Scheme 1. Retrosynthetic Analysis of the Basiliskamides
Scheme 2. Synthesis and Stereochemical Assignment of
Homoallylic Alcohol 9
through two chiral organosilane additions, we rationalized
that anti-selective addition of silane reagent 7, followed by
complementary syn-selective reaction with (Z)-crotylboronate
reagent 8,9 would efficiently provide the fully elaborated
C5-C12 fragment. Vital to our synthetic route is the
stereochemical flexibility inherent to these protocols, as the
absolute configuration of the natural product was not certain
from the isolation text.
recently determined through chemical synthesis of its enan-
tiomer.7 Despite the similar structures, YM-47522 possesses
a biological profile remarkably different from that of
basiliskamide A, displaying greater than 20-fold loss in
activity against C. albicans and A. fumigatus. Interestingly,
the gross structure of YM-47522 is incorporated into the
natural product nagahamide A,8 a seven-residue depsipeptide
possessing weak antibacterial activity against E. coli and S.
aureus. In addition to the complete stereochemical determi-
nation of the natural products, total synthesis of basiliska-
mides A and B should facilitate investigation of the structural
determinants of the biological activity in this class of
molecules.
Our retrosynthetic analysis of the basiliskamides is outlined
in Scheme 1. Initial bond disconnection at the conjugated
(E,Z)-diene suggests coupling between the known stannane
37 and vinyl iodide 4, which upon selective deprotection and
acylation provides access to both natural products. Homoal-
lylic alcohol 5 can be derived in a stereoselective manner
using two successive crotylmetal addition reactions. While
the stereochemical configuration of 5 is readily accessible
Accordingly, using the chiral organosilane methodology
developed in our laboratory,10 addition of (R,E)-711 to
aldehyde 612 afforded homoallylic alcohol 9 in 74% yield
with high diastereoselectivity (Scheme 2). In accordance with
literature precedent, a TiCl4-mediated addition proceeded
through an open transition state: presumably, a six-
membered chelate affected a synclinal relationship between
the aldehyde carbonyl and the nucleophilic alkene, heavily
favoring the formation of an anti-homoallylic alcohol. To
confirm the stereochemical outcome of this reaction, we
initiated a synthetic sequence to form acetonide 10. 1H NMR
analysis of this material at 400 MHz, however, proved
difficult as a result of overlapping resonances of seven
protons adjacent to oxygen. Exchange of the benzyl ether to
1
the corresponding acetate yielded compound 11, whose H
(2) (a) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990,
31, 7099-7100. (b) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron. Lett.
1990, 31, 945-948. (c) Rychnovsky, S. D.; Rogers, B.; Yuang, G. J. Org.
Chem. 1993, 58, 3511-3515.
(3) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092-4096.
(4) Although the text of ref 1 correctly indicates the stereochemistry of
basiliskamides A and B, the published structures are inadvertently illustrated
as the enantiomers of each natural product (personal communication with
R. J. Andersen).
NMR was readily interpretable. The 3JH7,H8 coupling constant
of 9.6 Hz is consistent with a trans-diaxial relation and thus
an anti-addition of organosilane 7.
En route to common intermediate 4, homoallylic alcohol
9 was protected as the TIPS ether in near-quantitative yield
(5) During publication, a recent report of this assignment came to our
attention: Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2004, 21, 1-49.
(6) (a) Shibazaki, M.; Sugawara, T.; Nagai, K.; Shimizu, Y.; Yamaguchi,
H.; Suzuki, K. J. Antibiot. 1996, 49, 340-344. (b) Suguwara, T.; Shibazaki,
M.; Nakahara, H.; Suzuki, K. J. Antibiot. 1996, 49, 345-348.
(7) Ermolenko, M. S. Tetrahedron Lett. 1996, 37, 6711-6712.
(8) Okada, Y.; Matsunaga, S.; Van Soest, R. W. M.; Fusetani, N. Org.
Lett. 2002, 4, 3039-3042.
(9) Roush, W. R.; Kaori, A.; Powers, D. B.; Palkowitz, A. D.; Halterman,
R. L. J. Am. Chem. Soc. 1990, 112, 6339-6348.
(10) (a) Panek, J. S.; Beresis, R. J. Org. Chem. 1993, 58, 809-811. (b)
Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316. (c) Jain, N.
F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996, 118, 12475-12476.
(11) Beresis, R. T.; Solomon, J. S.; Yang, M. G.; Jain, N. F.; Panek, J.
S. Org. Synth. 1998, 75, 78-88.
(12) Seo, M. H.; Lee, Y. Y.; Goo, Y. M. Bull. Korean Chem. Soc. 1996,
17, 314-321.
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