using HBr furnished substituted glutamic acid 410 (Scheme 82). Dinsmore et al.83 described the use of a modified ring-switching strategy for the synthesis of glutamate antagonist (2S)-2-amino-3(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)propionate 417 and related compounds having two asymmetric centres, from pyroglu-
S
O N
+
AcO
O
N
Iminium ion addition
S
N
Me
Ph 373
O
Ph
374
Me H
O S
N Ph Ph 376
N
Me
375
OH
O
S
anti-aldol addition
O
N
9 steps
H
O
N
H
Me
(-)-Stemoamide 377
O Scheme 75.
O
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
( )n
COOtBu 1. base, THF, −78 oC
N
COOtBu ( )n
N
COOtBu
N
+
2. PhCH2Br 3. NaBH4, MeOH
O N 378
( )n Ph
O
Ph
O
R HN
HN
Ph
Ph 380
379 Scheme 76.
TDSO
TDSO
TDSO
LiEt3BH, THF O
N
−78 oC
COOtBu
MeOH, HO
N
1.TBAF, THF MeO
PPTS
COOt
Bu
AcO
AcO
N
COO Bu
COO Bu
AcO tBuOAc,
1-propenyl bromide LiCuBr.Me 2S BF3.Et2O
t
2.AcCl, Et3N CH2Cl2
t
Boc 383
Boc 382
Boc 381
MeO
N
N
Boc
HClO4
0 oC
t
COO Bu
N H 386
Boc
384
385 AcO
COOtBu
AcO
1. Grubb's cat.
Allyl glycine N
NMM, isopropyl chloroformate THF, −30 oC
COOtBu NHCbz
O
N
2. NaBH4-NiCl2, MeOH
COOtBu O
NHCbz 387
388 Scheme 77.
R O
BtH, SOCl2
COOH
N Z 389
O
N Z 390a
COBt + H2N
H N
CH3CN/H2O
COOH
O
Et3N
390b
N Z
O
391 Scheme 78.
i. LiHMDS, CbzCl
H MeOOC
N H 111
O
ii. nBuMgBr, TMEDA
i. Ph3SiH, BF3.OEt2
H MeOOC
NH
O
Cbz 392
H
H MeOOC
then vinylMgBr
H
H
i. DIBAL, CH 2Cl2
N
HO
Cbz 393
Cbz 394 H
H HO
N
1-hexen-3-one Grubb's II generation Catalyst
N
Pd(OH)2, EtOH
HO
H
H N
Cbz
H 396a
O 395 Scheme 79.
HO +
H
H N
H 396b
COOH R
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
i. PhMgBr ii. 1,2-di-thioethane BF3Et2O
COOEt
N Boc 319
S
S
397a
Ac2O, Et3N
S
S
F
F
F
NH2
R= Et, Me COOR 399b
COOEt
HCl/MeOH
NHAc COOEt
399a
COOEt
Ph
N 397b
Ph
HF/pyridine 398
Ph
COOEt
F
NOBF4
NHAc
Ph
+
NH2
Ph
(Boc)2O
F
LiOH
Ph
F
NHBoc
400
COOH
Scheme 80.
SOCl2 O
COOH
N H
(Boc)2O, DMAP
MeOH
O
COOMe
N H
Et3N, CH2Cl2
O
N Boc
1. LiN(SiMe3)2/THF COOMe 2. MeI
402
17 Me
Me 401
Me +
O
COOR
N H 403
O
N H 405
1. LiOH/ H2O/THF
1. LiOH/ H2O/THF
2. TFA/CH 2Cl2
2. TFA/CH 2Cl2
Me
Me
NH2
Me
NH2
COOH
HOOC
COOH
HOOC
COOR
406
404 Scheme 81.
NMe2
H
H O
N
COOMe
DIBAL-H Hexane
(ButO)CH(NMe2)2 MeOCH2CH2OMe
O
Boc 131
COOMe
N
H
O
THF, −70 oC
Boc 407
COOMe
Boc 408 H
H H
H LiOMe, MeOH THF
N
9M aq. HBr MeOOC HN
reflux
COOMe
Boc 409
HOOC H2N
COOH
410 Scheme 82.
tamic acid (Scheme 83). Aldehydic group was introduced at C-4 of N-protected pyroglutamate 411. The resultant compound 412 on amination with NH4OAc–AcOH, followed by reaction with ClSO2NCO gave diastereomers 414 and 415, subsequent reaction with K2CO3–EtOH, followed by hydrolysis afforded 417. Langlois84a,b et al. described the diastereospecific formal synthesis of (2R,3S)-2-amino-tetradeca-5,7-dien-3-ol 423, a natural product isolated from xestopongia species using epoxidation and epoxide ring-opening sequences in native pyroglutamate moiety
(Scheme 84). Compound 418 was converted to 419, which after O-deprotection at C-4 and O-protection at C-5 gave 420. Compound 420 on iodonation using NaI in DMF gave 421, which on hydrogenolysis using H2–Pd/C was converted to 422. Compound 422 on reaction with KCN in the presence of EtOH–THF underwent ring opening to give 423. Ring opening of N-alkoxycarbonyl c-lactam 424 with lithium methylphenylsulfone, resulted in the synthesis of enantiopure cis 2,5-disubstituted pyrrolidines85 (Scheme 85). Pyroglutamic acid
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
NH2 H
OHC O
ClSO2NCO
NH4OAc-AcOH
LiHMDS HCOOMe
COOtBu
N
H
O
COO Bu
N
COOtBu
O
t
NH2
H N
H 2N
HN
H HN
O H O
CH2Cl2
COOtBu 413
COOtBu 412
411
COOtBu
N
+ COOtBu
N
O
K2CO3-EtOH O
COOt
HN
heat
COOtBu
N
O COOtBu O HN COOtBu 416
COOt
Bu
Bu
415
414
HN O HCl
HN COOH
O H 2N 417 Scheme 83.
O
O
OH
OR
O
N
N
O
0.1N. HCl MsCl-Py
OR
O
Boc R= OMs 420
Boc R= CH(Me)OEt 419
Ph 418 OH
R
N
OH NHBoc
NaI DMF
O
N
I
H2/Pd/C O
N
Boc
CH3
EtOH-THF KCN
Boc 422
421
COOEt OH 423
Scheme 84.
O OR O
PhSO2CH2Li
O
PhO2S
OR
THF, −72 ºC
N
O
OR
NHCOOBn
COOBn O
NHCOOBn 426
425
R= tBu 424 H2, 1 atm Pearlman's Catalyst H3C
O
Na-Hg Amalgam
OR LiAlH4 N H 427
OH H3C
O
N H 428
Scheme 85.
derivative 424 on reaction with methylphenylsulfone in nBuLi using THF as a solvent, followed by desulfonylation using Na–Hg and Pearman’s catalyst afforded compound 425, which after hydrogenation followed by reaction with LiAlH4 afforded 428. New diastereoselective synthetic route for 2-substituted cis(2S,5S)-and trans-(2S,5R)-5-alkylprrolidinones as indolizidine and pyrrolizidine scaffolds has been reported by Mota et al.86 (Scheme 86).
Oba et al.87 reported the synthesis and reactions of novel 3,4didehydropyroglutamate derivatives through hydrogenation and ring-opening sequences with H2 and Pd/C in the presence of CH3OH. The ABO ester 432 on hydrogenation followed by ring opening afforded L-glutamic acid (Scheme 87). Another ring-opening strategy via copper (1) mediated crosscoupling of pyroglutamic acid-derived organo zinc reagent with acid chloride was reported by Hjelmgaard et al.88 (Scheme 88).
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
O
PhO2S
O
OR NHCbz
O
H
Na-Hg Na2HPO4/MeOH
430
429
H
H2 OR Pd(OH) 2 NHCbz
OR N H 431
O
Scheme 86.
O
N
ABO
1. H2, Pd/C, CH3OH
Makino et al. described89 stereoselective synthesis of (S)-(+)lycoperdic acid through an endo selective hydroxylation of the chiral bicyclic lactam enolate with MoOPH (Scheme 89). Lienolate-derived reaction of 19 with allyl bromide afforded 4-allyl derivative 439a, which on further reaction with LDA and MoOPH gave 4-allyl-4-hydroxy derivative 439b. Allyl group of 439b was subjected to hydroboration–oxidation sequences to get diol 440. Compound 440 after a sequence of reactions was converted to (+)-lycoperdic acid 442. Cohen et al. described the synthesis of (S)-(+)-lycoperdic acid90 442 starting with pyroglutamic acid derivative 443 (Scheme 90). Bromo lactam compound 443, when subjected to tandem oxidation–annulation reaction with Jones reagent at 0 °C followed by workup with potassium carbonate delivered spirolactam 444a. Sequential Boc protection and TBAF desilyation afforded pyroglu-
L-Glutamic acid 433
2. 1M HCl Reflux then Dowex 50W-X8
Boc 432 ABO= 2,7,8-trioxabicyclo[3.2.1]octane Scheme 87.
Compound 18 after tosylation, followed by reaction with NaI and MeCN was converted to iodo products 434 and subsequently to organo zinc compound 435. Compound 435 on reaction with CuCN2LiCl and RCOCl gave 438a and 438b on the one hand and through acidification afforded 436 or 437 on the other hand.
1. TsCl, Et3N, DMAP
O CH2Cl2 2. NaI, MeCN, heat
N H 18
OH
N H 434
I
0.1M HCl
Zn O DMA, 0 ºC
N H
ZnI
O 435 CuCN.2LiCl RCOCl
NHR
H
N H 436
O
and/or
+
O
O
N H 438a
R= H 437
N Ph O 438b
Scheme 88.
H O
N O
HO
H
LDA Allyl bromide -78oC
O
N
O
MoOPH
N
-78oC
O
Ph
O Ph 439b
Ph
439a
19
H
LDA
O OH O HO
BH3·THF, THF, 0oC
H
O
then CH2Cl2, NaOH
H
i. Jones' reagent
O
acetone
N
N
O
O
Ph
Ph 441a
440
O
H
O i. RuCl3, NaIO4 CCl4/CH3CN/H2O
H O
N H 441b
O O
Ph
i. 6M HCl reflux
O Scheme 89.
O
COOH NH2 COOH
O
(+)-lycoperdic acid 442
O
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
OTBS O
O
O
i. Jones reagent acetone
Br O
O
(Boc)2O, DMAP O
ii. K2CO3, acetone
N H 443
OTBDPS
O
ii. TBAF, AcOH
N H
N H
OTBDPS
444a
444b
OH
O HOOC
O
O
O
i. RuCl3, NaIO4 CCl4/CH3CN ii. TMSCHN2
O
EtOAc/ MeOH
i. 6M HCl reflux ii. ion exchange chromatography
COOH
N H 444c
-
COO H3N (+)-Lycoperdic acid 442
+
Scheme 90.
O
OMOM
N
R
O
O
Et2AlCl, Cyclopentadiene Toluene, −78 ºC
OMOM
N
R O
445
446 Scheme 91.
taminol 444b. Oxidation of 444b with RuCl3 followed by exposure of crude mixture to TMSCHN2 afforded methyl ester 444c which after acidic hydrolysis followed by purification yielded the desired (S)-(+)-lycoperdic acid 442. 3.2. Use of N-derivatized pyroglutamates for asymmetric synthesis 3.2.1. Diels–Alder reactions Highly asymmetric Diels–Alder reactions have been carried out using (S)-pyroglutamic acid derivatives as chiral dienophiles. Asymmetric Diels–Alder reaction of cyclopentadiene with chiral dienophile 445 derived from (S)-pyroglutamic acid derivatives in
O R
R N
O
O
N
OO
O R1 447
a. R= COOEt, R1= H b. R= COOEt, R1= Me
R1 448
O
the presence of a Lewis acid catalyst such as diethylaluminium chloride in toluene afforded cyclo adducts 446 with high stereoselectivity91 (Scheme 91). Strong chiral influence of pyroglutamate has also been utilized in diene component of Diels–Alder reaction. Menezes et al. have explored the use of ethyl-N-dienyl pyroglutamates as novel asymmetric diene where chiral cyclohexenyl amine derivatives 448 were obtained in good yields92 (Scheme 92). Defoin et al.93 have carried out asymmetric hetero Diels–Alder cycloadditions using chiral N-dienyl lactam and acyl nitrosodienophiles (Scheme 93). 3.2.2. Radical cyclization Asymmetric synthesis of pyrrolidinones by radical cyclization of N-allylic pyroglutamates which were synthesized from ethyl-(S)pyroglutamate has been carried out94 (Scheme 94). 3.2.3. N-Acylations/alkylations of native pyroglutamates Boisse et al. discovered95 synthetic strategies for new comptothecin analogs starting with pyroglutamic acid derivative. In one of the approaches methyl pyroglutamate after N-benzoylation with 2-nitrobenzoyl chloride in the presence of NaH, followed by reductive cyclization with SnCl2 in ethanol afforded modified precursor of camptothecins 457 (Scheme 95).
Scheme 92.
MeOOC
MeOOC N
O
N
O
RCON=O
449
450 Scheme 93.
MeOOC +
N
O
O
O
NCOR
NCOR 451
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
1. R2CH=C(R)3CHR1Br/THF/ I Sonification, Bu4NBr, KOH EtOOC
N H
O 2. LiAlH4/ SiO4 3. CH3SO2Cl/NEt3 4. NaI/ acetone
452
N
O
R3 R1
AIBN Bu3SnH, PhH reflux
N
O
R2
R2
R3
R1
R3
453
O
N +
R1 455
R2
454 Scheme 94.
O
COOMe
N H
O
NaH, THF then
COOMe
N
2-nitrobenzoyl chloride
N
COOMe
N
NO2
O
111
SnCl2, EtOH
O R1
456
R2
457
Scheme 95.
458
1. NaH, CH3COSCH2CH(CH3)COCl O
N H 177
COOEt
O
o
2. TFA, 0 C 3. HSCH2CH2NH2
N
N
CF3COOH
COOR H N
O
N
COOEt
CH3
COOH H N
H2/Pd
COOEt
O
O 460
SH
O 459
O
COOR
CH3 CH2CH2Ph
461
CH3 CH2CH2Ph
Scheme 96.
H
AcO
COOMe
N
1. SnX4, CH2Cl2 −78 ºC
X H
Boc
462
H
COOMe
N
Boc X= Cl
Bu4NOAc toluene or NaN3.DMF
R H
N
COOMe
Boc R= OAc, N3
463
464
Scheme 97.
In an attempt to develop potent ACE inhibitors such as 459 and 461 derived from pyroglutamates, N-acylations of pyroglutamates have been reported96a,b (Scheme 96). These N-acylations have been accomplished by the reaction of pyroglutamate derivative 177 with NaH and acid chloride for the synthesis of modified captopril analog 459, and with NaH and p-nitrophenylester of Z-Ala-OH for the synthesis of enalapril analog 461. Hanessian et al.97 reported the synthesis of 6-substituted hydroindole 2-carboxylic acids from pyroglutamic acid derivatives, where compound 462 on reaction with SnX4 was converted to bicyclic ester 463, and the resulting product was subsequently converted to 464 using Bu4NOAc in toluene (Scheme 97). Straight forward ring expansion of pyroglutamates to Perhydro1,3-diazepine-2,4-diones was reported by Stevens et al.98 (Scheme 98).
Bourry et al. described99 their studies on pyrrolidinones oxidation and rearrangements in the hexahydrobenz[f]indolizine-3,10dione series (Scheme 99). N-Benzyl pyroglutamic acid 466 on reaction with thionyl chloride and ClCH2CH2Cl afforded compounds 467a–467c, where compound 467a was converted to pyrrolinone 468 with HCl and O2 at room temperature. Enders et al. delivered a synthetic strategy for enantiopure triazolium salts from pyroglutamic acid and their evaluation in the benzoin condensation (Scheme 100). Pyroglutamic acid after esterification followed by reaction with phenyl magnesium bromide yielded substituted c-bytyrolactam 112a. Reduction of tertiary alcohol group of compound 112a led to lactam 469, which was then converted to triazolium salt 470100 under usual conditions. Dudot et al. described the synthesis of chiral pyroglutamate amines through hydrogenation followed by alkaline hydrolytic
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
COOR1
O O
NaH
COOR1
N H
O
COOR1
N
R2NCX N-
177
NR2
NH
O
O
R1=Bn R2=Ph
R2 465b
465a Scheme 98.
O
COOH
N Ph 466
OH
O
1. SOCl2 O ClCH2CH2Cl2 2. AlCl 3
O +
N
O
N
467b
467a
O +
O
N
HOOC 467c
conc. HCl, O2
OH
O
N
468 Scheme 99.
Ph
i. SOCl2, MeOH O
COOH
N H 17
ii. PhMgBr, THF
O
N H 112a
Ph
t-BuLi, Et3SiH
Ph
DCM
O
N H 469
OH
Ph
Ph i. Me3O+BF4-, DCM
N
ii. PhNHNH2, DCM iii. HC(OMe)3, 80 oC Ph
N
Ph
N+ BF4470
Scheme 100.
O
H CH3
N
NHPh
PhOOC
1. H2, Pd/C, MeOH 2. NaOH, MeOH 3. Separation
O HO
Ph 471a
H CH3
N
H NHPh Ph 471b
1. LiAlH4 2. H2, Pd(OH)2/C
O
H CH3
N HH
NHPh
472
Scheme 101.
cleavage of benzoyl ester101 (Scheme 101). Compound 471a was subjected to hydrogenation, followed by alkaline hydrolytic cleavage to get 471b which on reduction afforded diamine 472. Zampella et al.102 discovered amphiasterins; a new family of cytotoxic metabolites from the marine sponge plakortis quasiamphiaster, which is N-alkylated pyroglutamic acid unit (Scheme 102). Bourry et al.103 carried out studies on pyrrolidones. They described an improved synthesis of N-arylmethyl pyroglutamic acids (Scheme 103). They have also carried out studies on pyrrolidinones with an objective to improve the anticancer properties of methyl N-(3,4,40 ,5-tetramethoxybenzhydryl)pyroglutamate (HEI 81)104 (Scheme 104). In our recent publication we described the synthesis of N-[30 (acetylthio) alkanoyl] and N-[30 -mercaptoalkanoyl]-4-a-(S)-(phe-
O
COOCH3
N
OH
OH (CH)m O
O
(CH)n
(CH)m O
473a
O
(CH)n
473b Scheme 102.
nyl methyl) pyroglutamic acids and proline as potent ACE inhibitors. Lithium enolate-derived N-acylation of 4-a(S)-phenylmethyl pyroglutamate 478 with 3-acetylthioalkanoyl chloride and 3-acet-
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
N H 111
COOCH3
O
ArCH2Cl
NaH
N- + COOCH3 Na 474a
O
O
COOCH3
N
N
COOH O
O
O
O 474b
O
O
475
Scheme 103.
OSiMe3 O
O O
+ COOMe
N
H -O(SiMe3)2
O O
SiMe3
COOMe
N
+
O O O
O
476a
O
476b
477 Scheme 104.
Ph
Ph O
N H 478
COOtBu
LiHMDS, −78 oC
O
CH3COSCH2CH(R)COCl
TFA/anisole
COOtBu O
N O
S R R=H, Me 479
Ph
Ph
O
N O R R=H, Me 480a
DCHA/Et2O COOH O EtOAc/1M HCl S
Ph
O
N O
COO- DCHA O S R R=H, Me 480b
2 M H2SO4
O
N
COOH
O R R=H, Me 481
SH
Scheme 105.
ylthio-2(S)-methyl alkanoyl chloride afforded compound 479. Subsequent deprotection and purification yielded the desired ACE inhibitors 481105 (Scheme 105). Hanessian et al.106 reported the N-acyloxyiminium ion azaPrins route to octahydroindoles leading to total synthesis and structural confirmation of the antithrombolic marine natural product oscillarin (Scheme 106). Pyroglutamic acid derivative 482 after Boc deprotection was subjected to N-acylation using 483 as an acylating agent to get 484. The resultant material was converted to precursor 486 by coupling with proline derivative 485, compound 486 on deprotection under acidic condition afforded oscillarin 487. They have also described the total synthesis and structural assignment of the marine natural product Dysinosin A: a novel inhibitor of thrombin and Factor vlla107a (Scheme 107), utilizing a carbon construct strategy that generates subunits originating from L-glutamic acid, whereas Carroll et al. reported the isolation and structure determination of this new marine natural product Dysinosin A.107b Daiya et al.108 described diastereoselective heterogeneous catalysis of 2-methyl nicotinic acid 496 using pyroglutamic as chiral auxiliary (Scheme 108). Methyl pyroglutamate 111 on reaction with 2-methyl-nicotinoyl chloride (generated in situ by reaction of 2-methyl nicotinic acid 494 with thionyl chloride) under Schautann Baumann conditions afforded N-acylated pyroglutamate 495
having side chain corresponding to 2-methyl nicotinic acid, which on catalytic hydrogenation afforded N-(Z-methyl piperidine-3-oyl) methyl pyroglutamate 496 with reduction of N-acyl side chain. Lee et al.109 carried out asymmetric synthesis of trans-1-aminoindolo[2,3-a]quinolizidine 502. N-Benzyloxy carbonyl 2(S)-methyl pyroglutamate 497 on reaction with arylethylamine in the presence of Me3Al underwent ring opening. The resultant product on subsequent reduction afforded 499, which upon dehydration coupled with cyclization gave a tricyclic compound 500. Compound 500 on hydrogenation using H2/Pd–C followed by reduction afforded the desired molecule 502 (Scheme 109). Belvisi et al. reported110 stereoselective synthesis of conformationally constrained unnatural proline-based amino acids and peptidomimetics, N-Boc 4-allyl pyroglutamate derivative 503 was subjected to reduction, allylation sequence on lactam carbonyl thereby furnishing stereoisomers 505 and 506 which on treatment with Grubb’s catalyst, followed by hydrogenolysis gave 508 and 510 as stereoisomers (Scheme 110). Stereoselective alkylation of a bicyclic lactam derived from pyroglutamic acid has been reported by Zhang et al.111 (Scheme 111). Zhang et al.112 described a convenient and versatile synthesis of 6,5- and 7,5-fused lactams as peptidomimetics starting with pyroglutamate derivatives (Scheme 112). N-Boc-2(S)-ethyl pyroglutamate 131 was converted to its corresponding 4-cinnamyl
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
H 1. TFA, CH 2Cl2 then EDC HOBt, CH2Cl2
H
MOMO AcO H
PhH N
COOMe
N
MOMO
Boc
H Ph
Ph O 2. NaOMe/ MeOH 3. MOMCl,iPr2NEt, CH2Cl2
482
O
COOH 483
NH O
O H N aq.HCl/THF. 6M HO
N Boc
N
N
H
N
O
Ph
NHBoc 485
H O H N
H
Boc N
Ph MOMO 484
H
MOMO
1. LiOH, H2O/THF 2. EDC, HOBt, Et3N NH2 HCl COOMe N
COOMe
N
N
O
NHBoc
NH2
HN
Ph
NH
NH
O
O Ph
Ph
MOMO
HO
486
Oscillarin
487 Scheme 106.
MOMO OMe
MOMO H + H
H N
RO
H BopCl
COOH
(i-Pr2) NEt MeCN
O HN COOMe
488
NH2
MOMO
MOMO
H
N COOMe
MeO
TBDPSO
N
O
NH
489
+ N
Boc
490
O
NHBoc
491 HO
MOMO HO
MOMO
H
H
1. LiOH, H2O/THF H
2. EDC, HOBt, Et3N MeO NH RO
N O
1. TBAF, THF
2. Py-SO3, Bu2SnO, CH2Cl2 CO 3. TFA, CH 2Cl2
H
CO MeO NH
HN HO3SO
O
N O
HN
O dysinosin A
N
N
492 BocHN
493
NBoc
H2N
NH
Scheme 107.
COOH O
+ O
N H 111
COOMe
N
1. SOCl2 CH3 494
N
COOMe O
2. NEt3,CHCl3 reflux N 495
CH3
O
COOMe
N
H2(cat.)
O N H
CH3 496
Scheme 108.
derivative 515, which after deprotection of Boc group followed by Lienolate-derived N-acylation with Boc (D)-ser-Bzl-Osu afforded
compound 517. Compound 517 on hydrogenolysis using H2/Pd–C was converted to N-acylated products 518 with deprotection of
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O O
arylethylamine N
COOMe
Ar
Cbz
O H MeO
497
498
Me3Al, CH2Cl2
DIBALH
N H
N
THF
H2, Pd/C N
O
500
499
N
O
H
N
N HH H2N
THF, −78 oC
H H2N
H
CH2Cl2, −78 oC
CbzHN
LiAlH4-AlCl3
Ar
MeOH
H CbzHN
O
HO
NHCbz
Ar
BF3.Et2O
Ar
H 502
H 501 Scheme 109.
H
H
H LiEt3BH, THF O
o COOMe −78 C
N
HO
N
COOMe
Boc
Boc
Boc 503
505
504
H
H H2/Pd/C
Grubb's cat.
