- Email: [email protected]
Flexible approach for the asymmetric synthesis of (−)-hyacinthacine A1 and its 7a-epimer
Accepted Manuscript Flexible Approach for the Asymmetric Synthesis of (-)-Hyacinthacine A1 and its 7aepimer Chang-Mei Si, Zhuo-Ya Mao, Rong-Guo Ren, Zhen-Ting Du, Bang-Guo Wei PII:
S0040-4020(14)01250-2
DOI:
10.1016/j.tet.2014.08.056
Reference:
TET 25957
To appear in:
Tetrahedron
Received Date: 26 June 2014 Revised Date:
14 August 2014
Accepted Date: 22 August 2014
Please cite this article as: Si C-M, Mao Z-Y, Ren R-G, Du Z-T, Wei B-G, Flexible Approach for the Asymmetric Synthesis of (-)-Hyacinthacine A1 and its 7a-epimer, Tetrahedron (2014), doi: 10.1016/ j.tet.2014.08.056. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
Flexible Approach for the Asymmetric Synthesis of (-)-Hyacinthacine A1 and its 7a-epimer
RI PT
Leave this area blank for abstract info.
Chang-Mei Sia,b, Zhuo-Ya Maoa,b, Rong-Guo Ren a, Zhen-Ting Dua,*and Bang-Guo Weib,* a. College of Science, Northwest A&F University, Yangling, Shaanxi Province 712100, China, b. Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China
O
O
N Boc 7
H
O
N Boc
OTBS
EP AC C
H
OH
OH (-)-7a-epi-1
TE D
10
NaBH4 CeCl3 OTBS
OH
7a N
O
AllylMgCl
M AN U
N OTBS Boc 9 AllylB(OR)2
O
O
SC
O
O
O
7a N
N Boc 8
OTBS
OH OH OH
1 (-)- hyacinthacine A1
1
ACCEPTED MANUSCRIPT
Tetrahedron journal homepage: www.elsevier.com
RI PT
Flexible Approach for the Asymmetric Synthesis of (-)-Hyacinthacine A1 and its 7a-epimer Chang-Mei Sia,b, Zhuo-Ya Maoa,b, Rong-Guo Renb, Zhen-Ting Dua,∗ and Bang-Guo Weib,∗
SC
a. College of Science, Northwest A&F University, Yangling, Shaanxi Province, 712100, China b. Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China
ABSTRACT
Article history: Received Received in revised form Accepted Available online
The diastereoselective nucleophilic addition of organic boronic ester to 3-hydroxy-2-substituted N-acyliminium ions 9 led to the formation of 2,5-cis- pyrrolidine 10, from which a convenient synthesis of (-)-7a-epi-1 was developed. In addition, an efficient asymmetric synthesis of (-)-hyacinthacine A1 1 was achieved through the reduction/ring-opening process.
M AN U
ARTICLE INFO
1. Introduction
TE D
Keywords: Lactam Nucleophilic Addition Asymmetric synthesis Alkaloid Hyacinthacine
AC C
EP
Iminosugars (azasugars or iminocyclitols), the analogues of monosaccharides with nitrogen replacing the oxygen in the ring, are considered as mimics of sugars.1 Most of these polyhydroxylated pyrrolizidine alkaloids (Figure 1) and their structural motif proved to be a rich source of glycosidase or glycosyltransferase inhibitors. For example, australine 2 (IC50 = 5.8 µM),2 alexine 3 (IC50 = 11 µM)3 and hyacinthacine A2 4a (IC50 = 8.6 µM),4 are not only selective inhibitors of amyloglucosidase, but also demonstrate potential application as antiviral, anticancer, antidiabetic and antiobesity drugs.5 However, these iminosugars do not exhibit significant inhibition of β-glucosidases.6 Among them, 3-(hydroxymethyl) pyrrolizidines, which were isolated from bluebells (Hyacinthoides nonscripta),7a grape hyacinths (Muscari armeniacum)4 and from the bulbs of Scilla peruviana,7b Scilla sibirica,7cand Scilla socialis,7d are of particular interest. For example, (+)-hyacinthacine A1 1, isolated in 2000 from the bulbs of Muscari armeniacum (Hyacinthaceae) in less than 0.0005% yield,4 displays good inhibitory activity against β-galactosidase from rat intestinal lactase (IC50 = 4.4 µM) and is also a moderate inhibitor of both α-l-fucosidase from rat epididymis (IC50 = 46 µM) and amyloglucosidase from Aspergillus niger (IC50 = 25 µM). Due to the diverse biological activities in particular specific glycosidase inhibition, and the intriguing structure of (+)-hyacinthacine A1 1 and their analogous, considerable efforts ∗ Corresponding authors. (+86)-21-5423-7757 (B.-G.; W.); e-mail addresses: [email protected] (Z.-T.; D); [email protected] (W.B.-G.).
2009 Elsevier Ltd. All rights reserved.
have been contributed to their synthesis and enantioselective synthetic methods have been reported.8 H 7a
N
OH 1 3
HO
H
OH
OH
N
OH OH
N OH
1 hyacinthacine A1 H
H
OH
N OH
HO
several
2 australine HO
OH
H
OH
R
OH hyacinthacines A2, A3 4a A2 (R= H) 4b A3 (R= Me)
OH
N X
Y
3 alexine
OH
HO OH
HO
OH
hyacinthacine B3, B7
H N
OH OH
OH 6 (-)-uniflorine A
5a B3 (X= Me, Y=H) 5b B7 (X= H, Y=Me)
Figure 1. The structures of several natural products
The generation of four chiral centers in the pyrrolizidine skeleton is the most challenging part for the asymmetric synthesis of (+)-hyacinthacines. As a continuation of our interest in pursuing chiral building blocks and utilizing them in the synthesis of iminosugars,9 ceramides,10 piperidine11 and
2
pyrrolidine12 alkaloids, as well as divergent synthesis of MANUSCRIPT ACCEPTED O depsipeptides,13 we decided to develop an approach for the O O divergent synthesis of iminosugars using chiral lactam 7, which ref. 9,10 + AllylB 7 was readily available from D-glutamic acid. Herein, we present R O N this concise and flexible approach for the synthesis of OTBS Boc (-)-hyacinthacine A1 1 and its epimer 7a-epi-1.
7a
B
O
O
O
O
AllylMgCl N
OH
A
OH 1 (-)- hyacinthacine A1
N Boc
NaBH4 O CeCl3 OTBS
N Boc 7
8
11 R = OAc;12 R = OH 15 13 R = OMe;14 R = SO2Ph Lewis acid BF3·Et2O BF3·Et2O BF3·Et2O ZnCl2 BF3·Et2O TMSOTf TiCl4 ZnCl2 MgBr2
OTBS
N
1 3
O
O
OH
OH (-)-7a-epi-1
N Boc 10
O
O AllylB(OR)2
TE D
7a
OH
OTBS
N Boc
OTBS
EP
AC C
N,O-acetals 11-14 were prepared from lactam 7, a derivative from D-glutamic acid in 73% overall yield.9,10a Initially, the treatment of N,O-acetal 11 with allylboronic acid under Pyne’s reaction conditions did not give any desired product 10. But when the corresponding boronate, 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 15, was used, compound 10 could be afforded in 36% yield with high diastereoselectivity (Table 1 entry 1). In order to improve the yield of 10, various leaving groups of N,O-acetal were used, the yields did not get any better (Table 1 entries 2-4). Fortunately, the aminal 12 (R = OH) turned out to be an excellent substrate for this allylation, and the yield of 10 could reach 61% when the reaction was conducted at -40 °C (Table 1 entry 5). Although several Lewis acids were screened, the results proved to be fruitless (Table 1 entries 6-9). Table 1. The asymmetric alkylation of N,O-acetal 11-14.
Y %[b] 36 27 22 <5 61 43 17 19 23
dr[c] >99:1 >99:1 >99:1 ->99:1 >99:1 >99:1 >99:1 >99:1
The stereochemistry of 10 was assigned as 2,5-cis form, which can be rationalized by the Bürgi–Dunitz angle (BD angle). 16 The nucleophilic reagent attacked more stable conformation in the transition state A (Scheme 1) along the 107o by the C=N bond.17 Due to the influential steric effect of the acetal group, the attack towards downside should be more favorable than that of upside. Thus, nucleophilic addition to the transition state would produce the same facial to CH2OTBS group eventually, that’s a 2,5-cis chiral stereochemistry of 10.
R
O
N Boc OTBS 11-14
O
O
N Boc OTBS
LA
10
9
Figure 2. Two different asymmetric allylations
2. Results and discussion
R OH OAc OMe SO2Ph OH OH OH OH OH
[a] Reactions were performed with 11, 12, 13 or 14 (0.93 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.27 mL, 1.39 mmol) in CH2Cl2 (20 mL) at -78 oC to -40 oC overnight, [b] Isolated yield. [c] dr was determined by 1H NMR or HPLC.
O
H
T oC -78 -78 ~ -40 -78 ~ -40 -78 ~ -40 -78 ~ -40 -78 ~ -40 -78 ~ -40 -78 ~ -40 -78 ~ -40
RI PT
Entry[a] 1 2 3 4 5 6 7 8 9
SC
OH
H
N Boc OTBS 10
M AN U
The nucleophilic addition of allylic boronic ester to N-acyliminium ions for the formation of cis 5-sbstituted-4-hydroxypyrrolidine-2-one or 6-substituted-5-hydroxypiperidin-2-ones was first reported by Batey in 1999.14a On the basis of this pioneered work, Pyne achieved an asymmetric method through diastereoselective borono-Mannich reaction of boronic acids and potassium trifluoroborate to cyclic N-acyliminium ions.14b Encouraged by these results, we envisioned that the 2,5-cis allylation could be realized through diastereoselectively nucleophilic addition of N-acyliminium ions 9 with allyl borate or its corresponding ester, and the corresponding product could provide the right stereochemistry for C 7a in (-)-7a-epi-hyacinthacine A1. While the 2,5-trans allylation could be achieved by the nucleophlic addition of lactam 7 using Grignard reagents and subsequent diastereoselective reduction sequence.15 Both strategies are outlined retrosynthetically in Figure 2.
O
O
Lewis Acid
Nu disfavored attack
O
O
C favored attack Nu
H
N
OTBS CO2t-Bu
A
Scheme 1.The proposed mechanism of nucleophilic addition
To further confirm the stereochemistry of C3 position, we decided to synthesize the (-)-7a-epi-hyacinthacine A1. Hydroboration of 10 with BH3.SMe2 in tetrahydrofuran at room temperature, followed by oxidative hydrolysis with H2O2, gave primary alcohol 16 in 74% overall yield (Scheme 2)18. Mesylation of compound 16 with methanesulfonyl chloride in the presence of triethylamine and subsequent treatment with TESOTf/2,6-lutidine could generate the cyclized product 17 in one-pot fashion in 75% overall yield. Finally, deprotection of compound 17 with MeOH/(COCl)2 at room temperature for overnight gave the HCl salt of (-)-7a-epi-hyacinthacine A1 {[α]D25 -38.8 (c 0.50, H2O); lit 8i ([α]D25 +56.5 (c 0.12, H2O)} in quantitative yield. The NMR spectroscopic data of synthetic 7a-epi-1 was identical to the data of isolated
3
Scheme 2, Reagents and conditions: (a). BH3·THF, THF, 0 oC, overnight, then aq. NaOH, H2O2, 2 h, 74%; (b). MsCl, Et3N, CH2Cl2, 0 oC, 1 h; TESOTf, 2,6-lutidine, CH2Cl2, -78 oC~rt, 24h, 75%; (c). (COCl)2, CH3OH, overnight, 100%.
