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The Synthesis of Nonactic Acid. Its Derivatives and Nonactin itself
Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 18 O 1996 Elsevier Science B.V. All rights reserved.
229
The Synthesis of Nonactic Acid. Its Derivatives and Nonactin itself Ian Fleming and Sunil K. Ghosh 1.
INTRODUCTION The actin antibiotics, of which several are represented by the structures 1-9, occur in various
Streptomyces species (1,2). The structures were elucidated as 32-menibered macrocyclic tetraesters. Nonactin itself was isolated in 1955 by Prelog and his co-workers (1) as the first member of the family, and is its lowest homologue and most symmetrical member. All members of the actin family exhibit antimicrobial and antifungal activity, which increase with increasing size of R, and insecticidal activity against mites (3).
0=^
H
\ „^2
H I
^••H
H"/ 0
L /^ W"H
HMV
Y XT
=0
H„ H
1 2 3 4 5 6 7 8 9
nonactin monactin dinactin trinactin tetranactin macrotetralide G macrotetralidc D macrotetralide C macrotetralide B
R' Me Me Me Me Et Et Et Et Et
R3
R2
R3
Me Me Et Et Et Me Me Me Pr*
Me Me Me El Et FV Et Pi^
Et
R^ Me Et Et Et Et Me Pr' Pr* Pr'
It was the first naturally occurring crown ether, and the earliest for which the antibiotic activity could be traced to its ionophoric properties (4). The actins give one-to-one complexes with many alkali and alkaline earth metal ions, with nonactin showing selectivity in the order NH4+ > K+ = Rb+ > Cs+ > Na+ > Ba2+ (5). The first X-ray crystal structure of an ionophore-metal complex was obtained from the nonactin-potassium thiocyanate complex (6). The potassium is bound by coordination to all four tetrahydrofuran oxygens and to the four ester carbonyl oxygens, which creates overall a "tennis ball seam" conformation to the carbon framework as it wraps around the metal. Nonactin is composed of two subunits of the (-i-)-nonactic acid 10 and two subunits of the (-)nonactic acid 12, joined together by lactone linkages in an alternating sequence to give overall the
230 meso configuration (S4 symmetry) (7). The name nonacnn came from its having no optical acrivity, a puzzling feature until the meso structure was deduced. A satisfactory synthesis requires separately each of the enantiomeric nonactic acids, followed by coupling in an alternating sequence, and ring closure. A number of syntheses of nonactic acid and its esters, both racemic and enantiomerically enriched, have been developed over the past twenty years, and four syntheses of the natural product itself. The literature up to 1980 has been thoroughly reviewed (8). OH
.A^oWcOzR H 10 R=H 11 R=Me
(4-)-nonactic acid methyl (+)-nonactate
12 R=H 13 R=Me
H=
(-)-nonactic acid methyl (-)-nonactate
yKA^\^^0,^ H^H_
14 15
2.
R=H R=Me
(+)-8-epinonactic acid methyl (+)-8-epinonactate
16 R=H 17 R=Me
(-)-8-epinonactic acid methyl (-)-8-epinonactale
THE SYNTHESIS OF NONACTIC ACID AND ITS DERIVATIVES The major challenge in the synthesis of nonactic acid is the control of the relative
stereochemistry between the four stereogenic centres, which have 1,2- and
1,3-acyclic
stereochemical relationships (C-2 to C-3 and C-6 to C-8, respectively) and a 1,4-cyclic relationship (C-3 to C-6) on the tetrahydrofuran ring. These challenges have made nonactic acid a favourite target of synthetic chemists intent upon proving the capacity of a method of stereocontrol they have developed. There is much overlap from route to route, as people have often used their new method to set up only one or two of the stereochemical relationships, and have then been content to complete the synthesis using established routes. We distinguish seven common themes among the approaches used for the synthesis of nonactic acid, and have classified them by the methods, numbered 1-7 in Scheme 1, used for the construction of the a.s-2,5-disubstituted tetrahydrofuran derivative 18 (9). These are: 1. Hydrogenation of a 2,5-disubstituted furan. 2. Hydrogenation of the Bartlett type intermediate. 3. Cyclisation of a 1,4-diol derivative. 4. Electrophilic cyclisation of an unsaturated alcohol or enol. 5. Intramolecular conjugate addition of an alkoxide with R^ electron-withdrawing. 6. From a bicyclic intermediate. 7. Ireland-Claisen rearrangement. The first two approaches, 1 and 2, are based on 5)'«-stereospecific catalytic hydrogenation to control the stereochemistry around the tetrahydrofuran ring. The approach 1 has the disadvantage
231 that it only controls the cis stereochemistry of C-3 and C-6. The approach 2, which shows control from C-6 to the newly developing centre at C-3, as well as being syn stereospecific in creating the centres C-2 and C-3, is popular, and has been applied especially by those research groups who were principally demonstrating a method of 1,3 control for the relationship between C-6 and C-8. Approach 3 is challenging, since it requires a method for controlling the 1,4 relationship between C3 and C-6 in an open chain. Approaches 4 and 5 have not proved easy for setting up C-3 and C-6 with the cis arrangement, in contrast to the approach 6, which is effective for this part of the problem, but has difficulties with the control of C-2 and C-8. The approach 7 has only been used once, with C-2, C-3 and C-6 well controlled by the stereospecificity of the Ireland-Claisen rearrangement, but lacks control at C-8.
^•J3
^'^XK^'
RUCX'^' ftO
RL ^
>k .R^
H
H HO OH
18
= OH
Scheme 1 2.1 Hydrogenation of Substituted Furan Derivatives Although one of the earliest approaches to the synthesis of nonactic acid involved catalytic hydrogenation of an appropriately 2,5-disubstituted furan, the hydrogenation of furan derivatives is limited by the formidable problem of controlling the well separated acyclic stereocentres at C-2 and C-8. The first synthesis of racemic nonactic acid diastereoisomers was carried out by Beck and Henseleit (10) in 1971 (Scheme 2). Methylation of 2-methoxycarbonylmethylfuran 19 gave a mixture of the a-methyl derivative 20 (43%) and the a,a'-dimethyl derivative, which were separated by chromatography. Friedel-Crafts alkylation of 20 with 3-methyl-3-butene-2-one gave the ketofuran 2 1 , which on hydrogenation over rhodium on alumina gave a mixture of the diastereoisomeric d5-2,5-disubstituted tetrahydrofurans 22. Baeyer-Villiger oxidation of the ketone 22 with trifluoroperoxyacetic acid regioselectively gave the ester 23, and hydrolysis followed by esterification gave a mixture of diastereoisomeric nonactic acid methyl esters 24 in 70% yield. The
232 stereochemical control of C-3 and C-6 during hydrogenation was good, but no stereochemical control was observed for C-2 and C-8.
a.
l.NaH.THF
C02Me
C02Me
2. Mel
•
19
20 43%
^
r \ 0
^
I
6
BF3.0Et2
20
^
r \
11 ^
^
60%
CF3CO3H, Na2HP04 73%
H2,Rh/Ai203 ^
89%
^
^r-\
J
C02Me
H^ H
21
22 l.KOH 2. HsO-"
9^^ H ^ H T
COiMe
3.CH2N2 70%
23
Scheme 2 Gerlach and Wetter (11) achieved rather better levels of control, also using catalytic hydrogenation for the relative stereochemistry between C-3 and C-6 (Scheme 3). 2-Furylacetone 25 was prepared by a Darzens glycidic ester synthesis from furfural, and was functionalised at the 5position using Eschenmoser's 2-chloro-N-cyclohexyl-propionaldonitrone 26 in the presence of
l.NaOMe,
^N^SS/
MeCHClC02Et
ci
«.;J0
^ 26
OHC
o
3.H2SO4
27
25
43% HCl, H2O
o
AgBF4
CHO
l.Cr03,H2S04 2. CH2N2 27% (from 25)
NaOMe,MeOH NaBH4
9
F~^
C02Me
O
H2,Rh
29
30:31 = 1:4
OH
/—V
OH C02Me ^
CO2MC
98% 32
32:8-epi-32 = 7:10
8-epi-32
Scheme 3 silver tetrafluoroborate (12). The nitrone 27 was hydrolysed to give the aldehyde 28, which was oxidised with chromic acid and esterified to give the ketoester 29 in poor yield. Hydrogenation of
233 the furan ring in 29 over rhodium produced a mixture, diastereoisomeric at C-2, of tetrahydrofurans 30 and 31, which were separated by chromatography. Base-catalysed epimerisation at C-2 favoured (80:20) the natural threo relationship between C-2 and C-3, and the unwanted isomer 30, on equilibration with a catalytic amount of sodium methoxide, could be converted into its diastereoisomer 31. The reduction of the ketone 31 with sodium borohydride took place with poor selectivity, unfavourable to the natural product (7:10), but the methyl nonactate 32 and methyl 8epinonactate could be separated chromatographically. Schmidt and co-workers (13) also synthesised nonactic acid by hydrogenation of a 2,5disubstituted furan derivative (Scheme 4), which they initially carried out in the racemic series. The reaction of 2-lithiofuran with propylene oxide gave the alcohol, which was converted to the acetate 33. The introduction of the three carbon carboxylic acid unit was achieved by Vilsmeier formylation and a Wittig reaction on the aldehyde 34, followed by carbonylation of the alkene 35, catalysed by a complex of |i-dichloro-bis(7i-hexa-l,5-diene)dirhodium(I) with triphenylphosphine. Oxidation of the resulting aldehyde 36 with silver(I) oxide, followed by esterification gave the ester 37. As with the earlier syntheses, they observed poor control for C-2 and C-8 during hydrogenation of 37 over rhodium on alumina, which produced methyl nonactate as a mixture of diastereoisomers 38, 39, 40 and 41 in a ratio of 25:25:25:25. They examined the possibility of equilibrating these diastereo-
Ph3P=CH2 L'
O
2.AC20
O
oocw.
33
Rha)cat.
g,^^
O
57%
34
9^^
/x,^^^4N^^C02Me u ^ u =
CHO
f-^
CHO
l.Ag20
C02Me
+
H2, Rh/Al203
39
OH
I—V
9"
f-\
• ^ ^ ^ ^
^
X^^C02MQ
^ ' ' ^ V ^ p . ^ v ^ CO2MC
Cr(VI) H2,Ni
^
42
O
I—V
C02Me
H^ H I
H^ H = 43
41
39 -I- 40 + 41
l.TsCl 2. KOAc
-• 3. KOH, MeOH
8-epi-39 + 8-epi-40 + 8-epi-41
4. CH2N2
separate
C02Me 44
Scheme 4 isomers, first by oxidising the 8-hydroxy group to the 8-keto, and regenerating the 8-hydroxy group by catalytic hydrogenation, which gave the mixture of 3 8 , 3 9 , 40 and 41 now in a ratio of
234 19.1:10.8:30.5:39.6. Secondly they found that a Walden inversion sequence could be used to change the relative configuration at C-8. Still in the racemic series, they found that the 8-tosylates gave the C-8 diastereoisomeric acetates on Walden inversion, and hydrolysis gave the diastereoisomers 38,39, 40 and 41 in a ratio of 36.9:32.7:9.6:20.8. The ratio of 8-normal to 8-epi i.e. 38+39 : 40+41 was about 7:3. The racemic methyl nonactate 38 could be separated from the other diastereoisomers by chromatography. Methyl 2-epinonactate 39 could be equilibrated with sodium methoxide to a mixture of methyl nonactate 38 and methyl 2-epinonactate 39 in a ratio of 60:40. Following this exploratory work, the Schmidt group (13) reported the first homochiral synthesis of methyl (-)- and (+)-nonactate using (5)-propylene oxide as the only enantiomerically pure starting material (Scheme 4). This gave the mixture of diastereoisomeric methyl nonactates 38, 39,40 and 41, all with the (5)-configuration at C-8, and chromatographic separation provided 25% of the natural (-) ester 38. The mixture of the other three diastereoisomers (39+40+41) was converted by Walden inversion into a mixture of the same three compounds with C-8 inverted, from which (+)-methyl (25',35,67?,8/?)-nonactate 44 could be isolated in approximately the same amount as its enantiomer 38. White and his co-workers (14) used a Friedel-Crafts acylation of l-(2-furyl)-2-propanol 45, prepared using the same chemistry as Schmidt's (13a), gave the 2,5-disubstituted furan 46 (Scheme 5). Hydrogenation of the furan 46 over rhodium resulted in the c/^-fused tetrahydrofuran alcohol ?"
/"I
Ac20,BF3.0Et2
OAc
OAc
45
2. NaOH, MeOH 52%
2. CrOs, H^ 3. BF3, MeOH 89%
49
^AXV^C CO2H
l.Ph3P,Et02CN=NC02Et,PhC02H
CO2H
9"
,
^
C02Me
2.NaOMe,McOH 90%
Scheme 5 47, which was oxidised with chromic acid to the diastereoisomeric mixture of ketones 48. The last carbon was introduced by a Wittig reaction on the ketone 48 with methylenetriphenylphosphorane,
235
and the correct oxidation state was obtained by hydroboration, followed by Jones oxidation and esterification, to give the keto esters 50 and 5 1 . The hydroboration took place with high regioselectivity and moderate stereoselectivity (2:1) in favour of the unwanted diastereoisomer 51. The diastereoisomers 50 and 51 were separated, and L-Selectride reduction of the derived acid 52 gave again largely the wrong diastereoisomer, 8-epinonactic acid 54, but the configuration at C-8 could be corrected on the derived ester 55 using a Mitsunobu reaction to give methyl nonactate 56. Still's synthesis (15) (Scheme 6) is unique in having excellent stereocontrol over the larger distances, C-2 to C-8 and C-3 to C-6, but is let down by not solving the problem of relating the C-2 and C-8 pair to the C-3 and C-6 pair. Based on the conformational preference of macrocyclic intermediates (16), the stereogenic centre at C-8 provided stereocontrol for enolate methylation at C2, beautifully solving the problem that most besets the approach using the hydrogenation of a furan 1. Pb(0Ac)4, BF3 2. NaOH, McOH
r^
,
59 O
""
0
-=.
CO2H
OH
Corey-Nicolaou
,—(^ ^—1
C °/ =o^ ^i 0. 25-40% •* "O
1. base 2.Md
62
Scheme 6 to establish the relative stereochemistry of C-3 and C-6. The macrocyclic intermediates were constructed using the 2,5-disubstituted furan 59 attached to various spacer groups as in the hydroxy acid 60. Macrolactonisation using the Corey-Nicolaou thiopyridyl ester method gave the lactone 61 having a p-xylyl spacer, which, of those tried, proved to give the best results. Methylation of this lactone gave the diastereoisomer 62 with excellent selectivity (>70:1). Lithium aluminium hydride reduction followed by catalytic hydrogenation provided a 1:1 mixture of the reduced nonactic acid derivative 63 and its diastereoisomer 64. 2.2 Hydrogenation of a Bartlett Type Intermediate The Bartlett approach is based on the hydrogenation of a double bond exocyclic to a tetrahydrofuran ring, simultaneously establishing the desired stereochemical relationship between C2 and C-3, because of the syn stereospecificity of the reaction, and between C-3 and C-6, because hydrogenation takes place stereoselectively on the less hindered face, anti to the side chain on C-6.
236
This approach is very popular because all that is left to control is the 1,3-diol stereochemistry between C-6 and C-8. In 1977, Bartlett and Jemstedt (17) developed a stereocontrolled synthesis of 1,3-diols from homoallylic alcohols (Scheme 7). They found that diethyl 4-penten-2-yl phosphate 65 undergoes an intramolecular cyclisation in the presence of iodine to set up both groups in the ring 66 cis and presumably diequatorial. Arbuzov reaction then gives the cyclic phosphate 67 more than 90% diastereochemically pure. EtO OEt
EiO O
OEt
I2. MeCN, 2 5 X
87%
•V-^ r
-EU
EtO
o>"-o 67
66
65
Scheme 7 In their first and racemic synthesis of methyl nonactate 75 (Scheme 8), Bartlett and Jernstedt (18) introduced the 1,3-relationship between C-6 and C-8 in a diastereoselective manner from the diene 68, which gave the analogous cyclic phosphate. Upon treatment with sodium methoxide, the phosphate gave the epoxide 69, which was converted into the syn-l,3-d\o\ 70. Acetylation of the diol followed by ozonolysis gave the aldehyde 71. Aldol condensation of the aldehyde with the silyl
2. NaOMe, THF
1. Ac20,Py 2.03,CH2Cl2
^
^
1. MeCH=C(0Me)0SiMe3 TiCl4, CH2CI2, -78°C
OAc OAc
CHO
3. Me2S
2. CrOs, Me2C0, H2SO4
95%
90%
^
^.
OAc OAc CO2MC
71
l.K2C03,MeOH
H2, Rh/Al203
C02Me
2. (C02H)2 80%
87%
CO2MC
icis:trans = ^5:\5)
l.Et02CN=NC02Et PPh3, PhC02H, THF
^
C02Me
2. NaOMe, MeOH 95%
Scheme 8
enol ether of methyl propanoate in the presence of titanium tetrachloride at -78 °C followed by Jones oxidation of the aldol product gave the p-keto ester 72. The tetrahydrofuran ring was constructed by acetate cleavage and dehydration with oxalic acid giving methyl (E)-8-epi-2,3-dehydrononactate 73 as a single geometrical isomer. The C-2 and C-3 stereocentres of methyl nonactate were then
237 generated stereospecifically by hydrogenation of the double bond using rhodium on alumina, and at the same time the C-3 and C-6 centres were produced selectively (cisitrans = 85:15). Finally, the C-8 centre in the 8-epinonactate 74 was corrected through a Mitsunobu inversion-and-hydrolysis procedure to give methyl nonactate 75. In continuation of this work on acyclic stereocontrol, Bartlett and his co-workers developed a better method for the stereocontrol led synthesis of 1,3-diol derivatives, finding that a rerr-butyl carbonate group was better than the phosphate group in iodocyclisation (19), and applied this technique in an enantiodivergent synthesis (20) of both nonactic acids using the enantiomerically pure carbonate 84, synthesised by the route shown in Scheme 9. Starting in the chiral pool, dimethyl (5')-(-)-malate 76 was converted successively to the diol 77, the epoxide 78 and the dienol 79. Iodocyclisation of the r^rr-butyl carbonate 80 took place with good diastereoselectivity (cis:trans = 6.5:1) to give the cis cyclic carbonate 81, which was reduced with tributylstannane to give the carbonate 82. Ozonolysis gave the aldehyde 83, and the same sequence of steps as in the earlier, racemic synthesis (Scheme 8) then gave the p-keto ester 84, which was the common intermediate for both enantiomers of nonactic acid.
Me02C
OH A^COsMe
l.Tia4,CH2Cl2,-78X
_—.
,
l.TsCl,Py 2. PPTS 3. K2C(^
OEt 1. Ll ^ .PPTS 1.
O^
1^
2. MeCH=C(0Me)0SiMe3 3. C1O3, H2SO4 75%
84 Scheme 9
Methanolysis of the carbonate protecting group in 84 (Scheme 10) followed by oxalic acidcatalysed dehydration gave the (+)-enantiomer, (65,8/?)-(E)-2,3-dehydrononactate 85, hydrogenation of which gave the (-) enantiomer 86 of methyl 8-epinonactate as the major product (88%). For the synthesis of methyl (+)-nonactate 88 from the common intermediate 84, the p-keto ester group was used in a nucleophilic attack to invert the configuration at C-6, with the cyclic carbonate group acting as the leaving group. The dehydrononactate 87 thus produced was then converted mostly (88%) to methyl (+)-nonactate 88 by hydrogenation. The methyl (-)-8-
238 epinonactate 86 and methyl (+)-nonactate 88 were used for the synthesis of nonactin itself (Section 3.2). O OH
l.K2C03,MeOH
C02Me
^
C02Me 2. (C02H)2 84 O 76% 1 KH,HMPA.THF 92% C-6 inversion
85
I H2, Rh/Al203
C02Me
100%
C02Me
lH2,Rh/Al203
H^'HE 86
100%
C02Me
Scheme 10 Johnson and his co-workers developed two routes for the diol 95 corresponding to the carbonate 82 of Bartlett's synthesis. In their first approach (Scheme 11) (21), they coupled the acetal 89, derived from (/?,/?)-2,4-pentanediol and 4-pentenal, with a-trimethylsilylacetone or the trimethylsilyl enol ether of acetone in the presence of titanium tetrachloride. The reaction took place OSiMes ^/^^^
O
or
Q O ^Q
TiCl4, CH2CI2
-^
o
89% or 93% 90
A
90:91=97:3
OTBDMS
o 91
OTBDMS
iiiiiL
1. TBDMSCl, imidazole
O
9
L-Selectride OH
9
2. HPLC 92 l.Ac20,Py 2. BU4NF 3. PCC 90%
,„„l^ OAc 9 x^\.'^' 94
93 + 8-epi-93 4:l l.base 2. deacetylation
vx''^^^ + 8-epi-94
OH OH
3 chromatography 75%
95
Scheme 11 with high diastereoselectivity (90:91 = 97:3). The rerr-butyldimethylsilyl ether 92 of the major diastereoisomer was reduced with L-Selectride to give a 4:1 mixture of syn 93 and anti (8-epi-93, nonactic acid numbering) isomers, which was quantitatively converted to the corresponding acetates.
239 Desilylation with tetrabutylammonium fluoride gave a mixture of hydroxy acetates, which were oxidised with pyridinium chlorochromate to the ketoacetates 94. p-Elimination under basic conditions and deacetylation gave the mixture of diols 95 and 8-epi-95, which were separated by chromatography. In their second approach (Scheme 12), Johnson and his co-workers used the acetal 96 derived from (35)-butane-l,3-diol instead of from (/?,/?)-2,4-pentanediol (22). As in the earlier work, the Mukaiyama aldol condensation of acetal 96 with acetone trimethylsilyl ether gave a mixture of diastereoisomers 97 and 98 in a ratio of 96:4. In contrast, however, the removal of the chiral auxiliary was achieved without the need for first reducing the ketone group. Oxidation of the aldol OH
^ 97 O
l.PCC
OH
2. Bn2NH2'' CF3CO2" 82%
97:98 = 96:4
n-Bu3B, NaBH4
OH OH
78%
99
98
100 + 2-epi-100 97:3
Scheme 12 product 97 to the aldehyde allowed a selective p-elimination with dibenzylammonium trifluoroacetate. 5j^z-stereoselective reduction of the free aldol product 99 by Narasaka's method (23) using tributylborane and sodium borohydride gave a 97:3 mixture rich in the (2/?,45)-oct-7-ene2,4-diol 100, the diol intermediate in Bartlett's synthesis. Lygo and his co-workers (24) have demonstrated that ether substituents a or p to an epoxide remain unaffected during the reaction of an epoxide with p-ketoester dianions yielding e-hydroxy-pketoesters. These intermediates can be easily cyclised to the cycHc enol ethers needed for the Bartlett O- O"
OMe l.NaH,BnBr 2. MCPBA
102 OBn
l.H2.Pd/C C02Me 104
2.H2,Rh/Al203 95%
54% from 101
OBn OH 103
101 OBn
(C02H)2
CO2MC
OH I—y
OH
^ T ^ H T 105
I—^
-^^-^T^nO^-^ H
1:1
CO2MC
H
106
Scheme 13 approach. Thus the epoxy ether 101 and the p-ketoester dianion 102 gave in one pot the (9-benzylprotected dehydrononactate intermediate 104 as a mixture of diastereoisomers (Scheme 13).