505
CH2Cl2
EtOH
N
H
COOMe
N
H
508
507
H
H
H H2/Pd/C
Grubb's cat. N
COOMe
COOMe
Boc
Boc
H
+ 506 COOMe
N
H
CH2Cl2 H
Boc
N
COOMe
EtOH H
Boc
506
N
COOMe
Boc 510
509 Scheme 110.
O
Ph N
H 511
O
O 1. Base 2. RX
R
Ph N
O
O +
N
R
H
H
512
R
Ph
513
O
HOOC
N Boc
R= CH2CH=CH2 514
Scheme 111.
o-benzyl group of side chain. Compound 518 on the reduction of lactam carbonyl with LiBEt3H followed by acid-catalyzed dehydration cyclization sequences gave 520. Compound 520 upon alkaline hydrolysis afforded the desired peptidomimetics 521. An expedient synthesis of (+)-trans-5-allyl hexahydroindolizidin-3-one was carried out by Potts et al.113 (Scheme 113). Thanh et al. reported114 enantioselective synthesis of indolizidine ()-237A [(3R,5S,8aR)-3-butyl-5-(1-oxopropyl)octahydroindolizine], starting from pyroglutamate derivative. Compound 524 on nucleophilic addition with (CH3O)2PO–CH2CO–C(OEt2)Et produced 525 which after hydrogenation with H2 (1 bar), PtO2 in methanol followed by cyclization gave 527 and the resultant material was reduced with NaBH3CN to afford a stereoisomer of ()Myrmicarine 237A (Scheme 114).
Legrand et al. reported115 studies on condensation of pyrrolidinones with silyl derivatives. Trimethoxyphenyl naphthylcarbinol trimethyl silyl ether was condensed with the methyl N-trimethylsilyl pyroglutamate affording two separable esters (Scheme 115). 3.3. Functionalization at C-2, C-3, C-4, of pyroglutamates Yamada et al. established116 an efficient asymmetric synthesis of the functionalized pyroglutamate core unit common to oxazolomycin and neooxazolomycin (Scheme 116). Pyroglutamic acid derivative 533 on protection of carboxylic group as t-butyl ester and subsequent N-methylation afforded 534. Compound 534 on debenzylation at C-3 followed by carboxymethylation of resultant alcoholic functionality delivered a carbonate 535. The quarterniza-
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
Ph
O
LiHMDS, THF Cinnamyl Bromide −78 oC
COOEt
N Boc
Ph
O
COOEt
N
O
N H
Boc
516
515
319 Ph
Ph
H2/Pd/C O
COOEt
N
O
MeOH
Ph
LiBEt3H COOEt THF, −78 oC
N
O BnO
LIHMDS, THF −30 oC Boc(D)-Ser COOEt (Bzl)-OSu
TFA, CH 2Cl2
TFA(Cat), CH 2Cl2 HO
COOEt
N
O HO
NHBoc
O HO
NHBoc
517
519
518
O
H
Ph
O LiOH, H2O/THF
N
BocHN
H
Ph
N
BocHN
COOEt
O
NHBoc
COOH
O 521
520 Scheme 112.
O
COOEt
thesized core unit 540 could be a useful scaffold for stereoselective functionalization corresponding to the oxazolomycin’s polyene segments. Panday et al. have reported117 the simple pathway for the synthesis of ()-bulgecinine (Scheme 117) starting with pyroglutamate derivative. Bicyclic lactam derivative 541 was converted to 6-a-hydroxy substituted product 543 via epoxidation and ringopening sequences. OH group at C-6 was protected prior to hydrolysis of bicyclic ring to get 4-benzyloxy pyroglutaminol, in which OH group at C-5 was also protected with ethyl vinyl ether in the presence of acid catalyst to get 546 followed by protection of free
H t
BuOK
N H 522
O
N
EtOOC 523 Scheme 113.
tion of C-2 followed by the introduction of exomethylene group at C-3 was carried out by internal nucleophilic trap of the carbonate 535 and lactone opening with the phenylselenide anion. The syn-
O
nBu
(CH3O)2PO-CH2-CO-C(OEt)2-Et
N Cbz
OEt OEt
KHMDS THF, 0 oC
CHO
nBu
N Cbz
524
525
1. H2(1bar), PtO2, MeOH, RT
nBu
1. TFA-H 2O nBu
N H
2.H2(1bar),Pt/C, MeOH, RT
526
O (OEt)2
nBu
N
+
O (+)-myrmicarine 237B 529
528 Scheme 114.
HCl (1eq.) O
nBu
N
O (−)-myrmicarine 237A
NaBH3CN
N
K2CHO3 527
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
OSiMe3 O
COOMe
N
O
H+, 130 oC
+ Ph
SiMe3 530
COOMe
N
O
COOMe
N
-Me3SiOSiMe3
531
R'
R''
R''
R' 532b
532a Scheme 115.
OBn O
COOH
N H
OBn
i. t-BuOAc 70% HClO4
1. H2, Pd/C, MeOH O
ii. MeI, NaH, THF
N Me
533
OH
O
NaHMDS N Me
2. ClCOOMe, Py
534
OCOOMe O
COOtBu
O
COOtBu
O + COOtBu
N Me 536
535
O
N Me
COOH
i. Ph2Se2 NaBH4, EtOH
COOtBu
ii. CH2N2
537
CH2N2
SePh O
N Me
COOMe
H2O2
COOtBu
THF
COOMe O
538
Zn(BH4)2 Et2O
COOtBu
N Me
OH O
COOtBu
N Me 540
539 Scheme 116.
OH
O
O
SmI2
t-BuOOH K2CO3-n-Bu4NF DMF
N O
O
N
THF-MeOH
542
544 OCOPh
OCOPh OEt
CH2=CHOEt
OH
O
H+
OCHMe
N H
OEt
(Boc)2O DMAP
O
N Boc
OCOPh
OCOPh OEt OCHMe N
MeOH,
H+ MeO
Boc 548
OCHMe
547
546
545
DIBAL-H Hexane-THF HO
Ph 543
OCOPh
N H
O
Ph
541
O
N
O
Ph
CF3COOH
PhCOCl CH2Cl2-Et3N O
N
O
Ph
THF-H2O
O
OCOPh
OH
N H 549
OCOPh Me3SiCN SnCl4 NC CH2Cl2
N H 550
OH
OH HCl HOOC
OH N H (−)-bulgecinine 551
Scheme 117.
NH to N-Boc. Compound 547 was subjected to reduction of lactam carbonyl with DIBAL-H to get 548. Treatment of 548 with MeOH/ HCl led to the protection of OH group at C-2 as OMe and deprotection at C-5. The resultant product 549 on the introduction of cyano group at C-2 followed by acidic hydrolysis afforded ()-bulgecinine.
Lenda et al. reported118 synthetic strategies for new tetrazole and triazole substituted pyroglutamic acid and proline derivatives (Scheme 118). Dimethyl-2,4-dibromoglutarate 552a was allowed to react with sodium azide, where mono-substituted derivative 552b was obtained as a major product. 1,3-dipolar addition of azide 552b with acetylene afforded 1,2,3-triazole derivative 553a. The
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
Br
Br
MeOOC
Br
NaN3 acetone
COOMe
N3
MeOOC 552b
552a
N Br N
N
MeOOC
COOMe
COOMe
NaN3 acetone
N3 N
N
COOMe
N
COOMe
COOMe
COOMe
553b COOMe
N N
COOMe
O
N
COOH
N
COOH
N
i. BH3·THF
N
N H
Pd/C, MeOH
MeOOC
553a
HOOC
acetylene COOMe
ii. 6M HCl propylene oxide, CH2Cl2 N H
HOOC
554
555 Scheme 118.
triazole derivative was subsequently reacted with 3 equiv of sodium azide to give 553b. Compound 553b on hydrogenation furnished the corresponding substituted pyroglutamic acid 554 via an intramolecular aminolysis. Lactam 554 on selective reduction with BH3 in THF followed by acid hydrolysis and subsequent neutralization with propylene oxide yielded fully deprotected (±)-4(4,5-substituted-1H-1,2,3-triazol-1-yl) proline derivative 555. In an attempt to carry out total synthesis of novel amino acid antibiotic TAN-950, Tsubotani et al. have made asymmetric use119 of (S)-pyroglutamate without prior modification through functionalization at C-4 (Scheme 119). Later on in their studies on the reactivity of pyroglutamates towards the asymmetric synthesis of 4-substituted pyroglutamates, Baldwin et al. reported120 that reactions of lithium enolate-derived from 2(S)-pyroglutamates with various electrophiles, give exclusively 4-a-substituted products (Scheme 120). Subsequently in our continuing studies121 on the behaviour of protected pyroglutamate towards electrophiles we reported detailed studies on chiral alkylation and aldol reaction at C-4 of pyroglutamates through their lithium enolates (Scheme 121) where alkylation at C-4 gave exclusively 4-a-products, whereas aldol reactions afforded 4-a- and 4-b-substituted aldol adducts 566 and 567 in the ratio of 4:1. We have also explored122 the direct synthetic pathway for 4(S)-substituted pyroglutamate through 1,3-dipolar addition of
R
O
N
2. Electrophile
N Boc
COOMe
560
N
N
COOMe
Dioxane/H2O
556
O
N
557 COOH
1. NaOH 2. CF3COOH
HO
Boc
Boc
131
COOtBu
menthylacrylate with amino acid Schiff’s bases followed by hydrogenolytic sequences (Scheme 122). These 4-substituted pyroglutamate and prolinates are part of many of the bioactive molecules. As a part of their work on the synthesis of nonproteinogenic amino acids, Bowler et al. reported123 reactions of lactam enolates of L-pyroglutamic acid derivatives with various electrophilic imines and found that the reaction proceeds in good yield with complete stereospecificity at C-4 and impressive stereo selectivity at the third asymmetric centre (Scheme 123). Young et al.124 reported double stereo differentiation in aldol reaction of pyroglutamic urethane esters 576 (Scheme 124) and the same authors reported the use of acid and aldehyde of pyroglutamate in ring switching reaction leading to lactone 580 as kinetic products125 (Scheme 125). The 4-substituted pyroglutamate 577 by ozonolysis was converted to aldehyde, in which aldehydic
H2NOH·HCl O
N
Scheme 120.
1. LDA or LiN(TMS)2/THF 2. i-PrOCHO
O
Boc
Boc 559
OHC O
1. LDA or LiHMDS
COOtBu
NH2 HN O TAN-950 558 Scheme 119.
O
COOMe
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
OH
OH
R'
O
O
E
N Z 561
R'
R'
562
1. LiHMDS, THF, −78 oC
E O abs MeOH, 50psi
N H 564
+
2. R'CHO, THF, −78 oC
H2, 10%Pd,C
H2, 10%Pd,C E abs EtOAc O
N Z
N H
E
566
H2, 10%Pd,C abs MeOH, 50psi
OH
OH
R'
R'
R'
O
H2, 10%Pd,C E abs EtOAc O
N Z
H2, 10%Pd,C E
N H
abs MeOH, 50psi
O
N H
565
563
E
567
Scheme 121.
O
O
O
R'
O
568 +
LiBr/ TMEDA
R''
THF
R'
R'-CH=N-CH-COOMe
O
COOMe N H 571
Ph H
H Tos NH
COOMe
N H
570
R''
R''
H2/Pd-C
569
TMEDA= N,N,N',N'-tetra methyl ethylene diamine Scheme 122.
Tos
H N
H Ph
H
+
1. Lactam enolate O
N
2. LiHMDS
COOBzl
O
572
N
COOBzl
N
H
Ph
Boc
Ts
O
N
Boc
Boc
573
574
COOBzl
Scheme 123.
H
Ph N O
N
Ph
Tos
H
NH
H Ts
COOCH2Ph O
Boc 575
COOCH2Ph
N Boc 576
Scheme 124.
group on reduction was converted to alcohol 579 to get ring switched lactone 580. Diastereoselective formation of a quaternary centre in pyroglutamate derivative was reported by Oliveira et al.126 (Scheme 126). Lithium enolate-derived alkylation of pyroglutamic acid derivative 581 with N-Boc-bromomethylindole 582 in the presence of DMPU, furnished intermediate 583, where lactam part of 583 on alkaline hydrolysis with LiOH gave 584 which after deprotection afforded ()-monatin 586.
O
OH H
H 1. O3-CH2Cl2, -78oC
O
N
COOtBu
2. Ph3P
O
N
H
H NaBH3CN COOtBu MeOH
O
N
Boc
Boc
Boc
577
578
579 Scheme 125.
H COOtBu
O 580
COOtBu NHBoc O
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
1. LiHMDS, THF, −78 oC 2. DMPU, −78 oC
CBzO
OCBz
OTBS O
OTBS
N
Br , −78 oC
3.
Boc
N Boc
581
O
N
N
LiOH, THF H2O
Boc
Boc 583
582
COOH
OTBS Jones' reagent, 0 oC NHBoc OH HOOC acetone
NHBoc HOOC OH
N
N
Boc
Boc 585
584 COOH NH2 HOOC OH N H (−)-Monatin 586 Scheme 126.
N(CH3)2 H
H
O
H
COOR
N
HN
OHC
H O
N
COOR
H
COOR
O
HN O 2 (Willardiine) 590
COOR
588
587
HN
COOR
N
COOR
H
O
589
COOH
Scheme 127.
novel dehydrofluorination (Scheme 128). Substrate 591 on reaction with triethylamine in CH2Cl2 was converted to compound 592b, along with compound 592a, in which compound 592b after catalytic hydrogenation using Pd–BaSO4 in ethanol afforded 593a
Dinsmore et al. reported the extension of ring switching strategy to the glutamate antagonist 2-(pyrimidin-2,4-dione-5-ylmethyl)-(2S)-glycine 590127 (Scheme 127). Qiu et al.128 carried out the synthesis of 4-monofluoromethylenyl 594 and cis-monofluoromethyl-L-pyroglutamic acid 595 via a
H F2HC
F2HC
F
Et3N, CH2Cl2 O
COOtBu
N
O
Boc 591
N
Boc
Boc
592a
592b
COOtBu
TFA CH2Cl2
H F
Pd-BaSO4 EtOH
O
FH2C
H3C 592b
+ COOtBu
N
+ O
COOtBu
N
O
COO
N
Boc
Boc
593a
593b
tBu
O
594
FH2C 593b
TFA CH2Cl2
O
N H
N H 595
Scheme 128.
COOH
COOH
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
Cl
Cl
O
HO
O
COOMe
N
PPh3, DEAD, THF, −0 oC
O
COOMe
N
2. Ac 2O Pyridine
RO
COOMe
N
Boc
Boc R= Ac
597
598
Boc 596
O
1.LiBEt3H THF, −78 oC
4-chloro-1-naphthol
Cl
O TMSCN,BF3.Et2O NC
CH2Cl2, −60 oC
COOMe
N Boc 599
Scheme 129.
Stevens et al.130 reported the regioselectivity in the alkylation of pyroglutamates (Scheme 130). N-Boc benzyl pyroglutamate was converted to its 4-carboxylate 601 using Li enolate chemistry, which on further generating lithium enolate at position C-2 and subsequent reaction with electrophiles afforded 604. In the same way [1,2] Boc migration during pyroglutamate alkylations has also been reported by the same group131 (Scheme 131). Kotoh et al.132 carried out stereoselective synthesis of Nuphor quinolizidine alkaloid ()-deoxynupharidines 618–619 (Scheme
and 593b and subsequently 593b on hydrolysis using TFA gave the desired compound 595. Zhang et al.129 carried out the synthesis of N-Boc-4-O-substituted-5-cynomethyl pyroglutamate 599 (Scheme 129). 4-Hydroxypyroglutamate derivative 596 on Mitsunobu reaction with 4choro-1-nepthol afforded 597, which after reduction at C-5 using LiBEt3H, followed by induction of cyano group at C-5 on reaction with TMSCN and BF3Et2O gave the desired target molecule 599.
OR' R'OOC
O
2 eq. LiHMDS/ −78 oC O
COOBn
N Boc
ClCOOR1
3 eq. −78 oC, THF
3eq. LiHMDS, THF O
COOBn
N
Li+ O-
−78 C o
Boc R= Me 601
600
N
COOBn
Boc 602
OR' R'OOC
O Li
+
O-
(-)Li+ COOBn
N Boc
1. 3 eq. RX/ −78 oC
R O
2. H2O/NH4OH NH4Cl(sat)
N
COOBn
Boc R= CH2Cl, Et, Allyl 604
603 Scheme 130.
E EX O
N
COOR
E
OLi+
N
COOR OtBu
O
LiHMDS EX
O
R' 608
607 Scheme 131.
N
COOR
LiHMDS EX
O
N
R' R'= Boc
R'
605
606
COOR
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
132). Compound 609 on reaction with LiBEt3H, followed by witting reaction gave amide 611, where amidic part was transformed into aldehydic ester 612 by using DIBAL and subsequently resultant aldehyde 612 on acidic hydrolysis was converted to 613, which on deamination with SmI2 in THF–HMPA and methanol gave sixmembered ring product 614. N-Alkylation of 614 with 3-bromo2-methyl propane in the presence of NaH provided 615, which on reaction with Grubb’s catalyst was converted to 616. Compound 616 was treated with 3-lithiofuran, subsequently reduced with NaBH4, finally subjected to hydrogenolysis using Pd(OH)2 thereby affording diastereomers 618 and 619. Merino et al. described133 the diastereoselective approach with an objective to synthesize 4-hydroxy derivatives 623 (Scheme 133). 3-Hydroxy-pyrrolidinone 620 after protection of all the functional groups was converted to 622 which on reaction with H5IO6 and NaH2PO4 gave target molecule 623.
Me
Langlois et al. achieved the total synthesis of salinosporamideA, a potent proteasome inhibitor, starting from pyroglutamate derivative134 (Scheme 134). Compound 624 was converted to 625 on reaction with N-methylnitrone in toluene through 1,3-dipolar addition and resulting adduct 625 was subjected to hydrogenolysis leading to ring opening, methylation of amino group and subsequently cope elimination to afford salinosporamide-A 628. Hill et al. synthesized135 stereocontrolled spirocyclic bislactams derived from pyroglutamic acid, compound 629 on reaction with NaH and BrCH2CN afforded 630 which on treatment with NaBH4 and COCl2 underwent reduction coupled with cyclization to give spirobicyclic lactams 631 and 632 (Scheme 135). Herdeis et al.136 carried out a stereoselective synthesis of 3substituted (S)-pyroglutamic acid and glutamic acids through ABO ester derivatives (Scheme 136). Pyroglutamic acid was converted to its ester through condensation, which after protection
Me NaH, THF
LiBEt3H, THF O
−78 oC
COOMe
N
HO
(EtO)2P(O)CH2CON(Me)OMe
COOMe
N
Boc
Boc
609
610
Me
Me
O DIBAL, THF
Me COOMe
N
N
OMe
Boc
Me 1. NaHMDS, Ph3PCH3+Br-
OHC
−78 oC
N
COOMe
Boc 612
611
Me HMPA, MeOH 0 oC
N H 614
O
COOMe
N H 613
Me
3-bromo-2methylpropene
SmI2, THF
THF, −78 oC 2. TFA, CH 2Cl2
2 mol% Grubb's cat N
o
NaH, DMF, 20 C
O
Benzene, 60 oC
615 Me
Me H N
O
(a) 3-lithiofuran, THF, −78 oC
Me
H
(b) NaBH4, MeOH
H
H2, Pd(OH)2
N O
N
O
617
616
+ H
N
MeOH, rt
Me (S)-furan
Me
Me
O
Me
Me
618
619
Scheme 132.
OH O O
N H 620
O
OR
OR 1. TBSCl, THF or 2. PhCOCl
(Boc)2O
O O
N H R= tBuMe2Si R= PhCO 621
O
DMAP
H5IO6, then NaClO2
MeOOC
622
N Boc 623
Scheme 133.
N Boc
OBz
NaH2PO4, then CH2N2
O O
O
O
1624
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
N
O
COOMe OBn
COOMe OBn
N-methylnitrone O
toluene, heat
N
R
624
625
EtOAc-MeOH
O
TFA
626
N+
COOMe OBn
O
N H
R= Boc R= H
OH
H2, Pd(OH)2
625
COOMe OBn
SmI2, THF
N
Boc
HN
OH
HN
O
N
I-
OH
MeI, THF
Et3N
COOMe OBn
O
N Boc
Boc 627
OH COOMe OBn
O
N Boc 628
Scheme 134.
17
O
NaH BrCH2CN
N
O
+
O
N
O
O Ph
O
O NaBH4 CoCl2
N
HN
HN
EtOOC CH2CN
EtOOC
Ph
629
O
N O
O Ph
630
Ph 631
632
Scheme 135.
17
3-hydroxymethyl-3 methyl-oxetane DCC, DMAP, CH2Cl2
O
N H 633
BF3.OEt2, CH2Cl2 Et3N,
O
O
0 oC
O
N
1. BuLi/DABCO, CbzCl, −78 o C, THF
N
2. BuLi/HMDS, (Boc)2O, −78 oC
O
CH3
1. Acc: Cbz 2. Acc: Boc 3. Acc: Moc 634
1. BuLi/HMDS, PhSeCl −78 oC, THF 2. mCPBA, DABCO
O
O O O
N Cbz
Acc 635
R
R O
CH3
636
RMgBr, CuBr, S(CH 3)2 −78 oC to −20 oC
O
Acc
3. BuLi/DABCO, CNCOOCH 3 −78 oC, THF
O O O
O
O O
N
O O O
1. H2/Pd/C, EtOAc/MeOH CH3
Cbz 637
2. TFA/H2O/CH2Cl2 3. Cs2CO3/H2O
O
N H
COOH
638 Scheme 136.
of –NH followed by oxidation was converted to ABO ester 635. Formation of epoxide at C-3, 4 of 635 following usual chemistry and subsequent ring opening with Grignard reagent afforded 637. Compound 637 after protection and deprotection sequences afforded the desired 3-substituted pyroglutamate 638.
Cienfuegos et al. reported stereoselective synthesis of conformationally constrained (2S,3S)-3-hydroxyornithine137 (Scheme 137). Cai et al.138 described the application of (S)-and (R)-methyl pyroglutamates as inexpensive, yet highly efficient chiral auxilia-
1625
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
Bn N
BnHN
O
OH
O
LiAlH4 O
O Ph 639
Bn 640
Bn
TFA, THF-H 2O
OH
CH2Cl2
N
N
639
CDI
OH
THF, Heat
N
Bn N
O
N H
O OR LiAlH4
CCl3COOH, CH2Cl2
O
N H
BnAcN
OH OEVE
BnAcN
OAc
Ac2O
OEVE
Py
N H
THF, heat
643
642 BnHN
N H 641
OH ethylvinylether O
O
Bn N
OAc
CH3COOH-H2O
OH
N
N
Ac
Ac
645
644 BnAcN
646 BnHN
OAc
Jones' Reagent
OH
3M HCl
acetone
COOH
N
COOH
N H
Ac 648
647 Scheme 137.
N
O
O
Ni O
N
O
N
R O
N
N
COOMe O
650
N
DBU, DMF R= Me
O Ni
R H O
N
Me
O
649
Me N
COOMe
651
N
R 1. MeOH/HCl 2. NH4OH 3. Dowex
O H
O
N H
+ COOH
652
O
NH
O Me
653 Scheme 138.
ries in the asymmetric Michael addition reactions (Scheme 138). Michael acceptor 650 reacts with Ni(II) complex to give exclusively 651. Compound 651 on treatment with methanoic HCl and subsequently treatment with NH4OH and Dowex yielded 3-substituted pyroglutamic acid 652. Langlois et al.139 reported the stereoselective formal synthesis of the proteasome inhibitor salinosporamide A, from (S)-methyl 2-hydroxymethylpyroglutamate through chemoselective O-protection (Scheme 139). Fujita et al. reported reactions of optically active 5-substituted2-pyrrolidinone derivatives having atropisomeric behaviours. They
carried out 3,5-cis-selective reactions of their enolates with electrophiles140 (Scheme 140). 3.4. Conversion of pyroglutamic acid into prolines Pyroglutamates can readily be converted into prolines. Rapoport et al. converted 4-phenylpyroglutamate 664 to 4-phenyl prolinate 665 by reducing with BH3THF in the presence of a catalytic amount of NaBH4141 (Scheme 141). Pyroglutamates could directly be converted into L-proline in 2step one-pot reaction. The conversion involves the treatment of
1626
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
N COOMe OBn
O
COOMe OBn
Cs2CO3, PMBBr
N H
O
DMF
COOMe OBn +
N-methylnitrone O toluene, heat
N
N
PMB
654 N
OH
HN
EtOAc-MeOH
N
OH
COOMe OBn
H2, Pd(OH)2
COOMe OBn
O
PMB
656
655 O
O
N
1. MeI, MeOH 2. Na2CO3, CH2Cl2
COOMe OBn
O
N
PMB
PMB 657
O
PMB
658
659
Scheme 139.