H
b
TE D
EP
O
O a
O
AC C
O
O
O
OTBS
NHBoc
N Boc OTBS 7
18
b
O
O
OTBS c NHBoc
20
HO
b
20 OH
+
O
O
O
O + N Boc OTBS 8
N Boc OTBS 19 b 20 O
O
N Boc OTBS 10
N
22
21
O
O
M AN U
Next we investigated the asymmetric synthesis of (-)-hyacinthacine A1 1 through nucleophilic addition of lactam 7 by allylmagnesium chloride and subsequent stereoselective reduction sequence.15 Thus, lactam 7 was treated with a solution of allylmagnesium chloride in dichloromethane at -78 oC, and the ring-opened product, i.e ketone 18, was generated in 10% yield, together with the inseparable additive product 19 in 87% combined yield (Scheme 3). Initially, we tried the reduction of the mixture 18 and 19 with sodium borohydride (NaBH4) in MeOH15, which afforded the alcohol 20 in low stereoselectivity18. To improve the stereoselectivity of compound 20, compounds 18 and 19 were treated with NaBH4 in the presence of CeCl3 separately. Unfortunately, both substrates gave very poor diastereoselectivity. Although EtOH was a good solvent for the reduction of similar structure 18 and 19, when 19 was treated with NaBH4 in EtOH, alcohol 20 was afforded still with moderate stereoselectivity (dr >75:25) in 94% combined yields. Compared the reaction condition to known method15, the only difference is the equivalent of sodium borohydride from 250 reduced to 10 times. We suspected that more rigid ring protecting group of dihydroxyl caused low stereoselectivity. Finally, treatment of mixtures of 20 with methanesulfonyl chloride and subsequent with t-BuOK smoothly generated the desired 8 in 66% yield and the minor isomer 10 in 21% yield, which was easily separated by column chromatography on silica gel.
SC
RI PT
Scheme 3, reagents and conditions: (a).Allylmagnesium chloride, CH2Cl2, (-)-7a-epi-hyacinthacine A18i. The free base of MANUSCRIPT ACCEPTED -78 oC, 1.5 h, 10% for 18, 87% for 19; (b). NaBH4, CeCl3, EtOH, 0 oC~rt, 4 h, (-)-7a-epi-hyacinthacine A1 was obtained, through Dowex 94%; (c). MsCl, Et3N, CH2Cl2, 0 oC, 0.5 h, t-BuOK, THF, 0 oC, 5 h, 66% for 25 50WX8 ion-exchange resin, as a pale yellow syrup {[α]D -45.3 8, 21% for 10. (c 0.36, H2O); lit8h ([α]D25 +47 (c 0.65, H2O)}. This further With the compound 8 in hand, the asymmetric synthesis of confirmed the stereochemistry outcome in the nucleophilic (-)-hyacinthacine A1 1 was quite straightforward as shown in addition of boronic ester 15 to N-acyliminium ions 9. Scheme 4. Following the synthetic sequence described above, the hydrogen chloride salt of (-)-hyacinthacine A1 1 {[α]D25 O O -7.7 (c 0.5, H2O)} was successfully prepared in 59% yield in 4 steps. The pure salt of (-)-hyacinthacine A1 1 was passed a b HO 10 OTBS through Dowex 50WX8 ion-exchange resin to give the free base 1 {[α]D25 -36.4 (c 0.30, H2O); lit 4 ([α] D25 +38.2 (c 0.23, N H2O)} which is colorless thick syrup. The spectral data of the Boc synthetic 1 were identical to the reported data.4 OH 16 H H O c OH O O O N N a HCl OTBS 8 HO OH OTBS N 7a-epi-1. HCl 17 Boc
OTBS
c
(-)-hyacinthacine A1 HCl 1. HCl
Scheme 4, Reagents and conditions: (a). BH3· THF, THF, 0 oC, overnight, NaOH, H2O2, 2 h, 79%; (b). MsCl, Et 3N, CH2Cl2, 0 oC, 1 h; TESOTf, 2,6-lutidine, CH2Cl2, -78 oC~rt, 24 h, 74%; (c). (COCl)2, CH3 OH, overnight, 100%.
3. Conclusions
In summary, an efficient method for the preparation of 2,5-cis-form 10 by a diastereoselective nucleophilic addition of boronic ester 15 to N-acyliminium ion 9 has been developed. Using this method, (-)-7a-epi-1 was synthesized. In addition, (-)-hyacinthacine A1 1 has also been synthesized by reduction/ring-opening process as the key steps. Further application of this strategy in the diversity-oriented synthesis of analogous is now in progress in our laboratory. 4. Experimental Section General: THF was distilled from sodium/benzophenone. Reactions were monitored by thin layer chromatography (TLC) on glass plates coated with silica gel with fluorescent indicator. Flash chromatography was performed on silica gel (300–400 mesh) with Petroleum/EtOAc as eluent. Optical rotations were measured on a polarimeter with a sodium lamp. HRMS were measured on a LCMS-IT-TOF apparatus. IR spectra were recorded using film on a Fourier Transform Infrared Spectrometer. NMR spectra were recorded at 400 MHz MHz, and chemical shifts are reported in δ (ppm) referenced to an internal TMS standard for 1H NMR and CDCl3 (77.0 ppm) for 13C NMR. 4.1 (3aR,4R,6S,6aS)-tert-Butyl 4-allyl-6-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-tet rahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (10) A solution of 12 (374 mg, 0.93 mmol) and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.27 mL, 1.39 mmol) in CH2Cl2 (20 mL) was cooled to -78 oC and stirred for 10 min. Then a solution of BF3.OEt2 (0.18 mL, 1.38 mmol) was
4
AC C
EP
TE D
M AN U
SC
RI PT
dropped slowly and the reaction mixture was stirred at -78 oC to MANUSCRIPT 2.62-2.54 (m, 1H), 2.28-2.18 (m, 1H), 1.46 (s, 9H), 1.41 (s, 3H), ACCEPTED o -40 C for overnight. The mixture was quenched with a saturated 1.34 (s, 3H), 0.92 (s, 9H), 0.09-0.07 (m, 6H) ppm; 13C NMR (100 NaHCO3 solution (10 mL) and warmed to room temperature. The MHz, CDCl3) δ 156.0, 134.8, 117.6, 107.9, 80.2, 80.1, 75.7, 68.0, organic phase was separated and the aqueous layer was extracted 62.9, 51.0, 38.4, 28.3, 27.9, 25.9, 25.6, 18.4, -5.4, -5.5 ppm; with CH2Cl2 for three times. The combined organic layers were HRMS (ESI) calcd for [C22H43NO6Si+Na+]: 468.2757, found: washed with brine, dried and concentrated. The residue was 468.2756. purified by flash chromatography on silica gel to give 10 (242 4.4 (3aR,4S,6S,6aS)-tert-Butyl mg) in 61% yield as a colorless oil. [α]D25 = +38.2 (c 0.48, 4-allyl-6-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-tet CHCl3); IR (film): νmax 2956, 2931, 2858, 1697, 1472, 1393, rahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (8) 1255, 1213, 1176, 1116, 1066, 972, 916, 837, 778, 739 cm-1; 1H NMR (400 MHz, CDCl3, rotamers) δ 5.86-5.72 (m, 1H), A solution of 20 (500 mg, 1.12 mmol) and TEA (1.3 mL, 8.97 5.13-5.05 (m, 2H), 4.70-4.63 (m, 1H), 4.43-4.36 (m, 1H), mmol) in dry CH2Cl2 (20 mL) was cooled to 0 oC, then a solution 4.10-3.55 (m, 4H), 2.65-2.40 (m, 1H), 2.25-2.05 (m, 1H), 1.44 (s, of MsCl (0.26 mg, 3.36 mmol) was slowly dropped. After being 12H), 1.29 (s, 3H), 0.88 (s, 9H), 0.05 (s, 6H) ppm; 13C NMR stirred for 0.5 h, the reaction was quenched with a saturated (100 MHz, CDCl3, rotamers) δ 154.1, 134.6, 134.4, 117.4, 111.5, NH4Cl solution and extracted with CH2Cl2 (30 mL × 3). The 83.8, 83.1, 82.0, 81.2, 79.7, 65.9, 64.4, 64.2, 63.3, 62.7, 38.0, combined organic layers were washed with brine, dried and 37.4, 28.4, 27.3, 26.0, 25.4, 18.4, -5.3, -5.5 ppm; HRMS (ESI) concentrated to give crude middle compound. The above crude calcd for [C22H41NO5Si+Na+]: 450.2652, found: 450.2651. compound was dissolved in dry THF (12 mL) and cooled to 0 oC. t-BuOK (252 mg, 2.24 mmol) was added in one portion and the 4.2 (3aS,6S,6aS)-tert-Butyl mixture was stirred for 5 h. The reaction mixture was quenched 4-allyl-6-((tert-butyldimethylsilyloxy)methyl)-4-hydroxy-2,2-d with a saturated NH4Cl solution and extracted with EtOAc (30 imethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate mL × 3). The combined organic layers were washed with brine, (19) dried and concentrated. The residue was purified by flash A solution of 7 (915 mg, 2.28 mmol) in dry DCM (20 mL) was chromatography on silica gel (PE/EA=30/1) to give 8 (317mg, treated with a solution of allylmagnesium chloride (3.35 mL, 66%) and 10 (101mg, 21%). The major 8 is colorless oil. [α]D25 = o 5.70 mmol, 1.7M in THF) at -78 C. Then the reaction was stirred +93.2 (c 0.88, CHCl3); IR (film): νmax 2976, 2952, 2930, 2858, for 1.5 h. The mixture was quenched with a solution of saturated 1692, 1478, 1399, 1371, 1331, 1277, 1216, 1177, 1108, 1065, NH4Cl and extracted with CH2Cl2 (30 mL × 3). The combined 974, 939, 908, 880, 861, 841, 779 cm-1; 1H NMR (400 MHz, organic layers were washed with brine, dried and concentrated. CDCl3, rotamers) δ 5.98-5.86 (m, 1H), 5.21-5.07 (m, 1H), 5.06-5.01 (m, 1H), 4.75-4.70 (m, 1H), 4.69-4.63 (m, 1H), The residue was purified by flash chromatography on silica gel (PE/EA=20/1) to give 18 (110 mg, 10 %), and 19 (951 mg, 87 %). 4.25-3.75 (m, 3H), 3.70-3.55 (m, 1H), 3.28-3.15 (m, 1/2H), The major 19 is colorless oil. [α]D25 = +71.7 (c 0.68, CHCl3); IR 2.90-2.75 (m, 1/2H), 2.50-2.32 (m, 1H), 1.54 (s, 3H), 1.48 (s, 9H), 1.37 (s, 3H), 0.89 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H) ppm; 13C (film): νmax 3369, 2955, 2931, 2857, 1715, 1629, 1500, 1472, -1 1 1368, 1253, 1166, 1104, 1052, 971, 837, 778 cm ; H NMR (400 NMR (100 MHz, CDCl3, rotamers) δ 154.5, 136.1, 135.8, 116.4, MHz, CDCl3) δ 5.89-5.75 (m, 1H), 5.14-5.07 (m, 2H), 4.57 (d, J 116.3, 111.1, 110.9, 81.7, 80.3, 79.9, 79.5, 64.6, 64.2, 63.5, 62.9, = 6.0 Hz, 1H), 4.41 (d, J = 6.0 Hz, 1H), 4.37-4.18 (m, 1H), 62.6, 61.9, 34.7, 33.0, 28.5, 25.8, 24.8, 18.1, -5.5, -5.6 ppm; 4.09-3.98 (m, 1H), 3.85-3.71 (m, 1H), 3.66 (dd, J = 10.2, 3.0 Hz, HRMS (ESI) calcd for [C22H41NO5Si+Na+]: 450.2652, found: 1H), 3.25-3.15 (m, 1H), 2.47 (dd, J = 13.8, 8.6 Hz, 1H), 1.56 (s, 450.2649. 