240
Hydrogenolysis using palladium on charcoal, followed by stereoselective hydrogenation of the double bond using Bartlett's conditions gave a 1:1 mixture of racemic methyl nonactate 105 and methyl 8-epinonactate 106, which were separated by chromatography. Lygo (25) has also developed a strategy for the synthesis of nonactic acids and its homologues, using the same chemistry, but starting from 3-butenol 107 instead (Scheme 14). Benzylation, epoxidation and regioselective epoxide opening with the same 3-ketoester dianion 102 gave the intermediate p-ketoester 109. Oxalic acid-catalysed dehydration and cyclisation gave the Bartlett-type intermediate 110. Hydrogenolysis and stereoselective hydrogenation gave the primary alcohol 111, which has all the stereocentres properly established except for C-8, and is suitable for the synthesis both of nonactic acid and its homologues. Oxidation of the alcohol using pyridinesulfur trioxide in dimethylsulfoxide and triethylamine gave the aldehyde 112 in 86% yield. 0" O"
l.NaH.BnBr OH
^
2.MCPBA
OBn I—.
110
•
102
.C02Me
0B„
92%
107
^
57% from 108
OBn OH
,ft«
109
1^« l.H2,Pd/C 9 "
/—V
Rh/AljOa 93%(d5:fran5 = 8:l)
^^l
SO3, DMSO =
86%
(C02H)2
/—\
112
'
Scheme 14 This aldehyde had already been converted (26) to methyl nonactate and methyl 8-epinonactate with high selectivity using titanium tetrachloride catalysed addition of dimethyl zinc and lithium dimethylcuprate, respectively. Lygo also found that dialkylzinc addition under different Lewis acid conditions gave different diastereoisomers with high selectivity (Scheme 15).
0«^vxt^V^C02Me H'^HE
112
• RA.^/3Wc02Me ^ ^ H^Hi 113 Et2Zn,TiCl4 R=Et 4:1 Et2Zn, BF3.0Et2 R=Et 1:10 Me2Zn,TiCl4 R=Me 24:1 Me2CuLi R=Me 1:4.5
A,X\^C02Mc H^Hi 114 85% 80% 85%^^ 78%^^
Scheme 15 Deschenaux and Jacot-Guillarmod synthesised the Bartlett intermediate 124 with a chiral pool source and the Narasaka 1,3-diol synthesis for the C-6 to C-8 relationship (Scheme 16) (27). Methyl (-)-(3/?)-3-hydroxybutanoate 115 (e.e. >99%) was converted to the p-ketoester 116. Reduction of the p-ketoalcohol using the Prasad version of the Narasaka method (23) with diethylmethoxyborane and sodium borohydride giving the diol 117. The acetonide 118 was homologated by way of the
241 alcohol 119 and tosylate 120 to give the nitrile 121 and hence the carboxylic acid 122. The imidazolide of the acid and the magnesium salt of monomethyl malonate gave the p-ketoester 123. Acid catalysed deprotection of the acetonide and concomitant cyclisation of the diol intermediate gave OLi
nS(99%ee)
9
y^
„6
''''
9
Li^^H4
^^^'-^^^ 118
0
W
9
y
9 ? ^
96% ^ ^ " V - ^ ^ v , ^ 119
0
Amberlyst-15 OH
c T
C02Me ^^^
in
''"^
l.TsCl,Py
2.BU4NCN
3.NaOH
j—y
9
9 ^
l.CO(Im)2
^"^.-'-'^^^ 2. COiMe 120 X=OTs 93% — ( 121 X=CN 80% C02)2Mg 122 X=C02H 70% 88% H2, OH .—y
-- --^1 o ^
123
y
^^^^
Rh/Al203
124 (95% ee)
H^ H Y
95%
125
Scheme 16 Bartlett's intermediate 124, and catalytic hydrogenation over rhodium on alumina gave methyl (-)-8epinonactate 125. Kim and Lee have developed syntheses of methyl (+)-nonactate 134 and of methyl (-)-8epinonactate 135 by way of Bartlett's intermediate 133 (=82) (Scheme 17) (28). They used a MO, iy^2
X\ l.TMSCI,Et3N ^-O TBDMSCl, N-0 . x ^ W 2.TsOH // \ nw imidazole // ' ' ^*S ^ • separation O O2 4. L-Selecuide 126 63% H2,Raney-Ni, o OH Et2B0Me, NaBH4 OH OH boric acid ^ l ^ I ^ o - m n x . . THF.-78°^ , A J k . O T B D M S '• Me^CCOMeh.PPTS 86% 86% 2. BU4NF 129 130 synianti = %:4 „_^
^..-v
^y^ I I 131
^„
l.TsCl,Et3N,DMAP 2. allylMgCl. Cul 3.TsOH
132
Q
^
am)2C0 73%
o / /o
^A^ I I
133
OH y ^ \ I \ n^\\^^ and x ^ ^ x x f ^ ^ ^ f v ' ^ H ^ HE 135 Scheme 17 dipolar cycloaddition to an acrylic acid group attached to Oppolzer's chiral auxiliary 126 to set up the Bartlett routes
OH \
75% y V I \
^^^^ I I
r>c\ XK ^C02Me
first stereogenic centre (29), and Narasaka's method again for the C-6 to C-8 relationship. The syn
242
1,3-diol 130 was synthesised from the isoxazoline 127 after protection of the hydroxy! group with r^rr-butyldimethylsilyl chloride by reductive cleavage with the Raney-nickel-boric acid system and the Narasaka reduction (23) of the p-ketoalcohol intermediate 129. The 1,3-diol 130 was converted to the diol 132 by standard synthetic transformations involving protection of the diol as its acetonide, and deprotection of the 0-silyl group to give the primary alcohol 131. Tosylation, copper-catalysed tosylate displacement with allylmagnesium chloride, and deprotection gave the diol 132, which was converted to its cyclic carbonate 133 (=82) using l,r-carbonyldiimidazole. The rest of the synthesis intersects with that of Bartlett and his co-workers (20). Kim and Lee also developed another enantioselective synthesis of methyl (-)-8-epinonactate (Scheme 18) (30) based on the same nitrile oxide cycloaddition product 127 used in their earlier synthesis. The enantiomerically enriched alcohol 127 (>98%e.e.e.) was converted to its iodide l.PPh3,12. iniidazole O" 0 " 2. < A ^ o M e N-0
N-0
3.CuI
127
H^ 137
I
1. chromatography 2. L-Selectride ^ 3. chromatography 75%
i I 136 °
59%
2. PCC 75%
1. H2,Raney-Ni, ^"^^^
2.(C02H)2 77%
H^ H= 138 " (major:minor = 91:9)
QT, V I \ /k^O-K/C02Me H H= 139
Scheme 18 using triphenylphosphine, iodine and imidazole, and the iodide treated with the dianion of methyl 2methylacetoacetate to give the p-ketoester 136. Reductive cleavage of the isoxazoline ring followed by oxalic acid-catalysed cyclisation gave the ketone 137 corresponding to Bartlett's intermediate. Rhodium catalysed hydrogenation followed by PCC oxidation provided the ketone 138 where the C-2, C-3 and C-6 centres are correctly established. The last centre at C-8 was regenerated by a stereoselective reduction of the ketone 138 with L-Selectride (14), which provided the methyl (-)-8epinonactate 139. Barrett and Sheth synthesised rerr-butyl (±)-8-0-rerr-butyldimethylsilylnonactate 145 by a stereoselective hydrogenation of 8-0-t-butyldimethylsilyldehydrononactate 144, the 8-epimer and 80-protected analogue of Bartlett's intermediate, and solved the C-6 to C-8 problem in a completely different way by another hydrogenation (Scheme 19) (31). 2,3,5-0-Triacetyl-D-ribonolactone produced the achiral diene 140 on treatment with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Hydrogenation of the diene stereoselectively (>97:3) gave the lactone 141, establishing the relative stereochemistry at C-6 and C-8. Diisobutylaluminium hydride reduction of the lactone gave the lactol 142. Wittig reaction, followed by catalytic hydrogenation over rhodium on alumina gave a lactone,
243
and protection of the free hydroxy group gave its silyl ether 143. Claisen condensation and dehydration gave the dehydrononactate intermediate 144, and the usual catalytic hydrogenation over rhodium on alumina then provided the O-silyl derivative 145 of racemic ten-butyl nonactate. AcO
OAc
OAc
DBU
AcO
DIBALH
O 140 l.Ph3P=CHC02Et 2. H2, Rh/Al203 TBDMSO
jP"
-AX.
85%
X ^ Q - ^ OH 142
OTBS
—'A Pd/CaCOs
94%
3. TBDMSCl 55%
CO2BU'
_/^^''
O 141
OLi
2. Ambcrlilc 120 h 75%
143 OTBS
H2,Rh/Al203 89%
144
90%
{cis:trans - ^5:\5)
145
Scheme 19 Sutherland and his co-workers developed a concise route for the synthesis of Barrett's intermediate 148, also using hydrogenation of a cyclic intermediate to establish the C-6 and C-8 OH
1. H2,Rh/Al203 O 2. PhCOCl, Py ,x^,>^^^
NaOMe, MeOH
MCPBA
3. Cr03, H-'
93% OBz
^^
/'^-S^Q'^O
H
BzO
148 147
146
Scheme 20 relationship (Scheme 20) (32). Catalytic hydrogenation of methyl hydroquinone, benzoylation and chromic acid oxidation gave the c/5-2,4-disubstituted cyclohexanone 146. Baeyer-Villiger oxidation ^^.^ss^CHO
L-(+)-diisopropyl tariaratc
+ ClMg.
^.
149 (£:Z = 96:4) OH OH
45% conversion OAc OAc
150 RuCl3,NaI04
96% ee K2CO3, MeOH
9^' 9^' CO2H
86%
x-^v^^>^0 H 154
153
Scheme 21 of this ketone took place regioselectively to give the lactone 147, which on methanolysis gave the racemic lactone 148. Sutherland and co-workers also developed an enantioselective route (Scheme
244 21) (32), based on Sharpless asymmetric epoxidation (33), for the synthesis of Barrett's intermediate 154. This synthesis of Barrett's intermediate also involves the synthesis of the diol 151, a diastereoisomer of the diol 70 in Bartlett's nonactic acid synthesis. 3-Butenylmagnesium bromide and crotonaldehyde gave the diene alcohol 149. The diol 151 was then made in 96% e.e. by kinetic resolution using Sharpless epoxidation, followed by reduction of the epoxide with red-Al. The diacetate 152 obtained from the diol was oxidised with ruthenium trichloride-sodium periodate (34) to give the acid 153, which was converted to Barrett's lactone 154, but now in homochiral form. Batmangherlich and Davidson developed an enantiodivergent route to both enantiomers of tenbutyl nonactate by way of the lactone 156, with C-6 obtained from the a-C of glutamic acid 155 (Scheme 22) (35). The hydroxylactone 156 was protected as its rerr-butyldimethylsilyl ether, which steps
silyl protection
HO2C—< CO2H NH2 155
I. hydrogenation ——1 ^ 2. desilylation 60% from 156
OLi 156
TBDMSO. 157
OBu'
,,^ / \ ^^ ^ , l.Swem HO^^^^COjBu^ ^ H H I 2.Ph3P=CHMe (-)-158 (95% one isomer) 50%
l.NBS.DMS0,H20
OH V"
2. Bu3onH 60%
/—V H^
CO2BU'
OH
,
V"
H H = 160
/ \ ^^ ^ , k^^.^C02Bu'
/"A H^H i 161
H
H =
159
160:161 = 1:4
Scheme 22 condensed with the lithium enolate of r^rr-butyl propionate to give the dehydro intermediate 157. Hydrogenation gave the tetrahydrofuran 158 with the correct stereochemistry required for C-2, C-3 and C-6. The chiral centre at C-8 was introduced in the wrong sense by a stereocontrolled bromohydrin formation on a c/^-olefm 159, controlled by the alkoxy group at C-6, and the bromine removed reductively. This gave a 1:4 mixture of r^rr-butyl (-)-nonactate 160 and rerr-butyl (-)-8epinonactate 161. OLi J hydrogcnauon
TsO.
(+)-158 90% one isomer
165 Scheme 23
For the synthesis of the (+)-enantiomer 165, the configuration at C-6 in the common intermediate 156 was inverted (Scheme 23). The p-toluenesulfonate 162 of the lactone 156 was
245 treated with the lithium enolate of tert-butyl propionate to give, by way of the epoxide 163, the (E)alcohol 164, duly inverting the stereochemistry at C-6. Hydrogenation of the dehydro derivative 164 then gave the alcohol (+)-158 with the desired stereochemistry at C-2 and C-3 as well. The centre at C-8 was then set up in the same way as before. Batmangherlich
and Davidson
(35) also resolved racemic methyl nonactate by
chromatographically separating its esters 167 and 168 with (5)-0-acetylmandelic acid (36).
Ph
Ph OAc
C02Me
OAq
^X'^'^vxt^O'W H ^H
167
C02Me
i
168
Honda and his co-workers synthesised methyl (+)-nonactate 179, setting up the C-6 to C-8 relationship by a chelation controlled allylsilane reaction on the aldehyde 169, and the C-3 centre by hydrogenation of the dehydro intermediate 176 carrying two methoxycarbonyl groups (37) (Scheme 24). The thiolactone 175 and dimethyl diazomalonate gave the dehydro intermediate 176 in the presence of dirhodium tetraacetate, by way of a sulfur-ylid rearrangement developed by these
OBn
SiMe3
1
TiCU
OBn OTHP
83%
OBn uan
l.HCl,H20
OBn OTHP
»-
3. Swem 4.NaC102, ^,,^^ KH2PO4, T 75%
2. DHP, PPTS 169
l.B2H6,THF 2.H202,NaOH
I—I
171 R=CH20H 172 R=CHO 173 R=C02H OBn
N2=C(C02Me)2, Rh2(OAc)4
2. Lawesson's reagent 83%
1. H2, Pd/C, 7 atm.
174 X=0 175 X=S C02Me
»
2. HCl, H2O, MeOH
177
C02Me
l.TBDMSCl, imidazole 2. KOBu\ Mel 100%
1. BU4NF 2. NaCl, DMSO, H2O
TBDMSO
OH
CO2MC ' C02Me
/-^ C02Me
C02Me H^H 1:1
i
180
Scheme 24 workers (38) and by Takano and his co-workers (39). The dehydro intermediate 176 was hydrogenated using different conditions (10% Pd-C, MeOH-5% HCl) from Bartlett's, and obtained a 4:1 mixture of cis and trans tetrahydrofurans 177. Protection of the hydroxyl group with ten-
246 butyldimethylsilyl chloride followed by methylation of the protected diester gave the ester 178. The stereochemical control for the C-8, C-6 and C-3 centres was good, but no control at C-2 was observed during Krapcho decarboxylation of the malonate derivative 178, which gave a 1:1 mixture of methyl (+)-nonactate 179 and its diastereoisomer at C-2 180.
2.3 Cyclisation of a 1,4-Diol Derivative. This approach requires both a method for setting up the C-3 and C-6 oxygen functions with the correct relative stereochemistry to give the c/5-2,5-disubstituted tetrahydrofuran ring, and their differenriation in order to use the selective displacement of one of them with inversion of configuration. Only two groups have used this approach. Takatori's group prepared both C-3 and C6 diastereoisomers, and made the overall synthesis convergent by separating them, and converting the wrong isomer into the right one with a Mitsunobu sequence. The Fleming group used two silicon-based approaches. In one, the C-3 and C-6 centres were set up with independent absolute control as C-Si bonds, which were later converted to C-0 bonds, and in the other they were set up by moving the chiral information along the chain. Takatori and his co-workers (40) started from the y-dithio-p-hydroxy ester 181 as a homochiral building block derived by yeast reduction of a ketone supplying C-3 ready resolved (Scheme 25). The ester 181 was methylated with stereocontrol at C-2 by the method of Frater (41), and the product converted by way of the C-1-reduced and protected intermediate 182 into the lithium OH l.LDA,THF TBDMSO ^ S ^ J k ^ C O ^ E t 2.McI,THF,HMPA ^S^^XlJ 3.LiAlH4 X^S
181
V^CHO BOMO i«^ bUMU 184 HMPA 73%
^^fpP'BOMO 82%
r
4:TBDMSC1
H" H = 187 "
OTBDMS
^ 182
TBDMSO OTBDMS I I . . o , ^X^ J l.separauon& recycle , OH ,«c 3. TsCl, DMAP, EtsN ^^MO
^
TBDMSO
^ ^ 8 2
49^^
, BOMO
OTBDMS l.Mel.CaCOs 2. PhgP, CBr4
l.ClO3,H2S04, OH^^Me^CO ^H 3.H2,Pd/C 43%
^
^^^
H^ H E 188 "
95%
TBDMSO I
OH
OTBDMS i
^ H^ H= 189
Scheme 25 acetylide 183 by way of the vinyldibromide. This acetylide was added to the known homochiral aldehyde 184 to give the alcohol 185 as a 1:1 mixture of diastereoisomers, but separation, and recycling of the undesired diastereoisomer by a Mitsunobu inversion-hydrolysis sequence (not illustrated, but taking place in 61% conversion yield), overcame the lack of selectivity. Catalytic hydrogenation provided the differentially protected 1,3,6,8-tetraol, which was tosylated to give the C-6 tosylated derivative 186. Deprotection of the C-1 and C-3 hydroxy groups gave the cis-
247
tetrahydrofuran derivative 187, the cyclisation taking place with complete inversion of configuration at C-6. Oxidation of the primary alcohol group gave a carboxylic acid, which was esterified with diazomethane and subjected to hydrogenolysis to give methyl (-)-nonactate 188, and hydrolysis gave (-)-nonactic acid 189. Fleming and his co-workers developed two independent methods for the synthesis of methyl nonactate by ring closure of 1,4-diol derivatives. The stereochemical control needed for the synthesis of the appropriately substituted 1,4-diol derivatives was based on their work on acyclic stereocontrol using organosilicon compounds, and their routes are unique, and in consequence uniquely long, in eschewing cyclic control almost completely. The three aspects of their method of stereocontrol are: the transposition of chiral information from C-1 to C-3 in the electrophilic substitution of allylsilanes (42), the setting up of stereogenic centres with a 1,3 relationship using the hydroboration of allylsilanes (43), and the setting up of stereogenic centres with a 1,2 relationship by alkylation of enolates having a p-silyl group (44). The hydroboration and enolate alkylations leave the phenyldimethylsilyl group in the molecule, and it is converted, with retention of configuration, into a hydroxy group at an appropriate stage (45). Perhaps the most striking feature of these methods of stereocontrol is the sense in which the word "control" really means control: with each method, it is possible to obtain relative stereochemistry in either sense, making the methods equally suitable for the synthesis of any diastereoisomer. In the first route (Scheme 26) (46), the 1,4 diol system was set up by independently introducing silyl groups with absolute stereochemical control, that at C-6 by a stereospecific allylsilane synthesis from a homochiral allylic alcohol derivative, and that at C-3 by conjugate addition of a silylcuprate to an a,p-unsaturated carboxylic acid attached to a chiral auxiliary. Formation of the c/5-2,5-disubstituted tetrahydrofuran was achieved by converting the phenyldimethylsilyl groups into hydroxy groups, and differentiating between them in order to ensure that inversion of configuration took place at the desired centre. The C-2 and C-3 relationship was estabUshed by anti-scltciiwt methylation of a p-silyl enolate, and the C-6 to C-8-relationship was set up by hydroboration-oxidation of a trans allylsilane. The (5)-propargylic alcohol 191 (70% e.e.) was prepared from the ketone 190 using (S)alpineborane following Brown's and Midland's procedures. The alcohol 191 was converted to its carbamate, semihydrogenation of the triple bond of which gave the c/5-alkene 192. Stereospecific silylcupration (47) then gave the (£')-allylsilane 193. Hydroboration with thexylborane followed by alkaline hydrogen peroxide oxidation gave the anti alcohol 194 with high selectivity {antr.syn =95:5). For the synthesis of the (-i-)-enantiomer, this alcohol was subjected to a Mitsunobu inversion to give the syn diastereoisomer, which was protected as its benzyl ether 195. The aldehyde group in 195 was unmasked, and a Wittig-Homer reaction using the phosphonate 196 carrying Koga's chiral auxiliary gave the a,p unsaturated imide 197. Silylcupration on this imide gave an inseparable mixture of diastereoisomeric bis-silyl derivatives 198 with poor selectivity (2:1) in favour of the isomer illustrated. Stereoselective methylation on the p-silyl ester gave the ester 199, conversion of the silyl groups to hydroxy using mercuric acetate and peracetic acid then gave the 1,4-diol derivative, which was hydrolysed to the acid 200. The only problem left to solve was to differentiate
248
the two hydroxy groups, which was achieved by treatment with an excess of benzenesulfonyl chloride. Two things happened: protection of the C-3 hydroxy group as the p-lactone 201 and benzenesulfonylation of the C-6 hydroxy group. The p-lactoneringopened in acidic methanol and ring closure promptly took place, with inversion of configuration at C-6 to give a mixture of 0OH
1. L i - s 2.BuLi,THF O ^
3.AC2O 61%
1. PhNCCEtsN
190
OCONHPh
^.
