5704
J . Org. Chem. 1996, 61, 5704-5705
fragment (4),7 the problem becomes focused on the
Syn th esis of Am p h oter icin B. A
preparation of the polyol segment 5. With the demon-
stration by Nicolaou that phosphonate 5 could be ob-
tained in a single step from the C19 methyl ester,5a our
synthetic objective is reduced to fragment 6. We antici-
pated convergent assemble of this fragment through a
stereoselective nitrile oxide cycloaddition of oxime 7 with
dipolarophile 8.8 This approach conferred several ben-
efits, including the following: segregation of the con-
served (C14-C19) and variable (C1-C13) regions in the
heptaene/pseudoheptaene macrolides, simultaneous es-
tablishment of the C13-C14 bond and the C15 stereo-
center, and straightforward differentiation of C1 and C19
for later adjustments leading to 6. Furthermore, the
cycloaddition reaction would lead to the direct placement
of the final oxidation state of the C16 side chain and
would offer reaction conditions compatible with an un-
protected alcohol at C17 to allow subsequent hemiketal
formation at C13.
The approach adopted to the C1-C13 fragment 7 took
advantage of its inherent symmetry by employing pro-
tected epoxy alcohol 9 for both the C2-C7 and C8-C13
segments.7b An expedient route to this key intermediate
was available from L-malic acid as described in Scheme
2. The previously reported hydroxy acetonide 109 was
converted to the monoprotected triol 11 for subsequent
dehydration via the secondary mesylate to epoxide 9 (68%
yield from 10). The elaboration of this intermediate to
the C1-C13 fragment 12 followed the convergent se-
quence previously reported.7b The nitrile oxide precursor
in the form of oxime 7 was realized by routine methods
in excellent overall yield (92%). The dipolarophile 8 was
prepared in a single step through an Evans asymmetric
aldol condensation of the boron enolate derived from the
crotyl imidate 1310 and the readily available â-(aryloxy)
Con ver gen t Str a tegy to th e P olyol Segm en t
of th e Hep ta en e Ma cr olid e An tibiotics
Glenn J . McGarvey,* J effrey A. Mathys, and
Kenneth J . Wilson
Department of Chemistry, University of Virginia,
Charlottesville, Virginia 22901
Received May 21, 1996
Amphotericin B (1) and nystatin A1 (2) are prominent
representatives of the clinically important heptaene/
pseudoheptaene subfamily of the polyene macrolide
antibiotics.1 For more than 30 years, amphotericin B has
been the preeminent drug for the treatment of serious
systemic fungal infections.2 The potent activity of these
compounds has been attributed to sterol-dependent ion
channel formation in membranes, favoring the ergosterol-
rich membranes of fungal cells.3 Unfortunately, the
therapeutic value of these agents is attenuated by their
accompanying mammalian toxicity, and efforts to gain
an understanding of this biological mechanism have been
hampered by the structural complexity of this family of
compounds. This has spurred synthetic studies on the
polyene macrolides,4 several of which have concluded in
successful total syntheses.5,6 We report herein on the
development of a concise synthetic strategy for ampho-
tericin B that offers promising generality for the prepara-
tion of structurally related heptaene and pseudoheptaene
macrolides.
(6) For syntheses of nonheptaene macrolide antibiotics see the
following. Mycoticin A: (a) Poss, C. S.; Rychnovsky, S. D.; Schreiber,
S. L. J . Am. Chem. Soc. 1993, 115, 3360-3361. (+)-Roxaticin (natu-
ral): (b) Mori, Y.; Asai, M.; Okumura, A.; Furukawa, H. Tetrahedron
1995, 51, 5299-5314. (c) Mori, Y.; Asai. M.; Kawade, J .-i.; Furukawa,
H. Tetrahedron 1995, 51, 5315-5330. (-)-Roxaticin (unnatural): (d)
Rychnovsky, S. D.; Hoye, R. C. J . Am. Chem. Soc. 1994, 116, 1753-
1765. Pimarolide: (e) Duplantier, A. J .; Masamune, S. J . Am. Chem.
Soc. 1990, 112, 7079-7081.