3H), 1.49 (s, 9H), 1.36 (s, 3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 4.5 General procedure for the synthesis of 16, 21: A solution of 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 153.8, 133.6, 118.4, olefins 8 or 10 (350 mg, 0.82 mmol) in dry THF (5 mL) was 112.3, 80.7, 63.1, 28.5, 26.0, 18.4 -5.3, -5.4 ppm; HRMS (ESI) treated with a solution of BH3.SMe2 (2.46 mL, 2.46 mmol) at 0 calcd for [C22H41NO6Si+H+]: 466.2601 found: 466.2602. o C. After being stirred for overnight at 0 oC to room temperature, 4.3 tert-Butyl the reaction mixture was cooled to 0 oC and treated with a 30 % H2O2 solution (5 mL). Then a 3M NaOH solution (5 mL) was (S)-2-(tert-butyldimethylsilyloxy)-1-((4S,5S)-5-(1-hydroxybut3-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylcarbamate (20) slowly dropped and the mixture was stirred for 2 h at 0 oC to room temperature. The resulting mixture was diluted with water A solution of 19 (710 mg, 1.60 mmol) and CeCl3 (474 mg, 1.92 and extracted with EtOAc (20 mL × 3), and the combined o mmol) in dry EtOH (20 mL) was cooled to 0 C, then NaBH4 organic layers were washed with brine for two times. Dried and (606 mg, 16.02 mmol) was added in several portion. After being concentrated, the residue was purified by flash chromatography o stirred for 4 h at 0 C, the mixture was concentrated and the on silica gel (PE/EA=4/1) to give 16, 21. residue was diluted with water. The resulting mixture was extracted with EtOAc (30 mL × 3) and the combined organic 4.5.1 (3aS,4S,6R,6aR)-tert-Butyl 4-((tert-butyldimethylsilyloxy)methyl)-6-(3-hydroxypropyl)-2, layers were washed with brine. Dried, filtered and concentrated, the residue was purified by flash chromatography on silica gel 2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxyla (PE/EA=10/1) to give 20 (670 mg, 94%). The minor could not te (16) isolate by flash chromatography on silica gel. The mixture of 20 16 (270 mg, 74%) as a colorless oil. [α]D25 = +12.4 (c 1.29, was a white solid. The major compound: IR (film): νmax 3283, CHCl3); IR (film): νmax 3445, 2931, 2858, 1694, 1472, 1462, 2982, 2929, 2856, 1673, 1539, 1370, 1309, 1252, 1221, 1171, 1397, 1367, 1333, 1255, 1213, 1174, 1117, 1062, 837, 779, 738 -1 1114, 1089, 1064, 1040, 1028, 985, 868, 839, 810, 773, 669 cm ; cm-1; 1H NMR (400 MHz, CDCl3, rotamers) δ 4.72 (dd, J = 5.6, 1 H NMR (400 MHz, CDCl3, rotamers) δ 6.00-5.88 (m, 1H), 1.2 Hz, 1H), 4.40 (dd, J = 5.6, 1.2 Hz, 1H), 4.13-3.80 (m, 2H), 5.21-5.19 (m, 1/2H), 5.17-5.14 (m, 1H), 5.13-5.11 (m, 1/2H), 3.76-3.55 (m, 4H), 2.25-2.15 (m, 1/2H), 1.87-1.78 (m, 1/2H), 4.15 (dd, J = 9.6, 5.2 Hz, 1H), 3.99 (dd, J = 8.8, 5.2 Hz, 1H), 1.75-1.58 (m, 3H), 1.57-1.52 (m, 1/2H), 1.48 (s, 12H), 1.42-1.36 3.94-3.83 (m, 3H), 3.70 (dd, J = 9.6, 2.8 Hz, 1H), 2.95 (brs, 1H),
5
AC C
EP
TE D
M AN U
SC
RI PT
838, 803, 778 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.66-4.26 (m, (m, 1/2H), 1.34 (s, 3H), 0.92 (s, 9H), 0.09 (s,ACCEPTED 3H), 0.08 (s, 3H) MANUSCRIPT 13 ppm; C NMR (100 MHz, CDCl3, rotamers) δ 154.5, 111.6, 84.7, 1H), 4.53-4.49 (m, 1H), 3.65-3.53 (m, 2H), 3.49 (dd, J = 10.0, 6.0 Hz, 1H), 3.15-3.07 (m, 1H), 3.06-2.95 (m, 2H), 2.12-2.02 (m, 84.3, 82.2, 81.4, 79.9, 79.8, 65.9, 64.6, 64.1, 63.2, 62.9, 62.5, 1H), 1.94-1.74 (m, 3H), 1.45 (s, 3H), 1.27 (s, 3H), 0.86 (s, 9H), 62.2, 30.0, 29.4, 28.8, 28.5, 27.4, 26.0, 25.5, 18.4, -5.3, -5.4 ppm; 0.02 (s, 6H); ppm; 13C NMR (100 MHz, CDCl3) δ 111.6, 85.9, HRMS (ESI) calcd for [C22H43NO6Si+Na+]: 468.2757, found: 468.2752. 82.8, 70.0, 67.1, 65.6, 55.0, 26.8, 26.0, 25.9, 24.5, 24.0, 18.2, -5.4, -5.5 ppm; HRMS (ESI) calcd for [C17H33NO3Si+H+]: 328.2308 4.5.2 (3aS,4S,6S,6aR)-tert-Butyl found: 328.2305. 4-((tert-butyldimethylsilyloxy)methyl)-6-(3-hydroxypropyl)-2, 4.7 General procedure for the synthesis of 1, 7a-epi-1: A solution 2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxyla of compound 17 or 22 (100 mg, 0.31 mmol) in dry MeOH (8 mL) te (21) was treated with a (COCl)2 (0.11 mL, 1.09 mmol). After being 25 21 (288 mg, 79%) as a colorless oil. [α]D = +89.4 (c 0.48, stirred overnight, the reaction mixture was concentrated to give CHCl3); IR (film): νmax 3455, 2930, 2858, 1689, 1472, 1379, crude salt. The crude salt was refluxed in EtOAc for 3h and 1251, 1210, 1174, 1107, 1060, 972, 940, 837, 778 cm-1; 1H NMR cooled to 0 oC, and then the resulting mixture was filtered to give (400 MHz, CDCl3, rotamers) δ 4.76-4.70 (m, 1H), 4.68-4.64 (m, title compound. 1H), 4.25-3.55 (m, 6H), 2.44-2.34 (m, 1H), 2.16-2.05 (m, 1/3H), 1.84-1.70 (m, 2H), 1.69-1.56 (m, 5/3H), 1.54 (s, 3H), 1.47 (s, 9H), 4.7.1 (-)-7a-epi -Hyacinthacine A1 Hydrogen chloride 1.37 (s, 3H), 0.90 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H) ppm; 13C (7a-epi-1) NMR (100 MHz, CDCl3, rotamers) δ 154.8, 111.0, 82.0, 81.8, white solid (easy deliquescence). [α]D25 = -38.8 (c 0.50, H2O); 80.5, 79.8, 75.3, 75.0, 74.7, 64.3, 64.0, 63.5, 62.7, 62.5, 62.3, {[α]D25 -38.8 (c 0.50, H2O); lit 8h ([α]D25 +56.5 (c 0.12, H2O)}; IR 61.8, 29.8, 29.2, 28.5, 25.8, 24.8, 24.0, 18.0, -5.5, -5.6 ppm; (film): νmax 3357, 2922, 2850, 1631, 1468, 1411, 1315, 1262, HRMS (ESI) calcd for [C22H43NO6Si+Na+]: 468.2757, found: 1025, 920, 806 cm-1; 1H NMR (400 MHz, D2O) δ 4.20 (dd, J = 468.2757. 10.8, 4.0 Hz, 1H), 4.10 (d, J = 4.0 Hz, 1H), 4.02 (dd, J = 9.3, 8.4 4.6 General procedure for the synthesis of 17, 22: A solution of Hz, 1H), 3.95 (dd, J = 13.2, 3.2 Hz, 1H), 3.85 (dd, J = 13.2, 9.3 alcohol 16 or 21 (250 mg, 0.56 mmol) in dry CH2Cl2 (15 mL) Hz, 1H), 3.76-3.71 (m, 1H), 3.50-3.42 (m, 1H), 3.26-3.16 (m, was cooled to 0 oC, and then MsCl (0.13 mL, 1.68 mmol) was 1H), 2.38-2.27 (m, 1H), 2.12-2.03 (m, 1H), 1.86-1.71 (m, 1H), dropped in one portion. The mixture was treated with TEA (0.62 1.69-1.57 (m, 1H) ppm; 13C NMR (100 MHz, D2O) δ 73.1, 72.7, 69.2, 64.2, 56.9, 49.2, 28.4, 25.3 ppm; HRMS (ESI) calcd for mL, 4.48 mmol) sowly and the resulted mixture was stirred for 1 h at the same temperature. The reaction was quenched with a [C8H15NO3+H+]: 174.1130, found: 174.1130. The free amine 7a-epi-1 was produced by passing the hydrochloride salt through saturated NH4Cl solution (20 mL) and extracted with CH2Cl2 (25 mL × 3). The combined organic layers were washed with brine a Dowex 50WX8 ion-exchange resin. Elution with 6 % ammonia afforded free base 7a-epi-1 as a pale yellow syrup. {[α]D25 -45.3 for two times, dried and concentrated to give crude product without further purification. The above crude product and (c 0.36, H2O); lit8h ([α]D25 +47 (c 0.65, H2O)}. 2,6-lutidine (0.32 mL, 2.69 mmol) were dissolved in CH2Cl2 (15 4.7.2 (-)-Hyacinthacine A1 Hydrogen chloride (1) mL) and cooled to -78 oC. The reaction was treated with TESOTf (0.58 mL, 2.58 mmol) and the mixture was allowed to warm to white solid (easy deliquescence). [α]D25 = -7.7 (c 0.50, H2O); IR room temperature and stirred for 24 h. The mixture was diluted (film): νmax 3332, 1634, 1417, 1344, 1185, 1131, 1033, 957, 920, with water and extracted with CH2Cl2 (30 mL × 3) and the 584 cm-1; 1H NMR (400 MHz, D2O) δ 4.24-4.15 (m, 3H), 3.96 combined organic layers were washed with brine. Dried and (dd, J = 13.2, 3.0 Hz, 1H), 3.81 (dd, J = 13.2, 5.1 Hz, 1H), concentrated, the residue was purified by flash chromatography 3.55-3.47 (m, 1H), 3.40 (ddd, J = 8.0, 5.1, 3.0 Hz, 1H), 3.19-3.11 on silica gel (MeOH/CH2Cl2=50/1) to give 17, 22. (m, 1H), 2.26-2.07 (m, 2H), 2.03-1.91 (m, 2H); ppm; 13C NMR (100 MHz, D2O) δ 71.8, 69.8, 69.2, 68.5, 56.8, 55.4, 26.0, 23.4 4.6.1 ppm; HRMS (ESI) calcd for [C8H15NO3+H+]: 174.1130, found: (3aS,4S,8aR,8bR)-4-((tert-Butyldimethylsilyloxy)methyl)-2,2-d 174.1135. The free amine 1 was produced by passing the imethyl-hexahydro-3aH-[1,3]dioxolo[4,5-a]pyrrolizine (17) hydrochloride salt through a Dowex 50WX8 ion-exchange resin. 17 (138 mg, 75%) as a colorless oil. [α]D25 = -10.9 (c 0.88, Elution with 6 % ammonia afforded free base 1 as a colorless thick syrup. {[α] D25 -36.4 (c 0.30, H2O); lit 4 ([α] D25 +38.2 (c CHCl3); IR (film): νmax 3479, 2931, 2859, 2714, 1464, 1385, -1 1 1223, 1159, 1078, 1029, 838, 781, 638 cm ; H NMR (400 MHz, 0.23, H2O)}. CDCl3) δ 4.77-4.73 (m, 1H), 4.43 (dd, J = 5.6, 2.8 Hz, 1H), 4.04 Acknowledgments (dd, J = 12.0, 1.2 Hz, 1H), 3.86 (dd, J = 12.0, 4.8 Hz, 1H), 3.62-3.52 (m, 1H), 3.30-3.20 (m, 1H), 3.13-3.03 (m, 1H), We thank the National Natural Science Foundation of China 2.33-2.23 (m, 1H), 2.03-1.93 (m, 2H), 1.80-1.69 (m, 1H), 1.53 (s, (21272041, 21072034, 20832005), and Key Laboratory of 13 3H), 1.31 (s, 3H), 0.89 (s, 9H), 0.08 (s, 6H) ppm; C NMR (100 Synthetic Chemistry of Natural Substances, SIOC of Chinese MHz, CDCl3) δ 114.1, 83.9, 80.5, 71.3, 67.7, 59.6, 49.2, 28.8, Academy of Sciences for financial support. The authors thank Dr. 27.5, 26.2, 25.8, 25.4, 18.2, -5.6, -5.7 ppm; HRMS (ESI) calcd Han-Qing Dong (Arvinas Inc) for helpful suggestions and also for [C17H33NO3Si+H+]: 328.2308, found: 328.2306. thank Shuai Zheng for studying on the reduction of compounds 18 as well as 19 in one pot. 4.6.2 (3aS,4S,8aS,8bR)-4-((tert-Butyldimethylsilyloxy)methyl)-2,2-d imethyl-hexahydro-3aH-[1,3]dioxolo[4,5-a]pyrrolizine (22) 22 (136 mg, 74%) as a colorless oil. [α]D25 = -2.6 (c 0.26, CHCl3); IR (film): νmax 3342, 2928, 2856, 1380, 1260, 1208, 1099, 1043,
References and notes 1.