2.H2,Pd/CaC03 PbO, MnCl2 91% OH
5-alpine borane, THF
SiMe2Ph
9
) ^O
192
ij
h. 70% ee
l.BuUTHF 2.CuI,Ph3P
SiMe2Ph
2. H2O2, NaOH 82%
3. PhMe2SiLi 73%
1.4-02NC6H4C02H,Ph3P, Et02cN=NC02Et 2. NaOH, MeOH
1. thexylborane
OBn SiMe2Ph
l.TsOH,Me2CO,H20 Ph3C0-.,,
3.BnOC(CCl3)=NH,TfOH
rs
•(EiO)20P'^^^ 0 0 86% 196 Ph3C0—., l.McOMgBr 2. LiHMDS
194 Ph3C0—. OBn SiMe2Ph
^-
3. McI, DMPU 73%
197 OBn SiMe2Ph
PhS02Cl, Py C02H'
PhMe2Si
64%
199 OBn 0S02Ph
OH y — y
l.TsOH,MeOH O
2.H2,Pd/C 83%
C02Me
C02Me H 202
HE 203
Scheme 26 benzyl methyl (-i-)-nonactate together with other diastereoisomers. Removal of the benzyl protection by hydrogenolysis gave methyl (+)-nonactate 202, which was separated from the other isomers with the major byproduct being its C-2 and C-3 diastereoisomer 203. Two successive reactions independently setting up stereogenic centres has an arithmetical advantage, at some expense in overall yield, with respect to the enantiomeric purity of the major product, as Horeau (48) and Eliel (49) have pointed out. Although the selectivity in the steps leading to 191 and 198 are only 85:15 and 67:33, respectively, the methyl (+)-nonactate 202 and its enantiomer were obtained at the end of the sequence in a ratio of 92:8. This is because the proportion of the major enantiomer 202 is obtained by multiplying 0.85 by 0.67, whereas the proportion of the minor enantiomer is obtained by multiplying 0.15 by 0.33. The enantiomeric purity of the
249 intermediate alcohol 191 could be raised to >97% e.e. by three recrystallisations of its 3,5dinitrobenzoate 204, which would make the whole synthesis capable of delivering methyl nonactate of >99% enantiomeric purity (50).
3,5-(02N)2C6H3COCl T'^v
Et3N,DMAP
^ ^
98%
In the second route (51), Fleming and Ghosh developed an enantiodivergent approach in order to synthesise both enantiomers. Two silyl groups were set up on adjacent centres, destined to become C-3 and C-4, with a known 1,2-relationship between them. The silyl group on C-4 was then made part of an allylsilane 212 so that the stereochemical information could be moved three atoms along the chain by epoxidation, leaving a 1,4 relationship between the remaining silyl group at C-3 and the incoming oxygen atom at C-6 in the alcohol 215. The C-6 to C-8 relationship could then be controlled in either sense by reduction of a p-hydroxyketone using Evans's and Narasaka's methods, and the C-2 to C-3 relationship could be set up reliably by enolate methylation. By a suitable choice of reactions, the common intermediate 215 was converted into both (+)- and (-)-nonactic acid derivatives. The synthesis of the first homochiral intermediate 209 is shown in Scheme 27. The dimethyl meso 3,4-bistolyldimethylsilyladipate 205 was prepared by a samarium(II) iodide induced coupling ^ O ^ ^ SiMe2Tol l.LiOH,MeOH„THF SiMe2ToI Sml2, THF, DMPU ,C02Me '^5^C02Me " i r n r T T T — ^ Me02C' 2.DCC CH2(C02Me)2 SiMe2Tol ToIMe2Si SiMc2Tol 72% 205 206
'U
5'^^^™ ,.Mc3Si(CH,),0H, CO2H ix:c, DMAP •
HO2C ^ r ^^
84% from 205
207
o
2. H2, Pd/C %:4
TolMe2Si CO2H
Me-iSi' O
SiMe2Tol 209
Scheme 27 of the methyl (Z)-2-tolyldimethylsilylacrylate in THF-DMPU in the presence of dimethyl malonate (52). The homochiral mono 2-trimethylsilylethyl ester 209 of the dicarboxylic acid was prepared from the dimethyl ester 205 in four steps. Lithium hydroxide gave the dicarboxylic acid, which was
250 converted into the meso anhydride 206 by treatment with dicyclohexylcarbodiimide. Diastereoselective opening of the me5o-anhydride with Heathcock*s /?-(+)-2-naphthylethanol (99.7% e.e.) (53), the enantiomeric purity of which was raised by Horeau's method (54), gave a 96:4 mixture of diastereoisomeric mono-esters 207 and 208. Esterification of the mixture with 2trimethylsilylethanol gave the mixture of diastereoisomeric diesters, which was hydrogenolysed to give the mono-ester 209 with an e.e. of 92%. The allylsilane 212 and the common intermediate 215 were made from this monoester (Scheme 28). The lithium dianion of the acid-ester 209 was treated with the aldehyde 210 and the mixture of four diastereoisomeric aldols 211 esterified with diazomethane. The four possible diastereoisomers, present in a ratio of 76:9:9:6 were separated and the 2-trimethylsilylethyl ester group removed by treatment with tetrabutylammonium fluoride. The individual diastereoisomeric 1.2LDA,THF,DMPU CHO McsSi 2. O J )
TolMe2S MesSi' O
SiMe2Tol
3. CH2N2 75%
209
211a and 211b: 3. PhS02Cl, Py 4. collidine, heat
SiMe2Tol
211c and 211d: O O 3. Me2NCH(OCH2Bu')2 ^—^ CHCI3, reflux 93% SiMe2Tol .^^^^Ji^^^CQ^H
KH,THF O
O
OSiMe2Tol 214
^\
SiMe2Tol 2. Bu4NfF, THF
P OH SiMe2Tol 4:5,5:6 211a synsyn 76% 211b anu,syn 9% 211c syn,anu 9% 21 Id anti.anti 6%
TolMe2Si SiMc2Tol ^ = Hi
l.KOH,THF,MeOH 2.MCPBA,Na2HP04 O \ CH2CI2 92%
O jC,^^ / / OH O - ^ 213
O
H2,Pt02,MeOH 87% from 213 O 215
Scheme 28 hydroxy acids were each converted to the required trans allylsilane 212, by syn stereospecific decarboxylative elimination by way of their p-lactones for the acids derived from the esters 211a and 211b, and by and stereospecific decarboxylative elimination for the acids derived from the esters 211c and 21 Id, following chemistry developed earlier (55). The methyl ester was hydrolysed to the acid, which was epoxidised using m-chloroperoxybenzoic acid. The epoxide must have been produced with high anti stereoselectivity (antr.syn = 97:3), but it rearranged to the 7-lactone 213 by a stereospecific 1,2-shift of the silyl group from C-4 to C-5, probably with retention of configuration at C-4 and inversion at C-5 (56). The alcohol 213 on treatment with potassium hydride under the conditions of standard Peterson olefmation underwent stereoselective eliminative rearrangement, well precedented in the work of Yamamoto (57), to give the unsaturated acid 214. Deprotection of the 0-
251 silyl ether and hydrogenation of the double bond gave the hydroxy acid 215 in 41% overall yield from the adipate ester 205. The hydroxy acid 215 was the common intermediate for the synthesis of both methyl (+)-nonactate 220 (Scheme 29) and benzyl (-)-nonactate 227 (Scheme 30). The ketal 215 was hydrolysed with pyridinium tosylate and the ketoalcohol reduced stereoselective^ to the and 1,3-diol 216 (antiisyn = 96:4) using Evans's method (58). The C-6 and C-8 hydroxyl groups were differentiated by formation of the seven-membered lactone 217 using Mukaiyama's method (59). The minor enantiomer of the lactone 217 was largely removed because the racemate crystallised, thereby improving the e.e. from 92% to >99%. The 8-hydroxy group was SiMe2Tol ,C02H l.PPTS,Me2C0 O
O
u y OH 215
SiMe2Tol CO2H
l.TBDMSCl, imidazole 2. LDA, THF, DMPU SiMe2Tol • TBDMSO 3. Mel
O.
92%
TBDMSO
1^
2. separate from racemate 90%
2. Me4NBH(OAc)4 87%
SiMe2Tol
0 218
l.TsCl,DMAP,Py ^. 2. TsOH, MeOH
KBr, AcOOH ^> NaOAc, AcOH 73%
C02Me 220
91%
Scheme 29 protected as its rerr-butyldimethylsilyl ether, and the lithium enolate was methylated to give the lactone 218. Conversion of the tolyldimethylsilyl group into the hydroxyl group with retention of configuration at C-3 was achieved using potassium bromide in peroxyacetic acid, and the hydroxy group in 219 was converted into its tosylate. Methanolysis opened the lactone ring and allowed the free hydroxyl group to displace the tosylate, giving methyl (+)-nonactate 220. The overall yield of (+)-methyl nonactate from the common intermediate 215 was 47%. For the synthesis of benzyl (-)-nonactate (Scheme 30), the hydroxy acid 215 was esterified and deketalised to give the ketoester 221. Stereoselective reduction of the ketone group using Prasad's modification of Narasaka's method (23) gave the syn 1,3-diol (syn:anti = 90:10), which was converted to its acetonide 222. Stereoselective methylation of the open-chain p-silyl ester gave only the ester 223 with the anti relationship between the incoming methyl group on C-2 and the resident silyl group on C-3. Differentiation of the C-6 and C-8 hydroxyl groups was achieved by removing the acetonide, hydrolysing the ester group, and forming the seven-membered lactone 224 using Mukaiyama's procedure (59). As in the earlier sequence, this lactone was enantiomerically enriched (from 92% to >96% e.e.) by removal of the crystalline racemic lactone. The free hydroxyl group in the lactone 224 was protected with r^rr-butyldimethylsilyl chloride, and the lactone opened
252 with sodium benzyloxide to give the benzyl ester in quantitative yield. The C-6 hydroxy group was then converted to its tosylate 225, and the C-3 tolyldimethylsilyl group to hydroxyl, as before. The intramolecular displacement with inversion at C-6 226 then gave directly benzyl (-)-nonactate 227. The overall yield of benzyl (-)-nonactate from the intermediate 215 was 35%. l.Bu2BOMe,NaBH4 SiMe2Tol THF, MeOH C02Me
SiMe2ToI I.CH2N2 CO2H 2. PPTS, Me2C0 86% 215
—
^.
2. (MeO)2CMe2.PPTS
SiMe2Tol 1. PPTS, MeOH 2 cOiMe 2. KOH, THF, McOH
SiMe2Tol C02Me l . L D A , T H F , D M P U ^ 8 ^ ^ 6
r
2. Mel
3. CI-^N"^ Et3N
89% less ??%
4. separate from racemate 83% l.TBDMSCl, imidazole 2.NaOBn,BnOH,THF
"^
^V-/^^'^'^™3.TsaDMAP,Py g \ 85%
SiMe2Tol ^C02Bn
jj TBDMSO
OTs
225
224
KBr, AcOOH AcOH 78%
OH TsO ^ ^ i 226
H ^H
i
227
Scheme 30
2.4 Electrophilic Cydisation of y,8-Unsaturated Alcohols and Enols In their synthesis of racemic methyl nonactate 233 and its 8-epimer 234 (Scheme 31) (26), Baldwin and Mclver controlled the stereochemistry of C-2 and C-3 by conjugate addition of homoallylmagnesium bromide to 2,2-dimethyl-3(2H)-furanone 228 and methylation of the regenerated enolate, which took place with high selectivity (10:1) in favour of the trans dialkylfuranone 229. Conversion of the ketone to the oxime followed by fragmentation with thionyl chloride and protection gave the nitrile, and the now free alcohol group was protected as its 2,6dichlorobenzyl ether 230 {anti:syn = 32:1). Conversion to the corresponding aldehyde with diisobutylaluminium hydride^ followed by exposure to iodine in acetonitrile gave the cyclic iodoaldehyde, which was oxidised to the corresponding acid 231. The iodoetherification took place stereoselectively in favour of the desired stereochemistry at C-6 {cis'.trans = 50:1). Dithiane addition and esterification gave the masked aldehyde 232. After removal of the protecting group, the aldehyde was treated with dimethylzinc in the presence of titanium tetrachloride to give methyl
253
nonactate 233 and methyl 8-epinonactate 234 in a ratio of 24:1. The same reaction using lithium dimethyl cuprate took place selectively (4.5:1) in favour of methyl 8-epinonactate 234 1.
%,y-^MgBT
W
CuBr, MeaS
OCH2C6H3CI2 CN
. SCX:i2, CCI4
^>
•!
2. LDA, THF, Mel
228
l.NH20H,Py
229
56%
3.NaH,THF 4.2,6-Cl2C6H4CH2Br 59%
anti'.syn 10:1
l.DIBALH
C02Me
^-
2.12, MeCN 3.CrO3,H2S04 54% 1. HgO, BF3.0Et2
C02Me
^.
Me2Zn,TiCl4 Mc2CuLi
24:1 1:4.5
2. Me2Zn, T i C ^ 65% orMe2CiiLi 60%
Scheme 31 Walkup and Park synthesised not only methyl (±)-nonactate 240a but also (±)-homononactate 240b and (±)-bis- 240c and trishomononactate 240d (Scheme 32) (60) starting from hexa-4,5dienal and the appropriate lithium enolate 235 in each case. The relative stereochemistry of C-6 and OLi
Me4N-' (AcO)3BH!•
OHC^x--^^'
MeCN, AcOH, - 4 0 X 236a 236b 236c 236d
235
OH OH
R=Me R=Et R=Pr' R=Bu'
55% 58% 55% 55%
OTBDMS
TBDMSCl,
l.Hg(02CCF3)2
IN
imidazole 237a R=Me 237b R=El 237c R=Pr^ 237d R=Bu'
90% 90:10 80% 96:4 90% 99:1 84% >99:1
OH
H2, Rh/Al203 C02Me
y—X CO2MC
CO2MC H^H
cis: trans >98:2 239a R=Me 87% 239b R=Et 70% 239c R=Pr^ 80% 239d R=Bu' 80%
^.
2. PdCl2 cat., CuCl, 238a R=Me >98% CO, McOH 238b R=Et >98% 238c R=Pr' >98% 238d R=Bu' 25% + 6-silyloxy-8-ol 75%
240a-d
1:1
:
241a-d
Scheme 32 C-8 was controlled by Evans' reduction (58) of the p-hydroxyketones 236 giving the anti 1,3-diols 237. The y-silyloxyallenes 238 were then subjected to a one-pot procedure already developed by
254 these workers involving oxymercuration coupled to a palladium-catalysed methoxycarbonylation (61), which gave the tetrahydrofurans 239 with high stereoselectivity (cis.trans >98:2). This short sequence of reactions established efficiendy the required stereochemistry at C-8, C-6 and C-3, but, unfortunately, the final stereogenic centre at C-2 was generated with no control, catalytic hydrogenation gave a 1:1 mixture of the desired products 240 and their C-2 diastereoisomers 241. Iqbal and his co-workers reported a synthesis of 2,5-disubstituted tetrahydrofurans from Y,6unsaturated alcohols (Scheme 33) (62). The stereochemistry of the C-2 and C-3 centres was set up with some selectivity by reduction of the p-ketoester 242. Epoxidation of the terminal double bond
u
I.NaH 2.BuLi
C02Me
NaBH4
C02Me
243 53% OH
CI
V^-N.X^C02Me
242
244
,C02Me
MCPBA ^>
+ Ho..,^,,X^
m.^^^^^}^
78%
245
243
89:11
246
Scheme 33 of the major alcohol 243 with w-chloroperoxybenzoic acid was surprisingly well controlled, with the epoxide undergoing cyclisation under the reaction conditions to give the cis and trans tetrahydrofurans 245 and 246 in a ratio of 89:11. The major product, the alcohol 245, is the racemic methyl ester corresponding to the intermediate 158 in the Davidson and Batmangherlich synthesis of rerr-butyl nonactate (Scheme 22).
o- o-
> T ^ - . XX OMe
TBDMSO.
O
l.NPSP,Znl2 '^^™S0 n-^ • / \ ^ /\^C02Mc 2. separation » | jj O j
250
H2, Raney Ni 75psi 86%
OTBDMS
249 C02Me
2. Lindlar 65%
.TBDMSO,
248
247 1. base, Mel
CO2MC ^g^^
TBDMSO ^^v
38% /—V
^^
C02Me
252
^^^^
251
^'^\^n'i^-^
CO2H
253 Scheme 34
Ley also used the alkylation of a p-dicarbonyl dienolate 248 to assemble the precursor 250 for an electrophile-induced cyclisation (Scheme 34) (63). The enol of the p-ketoester 250 underwent
255 cyclisation with N-phenylselenophthalimide (NPSP) to give a separable mixture of two diastereoisomers, from which the selenide 251 with the correct C-6 to C-8 stereochemistry was isolated. Raney nickel induced hydrogenolysis of the now superfluous selenide as well as saturation of the C-2 to C-3 double bond, as in Bartlett's synthesis, and gave the 0-silyl protected methyl nonactate 252, which was converted to nonactic acid 253.
2.5 Intramolecular Conjugate Addition ofAlkoxides Gerlach and Wetter established the relative stereochemistry between C-6 and C-8 at the beginning of the synthesis, and made the tetrahydrofuran ring by an intramolecular conjugate addition of the C-6 alkoxide to an a,p-unsaturated ester (Scheme 35) (11). The 1,3-diketone 254, prepared from the dianion of acetylacetone, was reduced with sodium borohydride to give a mixture of the diols 255 and 256 (3:2), which were separated by chromatography. The undesired erythro diastereoisomer was converted to the desired three isomer by tosylation, displacement with acetate ion and hydrolysis, and the combined crops of threo diol 256 were acetylated. Ozonization of the diacetate followed by Wittig reaction of the aldehyde 257 with the carbanion of pmethoxycarbonylethyl diethyl phosphonate gave a mixture of (£") and (Z) isomers 258 {E:Z 85:15). Base catalysed cyclisation of the a,p-unsaturated ester 258 (E:Z = 7:3) gave a mixture in ratios of 100:68:56:71 in which methyl (±)-nonactate 259 was the major product, separated as its rerr-butyl ether and ester. OH OH O
lin
O
o
KNH2
o
255
NaBH4
l.TsCl 2. separate
70% "^ 255:256 3:2 OH OH
3. NaOAc
4. KOH
13%
256 OH OH
1. AC2O
OAc OAc
^> 2. O3, Me2S
256
(ElO)20P^ C02Me ^CHO
257
l.KOH,MeOH.MeCN :N C02Me 258
£;Z7:3
2. CH2N2, H-' 97%
9«
1
66%
r\
C02Me
H^Hi 259
Scheme 35 Sun and Fraser-Reid reported a synthesis of methyl (-)-nonactate starting from D-ribose, C-4 of which (sugar numbering) provided C-6 (nonactin numbering) of the tetrahydrofuran ring (Scheme 36) (64). The ribose-derived aldehyde 260, was converted to the ketone 261 by a Wittig reaction followed by hydrolysis of the enol ether. Raney nickel catalysed hydrogenation of the ketone 261
256 provided the (S)-alcohol 262a with the correct C-8 stereochemistry for methyl (-)-nonactate 265 with high selectivity (9:1), probably stemming from chelation of the nickel to the ring oxygen atoms. In addition, the minor isomer was converted into the major by displacement of its sulfonate with sodium benzoate. The alcohol 262a was hydrolysed and protected as its acetonide to give the aldose 263, which was treated with the phosphorane. Wittig reaction took place followed by intramolecular
OHC
yOy
OMe
6j0
yOy
A
260
H2.Ni /^
o3o
'^'^
A
"I—\ ^ COMe
y—V ^ OMe
2 steps /
\ ^
1. separate 262a 2. HsO""
oTo
3.Me,C(OMe),
A 261
262a R^=OH,R2=H90% 262b R ' = H , R 2 = 0 H 10%
HO
1. Ph3PYC02Me ^^
l.benzoylate
^ ^ 3 3. Me2NCH(OR)2 X^o^^^'"^' ^ ^ 4. Ac20,heat H H i 'V' "^ 5. H2, Pd 255 ^^ '^ ^ 6. NaOMe 263 264 78% Scheme 36 conjugate addition of the alkoxide on the unsaturated ester under kinetic control to give a 1:3 mixture /\^0E ^
^
2. separate / 3.NaOMe 4. separate and recycle
of the two C-2 diastereoisomers, with the desired isomer 264 the minor component. Under kintetic control, the side-chain at C-3 (nonactin numbering) remains on the upper surface as illustrated, an observation of Moffatt and his co-workers (65). The ratio was improved to 3:2 by equilibration with sodium methoxide by a p-elimination-readdition pathway. After three cycles of equilibration and separation, 90% of the mixture had been converted into the diastereoisomer 264. The acetonide group in the benzoate of 2 6 4 was hydrolysed and the resulting diol subjected to Eastwood deoxygenation (66), which gave the corresponding dihydrofuran. Hydrogenation over palladium then gave methyl (-)-nonactate 265. Sun and Fraser-Reid also synthesised the (+)-enantiomer from the same starting material, which required that the configuration at C-4 be inverted (Scheme 37). The early intermediate 261 prepared from D-ribose was treated with base, which caused epimerisation to give the thermodynamically more stable isomer 266, with an equilibrium ratio of 9:1 as expected from Moffatt's precedents, but surprising at first sight, given that the side chain is endo in the bicyclic system. Nickel-catalysed hydrogenation, selective enough to give the alcohol 267 to the extent of 75%, deprotection of the acetal, and protection of the diol as its acetonide gave the aldose 268. The aldose was treated with the nitrile analogue of the same phosphorane as before to give an epimeric mixture of the nitriles 269. This mixture was epimerised in a few cycles, with separation after each cycle, finally providing the nitrile 270 in 84% yield. The nitrile was used in this sequence because it behaved better in the equilibration steps than the corresponding ester. Eastwood deoxygenation.
257 hydrogenation of the dihydrofuran, and conversion of the nitrile to the methyl ester gave methyl (+)nonactate 271. O
/
V^y Q
OH
OMe
Q
NaOMe, MeOH MeOH NaOMe,
O
OMe
^Jl^ ^ ^ ^^'^\.
90% epimerisation
Q
261
Q 266
PhsP^CN
A
268 OH CN
OH
OMe
JC^^V"
2. separate
J
^
1.H30-' 2. Me2C(OMe)2
267 OH
2. NaOMe 93%
Ov^O
H2. Ni
CN
l.NaOEt,ElOH 2. separate 3. recycle and separate 84%
0^0
A
l.benzoylate 2. HsO"^ 269 3. Me2NCH(OR)2 OH ^-AczO^heat JC4^.K^C02Me 5.H2,Pd 6.H2O2 7. NOCl 8. CH2N2 9. NaOMe
0^0
A
270
Scheme 37 2.6 From Bicyclic Intermediates White and his co-workers were the first to use a bicyclic intermediate to control the relative stereochemistry (Scheme 38) (14). They set up the 8-oxa-bicyclo[3.2.1]octene 273 using O
vV Br
fl
Zn-Cu 272
Br
° ^
q
2.""v^j^O ""2.^^ "'^"^ CF3CO3H, Na2HP04 273 .C02Me 220 T
1. NaOMe O 2.NaH,CS2,MeI 71%
274
92% C02Me
MeS2C0 " 1 " 275 OHC
1, (Sia)2BH
CrOs
C02Me
^.
