Total synthesis of (+)-ambruticin S

Full text of DOI:10.1021/ja011867f

12432
J. Am. Chem. Soc. 2001, 123, 12432-12433
Scheme 2
Total Synthesis of (+)-Ambruticin S
Thomas A. Kirkland, John Colucci, Leo S. Geraci,
Matthew A. Marx, Matthias Schneider,
David E. Kaelin, Jr., and Stephen F. Martin*
Department of Chemistry and Biochemistry
The UniVersity of Texas, Austin, Texas 78712
ReceiVed July 31, 2001
Ambruticin S (1), a structurally novel antifungal antibiotic, was
isolated from fermentation extracts of Polyangium cellulosum Var.
fulVum in 1977 by researchers at Warner Lambert.1 The absolute
configuration of 1 was established several years later through the
independent synthesis of ozonolysis fragments.2 The potent in
vivo antifungal activity and low toxicity of ambruticin S and many
of its derivatives coupled with its unique structural features, most
notably a divinyl cyclopropane, make it a compelling target for
synthesis.3 However, despite numerous synthetic efforts, only
Kende has reported the enantioselective synthesis of 1.4
Our attraction to ambruticin S owed its origins to our long-
standing involvement in developing enantioselective methods for
the synthesis of natural products containing hydropyran and
cyclopropane rings. These interests inspired the retrosynthetic
analysis of 1 that is depicted in Scheme 1. Disconnection at the
two disubstituted olefinic linkages led to three fragments that
would serve as our initial subgoals. These structural subunits were
the A-ring aldehyde 2, the bifunctionalized B-ring cyclopropane
3, and the C-ring sulfone 4. Each of these fragments embodies a
similar degree of stereochemical and functional complexity,
thereby allowing the synthesis to be highly convergent. We now
report the successful implementation of this strategy to the total
synthesis of (+)-ambruticin S.
but this was esterified in situ by acidification of the mixture with
H2SO4 to give 7 in 70% overall yield from 6. The epimerization
at C(3) and saponification of a compound related to C(3)-epi-7
has been previously reported.6 Selective protection of the primary
alcohol of triol 7 as a TES ether followed by protection of the
two secondary alcohols as TBS ethers was accomplished in a
one-pot process to provide 8. Selective deprotection of the TES
group and oxidation of the resulting primary alcohol with Dess-
Martin periodinane7 afforded the requisite aldehyde 2.
The enantioselective intramolecular cyclopropanation of allylic
diazoacetates that we and Doyle have jointly developed served
as the key step in the synthesis of sulfone 3 (Scheme 3).8 Thus,
reaction of diazoacetate 9 with Rh2[5(S)-MEPY]4 provided the
known cyclopropyl lactone 10 in 80% yield (92% ee).9 The
lactone ring of 10 was opened by using morpholine and AlMe3,
and the resulting alcohol was protected as its TBS ether to provide
amide 11.10 Epimerization R to the cyclopropyl amide group in
11 to give 12 was driven by release of steric congestion about
the all-cis, trisubstituted cyclopropane ring. Hydride reduction
of the amide moiety in 12 with LDA and borane-ammonia
according to the Myers protocol provided alcohol 13,11 which
was converted into the benzothiazole sulfone 3 by a Mitsunobu
reaction followed by oxidation of the intermediate sulfide.
Benzothiazole sulfone 3 was specifically selected for coupling
with the aldehyde 2 because 1,2-elimination of the intermediate
hydroxy sulfone adduct would proceed spontaneously, thus
obviating production of a cyclopropyl carbinyl radical that might
undergo ring opening under standard Julia conditions.12 Indeed,
this methodology has been previously employed to join cyclo-
propyl sulfones to aldehydes.13 In the event, addition of NaHMDS
to a solution of 2 and 3 provided a mixture (2.6:1) of isomeric
E- and Z-alkenes. Although this mixture was difficult to separate,
the corresponding primary alcohols were readily separable. Hence,
The synthesis of A-ring aldehyde 2 commenced with the Wittig
olefination of aldehyde 55 to provide ester 6 (Scheme 2). The
acetonides in 6 were cleaved with H2SO4 in MeOH. Excess
NaOMe was added, and the reaction mixture was heated under
reflux (24 h) to equilibrate the various Michael adducts and furnish
the thermodynamically more stable hydropyran 7. Small quantities
of the corresponding acid were also produced during this process,
Scheme 1
(6) Liu, L.; Donaldson, W. A. Synlett 1996, 103-104. See also: Michelet,
V.; Adiey, K.; Bulic, B.; Geneˆt, J.-P.; Dujardin, G.; Rossignol, S.; Brown,
E.; Toupet, L. Eur. J. Org. Chem. 1999, 2885-2892.
(7) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(8) (a) Doyle, M. P.; Pieters, R. J.; Martin, S. F.; Austin, R. E.; Oalmann,
C. J.; Mu¨ller, P. J. Am. Chem. Soc. 1991, 113, 1423-1424. (b) Doyle, M. P.;
Austin, R. E.; Bailey, S. A.; Dwyer, M. P.; Dyatkin, A. B.; Kalinin, A. V.;
Kwan, M. M. Y.; Liras, S.; Oalmann, C. J.; Pieters, R. J.; Protopopova, M.
N.; Raab, C. E.; Roos, G. H. P.; Zhou, Q.-L.; Martin, S. F. J. Am. Chem. Soc.
1995, 117, 5763-5775.
(1) (a) Connor, D. T.; Greenough, R. C.; von Strandtmann, M. J. Org.
Chem. 1977, 42, 3664-3669. (b) Connor, D. T.; von Strandtmann, M. J. Org.
Chem. 1978, 43, 4606-4607.