(a) Casiraghi, G.; Zanardi, F.; Rassu, G. and Pinna, L. Org. Prep. Proced. Int. 1996, 28, 641; (b) Stütz, A. E. (Ed.), Iminosugars as Glycosidase Inhibitors, Wiley-VCH, Weinheim,
6
16. (a) Fleming, I. Molecular orbitals and organic chemical ACCEPTED MANUSCRIPT reactions. New York: Wiley, 2010; (b) Bürgi, H. B.; Dunitz, J. D.;
5.
6. 7.
10. 11.
12. 13.
14.
15.
AC C
9.
EP
TE D
8.
RI PT
4.
SC
3.
Lehn, J. M.; Wipff, G. Tetrahedron 1974, 30, 1563. 17. Lodge, E. P. and Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353. 18. Kellehera, F. and Kelly, S. Tetrahedron Lett. 2006, 47, 3005. 19. (a) Yamazaki, N. and Kibayashi, C. J. Am. Chem. Soc. 1989, 111, 1396; (b) Ikota, N. Tetrahedron Lett. 1992, 33, 2553; (c) Yoda, H.; Oguchi, T.; Takabe, K. Tetrahedron: Asymmetry 1996, 7, 2113.
M AN U
2.
Germany, 1999; (c) Asano, N.; Nash, R. J.; Molyneux, R. J. and Fleet, G. W. J. Tetrahedron: Asymmetry, 2000, 11, 1645; (d) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J. and Nash, R. J. Phytochemistry, 2001, 56, 265; (e) Jung, K.-H. and Schmidt, R. R. Carbohydrate-Based Drug Discovery, Wong, C.-H., Ed.; John Wiley and Sons, New York, 2003, pp. 609; (f) Asano, N. Cell. Mol. Life Sci. 2009, 66, 1479; (f) Nash, R. J.; Kato, A.; Yu, C.-Y.; Fleet, G. W. J. Future Med. Chem. 2011, 3, 1513. (a) Molyneux, R. J.; Benson, M.; Wong, R. Y.; Tropea, J. E. and Elbein, A. D. J. Nat. Prod. 1988, 51, 1198; (b) Kato, A.; Kano, E.; Adachi, I.; Molyneux, R. J.; Watson, A. A.; Nash, R. J.; Fleet, G.W. J.; Wormald, M. R.; Kizu, H.; Ikeda, K. and Asano, N. Tetrahedron: Asymmetry, 2003, 14, 325. (a) Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.; Derome, A. E.; Hamor, T. A.; Scofield, A. M. and Watkin, D. J. Tetrahedron Lett. 1988, 29, 2487; (b) Scoffield, A. M.; Rossiter, J. T.; William, P.; Kite, G. C.; Nash, R. J.; Fellows, L. E. Phytochemistry 1990, 29, 107; (c) Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.; Girdhar, A.; Ramsden, N. G.; Peach, J. M.; Hegarty, M. P. and Scofield, A. M. Phytochemistry 1990, 29, 111. Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato, A.; Adachi, I.; Watson, A. A.; Nash, R. J. and Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1. (a) Horii, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N. and Matsui, K. J. Med. Chem. 1986, 29, 1038; (b) Fischer, P. B.; Collin, M.; Karlsson, G. B.; James, W.; Butters, T. D.; Davis, S. J.; Gordon, S.; Dwek, R. A. and Platt, F. M. J. Virol. 1995, 69, 5791. Royzen, M.; Taylor, M. T.; DeAngelis, A. and Fox, J. M. Chem. Sci. 2011, 2, 2162. (a) Kato, A.; Adachi, I.; Miyauchi, M.; Ikeda, K.; Komae, T.; Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J.; Wormald, M. R.; Fleet, G. W. J. and Asano, N. Carbohydr. Res. 1999, 316, 95; (b) Asano, N.; Ikeda, K.; Kasahara, M.; Arai, Y. and Kizu, H. J. Nat. Prod. 2004, 67, 846; (c) Yamashita, T.; Yasuda, K.; Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J. and Asano, N. J. Nat. Prod. 2002, 65, 1875; (d) Kato, A.; Kato, N.; Adachi, I.; Hollinshead, J.; Fleet, G. W. J.; Kuriyama, C.; Ikeda, K.; Asano, N. and Nash, R. J. J. Nat. Prod. 2007, 70, 993. For a racemic synthesis, see: (a) Donohoe, T. J.; Sintim, H. O.; Hollinshead, J. J. Org. Chem. 2005, 70, 7297; (b) Donohoe, T. J. and Thomas, R. E. Chem. Rec. 2007, 7, 180. For an asymmetric synthesis, see: (c) Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett. 2005, 7, 2587; (d) Izquierdo, I.; Plaza, M. T.; Tamayo, J. A. and Sánchez-Cantalejo, F. Eur. J. Org. Chem. 2007, 6078; (e) Chandrasekhar, S.; Parida, B. B.; Rambabu, C. J. Org. Chem. 2008, 73, 7826; (f) Reddy, P. V.; Veyron, A.; Koos, P.; Bayle, A.; Greene, A. E.; Delair, P. Org. Biomol. Chem. 2008, 6, 1170; (g) Donohoe, T. J.; Thomas, R. E.; Cheeseman, M. D.; Rigby, C. L.; Bhalay, G.; Linney, I. D. Org. Lett. 2008, 10, 3615; (h) Izquierdo, I.; Plaza, M. T.; Tamayo, J. A.; Franco, F.; Sánchez-Cantalejo, F. Tetrahedron 2010, 66, 3788; (i) D’Adamio, G.; Goti, A.; Parmeggiani, C.; Moreno-Clavijo, E.; Robina, I. and Cardona, F. Eur. J. Org. Chem. 2011, 7155. Wang, X.-L.; Huang, W.-F.; Lei, X.-S.; Wei, B.-G.; Lin, G.-Q. Tetrahedron 2011, 67, 4919. Huang, W.-F.; Li, Q.-R.; Chao, L.-M.; Lei, X.-S.; Wei, B.-G. Tetrahedron Lett. 2010, 51, 4317. (a) Liu, R.-C.; Wei, J.-H.; Wei, B.-G.; Lin, G.-Q. Tetrahedron: Asymmetry 2008, 19, 2731; (b) Liu, R.-C.; Huang, W.; Ma, J.-Y.; Wei, B.-G.; Lin, G.-Q. Tetrahedron Lett. 2009, 50, 4046. (c) Feng, T.; Si, C.-M; Liu, R.-C.; Fan, X.; Wei, B.-G. Chin. J. Org. Chem. 2013, 33, 1291. Zhou, Q.-R.; Wei, X.-Y.; Li, Y.-Q.; Huang, D. and Wei, B.-G. Tetrahedron 2014, 70, 4799. (a) Ma, J.-Y.; Xu, L.-F.; Huang, W.-F.; Wei, B.-G.; Lin, G.-Q. Synlett 2009, 1307; (b) Ma, J.-Y.; Huang, W.; Wei, B.-G. Tetrahedron Lett. 2011, 52, 4598; (c) Huang, W.; Ren, R.-G.; Dong, H.-Q.; Wei, B.-G.; Lin, G.-Q. J. Org. Chem. 2013, 78, 10747.. (a) Batey, R. A.; MacKay, D. B. and Santhakumar, V. J. Am. Chem. Soc. 1999, 121, 5075; (b) Morgan, I. R.; Yazici, A.; Pyne, S. G. Tetrahedron 2008, 64, 1409. Sengoku, T.; Satoh, Y.; Oshima, M.; Takahashi, M.; Yoda, H. Tetrahedron 2008, 64, 8052.
ACCEPTED MANUSCRIPT
RI PT
Supporting Information
SC
Flexible Approach for the Asymmetric Synthesis of (-)-Hyacinthacine A1 and its 7a-epimer
M AN U
Chang-Mei Sia,b, Zhuo-Ya Maoa,b, Rong-Guo Ren a, Zhen-Ting Dua,* and Bang-Guo Weib,*
a. College of Science, Northwest A&F University, Yangling, Shaanxi Province, 712100, China E-mail: [email protected]
b. Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China Fax: (+86)-21-5423-7757
Contents
EP
TE D
E-mail: [email protected]
AC C
Copies of 1H NMR and 13C NMR Spectrum…………………………………………….......S2~S11
S1
AC C EP
S2
M AN U
TE D
SC
RI PT
ACCEPTED MANUSCRIPT
AC C EP
S3
M AN U
TE D
SC
RI PT
ACCEPTED MANUSCRIPT
S4
M AN U
TE D
EP
AC C
SC
RI PT
ACCEPTED MANUSCRIPT
AC C EP
S5
M AN U
TE D SC
RI PT
ACCEPTED MANUSCRIPT
AC C EP
S6
M AN U
TE D
SC
RI PT
ACCEPTED MANUSCRIPT
AC C EP
S7
M AN U
TE D
SC
RI PT
ACCEPTED MANUSCRIPT
AC C EP TE D
S8
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C EP
S9
RI PT
SC
M AN U
TE D
ACCEPTED MANUSCRIPT
AC C EP
S10
M AN U
TE D
SC
RI PT
ACCEPTED MANUSCRIPT
AC C EP
S11
M AN U
TE D SC
RI PT
ACCEPTED MANUSCRIPT
S0040-4020(14)01250-2
DOI:
10.1016/j.tet.2014.08.056
Reference:
TET 25957
To appear in:
Tetrahedron
Received Date: 26 June 2014 Revised Date:
14 August 2014
Accepted Date: 22 August 2014
Please cite this article as: Si C-M, Mao Z-Y, Ren R-G, Du Z-T, Wei B-G, Flexible Approach for the Asymmetric Synthesis of (-)-Hyacinthacine A1 and its 7a-epimer, Tetrahedron (2014), doi: 10.1016/ j.tet.2014.08.056. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
Flexible Approach for the Asymmetric Synthesis of (-)-Hyacinthacine A1 and its 7a-epimer
RI PT
Leave this area blank for abstract info.