»•
95%
2. H2O2, HO"
278:279= 1:1
^ OHC.,^ H
46% 1. separate 278 2. MeMgl
64%
HE 279
C02Me
C02Me 280
A ^
1:1
281
Scheme 38 Hoffmann's cycloaddition (67) of the oxyallyl cation 272, generated from 2,4-dibromopentan-2-one with LeGoff s zinc-copper couple (68). Hydrogenation followed by Baeyer-Villiger oxidation gave the lactone 274, with C-2, C-3 and C-6 correctly set up. Methanolysis gave a single hydroxyester,
258 which was converted into its xanthate 275. The xanthate on pyrolysis provided the terminal alkene 276,
which was subjected to hydroboration-oxidation to give the primary alcohol 277.
Unfortunately, the configurational identity at C-2 was lost during the hydroboration-oxidation, the alcohol proving to be a 1:1 mixture of C-2 epimers. These were separated after converting the alcohol 277 to the mixture of aldehydes 278 and 279, and treatment of the isomer 278 with methylmagnesium iodide gave methyl nonactate 280 and methyl 8-epinonactate 281 with no selectivity, a problem that was solved later by Baldwin and Mclver (Scheme 31). Warm and Vogel used 7-oxabicyclo[2.2.1]heptan-2-one 284 to control the relative stereochemistry of C-2 and C-3 of methyl nonactate. They also resolved it, and used the (+)enantiomer to synthesise methyl (+)-nonactate (Scheme 39), and the (--)-enantiomer to synthesise methyl (-)-nonactate (69). Zinc iodide-catalysed Diels-Alder reaction between furan and 1cyanovinyl acetate gave the adduct 282, which was saponified to give the racemic ketone. This was hydrogenated using palladium on charcoal, and the enantiomers (+)- and (-)284 were resolved by chromatography of their sulfoximides 285 and 286. Pyrolysis of each diastereoisomer gave the
Aco^cN
"^o^
^ ^ ^OAcC 282
^ C N
2.H2.P(1A:
^-^^
^ ^
4:1 O
42% each
OH
O
' ,
5-
285
(+)-284
l.KHMDS 2. Mel ^> 3. separate from dimethyl product 4. MCPBA, NaHCO^ 59% ,C02Me
C02Me 288:289 1:3 289 1 l.KOH 2. CH2N2 288:289 3 (36%): 4 (27%)
L-Seleciride ^. 82%
C02Me
4
CO2MC
290:291 10:1 l.PhC02H,Ph3P,DEAD
|
2. NaOMe, MeOH 85%
Scheme 39 enantiomerically pure ketones 284 (>99% e.e.). Methylation of the bicyclic ketone (+)-284 followed by Baeyer-Villiger oxidation gave the unstable oxoacetal 287. Addition of one equivalent of the silyl enol ether of acetone to a 1:1 mixture of the acetal 287 and titanium tetrachloride gave a 1:3 mixture of the ketone 288 and its trans isomer 289. However, the undesired isomer 289 could be equilibrated on treatment with potassium hydroxide, by p-elimination and readdition. Acidification
259 and esterification with diazomethane gave the ketones 288 and 289, as a 4:3 mixture. Reduction of the ketone 288 with L-Selectride gave a 10:1 mixture of methyl (+)-8-epinonactate 290 and methyl (+)-nonactate 291. Mitsunobu inversion of the major product and treatment with sodium methoxide gave methyl (+)-nonactate 291. The enantiomeric bicyclic ketone (-)-284 similarly provided methyl (-)-nonactate.
2.7 Ireland-Claisen Rearrangement Ireland and Vevret developed a route for the synthesis of both (+)- and (-)-nonactic acids, with the stereochemistry at C-6 derived from C-4 of D-gulonolactone and D-mannose, respectively (70). For the synthesis of (+)-nonactic acid 301 (Scheme 40), the furanoid glycal 295 was prepared in 10 steps from D-gulonolactone 292 by fairly straightforward functional group manipulations. The
HO
6H«
MOMO
0
0
l.HCl,MeOH 2. Me2NCH(OMe)2 3. AC20,130°C
•
3. NaH, BnCl, DMF
o^^o-^
H ^ 294 MOMO
l.Li,NH3 2.CCl4,Ph3P MOMO
293
HO V-^
l.BuLi 2.EtC0Cl
OBn 3.Li,NH3
^.
2. CH2N2
C02Me H ^H 299 47% or 54% _
H2,Pt/C C02Me ^> 44% from 295
MOMO
3. LDA, THF, -78°C
H^ 295
11% from 292 r=^
1
OBn 4. 9-BBN 5. NaOH, H2O2 6. P2O5, CH2(OMe)2 OSiMcs"
I
292
\-4
1. 25°C
l.Me2C0,H-' 2. DIBALH
OH
4. MeaSiCl
H^ 296 l.HCl,MeOH 2. Swem
MOMO
K0H,H20
V—TV
H ^H 298 298:2-epi-298 86:14
3. Mc2CuLi or McMgBr
^
CO2H
95%
C02Me
300 53%^r40%
Scheme 40 glycal 295 was converted into its propionate ester, which on treatment with lithium diisopropyl amide in THF and trimethylsilyl chloride gave the £-trimethylsilyl enol ether 296. The key step, the Ireland-Claisen rearrangement (71) setting up the stereochemistry at C-2 and C-3, took place at room temperature, and the product mixture was esterified to give a mixture of the C-2 diastereoisomeric
260 esters 297. Catalytic hydrogenation gave the corresponding mixture of esters 298 (86-89:14-11) in favour of the desired isomer. Evidently the Claisen rearrangement had taken place largely with the boat-like transition structure, and suprafacially on the dihydrofuran ring. Deprotection followed by Swem oxidation gave the aldehyde. No stereochemical control was observed in the dimethylcuprate addition to the aldehyde, which gave both diastereoisomers 299 and 300 in approximately equal amounts, in contrast to Baldwin's observation of good control, although in the wrong sense, in this reaction (Scheme 31). They observed somewhat better control when methylmagnesium bromide was used. The enantiomeric glycal 305 was prepared from the D-mannose 302 in 11 similar steps (Scheme 41), and (-)-nonactic acid 310 prepared from it exactly as described for the (+)-enantiomer 301 (Scheme 40).
V
OH l.Me2C0,H-' .OH 2. NaH, BnCI, DMF HO^ 'V-^^^^^*^" HO^'^^^O-^OH 302 Q' -Q
I.Li,NH3 2.CCl4.Ph3PMOMO
^ ^ O ' ^ O B n 3.Li,NH3 ^ H 36% 304 36% from from 302 302
H2, Rh/C
I
jiQ V-a
l.BuLi 2. EtCOCl
3.NaOH.H202 4. KH, MCOCH2CI
MOMO
^ V ^ >> 3.LDA,THF. H^ -78°C 3^5 305 4. Me.SiCL MesSiCl, 25°C 5. CH2N2
V
C02Me
49% from 305
I.AC20,130°C 2. 9-BBN
3.HCl,MeOH O ' ^ r ^ O ' ^ O cB n 4. Me2NCH(OMe)2, CH2CI2 V-n " 303 Me2N f ^ -i^-
MOMO
MOMO M UMU
O^^O
H" H I 307
l.HCi,MeOH 2. Swem
k^^^tN^C02Me H H^ 306
x ' ^ . X h Q ' t v ^ CO2MC H "^ H =
3. Me2CuLi
308 40% OH
307:2-epi-307 89:11
r ^ H^ H= 309 45%
. - ^ X x t ^ Q ' t ^ C02Me
KOH, H2O
H "^ H 308
*- -'^"'^^o'^V' CO2H H ^ H= 310
Scheme 41
3.
SYNTHESES OF NONACTIN The synthesis of nonactin requires that the (+)- and (-)-nonactic acid units be joined together in
an alternating sequence, followed by closing the ends to give the macrocycle. There are two possibihries for ring-formation: (i) cyclodimerisation of a "dimer" and (ii) unimolecular cyclisation of
261 a "tetramer." Both strategies have been used, with several different ways to assemble the dimer and tetramer. In one strategy, the differentially protected nonactic acid enantiomers are coupled to give the protected dimer using standard esterification techniques that preserve the configuration at C-8. In the other strategy, the linear units are coupled by taking one enantiomer of nonactic acid, and using it as a carboxylate nucleophile to displace, with inversion of configuration, the 8-methanesulfonate or tosylate of the 8-epi-diastereoisomer of the other enantiomer, protected at the carbonyl group. 3.1 Synthesis ofNonactin by Unimolecular Cyclisation The first synthesis of nonactin was reported by Gerlach and his co-workers (Scheme 42) (72) in 1975 by the cyclisation of a linear tetraester, but the linear tetraester 317 was a mixture of diastereoisomers because it was made from racemic nonactic acid 311 (prepared in Scheme 35).
CO2H
[ I
(+)-311 •^ Bu'OsCMe, MeSOsH 70%
NaH,BnBr ^ OBn
CO2BU'
Py, C i O z S - f J -
70%
COzBu^
H2, Pd/C CO2BU'
C02Bu^
I.CF3CO2H 2. H2, Pd/C
i
4. AgC104, MeCN, 10--*M 5. separate
nonactin (10%) + other diastereoisomers (30%)
Scheme 42 Appropriately protected monomers, the racemic benzyl ether 312 and the racemic rerr-butyl ester 313, were coupled using the mixed anhydride with 2,4,6-trimethylbenzenesulfonyl chloride to give
262 the protected dimer 314 as a mixture, inevitably, of four diastereoisomers, all racemic. Treatment with trifluoroacetic acid removed the rerr-butyl ester group from one portion of the dimer to give the acid 315, and catalytic hydrogenolysis removed the benzyl ether group from the other portion to give the alcohol 316. Activation of the acid 315 with 2,4,6-trimethylbenzenesulfonyl chloride and coupling with the alcohol 316 gave the linear tetramer 317, this time as a mixture of eight racemic diastereoisomers. Deprotection of the rerr-butyl ester with trifluoroacetic acid and of the benzyl ether by hydrogenolysis gave the free linear tetramer, which was cyclised by the Mukaiyama thioester method (73). At this stage the complexity of the mixture became rather less, since there are only four possible diastereoisomers, assuming that there is complete preservation of stereochemical integrity within each nonactic acid unit. Of these four diastereoisomers, three were isolated by chromatography in a ratio of 1:5:2, and the last proved to be nonactin 1. Schmidt and his co-workers (74) were the first to report a synthesis of nonactin from enantiomerically enriched components (Scheme 43). Potassium (-)-nonactate 321, prepared from
4^is^C02Bn H ^H =
H
Asx/o^C02H
H
H
(+)-319 i TsCl,Py 85% ,—V
OTs
H = (-)-320"
OH
An
OTs
C02Bn . A ^ ^ V ^ ^ ^ z "
OH
1
y
O
:
,
1
OH
I
V
C02Bn
O C02Bn
H ^ H = •
H ^H
324
H" H E
I l.H2,Pd/C 2.KHCO3 OH
r—.
O
=
OTs
J—.
-^^oW^o-^-^oV^^^'
/-^
O C02Bn
/ ^ oH^ t H^ =- ^ o
327
OH
y
i
O
r
i
.
O
| 7 4 % from 324 I y 1
O
r
y
v ^C02Bn
H "^ H =
H^H
H "^ H =
H
H
328
I l.H2,Pd/C 2. (PyS)2,Ph3P I 3.AgC104,bei benzene 20% nonactin Scheme 43 the acid 318 (=38) was coupled, with inversion of configuration at C-8, with the 8-epi-tosylate 322, derived from benzyl (+)-8-epi-nonactate 319 (prepared from the methyl ester 40), to produce
263 benzyl (-)-nonactinoyl-(+)-nonactate 324. The diester 325 was prepared similarly using potassium (-)-8-epinonactate 323 and the same 8-epi-tosylate 322 used before. Hydrogenolysis of the "dimer" 324, and conversion to the potassium salt with potassium bicarbonate gave the left-hand component 326. Tosylation of the alcohol 325 gave the 8-tosylate 327, which gave the linear tetraester 328, again with inversion of configuration at C-8, on treatment with the potassium salt 326. Hydrogenolysis, activation and cyclisation following Gerlach produced nonactin in 20% yield together with C-2 and C-8 epinonactins in 12% yield. Fleming and Ghosh synthesised nonactin by cyclisation of the linear tetramer 335 assembled from methyl (+)-nonactate and benzyl (-)-nonactate (Scheme 44) (75). The (9-protected (+)-nonactic
C02Me (+)-329 I l.TBDMSCl, imidazole 2. KOH, THF, MeOH 98% TBDMSO
331 DCC, DMAP 93% TBDMSO C02Bn H ^ H = 100% H2,Pd/C TBDMSO
/—V
TsOH,AcOH 98%
O
Ov^o^^
H
C02Bn
H^A
H E
U H
^
U H
'
334 CI
DMAP, ClOC C ^ C l
95%
CI TBDMSO C02Bn H
H
H
H =
H ^ H =
335
l.H2,Pd/C 2TsOH, AcOH, H2O 3. CI
t
nonactin
DMAP, ClOC • ^ - C I
69%
CI
Scheme 44 acid 330 was prepared from the hydroxyester 329 (=220), and coupled with benzyl (-)-nonactate 331 (=227), without inversion at C-8, to give the dimeric ester 332. A portion of this dimer was hydrogenolysed with palladium on charcoal to give the acid 333, while the other portion was
264 deprotected at the hydroxy group using acid to give the alcohol 334. The acid 333 was coupled to the alcohol 334 using the Yamaguchi mixed anhydride method (76) to give the protected linear tetramer 335. The protecting groups were removed to give the free tetramer, which was cyclised in high yield (73%), the best so far achieved, again using Yamaguchi's method. There was no improvement in yield when potassium tetrafluoroborate was present, indicating that coordination to potassium did not help the cyclisation. 3. 2 Synthesis ofNonactin by Cyclodimerisation Schmidt and his co-workers also reported the synthesis of nonactin (Scheme 45) (77) by cyclodimerisation of (-)-nonactinyl-(+)-nonactic acid 336 (=326), which was treated successively OH y i H "^ H
O
=
y y H "^ H
336
/V^V'-carbonyldiimidazole, DBU i
or (PyS)2,Ph3P
"poor yield"
nonactin
Scheme 45 either with carbonyldiimidazole and diazabicycloundecen or with the bispyridyl 2-disulphide and triphenylphosphine to give nonactin in "poor" yield in both cases.
H^ H I (-)-338 ^ MsCl, EI3N, DMAP 91% OMs / — ^ C02Me H
H = 340
C02Me H ^ H = 341 I LiSPr",HMPA 1 CO2H H ^ H l.(PhO)2POCl,Et3N I 2. heat, C6H6, DMAP 16% nonactin + cyclic "dimer" and "oligomers" and polymer
Scheme 46 Bartlett and his co-workers (20) synthesised nonactin by the cyclodimerisation approach (Scheme 46). The potassium salt 339 of (4-)-nonactic acid 337 (=87) and the mesylate 340 of the
265 (-)-8-epiester 338 (=86) gave the dimeric ester 341 with inversion of configuration at C-8, as in Schmidt's synthesis, but working with the enantiomer of each component. The methyl ester was cleaved by lithium n-propyl mercaptide with some difficulty, and with some (25%) epimerisation at the C-2 positions of the nonactic acid units to give the acid 342. Macrolactonisation using Masamune*s procedure (78), gave nonactin in 16% yield, accompanied by the cyclic "dimer" and "oligomers" and polymers. Fleming and Ghosh also synthesised nonactin by cyclodimerisation of the acid derived from the benzyl ester 343 (=334) using Yamaguchi conditions (Scheme 47) (75). Nonactin was isolated in lower yield than by the linear tetramer method, presumably because of the problem of "dimer" and "oligomer" formation.
Q^
o-^^-^/?k^^^^^" H H E 343
l.H2,Pd/C 2.
CI
aoc-0"Ci DMAP a
nonactin (52%) + cyclic "dimer" and "oligomers" and polymer Scheme 47 CONCLUSIONS The syntheses of nonactic acid and its derivatives illustrate many of the most popular methods of stereocontrol used in synthesis. There are examples of absolute control based on (a) resolution, (b) Sharpless asymmetric epoxidation and other methods of kinetic recognition, including an enzymatically controlled reduction, (c) the use of chiral auxiliaries, and (d) starting materials from the chiral pool such as sugars, and malic and glutamic acid. Relative stereochemical control has been achieved by such devices as (a) control on bicyclic frameworks, (b) the use of many different cyclic structures, especially five-membered rings with a predictable stereochemical bias, (c) the similar use of cyclic transition structures for hydride delivery, for enolate alkylations, the Ireland-Claisen rearrangement, and for ring-forming reactions, t>oth pericyclic and ionic, and (d) by the independent synthesis of separated stereogenic centres with absolute control. There are examples of such themes as (a) kinetic and thermodynamic control, (b) of convergent and linear synthesis, (c) of the recycling of unwanted disastereoisomers by Mitsunobu and other inversion processes, and by repeated equilibration and separation, and (d) of the problems of controlling distant stereogenic centres. And there are examples of a very wide range of the common reactions of organic chemistry, including those used in C-C bond-formation, functional group manipulation, and protecting group tactics. The syntheses illustrated here would, on their own, make a surprisingly good basis for an introductory course in organic synthesis.
266 REFERENCES 1
R. Corbaz, L. Ettlinger, E. Gaumann, W. Keller-Schierlein, F. Kradolfer, L. Neipp, V. Prelog and H. Zohner, Helv, Chim. Acta, 1955, 38, 1445.
2
(a) W. Keller-Schierlein, Fortschr. Chem. Org. Naturst., 1968, 26, 161; (b) W. Keller-Schierlein, Fortschr. Chem. Org. Naturst., 1973, 30, 313; (c) J. Dominguez, J. D. Dunitz, H. Gerlach and V. Prelog, Helv. Chim. Acta, 1962, 45, 129; (d) H. Gerlach and V. Prelog, Justus Liebigs Ann. Chem., 1963, 669, 121; (e) J. H. Prestegard and S. I. Chan, / . Am. Chem. Soc, 1970, 92, 4440; (f) M. Dobler, "lonophores and their Structure", Wiley, New York, 1981; (g) B. T. Kilbourn, J. D. Dunitz, L. A. R. Pioda and W. Simon, J. Mol. Biol, 1967, 30, 559.
3
(a) K. H. Wallhausser, G. Ruber, G. Nessenmann, P. Prave and K. Zept, Arzneimittelforschung, 1964, 14, 356; (b) K. Ando, H. Oishi, S. Hirano, T. Okutani, K. Suzuki, H. Okasaki, M. Sawada and T. Sagawa, J. Antibiot., 1971, 24, 347.
4
(a) S. N. Graven, H. A. Lardy and S. Estrada-0, Biochemistry, 1967, 6, 365; (b) S. N. Graven, H. A. Lardy, D. Johnson and A. Rutter, Biochemistry, 1966, 5, 1729.
5
D. H. Haynes and B. C. Pressman, J. Membr. Biol, 1974, 18, 1.
6
M. Dobler, J. D. Dunitz and B. T. Kilbourn, Helv. Chim. Acta, 1969, 52, 2573.
7
K. Mislow, Croat. Chem. Acta, 1985, 58, 353.
8
P. A. Bartlett, Tetrahedron, 1980, 36, 2. '
9
J.-C. Harmange, B. Figadere, Tetrahedron Asymmetry, 1993, 4, 1711.
10 G. Beck and E. Henseleit, Chem. Ber., 1971,104, 21. 11 H. Gerlach and H. Wetter, Helv. Chim. Acta, 1974, 57, 2306. 12 U. M. Kempe, T. K. Das Gupta, K. Blatt, P. Gygax, D. Felix and A. Eschenmoser, Helv. Chim. Acta, 1972,55,2187. 13 (a) J. Gombos, E. Haslinger, H. Zak and U. Schmidt, Monatsh. Chem., 1975, 106, 219; (b) U. Schmidt, J. Gombos, E. Haslinger and H. Zak, Chem. Ber., 1976, 109, 2628; (c) H. Zak and U. Schmidt, Angew. Chem. Int. Ed. Engl, 1975, 14, 432. 14 M. J. Arco, M. H. Trammell and J. D. White, /. Org. Chem., 1976, 41, 2075. 15 W. C. Still, L. J. MacPherson, T. Harada, J. F. Callahan and A. L. Rheingold, Tetrahedron, 1984, 40, 2275. 16 W. C. Still and I. Galynker, Tetrahedron, 1981, 37, 3981. 17 P. A. Bartlett and K. K. Jemstedt, J. Am. Chem. Soc, 1977, 99, 4829. 18 P. A. Bartlett and K. K. Jemstedt, Tetrahedron Lett., 1980, 21, 1607. 19 P. A. Bartlett, J. D. Meadows, E. G. Brown, A. Morimoto and K. K. Jemstedt, J. Org. Chem., 1982, 47, 4013. 20 P. A. Bartlett, J. D. Meadows and E. Ottow, J. Am. Chem. Soc, 1984, 106, 5304. 21 W. S. Johnson, C. Edington, J. D. Elliott and I. R. Silverman, / . Am. Chem. Soc, 1984, 106, 7588. 22 I. R. Silverman, C. Edington, J. D. Elliott and W. S. Johnson, J. Org. Chem., 1987, 52, 180. 23 K. Narasaka and F.-C. Pai, Tetrahedron,
1984, 40, 2233. See also, K.-M. Chen, G. E.
Hardtmann, K. Prasad, O. Repic and M. J. Shapiro, Tetrahedron Lett., 1987, 28, 155.