(7) For previous studies in these laboratories: (a) McGarvey, G. J .;
Williams, J . M.; Hiner, R. N.; Matsubara, Y.; Oh, T. J . Am. Chem.
Soc. 1986, 108, 4943-4952. (b) McGarvey, G. J .; Mathys, J . A.; Wilson,
K. J .; Overly, K. R.; Buonora, P. T.; Spoors, P. G. J . Org. Chem. 1995,
60, 7778-7790.
(8) For a recent review: Easton, C. J .; Hughes, C. M. M.; Savage,
G. P.; Simpson, G. W. Adv. Heterocycl. Chem. 1994, 60, 261-327.
(9) Merifield, E.; Steele, P. G.; Thomas, E. J . J . Chem. Soc., Chem.
Commun. 1987, 1826-1828.
It had been demonstrated that amphotericin B (1) may
be realized from the protected aglycon 3,5a which, in turn,
can be assembled through the fusion of the polyene and
polyol fragments 4 and 5, respectively (Scheme 1).
Having efficient access already available to the C21-C37
(10) Evans, D. A.; Sjogren, E. B.; Bartroli, J .; Dow, R. L. Tetrahedron
Lett. 1986, 27, 4957-4960.
(11) This was conveniently prepared in multigram quantities from
1,3-propanediol through the following sequence: (a) p-anisaldehyde,
PhH (- H2O), 100%; (b) DIBAL, CH2Cl2, 84%; (c) PCC, CH2Cl2, 53%.
(12) Moriya, O.; Tanenaka, H.; Iyoda, M.; Urata, Y.; Endo, T. J .
Chem. Soc., Perkin Trans. 1 1994, 413-417.
(1) Omura, S.; Tanaka, H. In Macrolide Antibiotics: Chemistry,
Biology, and Practice; Omura, S., Ed.; Academic Press: New York,
1984; pp 351-404. We refer to those structures that differ from a
heptaene macrolide antibiotic (e.g., 1) by saturation at C28-C29 as
pseudoheptaene macrolide antibiotics (e.g., 2).
(13) The relative rates of these two methods of nitrile oxide
formation were qualitatively assessed by monitoring the rates of
disappearance of the hydroximoyl chloride and tributylstannyl oxime
by thin layer chromatography (SiO2, 1:1, Et2O:petroleum ether). The
hydroximoyl chloride was consumed in approximately
1 h upon
(2) Gallis, H. A.; Drew, R. H.; Pickard, W. W. Rev. Infect. Dis. 1990,
12, 308-329.
treatment with Et3N, whereas the tributylstannyl oxime persisted after
4-6 h when treated with tBuOCl.
(3) Brajtburg, J .; Powderly, W. G.; Kobayashi, G. S.; Medoff, G.
Antimicrob. Agents Chemother. 1990, 34, 183-188.
(14) The furoxan product resulting from the dimerization of the
nitrile oxide could be isolated and identified by 1H NMR.
(15) Baraldi, P.; Barco, A.; Benetti, S.; Manfredini, S.; Simoni, D.
Synthesis 1987, 276-278.
(4) For a review: Beau, J .-M. In Recent Progress in the Chemical
Synthesis of Antibiotics; Lukacs, G., Ohno, M., Eds.; Springer-Verlag:
Berlin, 1990; pp 135-182.
(16) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull.
1981, 29, 1475-1478.
(17) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4156-4156.
(18) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981,
37, 2091-2096.
(5) Total synthesis of amphotericin B: (a) Nicolaou, K. C.; Ogilvie,
W. W. Chemtracts-Org. Chem. 1990, 3, 327-349. 19-Dehydroampho-
teronolide B: (b) Kennedy, R. M.; Abiko, A.; Takenasa, T.; Okumoto,
H.; Masamune, S. Tetrahedron Lett. 1988, 29, 451-454.
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