Chang-Mei Sia,b, Zhuo-Ya Maoa,b, Rong-Guo Ren a, Zhen-Ting Dua,*and Bang-Guo Weib,* a. College of Science, Northwest A&F University, Yangling, Shaanxi Province 712100, China, b. Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China
O
O
N Boc 7
H
O
N Boc
OTBS
EP AC C
H
OH
OH (-)-7a-epi-1
TE D
10
NaBH4 CeCl3 OTBS
OH
7a N
O
AllylMgCl
M AN U
N OTBS Boc 9 AllylB(OR)2
O
O
SC
O
O
O
7a N
N Boc 8
OTBS
OH OH OH
1 (-)- hyacinthacine A1
1
ACCEPTED MANUSCRIPT
Tetrahedron journal homepage: www.elsevier.com
RI PT
Flexible Approach for the Asymmetric Synthesis of (-)-Hyacinthacine A1 and its 7a-epimer Chang-Mei Sia,b, Zhuo-Ya Maoa,b, Rong-Guo Renb, Zhen-Ting Dua,∗ and Bang-Guo Weib,∗
SC
a. College of Science, Northwest A&F University, Yangling, Shaanxi Province, 712100, China b. Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China
ABSTRACT
Article history: Received Received in revised form Accepted Available online
The diastereoselective nucleophilic addition of organic boronic ester to 3-hydroxy-2-substituted N-acyliminium ions 9 led to the formation of 2,5-cis- pyrrolidine 10, from which a convenient synthesis of (-)-7a-epi-1 was developed. In addition, an efficient asymmetric synthesis of (-)-hyacinthacine A1 1 was achieved through the reduction/ring-opening process.
M AN U
ARTICLE INFO
1. Introduction
TE D
Keywords: Lactam Nucleophilic Addition Asymmetric synthesis Alkaloid Hyacinthacine
AC C
EP
Iminosugars (azasugars or iminocyclitols), the analogues of monosaccharides with nitrogen replacing the oxygen in the ring, are considered as mimics of sugars.1 Most of these polyhydroxylated pyrrolizidine alkaloids (Figure 1) and their structural motif proved to be a rich source of glycosidase or glycosyltransferase inhibitors. For example, australine 2 (IC50 = 5.8 µM),2 alexine 3 (IC50 = 11 µM)3 and hyacinthacine A2 4a (IC50 = 8.6 µM),4 are not only selective inhibitors of amyloglucosidase, but also demonstrate potential application as antiviral, anticancer, antidiabetic and antiobesity drugs.5 However, these iminosugars do not exhibit significant inhibition of β-glucosidases.6 Among them, 3-(hydroxymethyl) pyrrolizidines, which were isolated from bluebells (Hyacinthoides nonscripta),7a grape hyacinths (Muscari armeniacum)4 and from the bulbs of Scilla peruviana,7b Scilla sibirica,7cand Scilla socialis,7d are of particular interest. For example, (+)-hyacinthacine A1 1, isolated in 2000 from the bulbs of Muscari armeniacum (Hyacinthaceae) in less than 0.0005% yield,4 displays good inhibitory activity against β-galactosidase from rat intestinal lactase (IC50 = 4.4 µM) and is also a moderate inhibitor of both α-l-fucosidase from rat epididymis (IC50 = 46 µM) and amyloglucosidase from Aspergillus niger (IC50 = 25 µM). Due to the diverse biological activities in particular specific glycosidase inhibition, and the intriguing structure of (+)-hyacinthacine A1 1 and their analogous, considerable efforts ∗ Corresponding authors. (+86)-21-5423-7757 (B.-G.; W.); e-mail addresses: [email protected] (Z.-T.; D); [email protected] (W.B.-G.).
2009 Elsevier Ltd. All rights reserved.
have been contributed to their synthesis and enantioselective synthetic methods have been reported.8 H 7a
N
OH 1 3
HO
H
OH
OH
N
OH OH
N OH
1 hyacinthacine A1 H
H
OH
N OH
HO
several
2 australine HO
OH
H
OH
R
OH hyacinthacines A2, A3 4a A2 (R= H) 4b A3 (R= Me)
OH
N X
Y
3 alexine
OH
HO OH
HO
OH
hyacinthacine B3, B7
H N
OH OH
OH 6 (-)-uniflorine A
5a B3 (X= Me, Y=H) 5b B7 (X= H, Y=Me)
Figure 1. The structures of several natural products
The generation of four chiral centers in the pyrrolizidine skeleton is the most challenging part for the asymmetric synthesis of (+)-hyacinthacines. As a continuation of our interest in pursuing chiral building blocks and utilizing them in the synthesis of iminosugars,9 ceramides,10 piperidine11 and
2
pyrrolidine12 alkaloids, as well as divergent synthesis of MANUSCRIPT ACCEPTED O depsipeptides,13 we decided to develop an approach for the O O divergent synthesis of iminosugars using chiral lactam 7, which ref. 9,10 + AllylB 7 was readily available from D-glutamic acid. Herein, we present R O N this concise and flexible approach for the synthesis of OTBS Boc (-)-hyacinthacine A1 1 and its epimer 7a-epi-1.
7a
B
O
O
O
O
AllylMgCl N
OH
A
OH 1 (-)- hyacinthacine A1
N Boc
NaBH4 O CeCl3 OTBS
N Boc 7
8
11 R = OAc;12 R = OH 15 13 R = OMe;14 R = SO2Ph Lewis acid BF3·Et2O BF3·Et2O BF3·Et2O ZnCl2 BF3·Et2O TMSOTf TiCl4 ZnCl2 MgBr2
OTBS
N
1 3
O
O
OH
OH (-)-7a-epi-1
N Boc 10
O
O AllylB(OR)2
TE D
7a
OH
OTBS
N Boc
OTBS
EP
AC C
N,O-acetals 11-14 were prepared from lactam 7, a derivative from D-glutamic acid in 73% overall yield.9,10a Initially, the treatment of N,O-acetal 11 with allylboronic acid under Pyne’s reaction conditions did not give any desired product 10. But when the corresponding boronate, 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 15, was used, compound 10 could be afforded in 36% yield with high diastereoselectivity (Table 1 entry 1). In order to improve the yield of 10, various leaving groups of N,O-acetal were used, the yields did not get any better (Table 1 entries 2-4). Fortunately, the aminal 12 (R = OH) turned out to be an excellent substrate for this allylation, and the yield of 10 could reach 61% when the reaction was conducted at -40 °C (Table 1 entry 5). Although several Lewis acids were screened, the results proved to be fruitless (Table 1 entries 6-9). Table 1. The asymmetric alkylation of N,O-acetal 11-14.
Y %[b] 36 27 22 <5 61 43 17 19 23
dr[c] >99:1 >99:1 >99:1 ->99:1 >99:1 >99:1 >99:1 >99:1
The stereochemistry of 10 was assigned as 2,5-cis form, which can be rationalized by the Bürgi–Dunitz angle (BD angle). 16 The nucleophilic reagent attacked more stable conformation in the transition state A (Scheme 1) along the 107o by the C=N bond.17 Due to the influential steric effect of the acetal group, the attack towards downside should be more favorable than that of upside. Thus, nucleophilic addition to the transition state would produce the same facial to CH2OTBS group eventually, that’s a 2,5-cis chiral stereochemistry of 10.
R
O
N Boc OTBS 11-14
O
O
N Boc OTBS
LA
10
9
Figure 2. Two different asymmetric allylations
2. Results and discussion
R OH OAc OMe SO2Ph OH OH OH OH OH
[a] Reactions were performed with 11, 12, 13 or 14 (0.93 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.27 mL, 1.39 mmol) in CH2Cl2 (20 mL) at -78 oC to -40 oC overnight, [b] Isolated yield. [c] dr was determined by 1H NMR or HPLC.
O
H
T oC -78 -78 ~ -40 -78 ~ -40 -78 ~ -40 -78 ~ -40 -78 ~ -40 -78 ~ -40 -78 ~ -40 -78 ~ -40
RI PT
Entry[a] 1 2 3 4 5 6 7 8 9
SC
OH
H
N Boc OTBS 10
M AN U
The nucleophilic addition of allylic boronic ester to N-acyliminium ions for the formation of cis 5-sbstituted-4-hydroxypyrrolidine-2-one or 6-substituted-5-hydroxypiperidin-2-ones was first reported by Batey in 1999.14a On the basis of this pioneered work, Pyne achieved an asymmetric method through diastereoselective borono-Mannich reaction of boronic acids and potassium trifluoroborate to cyclic N-acyliminium ions.14b Encouraged by these results, we envisioned that the 2,5-cis allylation could be realized through diastereoselectively nucleophilic addition of N-acyliminium ions 9 with allyl borate or its corresponding ester, and the corresponding product could provide the right stereochemistry for C 7a in (-)-7a-epi-hyacinthacine A1. While the 2,5-trans allylation could be achieved by the nucleophlic addition of lactam 7 using Grignard reagents and subsequent diastereoselective reduction sequence.15 Both strategies are outlined retrosynthetically in Figure 2.
O
O
Lewis Acid
Nu disfavored attack
O
O
C favored attack Nu
H
N
OTBS CO2t-Bu
A
Scheme 1.The proposed mechanism of nucleophilic addition
To further confirm the stereochemistry of C3 position, we decided to synthesize the (-)-7a-epi-hyacinthacine A1. Hydroboration of 10 with BH3.SMe2 in tetrahydrofuran at room temperature, followed by oxidative hydrolysis with H2O2, gave primary alcohol 16 in 74% overall yield (Scheme 2)18. Mesylation of compound 16 with methanesulfonyl chloride in the presence of triethylamine and subsequent treatment with TESOTf/2,6-lutidine could generate the cyclized product 17 in one-pot fashion in 75% overall yield. Finally, deprotection of compound 17 with MeOH/(COCl)2 at room temperature for overnight gave the HCl salt of (-)-7a-epi-hyacinthacine A1 {[α]D25 -38.8 (c 0.50, H2O); lit 8i ([α]D25 +56.5 (c 0.12, H2O)} in quantitative yield. The NMR spectroscopic data of synthetic 7a-epi-1 was identical to the data of isolated
3
Scheme 2, Reagents and conditions: (a). BH3·THF, THF, 0 oC, overnight, then aq. NaOH, H2O2, 2 h, 74%; (b). MsCl, Et3N, CH2Cl2, 0 oC, 1 h; TESOTf, 2,6-lutidine, CH2Cl2, -78 oC~rt, 24h, 75%; (c). (COCl)2, CH3OH, overnight, 100%.