267 24 B. Lygo, N. O'Connor and P. R. Wilson, Tetrahedron, 1988, 44, 6881. 25 B. Lygo, Tetrahedron, 1988, 44, 6889. 26 S. W. Baldwin and J. M. Mclver, J. Org. Chem., 1987, 52, 320. 27 P.-F. Deschenaux and A. Jacot-Guillarmod, Helv. Chim. Acta, 1990, 73, 1861. 28 B. H. Kim and J. Y. Lee, Tetrahedron Utt., 1992, 33, 2557. 29 B. H. Kim, J. Y. Lee, K. Kim and D. Whang, Tetrahedron Asymmetry, 1991, 2, 27 and 1359. 30 B. H. Kim and J. Y. Lee, Tetrahedron Utt., 1993, 34, 1609. 31 A. G. M. Barrett and H. G. Sheth, J. Chem. Soc, Chem. Commun., 1982, 170. 32 P. C. B. Page, J. F. Carefull, L. H. Powell and L O. Sutherland, / . Chem. Soc, Chem. Commun., 1985, 822. 33 R. A. Johnson and K. B. Sharpless, in Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming, Pergamon, Oxford 1991, Vol. 7, ed. S. V. Ley, Ch. 3.2, pp. 389-436. 34 H. J. Karlsen, T. Katsuki, V. S. Martin and K. B. Sharpless, J. Org. Chem., 1981, 46, 3936. 35 S. Batmangherlich and A. H. Davidson, J. Chem. Soc, Chem. Commun., 1985, 1399. 36 J. K. Whitesell and D. Reynolds, J. Org. Chem., 1983, 48, 3548. 37 T. Honda, H. Ishige, J. Araki, S. Akimoto, K. Hirayama and M. Tsubuki, Tetrahedron, 1992, 48, 79. 38 T. Kametani, K. Kawamura and T. Honda, J. Am. Chem. Soc, 1987, 109, 3010. 39 S. Takano, S. Tomita, M. Takahashi and K. Ogasawara, Synthesis, 1987, 1116. 40 K. Takatori, N. Tanaka, K. Tanaka, M. Kajiwara, Heterocycles, 1993, 36, 1489. 41 G. Frater, U. Muller and W. Gunther, Tetrahedron, 1984, 40, 1269. 42 M. J. C. Buckle, I. Fleming and S. Gil, Tetrahedron Lett., 1992, 33, 4479 and references therein. 43 I. Fleming and N. J. Lawrence, /. Chem. Soc, Perkin Trans. 1, 1992, 3309. 44 R. A. N. C. Crump, I. Fleming, J. H. M. Hill, D. Parker, N. L. Reddy and D. Waterson, J. Chem. Soc, Perkin Trans. 1, 1992, 3277. 45 I. Fleming and P. E. J. Sanderson, Tetrahedron Lett., 1987, 28, 4229. 46 M. Ahmar, C. Duyck and I. Fleming, Pure Appl. Chem., 1994, 66, 2049. 47 I. Fleming, D. Higgins, N. J. Lawrence and A. P. Thomas, J. Chem. Soc, Perkin Trans. I, 1992, 3331. 48 J. P. Vigneron, M. Dhaenens and A. Horeau, Tetrahedron,
1973, 29, 1055. See also V.
Rautenstrauch, Bull. Soc. Chim. Fr., 1994, 131, 515. 49 T. Kogure and E. L. Eliel, J. Org. Chem., 1984, 49, 576. See also, M. M. Midland and J. Gabriel, / . Org. Chem., 1985, 50, 1144; C. S. Poss and S. L. Schreiber, Ace Chem. Res., 1994, 27, 9. 50 U. Ghosh, unpublished work. 51 I. Fleming and S. K. Ghosh, /. Chem. Soc, Chem. Commun., 1994, 2285. 52 I. Fleming and S. K. Ghosh, /. Chem. Soc, Chem. Commun., 1992, 1775. 53 P. D. Theisen and C. H. Heathcock, J. Org. Chem., 1988, 53, 2374 and 1993, 58, 142. 54 I. Fleming and S. K. Ghosh, J. Chem. Soc, Chem. Commun., 1994, 99. 55 I. Fleming, S. Gil, A. K. Sarkar and T. Schmidlin, /. Chem. Soc, Perkin Trans. I, 1992, 3351. 56 I. Fleming and S. K. Ghosh, J. Chem. Soc, Chem. Commun., 1992, 1777.
268
57 K. Yamamoto, T. Kimura and Y. Tomo, Tetrahedron Lett., 1984, 25, 2155. 58 D. A. Evans, K. T. Chapman and E. M. Carreira, /. Am. Chem. Soc, 1988, 110, 3560. 59 T. Mukaiyama, M. Usui and K. Saigo, Chem. Lett., 1976, 49. 60 R. D. Walkup and G. Park, J. Am. Chem. Soc, 1990, 112, 1597. 61 R. D. Walkup and G. Park, Tetrahedron Utt., 1987, 28, 1023. 62 J. Iqbal, A. Pandey and B. P. S. Chauhan, Tetrahedron, 1991, 47, 4143. 63 S. V. Ley, Chem. Ind. (London), 1985, 101. 64 K. M. Sun and B. Fraser-Reid, Can. J. Chem., 1980, 58, 2732. 65 H. Ohnii, G. H. Jones, J. G. Moffatt, M. L. Maddox, A. T. Christensen and S. K. Byram, J. Am. Chem. Soc, 1975, 97, 4602. 66 F. W. Eastwood, K. J. Harrington, J. S. Josan and J. L. Pura, Tetrahedron Lett., 1970, 5223. 67 H. M. R. Hoffmann, K. E. Clemens and R. H. Smithers, J. Am. Chem. Soc, 1972, 94, 3940. See also R. Noyori, S. Makino and H. Takaya, J. Am. Chem. Soc, 1971, 93, 1272. 68 E. LeGoff, / . Org. Chem., 1964, 29, 2048. 69 A. Warm and P. Vogel, Helv. Chim. Acta, 1987, 70, 690. 70 R. E. Ireland and J.-P. Vevert, / . Org. Chem., 1980, 45, 4259. R. E. Ireland and J.-P. Vevert, Can. J. Chem., 1981,59,572. 71 R. E. Ireland, R. H. Mueller and A. K. Willard, / . Am. Chem. Soc, 1976, 98, 2868. 72 H. Gerlach, K. Oertle, A. Thalmann and S. Servi, Helv. Chim. Acta, 1975, 58, 2036. 73 T. Endo, S. Ikenaga and T. Mukaiyama, Bull. Chem. Soc Jpn., 1970, 43, 2632. See also E. J. Corey, K. C. Nicolaou and L. S. Melvin, J. Am. Chem. Soc, 1975, 97, 653. 74 J. Gombos , E. Haslinger, H. Zak and U. Schmidt, Tetrahedron Lett., 1975, 3391. U. Schmidt, J. Gombos, E. Haslinger and H. Zak, Chem. Ber., 1976, 109, 2628. 75 I. Fleming and S. K. Ghosh, J. Chem. Soc, Chem. Commun., 1994, 2287 76 J. Inanaga, K. Hirata, H. Saeki, T. Katsuki and M. Yamaguchi, Bull. Chem. Soc Jpn., 1979, 52, 1989. See also: M. Hikota, Y. Sakurai, K. Horita and O. Yonemitsu, Tetrahedron Lett., 1990, 31, 6367. 77 J. Gombos, E. Haslinger, A. Nikiforov, H. Zak and U. Schmidt, Monatsh. Chem., 1975, 106, 1043. 78 T. Kaiho, S. Masamune and T, Toyoda, J. Org. Chem., 1982, 47, 1612.
229
The Synthesis of Nonactic Acid. Its Derivatives and Nonactin itself Ian Fleming and Sunil K. Ghosh 1.
INTRODUCTION The actin antibiotics, of which several are represented by the structures 1-9, occur in various
Streptomyces species (1,2). The structures were elucidated as 32-menibered macrocyclic tetraesters. Nonactin itself was isolated in 1955 by Prelog and his co-workers (1) as the first member of the family, and is its lowest homologue and most symmetrical member. All members of the actin family exhibit antimicrobial and antifungal activity, which increase with increasing size of R, and insecticidal activity against mites (3).
0=^
H
\ „^2
H I
^••H
H"/ 0
L /^ W"H
HMV
Y XT
=0
H„ H
1 2 3 4 5 6 7 8 9
nonactin monactin dinactin trinactin tetranactin macrotetralide G macrotetralidc D macrotetralide C macrotetralide B
R' Me Me Me Me Et Et Et Et Et
R3
R2
R3
Me Me Et Et Et Me Me Me Pr*
Me Me Me El Et FV Et Pi^
Et
R^ Me Et Et Et Et Me Pr' Pr* Pr'
It was the first naturally occurring crown ether, and the earliest for which the antibiotic activity could be traced to its ionophoric properties (4). The actins give one-to-one complexes with many alkali and alkaline earth metal ions, with nonactin showing selectivity in the order NH4+ > K+ = Rb+ > Cs+ > Na+ > Ba2+ (5). The first X-ray crystal structure of an ionophore-metal complex was obtained from the nonactin-potassium thiocyanate complex (6). The potassium is bound by coordination to all four tetrahydrofuran oxygens and to the four ester carbonyl oxygens, which creates overall a "tennis ball seam" conformation to the carbon framework as it wraps around the metal. Nonactin is composed of two subunits of the (-i-)-nonactic acid 10 and two subunits of the (-)nonactic acid 12, joined together by lactone linkages in an alternating sequence to give overall the
230 meso configuration (S4 symmetry) (7). The name nonacnn came from its having no optical acrivity, a puzzling feature until the meso structure was deduced. A satisfactory synthesis requires separately each of the enantiomeric nonactic acids, followed by coupling in an alternating sequence, and ring closure. A number of syntheses of nonactic acid and its esters, both racemic and enantiomerically enriched, have been developed over the past twenty years, and four syntheses of the natural product itself. The literature up to 1980 has been thoroughly reviewed (8). OH
.A^oWcOzR H 10 R=H 11 R=Me
(4-)-nonactic acid methyl (+)-nonactate
12 R=H 13 R=Me
H=
(-)-nonactic acid methyl (-)-nonactate
yKA^\^^0,^ H^H_
14 15
2.
R=H R=Me
(+)-8-epinonactic acid methyl (+)-8-epinonactate
16 R=H 17 R=Me
(-)-8-epinonactic acid methyl (-)-8-epinonactale
THE SYNTHESIS OF NONACTIC ACID AND ITS DERIVATIVES The major challenge in the synthesis of nonactic acid is the control of the relative
stereochemistry between the four stereogenic centres, which have 1,2- and
1,3-acyclic
stereochemical relationships (C-2 to C-3 and C-6 to C-8, respectively) and a 1,4-cyclic relationship (C-3 to C-6) on the tetrahydrofuran ring. These challenges have made nonactic acid a favourite target of synthetic chemists intent upon proving the capacity of a method of stereocontrol they have developed. There is much overlap from route to route, as people have often used their new method to set up only one or two of the stereochemical relationships, and have then been content to complete the synthesis using established routes. We distinguish seven common themes among the approaches used for the synthesis of nonactic acid, and have classified them by the methods, numbered 1-7 in Scheme 1, used for the construction of the a.s-2,5-disubstituted tetrahydrofuran derivative 18 (9). These are: 1. Hydrogenation of a 2,5-disubstituted furan. 2. Hydrogenation of the Bartlett type intermediate. 3. Cyclisation of a 1,4-diol derivative. 4. Electrophilic cyclisation of an unsaturated alcohol or enol. 5. Intramolecular conjugate addition of an alkoxide with R^ electron-withdrawing. 6. From a bicyclic intermediate. 7. Ireland-Claisen rearrangement. The first two approaches, 1 and 2, are based on 5)'«-stereospecific catalytic hydrogenation to control the stereochemistry around the tetrahydrofuran ring. The approach 1 has the disadvantage
231 that it only controls the cis stereochemistry of C-3 and C-6. The approach 2, which shows control from C-6 to the newly developing centre at C-3, as well as being syn stereospecific in creating the centres C-2 and C-3, is popular, and has been applied especially by those research groups who were principally demonstrating a method of 1,3 control for the relationship between C-6 and C-8. Approach 3 is challenging, since it requires a method for controlling the 1,4 relationship between C3 and C-6 in an open chain. Approaches 4 and 5 have not proved easy for setting up C-3 and C-6 with the cis arrangement, in contrast to the approach 6, which is effective for this part of the problem, but has difficulties with the control of C-2 and C-8. The approach 7 has only been used once, with C-2, C-3 and C-6 well controlled by the stereospecificity of the Ireland-Claisen rearrangement, but lacks control at C-8.
^•J3
^'^XK^'
RUCX'^' ftO
RL ^
>k .R^
H
H HO OH
18
= OH
Scheme 1 2.1 Hydrogenation of Substituted Furan Derivatives Although one of the earliest approaches to the synthesis of nonactic acid involved catalytic hydrogenation of an appropriately 2,5-disubstituted furan, the hydrogenation of furan derivatives is limited by the formidable problem of controlling the well separated acyclic stereocentres at C-2 and C-8. The first synthesis of racemic nonactic acid diastereoisomers was carried out by Beck and Henseleit (10) in 1971 (Scheme 2). Methylation of 2-methoxycarbonylmethylfuran 19 gave a mixture of the a-methyl derivative 20 (43%) and the a,a'-dimethyl derivative, which were separated by chromatography. Friedel-Crafts alkylation of 20 with 3-methyl-3-butene-2-one gave the ketofuran 2 1 , which on hydrogenation over rhodium on alumina gave a mixture of the diastereoisomeric d5-2,5-disubstituted tetrahydrofurans 22. Baeyer-Villiger oxidation of the ketone 22 with trifluoroperoxyacetic acid regioselectively gave the ester 23, and hydrolysis followed by esterification gave a mixture of diastereoisomeric nonactic acid methyl esters 24 in 70% yield. The
232 stereochemical control of C-3 and C-6 during hydrogenation was good, but no stereochemical control was observed for C-2 and C-8.
a.
l.NaH.THF
C02Me
C02Me
2. Mel
•
19
20 43%
^
r \ 0
^
I
6
BF3.0Et2
20
^
r \
11 ^
^
60%
CF3CO3H, Na2HP04 73%
H2,Rh/Ai203 ^
89%
^
^r-\
J
C02Me
H^ H
21
22 l.KOH 2. HsO-"
9^^ H ^ H T
COiMe
3.CH2N2 70%
23
Scheme 2 Gerlach and Wetter (11) achieved rather better levels of control, also using catalytic hydrogenation for the relative stereochemistry between C-3 and C-6 (Scheme 3). 2-Furylacetone 25 was prepared by a Darzens glycidic ester synthesis from furfural, and was functionalised at the 5position using Eschenmoser's 2-chloro-N-cyclohexyl-propionaldonitrone 26 in the presence of
l.NaOMe,
^N^SS/
MeCHClC02Et
ci
«.;J0
^ 26
OHC
o
3.H2SO4
27
25
43% HCl, H2O
o
AgBF4
CHO
l.Cr03,H2S04 2. CH2N2 27% (from 25)
NaOMe,MeOH NaBH4
9
F~^
C02Me
O
H2,Rh
29
30:31 = 1:4
OH
/—V
OH C02Me ^
CO2MC
98% 32
32:8-epi-32 = 7:10
8-epi-32
Scheme 3 silver tetrafluoroborate (12). The nitrone 27 was hydrolysed to give the aldehyde 28, which was oxidised with chromic acid and esterified to give the ketoester 29 in poor yield. Hydrogenation of
233 the furan ring in 29 over rhodium produced a mixture, diastereoisomeric at C-2, of tetrahydrofurans 30 and 31, which were separated by chromatography. Base-catalysed epimerisation at C-2 favoured (80:20) the natural threo relationship between C-2 and C-3, and the unwanted isomer 30, on equilibration with a catalytic amount of sodium methoxide, could be converted into its diastereoisomer 31. The reduction of the ketone 31 with sodium borohydride took place with poor selectivity, unfavourable to the natural product (7:10), but the methyl nonactate 32 and methyl 8epinonactate could be separated chromatographically. Schmidt and co-workers (13) also synthesised nonactic acid by hydrogenation of a 2,5disubstituted furan derivative (Scheme 4), which they initially carried out in the racemic series. The reaction of 2-lithiofuran with propylene oxide gave the alcohol, which was converted to the acetate 33. The introduction of the three carbon carboxylic acid unit was achieved by Vilsmeier formylation and a Wittig reaction on the aldehyde 34, followed by carbonylation of the alkene 35, catalysed by a complex of |i-dichloro-bis(7i-hexa-l,5-diene)dirhodium(I) with triphenylphosphine. Oxidation of the resulting aldehyde 36 with silver(I) oxide, followed by esterification gave the ester 37. As with the earlier syntheses, they observed poor control for C-2 and C-8 during hydrogenation of 37 over rhodium on alumina, which produced methyl nonactate as a mixture of diastereoisomers 38, 39, 40 and 41 in a ratio of 25:25:25:25. They examined the possibility of equilibrating these diastereo-
Ph3P=CH2 L'
O
2.AC20
O
oocw.
33
Rha)cat.
g,^^
O
57%
34
9^^
/x,^^^4N^^C02Me u ^ u =
CHO
f-^
CHO
l.Ag20
C02Me
+
H2, Rh/Al203
39
OH
I—V
9"
f-\
• ^ ^ ^ ^
^
X^^C02MQ
^ ' ' ^ V ^ p . ^ v ^ CO2MC
Cr(VI) H2,Ni
^
42
O
I—V
C02Me
H^ H I
H^ H = 43
41
39 -I- 40 + 41
l.TsCl 2. KOAc
-• 3. KOH, MeOH
8-epi-39 + 8-epi-40 + 8-epi-41
4. CH2N2
separate
C02Me 44
Scheme 4 isomers, first by oxidising the 8-hydroxy group to the 8-keto, and regenerating the 8-hydroxy group by catalytic hydrogenation, which gave the mixture of 3 8 , 3 9 , 40 and 41 now in a ratio of
234 19.1:10.8:30.5:39.6. Secondly they found that a Walden inversion sequence could be used to change the relative configuration at C-8. Still in the racemic series, they found that the 8-tosylates gave the C-8 diastereoisomeric acetates on Walden inversion, and hydrolysis gave the diastereoisomers 38,39, 40 and 41 in a ratio of 36.9:32.7:9.6:20.8. The ratio of 8-normal to 8-epi i.e. 38+39 : 40+41 was about 7:3. The racemic methyl nonactate 38 could be separated from the other diastereoisomers by chromatography. Methyl 2-epinonactate 39 could be equilibrated with sodium methoxide to a mixture of methyl nonactate 38 and methyl 2-epinonactate 39 in a ratio of 60:40. Following this exploratory work, the Schmidt group (13) reported the first homochiral synthesis of methyl (-)- and (+)-nonactate using (5)-propylene oxide as the only enantiomerically pure starting material (Scheme 4). This gave the mixture of diastereoisomeric methyl nonactates 38, 39,40 and 41, all with the (5)-configuration at C-8, and chromatographic separation provided 25% of the natural (-) ester 38. The mixture of the other three diastereoisomers (39+40+41) was converted by Walden inversion into a mixture of the same three compounds with C-8 inverted, from which (+)-methyl (25',35,67?,8/?)-nonactate 44 could be isolated in approximately the same amount as its enantiomer 38. White and his co-workers (14) used a Friedel-Crafts acylation of l-(2-furyl)-2-propanol 45, prepared using the same chemistry as Schmidt's (13a), gave the 2,5-disubstituted furan 46 (Scheme 5). Hydrogenation of the furan 46 over rhodium resulted in the c/^-fused tetrahydrofuran alcohol ?"
/"I
Ac20,BF3.0Et2
OAc
OAc
45
2. NaOH, MeOH 52%
2. CrOs, H^ 3. BF3, MeOH 89%
49
^AXV^C CO2H
l.Ph3P,Et02CN=NC02Et,PhC02H
CO2H
9"
,
^
C02Me
2.NaOMe,McOH 90%
Scheme 5 47, which was oxidised with chromic acid to the diastereoisomeric mixture of ketones 48. The last carbon was introduced by a Wittig reaction on the ketone 48 with methylenetriphenylphosphorane,
235
and the correct oxidation state was obtained by hydroboration, followed by Jones oxidation and esterification, to give the keto esters 50 and 5 1 . The hydroboration took place with high regioselectivity and moderate stereoselectivity (2:1) in favour of the unwanted diastereoisomer 51. The diastereoisomers 50 and 51 were separated, and L-Selectride reduction of the derived acid 52 gave again largely the wrong diastereoisomer, 8-epinonactic acid 54, but the configuration at C-8 could be corrected on the derived ester 55 using a Mitsunobu reaction to give methyl nonactate 56. Still's synthesis (15) (Scheme 6) is unique in having excellent stereocontrol over the larger distances, C-2 to C-8 and C-3 to C-6, but is let down by not solving the problem of relating the C-2 and C-8 pair to the C-3 and C-6 pair. Based on the conformational preference of macrocyclic intermediates (16), the stereogenic centre at C-8 provided stereocontrol for enolate methylation at C2, beautifully solving the problem that most besets the approach using the hydrogenation of a furan 1. Pb(0Ac)4, BF3 2. NaOH, McOH
r^
,
59 O
""
0
-=.
CO2H
OH
Corey-Nicolaou
,—(^ ^—1
C °/ =o^ ^i 0. 25-40% •* "O
1. base 2.Md
62
Scheme 6 to establish the relative stereochemistry of C-3 and C-6. The macrocyclic intermediates were constructed using the 2,5-disubstituted furan 59 attached to various spacer groups as in the hydroxy acid 60. Macrolactonisation using the Corey-Nicolaou thiopyridyl ester method gave the lactone 61 having a p-xylyl spacer, which, of those tried, proved to give the best results. Methylation of this lactone gave the diastereoisomer 62 with excellent selectivity (>70:1). Lithium aluminium hydride reduction followed by catalytic hydrogenation provided a 1:1 mixture of the reduced nonactic acid derivative 63 and its diastereoisomer 64. 2.2 Hydrogenation of a Bartlett Type Intermediate The Bartlett approach is based on the hydrogenation of a double bond exocyclic to a tetrahydrofuran ring, simultaneously establishing the desired stereochemical relationship between C2 and C-3, because of the syn stereospecificity of the reaction, and between C-3 and C-6, because hydrogenation takes place stereoselectively on the less hindered face, anti to the side chain on C-6.
236
This approach is very popular because all that is left to control is the 1,3-diol stereochemistry between C-6 and C-8. In 1977, Bartlett and Jemstedt (17) developed a stereocontrolled synthesis of 1,3-diols from homoallylic alcohols (Scheme 7). They found that diethyl 4-penten-2-yl phosphate 65 undergoes an intramolecular cyclisation in the presence of iodine to set up both groups in the ring 66 cis and presumably diequatorial. Arbuzov reaction then gives the cyclic phosphate 67 more than 90% diastereochemically pure. EtO OEt
EiO O
OEt
I2. MeCN, 2 5 X
87%
•V-^ r
-EU
EtO
o>"-o 67
66
65
Scheme 7 In their first and racemic synthesis of methyl nonactate 75 (Scheme 8), Bartlett and Jernstedt (18) introduced the 1,3-relationship between C-6 and C-8 in a diastereoselective manner from the diene 68, which gave the analogous cyclic phosphate. Upon treatment with sodium methoxide, the phosphate gave the epoxide 69, which was converted into the syn-l,3-d\o\ 70. Acetylation of the diol followed by ozonolysis gave the aldehyde 71. Aldol condensation of the aldehyde with the silyl
2. NaOMe, THF
1. Ac20,Py 2.03,CH2Cl2
^
^
1. MeCH=C(0Me)0SiMe3 TiCl4, CH2CI2, -78°C
OAc OAc
CHO
3. Me2S
2. CrOs, Me2C0, H2SO4
95%
90%
^
^.
