Enantioselective total synthesis of antifungal agent Sch 38516

Full text of DOI:10.1021/ja9626603

10926
J. Am. Chem. Soc. 1996, 118, 10926-10927
must await the results of ongoing studies, it is notable that with
the (S)-antipode of the chiral auxiliary, little or no diastereofacial
selectivity is observed (10:1 endo:exo selectivity).11 Subjection
of 4b to HCl (THF) to effect the removal of the acetonide group,
treatment of the resulting diol with Pd(OH)2 and HCl under
300 psi H2 (MeOH), and conversion of the product hemiacetal
(7:1 ratio of R:â anomers) to methoxy acetal 6 proceeded in
79% overall yield after silica gel chromatography (>98%
R-methoxy anomer).
Enantioselective Total Synthesis of Antifungal
Agent Sch 38516
Zhongmin Xu, Charles W. Johannes, Sarri S. Salman, and
Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry
Center, Boston College
Chestnut Hill, Massachusetts 02167
We next outfitted the carbohydrate nucleus with the appropri-
ate protecting and functional groups essential for stereoselective
glycosylation and completion of the total synthesis. Protection
of the primary amine by treatment with S-ethyl trifluorothio-
acetate,12 acylation of the two secondary carbinols, and conver-
sion of the methyl glycoside to the corresponding acetoxy
derivative delivered the fully protected 7 (85% yield; >98% R
anomer).13 Treatment of 7 with thiophenol and SnCl4,14
followed by subjection of the resulting thioglycoside with
diethylaminosulfur trifluoride and N-bromosuccinamide gave
rise to the formation of fluorinated carbohydrate 8 in 65%
purified overall yield.15c
ReceiVed July 31, 1996
The paucity of stereogenic centers in the macrolactam region
of Sch 385161 demands effective control of distal asymmetric
induction, rendering the stereoselective preparation of this
antifungal agent a challenging problem in chemical synthesis.
In addition, the target molecule, which is also known as
fluvirucin B1,2 contains a novel carbohydrate moiety that
appears as part of a natural product for the first time. We
envisioned that a direct approach to the enantiocontrolled
assembly of Sch 38516 would involve the following: (1) the
attachment of carboxylic acid I to the amine segment II (fIII,
Scheme 1; P ) protecting group); (2) diastereoselective gly-
cosidation to obtain IV; (3) transition metal-catalyzed 14-
membered ring closing metathesis of IV to reach V; and (4)
diastereoselective hydrogenation of V, dictated by the confor-
mational preferences of the macrocyclic ring,3 which would
establish the remote C6 stereogenic center.
In this context, we recently disclosed the enantioselective
synthesis of I and II (P ) TBS),4 wherein various metal-
catalyzed reactions, particularly the diastereo- and enantiose-
lective Zr-catalyzed carbomagnesations,5 played a pivotal role.
We report here the first total synthesis of Sch 38516. The
successful implementation of the enantioselective synthesis
highlights the stereoselective construction of the requisite
carbohydrate unit, its efficient and diastereoselective coupling
to the acyclic diene and a competent Mo-catalyzed ring-closing
metathesis of the diene-carbohydrate ensemble.
After extensive investigation of a variety of protocols, we
established that when 1 equiv of diene 11 and 1.1 equiv of
fluorocarbohydrate 8 are treated with SnCl2 and silver perchlo-
rate in the presence of 4 Å molecular sieves,15 lycosylated diene
12 is formed as a single stereoisomer (>98%) in 92% yield
after silica gel chromatography. The stage was thus set for the
Mo-catalyzed ring closing metathesis of the fully functionalized
12. Heating of 12 to 60 °C in benzene in the presence of 20
mol% of freshly prepared Mo(CHCMe2Ph)(N(2,6-(i-Pr)2C6H3))-
(OCMe(CF3)2)216 led us to macrolactam 13,17 which was isolated
after 10 h in 90% purified yield as a single alkene isomer
(>98%). It must be noted that the facile catalytic ring closure
of 12 was crucial to the completion of the total synthesis, as all
attempts to effect glycosylation between the hydroxyl aglycon
(ring closed product of 11) and a gamut of carbohydrate
derivatives failed. This is probably due to the low solubility
of the macrolactam carbinol substrate in organic solvents;18 in
contrast, acyclic diene 11 is readily dissolved in most solvents
and can be easily manipulated under a variety of conditions.
Stereoselective hydrogenation of the trisubstituted olefin in 13,
where H2 addition occurs by peripheral attack,3 delivered 14 as
As illustrated in Scheme 2, stereocontrolled carbohydrate
synthesis began with catalytic asymmetric dihydroxylation6 of
the inexpensive and commercially available ethyl sorbate 1,
followed by protection of the resulting nonracemic unsaturated
ester as its derived acetonide to give 2 in 52% overall yield
(80% ee, chiral GLC analysis). Subjection of 2 with O3,
reduction with dimethyl sulfide, and treatment of the chiral
aldehyde with N-benzylhydroxylamine afforded nitrone 3a (30%
overall yield). When 3a was heated to 85 °C in the presence
of vinylene carbonate, as reported by DeShong and co-workers,7
the [3 + 2] cycloaddition products 4a and 5a were formed as
a 3.5:1 mixture of endo diastereomers (95:5 endo:exo, 52%
yield). In addressing this shortcoming, we discovered that when
(R)-N-hydroxyl-R-methylbenzylamine deriVatiVe8 3b is used
instead,9 the cycloaddition proceeds under identical conditions
to afford 4b with 20:1 diastereoselectiVity in 69% isolated yield
1
a single diastereomer (minor isomer not detected by H NMR
analysis). When 14 was subjected to hydrazine in MeOH,
removal of the two acetoxy units and the deprotection of the
amide trifluoroacetate group was effected smoothly, releasing
Sch 38516 in 96% yield as a white solid. The synthetic
compound proved identical by 1H NMR, 13C NMR, IR, HRMS,
and TLC to an authentic sample of natural Sch 38516.