H
b
TE D
EP
O
O a
O
AC C
O
O
O
OTBS
NHBoc
N Boc OTBS 7
18
b
O
O
OTBS c NHBoc
20
HO
b
20 OH
+
O
O
O
O + N Boc OTBS 8
N Boc OTBS 19 b 20 O
O
N Boc OTBS 10
N
22
21
O
O
M AN U
Next we investigated the asymmetric synthesis of (-)-hyacinthacine A1 1 through nucleophilic addition of lactam 7 by allylmagnesium chloride and subsequent stereoselective reduction sequence.15 Thus, lactam 7 was treated with a solution of allylmagnesium chloride in dichloromethane at -78 oC, and the ring-opened product, i.e ketone 18, was generated in 10% yield, together with the inseparable additive product 19 in 87% combined yield (Scheme 3). Initially, we tried the reduction of the mixture 18 and 19 with sodium borohydride (NaBH4) in MeOH15, which afforded the alcohol 20 in low stereoselectivity18. To improve the stereoselectivity of compound 20, compounds 18 and 19 were treated with NaBH4 in the presence of CeCl3 separately. Unfortunately, both substrates gave very poor diastereoselectivity. Although EtOH was a good solvent for the reduction of similar structure 18 and 19, when 19 was treated with NaBH4 in EtOH, alcohol 20 was afforded still with moderate stereoselectivity (dr >75:25) in 94% combined yields. Compared the reaction condition to known method15, the only difference is the equivalent of sodium borohydride from 250 reduced to 10 times. We suspected that more rigid ring protecting group of dihydroxyl caused low stereoselectivity. Finally, treatment of mixtures of 20 with methanesulfonyl chloride and subsequent with t-BuOK smoothly generated the desired 8 in 66% yield and the minor isomer 10 in 21% yield, which was easily separated by column chromatography on silica gel.
SC
RI PT
Scheme 3, reagents and conditions: (a).Allylmagnesium chloride, CH2Cl2, (-)-7a-epi-hyacinthacine A18i. The free base of MANUSCRIPT ACCEPTED -78 oC, 1.5 h, 10% for 18, 87% for 19; (b). NaBH4, CeCl3, EtOH, 0 oC~rt, 4 h, (-)-7a-epi-hyacinthacine A1 was obtained, through Dowex 94%; (c). MsCl, Et3N, CH2Cl2, 0 oC, 0.5 h, t-BuOK, THF, 0 oC, 5 h, 66% for 25 50WX8 ion-exchange resin, as a pale yellow syrup {[α]D -45.3 8, 21% for 10. (c 0.36, H2O); lit8h ([α]D25 +47 (c 0.65, H2O)}. This further With the compound 8 in hand, the asymmetric synthesis of confirmed the stereochemistry outcome in the nucleophilic (-)-hyacinthacine A1 1 was quite straightforward as shown in addition of boronic ester 15 to N-acyliminium ions 9. Scheme 4. Following the synthetic sequence described above, the hydrogen chloride salt of (-)-hyacinthacine A1 1 {[α]D25 O O -7.7 (c 0.5, H2O)} was successfully prepared in 59% yield in 4 steps. The pure salt of (-)-hyacinthacine A1 1 was passed a b HO 10 OTBS through Dowex 50WX8 ion-exchange resin to give the free base 1 {[α]D25 -36.4 (c 0.30, H2O); lit 4 ([α] D25 +38.2 (c 0.23, N H2O)} which is colorless thick syrup. The spectral data of the Boc synthetic 1 were identical to the reported data.4 OH 16 H H O c OH O O O N N a HCl OTBS 8 HO OH OTBS N 7a-epi-1. HCl 17 Boc
OTBS
c
(-)-hyacinthacine A1 HCl 1. HCl
Scheme 4, Reagents and conditions: (a). BH3· THF, THF, 0 oC, overnight, NaOH, H2O2, 2 h, 79%; (b). MsCl, Et 3N, CH2Cl2, 0 oC, 1 h; TESOTf, 2,6-lutidine, CH2Cl2, -78 oC~rt, 24 h, 74%; (c). (COCl)2, CH3 OH, overnight, 100%.
3. Conclusions
In summary, an efficient method for the preparation of 2,5-cis-form 10 by a diastereoselective nucleophilic addition of boronic ester 15 to N-acyliminium ion 9 has been developed. Using this method, (-)-7a-epi-1 was synthesized. In addition, (-)-hyacinthacine A1 1 has also been synthesized by reduction/ring-opening process as the key steps. Further application of this strategy in the diversity-oriented synthesis of analogous is now in progress in our laboratory. 4. Experimental Section General: THF was distilled from sodium/benzophenone. Reactions were monitored by thin layer chromatography (TLC) on glass plates coated with silica gel with fluorescent indicator. Flash chromatography was performed on silica gel (300–400 mesh) with Petroleum/EtOAc as eluent. Optical rotations were measured on a polarimeter with a sodium lamp. HRMS were measured on a LCMS-IT-TOF apparatus. IR spectra were recorded using film on a Fourier Transform Infrared Spectrometer. NMR spectra were recorded at 400 MHz MHz, and chemical shifts are reported in δ (ppm) referenced to an internal TMS standard for 1H NMR and CDCl3 (77.0 ppm) for 13C NMR. 4.1 (3aR,4R,6S,6aS)-tert-Butyl 4-allyl-6-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-tet rahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (10) A solution of 12 (374 mg, 0.93 mmol) and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.27 mL, 1.39 mmol) in CH2Cl2 (20 mL) was cooled to -78 oC and stirred for 10 min. Then a solution of BF3.OEt2 (0.18 mL, 1.38 mmol) was
4
AC C
EP
TE D
M AN U
SC
RI PT
dropped slowly and the reaction mixture was stirred at -78 oC to MANUSCRIPT 2.62-2.54 (m, 1H), 2.28-2.18 (m, 1H), 1.46 (s, 9H), 1.41 (s, 3H), ACCEPTED o -40 C for overnight. The mixture was quenched with a saturated 1.34 (s, 3H), 0.92 (s, 9H), 0.09-0.07 (m, 6H) ppm; 13C NMR (100 NaHCO3 solution (10 mL) and warmed to room temperature. The MHz, CDCl3) δ 156.0, 134.8, 117.6, 107.9, 80.2, 80.1, 75.7, 68.0, organic phase was separated and the aqueous layer was extracted 62.9, 51.0, 38.4, 28.3, 27.9, 25.9, 25.6, 18.4, -5.4, -5.5 ppm; with CH2Cl2 for three times. The combined organic layers were HRMS (ESI) calcd for [C22H43NO6Si+Na+]: 468.2757, found: washed with brine, dried and concentrated. The residue was 468.2756. purified by flash chromatography on silica gel to give 10 (242 4.4 (3aR,4S,6S,6aS)-tert-Butyl mg) in 61% yield as a colorless oil. [α]D25 = +38.2 (c 0.48, 4-allyl-6-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-tet CHCl3); IR (film): νmax 2956, 2931, 2858, 1697, 1472, 1393, rahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (8) 1255, 1213, 1176, 1116, 1066, 972, 916, 837, 778, 739 cm-1; 1H NMR (400 MHz, CDCl3, rotamers) δ 5.86-5.72 (m, 1H), A solution of 20 (500 mg, 1.12 mmol) and TEA (1.3 mL, 8.97 5.13-5.05 (m, 2H), 4.70-4.63 (m, 1H), 4.43-4.36 (m, 1H), mmol) in dry CH2Cl2 (20 mL) was cooled to 0 oC, then a solution 4.10-3.55 (m, 4H), 2.65-2.40 (m, 1H), 2.25-2.05 (m, 1H), 1.44 (s, of MsCl (0.26 mg, 3.36 mmol) was slowly dropped. After being 12H), 1.29 (s, 3H), 0.88 (s, 9H), 0.05 (s, 6H) ppm; 13C NMR stirred for 0.5 h, the reaction was quenched with a saturated (100 MHz, CDCl3, rotamers) δ 154.1, 134.6, 134.4, 117.4, 111.5, NH4Cl solution and extracted with CH2Cl2 (30 mL × 3). The 83.8, 83.1, 82.0, 81.2, 79.7, 65.9, 64.4, 64.2, 63.3, 62.7, 38.0, combined organic layers were washed with brine, dried and 37.4, 28.4, 27.3, 26.0, 25.4, 18.4, -5.3, -5.5 ppm; HRMS (ESI) concentrated to give crude middle compound. The above crude calcd for [C22H41NO5Si+Na+]: 450.2652, found: 450.2651. compound was dissolved in dry THF (12 mL) and cooled to 0 oC. t-BuOK (252 mg, 2.24 mmol) was added in one portion and the 4.2 (3aS,6S,6aS)-tert-Butyl mixture was stirred for 5 h. The reaction mixture was quenched 4-allyl-6-((tert-butyldimethylsilyloxy)methyl)-4-hydroxy-2,2-d with a saturated NH4Cl solution and extracted with EtOAc (30 imethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate mL × 3). The combined organic layers were washed with brine, (19) dried and concentrated. The residue was purified by flash A solution of 7 (915 mg, 2.28 mmol) in dry DCM (20 mL) was chromatography on silica gel (PE/EA=30/1) to give 8 (317mg, treated with a solution of allylmagnesium chloride (3.35 mL, 66%) and 10 (101mg, 21%). The major 8 is colorless oil. [α]D25 = o 5.70 mmol, 1.7M in THF) at -78 C. Then the reaction was stirred +93.2 (c 0.88, CHCl3); IR (film): νmax 2976, 2952, 2930, 2858, for 1.5 h. The mixture was quenched with a solution of saturated 1692, 1478, 1399, 1371, 1331, 1277, 1216, 1177, 1108, 1065, NH4Cl and extracted with CH2Cl2 (30 mL × 3). The combined 974, 939, 908, 880, 861, 841, 779 cm-1; 1H NMR (400 MHz, organic layers were washed with brine, dried and concentrated. CDCl3, rotamers) δ 5.98-5.86 (m, 1H), 5.21-5.07 (m, 1H), 5.06-5.01 (m, 1H), 4.75-4.70 (m, 1H), 4.69-4.63 (m, 1H), The residue was purified by flash chromatography on silica gel (PE/EA=20/1) to give 18 (110 mg, 10 %), and 19 (951 mg, 87 %). 4.25-3.75 (m, 3H), 3.70-3.55 (m, 1H), 3.28-3.15 (m, 1/2H), The major 19 is colorless oil. [α]D25 = +71.7 (c 0.68, CHCl3); IR 2.90-2.75 (m, 1/2H), 2.50-2.32 (m, 1H), 1.54 (s, 3H), 1.48 (s, 9H), 1.37 (s, 3H), 0.89 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H) ppm; 13C (film): νmax 3369, 2955, 2931, 2857, 1715, 1629, 1500, 1472, -1 1 1368, 1253, 1166, 1104, 1052, 971, 837, 778 cm ; H NMR (400 NMR (100 MHz, CDCl3, rotamers) δ 154.5, 136.1, 135.8, 116.4, MHz, CDCl3) δ 5.89-5.75 (m, 1H), 5.14-5.07 (m, 2H), 4.57 (d, J 116.3, 111.1, 110.9, 81.7, 80.3, 79.9, 79.5, 64.6, 64.2, 63.5, 62.9, = 6.0 Hz, 1H), 4.41 (d, J = 6.0 Hz, 1H), 4.37-4.18 (m, 1H), 62.6, 61.9, 34.7, 33.0, 28.5, 25.8, 24.8, 18.1, -5.5, -5.6 ppm; 4.09-3.98 (m, 1H), 3.85-3.71 (m, 1H), 3.66 (dd, J = 10.2, 3.0 Hz, HRMS (ESI) calcd for [C22H41NO5Si+Na+]: 450.2652, found: 1H), 3.25-3.15 (m, 1H), 2.47 (dd, J = 13.8, 8.6 Hz, 1H), 1.56 (s, 450.2649. 