OAc OAc CO2MC
71
l.K2C03,MeOH
H2, Rh/Al203
C02Me
2. (C02H)2 80%
87%
CO2MC
icis:trans = ^5:\5)
l.Et02CN=NC02Et PPh3, PhC02H, THF
^
C02Me
2. NaOMe, MeOH 95%
Scheme 8
enol ether of methyl propanoate in the presence of titanium tetrachloride at -78 °C followed by Jones oxidation of the aldol product gave the p-keto ester 72. The tetrahydrofuran ring was constructed by acetate cleavage and dehydration with oxalic acid giving methyl (E)-8-epi-2,3-dehydrononactate 73 as a single geometrical isomer. The C-2 and C-3 stereocentres of methyl nonactate were then
237 generated stereospecifically by hydrogenation of the double bond using rhodium on alumina, and at the same time the C-3 and C-6 centres were produced selectively (cisitrans = 85:15). Finally, the C-8 centre in the 8-epinonactate 74 was corrected through a Mitsunobu inversion-and-hydrolysis procedure to give methyl nonactate 75. In continuation of this work on acyclic stereocontrol, Bartlett and his co-workers developed a better method for the stereocontrol led synthesis of 1,3-diol derivatives, finding that a rerr-butyl carbonate group was better than the phosphate group in iodocyclisation (19), and applied this technique in an enantiodivergent synthesis (20) of both nonactic acids using the enantiomerically pure carbonate 84, synthesised by the route shown in Scheme 9. Starting in the chiral pool, dimethyl (5')-(-)-malate 76 was converted successively to the diol 77, the epoxide 78 and the dienol 79. Iodocyclisation of the r^rr-butyl carbonate 80 took place with good diastereoselectivity (cis:trans = 6.5:1) to give the cis cyclic carbonate 81, which was reduced with tributylstannane to give the carbonate 82. Ozonolysis gave the aldehyde 83, and the same sequence of steps as in the earlier, racemic synthesis (Scheme 8) then gave the p-keto ester 84, which was the common intermediate for both enantiomers of nonactic acid.
Me02C
OH A^COsMe
l.Tia4,CH2Cl2,-78X
_—.
,
l.TsCl,Py 2. PPTS 3. K2C(^
OEt 1. Ll ^ .PPTS 1.
O^
1^
2. MeCH=C(0Me)0SiMe3 3. C1O3, H2SO4 75%
84 Scheme 9
Methanolysis of the carbonate protecting group in 84 (Scheme 10) followed by oxalic acidcatalysed dehydration gave the (+)-enantiomer, (65,8/?)-(E)-2,3-dehydrononactate 85, hydrogenation of which gave the (-) enantiomer 86 of methyl 8-epinonactate as the major product (88%). For the synthesis of methyl (+)-nonactate 88 from the common intermediate 84, the p-keto ester group was used in a nucleophilic attack to invert the configuration at C-6, with the cyclic carbonate group acting as the leaving group. The dehydrononactate 87 thus produced was then converted mostly (88%) to methyl (+)-nonactate 88 by hydrogenation. The methyl (-)-8-
238 epinonactate 86 and methyl (+)-nonactate 88 were used for the synthesis of nonactin itself (Section 3.2). O OH
l.K2C03,MeOH
C02Me
^
C02Me 2. (C02H)2 84 O 76% 1 KH,HMPA.THF 92% C-6 inversion
85
I H2, Rh/Al203
C02Me
100%
C02Me
lH2,Rh/Al203
H^'HE 86
100%
C02Me
Scheme 10 Johnson and his co-workers developed two routes for the diol 95 corresponding to the carbonate 82 of Bartlett's synthesis. In their first approach (Scheme 11) (21), they coupled the acetal 89, derived from (/?,/?)-2,4-pentanediol and 4-pentenal, with a-trimethylsilylacetone or the trimethylsilyl enol ether of acetone in the presence of titanium tetrachloride. The reaction took place OSiMes ^/^^^
O
or
Q O ^Q
TiCl4, CH2CI2
-^
o
89% or 93% 90
A
90:91=97:3
OTBDMS
o 91
OTBDMS
iiiiiL
1. TBDMSCl, imidazole
O
9
L-Selectride OH
9
2. HPLC 92 l.Ac20,Py 2. BU4NF 3. PCC 90%
,„„l^ OAc 9 x^\.'^' 94
93 + 8-epi-93 4:l l.base 2. deacetylation
vx''^^^ + 8-epi-94
OH OH
3 chromatography 75%
95
Scheme 11 with high diastereoselectivity (90:91 = 97:3). The rerr-butyldimethylsilyl ether 92 of the major diastereoisomer was reduced with L-Selectride to give a 4:1 mixture of syn 93 and anti (8-epi-93, nonactic acid numbering) isomers, which was quantitatively converted to the corresponding acetates.
239 Desilylation with tetrabutylammonium fluoride gave a mixture of hydroxy acetates, which were oxidised with pyridinium chlorochromate to the ketoacetates 94. p-Elimination under basic conditions and deacetylation gave the mixture of diols 95 and 8-epi-95, which were separated by chromatography. In their second approach (Scheme 12), Johnson and his co-workers used the acetal 96 derived from (35)-butane-l,3-diol instead of from (/?,/?)-2,4-pentanediol (22). As in the earlier work, the Mukaiyama aldol condensation of acetal 96 with acetone trimethylsilyl ether gave a mixture of diastereoisomers 97 and 98 in a ratio of 96:4. In contrast, however, the removal of the chiral auxiliary was achieved without the need for first reducing the ketone group. Oxidation of the aldol OH
^ 97 O
l.PCC
OH
2. Bn2NH2'' CF3CO2" 82%
97:98 = 96:4
n-Bu3B, NaBH4
OH OH
78%
99
98
100 + 2-epi-100 97:3
Scheme 12 product 97 to the aldehyde allowed a selective p-elimination with dibenzylammonium trifluoroacetate. 5j^z-stereoselective reduction of the free aldol product 99 by Narasaka's method (23) using tributylborane and sodium borohydride gave a 97:3 mixture rich in the (2/?,45)-oct-7-ene2,4-diol 100, the diol intermediate in Bartlett's synthesis. Lygo and his co-workers (24) have demonstrated that ether substituents a or p to an epoxide remain unaffected during the reaction of an epoxide with p-ketoester dianions yielding e-hydroxy-pketoesters. These intermediates can be easily cyclised to the cycHc enol ethers needed for the Bartlett O- O"
OMe l.NaH,BnBr 2. MCPBA
102 OBn
l.H2.Pd/C C02Me 104
2.H2,Rh/Al203 95%
54% from 101
OBn OH 103
101 OBn
(C02H)2
CO2MC
OH I—y
OH
^ T ^ H T 105
I—^
-^^-^T^nO^-^ H
1:1
CO2MC
H
106
Scheme 13 approach. Thus the epoxy ether 101 and the p-ketoester dianion 102 gave in one pot the (9-benzylprotected dehydrononactate intermediate 104 as a mixture of diastereoisomers (Scheme 13).
240
Hydrogenolysis using palladium on charcoal, followed by stereoselective hydrogenation of the double bond using Bartlett's conditions gave a 1:1 mixture of racemic methyl nonactate 105 and methyl 8-epinonactate 106, which were separated by chromatography. Lygo (25) has also developed a strategy for the synthesis of nonactic acids and its homologues, using the same chemistry, but starting from 3-butenol 107 instead (Scheme 14). Benzylation, epoxidation and regioselective epoxide opening with the same 3-ketoester dianion 102 gave the intermediate p-ketoester 109. Oxalic acid-catalysed dehydration and cyclisation gave the Bartlett-type intermediate 110. Hydrogenolysis and stereoselective hydrogenation gave the primary alcohol 111, which has all the stereocentres properly established except for C-8, and is suitable for the synthesis both of nonactic acid and its homologues. Oxidation of the alcohol using pyridinesulfur trioxide in dimethylsulfoxide and triethylamine gave the aldehyde 112 in 86% yield. 0" O"
l.NaH.BnBr OH
^
2.MCPBA
OBn I—.
110
•
102
.C02Me
0B„
92%
107
^
57% from 108
OBn OH
,ft«
109
1^« l.H2,Pd/C 9 "
/—V
Rh/AljOa 93%(d5:fran5 = 8:l)
^^l
SO3, DMSO =
86%
(C02H)2
/—\
112
'
Scheme 14 This aldehyde had already been converted (26) to methyl nonactate and methyl 8-epinonactate with high selectivity using titanium tetrachloride catalysed addition of dimethyl zinc and lithium dimethylcuprate, respectively. Lygo also found that dialkylzinc addition under different Lewis acid conditions gave different diastereoisomers with high selectivity (Scheme 15).
0«^vxt^V^C02Me H'^HE
112
• RA.^/3Wc02Me ^ ^ H^Hi 113 Et2Zn,TiCl4 R=Et 4:1 Et2Zn, BF3.0Et2 R=Et 1:10 Me2Zn,TiCl4 R=Me 24:1 Me2CuLi R=Me 1:4.5
A,X\^C02Mc H^Hi 114 85% 80% 85%^^ 78%^^
Scheme 15 Deschenaux and Jacot-Guillarmod synthesised the Bartlett intermediate 124 with a chiral pool source and the Narasaka 1,3-diol synthesis for the C-6 to C-8 relationship (Scheme 16) (27). Methyl (-)-(3/?)-3-hydroxybutanoate 115 (e.e. >99%) was converted to the p-ketoester 116. Reduction of the p-ketoalcohol using the Prasad version of the Narasaka method (23) with diethylmethoxyborane and sodium borohydride giving the diol 117. The acetonide 118 was homologated by way of the
241 alcohol 119 and tosylate 120 to give the nitrile 121 and hence the carboxylic acid 122. The imidazolide of the acid and the magnesium salt of monomethyl malonate gave the p-ketoester 123. Acid catalysed deprotection of the acetonide and concomitant cyclisation of the diol intermediate gave OLi
nS(99%ee)
9
y^
„6
''''
9
Li^^H4
^^^'-^^^ 118
0
W
9
y
9 ? ^
96% ^ ^ " V - ^ ^ v , ^ 119
0
Amberlyst-15 OH
c T
C02Me ^^^
in
''"^
l.TsCl,Py
2.BU4NCN
3.NaOH
j—y
9
9 ^
l.CO(Im)2
^"^.-'-'^^^ 2. COiMe 120 X=OTs 93% — ( 121 X=CN 80% C02)2Mg 122 X=C02H 70% 88% H2, OH .—y
-- --^1 o ^
123
y
^^^^
Rh/Al203
124 (95% ee)
H^ H Y
95%
125
Scheme 16 Bartlett's intermediate 124, and catalytic hydrogenation over rhodium on alumina gave methyl (-)-8epinonactate 125. Kim and Lee have developed syntheses of methyl (+)-nonactate 134 and of methyl (-)-8epinonactate 135 by way of Bartlett's intermediate 133 (=82) (Scheme 17) (28). They used a MO, iy^2
X\ l.TMSCI,Et3N ^-O TBDMSCl, N-0 . x ^ W 2.TsOH // \ nw imidazole // ' ' ^*S ^ • separation O O2 4. L-Selecuide 126 63% H2,Raney-Ni, o OH Et2B0Me, NaBH4 OH OH boric acid ^ l ^ I ^ o - m n x . . THF.-78°^ , A J k . O T B D M S '• Me^CCOMeh.PPTS 86% 86% 2. BU4NF 129 130 synianti = %:4 „_^
^..-v
^y^ I I 131
^„
l.TsCl,Et3N,DMAP 2. allylMgCl. Cul 3.TsOH
132
Q
^
am)2C0 73%
o / /o
^A^ I I
133
OH y ^ \ I \ n^\\^^ and x ^ ^ x x f ^ ^ ^ f v ' ^ H ^ HE 135 Scheme 17 dipolar cycloaddition to an acrylic acid group attached to Oppolzer's chiral auxiliary 126 to set up the Bartlett routes
OH \
75% y V I \
^^^^ I I
r>c\ XK ^C02Me
first stereogenic centre (29), and Narasaka's method again for the C-6 to C-8 relationship. The syn
242
1,3-diol 130 was synthesised from the isoxazoline 127 after protection of the hydroxy! group with r^rr-butyldimethylsilyl chloride by reductive cleavage with the Raney-nickel-boric acid system and the Narasaka reduction (23) of the p-ketoalcohol intermediate 129. The 1,3-diol 130 was converted to the diol 132 by standard synthetic transformations involving protection of the diol as its acetonide, and deprotection of the 0-silyl group to give the primary alcohol 131. Tosylation, copper-catalysed tosylate displacement with allylmagnesium chloride, and deprotection gave the diol 132, which was converted to its cyclic carbonate 133 (=82) using l,r-carbonyldiimidazole. The rest of the synthesis intersects with that of Bartlett and his co-workers (20). Kim and Lee also developed another enantioselective synthesis of methyl (-)-8-epinonactate (Scheme 18) (30) based on the same nitrile oxide cycloaddition product 127 used in their earlier synthesis. The enantiomerically enriched alcohol 127 (>98%e.e.e.) was converted to its iodide l.PPh3,12. iniidazole O" 0 " 2. < A ^ o M e N-0
N-0
3.CuI
127
H^ 137
I
1. chromatography 2. L-Selectride ^ 3. chromatography 75%
i I 136 °
59%
2. PCC 75%
1. H2,Raney-Ni, ^"^^^
2.(C02H)2 77%
H^ H= 138 " (major:minor = 91:9)
QT, V I \ /k^O-K/C02Me H H= 139
Scheme 18 using triphenylphosphine, iodine and imidazole, and the iodide treated with the dianion of methyl 2methylacetoacetate to give the p-ketoester 136. Reductive cleavage of the isoxazoline ring followed by oxalic acid-catalysed cyclisation gave the ketone 137 corresponding to Bartlett's intermediate. Rhodium catalysed hydrogenation followed by PCC oxidation provided the ketone 138 where the C-2, C-3 and C-6 centres are correctly established. The last centre at C-8 was regenerated by a stereoselective reduction of the ketone 138 with L-Selectride (14), which provided the methyl (-)-8epinonactate 139. Barrett and Sheth synthesised rerr-butyl (±)-8-0-rerr-butyldimethylsilylnonactate 145 by a stereoselective hydrogenation of 8-0-t-butyldimethylsilyldehydrononactate 144, the 8-epimer and 80-protected analogue of Bartlett's intermediate, and solved the C-6 to C-8 problem in a completely different way by another hydrogenation (Scheme 19) (31). 2,3,5-0-Triacetyl-D-ribonolactone produced the achiral diene 140 on treatment with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Hydrogenation of the diene stereoselectively (>97:3) gave the lactone 141, establishing the relative stereochemistry at C-6 and C-8. Diisobutylaluminium hydride reduction of the lactone gave the lactol 142. Wittig reaction, followed by catalytic hydrogenation over rhodium on alumina gave a lactone,
243
and protection of the free hydroxy group gave its silyl ether 143. Claisen condensation and dehydration gave the dehydrononactate intermediate 144, and the usual catalytic hydrogenation over rhodium on alumina then provided the O-silyl derivative 145 of racemic ten-butyl nonactate. AcO
OAc
OAc
DBU
AcO
DIBALH
O 140 l.Ph3P=CHC02Et 2. H2, Rh/Al203 TBDMSO
jP"
-AX.
85%
X ^ Q - ^ OH 142
OTBS
—'A Pd/CaCOs
94%
3. TBDMSCl 55%
CO2BU'
_/^^''
O 141
OLi
2. Ambcrlilc 120 h 75%
143 OTBS
H2,Rh/Al203 89%
144
90%
{cis:trans - ^5:\5)
145
Scheme 19 Sutherland and his co-workers developed a concise route for the synthesis of Barrett's intermediate 148, also using hydrogenation of a cyclic intermediate to establish the C-6 and C-8 OH
1. H2,Rh/Al203 O 2. PhCOCl, Py ,x^,>^^^
NaOMe, MeOH
MCPBA
3. Cr03, H-'
93% OBz
^^
/'^-S^Q'^O
H
BzO
148 147
146
Scheme 20 relationship (Scheme 20) (32). Catalytic hydrogenation of methyl hydroquinone, benzoylation and chromic acid oxidation gave the c/5-2,4-disubstituted cyclohexanone 146. Baeyer-Villiger oxidation ^^.^ss^CHO
L-(+)-diisopropyl tariaratc
+ ClMg.
^.
149 (£:Z = 96:4) OH OH
45% conversion OAc OAc
150 RuCl3,NaI04
96% ee K2CO3, MeOH
9^' 9^' CO2H
86%
x-^v^^>^0 H 154
153
Scheme 21 of this ketone took place regioselectively to give the lactone 147, which on methanolysis gave the racemic lactone 148. Sutherland and co-workers also developed an enantioselective route (Scheme
244 21) (32), based on Sharpless asymmetric epoxidation (33), for the synthesis of Barrett's intermediate 154. This synthesis of Barrett's intermediate also involves the synthesis of the diol 151, a diastereoisomer of the diol 70 in Bartlett's nonactic acid synthesis. 3-Butenylmagnesium bromide and crotonaldehyde gave the diene alcohol 149. The diol 151 was then made in 96% e.e. by kinetic resolution using Sharpless epoxidation, followed by reduction of the epoxide with red-Al. The diacetate 152 obtained from the diol was oxidised with ruthenium trichloride-sodium periodate (34) to give the acid 153, which was converted to Barrett's lactone 154, but now in homochiral form. Batmangherlich and Davidson developed an enantiodivergent route to both enantiomers of tenbutyl nonactate by way of the lactone 156, with C-6 obtained from the a-C of glutamic acid 155 (Scheme 22) (35). The hydroxylactone 156 was protected as its rerr-butyldimethylsilyl ether, which steps
silyl protection
HO2C—< CO2H NH2 155
I. hydrogenation ——1 ^ 2. desilylation 60% from 156
OLi 156
TBDMSO. 157
OBu'
,,^ / \ ^^ ^ , l.Swem HO^^^^COjBu^ ^ H H I 2.Ph3P=CHMe (-)-158 (95% one isomer) 50%
l.NBS.DMS0,H20
OH V"
2. Bu3onH 60%
/—V H^
CO2BU'
OH
,
V"
H H = 160
/ \ ^^ ^ , k^^.^C02Bu'
/"A H^H i 161
H
H =
159
160:161 = 1:4
Scheme 22 condensed with the lithium enolate of r^rr-butyl propionate to give the dehydro intermediate 157. Hydrogenation gave the tetrahydrofuran 158 with the correct stereochemistry required for C-2, C-3 and C-6. The chiral centre at C-8 was introduced in the wrong sense by a stereocontrolled bromohydrin formation on a c/^-olefm 159, controlled by the alkoxy group at C-6, and the bromine removed reductively. This gave a 1:4 mixture of r^rr-butyl (-)-nonactate 160 and rerr-butyl (-)-8epinonactate 161. OLi J hydrogcnauon
TsO.
(+)-158 90% one isomer
165 Scheme 23
For the synthesis of the (+)-enantiomer 165, the configuration at C-6 in the common intermediate 156 was inverted (Scheme 23). The p-toluenesulfonate 162 of the lactone 156 was
245 treated with the lithium enolate of tert-butyl propionate to give, by way of the epoxide 163, the (E)alcohol 164, duly inverting the stereochemistry at C-6. Hydrogenation of the dehydro derivative 164 then gave the alcohol (+)-158 with the desired stereochemistry at C-2 and C-3 as well. The centre at C-8 was then set up in the same way as before. Batmangherlich
and Davidson
(35) also resolved racemic methyl nonactate by
chromatographically separating its esters 167 and 168 with (5)-0-acetylmandelic acid (36).
Ph
Ph OAc
C02Me
OAq
^X'^'^vxt^O'W H ^H
167
C02Me
i
168
Honda and his co-workers synthesised methyl (+)-nonactate 179, setting up the C-6 to C-8 relationship by a chelation controlled allylsilane reaction on the aldehyde 169, and the C-3 centre by hydrogenation of the dehydro intermediate 176 carrying two methoxycarbonyl groups (37) (Scheme 24). The thiolactone 175 and dimethyl diazomalonate gave the dehydro intermediate 176 in the presence of dirhodium tetraacetate, by way of a sulfur-ylid rearrangement developed by these
OBn
SiMe3
1
TiCU
OBn OTHP
83%
OBn uan
l.HCl,H20
OBn OTHP
»-
3. Swem 4.NaC102, ^,,^^ KH2PO4, T 75%
2. DHP, PPTS 169
l.B2H6,THF 2.H202,NaOH
I—I
171 R=CH20H 172 R=CHO 173 R=C02H OBn
N2=C(C02Me)2, Rh2(OAc)4
2. Lawesson's reagent 83%
1. H2, Pd/C, 7 atm.
174 X=0 175 X=S C02Me
»
2. HCl, H2O, MeOH
177
C02Me
l.TBDMSCl, imidazole 2. KOBu\ Mel 100%
1. BU4NF 2. NaCl, DMSO, H2O
TBDMSO
OH
CO2MC ' C02Me
/-^ C02Me
C02Me H^H 1:1
i
180
Scheme 24 workers (38) and by Takano and his co-workers (39). The dehydro intermediate 176 was hydrogenated using different conditions (10% Pd-C, MeOH-5% HCl) from Bartlett's, and obtained a 4:1 mixture of cis and trans tetrahydrofurans 177. Protection of the hydroxyl group with ten-
246 butyldimethylsilyl chloride followed by methylation of the protected diester gave the ester 178. The stereochemical control for the C-8, C-6 and C-3 centres was good, but no control at C-2 was observed during Krapcho decarboxylation of the malonate derivative 178, which gave a 1:1 mixture of methyl (+)-nonactate 179 and its diastereoisomer at C-2 180.