E E O
N OR2
O
N OR2
R1
660
-
N
E+
OR2
R1
O R1
OR2
662
661
N H
O
663
Scheme 140.
pyroglutamic acid with triethyl oxonium fluoro borate and reduction of the resulting crude imino ether with NaBH4142 (Scheme 142). We have also reported a simple procedure121 for the conversion of 4-substituted pyroglutamates to 4-substituted prolinates 669 via the conversion of pyroglutamate to thio lactam followed by reduction to the corresponding prolinate in the presence of nickel boride generated in situ (Scheme 143). Drauj et al. have converted143 L-pyroglutamate 111 to 5,5-dichloro-N-chloro carbonyl 2(S)-methyl pyroglutamate 670 on reaction with COCl2 in dichloromethane at 0 °C with the elimination of HCl and CO2. Compound 670 on reaction with Bu3N gave 671 with the elimination of HCl at positions 4 and 5 leading to induction of double bond. Compound 671 on hydrogenation using Pd/C with Bu3N gave unsaturated product 672, which on further hydrogenation gave saturated products 673. Compound 673 after several protection and deprotection sequences afforded L-proline (Scheme 144). Harris et al.144 reported the synthesis of cyclic proline containing peptides via ring-closing metathesis (Scheme 145). N-Acyl-5allyl diene 677, which was obtained from pyroglutamic acid was
Ph
Ph BH3·THF O
N
COOtBu
NaBH4
COOtBu
N PhF1
PhF1
665
664 Scheme 141.
O
N H 17
COOH
triethyloxonium fluoroborate NaBH4
N H 666
COOH
Scheme 142.
Ph
Ph
Ph Nickel boride
Lawessons reagent O
N H 667
E
CH2Cl2, rt
S
N H 668
Scheme 143.
E
N H 669
E
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
COCl2, CH2Cl2
COOMe
N H
0 oC, -HCl, -CO2
H
Bu3N, 70 oC
Cl Cl
COOMe
N O
111
Cl
-Bu3NHCl
O
Cl
H
H
-Bu3NHCl
H2, Pd/C
COOMe
N
Cl 671
670
H2, Pd/C, Bu3N
COOMe
N
COOMe
N
H
H+, H2O -CO2
+ N
COOMe
H O
O
Cl
673
672
H
Cl 674
H H+, H2O -CH3OH
+ N H
COOH
H
Basic ion exchange
COOH
N H
H
675
676 Scheme 144.
COOtBu
N
COOtBu
Grubbs' cat. (20%) CH2Cl2/reflux
O
O N
N
COOBn
COOBn 678
677 Scheme 145.
1. LiHMDS O
O
COOH
N
N
2.
Ph 177
COOH
N
O
COOCH2Ph
N Ph
680
toluene
Raney Ni S
COOCH2Ph
N Ph
681
682
H2, Pd/C (10%)
+ COOH
N
COOCH2Ph
CH3OH, 2h
N H
Ph
Ph 683
Et3N
Ph
Lawesson's reagent
PhCH2Br
N
PhCH2Br O
Ph 679
Br
Et3N
Pd/C (10%) COOH H2
685
684 Scheme 146.
COOH
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
subjected to cyclization in the presence of Grubb’s catalyst to afford the expected cyclononenes 678. Chen et al. reported a convenient method for the synthesis of trans-4-cyclohexyl-L-proline145 (Scheme 146). N-Benzyl pyroglutamic acid was reacted with bromocyclohexene in the presence of LiHMDS, followed by hydrogenolysis with Pd/C to get 4-substituted N-benzyl pyroglutamic acid 680 which was condensed with PhCH2Br to get ester 681. Treatment of 681 with Lawesson’s reagents, followed by reduction with Raney Ni afforded 683 and 684. Both these products were subjected further to hydrogenolysis using H2/Pd–C to get 4-cyclohexyl proline 685. Langlois et al.146 reported diastereoselective syntheses of (2S,3S,4S)-3-hydroxy-4-methylproline 691, a common constituent of several antifungal cyclopeptides (Scheme 147). Compound 686 on reduction using BH3–DMS was converted to 687, resultant material on hydrogenolysis, followed by NH protection was converted to 688. Treatment of 688 with TBDMSCl gave 689 and sub-
OH
sequent reaction with NaIO4–RuCl3 followed by acidic hydrolysis afforded the desired molecule 691. Two separate and distinct syntheses of stereospecifically deuterated samples of (2S)-proline were reported by Barraclough et al.147 (Scheme 148). Compound 131 on reduction using H3BSMe2, followed by acidic hydrolysis afforded proline 666. Oba et al.148 carried out the synthesis of non-proteinogenic amino acids using Michael addition to unsaturated orthopyroglutamate derivative (Scheme 149). Unsaturated pyroglutamate derivative 166 on reaction with Gilman reagent delivered a compound 693 having methyl group at C-3. The ABO ester functionality of 693 was converted to methyl ester through ester exchange reaction with MeOH/HCl. The N-Boc group of 693 which was deprotected during acidic conditions was protected again with Boc group to afford 694. Reduction of lactam carbonyl of 694 with BH3THF followed by deprotection of methyl ester of 695 in refluxing 1 M. HCl and subsequently ion exchange treatment with DOWEX 50WX8
OH OH 1. H2/Pd/C
BH3-DMS
O
N
N
86%
OH
2. (Boc)2O
Ph
R 686
Boc
R
688
687 OSit-BuMe2
OR2 OR1
NaIO4-RuCl3
Boc
OH 6M HCl + N Cl- H2
COOH
N
CCl4-CH3CN-H2O R1=R2=OSit-BuMe2 R1=H, R2=OSit-BuMe2
N
TBDMSCl
N
O
Ph
O
OH
Boc
689
COOH
691
690 Scheme 147.
H3B·SMe2
(Boc)2O, DMAP O
COOMe
N H 111
CH3CN
131
THF, 0 oC
6M HCl N
COOMe
reflux
N H 666
Boc 692
COOH
Scheme 148.
Me
Me
O
N
ABO
Me2CuLi
O
Boc
N
ABO
HCl, MeOH then
O
(Boc)2O, DMAP
Boc
Boc 693
166
694 Me
Me BH3-THF N
COOMe
1M HCl then Dowex 50WX8
Boc 695
N H 696
Scheme 149.
N
COOH
COOMe
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
1629
OBn
i. LiBEt3H, THF
LiHMDS, BnOCH2Cl O
COOEt
N
O
HMPA, THF
COOEt
N
Boc 319
Boc 697 OR
OR i. MeMgBr, CuBr-Me 2S BF3-OEt2, Et2O MeO
ii. p-TsOH, MeOH
N
COOEt
ii. (Boc)2O, NaHCO3
Jones' reagent Me
N
COOEt
acetone
Boc
Boc
699a, R= Bn H2, Pd/C, MeOH 699b, R= H
698
Me N Me HOOC
O Me2NH, EDC
Me
N
COOEt
L-ProCN, EDC
Me
HOBt, Et3N
COOEt
N
Boc
Boc
700
701a, R= Et NaOH, MeOH 701b, R= OH
Me
Me N Me
N Me
O
O N
Me
HOBt, Et3N
p-TsOH, EtOH
N Me
N Boc
O
CN
702
N H
O CN
703 Scheme 150.
resin furnished (2S,3S)-3-methylene proline 696 in quantitative yield. Kondo et al.149 discovered long acting N-(cyanomethyl)-N-alkyl-L-prolinamide inhibitors of dipeptidyl peptidase IV (Scheme 150) starting with pyroglutamic acid derivative. Lithium enolatederived alkylation of N-protected ethyl-L-pyroglutamate 319 with benzyloxymethyl chloride afforded 4-substituted pyroglutamate 697. Partial reduction of cyclic imide carbonyl of 697, followed by acetalization gave the methyl acetal 698. Stereoselective 5 amethylation of 698 with methyl Grignard reagent and copper(I) bromide-dimethylsulfide complex in the presence of boron trifluoride-etherate, followed by protection of deprotected nitrogen, led to 699a. Catalytic hydrogenation of 699a provided the alcohol 699b. Jone’s oxidation of 699b resulted in carboxylic acid 700, which on condensation with N,N-dimethyl amine produced 701a. Alkaline hydrolysis of compound 701a provided carboxylic acid 701b, which on peptide formation with (2S)-2-cyanopyrrolidine afforded 702. Acidic deprotection of 702 led to the desired compound 703. Einsiedel et al. developed a molecular building kit of fused-proline derived peptide mimetics allowing specific adjustment of the dihedral w-angle (Scheme 151). Unsaturated pyroglutamic acid derivative 704 on reaction with allyl bromide in the presence of TMSCl and HMPA, followed by reduction of lactam carbonyl deliv-
ered 706, which after deprotection of alcoholic group furnished prolinol derivative 707. Jones oxidation led to the formation of the C-3 functionalized proline 708. Amide formation between the asymmetric building block 708 and N-substituted glycine derivatives using coupling mixture HATU/HOAt allowed an efficient synthesis of RCM precursor 709. Olefin metathesis using Grubb’s II generation catalyst afforded seven-membered and eight-membered unsaturated bicyclic lactams 710. Aminolysis of 710 with methylamine delivered the model peptides 711.150 4. Conclusions Thus this review gives explicit information about the versatility and importance of pyroglutamate with special attention to asymmetric synthesis of bioactive molecules, natural products as well as chiral intermediates. On the one hand this important moiety has allowed the researchers to synthesize bioactive natural products such as anatoxin A, ()-bulgecinine and salinosporamide A, whereas on the other hand the use of pyroglutamic acid as a chiral precursor has enabled the researchers to explore the synthetic analysis for designed bioactive molecules such as ACE inhibitors like fosinipril, conformationally constrained peptides as well as peptidomimetics. Various derivatives of pyroglutamic acid have also been used to develop catalyst such as semicorrin metal com-
1630
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O O
Ph tBu Ph
Si
N
O
AllMgBr
O
N
TMSCl, HMPA
Boc
Boc
704
705
O N
Si
Ph tBu Ph
i. LiAlH4, Et2O ii. Et3SiH, BF3.Et2O
H2O, Me2O
N Boc
706
707
COOH
N Boc 708
COOMe
COOMe N H
Ph tBu Ph
OH CrO3, H2SO4
Bu4NF, HOAc
Boc
( )n
Si
( )n
( )n N
COOMe
N
n=1
Grubb's catalyst
HATU, HOBt, NEM, NMP
O
CH2Cl2
N Boc 709
O N Boc 710
NHCH3 ( )n H2NMe, EtOH
N
O
O N Boc 711 Scheme 151.
plexes or 2,5-disubstituted pyrrolidines. Therefore it may be concluded that pyroglutamate has undoubtedly emerged as an important chiral synthon and has provided researchers a useful chiral tool to exploit the reactivity differences within the molecule and to use it for the asymmetric synthesis of wide variety of bioactive compounds. The present review is an attempt to describe the useful and important applications on the use of this unique chiral synthon by the researchers all over the world in the recent past, and shall certainly be valuable, to make further progress and to develop new strategies for the asymmetric synthesis based on these literature reports. Acknowledgements The corresponding author is thankful to the University Grants Commission, New Delhi, India for financial assistance and to Central Drug Research Institute, Lucknow, UP, India for extending library facilities to us. References 1. (a) Ohfune, Y.; Tomita, M. J. Am. Chem. Soc. 1982, 104, 3511; (b) Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245. 2. Thottahil, J. K.; Moniot, J. L.; Mueller, R. H.; Wong, M. K. Y.; Kissick, T. P. J. Org. Chem. 1986, 51, 3140. 3. Langlois, N.; Andriamialisoa, R. Z. Tetrahedron Lett. 1988, 29, 3259. 4. Baldwin, J. E.; Moloney, M. G.; Shim, S. B. Tetrahedron Lett. 1991, 32, 1379. 5. Hamada, Y.; Tanada, Y.; Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 1991, 32, 5983.
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Contents lists available at ScienceDirect
Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Tetrahedron: Asymmetry Report Number 116
Pyroglutamic acid: a unique chiral synthon Sharad Kumar Panday a,*, Jagdish Prasad a, Dinesh Kumar Dikshit b a b
Department of Chemistry, Faculty of Engineering and Technology, M. J. P. Rohilkhand University, Bareilly, UP, India Medicinal Chemistry Division, Central Drug Research Institute, Lucknow, UP, India
a r t i c l e
i n f o
Article history: Received 26 March 2009 Accepted 8 June 2009 Available online 18 July 2009
a b s t r a c t jjj Ó 2009 Elsevier Ltd. All rights reserved.
Contents 1. 2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Asymmetric use of pyroglutamates with prior modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Reduction of carboxylic groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Activation of lactam carbonyl at C-5 by formation of thiolactam, imino, iminium ethers and as lactam acetals. . . . . . . . . . . . . . . . . . . Asymmetric use of pyroglutamates without prior modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Direct chain elongation reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Use of N-derivatized pyroglutamates for asymmetric synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Diels–Alder reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Radical cyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. N-Acylations/alkylations of native pyroglutamates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Functionalization at C-2, C-3, C-4, of pyroglutamates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Conversion of pyroglutamic acid into prolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Pyroglutamic acid or 5-oxo-proline has emerged as an important starting material for asymmetric synthesis of many natural products. From the first reported application of pyroglutamic acid in an asymmetric synthesis of Domoic acid 161a in 1982, the last two decades have witnessed an exponential outgrowth of publications on chemistry and asymmetric/biological uses of pyroglutamic acid.1b Derived from glutamic acid, derivatives of pyroglutamic acids are a cheap source of chirality. The advantage of pyroglutamic acid in asymmetric synthesis lies in a rigid five-membered skeleton with strong stereo-electronic influence of two different carbonyl entities in the molecule which can be differentially functionalized. These features of pyroglutamates have been extensively exploited
* Corresponding author. Tel./fax: +91 581 2529138. E-mail address: [email protected] (S.K. Panday). 0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2009.06.011
1581 1581 1581 1593 1605 1605 1611 1611 1611 1611 1616 1625 1629 1630 1630
and the present review makes an attempt to list out all the major advances in this area. Pyroglutamic acid has two differentially activated carbonyls. The asymmetric use of pyroglutamic acid has exploited their reactivity differences as such or by accentuating these by further derivatizations. The review is aimed to describe these developments and to explore further possibilities on the uses of pyroglutamic acid as a chiral synthon. In the present communication the major uses of pyroglutamic acid as a chiral synthon have been classified on the following lines. 2. Asymmetric use of pyroglutamates with prior modifications 2.1. Reduction of carboxylic groups The first use of pyroglutamates as chiral synthon in the synthesis of complex molecule was in the synthesis of ()-Domoic acid by Ofune et al.1a The N-protected pyroglutamic acid was reduced to
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the corresponding alcohol which was protected by TBS. This protected synthon has only one activated carbonyl which was a-alkylated in high enantiomeric excess. The reduction of carbonyl function and its subsequent protection by TBS not only excluded the deprotonation at C-2, that is, loss of chirality, but also influenced the a-approach of electrophile (Scheme 1). Similar reduction and protection sequence was also used2 in the synthesis of trans-4-cyclohexyl proline 24 (Scheme 2), an intermediate for the synthesis of fosinopril, a potent ACE inhibitor. In this case reaction of pyroglutaminol with benzaldehyde gave a bicyclic
system, where phenyl acquires an equatorial position. Alkylation of the lithio enolate proceeded with high facial selectivity to give 4-aproduct 24. Langlois et al. have carried out asymmetric synthesis of antihypertensive pyrrolidines3 34 by using 2-hydroxymethyl pyroglutamate 25 as a chiral synthon (Scheme 3). The protected 2hydroxymethylpyrrolidine-5-one was reduced to cyclic aminol 27 which was used in C–C-bond forming reaction at C-5. The carbonyl group in 29 was derivatized via thioketalization in the presence of TsOH followed by hydrogenation with Raney Ni to get
Boc
O
O
O 1. ClCO2Et/Et3N/THF, -10oC
N
terbutyldimethylsilyl chloride DMF/ imidazole
N
Boc
2. NaBH4/90%EtOH, -10oC HOOC 1
Boc
N
O
OH
3
2 O 1. LDA/THF/PhSeCl, -78oC to 0oC 2. O3/CH2Cl2, -78ºC, NaOAc, 0ºC
Boc
O OTMS
N
Boc
OTMS O 5
Bu
t
S
Bu
O
H O
N
BH3.DMS
Boc
HO
N
COOCH3 t
O S 6
OH O 7
Bu
S
t
Bu
O MeOH/p-TsOH, rt, 3h
O 1. Pyridinium dichromate, DMF, 40oC, 48h Boc N 2. CH2N2
HO
Boc N
OH
CHO H
Boc N
COOMe
Ph3P(Cl)CH2OCH3 / t-AmONa/ Benzene, rt
SePh CH-CHO H O3/CH2Cl2, -78oC
Boc N
COOMe
CHO 1. NBS/THF, rt 2. NaOAc COOMe
Boc N
12
COOMe MeOOC 12 CHO
Boc N COOMe MeOOC
CH=CHOMe H
Boc N MeOOC 11
MeOOC 10
PhSeCl/THF/Et3N/ H2O, rt
HO COOMe
MeOOC 9
OH 8
60%AcOH, 60oC, 24h
Bu
N
O
O
1. O3/CH2Cl2, -78oC, DMS, rt, 6h 2. CH2N2
t
S
t
H
135oC O 4
3. 2-methyl-2-ethyl-1,3dioxolane/p-TsOH, rt, 3h
Boc
S
Br- H Ph3+P
MeOOC
OH
H
Boc N
KOH
COOMe MeOOC
14
H
15
COOH
HN HOOC
16
COOH (-)-Domoic acid Scheme 1.
13 CH2OH 1. 2.5% KOH, rt 2. CF3COOH
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632 +
+
1. ROH/H O
COOH
N H 17
2. NaBH4
CH2OH
N H 18
O
N O 19
Ph
LAH,THF O
1. LDA 2. Br
PhCHO/H O
O
N O
Ph
Ph 20
CH2OH
N
Z-Cl/K2CO3
H2/Pd-C
CH2OH
N H 22
21
H2O-THF
1. Jones' oxidation 2. H2/Pd-C
CH2OH
N Z
COOH
N H
23
24 Scheme 2.
RO
Methylchloroformate RO DIBAH RO O O N N H COOCH3 R=H R=CH(CH3)OC2H5 R=CH(CH3)OC2H5 26 25 O
OH
N
Sodium enolate of 3',4'-methylenedioxy phenyl methyl ketone
COOCH3 27
O
O HO
RO TsOH
N
R=CH(CH3)OC2H5
N
N
O
COOCH3
O
O
COOCH3
O
O O
O
30
29
O
28 R'
H
R'' HO Reney Ni
HO 1. TsOH 29 2. Thioketalization
N COOCH3
OHC
O
32
Ph R''
1. PhMgBr
N COOCH3
O O
DMSO N COOCH3
O
R'=R''=S(CH2)2S 31
H
R'''
O O
N O
R'
2. KOH-MeOH heat
R'=R''=H R'''=OH R'=R'''=H R''=OH 34
33
SO3-Pyridine complex
O
Scheme 3.
compound 32. The resulting product on oxidation yielded an aldehyde 33 which was converted into the desired antihypertensive agent 34. Similarly the pyroglutamate-derived cyclic protected synthon has been used by Baldwin et al.4 for the generation of a Michael acceptor moiety which was used in one-pot Michael addition– alkylation sequence to yield stereodefined 3,4-disubstituted pyroglutamate derivative 36 (Scheme 4). Investigations reported by Hamada et al. on the asymmetric use of pyroglutamates with prior reduction of carbonyl group describe
the synthesis of the 2,3-dihydroxy-4-dimethylamino-5-methoxypentanoic acid5 46 a fragment of calyculins, starting from (S)-5(hydroxymethyl)-2-pyrrolidinones 18 (Scheme 5). Making use of pyroglutamic acid as a cheap chiral source, Langlois et al. reported the synthesis of enamidoaldehyde 49 as new common synthons for the preparation of analogs of sibiromycin and other antitumour antibiotics6 (Scheme 6). Compound 47 was converted into N-acylated derivative 48, by reaction with NaH and p-nitrobenzoyl chloride. Resultant N-acyl derivative 48 was converted into aldehyde 49 in three steps as shown in Scheme 6.
1584
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
N
1. LDA 2. PhSeBr 3. O3
H O
H2C O
19
Ph
N
H
PhH2C
COOCH3
COOCH3
Sodium amide/ HMPA Alkylation with O benzyl bromide
O
35
Ph
COOCH3
COOCH3
N Ph
LDA Electrophile
H
O
36
E O
N
H
O
Ph 37 Scheme 4.
HO
MPMCl, NaH O DMSO, rt, 24 h
N H
1. DDQ, CH2Cl2-H2O (19:1), rt, 4 h
O
N
MPMO
2. CH3I, NaH, THF, rt, 1 h
H3CO
MPM 38
18
1. LDA, THF, −78 ºC, 30 min 2. PhSeCl, −78 ºC, 30 min 3. aq. H2O2, EtOAc, rt H3 CO
O
39
O
N
N MPM
1. OsO4, N-methylmorpholine N-oxide toluene-acetone-water, rt 2. 2,2-dimethoxypropane, p-TsOH, H2O, rt
MPM 40
O
O
O
O
O 20 min then rt
N
H3CO
N H
H3CO
MPM
O H3CO
42
41 O 1. LiOH, THF, H2O, 0 ºC, 30 min 2. PhCH2NH2, DPPA, Et3N DMF, 0 ºC, 1 h, rt
O H3CO N 45
O
O N Boc
O H N
H3CO BocHN
O
Ph
1. TMSOTf, CH2Cl2, 0 ºC, 1 h 2. aq. HCHO, AcOH, 5%Pd/C H2, MeOH, rt, 60 h 3. 2,2-dimethoxypropane, p-TsOH-H2O, rt
O
HO H N
O
43
44
H3C
O
(Boc)2O, DMAP Et3N, rt
CAN, CH3N-H2O, 0 ºC
Ph 6M aq HCl, MeOH 130 ºC, 1.5 h
COOH OH
H3CO H3C
CH3
N
CH3
46 Scheme 5.
A publication by Woo et al. has described the asymmetric synthesis of a-amino acids by reaction at C-3, C-4 and C-5, of pyroglutamate derivatives starting from (S)-pyroglutamic acid derivative 50.7 They also reported ring opening through 2-lithio-1,3-dithiane at low temperature furnishing compound 52, whereas reaction of 50 with vinyl magnesium bromide followed by reduction afforded compound 51 (Scheme 7). Total synthesis of (+)-monomorine 67, a natural attractant for Pharaoh ant workers was carried out from chiral cyclic b-enaminoester derived from (S) pyroglutamic acid in seven steps by Saliou et al.8 (Scheme 8). Pyroglutaminol 18 after tosylation was converted to o-tosyl derivative 62. Compound 62 on reaction with di-n-propyl lithium cuprate was converted to compound 63 having
n-Bu group at position 5. Compound 63 on reaction with dimethylsulfate followed by treatment with Meldrum’s acid and on subsequent reaction with sodium methoxide furnished b-enaminoester 64 which on hydrogenation in the presence of H2/Raney Ni afforded 65 with the desired stereochemistry. Compound 65 after the protection of NH with benzyloxy carbonyl chloride followed by reduction of alcohol group to aldehyde, was subjected to Witting reaction with CH3COCH@PPh3 ylid. The resultant compound on hydrogenation had undergone deprotection, reduction and cyclization to give (+)-monomorine 67. Stereoselective methylation of bicyclic lactams derived from Dpyroglutamic acid 68 has been reported by Armstrong et al.9 The bicyclic compound 70 was converted to 4-methyl pyroglutaminol,
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
N H
HO
TBDMSO
NaH, KI
O
N H
O
N
TBDMSO
NO2C6H4COCl
O O2N
47
18
48 CHO
1. DIBAL-H 2. QCS 3. DMF-POCl3
N
R O
O2N 49 Scheme 6.
S 2-lithio-1,3-dithiane
1. Vinyl MgBr, THF
HO
LDA, THF, −78 ºC O to 44 ºC, MoOPh
O
N
OSiBu Ph2
Boc 53 HO
PhSe
OH
O
O
N Boc
OSiBut Ph2
57
N
N Boc
OSiBut Ph2
OSiBut Ph2
N Boc
55
OSiBut Ph2
OSiBut Ph2
59
N Boc
1. THF/CH2Cl2 2. BH3DMS. THF
H3C
N
OSiBut Ph2
Boc
56
58
H 54
H3C
CH3 Me2CuLi, Ether O −78 ºC
N
LDA, THF, −78 ºC then MeI
H2O2, Pyridine CH2Cl2, −78 ºC
O
H3 C
O
N
OSiBut Ph2
Boc 52
OSiBut Ph2
LDA, PhSeCl THF, −78 ºC
Boc OsO4.NMO
HN O
1. MeMgBr, ether 2. (i) TFA (ii) NaOH(2M) (iii) NaCNBH3
Boc 50
t
S
THF, −78 ºC
2. NaBH4, CeCl3, MeOH, 0 ºC OSiBut Ph2
HO HN Boc 51
OSiBut Ph2
60
Scheme 7.