3H), 1.49 (s, 9H), 1.36 (s, 3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 4.5 General procedure for the synthesis of 16, 21: A solution of 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 153.8, 133.6, 118.4, olefins 8 or 10 (350 mg, 0.82 mmol) in dry THF (5 mL) was 112.3, 80.7, 63.1, 28.5, 26.0, 18.4 -5.3, -5.4 ppm; HRMS (ESI) treated with a solution of BH3.SMe2 (2.46 mL, 2.46 mmol) at 0 calcd for [C22H41NO6Si+H+]: 466.2601 found: 466.2602. o C. After being stirred for overnight at 0 oC to room temperature, 4.3 tert-Butyl the reaction mixture was cooled to 0 oC and treated with a 30 % H2O2 solution (5 mL). Then a 3M NaOH solution (5 mL) was (S)-2-(tert-butyldimethylsilyloxy)-1-((4S,5S)-5-(1-hydroxybut3-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylcarbamate (20) slowly dropped and the mixture was stirred for 2 h at 0 oC to room temperature. The resulting mixture was diluted with water A solution of 19 (710 mg, 1.60 mmol) and CeCl3 (474 mg, 1.92 and extracted with EtOAc (20 mL × 3), and the combined o mmol) in dry EtOH (20 mL) was cooled to 0 C, then NaBH4 organic layers were washed with brine for two times. Dried and (606 mg, 16.02 mmol) was added in several portion. After being concentrated, the residue was purified by flash chromatography o stirred for 4 h at 0 C, the mixture was concentrated and the on silica gel (PE/EA=4/1) to give 16, 21. residue was diluted with water. The resulting mixture was extracted with EtOAc (30 mL × 3) and the combined organic 4.5.1 (3aS,4S,6R,6aR)-tert-Butyl 4-((tert-butyldimethylsilyloxy)methyl)-6-(3-hydroxypropyl)-2, layers were washed with brine. Dried, filtered and concentrated, the residue was purified by flash chromatography on silica gel 2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxyla (PE/EA=10/1) to give 20 (670 mg, 94%). The minor could not te (16) isolate by flash chromatography on silica gel. The mixture of 20 16 (270 mg, 74%) as a colorless oil. [α]D25 = +12.4 (c 1.29, was a white solid. The major compound: IR (film): νmax 3283, CHCl3); IR (film): νmax 3445, 2931, 2858, 1694, 1472, 1462, 2982, 2929, 2856, 1673, 1539, 1370, 1309, 1252, 1221, 1171, 1397, 1367, 1333, 1255, 1213, 1174, 1117, 1062, 837, 779, 738 -1 1114, 1089, 1064, 1040, 1028, 985, 868, 839, 810, 773, 669 cm ; cm-1; 1H NMR (400 MHz, CDCl3, rotamers) δ 4.72 (dd, J = 5.6, 1 H NMR (400 MHz, CDCl3, rotamers) δ 6.00-5.88 (m, 1H), 1.2 Hz, 1H), 4.40 (dd, J = 5.6, 1.2 Hz, 1H), 4.13-3.80 (m, 2H), 5.21-5.19 (m, 1/2H), 5.17-5.14 (m, 1H), 5.13-5.11 (m, 1/2H), 3.76-3.55 (m, 4H), 2.25-2.15 (m, 1/2H), 1.87-1.78 (m, 1/2H), 4.15 (dd, J = 9.6, 5.2 Hz, 1H), 3.99 (dd, J = 8.8, 5.2 Hz, 1H), 1.75-1.58 (m, 3H), 1.57-1.52 (m, 1/2H), 1.48 (s, 12H), 1.42-1.36 3.94-3.83 (m, 3H), 3.70 (dd, J = 9.6, 2.8 Hz, 1H), 2.95 (brs, 1H),
5
AC C
EP
TE D
M AN U
SC
RI PT
838, 803, 778 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.66-4.26 (m, (m, 1/2H), 1.34 (s, 3H), 0.92 (s, 9H), 0.09 (s,ACCEPTED 3H), 0.08 (s, 3H) MANUSCRIPT 13 ppm; C NMR (100 MHz, CDCl3, rotamers) δ 154.5, 111.6, 84.7, 1H), 4.53-4.49 (m, 1H), 3.65-3.53 (m, 2H), 3.49 (dd, J = 10.0, 6.0 Hz, 1H), 3.15-3.07 (m, 1H), 3.06-2.95 (m, 2H), 2.12-2.02 (m, 84.3, 82.2, 81.4, 79.9, 79.8, 65.9, 64.6, 64.1, 63.2, 62.9, 62.5, 1H), 1.94-1.74 (m, 3H), 1.45 (s, 3H), 1.27 (s, 3H), 0.86 (s, 9H), 62.2, 30.0, 29.4, 28.8, 28.5, 27.4, 26.0, 25.5, 18.4, -5.3, -5.4 ppm; 0.02 (s, 6H); ppm; 13C NMR (100 MHz, CDCl3) δ 111.6, 85.9, HRMS (ESI) calcd for [C22H43NO6Si+Na+]: 468.2757, found: 468.2752. 82.8, 70.0, 67.1, 65.6, 55.0, 26.8, 26.0, 25.9, 24.5, 24.0, 18.2, -5.4, -5.5 ppm; HRMS (ESI) calcd for [C17H33NO3Si+H+]: 328.2308 4.5.2 (3aS,4S,6S,6aR)-tert-Butyl found: 328.2305. 4-((tert-butyldimethylsilyloxy)methyl)-6-(3-hydroxypropyl)-2, 4.7 General procedure for the synthesis of 1, 7a-epi-1: A solution 2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxyla of compound 17 or 22 (100 mg, 0.31 mmol) in dry MeOH (8 mL) te (21) was treated with a (COCl)2 (0.11 mL, 1.09 mmol). After being 25 21 (288 mg, 79%) as a colorless oil. [α]D = +89.4 (c 0.48, stirred overnight, the reaction mixture was concentrated to give CHCl3); IR (film): νmax 3455, 2930, 2858, 1689, 1472, 1379, crude salt. The crude salt was refluxed in EtOAc for 3h and 1251, 1210, 1174, 1107, 1060, 972, 940, 837, 778 cm-1; 1H NMR cooled to 0 oC, and then the resulting mixture was filtered to give (400 MHz, CDCl3, rotamers) δ 4.76-4.70 (m, 1H), 4.68-4.64 (m, title compound. 1H), 4.25-3.55 (m, 6H), 2.44-2.34 (m, 1H), 2.16-2.05 (m, 1/3H), 1.84-1.70 (m, 2H), 1.69-1.56 (m, 5/3H), 1.54 (s, 3H), 1.47 (s, 9H), 4.7.1 (-)-7a-epi -Hyacinthacine A1 Hydrogen chloride 1.37 (s, 3H), 0.90 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H) ppm; 13C (7a-epi-1) NMR (100 MHz, CDCl3, rotamers) δ 154.8, 111.0, 82.0, 81.8, white solid (easy deliquescence). [α]D25 = -38.8 (c 0.50, H2O); 80.5, 79.8, 75.3, 75.0, 74.7, 64.3, 64.0, 63.5, 62.7, 62.5, 62.3, {[α]D25 -38.8 (c 0.50, H2O); lit 8h ([α]D25 +56.5 (c 0.12, H2O)}; IR 61.8, 29.8, 29.2, 28.5, 25.8, 24.8, 24.0, 18.0, -5.5, -5.6 ppm; (film): νmax 3357, 2922, 2850, 1631, 1468, 1411, 1315, 1262, HRMS (ESI) calcd for [C22H43NO6Si+Na+]: 468.2757, found: 1025, 920, 806 cm-1; 1H NMR (400 MHz, D2O) δ 4.20 (dd, J = 468.2757. 10.8, 4.0 Hz, 1H), 4.10 (d, J = 4.0 Hz, 1H), 4.02 (dd, J = 9.3, 8.4 4.6 General procedure for the synthesis of 17, 22: A solution of Hz, 1H), 3.95 (dd, J = 13.2, 3.2 Hz, 1H), 3.85 (dd, J = 13.2, 9.3 alcohol 16 or 21 (250 mg, 0.56 mmol) in dry CH2Cl2 (15 mL) Hz, 1H), 3.76-3.71 (m, 1H), 3.50-3.42 (m, 1H), 3.26-3.16 (m, was cooled to 0 oC, and then MsCl (0.13 mL, 1.68 mmol) was 1H), 2.38-2.27 (m, 1H), 2.12-2.03 (m, 1H), 1.86-1.71 (m, 1H), dropped in one portion. The mixture was treated with TEA (0.62 1.69-1.57 (m, 1H) ppm; 13C NMR (100 MHz, D2O) δ 73.1, 72.7, 69.2, 64.2, 56.9, 49.2, 28.4, 25.3 ppm; HRMS (ESI) calcd for mL, 4.48 mmol) sowly and the resulted mixture was stirred for 1 h at the same temperature. The reaction was quenched with a [C8H15NO3+H+]: 174.1130, found: 174.1130. The free amine 7a-epi-1 was produced by passing the hydrochloride salt through saturated NH4Cl solution (20 mL) and extracted with CH2Cl2 (25 mL × 3). The combined organic layers were washed with brine a Dowex 50WX8 ion-exchange resin. Elution with 6 % ammonia afforded free base 7a-epi-1 as a pale yellow syrup. {[α]D25 -45.3 for two times, dried and concentrated to give crude product without further purification. The above crude product and (c 0.36, H2O); lit8h ([α]D25 +47 (c 0.65, H2O)}. 2,6-lutidine (0.32 mL, 2.69 mmol) were dissolved in CH2Cl2 (15 4.7.2 (-)-Hyacinthacine A1 Hydrogen chloride (1) mL) and cooled to -78 oC. The reaction was treated with TESOTf (0.58 mL, 2.58 mmol) and the mixture was allowed to warm to white solid (easy deliquescence). [α]D25 = -7.7 (c 0.50, H2O); IR room temperature and stirred for 24 h. The mixture was diluted (film): νmax 3332, 1634, 1417, 1344, 1185, 1131, 1033, 957, 920, with water and extracted with CH2Cl2 (30 mL × 3) and the 584 cm-1; 1H NMR (400 MHz, D2O) δ 4.24-4.15 (m, 3H), 3.96 combined organic layers were washed with brine. Dried and (dd, J = 13.2, 3.0 Hz, 1H), 3.81 (dd, J = 13.2, 5.1 Hz, 1H), concentrated, the residue was purified by flash chromatography 3.55-3.47 (m, 1H), 3.40 (ddd, J = 8.0, 5.1, 3.0 Hz, 1H), 3.19-3.11 on silica gel (MeOH/CH2Cl2=50/1) to give 17, 22. (m, 1H), 2.26-2.07 (m, 2H), 2.03-1.91 (m, 2H); ppm; 13C NMR (100 MHz, D2O) δ 71.8, 69.8, 69.2, 68.5, 56.8, 55.4, 26.0, 23.4 4.6.1 ppm; HRMS (ESI) calcd for [C8H15NO3+H+]: 174.1130, found: (3aS,4S,8aR,8bR)-4-((tert-Butyldimethylsilyloxy)methyl)-2,2-d 174.1135. The free amine 1 was produced by passing the imethyl-hexahydro-3aH-[1,3]dioxolo[4,5-a]pyrrolizine (17) hydrochloride salt through a Dowex 50WX8 ion-exchange resin. 17 (138 mg, 75%) as a colorless oil. [α]D25 = -10.9 (c 0.88, Elution with 6 % ammonia afforded free base 1 as a colorless thick syrup. {[α] D25 -36.4 (c 0.30, H2O); lit 4 ([α] D25 +38.2 (c CHCl3); IR (film): νmax 3479, 2931, 2859, 2714, 1464, 1385, -1 1 1223, 1159, 1078, 1029, 838, 781, 638 cm ; H NMR (400 MHz, 0.23, H2O)}. CDCl3) δ 4.77-4.73 (m, 1H), 4.43 (dd, J = 5.6, 2.8 Hz, 1H), 4.04 Acknowledgments (dd, J = 12.0, 1.2 Hz, 1H), 3.86 (dd, J = 12.0, 4.8 Hz, 1H), 3.62-3.52 (m, 1H), 3.30-3.20 (m, 1H), 3.13-3.03 (m, 1H), We thank the National Natural Science Foundation of China 2.33-2.23 (m, 1H), 2.03-1.93 (m, 2H), 1.80-1.69 (m, 1H), 1.53 (s, (21272041, 21072034, 20832005), and Key Laboratory of 13 3H), 1.31 (s, 3H), 0.89 (s, 9H), 0.08 (s, 6H) ppm; C NMR (100 Synthetic Chemistry of Natural Substances, SIOC of Chinese MHz, CDCl3) δ 114.1, 83.9, 80.5, 71.3, 67.7, 59.6, 49.2, 28.8, Academy of Sciences for financial support. The authors thank Dr. 27.5, 26.2, 25.8, 25.4, 18.2, -5.6, -5.7 ppm; HRMS (ESI) calcd Han-Qing Dong (Arvinas Inc) for helpful suggestions and also for [C17H33NO3Si+H+]: 328.2308, found: 328.2306. thank Shuai Zheng for studying on the reduction of compounds 18 as well as 19 in one pot. 4.6.2 (3aS,4S,8aS,8bR)-4-((tert-Butyldimethylsilyloxy)methyl)-2,2-d imethyl-hexahydro-3aH-[1,3]dioxolo[4,5-a]pyrrolizine (22) 22 (136 mg, 74%) as a colorless oil. [α]D25 = -2.6 (c 0.26, CHCl3); IR (film): νmax 3342, 2928, 2856, 1380, 1260, 1208, 1099, 1043,
References and notes 1.