(9) Martin, S. F.; Dorsey, G. O.; Gane, T.; Hillier, M. C.; Kessler, H.;
Bhat, T. N.; Munshi, S.; Gulnik, S. V.; Topol, I. A. J. Med. Chem. 1998, 41,
1581-1597.
(2) Just, G.; Potvin, P. Can. J. Chem. 1980, 58, 2173-2177.
(3) For a review of the biology and chemistry of ambruticin, see: Williams,
D. R.; Li, J. J.; Hutchings, R. H. Org. Prep. Proc. Int. 2000, 32, 409-452.
(4) (a) Kende, A. S.; Fujii, Y.; Mendoza, J. S. J. Am. Chem. Soc. 1990,
112, 9645-9646. (b) Kende, A. S.; Mendoza, J. S.; Fujii, Y. Tetrahedron
1993, 49, 8015-8038.
(10) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12,
989-993.
(11) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511.
(12) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett.
1991, 32, 1175-1178.
(5) Regeling, H.; Chittenden, G. J. F. Recl. TraV. Chim. Pays-Bas 1989,
108, 330-334.
(13) Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996, 118, 10327-
10328.
10.1021/ja011867f CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/16/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 49, 2001 12433
Scheme 3
Scheme 4
selective removal of the primary TBS protecting group with
CF3CO2H gave a separable mixture of 14 (51% from 3) and its
Z-isomer. Oxidation of 14 with Dess-Martin periodinane deliv-
ered the aldehyde 15.
The key steps in the synthesis of the C-ring subunit 4 were a
ring-closing metathesis (RCM) and a [2,3]-Wittig rearrangement
(Scheme 4). Synthesis of the RCM precursor 20 began with
converting the known epoxide 1614 into its corresponding tosylate
17. Directed addition of the known alcohol 1815 to 17 proceeded
regioselectively according to the Hoffmann protocol with use of
a catalytic amount of BF3‚Et2O to provide 19.16 Hydride reduction
of 19 with LAH gave diene 20, which underwent facile RCM in
the presence of Grubbs’ catalyst,17 and subsequent oxidation of
the secondary alcohol moiety with catalytic TPAP/NMO afforded
the ketone 21. Chelation-controlled addition of propenylmagne-
sium bromide to 21 gave alcohol 22 with >10:1 diastereoselec-
tivity.18 The tertiary alcohol was alkylated with trimethyltinmethyl
iodide,19 and when the resulting allylic ether was treated with
n-BuLi, a rapid and highly diastereoselective (>20:1) [2,3]-Wittig
rearrangement ensued to give 23.20 This alcohol, which possesses
both the requisite S-stereochemistry at C(15) and E-olefin
geometry at C(16), was converted to the corresponding C-ring
phenyl sulfone 4 by sequential reaction with thiophenyl succin-
imide in the presence of PBu3 followed by oxidation with
ammonium molybdate/H2O2.21
The key transformation in the end-game was the Julia coupling
of the aldehyde 15 with the C-ring sulfone 4. Deprotonation of 4
with n-BuLi and addition of 15 provided a mixture of diastere-
omeric hydroxy sulfones that was treated with Na/Hg to deliver
an inseparable mixture of 24 and its Z-isomer (E/Z ≈ 10:1).
Removal of the TBS ethers with HF‚pyridine followed by
separation of the diastereoisomers by HPLC and saponification
of the methyl ester group with LiOH provided (+)-ambruticin S
(1).22
This highly convergent synthesis of 1 required a total of 28
steps with only 13 steps (9.2% overall yield) in the longest linear
sequence from the known cyclopropyl lactone 10. The synthesis
features a catalytic enantioselective cyclopropanation for the
construction of the central B ring component, a RCM to prepare
the C-ring, and both traditional and modified Julia couplings in
the fragment assembly steps that preferentially form the requisite
E-alkenes.
Acknowledgment. We thank the National Institutes of Health, the
Robert A. Welch Foundation, Pfizer, Inc., Merck Research Laboratories,
and the Alexander von Humboldt Stiftung for their generous support of
this research. We also thank Pfizer, Inc. for a sample of natural ambruticin
and Professor Kende (University of Rochester) for providing us with 1H
NMR spectra of ambruticin and an advanced intermediate in his synthesis.
(14) Raifield, Y. E.; Nikitenko, A. A.; Arshava, B. M.; Mikerin, I. E.;
Zilberg, L. L.; Vid, G. Y.; Lang, S. A., Jr.; Lee, V. J. Tetrahedron 1994, 50,
8603-8616.
(15) Andersen, M. W.; Hildebrant, B.; Dahmann, G.; Hoffmann, R. W.
Chem. Ber. 1991, 124, 2127-2139.
1
Supporting Information Available: Copies of H NMR spectra of
all compounds and 1H and 13C NMR spectral data and HRMS for
compounds 7, 2, 3, 15, 21, 4, and 1 (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) Brandes, A.; Eggert, U.; Hoffmann, H. M. R. Synlett 1994, 745-747.
(17) Schwab, P. E.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
(18) Davidson, A. H.; Wallace, I. H. J. Chem. Soc., Chem. Commun. 1986,
1759-1760 and references therein.
JA011867F
(19) Seyferth, D.; Andrews, S. B. J. Organomet. Chem. 1971, 30, 151-
166.
(22) The 1H NMR spectrum of the methyl ester of ambruticin S was
consistent with that reported,4b and synthetic ambruticin S was identical with
an authentic sample of natural ambruticin S by TLC, 1H and 13C NMR
(including HMQC), mass spectrum, and optical rotation.
(20) For a review, see: Mikami, K.; Nakai, T. Synthesis 1991, 594-604.
(21) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963,
28, 1140-1142.