HO
N H
tosylate O TsO
H nBu
63
HCl, MeOH, LAH, ether
nBu
N H
COOCH3
R
65 H2, Pd-C, 10%, atm N Cbz
1. MeSO4 O 2. Meldrum's acid Ni(acac)2, CHCl3 3. MeONa, MeOH 1. ClCOOCH2Ph 2. PCC, CH2Cl2
H
H2, RaneyNi, 100bar
H N H 64
N H
N H
62
18 H nBu
nPr2CuLi O Ether-CH2Cl2nBu −30 ºC
H
3. CH3=CO-CH=PPh3, THF 4. H2, PtO2, atm
H
nBu
N H
R
H3C
66
67 Scheme 8.
(+)-monomorine
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
deprotection of hydroxyl groups with trifluoroacetic acid afforded (+)-hyacinthacine B1 80. Moeller et al. have modified carboxylic functional group of pyroglutamates with an objective to synthesize spirocyclic Lpyroglutamide building blocks12 86 (Scheme 12). Pyroglutamic acid was converted to its menthyl ester followed by deprotection at C-2 using Pt wire, n-Bu4PF6 and methanol as a solvent to afford C-2 methoxylated menthyl ester 82 which on reaction with allyltrimethylsilane and TiCl4 was converted to C-2 alkylated product 83. Compound 83 on reaction with methanolic ammonia and NaCN was converted to primary amide 84. Compound 84 on oxidation with aqueous OsO4/NaIO4 followed by reaction with triethylsilane and TFA using nitro methane as a solvent underwent hydrodehydroxylation to give 86 as building block. Magni et al. carried out the synthesis of (R)-3-[(S)-(5-oxo-2pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid (Pidotimod) 90 as an immunostimulating agent13a,b from pyroglutamic acid (Scheme 13). Here pyroglutamic acid was treated with ethyl L-thiaazolidine 4-carboxylate in the presence of DCC and CH2Cl2 to afford compound 88, which upon alkaline hydrolysis gave carboxylic acid
which on reduction afforded 2,4-dimethyl pyrrolidone 72 the chiral antipode, which was converted to N-protected cis-2,4-dimethylglutamide 73 in three steps (Scheme 9). Kohn et al.10 carried out the synthesis and characterization of chiral 1,2-diamines from pyroglutamic acid where pyroglutamic acid 17 on reaction with anhydrous chloral in the presence of toluene afforded bicyclic derivative 74 which on reaction with primary amine in toluene underwent ring opening of the oxazolidinone ring of bicyclic aminal 74 to furnish pyroglutamoyl amide derivative 75. Compound 75 on reduction of lactam carbonyl as well as amidic carbonyl group with lithium aluminium hydride furnished the desired 1,2-diamines 76 (Scheme 10). Sengoku et al.11 carried out asymmetric synthesis of pyrrolizidine alkaloids (+)-hyacinthacine B1 and (+)-B2. The representative synthesis of (+)-hyacinthacine B1 is described here (Scheme 11). Pyroglutamic acid derivative 77 on catalytic sharpless asymmetric dihydroxylation(AD) with AD-mix-a [(DHQ)2 PHAL ligand] afforded compound 78, which after protection, deprotection coupled with cyclization afforded compound 79. Deprotection of compound 79 with tetrabutyl ammonium fluoride in THF followed by
O
ROH/H
O
COOH
N H 68
1. NaBH4 COOR 2. PhCHO/H+ O
N H
Ph 70
OH
N H
t
1. CBr4/PPh3, pyridine
H
2. Bu3SnH, AIBN reflux toluene
H O
71
3. pTSA, H2O/MeOH
O
H3 C
O
N
69
H3C
1. LDA, THF, −78 ºC 2. MeI
H
H
+
H
CH3
N H
1. Boc anhydride H3C Et3N Boc N 2. AlMe3/NH3 H CH2Cl2
CH3 NH2 O 73
72 Scheme 9.
O
anhydrous chloral O toluene, 40 h
COOH
N H
RNH2, toluene reflux, 2 h
O
N
O
O
17
Cl3C
O
N H RHN 75
74
LiAlH4 reflux, 2 h
N H 76 RHN
Scheme 10.
O
O
O
O AD-mix-alpha[(DHQ)2PHAL ligand] HO OTBS t-BuOH/ H O
N
N
2
OH
Cbz
Cbz 78
77 H
O
H O
N TBSO
OH OH
i. Bu4NF, HF OTBS ii. TFA, H2O
N
OH
HO hyacinthacine B1 80
79 Scheme 11.
i. TBSCl, Et3N ii. MsCl, Et3N OTBS
iii. H2, Pd/C, EtOH
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
[O] Pt wire
Menthol, DCC/DMAP O
CH2Cl2
COOH
N H
O
COOR n-Bu4PF6/MeOH
N H
17
COOR O
82
81 SiMe3
COOR O
TiCl4, CH2Cl2
O
NaCN
H2O
N H
83
84
O
O Et3SiH/TFA
NH
O
OsO4/NaIO4
CONH2
NH3/MeOH
N H
OMe
N H
NH O
MeNO2
N H
N H
OH
86
85 Scheme 12.
S O
COOH
N H
+
HN
S DCC CH2Cl2 O
N H
COOEt 87
17
S
−
OH N
O
O
N
N H
COOEt
O
COOH
89
88 S ImzCO HX
O
N
N H
COX
O
X= -OC2H5, -NH2, -NHC2H5
89
Scheme 13.
89. The carboxylic acid was converted to its derivatives 90 by reaction with various nucleophiles. Lin et al. synthesized14 (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxasole 96 as a cholinergic channel activator with potent cognitive and anxiolytic activities from pyroglutamic acid 17 (Scheme 14). Pyroglutamic acid was converted to its methyl ester in situ and was subjected to Claisen condensation with acetone oxime dianion, thereby affording compound 93. The acetone oxime component in compound 93 in the presence of H2SO4 as a catalyst underwent cyclization to afford 94, which on reduction of lactam amide with borane, followed by N-methylation gave the desired ABT-418 derivative 96. Benoit Rigo et al. investigated15 various N- and C-protection and deprotection sequences in native pyroglutamate with an aim to develop different reaction methodologies for the synthesis of bioactive molecules (Scheme 15).
O
N H 17
COOH
Reaction of pyroglutamic acid chloride with isopropylidine malonate (Meldrum’s acid) is reported to give C-acylated Meldrum’s derivative whose methanolysis gave b-keto ester 103 (Scheme 16), however the reaction of acyl chloride with sodium salt of Meldrum’s acid (isopropylidene malonate) in pyridine could not be repeated by Rigo et al.15,16 Nagasaka et al.17 established a new approach to get two enantiomers of 5,5-disubstituted 2-pyrrolidinones 108 with specified configuration starting from pyroglutamic acid through its bicyclic lactam (2R,5S)-2-aryl-1-aza 3-oxabicyclo[3.3.0]oct-5-en-7-one 105 (Scheme 17). Bicyclic lactam 105 was deprotonated at C-5 by NaH and the resultant anion on Michael addition with methyl acrylate gave two diastereomeric Michael adducts 106 and 107, which were separated and pure compound 107 on acidic hydrolysis afforded the desired 5,5-disubstituted 2-pyrrolidinone 108.
1. MeOH, SOCl2 2. LiCH2CNOLi(Me)
O
Me N H 93
O
NOH
H2SO
O
Me N H 94
O
N
1. BH3, THF 2. (i) HCHO (ii) HCOOH
1. MeOH, SOCl2 2. NaH, MeI 3. LiCH2CNOLi(Me) 1. H2SO4 O
Me N Me 95
O
2. (i) BH3, THF (ii) CsF
NOH
Me N Me (ABT-418) 96
Scheme 14.
O
N
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
Pyroglutamic Acid HMDS
N
O
1. (CF3CO)2O
1. MeOCOCl 2. (COCl)2 O
COCl
COOMe 98
N 97
COOSiMe3
2. SOCl2
N
O
COCl
COCF3 99
SiMe3 (CF3CO)2O
COOSiMe3
N
O
(CF3CO)2O O CF3
COCF3 100
CF3
O
N
O
O
O 101
Scheme 15.
pyroglutamate derivative 110 through self-reproduction of chirality (Scheme 18). Ostendorf et al.19 established the synthesis of enantiopure hydroxyamidines 116, utilizing base-catalyzed enantioselective reactions such as Michael reaction (Scheme 19). Methyl pyroglutamate 111 was treated with PhMgBr at low temperature to afford tertiary alcohol, which was converted to silyl ether 112 with TBDMSOTf. Compound 112 on N-derivatization with acrylonitrile afforded compound 113 which on reductive amination of cyano group followed by N-Boc protection afforded compound 114. Compound 114 after a sequence of reactions furnished the desired bicyclic amidine 116. Acevedo et al.20 synthesized sterically constrained L-glutamine analogues (3S,4R)-3,4-dimethyl-L-glutamine 123 and (3S,4R)-3,4dimethyl-L-pyroglutamic acid from pyroglutamic acid (Scheme 20). Compound 117 already discussed1a on methylation with dimethyl lithium cuprate followed by reaction with MeI/Et2O afforded 118 which after a sequence of reactions was converted to the desired glutamine analogue 123. Marchalin et al. developed new methodology for the synthesis of (S)-thieno[f]indolizinedione 125 from N-alkylated (S)-pyroglutamic acid21 124 (Scheme 21). Olson et al.22a,b carried out reduction–iodination of methyl Nbenzyl pyroglutamate 126 to get iodide 127, which on reaction
O O OMe O
O
O
N
N H
HO O O
F3C 102
O
O
103 -
O O + DMF
O
O
Cl N O O
F3C
+
O
No reaction
O O
104
+ PY
O O Scheme 16.
In our studies on the asymmetric use of pyroglutamic acid we synthesized18 a-benzyl derivative through condensation of pyroglutamic acid with trimethylacetaldehyde to get a bicyclic derivative 109 as a chiral auxiliary which on deprotonation with LiHMDS followed by reaction with electrophiles gave chiral a-substituted
H O
O
N O Ar
COOMe
1. CH2=CHCOOMe N
2. NaH 3. DMSO.THF
+
COOMe O
N
O
O
Ar 105
Ar 107
106
107
AcOH.THF-H2O rt
COOMe O
N H
HO
108 Scheme 17.
H THF/Dioxane, TFA O
N H 17
COOH
trimethylacetaldehyde
O
N H O
109 Scheme 18.
O
1. LiHMDS, THF −78 ºC 2. Electrophile
R O
N
O H O R= -CH2Ph 110
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
PhMgBr O COOMe TBDMSOTf
N H
CN
Ph Ph OR
N H
O
1. Lawesson's reagent Ph S Ph 2. TBAF
N
114
BocHN
OTBDMS
113
Ph 1. MeI Ph 2. TFA OH 3. NaOH
N
OTBDMS
BocHN
, CoCl2 Ph 1. NaBH4 2. (Boc)2O Ph
N
NC
112a, R=H 112b, R=TBDMS
111
O
N
Ph Ph
N
OH 116
115
Scheme 19.
O
1. (CH3)2CuLi, Et2O, −78 ºC
OTBS
N
O
2. CH3I, Et2O, −78 ºC
2. HOAc, −78 ºC
Boc
Boc
4
118
+ O
OTBS
N
O
OTBS
N
119
1. LiHMDS, THF, −78 ºC
OTBS
N
1. CrO3, H2SO4 O
acetone, 0 ºC
N
COOH
Boc
Boc
Boc
118
119
120
Ni-Pr a. i-PrHN
OtBu 121
O
NH3, KCN O
b. BF3.OEt2 c. C6H12, CH2Cl2
COOtBu
N
NHBoc
H2N
THF
COOtBu
Boc 122
123 Scheme 20.
HOOC
N
O
1. SOCl2
O
Altman et al. carried out the synthesis of (S)-5-(aminoxymethyl)pyrrolidone 130 from (S)-5-(hydroxymethyl)pyrrolidone 18 through Mitsunobu reaction with hydrazoic acid followed by the hydrogenation of the resulting azide23 (Scheme 23). Wei et al.24 synthesized (S)-5-alkenyl-2-pyrrolinones 132 from N-Boc protected methylpyroglutamate 131. Ester group of compound 131 was reduced to the corresponding aldehyde with diisobutylaluminium hydride at 78 °C. Witting reaction followed by oxidation with pyridinium chlorochromate (PCC) afforded (S)-5alkenyl-2-pyrrolidinones (Scheme 24). Langlois25 et al. carried out stereoselective synthesis of (2S)-2hydroxymethylglutamic acid 136 starting from (S)-pyroglutaminol
H N
2. AlCl3
O
S
S 124
125 Scheme 21.
with vinyl magnesium bromide and dilithium tetrachloro cuprate gave 128, a precursor for peptide mimetic of the thyrotropinreleasing hormone (Scheme 22).
O
N
COOMe
1. NaBH4 2. TsCl, DMAP
I O
3. NaI, Me2CO
Bn 126
MgBr
N
Li2CuCl4
Bn 127
N Bn 129 Scheme 22.
N Bn 128
O
O
O
O
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
OH O
N H 18
1. HN3, DEAD, Ph3P
salt to afford 141 which on treatment with CH3I was converted to quaternary ammonium salt 142. Compound 142 on passing through alkaline Dowex-550A afforded (±)-deoxydysibetaine (Scheme 27). Villeneuve et al.28 carried out the synthesis of pyroglutamic acid fatty esters 145 through lipase-catalyzed esterification with medium chain alcohols (Scheme 28). Langlois et al.29 carried out diastereoselective synthesis of (±)deoxydysibetaine 152 which was prepared from methyl pyroglutamate through a regioselective Mannich reaction at C-2 (Scheme 29). Compound 146 on reaction with MsCl in pyridine followed by the introduction of azide group at position 2 using NaN3 was converted to 148, which on hydrogenation in the presence of H2/ Pd–C afforded 149. The resultant amine 149 on reaction with CH3I–iPr2NEt was converted to 151 and the desired product (±)deoxydysibetaine 152 was obtained from 151 according to the procedure already described in Scheme 27. Itoh et al.30 carried out asymmetric synthesis of 1-substituted 1,2,3,4-tetrahydro-b-carbolines employing pyroglutamic acid derivative as a chiral auxiliary (Scheme 30). Puschel et al. described the synthesis of pyrrolidinone PNA; novel conformationally restricted PNA analogues, for example, (3R,5R)(3S,5S)pyroglutamate-PNA monomers31 (Scheme 31). Compound 156, derived from pyroglutamic acid on reaction with MoOPh in the presence of LiHMDS and BuLi followed by the protection of OH group and deprotection of Boc group using Bomchloride and TFA was converted to 3-substituted product 158, which on reaction with NaH and BrCH2COOMe afforded N-acylated product 159. Compound 159 after deprotection gave an alcohol 160 which was converted to 162 by similar steps as described in Scheme 29. Compound 162 on hydrogenation with H2/Pd–C, followed by protection of amino group using Boc and subsequent reaction with H2 and Pd(OH)2 afforded 163 with deprotection of Bom. Further
NH2
O
N H 130
2. H2, Pd/C, EtOH Scheme 23.
O
N Boc 131
COOMe
1. DIBALH, PhMe
R
O
N
2. Ph3P=CHR 3. PCC
Boc 132
Scheme 24.
18 through a bicyclic silyloxypyrrole derived from versatile unsaturated lactam (Scheme 25). Compound 133 on reaction with SnCl4 and NaHCO3 was converted to 134 having hydroxyl group at position 5, which on reaction with Me3SiCN, SnCl4 followed by acidic hydrolysis afforded 136. Davies et al. achieved the synthesis and explored the utility of the 3,3-dimethyl-5-substituted-2-pyrrolidinone 140 using pyroglutamic acid as a chiral auxiliary26 (Scheme 26). Compound 18 on reaction with 2,2,dimethoxypropane in the presence of pTSA, followed by double alkylation at position 7 using LDA and MeI was converted to 138 which on acidic hydrolysis was changed to 4-substituted pyroglutaminol 139. Treatment of 139 with TBDMSCl in DMF afforded the desired product 140. Langlois et al. synthesized racemic and enantiopure (±)-deoxydysibetaine 143 from methyl pyroglutamate27 111. Compound 111 was deprotonated with LiHMDS and alkylated with Eschenmoser’s
Et3N/TBSOTf
OH O
O
N H 18
N
Bu
SnCl4
SiO
N
O Ph
35
Ph
OH O
t
CH2Cl2
NaHCO3 O 133 COOH
CN Me3SiCN
N
O
6M HCl
N
SnCl4
O
O
Ph
H3N Cl -
Ph 135
134
COOH OH
+
1. HCl 136
Scheme 25.
O OH O
N H
N
toluene, pTSA, heat
O
18
3. LDA, −78 ºC 4. MeI, −78 ºC
137
O
O MeOH
N
pTSA, heat O
138
1. LDA, −78 ºC 2. MeI, −78 ºC
2,2-dimethoxy propane
1. TBDMSCl, DMF.Im NH or Ph3CCl, DMAP OH NEt3, CH2Cl2 139
Scheme 26.
O NH R R= CH2OTBS R= CH2OCPh3 140
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O O
LiHMDS, THF Eschenmoser salt
COOMe
N H
O
CH3I
N
N H
111
O
OMe
THF
O
141
Dowex, 550A O
-
N+
N H
I-
142 O
OH
OMe
ON+
N H (±) 143
Scheme 27.
O
H2SO4 + C H OH 2 5 reflux, 24 h COOH
N H 17
Candida antarctica lipase
O
COOC2H5
N H 144
O
R=2-methyl-2-butanol
N H 145
COOR
Scheme 28.
R
R COOCH3 OH
O
R
MsCl-Py
COOCH3 OMs
O
N H 146
NaN3 DMF
N H 147
O
N H 148
COOCH3 H2-Pd/C N3
R
O
N H 149
MeI-iPr2NEt
HCHO H2, Pd/C
R
O
COOMe NH2
O
MeI
N H 150
R
R COOMe N+
N H 151
COOMe NMe2
Dowex, 550A OH-
I-
O
COOMe N+
N H R= H R= OH 152
Scheme 29.
N O
N
ClCOOCH2CCl3 N R
153
N
O
O
N
COOCH2CCl3
H
N H 155
Bu3Sn CH2Cl2, −40 ºC
N
NaOH, THF, -H2O
COOCH2CCl3
H
N R O 154 Scheme 30.
reaction of 163 under Mitsunobu conditions, followed by alkaline hydrolysis afforded 165. Oba et al.32 established novel stereocontrolled approach to conformationally constrained analogues of L-glutamic acid and L-proline via stereoselective cyclopropanation of 3,4-didehydro-Lpyroglutamic ABO ester. Compound 166 was subjected to 1,3-dipolar cycloaddition with CH2N2, followed by photolysis with benzophenone using Hg lamp and compound 168 thus obtained on hydrolysis with MeOH–HCl was converted to methyl ester 169 with deprotection of Boc group. N-Protected compound 170
on reduction with BH3–THF followed by acidic hydrolysis on Dowex 50-X8 afforded 172 (Scheme 32). Herdeis et al.33 carried out the synthesis of unsaturated orthopyroglutamic ABO ester 166 from pyroglutamic acid (Scheme 33). Pyroglutamic acid was converted to its alkenyl ester, which on reaction with mCPBA, followed by reaction with zirconocene catalyst and silver perchlorate afforded ABO ester 174, which was converted to N-protected compound 175. Compound 175 upon oxidation under usual conditions, followed by oxidative deselenenylation using H2O2 afforded 166.
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
OH TBDPSO
a. LiHMDS, BuLi, THF N
O
Bom-chloride, DIEA CH2Cl2
TBDPSO
Boc
156
O TFA: CH Cl , 0 ºC 2 2
N
b. MoOPh
Boc 157 OBom
OBom NaH, BrCH2COOMe
TBDPSO N H
O
Et3N.3HF
TBDPSO
THF
158 OBom
N
OBom
NaN3, DMF
MsCl MsO O Pyridine
HO
O
N
160
O
N
COOMe 162
161 AZ
OH
163
1. H2, Pd/C, (Boc)2O, AcOEt 2. H2, Pd(OH)2/C MeOH
N3
80 ºC
COOMe
COOMe
THF
COOMe
159 OBom
BocHN
O
N
1. adenine, PPh3 DEAD, dioxane BocHN O 2. N-benzyloxycarbonyl N -N'-methylimidazolium triflate CH2Cl2 COOMe
AZ LBiOH, THF BocHN
O then HCl
N 164
O
N
COOMe
165
COOH
Scheme 31.
N N CH2N2 O
ABO
N
ether
O
Boc 166 H O
N
H
H (Boc)2O, DMAP MeCN O COOMe
Boc 168 H
N
HCl-MeOH ABO 0 ºC
N
Boc 167 H
N H 169
H Hg-lamp(400W) ABO Benzophenone O MeCN, 0 ºC
H BH3-THF
COOMe
H
(*)
1M HCl H
H
Dowex 50-X8 COOMe
N
N H 172
Boc 171
Boc 170
*= ABO=5-methyl-2,7,8-trioxabicyclo[3,2,1]oct-lyl Scheme 32.
1. CH2=C(Me)CH2CH2OH O
N H
COOH
DCC, DMAP 2. mCPBA, CH2Cl2
N H 173
17 (Boc)2O, DMAP
CP2ZrCl2 AgClO4, CH2Cl2
O
O
O
N H
ABO
O
MeCN
N Boc 175
174
O NaN(SiMe3)2 ABO PhSeCl, DMPU THF, −78 ºC
PhSe 30% H2O2, THF O
N
O
ABO
Boc
N Boc 166
176 Scheme 33.
O
ABO
COOH
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
Stevens et al. reported a short and elegant synthetic pathway for the synthesis of 1,3-dioxo-hexahydropyrido[1,2-c][1,3]diazepine carboxylates, a new 1,3-diazepan-2,4-dione 181 containing bicyclic moiety, starting from pyroglutamate34 (Scheme 34). Compound 177 on reaction with LiHMDS was deprotected at C-2, resultant anion on reaction with electrophile afforded 178, where lactam carbonyl C–N bond was cleaved using NaH, RNCO to expend the ring and resulting product on reaction with electrophile in the presence of K2CO3 yielded 180. Compound 180 was subjected to cyclization with Grubb’s II generation catalyst thereby affording compound 181. Bourry et al. reported their studies on pyrrolidinones through reaction of methylene dichloride under Friedal–Crafts conditions, with an objective to synthesize a-hydroxymethyl ketone in the hexahydrobenzo[f]indolizine series35 (Scheme 35) using pyroglutamic acid as a chiral precursor. Mavromoustakos et al.36a,b reported the synthesis, binding studies and in vivo biological evaluation of antihypertensive analogues 188 using pyroglutamic acid as starting material (Scheme 36). Compound 111 on reaction with NaH, PhCH2Br, followed by reduction using LiBH4 was converted to N-benzyl methyl pyroglutaminol
186, which was converted to its o-tosyl derivative 187. Treatment of 187 with lithium imidazole afforded antihypertensive agent 188. Beal et al. described anodic oxidation/olefin metathesis strategy thereby developing a unified approach to the synthesis of bicyclic lactam peptidomimetics using pyroglutamic acid37 (Scheme 37). Pyroglutamic acid derivative 189 on acidic hydrolysis was converted to intermediate product and subsequent reaction with pyroglutamic acid, followed by amination using NH3 and MeOH afforded 190. Langlois et al. reported the tandem electrophilic and nucleophilic addition to bicyclic tert-butyl-dimethylsilyloxypyrrole derived from (S) pyroglutaminol38 (Scheme 38). 2.2. Activation of lactam carbonyl at C-5 by formation of thiolactam, imino, iminium ethers and as lactam acetals Suitably activated lactams and amides possess great synthetic utility for the construction of many of the nitrogen-containing heterocycles. Activation of the lactam is generally being carried out by conversion to thiolactam, imino, iminium ethers or as lactam ace-
R'
O
N H 177
LiHMDS, THF, −40 ºC O COOEt Electrophile R'=H, CH2Cl
Electrophile, K2CO3 acetone, reflux
N H 178
Grubb's 2nd generation catalyst, CH2Cl2, reflux R''' R'=H, H R''=Pr, Ph R'''=H, H
N
N
R'= H, H R''= Pr, Ph R'''= H, H
R''
O 180
N
NH
R'' O 179 COOEt
COOEt R' O
COOEt R'
O
R''NCO, NaH COOEt THF R'=H, H R'=Pr, ' Ph
R'
O N
N R''
R''' O 181
Scheme 34.
O
1. (CF3CO)2O 2. BF3.Et2O, CH2Cl2
COOH
N
CH2OH O
O O
+
N
1. (CF3CO)2O 2. BF3.Et2O
O
N
ClCH2CH2Cl O
O
O
O
O
O
182
184
183 Scheme 35.
1. SOCl2 O
COOH
N H
2. MeOH
NaH, THF O
COOMe PhCH2Br
N H
17
LiBH4, THF O
N 185
111
COOMe
25 ºC
Ph
+
OH O
N 186
DMAP or Et3N CH2Cl2 Ph
Li-N
TsCl
OTs O
N 187
N DMSO
Ph Scheme 36.
N O
N 188 Ph
N
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
H O
Boc N
O
COOMe 1. 3M HCl/EtOAc
N
Ph
NH
N H
O
O Ph
2. 17, EDCl, HOBt, CH2Cl2 3. NH3, MeOH
CONH2 N
190
189 Scheme 37.
t Bu
OH
1. SnCl4 SiO
O
N
N
2. NaHCO3 O 133
Ph
N O Ph
191
SnCl4
SnCl4 MeOH
SnCl4
Me3SiCN
MeOH
OMe O
O
Me3SiCH2CH=CH2
O 134
Ph
SnCl4
CN O
N
N
O
O
Ph
Ph 135
192
Scheme 38.