(a) Casiraghi, G.; Zanardi, F.; Rassu, G. and Pinna, L. Org. Prep. Proced. Int. 1996, 28, 641; (b) Stütz, A. E. (Ed.), Iminosugars as Glycosidase Inhibitors, Wiley-VCH, Weinheim,
6
16. (a) Fleming, I. Molecular orbitals and organic chemical ACCEPTED MANUSCRIPT reactions. New York: Wiley, 2010; (b) Bürgi, H. B.; Dunitz, J. D.;
5.
6. 7.
10. 11.
12. 13.
14.
15.
AC C
9.
EP
TE D
8.
RI PT
4.
SC
3.
Lehn, J. M.; Wipff, G. Tetrahedron 1974, 30, 1563. 17. Lodge, E. P. and Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353. 18. Kellehera, F. and Kelly, S. Tetrahedron Lett. 2006, 47, 3005. 19. (a) Yamazaki, N. and Kibayashi, C. J. Am. Chem. Soc. 1989, 111, 1396; (b) Ikota, N. Tetrahedron Lett. 1992, 33, 2553; (c) Yoda, H.; Oguchi, T.; Takabe, K. Tetrahedron: Asymmetry 1996, 7, 2113.
M AN U
2.
Germany, 1999; (c) Asano, N.; Nash, R. J.; Molyneux, R. J. and Fleet, G. W. J. Tetrahedron: Asymmetry, 2000, 11, 1645; (d) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J. and Nash, R. J. Phytochemistry, 2001, 56, 265; (e) Jung, K.-H. and Schmidt, R. R. Carbohydrate-Based Drug Discovery, Wong, C.-H., Ed.; John Wiley and Sons, New York, 2003, pp. 609; (f) Asano, N. Cell. Mol. Life Sci. 2009, 66, 1479; (f) Nash, R. J.; Kato, A.; Yu, C.-Y.; Fleet, G. W. J. Future Med. Chem. 2011, 3, 1513. (a) Molyneux, R. J.; Benson, M.; Wong, R. Y.; Tropea, J. E. and Elbein, A. D. J. Nat. Prod. 1988, 51, 1198; (b) Kato, A.; Kano, E.; Adachi, I.; Molyneux, R. J.; Watson, A. A.; Nash, R. J.; Fleet, G.W. J.; Wormald, M. R.; Kizu, H.; Ikeda, K. and Asano, N. Tetrahedron: Asymmetry, 2003, 14, 325. (a) Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.; Derome, A. E.; Hamor, T. A.; Scofield, A. M. and Watkin, D. J. Tetrahedron Lett. 1988, 29, 2487; (b) Scoffield, A. M.; Rossiter, J. T.; William, P.; Kite, G. C.; Nash, R. J.; Fellows, L. E. Phytochemistry 1990, 29, 107; (c) Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.; Girdhar, A.; Ramsden, N. G.; Peach, J. M.; Hegarty, M. P. and Scofield, A. M. Phytochemistry 1990, 29, 111. Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato, A.; Adachi, I.; Watson, A. A.; Nash, R. J. and Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1. (a) Horii, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N. and Matsui, K. J. Med. Chem. 1986, 29, 1038; (b) Fischer, P. B.; Collin, M.; Karlsson, G. B.; James, W.; Butters, T. D.; Davis, S. J.; Gordon, S.; Dwek, R. A. and Platt, F. M. J. Virol. 1995, 69, 5791. Royzen, M.; Taylor, M. T.; DeAngelis, A. and Fox, J. M. Chem. Sci. 2011, 2, 2162. (a) Kato, A.; Adachi, I.; Miyauchi, M.; Ikeda, K.; Komae, T.; Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J.; Wormald, M. R.; Fleet, G. W. J. and Asano, N. Carbohydr. Res. 1999, 316, 95; (b) Asano, N.; Ikeda, K.; Kasahara, M.; Arai, Y. and Kizu, H. J. Nat. Prod. 2004, 67, 846; (c) Yamashita, T.; Yasuda, K.; Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J. and Asano, N. J. Nat. Prod. 2002, 65, 1875; (d) Kato, A.; Kato, N.; Adachi, I.; Hollinshead, J.; Fleet, G. W. J.; Kuriyama, C.; Ikeda, K.; Asano, N. and Nash, R. J. J. Nat. Prod. 2007, 70, 993. For a racemic synthesis, see: (a) Donohoe, T. J.; Sintim, H. O.; Hollinshead, J. J. Org. Chem. 2005, 70, 7297; (b) Donohoe, T. J. and Thomas, R. E. Chem. Rec. 2007, 7, 180. For an asymmetric synthesis, see: (c) Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett. 2005, 7, 2587; (d) Izquierdo, I.; Plaza, M. T.; Tamayo, J. A. and Sánchez-Cantalejo, F. Eur. J. Org. Chem. 2007, 6078; (e) Chandrasekhar, S.; Parida, B. B.; Rambabu, C. J. Org. Chem. 2008, 73, 7826; (f) Reddy, P. V.; Veyron, A.; Koos, P.; Bayle, A.; Greene, A. E.; Delair, P. Org. Biomol. Chem. 2008, 6, 1170; (g) Donohoe, T. J.; Thomas, R. E.; Cheeseman, M. D.; Rigby, C. L.; Bhalay, G.; Linney, I. D. Org. Lett. 2008, 10, 3615; (h) Izquierdo, I.; Plaza, M. T.; Tamayo, J. A.; Franco, F.; Sánchez-Cantalejo, F. Tetrahedron 2010, 66, 3788; (i) D’Adamio, G.; Goti, A.; Parmeggiani, C.; Moreno-Clavijo, E.; Robina, I. and Cardona, F. Eur. J. Org. Chem. 2011, 7155. Wang, X.-L.; Huang, W.-F.; Lei, X.-S.; Wei, B.-G.; Lin, G.-Q. Tetrahedron 2011, 67, 4919. Huang, W.-F.; Li, Q.-R.; Chao, L.-M.; Lei, X.-S.; Wei, B.-G. Tetrahedron Lett. 2010, 51, 4317. (a) Liu, R.-C.; Wei, J.-H.; Wei, B.-G.; Lin, G.-Q. Tetrahedron: Asymmetry 2008, 19, 2731; (b) Liu, R.-C.; Huang, W.; Ma, J.-Y.; Wei, B.-G.; Lin, G.-Q. Tetrahedron Lett. 2009, 50, 4046. (c) Feng, T.; Si, C.-M; Liu, R.-C.; Fan, X.; Wei, B.-G. Chin. J. Org. Chem. 2013, 33, 1291. Zhou, Q.-R.; Wei, X.-Y.; Li, Y.-Q.; Huang, D. and Wei, B.-G. Tetrahedron 2014, 70, 4799. (a) Ma, J.-Y.; Xu, L.-F.; Huang, W.-F.; Wei, B.-G.; Lin, G.-Q. Synlett 2009, 1307; (b) Ma, J.-Y.; Huang, W.; Wei, B.-G. Tetrahedron Lett. 2011, 52, 4598; (c) Huang, W.; Ren, R.-G.; Dong, H.-Q.; Wei, B.-G.; Lin, G.-Q. J. Org. Chem. 2013, 78, 10747.. (a) Batey, R. A.; MacKay, D. B. and Santhakumar, V. J. Am. Chem. Soc. 1999, 121, 5075; (b) Morgan, I. R.; Yazici, A.; Pyne, S. G. Tetrahedron 2008, 64, 1409. Sengoku, T.; Satoh, Y.; Oshima, M.; Takahashi, M.; Yoda, H. Tetrahedron 2008, 64, 8052.
ACCEPTED MANUSCRIPT
RI PT
Supporting Information
SC
Flexible Approach for the Asymmetric Synthesis of (-)-Hyacinthacine A1 and its 7a-epimer
M AN U
Chang-Mei Sia,b, Zhuo-Ya Maoa,b, Rong-Guo Ren a, Zhen-Ting Dua,* and Bang-Guo Weib,*
a. College of Science, Northwest A&F University, Yangling, Shaanxi Province, 712100, China E-mail: [email protected]
b. Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China Fax: (+86)-21-5423-7757
Contents
EP
TE D
E-mail: [email protected]
AC C
Copies of 1H NMR and 13C NMR Spectrum…………………………………………….......S2~S11
S1
AC C EP
S2
M AN U
TE D
SC
RI PT
ACCEPTED MANUSCRIPT
AC C EP
S3
M AN U
TE D
SC
RI PT
ACCEPTED MANUSCRIPT
S4
M AN U
TE D
EP
AC C
SC
RI PT
ACCEPTED MANUSCRIPT
AC C EP
S5
M AN U
TE D SC
RI PT
ACCEPTED MANUSCRIPT
AC C EP
S6
M AN U
TE D
SC
RI PT
ACCEPTED MANUSCRIPT
AC C EP
S7
M AN U
TE D
SC
RI PT
ACCEPTED MANUSCRIPT
AC C EP TE D
S8
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C EP
S9
RI PT
SC
M AN U
TE D
ACCEPTED MANUSCRIPT
AC C EP
S10
M AN U
TE D
SC
RI PT
ACCEPTED MANUSCRIPT
AC C EP
S11
M AN U
TE D SC
RI PT
ACCEPTED MANUSCRIPT