2.3 Cyclisation of a 1,4-Diol Derivative. This approach requires both a method for setting up the C-3 and C-6 oxygen functions with the correct relative stereochemistry to give the c/5-2,5-disubstituted tetrahydrofuran ring, and their differenriation in order to use the selective displacement of one of them with inversion of configuration. Only two groups have used this approach. Takatori's group prepared both C-3 and C6 diastereoisomers, and made the overall synthesis convergent by separating them, and converting the wrong isomer into the right one with a Mitsunobu sequence. The Fleming group used two silicon-based approaches. In one, the C-3 and C-6 centres were set up with independent absolute control as C-Si bonds, which were later converted to C-0 bonds, and in the other they were set up by moving the chiral information along the chain. Takatori and his co-workers (40) started from the y-dithio-p-hydroxy ester 181 as a homochiral building block derived by yeast reduction of a ketone supplying C-3 ready resolved (Scheme 25). The ester 181 was methylated with stereocontrol at C-2 by the method of Frater (41), and the product converted by way of the C-1-reduced and protected intermediate 182 into the lithium OH l.LDA,THF TBDMSO ^ S ^ J k ^ C O ^ E t 2.McI,THF,HMPA ^S^^XlJ 3.LiAlH4 X^S
181
V^CHO BOMO i«^ bUMU 184 HMPA 73%
^^fpP'BOMO 82%
r
4:TBDMSC1
H" H = 187 "
OTBDMS
^ 182
TBDMSO OTBDMS I I . . o , ^X^ J l.separauon& recycle , OH ,«c 3. TsCl, DMAP, EtsN ^^MO
^
TBDMSO
^ ^ 8 2
49^^
, BOMO
OTBDMS l.Mel.CaCOs 2. PhgP, CBr4
l.ClO3,H2S04, OH^^Me^CO ^H 3.H2,Pd/C 43%
^
^^^
H^ H E 188 "
95%
TBDMSO I
OH
OTBDMS i
^ H^ H= 189
Scheme 25 acetylide 183 by way of the vinyldibromide. This acetylide was added to the known homochiral aldehyde 184 to give the alcohol 185 as a 1:1 mixture of diastereoisomers, but separation, and recycling of the undesired diastereoisomer by a Mitsunobu inversion-hydrolysis sequence (not illustrated, but taking place in 61% conversion yield), overcame the lack of selectivity. Catalytic hydrogenation provided the differentially protected 1,3,6,8-tetraol, which was tosylated to give the C-6 tosylated derivative 186. Deprotection of the C-1 and C-3 hydroxy groups gave the cis-
247
tetrahydrofuran derivative 187, the cyclisation taking place with complete inversion of configuration at C-6. Oxidation of the primary alcohol group gave a carboxylic acid, which was esterified with diazomethane and subjected to hydrogenolysis to give methyl (-)-nonactate 188, and hydrolysis gave (-)-nonactic acid 189. Fleming and his co-workers developed two independent methods for the synthesis of methyl nonactate by ring closure of 1,4-diol derivatives. The stereochemical control needed for the synthesis of the appropriately substituted 1,4-diol derivatives was based on their work on acyclic stereocontrol using organosilicon compounds, and their routes are unique, and in consequence uniquely long, in eschewing cyclic control almost completely. The three aspects of their method of stereocontrol are: the transposition of chiral information from C-1 to C-3 in the electrophilic substitution of allylsilanes (42), the setting up of stereogenic centres with a 1,3 relationship using the hydroboration of allylsilanes (43), and the setting up of stereogenic centres with a 1,2 relationship by alkylation of enolates having a p-silyl group (44). The hydroboration and enolate alkylations leave the phenyldimethylsilyl group in the molecule, and it is converted, with retention of configuration, into a hydroxy group at an appropriate stage (45). Perhaps the most striking feature of these methods of stereocontrol is the sense in which the word "control" really means control: with each method, it is possible to obtain relative stereochemistry in either sense, making the methods equally suitable for the synthesis of any diastereoisomer. In the first route (Scheme 26) (46), the 1,4 diol system was set up by independently introducing silyl groups with absolute stereochemical control, that at C-6 by a stereospecific allylsilane synthesis from a homochiral allylic alcohol derivative, and that at C-3 by conjugate addition of a silylcuprate to an a,p-unsaturated carboxylic acid attached to a chiral auxiliary. Formation of the c/5-2,5-disubstituted tetrahydrofuran was achieved by converting the phenyldimethylsilyl groups into hydroxy groups, and differentiating between them in order to ensure that inversion of configuration took place at the desired centre. The C-2 and C-3 relationship was estabUshed by anti-scltciiwt methylation of a p-silyl enolate, and the C-6 to C-8-relationship was set up by hydroboration-oxidation of a trans allylsilane. The (5)-propargylic alcohol 191 (70% e.e.) was prepared from the ketone 190 using (S)alpineborane following Brown's and Midland's procedures. The alcohol 191 was converted to its carbamate, semihydrogenation of the triple bond of which gave the c/5-alkene 192. Stereospecific silylcupration (47) then gave the (£')-allylsilane 193. Hydroboration with thexylborane followed by alkaline hydrogen peroxide oxidation gave the anti alcohol 194 with high selectivity {antr.syn =95:5). For the synthesis of the (-i-)-enantiomer, this alcohol was subjected to a Mitsunobu inversion to give the syn diastereoisomer, which was protected as its benzyl ether 195. The aldehyde group in 195 was unmasked, and a Wittig-Homer reaction using the phosphonate 196 carrying Koga's chiral auxiliary gave the a,p unsaturated imide 197. Silylcupration on this imide gave an inseparable mixture of diastereoisomeric bis-silyl derivatives 198 with poor selectivity (2:1) in favour of the isomer illustrated. Stereoselective methylation on the p-silyl ester gave the ester 199, conversion of the silyl groups to hydroxy using mercuric acetate and peracetic acid then gave the 1,4-diol derivative, which was hydrolysed to the acid 200. The only problem left to solve was to differentiate
248
the two hydroxy groups, which was achieved by treatment with an excess of benzenesulfonyl chloride. Two things happened: protection of the C-3 hydroxy group as the p-lactone 201 and benzenesulfonylation of the C-6 hydroxy group. The p-lactoneringopened in acidic methanol and ring closure promptly took place, with inversion of configuration at C-6 to give a mixture of 0OH
1. L i - s 2.BuLi,THF O ^
3.AC2O 61%
1. PhNCCEtsN
190
OCONHPh
^.
2.H2,Pd/CaC03 PbO, MnCl2 91% OH
5-alpine borane, THF
SiMe2Ph
9
) ^O
192
ij
h. 70% ee
l.BuUTHF 2.CuI,Ph3P
SiMe2Ph
2. H2O2, NaOH 82%
3. PhMe2SiLi 73%
1.4-02NC6H4C02H,Ph3P, Et02cN=NC02Et 2. NaOH, MeOH
1. thexylborane
OBn SiMe2Ph
l.TsOH,Me2CO,H20 Ph3C0-.,,
3.BnOC(CCl3)=NH,TfOH
rs
•(EiO)20P'^^^ 0 0 86% 196 Ph3C0—., l.McOMgBr 2. LiHMDS
194 Ph3C0—. OBn SiMe2Ph
^-
3. McI, DMPU 73%
197 OBn SiMe2Ph
PhS02Cl, Py C02H'
PhMe2Si
64%
199 OBn 0S02Ph
OH y — y
l.TsOH,MeOH O
2.H2,Pd/C 83%
C02Me
C02Me H 202
HE 203
Scheme 26 benzyl methyl (-i-)-nonactate together with other diastereoisomers. Removal of the benzyl protection by hydrogenolysis gave methyl (+)-nonactate 202, which was separated from the other isomers with the major byproduct being its C-2 and C-3 diastereoisomer 203. Two successive reactions independently setting up stereogenic centres has an arithmetical advantage, at some expense in overall yield, with respect to the enantiomeric purity of the major product, as Horeau (48) and Eliel (49) have pointed out. Although the selectivity in the steps leading to 191 and 198 are only 85:15 and 67:33, respectively, the methyl (+)-nonactate 202 and its enantiomer were obtained at the end of the sequence in a ratio of 92:8. This is because the proportion of the major enantiomer 202 is obtained by multiplying 0.85 by 0.67, whereas the proportion of the minor enantiomer is obtained by multiplying 0.15 by 0.33. The enantiomeric purity of the
249 intermediate alcohol 191 could be raised to >97% e.e. by three recrystallisations of its 3,5dinitrobenzoate 204, which would make the whole synthesis capable of delivering methyl nonactate of >99% enantiomeric purity (50).
3,5-(02N)2C6H3COCl T'^v
Et3N,DMAP
^ ^
98%
In the second route (51), Fleming and Ghosh developed an enantiodivergent approach in order to synthesise both enantiomers. Two silyl groups were set up on adjacent centres, destined to become C-3 and C-4, with a known 1,2-relationship between them. The silyl group on C-4 was then made part of an allylsilane 212 so that the stereochemical information could be moved three atoms along the chain by epoxidation, leaving a 1,4 relationship between the remaining silyl group at C-3 and the incoming oxygen atom at C-6 in the alcohol 215. The C-6 to C-8 relationship could then be controlled in either sense by reduction of a p-hydroxyketone using Evans's and Narasaka's methods, and the C-2 to C-3 relationship could be set up reliably by enolate methylation. By a suitable choice of reactions, the common intermediate 215 was converted into both (+)- and (-)-nonactic acid derivatives. The synthesis of the first homochiral intermediate 209 is shown in Scheme 27. The dimethyl meso 3,4-bistolyldimethylsilyladipate 205 was prepared by a samarium(II) iodide induced coupling ^ O ^ ^ SiMe2Tol l.LiOH,MeOH„THF SiMe2ToI Sml2, THF, DMPU ,C02Me '^5^C02Me " i r n r T T T — ^ Me02C' 2.DCC CH2(C02Me)2 SiMe2Tol ToIMe2Si SiMc2Tol 72% 205 206
'U
5'^^^™ ,.Mc3Si(CH,),0H, CO2H ix:c, DMAP •
HO2C ^ r ^^
84% from 205
207
o
2. H2, Pd/C %:4
TolMe2Si CO2H
Me-iSi' O
SiMe2Tol 209
Scheme 27 of the methyl (Z)-2-tolyldimethylsilylacrylate in THF-DMPU in the presence of dimethyl malonate (52). The homochiral mono 2-trimethylsilylethyl ester 209 of the dicarboxylic acid was prepared from the dimethyl ester 205 in four steps. Lithium hydroxide gave the dicarboxylic acid, which was
250 converted into the meso anhydride 206 by treatment with dicyclohexylcarbodiimide. Diastereoselective opening of the me5o-anhydride with Heathcock*s /?-(+)-2-naphthylethanol (99.7% e.e.) (53), the enantiomeric purity of which was raised by Horeau's method (54), gave a 96:4 mixture of diastereoisomeric mono-esters 207 and 208. Esterification of the mixture with 2trimethylsilylethanol gave the mixture of diastereoisomeric diesters, which was hydrogenolysed to give the mono-ester 209 with an e.e. of 92%. The allylsilane 212 and the common intermediate 215 were made from this monoester (Scheme 28). The lithium dianion of the acid-ester 209 was treated with the aldehyde 210 and the mixture of four diastereoisomeric aldols 211 esterified with diazomethane. The four possible diastereoisomers, present in a ratio of 76:9:9:6 were separated and the 2-trimethylsilylethyl ester group removed by treatment with tetrabutylammonium fluoride. The individual diastereoisomeric 1.2LDA,THF,DMPU CHO McsSi 2. O J )
TolMe2S MesSi' O
SiMe2Tol
3. CH2N2 75%
209
211a and 211b: 3. PhS02Cl, Py 4. collidine, heat
SiMe2Tol
211c and 211d: O O 3. Me2NCH(OCH2Bu')2 ^—^ CHCI3, reflux 93% SiMe2Tol .^^^^Ji^^^CQ^H
KH,THF O
O
OSiMe2Tol 214
^\
SiMe2Tol 2. Bu4NfF, THF
P OH SiMe2Tol 4:5,5:6 211a synsyn 76% 211b anu,syn 9% 211c syn,anu 9% 21 Id anti.anti 6%
TolMe2Si SiMc2Tol ^ = Hi
l.KOH,THF,MeOH 2.MCPBA,Na2HP04 O \ CH2CI2 92%
O jC,^^ / / OH O - ^ 213
O
H2,Pt02,MeOH 87% from 213 O 215
Scheme 28 hydroxy acids were each converted to the required trans allylsilane 212, by syn stereospecific decarboxylative elimination by way of their p-lactones for the acids derived from the esters 211a and 211b, and by and stereospecific decarboxylative elimination for the acids derived from the esters 211c and 21 Id, following chemistry developed earlier (55). The methyl ester was hydrolysed to the acid, which was epoxidised using m-chloroperoxybenzoic acid. The epoxide must have been produced with high anti stereoselectivity (antr.syn = 97:3), but it rearranged to the 7-lactone 213 by a stereospecific 1,2-shift of the silyl group from C-4 to C-5, probably with retention of configuration at C-4 and inversion at C-5 (56). The alcohol 213 on treatment with potassium hydride under the conditions of standard Peterson olefmation underwent stereoselective eliminative rearrangement, well precedented in the work of Yamamoto (57), to give the unsaturated acid 214. Deprotection of the 0-
251 silyl ether and hydrogenation of the double bond gave the hydroxy acid 215 in 41% overall yield from the adipate ester 205. The hydroxy acid 215 was the common intermediate for the synthesis of both methyl (+)-nonactate 220 (Scheme 29) and benzyl (-)-nonactate 227 (Scheme 30). The ketal 215 was hydrolysed with pyridinium tosylate and the ketoalcohol reduced stereoselective^ to the and 1,3-diol 216 (antiisyn = 96:4) using Evans's method (58). The C-6 and C-8 hydroxyl groups were differentiated by formation of the seven-membered lactone 217 using Mukaiyama's method (59). The minor enantiomer of the lactone 217 was largely removed because the racemate crystallised, thereby improving the e.e. from 92% to >99%. The 8-hydroxy group was SiMe2Tol ,C02H l.PPTS,Me2C0 O
O
u y OH 215
SiMe2Tol CO2H
l.TBDMSCl, imidazole 2. LDA, THF, DMPU SiMe2Tol • TBDMSO 3. Mel
O.
92%
TBDMSO
1^
2. separate from racemate 90%
2. Me4NBH(OAc)4 87%
SiMe2Tol
0 218
l.TsCl,DMAP,Py ^. 2. TsOH, MeOH
KBr, AcOOH ^> NaOAc, AcOH 73%
C02Me 220
91%
Scheme 29 protected as its rerr-butyldimethylsilyl ether, and the lithium enolate was methylated to give the lactone 218. Conversion of the tolyldimethylsilyl group into the hydroxyl group with retention of configuration at C-3 was achieved using potassium bromide in peroxyacetic acid, and the hydroxy group in 219 was converted into its tosylate. Methanolysis opened the lactone ring and allowed the free hydroxyl group to displace the tosylate, giving methyl (+)-nonactate 220. The overall yield of (+)-methyl nonactate from the common intermediate 215 was 47%. For the synthesis of benzyl (-)-nonactate (Scheme 30), the hydroxy acid 215 was esterified and deketalised to give the ketoester 221. Stereoselective reduction of the ketone group using Prasad's modification of Narasaka's method (23) gave the syn 1,3-diol (syn:anti = 90:10), which was converted to its acetonide 222. Stereoselective methylation of the open-chain p-silyl ester gave only the ester 223 with the anti relationship between the incoming methyl group on C-2 and the resident silyl group on C-3. Differentiation of the C-6 and C-8 hydroxyl groups was achieved by removing the acetonide, hydrolysing the ester group, and forming the seven-membered lactone 224 using Mukaiyama's procedure (59). As in the earlier sequence, this lactone was enantiomerically enriched (from 92% to >96% e.e.) by removal of the crystalline racemic lactone. The free hydroxyl group in the lactone 224 was protected with r^rr-butyldimethylsilyl chloride, and the lactone opened
252 with sodium benzyloxide to give the benzyl ester in quantitative yield. The C-6 hydroxy group was then converted to its tosylate 225, and the C-3 tolyldimethylsilyl group to hydroxyl, as before. The intramolecular displacement with inversion at C-6 226 then gave directly benzyl (-)-nonactate 227. The overall yield of benzyl (-)-nonactate from the intermediate 215 was 35%. l.Bu2BOMe,NaBH4 SiMe2Tol THF, MeOH C02Me
SiMe2ToI I.CH2N2 CO2H 2. PPTS, Me2C0 86% 215
—
^.
2. (MeO)2CMe2.PPTS
SiMe2Tol 1. PPTS, MeOH 2 cOiMe 2. KOH, THF, McOH
SiMe2Tol C02Me l . L D A , T H F , D M P U ^ 8 ^ ^ 6
r
2. Mel
3. CI-^N"^ Et3N
89% less ??%
4. separate from racemate 83% l.TBDMSCl, imidazole 2.NaOBn,BnOH,THF
"^
^V-/^^'^'^™3.TsaDMAP,Py g \ 85%
SiMe2Tol ^C02Bn
jj TBDMSO
OTs
225
224
KBr, AcOOH AcOH 78%
OH TsO ^ ^ i 226
H ^H
i
227
Scheme 30
2.4 Electrophilic Cydisation of y,8-Unsaturated Alcohols and Enols In their synthesis of racemic methyl nonactate 233 and its 8-epimer 234 (Scheme 31) (26), Baldwin and Mclver controlled the stereochemistry of C-2 and C-3 by conjugate addition of homoallylmagnesium bromide to 2,2-dimethyl-3(2H)-furanone 228 and methylation of the regenerated enolate, which took place with high selectivity (10:1) in favour of the trans dialkylfuranone 229. Conversion of the ketone to the oxime followed by fragmentation with thionyl chloride and protection gave the nitrile, and the now free alcohol group was protected as its 2,6dichlorobenzyl ether 230 {anti:syn = 32:1). Conversion to the corresponding aldehyde with diisobutylaluminium hydride^ followed by exposure to iodine in acetonitrile gave the cyclic iodoaldehyde, which was oxidised to the corresponding acid 231. The iodoetherification took place stereoselectively in favour of the desired stereochemistry at C-6 {cis'.trans = 50:1). Dithiane addition and esterification gave the masked aldehyde 232. After removal of the protecting group, the aldehyde was treated with dimethylzinc in the presence of titanium tetrachloride to give methyl
253
nonactate 233 and methyl 8-epinonactate 234 in a ratio of 24:1. The same reaction using lithium dimethyl cuprate took place selectively (4.5:1) in favour of methyl 8-epinonactate 234 1.
%,y-^MgBT
W
CuBr, MeaS
OCH2C6H3CI2 CN
. SCX:i2, CCI4
^>
•!
2. LDA, THF, Mel
228
l.NH20H,Py
229
56%
3.NaH,THF 4.2,6-Cl2C6H4CH2Br 59%
anti'.syn 10:1
l.DIBALH
C02Me
^-
2.12, MeCN 3.CrO3,H2S04 54% 1. HgO, BF3.0Et2
C02Me
^.
Me2Zn,TiCl4 Mc2CuLi
24:1 1:4.5
2. Me2Zn, T i C ^ 65% orMe2CiiLi 60%
Scheme 31 Walkup and Park synthesised not only methyl (±)-nonactate 240a but also (±)-homononactate 240b and (±)-bis- 240c and trishomononactate 240d (Scheme 32) (60) starting from hexa-4,5dienal and the appropriate lithium enolate 235 in each case. The relative stereochemistry of C-6 and OLi
Me4N-' (AcO)3BH!•
OHC^x--^^'
MeCN, AcOH, - 4 0 X 236a 236b 236c 236d
235
OH OH
R=Me R=Et R=Pr' R=Bu'
55% 58% 55% 55%
OTBDMS
TBDMSCl,
l.Hg(02CCF3)2
IN
imidazole 237a R=Me 237b R=El 237c R=Pr^ 237d R=Bu'
90% 90:10 80% 96:4 90% 99:1 84% >99:1
OH
H2, Rh/Al203 C02Me
y—X CO2MC
CO2MC H^H
cis: trans >98:2 239a R=Me 87% 239b R=Et 70% 239c R=Pr^ 80% 239d R=Bu' 80%
^.
2. PdCl2 cat., CuCl, 238a R=Me >98% CO, McOH 238b R=Et >98% 238c R=Pr' >98% 238d R=Bu' 25% + 6-silyloxy-8-ol 75%
240a-d
1:1
:
241a-d
Scheme 32 C-8 was controlled by Evans' reduction (58) of the p-hydroxyketones 236 giving the anti 1,3-diols 237. The y-silyloxyallenes 238 were then subjected to a one-pot procedure already developed by
254 these workers involving oxymercuration coupled to a palladium-catalysed methoxycarbonylation (61), which gave the tetrahydrofurans 239 with high stereoselectivity (cis.trans >98:2). This short sequence of reactions established efficiendy the required stereochemistry at C-8, C-6 and C-3, but, unfortunately, the final stereogenic centre at C-2 was generated with no control, catalytic hydrogenation gave a 1:1 mixture of the desired products 240 and their C-2 diastereoisomers 241. Iqbal and his co-workers reported a synthesis of 2,5-disubstituted tetrahydrofurans from Y,6unsaturated alcohols (Scheme 33) (62). The stereochemistry of the C-2 and C-3 centres was set up with some selectivity by reduction of the p-ketoester 242. Epoxidation of the terminal double bond
u
I.NaH 2.BuLi
C02Me
NaBH4
C02Me
243 53% OH
CI
V^-N.X^C02Me
242
244
,C02Me
MCPBA ^>
+ Ho..,^,,X^
m.^^^^^}^
78%
245
243
89:11
246
Scheme 33 of the major alcohol 243 with w-chloroperoxybenzoic acid was surprisingly well controlled, with the epoxide undergoing cyclisation under the reaction conditions to give the cis and trans tetrahydrofurans 245 and 246 in a ratio of 89:11. The major product, the alcohol 245, is the racemic methyl ester corresponding to the intermediate 158 in the Davidson and Batmangherlich synthesis of rerr-butyl nonactate (Scheme 22).
o- o-
> T ^ - . XX OMe
TBDMSO.
O
l.NPSP,Znl2 '^^™S0 n-^ • / \ ^ /\^C02Mc 2. separation » | jj O j
250
H2, Raney Ni 75psi 86%
OTBDMS
249 C02Me
2. Lindlar 65%
.TBDMSO,
248
247 1. base, Mel
CO2MC ^g^^
TBDMSO ^^v
38% /—V
^^
C02Me
252
^^^^
251
^'^\^n'i^-^
CO2H
253 Scheme 34
Ley also used the alkylation of a p-dicarbonyl dienolate 248 to assemble the precursor 250 for an electrophile-induced cyclisation (Scheme 34) (63). The enol of the p-ketoester 250 underwent
255 cyclisation with N-phenylselenophthalimide (NPSP) to give a separable mixture of two diastereoisomers, from which the selenide 251 with the correct C-6 to C-8 stereochemistry was isolated. Raney nickel induced hydrogenolysis of the now superfluous selenide as well as saturation of the C-2 to C-3 double bond, as in Bartlett's synthesis, and gave the 0-silyl protected methyl nonactate 252, which was converted to nonactic acid 253.