Fang et al. have carried out41 the annulation of diazomethylvinyl ketone with a variety of thiolactams prepared from (S)-pyroglutamic acid. Thiolactam derivative of pyroglutamic acid 209 was converted to 210 by Michael addition which was cyclized to get 211 in the presence of [Rh(OAc)2]2, W-2 and Ra-Ni. Resultant material on oxidation with OsO4 and H2S in methanol, followed by protection of OH group with TBSCl was converted to 212. Lithium enolate-derived reaction of 212 with t-butyl propionate afforded 213 which upon selective reduction of the double bond of side chain followed by deprotection afforded 214. Thus this synthetic strategy provided a novel route for dihydropyridones like ISO A58365A 214, the c-pyridone analog of the potent ACE inhibitor A58365A (Scheme 41). Rosset et al. have described42 the enantioselective synthesis of (5R)-2-(5-hexenyl)-5-nonyl-3,4-dihydro-2H-pyrrole and (2R,5R), 2-(5-hexenyl)-5-nonyl pyrrolidine, Monomorium minutum ant venum alkaloids, from (S)-pyroglutamic acid through lactam ether (Scheme 42). Both D- and L-pyroglutamic acids have been used43a,b with prior activation at C-5 for the synthesis of semicorrin metal complexes as enantioselective catalysts (Scheme 43). These semicorrins43b
tals. Among the activated lactams, lactam acetals are particularly useful as these react with both nucleophiles and electrophiles at C1 and C2, respectively, and with bifunctional reagents to form annulated products. Because of these reasons many workers have made use of pyroglutamates via the activation of the lactam carbonyl at C-5 of pyroglutamate. L-Pyroglutamic acid has been used as chiral starting material for the synthesis of anatoxin-a, a potent nerve depolarizing agent, via intermediacy of thiolactam.12 C–C bond formation at C-5 was effected by a sulfide contraction reaction39 (Scheme 39). Bachi et al. have described40 the synthesis of carbapenam-3carboxylates 207(a) and 207(b) starting from ethyl (S)-pyroglutamate which was converted to the corresponding 5-thioxo derivative for C–C bond formation at C-5 (Scheme 40). Compound 200 on reaction with ethyl-2-bromo-3-oxobutyrate, followed by hydrogenolysis with CH3COOH and TFA (20%) was converted to diastereomeric compounds 202, 203a and 203b, in which 203a on reaction with KOH and (Boc)2O afforded N-protected acid 204. Compound 204 was converted to its PNB ester 205 which after N-Boc deprotection followed by cyclization was converted to 207a and 207b using substituted carbodiimide.
Methyl bromo acetate in CH3CN tBuOOC
S
N
t BuOOC
CH2Cl2, PPh3, Et3N
COOCH3
2. LiBH4 in Et2O
N
Bu
Bu
193
194
O Ph3P+
1. Me2SO, CH2Cl2 OH
t
BuOOC
N
Oxalyl Chloride
CHO
t
BuOOC
Bu 195
N Bu 196
O t BuOOC
N
1. degassed N2, Pt/C, H2
Anatoxin A O
199
Bu 198 Scheme 39.
197
O
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
ethyl-2-bromo3-oxobutyrate O
COOH
N H 17
S
Et COOEt +
N H
N H
EtOOC
OH 202
203a
H 1M HCl Et in EtOAc HOOC
O
H Et COOEt + EtOOC
Et COOH
N
HOOC
Boc 204
201
COOEt
N H 203b
203a
H 1. KOH 2. DMAP, (Boc)2O, Et3N
COOEt
N H H3C
H
hydrogenation EtOOC Pt/C in H3C CH3COOH
EtOOC
COOEt NaHCO , CH Cl 3 2 2
N H 200
H dicyclohexylamine Et p-nitrobenzeldehyde KI, DMF HOOC
COOPNB
N Boc 205
H
H
CH2Cl2, Pyridine N H 206
COOPNB 1-(3'-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
+
N
N
O
O COOPNB
COOPNB 207b
207a Scheme 40.
N2
S O
O
X +
CH2 X=CHN2 X=OCH3 208
S
NaOH, THF
HN
1. [Rh(OAc)2]2 Benzene, reflux
N
O N
2. W-2, Ra-Ni, acetone
t
t BuOOC
COO Bu tBuOOC
211
210
209 OR
1. OsO4, Pyridine
OTBS
O
2. H2S, MeOH
N COOt Bu
R= H R= TBS 212
O
1. LiCA, THF, −78 ºC 2. t-Butylpropiolate, −78 ºC 3. AcOH, −78 ºC
t
BuOOC
N 213
COOtBu
TBSCl, NEt3, CH2Cl2
OH 1. W-2, Ra-Ni, acetone
O
2. HCOOH
N
HOOC
COOH ISO A 58365 A 214 Scheme 41.
225–228 possess several features that make them attractive ligands for enantioselective control of metal-catalyzed reactions. Singh et al. described44 a simple and efficient synthesis of 8methyl-3,8-diazabicyclo[3.2.1]octane (azatropane) and 3-substituted azatropanes using pyroglutamic acid as starting material and exploiting amide activation methodology (Scheme 44). Pyroglutamic acid was converted to N-methyl pyroglutamate which on reaction with Lawesson’s reagent was converted to the corresponding thio lactam. Treatment of thio lactam with methyl iodide in benzene, followed by reaction with nitro methane in the presence of triethylamine yielded nitroenamine 230. Nitroenamine
230 after catalytic hydrogenation over Pd–C in the presence of ammonium formate in absolute methanol afforded compound 231. Compound 231 on reduction of lactam carbonyl with LiAlH4 followed by N-alkylation under usual conditions furnished the desired compound 233. Liyanage et al. established45 the synthetic route for carbapyochelins via diastereoselective azidation of 5-(ethoxycarbonyl) methyl proline derivative (Scheme 45). Pyroglutamic acid derivative 234 on reduction of azide group, followed by EDC-mediated coupling of crude amine with O-benzyl salicylic acid afforded compound 235, which was subjected to the reduction
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
HOOC
1. MeOH, SOCl2 O 2. NaBH4, EtOH
N H
N
OAc HO
N 216
215
17 1. Lawesson's reagent 2. CH3I then MeONa-MeOH
OH 1. n-C9H19MgBr
MeS
ether-CH2Cl2
N
OH n-C9H19
N 218
217 n-C9H19
+
N X 219(a)
toluene
N X 219(b)
CBzCl NaHCO3 H2O
X= H
CBzCl NaHCO3 H2O
1. NaBH(OAc)3
OH
OH n-C9H19
Ac2O, Pyridine
OH HO
X= CBz
TsCl, Pyridine 2. [CH2=CH-(CH2)3]2CuLi
n-C9H19
X= H X= CBz
Me3Sil, CHCl3
R N CBZ
n-C9H19
R N H R= (CH2)4CH=CH2
R= (CH2)4CH=CH2 220
221
Scheme 42.
CN HOOC
H3COOC
O
N H 61
OEt
N 222
H3COOC
N H 223
CN
CN MeMgBr
222 CN
COOCH3
N H
N
N
Et2O
H H3 COOC
224
N
N H
COOCH3
H3 C CH3 H3 C OH 226 HO CH3
225
CN 225
COOtBu
CN (t-Bu)Me2SiCl, DMF
LiBH4 N
THF, 32 ºC
H HOH2C
N
imidazole, 40 ºC
H
CH2OH
227
N
N t Bu
OSi
OSi
t
Bu
228 Scheme 43.
Lawesson's reagent O
N Me
S
COOMe
COOMe
i. CH3I, PhH
O2N
ii. CH3NO2, Et3N, DMF
H
229b
229a
HCO2NH4
N Me
Pd-C, MeOH N H 231
LAH pellets O
THF
COOMe
230 Me N
Me N
N Me
RCl K2CO3 DMF
N H 232
Me N
N R 233
Scheme 44.
of ethyl ester group in the presence of lithium borohydride to give 236. Compound 236 on further hydrogenolysis followed by cyclization with Burgess reagent afforded 237. Compound 237 on deprotection of t-butyl group afforded the desired carbapyochelins 238. In a view to develop methodologies for the chirospecific synthesis of 5-butyl-2-heptyl pyrrolidines, Shiosaki et al. reported a pro-
cedure46 for the asymmetric synthesis of 5-substituted prolines from pyroglutamates, in which the key steps adopted were the thiolactam formation from lactam of pyroglutamates followed by induction of side chain at C-5 through sulfide contraction and reduction sequences (Scheme 46). Corey et al.47 have utilized C-5 centre of the pyroglutamate by reduction for the synthesis of poly functional, structurally defined
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
OBn N3 N Me 234
EtOOC
COOtBu
O
i. Pd/C, H2, EtOH
LiBH4. Et2O
ii. O-Bn-salicylic acid EDC, Et3N, DMAP
HN COOtBu
N Me
EtOOC 235
OBn
HN HO 236
O
i. Pd/C,H2, EtOH ii. Burgess reagent THF t COO Bu
O
N Me
OH
O TFA/DCM anisole
COOtBu
N Me
N
237
COOH N Me. TFA
N OH 238
Scheme 45.
R1 t
Bu O O
S
N
But O
R2 R2 =SOOCF3
O
Bu
Ph3P
ButO
( )5
CH2Cl2
ButO
O
Bu
PtO2,
( )5 N O
CH3
50Psi, H2
CH3 COOBu
N Bu
240
239 Pd/charcoal cyclohexane
COOBu CH ( )5 3 S
+ N
241
But O
( )5 N O
242
CH3
But O +
N O
Bu 243
( )5 CH3
Bu 244
Scheme 46.
catalyst 252, which finds use in the enantioselective addition of dialkylzinc reagents to aldehydes (Scheme 47). Wistard et al. have reported the synthesis of 5-substituted pyrrolidines from N-acylated pyroglutamic acid48a,b (Scheme 48). Agarwal et al. established a concise asymmetric approach to the bridged bicyclic tropane alkaloid (+)-Ferreiginine using enyne ringclosing metathesis49 (Scheme 49). Pyroglutamic acid was converted to its benzyl ester, followed by reduction using LiEt3BH 1. DIBAL-H THF, -78oC 2. pTSA
H O
COOEt
N
H H3CO
H
Methanol-Formalin
H trimethylsilylcyanide, CH2Cl2
COOEt
N
Stannic chloride, -40oC
COOEt 246
COOEt 245 Red, H2, W-II Reney-Ni
and MeOH/pTSA to afford C-5 methoxylated ester 257, which was subsequently subjected to C-5 allylation to afford 258 with stereoselectivity. Compound 258 on reduction followed by acetylenic carbon insertion under modified Witting conditions and subsequent hydrolysis of the resultant product afforded 260. Treatment of 260 with Grubb’s catalyst yielded 261 which after a sequence of reactions afforded the desired product (+)-ferreiginine 263.
H
NMe2
N
H N NMe2 H 250
H
H
PhMgBr, THF, 0oC
Ph Ph 249 LiAlH4 OH
NMe2
H
H
NMe2
N Me
251
Scheme 47.
H N
COOEt
COOEt 247
COOEt
COOEt 248
H NC
Ph Ph OH
H N
Ph Ph OH
KOH, CH3OH, H2O
COOEt 249
H Et2Zn
H
Ph Me Ph Zn O Me2N Et 252 N
1598
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
HO
HO
COOR''
N
COOR''
N
Nu Nu
COOR'
COOR' 253
COOR''
N
COOR'
254
255
Scheme 48.
1. iPr2EtN, BnBr O
COOH
N H
CH2Cl2 O 2. (Boc)2O, DMAP MeCN
COOBn
N
1. LiEt3BH, −78 ºC, THF
Boc 257 CH3COCN2PO(OEt)2
reduction COOBn
N
Boc N
Boc 260
259 Boc N
Me N 1. TFA, CH2Cl2, then K2CO3
H2O, DMF
PCy3 Ru Cl PCy Ph
N
Boc
PdCl2, CuCl2
Cl
2. CH2O, NaCNBH3 CH3CN
3
O
261
Grubb's 10 mol%
CHO K2CO3, MeOH
N
Boc 258
CH2Cl2
COOBn
N
Boc 256
17
BF3.OEt2 Allyltrimethylsilane −78 ºC, Et2O
MeO
2. MeOH, pTSA, 25 ºC
O
262
263
Scheme 49.
of this reaction is in the addition of trimethylsilane to various Nacyliminium ions bearing ester side chains. As a result the precursor 264 could be converted to its allylated derivative 265. Mandal et al. described an efficient synthesis of the constrained peptidomimetic 2-oxo-3-(N-9-fluorenyloxy carbonylamino)-1-azabicyclo[4.3.0]nonane-9-carboxylic acid from pyroglutamic acid51 (Scheme 51). N-Boc methyl pyroglutamate 131 on reaction with vinyl magnesium bromide afforded Micheal acceptor 266, which on reaction with Schiff’s base in the presence of Cs2CO3 followed by hydrogenation using Pd/C in EtOH/AcOH (9:1) coupled with cyclization, was converted to diastereomeric compounds 268a and 268b. Compound 268b was epimerized to 268C in the
Another approach for the preparation of pyrrolidine allylation products involving diastereoselective enzymatic ester hydrolysis (Scheme 50) has also been reported.50 An important application
XR3 '' R'O
N
COOR
COOR
N
Lewis acid
PG
PG
264
265 Scheme 50.
O
131
MeOOC
COOMe
vinylmagnesium bromide
COOtBu
(Ph)2=NCH2COOtBu NHBoc
o
THF, -40 C
CS2CO3, THF
NHBoc
O 266
267
H N
BocHN
O 268a
H NaHMDS
N
BocHN COOtBu
O
N O 269a
Ph
N O 268c
268b 1. TFA, Et3SiH, CH2Cl2 2. Fmoc-OSu, 10% Na2CO3 1,4-dioxane H H
FmocHN
10% Pd/C
EtOH/AcOH(9:1)
H
+ BocHN COOtBu
Ph
N
COOtBu
1. TFA, Et3SiH, CH2Cl2 2. Fmoc-OSu, 10% Na2CO3 1,4-dioxane H
+ FmocHN COOH
N
FmocHN
COOH O 269b Scheme 51.
N COOH O 269c
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
presence of NaHMDS. Treatment of each diastereoisomer of 268 under usual conditions afforded the desired stereospecific isomers of 269. Hanessian et al.52 synthesized N-acyloxyiminium ions generated from 4-substituted L-pyroglutamic esters with 4-(3-butenyl),4-(3-butynyl),4-(3-cinnamylmethyl) and 4-allenic ethers which subsequently underwent rapid Lewis acid-mediated carboxycyclization to afford stereodefined azacyclic compounds (Scheme 52). Conchon et al. described53 asymmetric synthesis of 3,5-disubstituted indolizidines by intramolecular addition of an allylsilane on an N-acyliminium ion derived from pyroglutamic acid. Compound 273 on reaction with benzylchloroformate in the presence of n-BuLi, followed by reduction was converted to 274, which on reaction with a-hydroxy b-trimethylsilyl-c-allyl derivative in the presence of SnCl4 was converted to 276 and subsequent reaction with PDC led to cyclization, thereby affording 278. Compound 278 after hydrogenation afforded isomers 279 and 280 (Scheme 53). Peng et al. reported the designing and synthesis of a 1,5-diazabicyclo[6,3,0]dodecane amino acid derivatives as novel dipeptide reverse-turn mimetics54 (Scheme 54). Pyroglutamic acid derivative 281 on reaction with TBSCl, followed by hydrogenation using Pd/C catalyst was converted to 282, which after N-acylation coupled with the deprotection of OH group afforded 283. Oxidation of side chain OH group of 283 followed by N-deprotection coupled with cyclization gave the desired compound 285. Angiolini et al. carried out55 synthesis of azabicyclo alkane amino acid scaffolds as reverse-turn inducer dipeptide mimics (Scheme 55). Compound 286 upon oxidation, followed by reaction with (±)-(Z)-a-phosphonoglycine trimethyl ester and subsequent protection of NH group afforded 287. Compound 287 on alkaline hydrolysis afforded 288, which on hydrogenolysis followed by
cyclization was converted to the desired molecules 289 and 290 as diastereomers. Ghammarti et al. described the synthesis of 1,5,6-10b-tetrahydro2H-pyrrolo[1,2-c]quinazoline-3-ones from pyroglutamic acid56 (Scheme 56). Danishefsky et al.57 described total synthesis of salinosporamide A, (Scheme 57) using pyroglutamic acid as a chiral starting material. Manzoni et al. reported the synthesis of spiroazabicycloalkane amino acid scaffolds as reverse-turn inducer dipeptide mimics58 starting from pyroglutamate (Scheme 58). Compound 303 on swern oxidation afforded aldehydic ester 304, which on witting reaction as described in Scheme 55 gave 305. Compound 305 after protection, deprotection and cyclization sequences afforded diastereomers 307a and 307b. Mulzer et al. synthesized rigid dipeptide mimetics. They have carried out stereocontrolled synthesis of all eight stereoisomers of 2-oxo-3-(N-Cbz-amino)-1-azabicyclo[4,3,0]nonane-9-carboxylic acid esters59 (Scheme 59). Compound 308 upon oxidation followed by witting reaction as described in Scheme 55 was converted to 310 and alkene component was subsequently reduced to get 311. Compound 311 after t-butyl ester hydrolysis, cyclization and conversion of carboxylic to its methyl ester afforded 312. Hussaini et al.60 reported a concise approach for the synthesis of cis-2,5-disubstituted pyrrolidines starting from pyroglutamic acid (Scheme 60). 5-Thioxo ethyl prolinate 200 was converted to 5alkylidine derivative 313 on reaction with diethyl bromomalonate in the presence of sodium bicarbonate. Compound 313 after Nbenzolylation afforded N-protected derivative 314. Compound 314 on hydrogenation in the presence of H2 (Pd–C), EtOH and CH2Cl2 gave N-benzoyl 2,5 disubstituted pyrrolidine 315. In another publication the same researchers have described a new methodology for the diastereoselective synthesis of 2,5-disubstituted pyrrolidine by the reduction of enamines derived from
H
H COOMe N
R'
H
Lewis acid
COOMe Lewis acid
R'=Me TMS
H O
X
N+ Boc
R'
H
O 271
N
COOMe
Boc 272 X= Cl, Br, aryl
270 Scheme 52.
1. SOCl2, NaBH4 HOOC
N H 61
O
2. TsCl, Et3N 3. Pr2CuLi, ether −20 ºC
Bu
O
N H 273
1. n-BuLi Benzylchloroformate 2. NaBH4, H2SO4 EtOH
H Bu Bu
OEt
N CBz 274
PDC, CH2Cl2
Bu
CBz
SiMe3 H
N
H2, Pd/C
CBz
MeOH
CBz
Bu
N+ R
275
R
OH
R
276
H
H Bu
N R 279
Bu
N
+ R Scheme 53.
280
O 277
OH R
H
N
N+
SnCl4 Bu
278
1600
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
1. TBSCl, N,N-diisoprpyl ethyl amine, CH2Cl2 TBSO
O O
COOH
N H
HO
N
2. H2, 10%, Pd/C, EtOAc
O
Bn 281
17
O
1. Boc-Dap(Z)-OH,EDC HOBT
HO
N,N-diisopropyl ethyl amine 2. TBAF, THF
CbzHN
O N H 282
O
Dess-Martin Periodinane
N O
CH2Cl2
O
O
O
N O
CbzHN
O
NHBoc 283
NHBoc 284
O
10%Pd/C,H2, MeOH
N O O
HN
NHBoc 285 Scheme 54.
Cbz 1. (COCl)2, DMSO, Et3N, CH2Cl2, −60 ºC
HO
(±)-(Z)-α−Phosphonoglycine trimethy lester
COOtBu
N
NBoc MeOOC
BuOK, CH2Cl2, −78 ºC, (Boc)2O, DMAP, THF
Ph 286
COOtBu
N
t
287
Ph
NHBoc HOOC
NaOH MeOH
287
COOtBu
N
1. H2, Pd/C, MeOH
Ph H2, Pd/C MeOH
N
N
2. Xylene, reflux BocHN
288
COOtBu +
O
COOtBu
N
BocHN
O 290
289
COOtBu COOMe NHBoc 291 Scheme 55.
O
N
O
COOH
SOCl2 O or ClCOCOCl
N
O
N N
COCl AlCl3 or SnCl4, CHCl3
O
N N
R
O R
R 292
294
293 Scheme 56.
pyroglutamic acid61 (Scheme 61). Compound 316 was converted to its N-Boc derivative which upon reduction in the presence of NaBH4 gave the desired product 318. Moloney et al. described62,144 a direct and versatile synthetic route for the reliable synthesis of trans-2,5-disubstituted pyrrolidines from pyroglutamic acid. N-Boc ethyl pyroglutamate 319 was reduced to 5-substituted product 320, which on reaction with PhSO2H gave 321 (Scheme 62).
Chan et al.63a–c described the conjugated addition of activated nitrogen nucleophiles, to a,b-unsaturated bicyclic lactams with an objective to synthesize enantiopure b-aminopyrrolidinones (Scheme 63) and a,b-diaminopyrrolidinones64 (Scheme 64), respectively, from (S)-pyroglutamic acid. Lithium enolate-derived Michael addition of 324 with di.tert-butyl azodicarboxylate afforded diamino lactam 325. This compound was transformed to the corresponding lactam 326 by deprotection with TFA which on
1601
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
Ph N
R' β-face R
O
COOBn
296
N
O
O
Me
O
297
O
H
ZnCl2
PMB
CHO
COOBn
PhS-H
OEt
PMB t
H
COOtBu
N
O
O BnO
COO Bu
PMB
O
R add β to C2
H α-face 295
N
-
R add α to C3
O
PMB BnOH
COOtBu
N
EtO
C
N
O
COOtBu Me
OH COOtBu
THF, −78 ºC O
OBn
Me
OBn OBn
299
298
300
H 1. CAN, CH3CN-H2O
H N
O
2. Na, liq.NH3, −78 ºC 3. NaBH4, THF-H2O (2:1) HO
Me 301
H
OH 1. BCl3, CH2Cl2, 0 ºC O CH2 OOBn OH 2. BOPCl, TEA, CH2Cl2 3. Ph3PCl2, Pyridine, Cl CH CN, rt 3
H N
OH O
Me
O
302 Salinosporamide A
Scheme 57.
Ot Bu N HO
Ot Bu
(COCl2)2, DMSO
N
Et3N, CH2Cl2
O COCF3 303
304
Ot Bu
Ot Bu (Boc)2O, DMAP N MeOOC
THF
O COCF3 NHCbz
t-BuOK, CH2Cl2, −78 ºC
O H COCF3
O
(±)-Z-α-Phosphonoglycine trimethy lester
N
MeOOC
O COCF3 NBoc Cbz
305
2. NaBH4,MeOH 3. MeOH, reflux
306
OtBu
Ot Bu
+
N
1. H2, Pd-C, MeOH
N
O
O
O
O
BocHN
BocHN 307a
307b Scheme 58.
hydrogenolysis using Pd/C in glacial acetic acid afforded 3,4 diamino pyroglutaminols 327a and 327b. Hara et al.65 described remarkable endo selectivity on hydroxylation of bicyclic lactam enolates 328 with MoOPD and MoOPH to afford hydroxylated products 329a and 329b (Scheme 65) derived from pyroglutamic acid. In another approach Bailey et al. described the diastereoselectivity during alkylation of bicyclic lactams66 (Scheme 66). Compound 330 on reaction with acetophenone dimethyl acetal using
pTSA (catalytic amount) was converted to the corresponding product 331a, which after Li enolate-derived benzylation reaction at C7 was converted to 331b. Colombo et al. reported67 synthesis of new bicyclic lactam peptidomimetics through ring-closing metathesis reactions (Scheme 67). N-Boc-5-allyl-L-proline methyl ester 332 was converted to 333 by acidic hydrolysis with deprotection of Boc group, compound 333 on reaction with 2 benzyl 2 benzyloxycarbonylamine but-3-enoic acid and PyBropR in the presence of DIEA and DMAP
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
MeOOC COOtBu
N
HO
Dess-Martin-Periodinane CH2Cl2
Boc 308
P(O)(OMe)2
COOtBu
N
O
NHCbz
KOtBu, CH2Cl2, −78 ºC
Boc 309
CbzHN
Pt/C, ethylacetate
COOtBu
N
CbzHN
Boc
MeOOC
COOtBu
N
H COOMe
310
Boc
HCl-gas, CH2Cl2 then SOCl2, MeOH. DMF then MeOH, Hunig's base
311 H N
CbzHN
COOMe
O 312
Scheme 59.
O
N H
BrCH(COOEt)2
Lawesson's reagent COOEt CH2Cl2
S
N H
144
COOEt
(EtOOC)2C
NaHCO3
200 EtOOC
PhCOCl, Et3N
N
DMAP, CH2Cl2
EtOOC
COOEt
COPh
COOEt
N H 313
EtOOC
H2(5atm)
COOEt
N
Pd/C, EtOH CH2Cl2
EtOOC
314
COPh 315
Scheme 60.
(Boc)2O, Et3N EtOOC
EtOOC PhOC
COOMe
N H
N
DMAP
PhOC
316
COOMe
NaBH4
EtOOC
OH N
PhOC
Boc 317
Boc 318
Scheme 61.