The present study records an efficient and enantioselective
synthesis of a novel carbohydrate moiety, where a readily
available chiral auxiliary is employed to render the key
cycloaddition highly diastereoselective (3b f 4b, Scheme 1).
The remarkably efficient transition metal-catalyzed macrocy-
clization of 12 illustrates that the ring closing metathesis strategy
(>98% endo:exo; H NMR analysis).10 Although the mecha-
nistic justification for the enhancement in π-facial selectivity
1
Scheme 1
S0002-7863(96)02660-1 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 44, 1996 10927
Scheme 2a
Acknowledgment. This research was generously supported by the
National Institutes of Health (GM-47480), the National Science
Foundation (NSF-9632278), and Pfizer. We are most grateful to
Professor Samuel J. Danishefsky for encouragement, advice, and a
generous gift of Sch 38516. We thank Professor P. DeShong and Dr.
D. Young for helpful discussions and technical advice and Drs. V. P.
Gullo and V. R. Hegde of the Schering-Plough Co. for samples of the
natural product and derivatives. Invaluable experimental assistance was
provided by Steven Scully and Gloria Hofilena. A.H.H. is an NSF
National Young Investigator, a Sloan Research Fellow, and a Camille
Dreyfus Teacher-Scholar.
Supporting Information Available: Experimental procedures and
spectral and analytical data for all reaction products (51 pages). See
any masthead page for ordering and Internet access information.
JA9626603
a AD mix-R, 1 equiv MeSO2NH2, t-BuOH, H2O. b 2,2-Dimethoxy-
propane, 5 mol% p-TsOH, 52% from 1. c O3, 8:1 CH2Cl2:MeOH, -78
°C; Me2S. d 1.0 equiv of (R)-N-hydroxy-R-methylbenzylamine, 20 h,
30% from 2. e 4 equiv of vinylene carbonate, C6H6, 85 °C, 38% for
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g
3a, 69% for 3b. f 4:1 THF:1.0 M HCl, 65 °C. Pd(OH)2 (50% by
(5) Diastereoselective carbomagnesation: (a) Hoveyda, A. H.; Xu, Z. J.
Am. Chem. Soc. 1991, 113, 5079-5080. (b) Houri, A. F.; Didiuk, M. T.;
Xu, Z.; Horan, N. R.; Hoveyda, A. H. J. Am. Chem. Soc. 1993, 115, 6614-
6624. Enantioselective carbomagnesation: (c) Morken, J. P.; Didiuk, M.
T.; Hoveyda, A. H. J. Am. Chem. Soc. 1993, 115, 6697-6698. (d) Visser,
M. S.; Heron, N. M.; Didiuk, M. T.; Sagal, J. F.; Hoveyda, A. H. J. Am.
Chem. Soc. 1996, 118, 4291-4298.
weight), 300 psi H2, 2.5 equiv of MeCOCl, MeOH. h 10% anhydrous
HCl in MeOH, 79% from 4b. i 1.5 equiv of CF3COSEt, 1.5 equiv
of Et3N, MeOH. j 10 equiv of Ac2O, pyridine, DMAP. k 1% H2SO4
in Ac2O, 0 °C, 1 h, 85% from 6. l 1.2 equiv of PhSH, 0.7 equiv of
SnCl4, 50 °C, 1 h. m 1.3 equiv of Et2NSF3, 1.5 equiv of NBS, 0 °C,
65% from 7.
(6) Xu, D.; Crispino, G.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114,
7570-7571.
(7) DeShong, P.; Dicken, C. M.; Leginus, J. M.; Whittle, R. R. J. Am.
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Scheme 3a
(8) For the preparation of the requisite chiral hydroxylamine, see:
Polonski, T.; Chimiak, A. Tetrahedron Lett. 1974, 2453-2456.
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(11) This experiment was carried out by Mr. Daniel La of these
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the secondary amine of the unmasked carbohydrate (product of hydrogena-
tion) could be protected, attempts to acylate the two secondary carbinols
and the hemiacetal hydroxyl group, under a variety of conditions, led to
the formation of complex mixtures of products.
(14) Nicolaou, K. C.; Randall, J. L.; Furst, G. T. J. Am. Chem. Soc.
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a 1.1 equiv of DCC, 1.2 equiv of HOBT, 22 °C, 8 h, 85%. b 48%
HF, MeCN, 22 °C, 20 min, 80%. c 2.2 equiv of AgClO4, 2.2 equiv of
SnCl2, 4 Å molecular sieves, 1.1 equiv of 8, -15 °C (1 h), 0 °C (1 h),
22 °C (2 h), Et2O, 92%. d 20 mol% Mo(CHCMe2Ph)N(2,6-(i-
Pr)2C6H3))(OCMe(CF3)2)2, C6H6, 60 °C, 10 h, 90%. e H2, 10% Pd(C),
EtOH, 72%. f 20 equiv of N2H4, MeOH, 24 h, 96%.
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