2.5 Intramolecular Conjugate Addition ofAlkoxides Gerlach and Wetter established the relative stereochemistry between C-6 and C-8 at the beginning of the synthesis, and made the tetrahydrofuran ring by an intramolecular conjugate addition of the C-6 alkoxide to an a,p-unsaturated ester (Scheme 35) (11). The 1,3-diketone 254, prepared from the dianion of acetylacetone, was reduced with sodium borohydride to give a mixture of the diols 255 and 256 (3:2), which were separated by chromatography. The undesired erythro diastereoisomer was converted to the desired three isomer by tosylation, displacement with acetate ion and hydrolysis, and the combined crops of threo diol 256 were acetylated. Ozonization of the diacetate followed by Wittig reaction of the aldehyde 257 with the carbanion of pmethoxycarbonylethyl diethyl phosphonate gave a mixture of (£") and (Z) isomers 258 {E:Z 85:15). Base catalysed cyclisation of the a,p-unsaturated ester 258 (E:Z = 7:3) gave a mixture in ratios of 100:68:56:71 in which methyl (±)-nonactate 259 was the major product, separated as its rerr-butyl ether and ester. OH OH O
lin
O
o
KNH2
o
255
NaBH4
l.TsCl 2. separate
70% "^ 255:256 3:2 OH OH
3. NaOAc
4. KOH
13%
256 OH OH
1. AC2O
OAc OAc
^> 2. O3, Me2S
256
(ElO)20P^ C02Me ^CHO
257
l.KOH,MeOH.MeCN :N C02Me 258
£;Z7:3
2. CH2N2, H-' 97%
9«
1
66%
r\
C02Me
H^Hi 259
Scheme 35 Sun and Fraser-Reid reported a synthesis of methyl (-)-nonactate starting from D-ribose, C-4 of which (sugar numbering) provided C-6 (nonactin numbering) of the tetrahydrofuran ring (Scheme 36) (64). The ribose-derived aldehyde 260, was converted to the ketone 261 by a Wittig reaction followed by hydrolysis of the enol ether. Raney nickel catalysed hydrogenation of the ketone 261
256 provided the (S)-alcohol 262a with the correct C-8 stereochemistry for methyl (-)-nonactate 265 with high selectivity (9:1), probably stemming from chelation of the nickel to the ring oxygen atoms. In addition, the minor isomer was converted into the major by displacement of its sulfonate with sodium benzoate. The alcohol 262a was hydrolysed and protected as its acetonide to give the aldose 263, which was treated with the phosphorane. Wittig reaction took place followed by intramolecular
OHC
yOy
OMe
6j0
yOy
A
260
H2.Ni /^
o3o
'^'^
A
"I—\ ^ COMe
y—V ^ OMe
2 steps /
\ ^
1. separate 262a 2. HsO""
oTo
3.Me,C(OMe),
A 261
262a R^=OH,R2=H90% 262b R ' = H , R 2 = 0 H 10%
HO
1. Ph3PYC02Me ^^
l.benzoylate
^ ^ 3 3. Me2NCH(OR)2 X^o^^^'"^' ^ ^ 4. Ac20,heat H H i 'V' "^ 5. H2, Pd 255 ^^ '^ ^ 6. NaOMe 263 264 78% Scheme 36 conjugate addition of the alkoxide on the unsaturated ester under kinetic control to give a 1:3 mixture /\^0E ^
^
2. separate / 3.NaOMe 4. separate and recycle
of the two C-2 diastereoisomers, with the desired isomer 264 the minor component. Under kintetic control, the side-chain at C-3 (nonactin numbering) remains on the upper surface as illustrated, an observation of Moffatt and his co-workers (65). The ratio was improved to 3:2 by equilibration with sodium methoxide by a p-elimination-readdition pathway. After three cycles of equilibration and separation, 90% of the mixture had been converted into the diastereoisomer 264. The acetonide group in the benzoate of 2 6 4 was hydrolysed and the resulting diol subjected to Eastwood deoxygenation (66), which gave the corresponding dihydrofuran. Hydrogenation over palladium then gave methyl (-)-nonactate 265. Sun and Fraser-Reid also synthesised the (+)-enantiomer from the same starting material, which required that the configuration at C-4 be inverted (Scheme 37). The early intermediate 261 prepared from D-ribose was treated with base, which caused epimerisation to give the thermodynamically more stable isomer 266, with an equilibrium ratio of 9:1 as expected from Moffatt's precedents, but surprising at first sight, given that the side chain is endo in the bicyclic system. Nickel-catalysed hydrogenation, selective enough to give the alcohol 267 to the extent of 75%, deprotection of the acetal, and protection of the diol as its acetonide gave the aldose 268. The aldose was treated with the nitrile analogue of the same phosphorane as before to give an epimeric mixture of the nitriles 269. This mixture was epimerised in a few cycles, with separation after each cycle, finally providing the nitrile 270 in 84% yield. The nitrile was used in this sequence because it behaved better in the equilibration steps than the corresponding ester. Eastwood deoxygenation.
257 hydrogenation of the dihydrofuran, and conversion of the nitrile to the methyl ester gave methyl (+)nonactate 271. O
/
V^y Q
OH
OMe
Q
NaOMe, MeOH MeOH NaOMe,
O
OMe
^Jl^ ^ ^ ^^'^\.
90% epimerisation
Q
261
Q 266
PhsP^CN
A
268 OH CN
OH
OMe
JC^^V"
2. separate
J
^
1.H30-' 2. Me2C(OMe)2
267 OH
2. NaOMe 93%
Ov^O
H2. Ni
CN
l.NaOEt,ElOH 2. separate 3. recycle and separate 84%
0^0
A
l.benzoylate 2. HsO"^ 269 3. Me2NCH(OR)2 OH ^-AczO^heat JC4^.K^C02Me 5.H2,Pd 6.H2O2 7. NOCl 8. CH2N2 9. NaOMe
0^0
A
270
Scheme 37 2.6 From Bicyclic Intermediates White and his co-workers were the first to use a bicyclic intermediate to control the relative stereochemistry (Scheme 38) (14). They set up the 8-oxa-bicyclo[3.2.1]octene 273 using O
vV Br
fl
Zn-Cu 272
Br
° ^
q
2.""v^j^O ""2.^^ "'^"^ CF3CO3H, Na2HP04 273 .C02Me 220 T
1. NaOMe O 2.NaH,CS2,MeI 71%
274
92% C02Me
MeS2C0 " 1 " 275 OHC
1, (Sia)2BH
CrOs
C02Me
^.
»•
95%
2. H2O2, HO"
278:279= 1:1
^ OHC.,^ H
46% 1. separate 278 2. MeMgl
64%
HE 279
C02Me
C02Me 280
A ^
1:1
281
Scheme 38 Hoffmann's cycloaddition (67) of the oxyallyl cation 272, generated from 2,4-dibromopentan-2-one with LeGoff s zinc-copper couple (68). Hydrogenation followed by Baeyer-Villiger oxidation gave the lactone 274, with C-2, C-3 and C-6 correctly set up. Methanolysis gave a single hydroxyester,
258 which was converted into its xanthate 275. The xanthate on pyrolysis provided the terminal alkene 276,
which was subjected to hydroboration-oxidation to give the primary alcohol 277.
Unfortunately, the configurational identity at C-2 was lost during the hydroboration-oxidation, the alcohol proving to be a 1:1 mixture of C-2 epimers. These were separated after converting the alcohol 277 to the mixture of aldehydes 278 and 279, and treatment of the isomer 278 with methylmagnesium iodide gave methyl nonactate 280 and methyl 8-epinonactate 281 with no selectivity, a problem that was solved later by Baldwin and Mclver (Scheme 31). Warm and Vogel used 7-oxabicyclo[2.2.1]heptan-2-one 284 to control the relative stereochemistry of C-2 and C-3 of methyl nonactate. They also resolved it, and used the (+)enantiomer to synthesise methyl (+)-nonactate (Scheme 39), and the (--)-enantiomer to synthesise methyl (-)-nonactate (69). Zinc iodide-catalysed Diels-Alder reaction between furan and 1cyanovinyl acetate gave the adduct 282, which was saponified to give the racemic ketone. This was hydrogenated using palladium on charcoal, and the enantiomers (+)- and (-)284 were resolved by chromatography of their sulfoximides 285 and 286. Pyrolysis of each diastereoisomer gave the
Aco^cN
"^o^
^ ^ ^OAcC 282
^ C N
2.H2.P(1A:
^-^^
^ ^
4:1 O
42% each
OH
O
' ,
5-
285
(+)-284
l.KHMDS 2. Mel ^> 3. separate from dimethyl product 4. MCPBA, NaHCO^ 59% ,C02Me
C02Me 288:289 1:3 289 1 l.KOH 2. CH2N2 288:289 3 (36%): 4 (27%)
L-Seleciride ^. 82%
C02Me
4
CO2MC
290:291 10:1 l.PhC02H,Ph3P,DEAD
|
2. NaOMe, MeOH 85%
Scheme 39 enantiomerically pure ketones 284 (>99% e.e.). Methylation of the bicyclic ketone (+)-284 followed by Baeyer-Villiger oxidation gave the unstable oxoacetal 287. Addition of one equivalent of the silyl enol ether of acetone to a 1:1 mixture of the acetal 287 and titanium tetrachloride gave a 1:3 mixture of the ketone 288 and its trans isomer 289. However, the undesired isomer 289 could be equilibrated on treatment with potassium hydroxide, by p-elimination and readdition. Acidification
259 and esterification with diazomethane gave the ketones 288 and 289, as a 4:3 mixture. Reduction of the ketone 288 with L-Selectride gave a 10:1 mixture of methyl (+)-8-epinonactate 290 and methyl (+)-nonactate 291. Mitsunobu inversion of the major product and treatment with sodium methoxide gave methyl (+)-nonactate 291. The enantiomeric bicyclic ketone (-)-284 similarly provided methyl (-)-nonactate.
2.7 Ireland-Claisen Rearrangement Ireland and Vevret developed a route for the synthesis of both (+)- and (-)-nonactic acids, with the stereochemistry at C-6 derived from C-4 of D-gulonolactone and D-mannose, respectively (70). For the synthesis of (+)-nonactic acid 301 (Scheme 40), the furanoid glycal 295 was prepared in 10 steps from D-gulonolactone 292 by fairly straightforward functional group manipulations. The
HO
6H«
MOMO
0
0
l.HCl,MeOH 2. Me2NCH(OMe)2 3. AC20,130°C
•
3. NaH, BnCl, DMF
o^^o-^
H ^ 294 MOMO
l.Li,NH3 2.CCl4,Ph3P MOMO
293
HO V-^
l.BuLi 2.EtC0Cl
OBn 3.Li,NH3
^.
2. CH2N2
C02Me H ^H 299 47% or 54% _
H2,Pt/C C02Me ^> 44% from 295
MOMO
3. LDA, THF, -78°C
H^ 295
11% from 292 r=^
1
OBn 4. 9-BBN 5. NaOH, H2O2 6. P2O5, CH2(OMe)2 OSiMcs"
I
292
\-4
1. 25°C
l.Me2C0,H-' 2. DIBALH
OH
4. MeaSiCl
H^ 296 l.HCl,MeOH 2. Swem
MOMO
K0H,H20
V—TV
H ^H 298 298:2-epi-298 86:14
3. Mc2CuLi or McMgBr
^
CO2H
95%
C02Me
300 53%^r40%
Scheme 40 glycal 295 was converted into its propionate ester, which on treatment with lithium diisopropyl amide in THF and trimethylsilyl chloride gave the £-trimethylsilyl enol ether 296. The key step, the Ireland-Claisen rearrangement (71) setting up the stereochemistry at C-2 and C-3, took place at room temperature, and the product mixture was esterified to give a mixture of the C-2 diastereoisomeric
260 esters 297. Catalytic hydrogenation gave the corresponding mixture of esters 298 (86-89:14-11) in favour of the desired isomer. Evidently the Claisen rearrangement had taken place largely with the boat-like transition structure, and suprafacially on the dihydrofuran ring. Deprotection followed by Swem oxidation gave the aldehyde. No stereochemical control was observed in the dimethylcuprate addition to the aldehyde, which gave both diastereoisomers 299 and 300 in approximately equal amounts, in contrast to Baldwin's observation of good control, although in the wrong sense, in this reaction (Scheme 31). They observed somewhat better control when methylmagnesium bromide was used. The enantiomeric glycal 305 was prepared from the D-mannose 302 in 11 similar steps (Scheme 41), and (-)-nonactic acid 310 prepared from it exactly as described for the (+)-enantiomer 301 (Scheme 40).
V
OH l.Me2C0,H-' .OH 2. NaH, BnCI, DMF HO^ 'V-^^^^^*^" HO^'^^^O-^OH 302 Q' -Q
I.Li,NH3 2.CCl4.Ph3PMOMO
^ ^ O ' ^ O B n 3.Li,NH3 ^ H 36% 304 36% from from 302 302
H2, Rh/C
I
jiQ V-a
l.BuLi 2. EtCOCl
3.NaOH.H202 4. KH, MCOCH2CI
MOMO
^ V ^ >> 3.LDA,THF. H^ -78°C 3^5 305 4. Me.SiCL MesSiCl, 25°C 5. CH2N2
V
C02Me
49% from 305
I.AC20,130°C 2. 9-BBN
3.HCl,MeOH O ' ^ r ^ O ' ^ O cB n 4. Me2NCH(OMe)2, CH2CI2 V-n " 303 Me2N f ^ -i^-
MOMO
MOMO M UMU
O^^O
H" H I 307
l.HCi,MeOH 2. Swem
k^^^tN^C02Me H H^ 306
x ' ^ . X h Q ' t v ^ CO2MC H "^ H =
3. Me2CuLi
308 40% OH
307:2-epi-307 89:11
r ^ H^ H= 309 45%
. - ^ X x t ^ Q ' t ^ C02Me
KOH, H2O
H "^ H 308
*- -'^"'^^o'^V' CO2H H ^ H= 310
Scheme 41
3.
SYNTHESES OF NONACTIN The synthesis of nonactin requires that the (+)- and (-)-nonactic acid units be joined together in
an alternating sequence, followed by closing the ends to give the macrocycle. There are two possibihries for ring-formation: (i) cyclodimerisation of a "dimer" and (ii) unimolecular cyclisation of
261 a "tetramer." Both strategies have been used, with several different ways to assemble the dimer and tetramer. In one strategy, the differentially protected nonactic acid enantiomers are coupled to give the protected dimer using standard esterification techniques that preserve the configuration at C-8. In the other strategy, the linear units are coupled by taking one enantiomer of nonactic acid, and using it as a carboxylate nucleophile to displace, with inversion of configuration, the 8-methanesulfonate or tosylate of the 8-epi-diastereoisomer of the other enantiomer, protected at the carbonyl group. 3.1 Synthesis ofNonactin by Unimolecular Cyclisation The first synthesis of nonactin was reported by Gerlach and his co-workers (Scheme 42) (72) in 1975 by the cyclisation of a linear tetraester, but the linear tetraester 317 was a mixture of diastereoisomers because it was made from racemic nonactic acid 311 (prepared in Scheme 35).
CO2H
[ I
(+)-311 •^ Bu'OsCMe, MeSOsH 70%
NaH,BnBr ^ OBn
CO2BU'
Py, C i O z S - f J -
70%
COzBu^
H2, Pd/C CO2BU'
C02Bu^
I.CF3CO2H 2. H2, Pd/C
i
4. AgC104, MeCN, 10--*M 5. separate
nonactin (10%) + other diastereoisomers (30%)
Scheme 42 Appropriately protected monomers, the racemic benzyl ether 312 and the racemic rerr-butyl ester 313, were coupled using the mixed anhydride with 2,4,6-trimethylbenzenesulfonyl chloride to give
262 the protected dimer 314 as a mixture, inevitably, of four diastereoisomers, all racemic. Treatment with trifluoroacetic acid removed the rerr-butyl ester group from one portion of the dimer to give the acid 315, and catalytic hydrogenolysis removed the benzyl ether group from the other portion to give the alcohol 316. Activation of the acid 315 with 2,4,6-trimethylbenzenesulfonyl chloride and coupling with the alcohol 316 gave the linear tetramer 317, this time as a mixture of eight racemic diastereoisomers. Deprotection of the rerr-butyl ester with trifluoroacetic acid and of the benzyl ether by hydrogenolysis gave the free linear tetramer, which was cyclised by the Mukaiyama thioester method (73). At this stage the complexity of the mixture became rather less, since there are only four possible diastereoisomers, assuming that there is complete preservation of stereochemical integrity within each nonactic acid unit. Of these four diastereoisomers, three were isolated by chromatography in a ratio of 1:5:2, and the last proved to be nonactin 1. Schmidt and his co-workers (74) were the first to report a synthesis of nonactin from enantiomerically enriched components (Scheme 43). Potassium (-)-nonactate 321, prepared from
4^is^C02Bn H ^H =
H
Asx/o^C02H
H
H
(+)-319 i TsCl,Py 85% ,—V
OTs
H = (-)-320"
OH
An
OTs
C02Bn . A ^ ^ V ^ ^ ^ z "
OH
1
y
O
:
,
1
OH
I
V
C02Bn
O C02Bn
H ^ H = •
H ^H
324
H" H E
I l.H2,Pd/C 2.KHCO3 OH
r—.
O
=
OTs
J—.
-^^oW^o-^-^oV^^^'
/-^
O C02Bn
/ ^ oH^ t H^ =- ^ o
327
OH
y
i
O
r
i
.
O
| 7 4 % from 324 I y 1
O
r
y
v ^C02Bn
H "^ H =
H^H
H "^ H =
H
H
328
I l.H2,Pd/C 2. (PyS)2,Ph3P I 3.AgC104,bei benzene 20% nonactin Scheme 43 the acid 318 (=38) was coupled, with inversion of configuration at C-8, with the 8-epi-tosylate 322, derived from benzyl (+)-8-epi-nonactate 319 (prepared from the methyl ester 40), to produce
263 benzyl (-)-nonactinoyl-(+)-nonactate 324. The diester 325 was prepared similarly using potassium (-)-8-epinonactate 323 and the same 8-epi-tosylate 322 used before. Hydrogenolysis of the "dimer" 324, and conversion to the potassium salt with potassium bicarbonate gave the left-hand component 326. Tosylation of the alcohol 325 gave the 8-tosylate 327, which gave the linear tetraester 328, again with inversion of configuration at C-8, on treatment with the potassium salt 326. Hydrogenolysis, activation and cyclisation following Gerlach produced nonactin in 20% yield together with C-2 and C-8 epinonactins in 12% yield. Fleming and Ghosh synthesised nonactin by cyclisation of the linear tetramer 335 assembled from methyl (+)-nonactate and benzyl (-)-nonactate (Scheme 44) (75). The (9-protected (+)-nonactic
C02Me (+)-329 I l.TBDMSCl, imidazole 2. KOH, THF, MeOH 98% TBDMSO
331 DCC, DMAP 93% TBDMSO C02Bn H ^ H = 100% H2,Pd/C TBDMSO
/—V
TsOH,AcOH 98%
O
Ov^o^^
H
C02Bn
H^A
H E
U H
^
U H
'
334 CI
DMAP, ClOC C ^ C l
95%
CI TBDMSO C02Bn H
H
H
H =
H ^ H =
335
l.H2,Pd/C 2TsOH, AcOH, H2O 3. CI
t
nonactin
DMAP, ClOC • ^ - C I
69%
CI
Scheme 44 acid 330 was prepared from the hydroxyester 329 (=220), and coupled with benzyl (-)-nonactate 331 (=227), without inversion at C-8, to give the dimeric ester 332. A portion of this dimer was hydrogenolysed with palladium on charcoal to give the acid 333, while the other portion was
264 deprotected at the hydroxy group using acid to give the alcohol 334. The acid 333 was coupled to the alcohol 334 using the Yamaguchi mixed anhydride method (76) to give the protected linear tetramer 335. The protecting groups were removed to give the free tetramer, which was cyclised in high yield (73%), the best so far achieved, again using Yamaguchi's method. There was no improvement in yield when potassium tetrafluoroborate was present, indicating that coordination to potassium did not help the cyclisation. 3. 2 Synthesis ofNonactin by Cyclodimerisation Schmidt and his co-workers also reported the synthesis of nonactin (Scheme 45) (77) by cyclodimerisation of (-)-nonactinyl-(+)-nonactic acid 336 (=326), which was treated successively OH y i H "^ H
O
=
y y H "^ H
336
/V^V'-carbonyldiimidazole, DBU i
or (PyS)2,Ph3P
"poor yield"
nonactin
Scheme 45 either with carbonyldiimidazole and diazabicycloundecen or with the bispyridyl 2-disulphide and triphenylphosphine to give nonactin in "poor" yield in both cases.
H^ H I (-)-338 ^ MsCl, EI3N, DMAP 91% OMs / — ^ C02Me H
H = 340
C02Me H ^ H = 341 I LiSPr",HMPA 1 CO2H H ^ H l.(PhO)2POCl,Et3N I 2. heat, C6H6, DMAP 16% nonactin + cyclic "dimer" and "oligomers" and polymer
Scheme 46 Bartlett and his co-workers (20) synthesised nonactin by the cyclodimerisation approach (Scheme 46). The potassium salt 339 of (4-)-nonactic acid 337 (=87) and the mesylate 340 of the
265 (-)-8-epiester 338 (=86) gave the dimeric ester 341 with inversion of configuration at C-8, as in Schmidt's synthesis, but working with the enantiomer of each component. The methyl ester was cleaved by lithium n-propyl mercaptide with some difficulty, and with some (25%) epimerisation at the C-2 positions of the nonactic acid units to give the acid 342. Macrolactonisation using Masamune*s procedure (78), gave nonactin in 16% yield, accompanied by the cyclic "dimer" and "oligomers" and polymers. Fleming and Ghosh also synthesised nonactin by cyclodimerisation of the acid derived from the benzyl ester 343 (=334) using Yamaguchi conditions (Scheme 47) (75). Nonactin was isolated in lower yield than by the linear tetramer method, presumably because of the problem of "dimer" and "oligomer" formation.
Q^
o-^^-^/?k^^^^^" H H E 343
l.H2,Pd/C 2.
CI
aoc-0"Ci DMAP a
nonactin (52%) + cyclic "dimer" and "oligomers" and polymer Scheme 47 CONCLUSIONS The syntheses of nonactic acid and its derivatives illustrate many of the most popular methods of stereocontrol used in synthesis. There are examples of absolute control based on (a) resolution, (b) Sharpless asymmetric epoxidation and other methods of kinetic recognition, including an enzymatically controlled reduction, (c) the use of chiral auxiliaries, and (d) starting materials from the chiral pool such as sugars, and malic and glutamic acid. Relative stereochemical control has been achieved by such devices as (a) control on bicyclic frameworks, (b) the use of many different cyclic structures, especially five-membered rings with a predictable stereochemical bias, (c) the similar use of cyclic transition structures for hydride delivery, for enolate alkylations, the Ireland-Claisen rearrangement, and for ring-forming reactions, t>oth pericyclic and ionic, and (d) by the independent synthesis of separated stereogenic centres with absolute control. There are examples of such themes as (a) kinetic and thermodynamic control, (b) of convergent and linear synthesis, (c) of the recycling of unwanted disastereoisomers by Mitsunobu and other inversion processes, and by repeated equilibration and separation, and (d) of the problems of controlling distant stereogenic centres. And there are examples of a very wide range of the common reactions of organic chemistry, including those used in C-C bond-formation, functional group manipulation, and protecting group tactics. The syntheses illustrated here would, on their own, make a surprisingly good basis for an introductory course in organic synthesis.
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