O
N
COOEt
LiBEt3H, THF
X
−78 ºC
N
COOEt
Boc X=OH or MeO
Boc 319
320
PhSO2H CaCl2, DCM
PhO2S
N
COOEt
Boc 321
Scheme 62.
EtOOC
EtOOC
R
Nitrogen nucleophile (RH) O
N Ph
MeOH, rt O 322
O
N Ph
O 323
Scheme 63.
afforded dipeptide 334. Compound 334 on cyclization in the presence of Grubb’s reagent, followed by catalytic hydrogenation gave the desired peptidomimetic 336.
Hanessian et al.68 reported design and synthesis of diversified azacyclic inhibitors of endothelin converting enzyme. A series of azacyclic phosphonic acids were synthesized from L-pyroglutamic acid (Scheme 68) N-Boc methyl pyroglutamate 131 on reaction with allyl bromide in the presence of LiHMDS was converted to 4-substituted diastereomeric products 337a and 337b, where compound 337a was converted to its dimethylphosphonates 338a and 338b. Further reaction of allyl intermediate 338a with BH3THF and NaOH, followed by tosylation and induction of the naphthalamide moiety gave 339. Compound 339 after a sequence of reaction was converted to 340. Brana et al.69 developed a route for the synthesis of spiro-bis-clactam utilizing a chemoselective Michael reaction as a key step for
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
EtOOC
N(Bn)OBn
RHNRN
N(Bn)OBn
LDA, then O
O
N
N
O
O
Ph 322
Ph
324
N(Bn)OBn
H2N
NH2
H2, Pd/C O
N
O
Ph
(RHN)RN
TFA, DCM, rt
O
BocN=NBoc
H2 N OH
CH2OH HOAc
N H
O
NH2
+
OH O
N H
326
325
N H
327a
327b
Scheme 64.
R'' H O
R''
HO
N O R'
1. base, THF, −78 ºC
HO R'' H
H +
O
N
2. MoOPD or MoOPH −78 ºC
O
N
O R'
R''= allyl 328
O R'
(endo)
(exo) 329b
329a Scheme 65.
the synthesis (Scheme 69). Methyl N-(-p-methoxybenzyl) pyroglutamate on deprotonation with LiHMDS followed by reaction with electrophiles gave 2-substituted product 342, which on hydrogenation with Raney Ni afforded spirobis cyclic lactam 343. Harris et al.70 developed a route for the synthesis of seven macrocyclic analogues of the neuroprotective tripeptide glycyl-L-prolyl-L-glutanic acid (GPE) using pyroglutamic acid (Scheme 70) as
a chiral precursor. N-Protected pyroglutamate 311 on selective reduction of lactam carbonyl group with LiEt3BH followed by BF3Et2O mediated allylation with allyltributylstannane was converted to 344 which after deprotection of Boc, followed by N-acylation gave 347. Compound 347 after cyclization under normal conditions afforded 348 which on hydrolysis of ethyl ester afforded acid 349. Subsequent reaction of 349 with 350 in the presence of BOP-Cl gave olefin 351. Treatment of olefin over PtO2 followed by immediate deprotection of Boc and esters group afforded 352. Langlois et al. described71 the synthesis of new polyhydroxylated indolizidines from bicyclic silyloxy pyrrole (Scheme 71). Compound 134 upon oxidation was converted to regioselective isomers 353 and 354, where bicyclic derivative 353 after deprotection followed by protection with TBDMSCl, and subsequent sodium enolate-derived reaction with allyl bromide gave N-allylated products 356 and 357 which on treatment with Grubb’s catalyst underwent cyclization to give 358. Compound 358 on oxidation with OsO4 gave diols 359 and 360.
CH2Ph
H
H
H O
OR''
N R' R'= R''= H 330
Toluene, toluene p-sulphonic acid
O
LDA, TsCl
N
acetophenone dimethyl acetal ZnCl2
N
PhCH2Br
O R'
O
O R'
R'' 331a
R'' 331b
Scheme 66.
Ph PyBrop(R) CbzHN
HCl/MeOH N
COOMe
N H 333
Boc 332
N
Toluene, reflux
COOMe
COOH
DIEA, DMAP, CH 2Cl2
O NHCbz Ph cis 334
N
COOMe
COOMe
10%Pd/C
Grubb's reagent
O
N
O
H2, EtOH NH2 Ph
NHCbz Ph 335
336 Scheme 67.
COOMe
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
R''
R''
LiHMDS, THF O
−78 oC
COOMe allylbromide,
N
O
+ COOMe O
N
Boc
Boc
131
Boc
337a R''
337b
R''
O MeO
N
R''= allyl
+
P
N
OMe
COOMe
1.(i) BH3.THF, THF, 0 oC (ii) NaOH, H2O2
O MeO
Boc
o 337a 1. Super hydride,THF, −78 C COOMe 2. Ac2O, Et3N, DMAP, DCM 3. P(OMe)3, BF3.OEt2, DCM −78 oC
338a
P
N
OMe
Boc
338a
2. TsCl, Et3N, DMAP, DCM N-(1,8-dicarboxynaphthalimido) Na+ salt, DMF
COOMe
338b R'''
R''' 1.LiOH.H2O, THF/H2O/MeOH(5:4:1) 2. i-Pr2NEt, EDCl, HOBt, H-Phe-OtBu.HCl, DCM
O MeO
P
N
COOMe
O NaO P
3. HCl(gas) dioxane, reflux 4. TMSBr, DCM then 1 equiv of NaOH 0.05M
OH
OMe Boc 339 R'''= N-(1,8-dicarboxynaphthalimido)ethyl
H N
N H
R''''
O HOOC R''''=CH2(3-indolyl) 340
Scheme 68.
O
N
O
1. LiHMDS/THF NO2 Ph COOMe 2. CAN, H O
COOMe O
N H
2
PMB 341
H2,Ni/Ra
NO2
NH
O
MeOH
N H Ph 343
Ph 342 Scheme 69.
O
N H 17
COOH
1. EtOH, SOCl2
1. LiEt 3BH,THF, −78 oC, H2O2, 0 oC
O
N
2. DMAP, (Boc) 2O CH3CN
CF3COOH, CH2Cl2
tBuO COOEt +
N H
H
COOEt
H N
COOH
DCC, Et3N
O
345
N
2. BF3.OEt2, allyltributyl stannane H CH2Cl2, −78 oC
COOtBu 311
N
H
CH2Cl2
H
N
COOEt
CH2Cl2 then DMSO
HN
CH2Cl2, 0 oC
H
N
H N
COOtBu
1. PtO2, H2, THF COOtBu
H
N
2. CF3COOH, CH2Cl2
COOtBu .HCl COOtBu 350
H N
COOH
H O
O COOH
NH2.TFA 352 Scheme 70.
H2N
+
NHCOOtBu
COOtBu
O
NHCOOtBu 351
COOH O
349
H O
H
N
Dioxane
NHCOOtBu
348
BOP-Cl, Et3N,
1M eq NaOH, H2O
O
COOEt O
346
347
Cl2(PCy3)2Ru=CHPh
COOEt
COOtBu 344
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
TBDMSO
SnCl4, −78 ºC O NaHCO3
N
OH N
O
CF3COOH
O
+
N
O
Ph 133
353
SnCl4, −78 ºC Me3SiCH2CH=CH2
N H
353
O
O
+
N
N
O
O
OTBDMS R= H R= TBDMS
357
356
OTBDMS 356
354
Allyl bromide
RO TBDMSCl Im., DMF 355
Second Grubb's cat.
O Ph
Ph
NaH-KI
O
N
O
Ph 134
THF, -H 2O
O
OsO4.NMO
N
O
OTBDMS O +
N
CH3COCH3-H2O
OTBDMS N
OH
358
OH
OH 359
OH 360
Scheme 71.
Deyine et al. reported stereoselective synthetic route for the synthesis of enantiopure 3,4,5-trisubstituted piperidines, using (S)-pyroglutaminol as a chiral precursor72 (Scheme 72). Davies et al. reported73 the synthesis of an external b-turn, based on the GLDV motif of cell adhesion proteins. Pyroglutamates 364 was converted to thio ester 366 then to 5-substituted product 367 which upon hydrogenation followed by treatment with MeOH–TFA gave 368 as starting material for cyclization to get 370 (Scheme 73). Gedu et al. established the synthesis of new isoquinolines 372 starting with pyroglutamic acid via substituted ketones74 (Scheme 74). Olivo et al. achieved75 the synthesis of ()-stemoamide 377 in 11 steps from 5 acetoxy-N-crotyl-pyrrolidinone. A chiral N-acyl thiazolidinethione synthesized as an intermediate was employed for stereoselective addition to a cyclic N-acyl iminium ion (Scheme 75). Manzoni et al. reported76 stereoselective alkylation approaches for the synthesis of eight enantiopure, sterically constrained Catetrasubstituted azabicyclo alkane amino acids (Scheme 76). Pyroglutamate derivative when reacted with benzyl bromide in the presence of base gave alkylated derivatives 379 and 380 as diastereoisomers. Bracci et al. described stereoselective synthesis of functionalized 2-oxo-1-azabicyclo alkane through a ring-closing metathesis reaction thereby able to construct a seven-membered lactam 388, starting with pyroglutamate derivatives77 (Scheme 77). Compound 381 on reduction, followed by reaction with MeOH and PPTS was converted to 383 with methoxy group at C-5 O-silyl derivative 383 was converted to O-acetyl derivative 384 so as to
avoid O-deprotection. Compound 384 was transformed to 5-propenyl proline 385 on reaction with propenyl bromide in the presence of Li, CuBrMe2S and BF3Et2O. Compound 385 after N-Boc deprotection followed by N-acylation was converted to 387. Compound 387 was subjected to cyclization in the presence of Grubb’s catalyst and followed by reduction in the presence of nickel boride thereby affording cyclized products 388. 3. Asymmetric use of pyroglutamates without prior modifications Even though the earlier studies on the asymmetric use of pyroglutamates required prior modifications such as reduction at C-2 or activation at C-5 so as to prevent racemization, however few of the reports are available describing asymmetric use of pyroglutamates without prior modifications. 3.1. Direct chain elongation reactions Katritzky et al.78 discovered an expedient route for the synthesis of N-Z-pyroglutamoyl-amino acid derivative by direct coupling of the C-terminus activated N-protected pyroglutamate (Scheme 78). Toyooka et al. discovered enantioselective synthesis of a hydroxyindolizidine alkaloid using pyroglutamic acid as a starting material79 (Scheme 79). Methyl pyroglutamate was first subjected to N-protection using benzyloxy carbonyl chloride and subsequent reaction with n-butyl magnesium bromide in the presence of TMEDA resulted in ring opening coupled with the introduction of nbutyl group thereby furnishing 392. Compound 392 on Martin’s
Ph
Ph N
Ph +
N O heat
OH O
N H 18
HN
O
O
N
OH
LAH, THF O
heat
N
O
O
Ph
Ph
361
362 Scheme 72.
OH N Ph 363
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
H O
H
NaHMDS COOtBu PhCH2Br
N H 364
t
O
COO Bu THF
N
THF, −78 oC
t
S
COO Bu
N Ph
365
H
366
O
F3COCHN
H
MeOOC
COOtBu
N
H2/Pd/C/60-200 PSi
H H
MeOOC
MeOH-TFA
N H
H
H
H
BuMgCl/Et 2O/0 oC
H
COOtBu
N
t
H
K2CO3/MeOH heat
COOtBu
N
O H
COOtBu
368
Ph
367
COCH2Br
MeOOC
Ph3P/Et3N, CH3CN
Ph
F3COCHN
F3COCHN H
H
P4S10
O H
NHCOCF3 369
NH2 370
Scheme 73.
O
O
O
PPA
N
N
o
140 C
371
R
R
372 Scheme 74.
transformation produced 2,5-cis-disubstituted pyrrolidine 393. Treatment of 393 with DIBAL followed by the addition of vinyl Grignard reagent to resultant aldehyde provided alcohol 394 as a mixture of diastereomers. The cross-metathesis reaction of 394 with 1-hexen-3-one in the presence of Grubbs II generation catalyst afforded the homologated product 395. Exposure of 395 to hydrogenation in the presence of Pearlman’s catalyst furnished the two indolizidines 396a and 396b, which were separated to get ()-396a as a major diastereomer and 396b as a minor isomer. Li et al. reported80 first enantioselective synthesis of (D)-2-tertbutoxycarbonylamino-5,5-difluoro-5-phenyl-pentanoic acid 400 with an objective to incorporate in growth hormone secretagogues (Scheme 80). N-Boc ethyl pyroglutamate 319 on treatment with phenyl magnesium bromide, followed by reaction with 1,2-thioe-
S S
thane in the presence of BF3Et2O afforded two compounds 397a and 397b. Subsequent N-acylation with acetic anhydride in the presence of triethylamine afforded the desired acetamide 398. Treatment of acetamide 398 with NOBF4, HF/pyridine, followed by deacetylation yielded amino carboxylic ester 399b which after protection of primary amine with Boc group followed by ester hydrolysis afforded the desired compound 400. Gu et al. reported81 a concise synthesis of (2S,4S)-4-methylglutamic acid 406 (Scheme 81) starting from pyroglutamic acid. Compound 402 on reaction with LiN(SiMe3)2 in THF and MeI was converted to isomers 403 and 405, which after alkaline hydrolysis followed by N-Boc deprotection afforded 404 and 406. Dieterich et al.82 reported the synthesis of (2S,3S)-[3-2H1]-4methylglutamic acid and (2S,3R)-[2,3-2H2]-4-methyleneglutamic acid. Compound 131 was converted to 4-[N,N-dimethyl amino]methylene derivative 407. Compound 407 on hydrido deamination with DIBAL-H afforded 4-methylene pyroglutamate 408. Compound 408 on reaction with LiOMe in the presence of MeOH, followed by acidic hydrolysis using HBr furnished substituted glutamic acid 410 (Scheme 82). Dinsmore et al.83 described the use of a modified ring-switching strategy for the synthesis of glutamate antagonist (2S)-2-amino-3(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)propionate 417 and related compounds having two asymmetric centres, from pyroglu-
S
O N
+
AcO
O
N
Iminium ion addition
S
N
Me
Ph 373
O
Ph
374
Me H
O S
N Ph Ph 376
N
Me
375
OH
O
S
anti-aldol addition
O
N
9 steps
H
O
N
H
Me
(-)-Stemoamide 377
O Scheme 75.
O
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
( )n
COOtBu 1. base, THF, −78 oC
N
COOtBu ( )n
N
COOtBu
N
+
2. PhCH2Br 3. NaBH4, MeOH
O N 378
( )n Ph
O
Ph
O
R HN
HN
Ph
Ph 380
379 Scheme 76.
TDSO
TDSO
TDSO
LiEt3BH, THF O
N
−78 oC
COOtBu
MeOH, HO
N
1.TBAF, THF MeO
PPTS
COOt
Bu
AcO
AcO
N
COO Bu
COO Bu
AcO tBuOAc,
1-propenyl bromide LiCuBr.Me 2S BF3.Et2O
t
2.AcCl, Et3N CH2Cl2
t
Boc 383
Boc 382
Boc 381
MeO
N
N
Boc
HClO4
0 oC
t
COO Bu
N H 386
Boc
384
385 AcO
COOtBu
AcO
1. Grubb's cat.
Allyl glycine N
NMM, isopropyl chloroformate THF, −30 oC
COOtBu NHCbz
O
N
2. NaBH4-NiCl2, MeOH
COOtBu O
NHCbz 387
388 Scheme 77.
R O
BtH, SOCl2
COOH
N Z 389
O
N Z 390a
COBt + H2N
H N
CH3CN/H2O
COOH
O
Et3N
390b
N Z
O
391 Scheme 78.
i. LiHMDS, CbzCl
H MeOOC
N H 111
O
ii. nBuMgBr, TMEDA
i. Ph3SiH, BF3.OEt2
H MeOOC
NH
O
Cbz 392
H
H MeOOC
then vinylMgBr
H
H
i. DIBAL, CH 2Cl2
N
HO
Cbz 393
Cbz 394 H
H HO
N
1-hexen-3-one Grubb's II generation Catalyst
N
Pd(OH)2, EtOH
HO
H
H N
Cbz
H 396a
O 395 Scheme 79.
HO +
H
H N
H 396b
COOH R
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
i. PhMgBr ii. 1,2-di-thioethane BF3Et2O
COOEt
N Boc 319
S
S
397a
Ac2O, Et3N
S
S
F
F
F
NH2
R= Et, Me COOR 399b
COOEt
HCl/MeOH
NHAc COOEt
399a
COOEt
Ph
N 397b
Ph
HF/pyridine 398
Ph
COOEt
F
NOBF4
NHAc
Ph
+
NH2
Ph
(Boc)2O
F
LiOH
Ph
F
NHBoc
400
COOH
Scheme 80.
SOCl2 O
COOH
N H
(Boc)2O, DMAP
MeOH
O
COOMe
N H
Et3N, CH2Cl2
O
N Boc
1. LiN(SiMe3)2/THF COOMe 2. MeI
402
17 Me
Me 401
Me +
O
COOR
N H 403
O
N H 405
1. LiOH/ H2O/THF
1. LiOH/ H2O/THF
2. TFA/CH 2Cl2
2. TFA/CH 2Cl2
Me
Me
NH2
Me
NH2
COOH
HOOC
COOH
HOOC
COOR
406
404 Scheme 81.
NMe2
H
H O
N
COOMe
DIBAL-H Hexane
(ButO)CH(NMe2)2 MeOCH2CH2OMe
O
Boc 131
COOMe
N
H
O
THF, −70 oC
Boc 407
COOMe
Boc 408 H
H H
H LiOMe, MeOH THF
N
9M aq. HBr MeOOC HN
reflux
COOMe
Boc 409
HOOC H2N
COOH
410 Scheme 82.
tamic acid (Scheme 83). Aldehydic group was introduced at C-4 of N-protected pyroglutamate 411. The resultant compound 412 on amination with NH4OAc–AcOH, followed by reaction with ClSO2NCO gave diastereomers 414 and 415, subsequent reaction with K2CO3–EtOH, followed by hydrolysis afforded 417. Langlois84a,b et al. described the diastereospecific formal synthesis of (2R,3S)-2-amino-tetradeca-5,7-dien-3-ol 423, a natural product isolated from xestopongia species using epoxidation and epoxide ring-opening sequences in native pyroglutamate moiety
(Scheme 84). Compound 418 was converted to 419, which after O-deprotection at C-4 and O-protection at C-5 gave 420. Compound 420 on iodonation using NaI in DMF gave 421, which on hydrogenolysis using H2–Pd/C was converted to 422. Compound 422 on reaction with KCN in the presence of EtOH–THF underwent ring opening to give 423. Ring opening of N-alkoxycarbonyl c-lactam 424 with lithium methylphenylsulfone, resulted in the synthesis of enantiopure cis 2,5-disubstituted pyrrolidines85 (Scheme 85). Pyroglutamic acid
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
NH2 H
OHC O
ClSO2NCO
NH4OAc-AcOH
LiHMDS HCOOMe
COOtBu
N
H
O
COO Bu
N
COOtBu
O
t
NH2
H N
H 2N
HN
H HN
O H O
CH2Cl2
COOtBu 413
COOtBu 412
411
COOtBu
N
+ COOtBu
N
O
K2CO3-EtOH O
COOt
HN
heat
COOtBu
N
O COOtBu O HN COOtBu 416
COOt
Bu
Bu
415
414
HN O HCl
HN COOH
O H 2N 417 Scheme 83.
O
O
OH
OR
O
N
N
O
0.1N. HCl MsCl-Py
OR
O
Boc R= OMs 420
Boc R= CH(Me)OEt 419
Ph 418 OH
R
N
OH NHBoc
NaI DMF
O
N
I
H2/Pd/C O
N
Boc
CH3
EtOH-THF KCN
Boc 422
421
COOEt OH 423
Scheme 84.
O OR O
PhSO2CH2Li
O
PhO2S
OR
THF, −72 ºC
N
O
OR
NHCOOBn
COOBn O
NHCOOBn 426
425
R= tBu 424 H2, 1 atm Pearlman's Catalyst H3C
O
Na-Hg Amalgam
OR LiAlH4 N H 427
OH H3C
O
N H 428
Scheme 85.
derivative 424 on reaction with methylphenylsulfone in nBuLi using THF as a solvent, followed by desulfonylation using Na–Hg and Pearman’s catalyst afforded compound 425, which after hydrogenation followed by reaction with LiAlH4 afforded 428. New diastereoselective synthetic route for 2-substituted cis(2S,5S)-and trans-(2S,5R)-5-alkylprrolidinones as indolizidine and pyrrolizidine scaffolds has been reported by Mota et al.86 (Scheme 86).
Oba et al.87 reported the synthesis and reactions of novel 3,4didehydropyroglutamate derivatives through hydrogenation and ring-opening sequences with H2 and Pd/C in the presence of CH3OH. The ABO ester 432 on hydrogenation followed by ring opening afforded L-glutamic acid (Scheme 87). Another ring-opening strategy via copper (1) mediated crosscoupling of pyroglutamic acid-derived organo zinc reagent with acid chloride was reported by Hjelmgaard et al.88 (Scheme 88).
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
O
PhO2S
O
OR NHCbz
O
H
Na-Hg Na2HPO4/MeOH
430
429
H
H2 OR Pd(OH) 2 NHCbz
OR N H 431
O
Scheme 86.
O
N
ABO
1. H2, Pd/C, CH3OH
Makino et al. described89 stereoselective synthesis of (S)-(+)lycoperdic acid through an endo selective hydroxylation of the chiral bicyclic lactam enolate with MoOPH (Scheme 89). Lienolate-derived reaction of 19 with allyl bromide afforded 4-allyl derivative 439a, which on further reaction with LDA and MoOPH gave 4-allyl-4-hydroxy derivative 439b. Allyl group of 439b was subjected to hydroboration–oxidation sequences to get diol 440. Compound 440 after a sequence of reactions was converted to (+)-lycoperdic acid 442. Cohen et al. described the synthesis of (S)-(+)-lycoperdic acid90 442 starting with pyroglutamic acid derivative 443 (Scheme 90). Bromo lactam compound 443, when subjected to tandem oxidation–annulation reaction with Jones reagent at 0 °C followed by workup with potassium carbonate delivered spirolactam 444a. Sequential Boc protection and TBAF desilyation afforded pyroglu-
L-Glutamic acid 433
2. 1M HCl Reflux then Dowex 50W-X8
Boc 432 ABO= 2,7,8-trioxabicyclo[3.2.1]octane Scheme 87.
Compound 18 after tosylation, followed by reaction with NaI and MeCN was converted to iodo products 434 and subsequently to organo zinc compound 435. Compound 435 on reaction with CuCN2LiCl and RCOCl gave 438a and 438b on the one hand and through acidification afforded 436 or 437 on the other hand.
1. TsCl, Et3N, DMAP
O CH2Cl2 2. NaI, MeCN, heat
N H 18
OH
N H 434
I
0.1M HCl
Zn O DMA, 0 ºC
N H
ZnI
O 435 CuCN.2LiCl RCOCl
NHR
H
N H 436
O
and/or
+
O
O
N H 438a
R= H 437
N Ph O 438b
Scheme 88.
H O
N O
HO
H
LDA Allyl bromide -78oC
O
N
O
MoOPH
N
-78oC
O
Ph
O Ph 439b
Ph
439a
19
H
LDA
O OH O HO
BH3·THF, THF, 0oC
H
O
then CH2Cl2, NaOH
H
i. Jones' reagent
O
acetone
N
N
O
O
Ph
Ph 441a
440
O
H
O i. RuCl3, NaIO4 CCl4/CH3CN/H2O
H O
N H 441b
O O
Ph
i. 6M HCl reflux
O Scheme 89.
O
COOH NH2 COOH
O
(+)-lycoperdic acid 442
O
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
OTBS O
O
O
i. Jones reagent acetone
Br O
O
(Boc)2O, DMAP O
ii. K2CO3, acetone
N H 443
OTBDPS
O
ii. TBAF, AcOH
N H
N H
OTBDPS
444a
444b
OH
O HOOC
O
O
O
i. RuCl3, NaIO4 CCl4/CH3CN ii. TMSCHN2
O
EtOAc/ MeOH
i. 6M HCl reflux ii. ion exchange chromatography
COOH
N H 444c
-
COO H3N (+)-Lycoperdic acid 442
+
Scheme 90.
O
OMOM
N
R
O
O
Et2AlCl, Cyclopentadiene Toluene, −78 ºC
OMOM
N
R O
445
446 Scheme 91.
taminol 444b. Oxidation of 444b with RuCl3 followed by exposure of crude mixture to TMSCHN2 afforded methyl ester 444c which after acidic hydrolysis followed by purification yielded the desired (S)-(+)-lycoperdic acid 442. 3.2. Use of N-derivatized pyroglutamates for asymmetric synthesis 3.2.1. Diels–Alder reactions Highly asymmetric Diels–Alder reactions have been carried out using (S)-pyroglutamic acid derivatives as chiral dienophiles. Asymmetric Diels–Alder reaction of cyclopentadiene with chiral dienophile 445 derived from (S)-pyroglutamic acid derivatives in
O R
R N
O
O
N
OO
O R1 447
a. R= COOEt, R1= H b. R= COOEt, R1= Me
R1 448
O
the presence of a Lewis acid catalyst such as diethylaluminium chloride in toluene afforded cyclo adducts 446 with high stereoselectivity91 (Scheme 91). Strong chiral influence of pyroglutamate has also been utilized in diene component of Diels–Alder reaction. Menezes et al. have explored the use of ethyl-N-dienyl pyroglutamates as novel asymmetric diene where chiral cyclohexenyl amine derivatives 448 were obtained in good yields92 (Scheme 92). Defoin et al.93 have carried out asymmetric hetero Diels–Alder cycloadditions using chiral N-dienyl lactam and acyl nitrosodienophiles (Scheme 93). 3.2.2. Radical cyclization Asymmetric synthesis of pyrrolidinones by radical cyclization of N-allylic pyroglutamates which were synthesized from ethyl-(S)pyroglutamate has been carried out94 (Scheme 94). 3.2.3. N-Acylations/alkylations of native pyroglutamates Boisse et al. discovered95 synthetic strategies for new comptothecin analogs starting with pyroglutamic acid derivative. In one of the approaches methyl pyroglutamate after N-benzoylation with 2-nitrobenzoyl chloride in the presence of NaH, followed by reductive cyclization with SnCl2 in ethanol afforded modified precursor of camptothecins 457 (Scheme 95).
Scheme 92.
MeOOC
MeOOC N
O
N
O
RCON=O
449
450 Scheme 93.
MeOOC +
N
O
O
O
NCOR
NCOR 451
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
1. R2CH=C(R)3CHR1Br/THF/ I Sonification, Bu4NBr, KOH EtOOC
N H
O 2. LiAlH4/ SiO4 3. CH3SO2Cl/NEt3 4. NaI/ acetone
452
N
O
R3 R1
AIBN Bu3SnH, PhH reflux
N
O
R2
R2
R3
R1
R3
453
O
N +
R1 455
R2
454 Scheme 94.
O
COOMe
N H
O
NaH, THF then
COOMe
N
2-nitrobenzoyl chloride
N
COOMe
N
NO2
O
111
SnCl2, EtOH
O R1
456
R2
457
Scheme 95.
458
1. NaH, CH3COSCH2CH(CH3)COCl O
N H 177
COOEt
O
o
2. TFA, 0 C 3. HSCH2CH2NH2
N
N
CF3COOH
COOR H N
O
N
COOEt
CH3
COOH H N
H2/Pd
COOEt
O
O 460
SH
O 459
O
COOR
CH3 CH2CH2Ph
461
CH3 CH2CH2Ph
Scheme 96.
H
AcO
COOMe
N
1. SnX4, CH2Cl2 −78 ºC
X H
Boc
462
H
COOMe
N
Boc X= Cl
Bu4NOAc toluene or NaN3.DMF
R H
N
COOMe
Boc R= OAc, N3
463
464
Scheme 97.
In an attempt to develop potent ACE inhibitors such as 459 and 461 derived from pyroglutamates, N-acylations of pyroglutamates have been reported96a,b (Scheme 96). These N-acylations have been accomplished by the reaction of pyroglutamate derivative 177 with NaH and acid chloride for the synthesis of modified captopril analog 459, and with NaH and p-nitrophenylester of Z-Ala-OH for the synthesis of enalapril analog 461. Hanessian et al.97 reported the synthesis of 6-substituted hydroindole 2-carboxylic acids from pyroglutamic acid derivatives, where compound 462 on reaction with SnX4 was converted to bicyclic ester 463, and the resulting product was subsequently converted to 464 using Bu4NOAc in toluene (Scheme 97). Straight forward ring expansion of pyroglutamates to Perhydro1,3-diazepine-2,4-diones was reported by Stevens et al.98 (Scheme 98).
Bourry et al. described99 their studies on pyrrolidinones oxidation and rearrangements in the hexahydrobenz[f]indolizine-3,10dione series (Scheme 99). N-Benzyl pyroglutamic acid 466 on reaction with thionyl chloride and ClCH2CH2Cl afforded compounds 467a–467c, where compound 467a was converted to pyrrolinone 468 with HCl and O2 at room temperature. Enders et al. delivered a synthetic strategy for enantiopure triazolium salts from pyroglutamic acid and their evaluation in the benzoin condensation (Scheme 100). Pyroglutamic acid after esterification followed by reaction with phenyl magnesium bromide yielded substituted c-bytyrolactam 112a. Reduction of tertiary alcohol group of compound 112a led to lactam 469, which was then converted to triazolium salt 470100 under usual conditions. Dudot et al. described the synthesis of chiral pyroglutamate amines through hydrogenation followed by alkaline hydrolytic
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COOR1
O O
NaH
COOR1
N H
O
COOR1
N
R2NCX N-
177
NR2
NH
O
O
R1=Bn R2=Ph
R2 465b
465a Scheme 98.
O
COOH
N Ph 466
OH
O
1. SOCl2 O ClCH2CH2Cl2 2. AlCl 3
O +
N
O
N
467b
467a
O +
O
N
HOOC 467c
conc. HCl, O2
OH
O
N
468 Scheme 99.
Ph
i. SOCl2, MeOH O
COOH
N H 17
ii. PhMgBr, THF
O
N H 112a
Ph
t-BuLi, Et3SiH
Ph
DCM
O
N H 469
OH
Ph
Ph i. Me3O+BF4-, DCM
N
ii. PhNHNH2, DCM iii. HC(OMe)3, 80 oC Ph
N
Ph
N+ BF4470
Scheme 100.
O
H CH3
N
NHPh
PhOOC
1. H2, Pd/C, MeOH 2. NaOH, MeOH 3. Separation
O HO
Ph 471a
H CH3
N
H NHPh Ph 471b
1. LiAlH4 2. H2, Pd(OH)2/C
O
H CH3
N HH
NHPh
472
Scheme 101.
cleavage of benzoyl ester101 (Scheme 101). Compound 471a was subjected to hydrogenation, followed by alkaline hydrolytic cleavage to get 471b which on reduction afforded diamine 472. Zampella et al.102 discovered amphiasterins; a new family of cytotoxic metabolites from the marine sponge plakortis quasiamphiaster, which is N-alkylated pyroglutamic acid unit (Scheme 102). Bourry et al.103 carried out studies on pyrrolidones. They described an improved synthesis of N-arylmethyl pyroglutamic acids (Scheme 103). They have also carried out studies on pyrrolidinones with an objective to improve the anticancer properties of methyl N-(3,4,40 ,5-tetramethoxybenzhydryl)pyroglutamate (HEI 81)104 (Scheme 104). In our recent publication we described the synthesis of N-[30 (acetylthio) alkanoyl] and N-[30 -mercaptoalkanoyl]-4-a-(S)-(phe-
O
COOCH3
N
OH
OH (CH)m O
O
(CH)n
(CH)m O
473a
O
(CH)n
473b Scheme 102.
nyl methyl) pyroglutamic acids and proline as potent ACE inhibitors. Lithium enolate-derived N-acylation of 4-a(S)-phenylmethyl pyroglutamate 478 with 3-acetylthioalkanoyl chloride and 3-acet-
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
N H 111
COOCH3
O
ArCH2Cl
NaH
N- + COOCH3 Na 474a
O
O
COOCH3
N
N
COOH O
O
O
O 474b
O
O
475
Scheme 103.
OSiMe3 O
O O
+ COOMe
N
H -O(SiMe3)2
O O
SiMe3
COOMe
N
+
O O O
O
476a
O
476b
477 Scheme 104.
Ph
Ph O
N H 478
COOtBu
LiHMDS, −78 oC
O
CH3COSCH2CH(R)COCl
TFA/anisole
COOtBu O
N O
S R R=H, Me 479
Ph
Ph
O
N O R R=H, Me 480a
DCHA/Et2O COOH O EtOAc/1M HCl S
Ph
O
N O
COO- DCHA O S R R=H, Me 480b
2 M H2SO4
O
N
COOH
O R R=H, Me 481
SH
Scheme 105.
ylthio-2(S)-methyl alkanoyl chloride afforded compound 479. Subsequent deprotection and purification yielded the desired ACE inhibitors 481105 (Scheme 105). Hanessian et al.106 reported the N-acyloxyiminium ion azaPrins route to octahydroindoles leading to total synthesis and structural confirmation of the antithrombolic marine natural product oscillarin (Scheme 106). Pyroglutamic acid derivative 482 after Boc deprotection was subjected to N-acylation using 483 as an acylating agent to get 484. The resultant material was converted to precursor 486 by coupling with proline derivative 485, compound 486 on deprotection under acidic condition afforded oscillarin 487. They have also described the total synthesis and structural assignment of the marine natural product Dysinosin A: a novel inhibitor of thrombin and Factor vlla107a (Scheme 107), utilizing a carbon construct strategy that generates subunits originating from L-glutamic acid, whereas Carroll et al. reported the isolation and structure determination of this new marine natural product Dysinosin A.107b Daiya et al.108 described diastereoselective heterogeneous catalysis of 2-methyl nicotinic acid 496 using pyroglutamic as chiral auxiliary (Scheme 108). Methyl pyroglutamate 111 on reaction with 2-methyl-nicotinoyl chloride (generated in situ by reaction of 2-methyl nicotinic acid 494 with thionyl chloride) under Schautann Baumann conditions afforded N-acylated pyroglutamate 495
having side chain corresponding to 2-methyl nicotinic acid, which on catalytic hydrogenation afforded N-(Z-methyl piperidine-3-oyl) methyl pyroglutamate 496 with reduction of N-acyl side chain. Lee et al.109 carried out asymmetric synthesis of trans-1-aminoindolo[2,3-a]quinolizidine 502. N-Benzyloxy carbonyl 2(S)-methyl pyroglutamate 497 on reaction with arylethylamine in the presence of Me3Al underwent ring opening. The resultant product on subsequent reduction afforded 499, which upon dehydration coupled with cyclization gave a tricyclic compound 500. Compound 500 on hydrogenation using H2/Pd–C followed by reduction afforded the desired molecule 502 (Scheme 109). Belvisi et al. reported110 stereoselective synthesis of conformationally constrained unnatural proline-based amino acids and peptidomimetics, N-Boc 4-allyl pyroglutamate derivative 503 was subjected to reduction, allylation sequence on lactam carbonyl thereby furnishing stereoisomers 505 and 506 which on treatment with Grubb’s catalyst, followed by hydrogenolysis gave 508 and 510 as stereoisomers (Scheme 110). Stereoselective alkylation of a bicyclic lactam derived from pyroglutamic acid has been reported by Zhang et al.111 (Scheme 111). Zhang et al.112 described a convenient and versatile synthesis of 6,5- and 7,5-fused lactams as peptidomimetics starting with pyroglutamate derivatives (Scheme 112). N-Boc-2(S)-ethyl pyroglutamate 131 was converted to its corresponding 4-cinnamyl
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
H 1. TFA, CH 2Cl2 then EDC HOBt, CH2Cl2
H
MOMO AcO H
PhH N
COOMe
N
MOMO
Boc
H Ph
Ph O 2. NaOMe/ MeOH 3. MOMCl,iPr2NEt, CH2Cl2
482
O
COOH 483
NH O
O H N aq.HCl/THF. 6M HO
N Boc
N
N
H
N
O
Ph
NHBoc 485
H O H N
H
Boc N
Ph MOMO 484
H
MOMO
1. LiOH, H2O/THF 2. EDC, HOBt, Et3N NH2 HCl COOMe N
COOMe
N
N
O
NHBoc
NH2
HN
Ph
NH
NH
O
O Ph
Ph
MOMO
HO
486
Oscillarin
487 Scheme 106.
MOMO OMe
MOMO H + H
H N
RO
H BopCl
COOH
(i-Pr2) NEt MeCN
O HN COOMe
488
NH2
MOMO
MOMO
H
N COOMe
MeO
TBDPSO
N
O
NH
489
+ N
Boc
490
O
NHBoc
491 HO
MOMO HO
MOMO
H
H
1. LiOH, H2O/THF H
2. EDC, HOBt, Et3N MeO NH RO
N O
1. TBAF, THF
2. Py-SO3, Bu2SnO, CH2Cl2 CO 3. TFA, CH 2Cl2
H
CO MeO NH
HN HO3SO
O
N O
HN
O dysinosin A
N
N
492 BocHN
493
NBoc
H2N
NH
Scheme 107.
COOH O
+ O
N H 111
COOMe
N
1. SOCl2 CH3 494
N
COOMe O
2. NEt3,CHCl3 reflux N 495
CH3
O
COOMe
N
H2(cat.)
O N H
CH3 496
Scheme 108.
derivative 515, which after deprotection of Boc group followed by Lienolate-derived N-acylation with Boc (D)-ser-Bzl-Osu afforded
compound 517. Compound 517 on hydrogenolysis using H2/Pd–C was converted to N-acylated products 518 with deprotection of
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O O
arylethylamine N
COOMe
Ar
Cbz
O H MeO
497
498
Me3Al, CH2Cl2
DIBALH
N H
N
THF
H2, Pd/C N
O
500
499
N
O
H
N
N HH H2N
THF, −78 oC
H H2N
H
CH2Cl2, −78 oC
CbzHN
LiAlH4-AlCl3
Ar
MeOH
H CbzHN
O
HO
NHCbz
Ar
BF3.Et2O
Ar
H 502
H 501 Scheme 109.
H
H
H LiEt3BH, THF O
o COOMe −78 C
N
HO
N
COOMe
Boc
Boc
Boc 503
505
504
H
H H2/Pd/C
Grubb's cat.
505
CH2Cl2
EtOH
N
H
COOMe
N
H
508
507
H
H
H H2/Pd/C
Grubb's cat. N
COOMe
COOMe
Boc
Boc
H
+ 506 COOMe
N
H
CH2Cl2 H
Boc
N
COOMe
EtOH H
Boc
506
N
COOMe
Boc 510
509 Scheme 110.
O
Ph N
H 511
O
O 1. Base 2. RX
R
Ph N
O
O +
N
R
H
H
512
R
Ph
513
O
HOOC
N Boc
R= CH2CH=CH2 514
Scheme 111.
o-benzyl group of side chain. Compound 518 on the reduction of lactam carbonyl with LiBEt3H followed by acid-catalyzed dehydration cyclization sequences gave 520. Compound 520 upon alkaline hydrolysis afforded the desired peptidomimetics 521. An expedient synthesis of (+)-trans-5-allyl hexahydroindolizidin-3-one was carried out by Potts et al.113 (Scheme 113). Thanh et al. reported114 enantioselective synthesis of indolizidine ()-237A [(3R,5S,8aR)-3-butyl-5-(1-oxopropyl)octahydroindolizine], starting from pyroglutamate derivative. Compound 524 on nucleophilic addition with (CH3O)2PO–CH2CO–C(OEt2)Et produced 525 which after hydrogenation with H2 (1 bar), PtO2 in methanol followed by cyclization gave 527 and the resultant material was reduced with NaBH3CN to afford a stereoisomer of ()Myrmicarine 237A (Scheme 114).
Legrand et al. reported115 studies on condensation of pyrrolidinones with silyl derivatives. Trimethoxyphenyl naphthylcarbinol trimethyl silyl ether was condensed with the methyl N-trimethylsilyl pyroglutamate affording two separable esters (Scheme 115). 3.3. Functionalization at C-2, C-3, C-4, of pyroglutamates Yamada et al. established116 an efficient asymmetric synthesis of the functionalized pyroglutamate core unit common to oxazolomycin and neooxazolomycin (Scheme 116). Pyroglutamic acid derivative 533 on protection of carboxylic group as t-butyl ester and subsequent N-methylation afforded 534. Compound 534 on debenzylation at C-3 followed by carboxymethylation of resultant alcoholic functionality delivered a carbonate 535. The quarterniza-
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
Ph
O
LiHMDS, THF Cinnamyl Bromide −78 oC
COOEt
N Boc
Ph
O
COOEt
N
O
N H
Boc
516
515
319 Ph
Ph
H2/Pd/C O
COOEt
N
O
MeOH
Ph
LiBEt3H COOEt THF, −78 oC
N
O BnO
LIHMDS, THF −30 oC Boc(D)-Ser COOEt (Bzl)-OSu
TFA, CH 2Cl2
TFA(Cat), CH 2Cl2 HO
COOEt
N
O HO
NHBoc
O HO
NHBoc
517
519
518
O
H
Ph
O LiOH, H2O/THF
N
BocHN
H
Ph
N
BocHN
COOEt
O
NHBoc
COOH
O 521
520 Scheme 112.
O
COOEt
thesized core unit 540 could be a useful scaffold for stereoselective functionalization corresponding to the oxazolomycin’s polyene segments. Panday et al. have reported117 the simple pathway for the synthesis of ()-bulgecinine (Scheme 117) starting with pyroglutamate derivative. Bicyclic lactam derivative 541 was converted to 6-a-hydroxy substituted product 543 via epoxidation and ringopening sequences. OH group at C-6 was protected prior to hydrolysis of bicyclic ring to get 4-benzyloxy pyroglutaminol, in which OH group at C-5 was also protected with ethyl vinyl ether in the presence of acid catalyst to get 546 followed by protection of free
H t
BuOK
N H 522
O
N
EtOOC 523 Scheme 113.
tion of C-2 followed by the introduction of exomethylene group at C-3 was carried out by internal nucleophilic trap of the carbonate 535 and lactone opening with the phenylselenide anion. The syn-
O
nBu
(CH3O)2PO-CH2-CO-C(OEt)2-Et
N Cbz
OEt OEt
KHMDS THF, 0 oC
CHO
nBu
N Cbz
524
525
1. H2(1bar), PtO2, MeOH, RT
nBu
1. TFA-H 2O nBu
N H
2.H2(1bar),Pt/C, MeOH, RT
526
O (OEt)2
nBu
N
+
O (+)-myrmicarine 237B 529
528 Scheme 114.
HCl (1eq.) O
nBu
N
O (−)-myrmicarine 237A
NaBH3CN
N
K2CHO3 527
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
OSiMe3 O
COOMe
N
O
H+, 130 oC
+ Ph
SiMe3 530
COOMe
N
O
COOMe
N
-Me3SiOSiMe3
531
R'
R''
R''
R' 532b
532a Scheme 115.
OBn O
COOH
N H
OBn
i. t-BuOAc 70% HClO4
1. H2, Pd/C, MeOH O
ii. MeI, NaH, THF
N Me
533
OH
O
NaHMDS N Me
2. ClCOOMe, Py
534
OCOOMe O
COOtBu
O
COOtBu
O + COOtBu
N Me 536
535
O
N Me
COOH
i. Ph2Se2 NaBH4, EtOH
COOtBu
ii. CH2N2
537
CH2N2
SePh O
N Me
COOMe
H2O2
COOtBu
THF
COOMe O
538
Zn(BH4)2 Et2O
COOtBu
N Me
OH O
COOtBu
N Me 540
539 Scheme 116.
OH
O
O
SmI2
t-BuOOH K2CO3-n-Bu4NF DMF
N O
O
N
THF-MeOH
542
544 OCOPh
OCOPh OEt
CH2=CHOEt
OH
O
H+
OCHMe
N H
OEt
(Boc)2O DMAP
O
N Boc
OCOPh
OCOPh OEt OCHMe N
MeOH,
H+ MeO
Boc 548
OCHMe
547
546
545
DIBAL-H Hexane-THF HO
Ph 543
OCOPh
N H
O
Ph
541
O
N
O
Ph
CF3COOH
PhCOCl CH2Cl2-Et3N O
N
O
Ph
THF-H2O
O
OCOPh
OH
N H 549
OCOPh Me3SiCN SnCl4 NC CH2Cl2
N H 550
OH
OH HCl HOOC
OH N H (−)-bulgecinine 551
Scheme 117.
NH to N-Boc. Compound 547 was subjected to reduction of lactam carbonyl with DIBAL-H to get 548. Treatment of 548 with MeOH/ HCl led to the protection of OH group at C-2 as OMe and deprotection at C-5. The resultant product 549 on the introduction of cyano group at C-2 followed by acidic hydrolysis afforded ()-bulgecinine.
Lenda et al. reported118 synthetic strategies for new tetrazole and triazole substituted pyroglutamic acid and proline derivatives (Scheme 118). Dimethyl-2,4-dibromoglutarate 552a was allowed to react with sodium azide, where mono-substituted derivative 552b was obtained as a major product. 1,3-dipolar addition of azide 552b with acetylene afforded 1,2,3-triazole derivative 553a. The
1619
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
Br
Br
MeOOC
Br
NaN3 acetone
COOMe
N3
MeOOC 552b
552a
N Br N
N
MeOOC
COOMe
COOMe
NaN3 acetone
N3 N
N
COOMe
N
COOMe
COOMe
COOMe
553b COOMe
N N
COOMe
O
N
COOH
N
COOH
N
i. BH3·THF
N
N H
Pd/C, MeOH
MeOOC
553a
HOOC
acetylene COOMe
ii. 6M HCl propylene oxide, CH2Cl2 N H
HOOC
554
555 Scheme 118.
triazole derivative was subsequently reacted with 3 equiv of sodium azide to give 553b. Compound 553b on hydrogenation furnished the corresponding substituted pyroglutamic acid 554 via an intramolecular aminolysis. Lactam 554 on selective reduction with BH3 in THF followed by acid hydrolysis and subsequent neutralization with propylene oxide yielded fully deprotected (±)-4(4,5-substituted-1H-1,2,3-triazol-1-yl) proline derivative 555. In an attempt to carry out total synthesis of novel amino acid antibiotic TAN-950, Tsubotani et al. have made asymmetric use119 of (S)-pyroglutamate without prior modification through functionalization at C-4 (Scheme 119). Later on in their studies on the reactivity of pyroglutamates towards the asymmetric synthesis of 4-substituted pyroglutamates, Baldwin et al. reported120 that reactions of lithium enolate-derived from 2(S)-pyroglutamates with various electrophiles, give exclusively 4-a-substituted products (Scheme 120). Subsequently in our continuing studies121 on the behaviour of protected pyroglutamate towards electrophiles we reported detailed studies on chiral alkylation and aldol reaction at C-4 of pyroglutamates through their lithium enolates (Scheme 121) where alkylation at C-4 gave exclusively 4-a-products, whereas aldol reactions afforded 4-a- and 4-b-substituted aldol adducts 566 and 567 in the ratio of 4:1. We have also explored122 the direct synthetic pathway for 4(S)-substituted pyroglutamate through 1,3-dipolar addition of
R
O
N
2. Electrophile
N Boc
COOMe
560
N
N
COOMe
Dioxane/H2O
556
O
N
557 COOH
1. NaOH 2. CF3COOH
HO
Boc
Boc
131
COOtBu
menthylacrylate with amino acid Schiff’s bases followed by hydrogenolytic sequences (Scheme 122). These 4-substituted pyroglutamate and prolinates are part of many of the bioactive molecules. As a part of their work on the synthesis of nonproteinogenic amino acids, Bowler et al. reported123 reactions of lactam enolates of L-pyroglutamic acid derivatives with various electrophilic imines and found that the reaction proceeds in good yield with complete stereospecificity at C-4 and impressive stereo selectivity at the third asymmetric centre (Scheme 123). Young et al.124 reported double stereo differentiation in aldol reaction of pyroglutamic urethane esters 576 (Scheme 124) and the same authors reported the use of acid and aldehyde of pyroglutamate in ring switching reaction leading to lactone 580 as kinetic products125 (Scheme 125). The 4-substituted pyroglutamate 577 by ozonolysis was converted to aldehyde, in which aldehydic
H2NOH·HCl O
N
Scheme 120.
1. LDA or LiN(TMS)2/THF 2. i-PrOCHO
O
Boc
Boc 559
OHC O
1. LDA or LiHMDS
COOtBu
NH2 HN O TAN-950 558 Scheme 119.
O
COOMe
1620
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
OH
OH
R'
O
O
E
N Z 561
R'
R'
562
1. LiHMDS, THF, −78 oC
E O abs MeOH, 50psi
N H 564
+
2. R'CHO, THF, −78 oC
H2, 10%Pd,C
H2, 10%Pd,C E abs EtOAc O
N Z
N H
E
566
H2, 10%Pd,C abs MeOH, 50psi
OH
OH
R'
R'
R'
O
H2, 10%Pd,C E abs EtOAc O
N Z
H2, 10%Pd,C E
N H
abs MeOH, 50psi
O
N H
565
563
E
567
Scheme 121.
O
O
O
R'
O
568 +
LiBr/ TMEDA
R''
THF
R'
R'-CH=N-CH-COOMe
O
COOMe N H 571
Ph H
H Tos NH
COOMe
N H
570
R''
R''
H2/Pd-C
569
TMEDA= N,N,N',N'-tetra methyl ethylene diamine Scheme 122.
Tos
H N
H Ph
H
+
1. Lactam enolate O
N
2. LiHMDS
COOBzl
O
572
N
COOBzl
N
H
Ph
Boc
Ts
O
N
Boc
Boc
573
574
COOBzl
Scheme 123.
H
Ph N O
N
Ph
Tos
H
NH
H Ts
COOCH2Ph O
Boc 575
COOCH2Ph
N Boc 576
Scheme 124.
group on reduction was converted to alcohol 579 to get ring switched lactone 580. Diastereoselective formation of a quaternary centre in pyroglutamate derivative was reported by Oliveira et al.126 (Scheme 126). Lithium enolate-derived alkylation of pyroglutamic acid derivative 581 with N-Boc-bromomethylindole 582 in the presence of DMPU, furnished intermediate 583, where lactam part of 583 on alkaline hydrolysis with LiOH gave 584 which after deprotection afforded ()-monatin 586.
O
OH H
H 1. O3-CH2Cl2, -78oC
O
N
COOtBu
2. Ph3P
O
N
H
H NaBH3CN COOtBu MeOH
O
N
Boc
Boc
Boc
577
578
579 Scheme 125.
H COOtBu
O 580
COOtBu NHBoc O
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
1. LiHMDS, THF, −78 oC 2. DMPU, −78 oC
CBzO
OCBz
OTBS O
OTBS
N
Br , −78 oC
3.
Boc
N Boc
581
O
N
N
LiOH, THF H2O
Boc
Boc 583
582
COOH
OTBS Jones' reagent, 0 oC NHBoc OH HOOC acetone
NHBoc HOOC OH
N
N
Boc
Boc 585
584 COOH NH2 HOOC OH N H (−)-Monatin 586 Scheme 126.
N(CH3)2 H
H
O
H
COOR
N
HN
OHC
H O
N
COOR
H
COOR
O
HN O 2 (Willardiine) 590
COOR
588
587
HN
COOR
N
COOR
H
O
589
COOH
Scheme 127.
novel dehydrofluorination (Scheme 128). Substrate 591 on reaction with triethylamine in CH2Cl2 was converted to compound 592b, along with compound 592a, in which compound 592b after catalytic hydrogenation using Pd–BaSO4 in ethanol afforded 593a
Dinsmore et al. reported the extension of ring switching strategy to the glutamate antagonist 2-(pyrimidin-2,4-dione-5-ylmethyl)-(2S)-glycine 590127 (Scheme 127). Qiu et al.128 carried out the synthesis of 4-monofluoromethylenyl 594 and cis-monofluoromethyl-L-pyroglutamic acid 595 via a
H F2HC
F2HC
F
Et3N, CH2Cl2 O
COOtBu
N
O
Boc 591
N
Boc
Boc
592a
592b
COOtBu
TFA CH2Cl2
H F
Pd-BaSO4 EtOH
O
FH2C
H3C 592b
+ COOtBu
N
+ O
COOtBu
N
O
COO
N
Boc
Boc
593a
593b
tBu
O
594
FH2C 593b
TFA CH2Cl2
O
N H
N H 595
Scheme 128.
COOH
COOH
1622
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
Cl
Cl
O
HO
O
COOMe
N
PPh3, DEAD, THF, −0 oC
O
COOMe
N
2. Ac 2O Pyridine
RO
COOMe
N
Boc
Boc R= Ac
597
598
Boc 596
O
1.LiBEt3H THF, −78 oC
4-chloro-1-naphthol
Cl
O TMSCN,BF3.Et2O NC
CH2Cl2, −60 oC
COOMe
N Boc 599
Scheme 129.
Stevens et al.130 reported the regioselectivity in the alkylation of pyroglutamates (Scheme 130). N-Boc benzyl pyroglutamate was converted to its 4-carboxylate 601 using Li enolate chemistry, which on further generating lithium enolate at position C-2 and subsequent reaction with electrophiles afforded 604. In the same way [1,2] Boc migration during pyroglutamate alkylations has also been reported by the same group131 (Scheme 131). Kotoh et al.132 carried out stereoselective synthesis of Nuphor quinolizidine alkaloid ()-deoxynupharidines 618–619 (Scheme
and 593b and subsequently 593b on hydrolysis using TFA gave the desired compound 595. Zhang et al.129 carried out the synthesis of N-Boc-4-O-substituted-5-cynomethyl pyroglutamate 599 (Scheme 129). 4-Hydroxypyroglutamate derivative 596 on Mitsunobu reaction with 4choro-1-nepthol afforded 597, which after reduction at C-5 using LiBEt3H, followed by induction of cyano group at C-5 on reaction with TMSCN and BF3Et2O gave the desired target molecule 599.
OR' R'OOC
O
2 eq. LiHMDS/ −78 oC O
COOBn
N Boc
ClCOOR1
3 eq. −78 oC, THF
3eq. LiHMDS, THF O
COOBn
N
Li+ O-
−78 C o
Boc R= Me 601
600
N
COOBn
Boc 602
OR' R'OOC
O Li
+
O-
(-)Li+ COOBn
N Boc
1. 3 eq. RX/ −78 oC
R O
2. H2O/NH4OH NH4Cl(sat)
N
COOBn
Boc R= CH2Cl, Et, Allyl 604
603 Scheme 130.
E EX O
N
COOR
E
OLi+
N
COOR OtBu
O
LiHMDS EX
O
R' 608
607 Scheme 131.
N
COOR
LiHMDS EX
O
N
R' R'= Boc
R'
605
606
COOR
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
132). Compound 609 on reaction with LiBEt3H, followed by witting reaction gave amide 611, where amidic part was transformed into aldehydic ester 612 by using DIBAL and subsequently resultant aldehyde 612 on acidic hydrolysis was converted to 613, which on deamination with SmI2 in THF–HMPA and methanol gave sixmembered ring product 614. N-Alkylation of 614 with 3-bromo2-methyl propane in the presence of NaH provided 615, which on reaction with Grubb’s catalyst was converted to 616. Compound 616 was treated with 3-lithiofuran, subsequently reduced with NaBH4, finally subjected to hydrogenolysis using Pd(OH)2 thereby affording diastereomers 618 and 619. Merino et al. described133 the diastereoselective approach with an objective to synthesize 4-hydroxy derivatives 623 (Scheme 133). 3-Hydroxy-pyrrolidinone 620 after protection of all the functional groups was converted to 622 which on reaction with H5IO6 and NaH2PO4 gave target molecule 623.
Me
Langlois et al. achieved the total synthesis of salinosporamideA, a potent proteasome inhibitor, starting from pyroglutamate derivative134 (Scheme 134). Compound 624 was converted to 625 on reaction with N-methylnitrone in toluene through 1,3-dipolar addition and resulting adduct 625 was subjected to hydrogenolysis leading to ring opening, methylation of amino group and subsequently cope elimination to afford salinosporamide-A 628. Hill et al. synthesized135 stereocontrolled spirocyclic bislactams derived from pyroglutamic acid, compound 629 on reaction with NaH and BrCH2CN afforded 630 which on treatment with NaBH4 and COCl2 underwent reduction coupled with cyclization to give spirobicyclic lactams 631 and 632 (Scheme 135). Herdeis et al.136 carried out a stereoselective synthesis of 3substituted (S)-pyroglutamic acid and glutamic acids through ABO ester derivatives (Scheme 136). Pyroglutamic acid was converted to its ester through condensation, which after protection
Me NaH, THF
LiBEt3H, THF O
−78 oC
COOMe
N
HO
(EtO)2P(O)CH2CON(Me)OMe
COOMe
N
Boc
Boc
609
610
Me
Me
O DIBAL, THF
Me COOMe
N
N
OMe
Boc
Me 1. NaHMDS, Ph3PCH3+Br-
OHC
−78 oC
N
COOMe
Boc 612
611
Me HMPA, MeOH 0 oC
N H 614
O
COOMe
N H 613
Me
3-bromo-2methylpropene
SmI2, THF
THF, −78 oC 2. TFA, CH 2Cl2
2 mol% Grubb's cat N
o
NaH, DMF, 20 C
O
Benzene, 60 oC
615 Me
Me H N
O
(a) 3-lithiofuran, THF, −78 oC
Me
H
(b) NaBH4, MeOH
H
H2, Pd(OH)2
N O
N
O
617
616
+ H
N
MeOH, rt
Me (S)-furan
Me
Me
O
Me
Me
618
619
Scheme 132.
OH O O
N H 620
O
OR
OR 1. TBSCl, THF or 2. PhCOCl
(Boc)2O
O O
N H R= tBuMe2Si R= PhCO 621
O
DMAP
H5IO6, then NaClO2
MeOOC
622
N Boc 623
Scheme 133.
N Boc
OBz
NaH2PO4, then CH2N2
O O
O
O
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
N
O
COOMe OBn
COOMe OBn
N-methylnitrone O
toluene, heat
N
R
624
625
EtOAc-MeOH
O
TFA
626
N+
COOMe OBn
O
N H
R= Boc R= H
OH
H2, Pd(OH)2
625
COOMe OBn
SmI2, THF
N
Boc
HN
OH
HN
O
N
I-
OH
MeI, THF
Et3N
COOMe OBn
O
N Boc
Boc 627
OH COOMe OBn
O
N Boc 628
Scheme 134.
17
O
NaH BrCH2CN
N
O
+
O
N
O
O Ph
O
O NaBH4 CoCl2
N
HN
HN
EtOOC CH2CN
EtOOC
Ph
629
O
N O
O Ph
630
Ph 631
632
Scheme 135.
17
3-hydroxymethyl-3 methyl-oxetane DCC, DMAP, CH2Cl2
O
N H 633
BF3.OEt2, CH2Cl2 Et3N,
O
O
0 oC
O
N
1. BuLi/DABCO, CbzCl, −78 o C, THF
N
2. BuLi/HMDS, (Boc)2O, −78 oC
O
CH3
1. Acc: Cbz 2. Acc: Boc 3. Acc: Moc 634
1. BuLi/HMDS, PhSeCl −78 oC, THF 2. mCPBA, DABCO
O
O O O
N Cbz
Acc 635
R
R O
CH3
636
RMgBr, CuBr, S(CH 3)2 −78 oC to −20 oC
O
Acc
3. BuLi/DABCO, CNCOOCH 3 −78 oC, THF
O O O
O
O O
N
O O O
1. H2/Pd/C, EtOAc/MeOH CH3
Cbz 637
2. TFA/H2O/CH2Cl2 3. Cs2CO3/H2O
O
N H
COOH
638 Scheme 136.
of –NH followed by oxidation was converted to ABO ester 635. Formation of epoxide at C-3, 4 of 635 following usual chemistry and subsequent ring opening with Grignard reagent afforded 637. Compound 637 after protection and deprotection sequences afforded the desired 3-substituted pyroglutamate 638.
Cienfuegos et al. reported stereoselective synthesis of conformationally constrained (2S,3S)-3-hydroxyornithine137 (Scheme 137). Cai et al.138 described the application of (S)-and (R)-methyl pyroglutamates as inexpensive, yet highly efficient chiral auxilia-
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S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
Bn N
BnHN
O
OH
O
LiAlH4 O
O Ph 639
Bn 640
Bn
TFA, THF-H 2O
OH
CH2Cl2
N
N
639
CDI
OH
THF, Heat
N
Bn N
O
N H
O OR LiAlH4
CCl3COOH, CH2Cl2
O
N H
BnAcN
OH OEVE
BnAcN
OAc
Ac2O
OEVE
Py
N H
THF, heat
643
642 BnHN
N H 641
OH ethylvinylether O
O
Bn N
OAc
CH3COOH-H2O
OH
N
N
Ac
Ac
645
644 BnAcN
646 BnHN
OAc
Jones' Reagent
OH
3M HCl
acetone
COOH
N
COOH
N H
Ac 648
647 Scheme 137.
N
O
O
Ni O
N
O
N
R O
N
N
COOMe O
650
N
DBU, DMF R= Me
O Ni
R H O
N
Me
O
649
Me N
COOMe
651
N
R 1. MeOH/HCl 2. NH4OH 3. Dowex
O H
O
N H
+ COOH
652
O
NH
O Me
653 Scheme 138.
ries in the asymmetric Michael addition reactions (Scheme 138). Michael acceptor 650 reacts with Ni(II) complex to give exclusively 651. Compound 651 on treatment with methanoic HCl and subsequently treatment with NH4OH and Dowex yielded 3-substituted pyroglutamic acid 652. Langlois et al.139 reported the stereoselective formal synthesis of the proteasome inhibitor salinosporamide A, from (S)-methyl 2-hydroxymethylpyroglutamate through chemoselective O-protection (Scheme 139). Fujita et al. reported reactions of optically active 5-substituted2-pyrrolidinone derivatives having atropisomeric behaviours. They
carried out 3,5-cis-selective reactions of their enolates with electrophiles140 (Scheme 140). 3.4. Conversion of pyroglutamic acid into prolines Pyroglutamates can readily be converted into prolines. Rapoport et al. converted 4-phenylpyroglutamate 664 to 4-phenyl prolinate 665 by reducing with BH3THF in the presence of a catalytic amount of NaBH4141 (Scheme 141). Pyroglutamates could directly be converted into L-proline in 2step one-pot reaction. The conversion involves the treatment of
1626
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
N COOMe OBn
O
COOMe OBn
Cs2CO3, PMBBr
N H
O
DMF
COOMe OBn +
N-methylnitrone O toluene, heat
N
N
PMB
654 N
OH
HN
EtOAc-MeOH
N
OH
COOMe OBn
H2, Pd(OH)2
COOMe OBn
O
PMB
656
655 O
O
N
1. MeI, MeOH 2. Na2CO3, CH2Cl2
COOMe OBn
O
N
PMB
PMB 657
O
PMB
658
659
Scheme 139.
E E O
N OR2
O
N OR2
R1
660
-
N
E+
OR2
R1
O R1
OR2
662
661
N H
O
663
Scheme 140.
pyroglutamic acid with triethyl oxonium fluoro borate and reduction of the resulting crude imino ether with NaBH4142 (Scheme 142). We have also reported a simple procedure121 for the conversion of 4-substituted pyroglutamates to 4-substituted prolinates 669 via the conversion of pyroglutamate to thio lactam followed by reduction to the corresponding prolinate in the presence of nickel boride generated in situ (Scheme 143). Drauj et al. have converted143 L-pyroglutamate 111 to 5,5-dichloro-N-chloro carbonyl 2(S)-methyl pyroglutamate 670 on reaction with COCl2 in dichloromethane at 0 °C with the elimination of HCl and CO2. Compound 670 on reaction with Bu3N gave 671 with the elimination of HCl at positions 4 and 5 leading to induction of double bond. Compound 671 on hydrogenation using Pd/C with Bu3N gave unsaturated product 672, which on further hydrogenation gave saturated products 673. Compound 673 after several protection and deprotection sequences afforded L-proline (Scheme 144). Harris et al.144 reported the synthesis of cyclic proline containing peptides via ring-closing metathesis (Scheme 145). N-Acyl-5allyl diene 677, which was obtained from pyroglutamic acid was
Ph
Ph BH3·THF O
N
COOtBu
NaBH4
COOtBu
N PhF1
PhF1
665
664 Scheme 141.
O
N H 17
COOH
triethyloxonium fluoroborate NaBH4
N H 666
COOH
Scheme 142.
Ph
Ph
Ph Nickel boride
Lawessons reagent O
N H 667
E
CH2Cl2, rt
S
N H 668
Scheme 143.
E
N H 669
E
1627
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O
COCl2, CH2Cl2
COOMe
N H
0 oC, -HCl, -CO2
H
Bu3N, 70 oC
Cl Cl
COOMe
N O
111
Cl
-Bu3NHCl
O
Cl
H
H
-Bu3NHCl
H2, Pd/C
COOMe
N
Cl 671
670
H2, Pd/C, Bu3N
COOMe
N
COOMe
N
H
H+, H2O -CO2
+ N
COOMe
H O
O
Cl
673
672
H
Cl 674
H H+, H2O -CH3OH
+ N H
COOH
H
Basic ion exchange
COOH
N H
H
675
676 Scheme 144.
COOtBu
N
COOtBu
Grubbs' cat. (20%) CH2Cl2/reflux
O
O N
N
COOBn
COOBn 678
677 Scheme 145.
1. LiHMDS O
O
COOH
N
N
2.
Ph 177
COOH
N
O
COOCH2Ph
N Ph
680
toluene
Raney Ni S
COOCH2Ph
N Ph
681
682
H2, Pd/C (10%)
+ COOH
N
COOCH2Ph
CH3OH, 2h
N H
Ph
Ph 683
Et3N
Ph
Lawesson's reagent
PhCH2Br
N
PhCH2Br O
Ph 679
Br
Et3N
Pd/C (10%) COOH H2
685
684 Scheme 146.
COOH
1628
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
subjected to cyclization in the presence of Grubb’s catalyst to afford the expected cyclononenes 678. Chen et al. reported a convenient method for the synthesis of trans-4-cyclohexyl-L-proline145 (Scheme 146). N-Benzyl pyroglutamic acid was reacted with bromocyclohexene in the presence of LiHMDS, followed by hydrogenolysis with Pd/C to get 4-substituted N-benzyl pyroglutamic acid 680 which was condensed with PhCH2Br to get ester 681. Treatment of 681 with Lawesson’s reagents, followed by reduction with Raney Ni afforded 683 and 684. Both these products were subjected further to hydrogenolysis using H2/Pd–C to get 4-cyclohexyl proline 685. Langlois et al.146 reported diastereoselective syntheses of (2S,3S,4S)-3-hydroxy-4-methylproline 691, a common constituent of several antifungal cyclopeptides (Scheme 147). Compound 686 on reduction using BH3–DMS was converted to 687, resultant material on hydrogenolysis, followed by NH protection was converted to 688. Treatment of 688 with TBDMSCl gave 689 and sub-
OH
sequent reaction with NaIO4–RuCl3 followed by acidic hydrolysis afforded the desired molecule 691. Two separate and distinct syntheses of stereospecifically deuterated samples of (2S)-proline were reported by Barraclough et al.147 (Scheme 148). Compound 131 on reduction using H3BSMe2, followed by acidic hydrolysis afforded proline 666. Oba et al.148 carried out the synthesis of non-proteinogenic amino acids using Michael addition to unsaturated orthopyroglutamate derivative (Scheme 149). Unsaturated pyroglutamate derivative 166 on reaction with Gilman reagent delivered a compound 693 having methyl group at C-3. The ABO ester functionality of 693 was converted to methyl ester through ester exchange reaction with MeOH/HCl. The N-Boc group of 693 which was deprotected during acidic conditions was protected again with Boc group to afford 694. Reduction of lactam carbonyl of 694 with BH3THF followed by deprotection of methyl ester of 695 in refluxing 1 M. HCl and subsequently ion exchange treatment with DOWEX 50WX8
OH OH 1. H2/Pd/C
BH3-DMS
O
N
N
86%
OH
2. (Boc)2O
Ph
R 686
Boc
R
688
687 OSit-BuMe2
OR2 OR1
NaIO4-RuCl3
Boc
OH 6M HCl + N Cl- H2
COOH
N
CCl4-CH3CN-H2O R1=R2=OSit-BuMe2 R1=H, R2=OSit-BuMe2
N
TBDMSCl
N
O
Ph
O
OH
Boc
689
COOH
691
690 Scheme 147.
H3B·SMe2
(Boc)2O, DMAP O
COOMe
N H 111
CH3CN
131
THF, 0 oC
6M HCl N
COOMe
reflux
N H 666
Boc 692
COOH
Scheme 148.
Me
Me
O
N
ABO
Me2CuLi
O
Boc
N
ABO
HCl, MeOH then
O
(Boc)2O, DMAP
Boc
Boc 693
166
694 Me
Me BH3-THF N
COOMe
1M HCl then Dowex 50WX8
Boc 695
N H 696
Scheme 149.
N
COOH
COOMe
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
1629
OBn
i. LiBEt3H, THF
LiHMDS, BnOCH2Cl O
COOEt
N
O
HMPA, THF
COOEt
N
Boc 319
Boc 697 OR
OR i. MeMgBr, CuBr-Me 2S BF3-OEt2, Et2O MeO
ii. p-TsOH, MeOH
N
COOEt
ii. (Boc)2O, NaHCO3
Jones' reagent Me
N
COOEt
acetone
Boc
Boc
699a, R= Bn H2, Pd/C, MeOH 699b, R= H
698
Me N Me HOOC
O Me2NH, EDC
Me
N
COOEt
L-ProCN, EDC
Me
HOBt, Et3N
COOEt
N
Boc
Boc
700
701a, R= Et NaOH, MeOH 701b, R= OH
Me
Me N Me
N Me
O
O N
Me
HOBt, Et3N
p-TsOH, EtOH
N Me
N Boc
O
CN
702
N H
O CN
703 Scheme 150.
resin furnished (2S,3S)-3-methylene proline 696 in quantitative yield. Kondo et al.149 discovered long acting N-(cyanomethyl)-N-alkyl-L-prolinamide inhibitors of dipeptidyl peptidase IV (Scheme 150) starting with pyroglutamic acid derivative. Lithium enolatederived alkylation of N-protected ethyl-L-pyroglutamate 319 with benzyloxymethyl chloride afforded 4-substituted pyroglutamate 697. Partial reduction of cyclic imide carbonyl of 697, followed by acetalization gave the methyl acetal 698. Stereoselective 5 amethylation of 698 with methyl Grignard reagent and copper(I) bromide-dimethylsulfide complex in the presence of boron trifluoride-etherate, followed by protection of deprotected nitrogen, led to 699a. Catalytic hydrogenation of 699a provided the alcohol 699b. Jone’s oxidation of 699b resulted in carboxylic acid 700, which on condensation with N,N-dimethyl amine produced 701a. Alkaline hydrolysis of compound 701a provided carboxylic acid 701b, which on peptide formation with (2S)-2-cyanopyrrolidine afforded 702. Acidic deprotection of 702 led to the desired compound 703. Einsiedel et al. developed a molecular building kit of fused-proline derived peptide mimetics allowing specific adjustment of the dihedral w-angle (Scheme 151). Unsaturated pyroglutamic acid derivative 704 on reaction with allyl bromide in the presence of TMSCl and HMPA, followed by reduction of lactam carbonyl deliv-
ered 706, which after deprotection of alcoholic group furnished prolinol derivative 707. Jones oxidation led to the formation of the C-3 functionalized proline 708. Amide formation between the asymmetric building block 708 and N-substituted glycine derivatives using coupling mixture HATU/HOAt allowed an efficient synthesis of RCM precursor 709. Olefin metathesis using Grubb’s II generation catalyst afforded seven-membered and eight-membered unsaturated bicyclic lactams 710. Aminolysis of 710 with methylamine delivered the model peptides 711.150 4. Conclusions Thus this review gives explicit information about the versatility and importance of pyroglutamate with special attention to asymmetric synthesis of bioactive molecules, natural products as well as chiral intermediates. On the one hand this important moiety has allowed the researchers to synthesize bioactive natural products such as anatoxin A, ()-bulgecinine and salinosporamide A, whereas on the other hand the use of pyroglutamic acid as a chiral precursor has enabled the researchers to explore the synthetic analysis for designed bioactive molecules such as ACE inhibitors like fosinipril, conformationally constrained peptides as well as peptidomimetics. Various derivatives of pyroglutamic acid have also been used to develop catalyst such as semicorrin metal com-
1630
S. K. Panday et al. / Tetrahedron: Asymmetry 20 (2009) 1581–1632
O O
Ph tBu Ph
Si
N
O
AllMgBr
O
N
TMSCl, HMPA
Boc
Boc
704
705
O N
Si
Ph tBu Ph
i. LiAlH4, Et2O ii. Et3SiH, BF3.Et2O
H2O, Me2O
N Boc
706
707
COOH
N Boc 708
COOMe
COOMe N H
Ph tBu Ph
OH CrO3, H2SO4
Bu4NF, HOAc
Boc
( )n
Si
( )n
( )n N
COOMe
N
n=1
Grubb's catalyst
HATU, HOBt, NEM, NMP
O
CH2Cl2
N Boc 709
O N Boc 710
NHCH3 ( )n H2NMe, EtOH
N
O
O N Boc 711 Scheme 151.
plexes or 2,5-disubstituted pyrrolidines. Therefore it may be concluded that pyroglutamate has undoubtedly emerged as an important chiral synthon and has provided researchers a useful chiral tool to exploit the reactivity differences within the molecule and to use it for the asymmetric synthesis of wide variety of bioactive compounds. The present review is an attempt to describe the useful and important applications on the use of this unique chiral synthon by the researchers all over the world in the recent past, and shall certainly be valuable, to make further progress and to develop new strategies for the asymmetric synthesis based on these literature reports. Acknowledgements The corresponding author is thankful to the University Grants Commission, New Delhi, India for financial assistance and to Central Drug Research Institute, Lucknow, UP, India for extending library facilities to us. References 1. (a) Ohfune, Y.; Tomita, M. J. Am. Chem. Soc. 1982, 104, 3511; (b) Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245. 2. Thottahil, J. K.; Moniot, J. L.; Mueller, R. H.; Wong, M. K. Y.; Kissick, T. P. J. Org. Chem. 1986, 51, 3140. 3. Langlois, N.; Andriamialisoa, R. Z. Tetrahedron Lett. 1988, 29, 3259. 4. Baldwin, J. E.; Moloney, M. G.; Shim, S. B. Tetrahedron Lett. 1991, 32, 1379. 5. Hamada, Y.; Tanada, Y.; Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 1991, 32, 5983.
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