Modular synthesis of the C9-C27 degradation product of aflastatin a via alkyne-epoxide cross-couplings

Article abstract of DOI:10.1021/ol800659z

A modular approach to the synthesis of complex polyketide natural products is demonstrated for the synthesis of the C9-C27 degradation product from aflastatin A. The product of the cross-coupling of C23-C27 terminal alkyne with C17-C22 epoxide underwent f

Full text of DOI:10.1021/ol800659z

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1811-1814
Modular Synthesis of the C9-C27
Degradation Product of Aflastatin A via
Alkyne-Epoxide Cross-Couplings
Omar Robles and Frank E. McDonald*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
fmcdona@emory.edu
Received March 21, 2008
ABSTRACT
A modular approach to the synthesis of complex polyketide natural products is demonstrated for the synthesis of the C9-C27 degradation
product from aflastatin A. The product of the cross-coupling of C23-C27 terminal alkyne with C17-C22 epoxide underwent functionalization
of the resulting internal alkyne, which was then coupled similarly with C9-C16 epoxide. This synthesis concluded with regio- and stereoselective
addition of methyl onto the internal alkyne followed by stereoselective hydroboration-oxidation.
The polyketide natural product aflastatin A (1) (Figure 1)
was isolated from the mycelium of Streptomyces sp. MRI
142 by Sakuda and co-workers.1 Aflastatin A was observed
to inhibit the biosynthesis of aflatoxin in Aspergillus para-
siticus, without significantly inhibiting the growth of this
aflatoxin-producing organism. The structure of aflastatin A
has been determined by chemical degradation and extensive
spectroscopic analysis,2 with recent revision of the chiral
centers at C8-C9 and C28-C31.2c Herein we report the
asymmetric synthesis of the aflastatin C9-C27 pentaac-
etonide degradation product (2) by iterative cross-coupling
of nucleophilic alkynes with electrophilic epoxides, followed
by functionalization of the internal alkynes.3,4
Our retrosynthetic analysis envisioned that the C9-C27
substructure could be efficiently assembled by coupling
modules 3, 4, and 5. Utilizing modern methods for stereo-
selective synthesis, each module was efficiently prepared.
Epoxide 3 was synthesized from the known homoallylic
alcohol 8 (Scheme 1),5 which arose from application of
Brown’s enantioselective crotylborane addition6 followed by
the diastereoselective crotyltrifluorosilane methodology of
Chemler and Roush (dr 11:1).5 After removal of the silyl
ether protective group from 8, the terminal acetonide was
(1) Sakuda, S.; Ono, M.; Furihata, K.; Nakayama, J.; Suzuki, A.; Isogai,
A. J. Am. Chem. Soc. 1996, 118, 7855.
(3) For an iterative aldol approach to the C9-C27 polyol, see: (a) Evans,
D. A.; Trenkle, W. C.; Zhang, J.; Burch, J. D. Org. Lett. 2005, 7, 3335.
(4) (a) Burova, S. A.; McDonald, F. E. J. Am. Chem. Soc. 2002, 124,
8188. (b) Burova, S. A.; McDonald, F. E. J. Am. Chem. Soc. 2004, 126,
2495.
(2) (a) Ikeda, H.; Matsumori, N.; Ono, M.; Suzuki, A.; Isogai, A.;
Nagasawa, H.; Sakuda, S. J. Org. Chem. 2000, 65, 438. (b) Higashibayashi,
S.; Czechtizky, W.; Kobayashi, Y.; Kishi, Y. J. Am. Chem. Soc. 2003, 125,
14379. (c) Sakuda, S.; Matsumori, N.; Furihata, K.; Nagasawa, H.
Tetrahedron Lett. 2007, 48, 2527.
(5) Chemler, S.; Roush, W. R. J. Org. Chem. 2003, 68, 1319.
(6) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293.
10.1021/ol800659z CCC: $40.75
Published on Web 04/10/2008
2008 American Chemical Society

Figure 1. Structure of aflastatin A (1) and retrosynthesis for 2.
selectively installed onto the C9,C11-diol under kinetic
conditions, leaving the C13 alcohol unprotected for diaste-
reoselective hydroxyl-directed vanadium-catalyzed epoxi-
dation (dr 8:1)7 to provide compound 3 after TMS protection
of the free alcohol.
from enyne 104 by oxidative cleavage of the terminal olefin
followed by aldehyde reduction to provide the C25-C27
diol and straightforward protective group manipulations.
Epoxyalkyne module 4 was synthesized (Scheme 2) from
the known enynol 9.8 The C21-C22 epoxide was introduced
by IBr-promoted cyclization of the derived C19-O-tert-
butylcarbonate (dr 9:1), followed by basic methanolysis of
the resulting cyclic iodocarbonate,9 and PMB protection of
the C19 alcohol to provide 4a bearing a triisopropylsilyl
(TIPS) substituent on the alkyne. The terminal alkyne 5 arose
Scheme 2. Synthesis of Modules 4 and 5
Scheme 1. Synthesis of Epoxide Module 3
With modules 3, 4, and 5 in hand, we began to assemble
the aflastatin C9-C27 degradation product (2) by first
coupling modules 4a and 5 (Scheme 3). Treatment of 5 with
10
1 equiv of n-butyllithium and BF3-OEt2 followed by
addition of the electrophilic epoxide 4a provided alkynyl
alcohol 11 in 73% isolated yield (Scheme 3). The resulting
(7) Mihelich, E. D.; Daniels, K.; Eickhoff, D. J. J. Am. Chem. Soc. 1981,
103, 7690.
(8) Park, S.-K.; Kim, S.-i.; Cho, I.-H. Bull. Korean Chem. Soc. 1995,
16, 12.
(9) Duan, J. J. W.; Smith, A. B. J. Org. Chem. 1993, 58, 3703.
1812
Org. Lett., Vol. 10, No. 9, 2008

C21-alcohol then regioselectively directed hydration of the
internal alkyne to the corresponding ꢀ-hydroxyketone 12,
via intramolecular platinum-catalyzed hydrosilylation and
Tamao-Fleming oxidation.11 The C21 hydroxyl group also
directed diastereoselective reduction of the ketone to provide
the syn-C21,C23-diol, which after protective group manipu-
lation afforded terminal alkyne 13.
Scheme 3
.
Cross-Coupling of Modules 4 and 5 To Form the
C17-C27 Sector (13)
The original plan to introduce a methyl group at C18 via
carbocupration of the terminal alkyne 13 and cross-coupling
of the resulting vinyl cuprate with epoxide 3 failed due to
the high degree of functionalization in both coupling patterns,
but returning to the reliable cross-coupling of the alkynyl
lithium from 13 with epoxide 3 provided an excellent yield
of alkynyl alcohol 14, provided that BF3-THF12 was utilized
(Scheme 4). After some protective group manipulations, the
introduction of the C18-methyl substituent was accomplished
by attachment of a bromomethylsilyl ether at O19 of 15,
which underwent radical cyclization followed by protiode-
silylation to stereoselectively afford the E-trisubstituted
alkene 16.13 Hydroboration-oxidation of the allylic alcohol
16 with BH3-THF initially favored the undesired (17R,18R)-
diastereomer instead of 18. With a chiral nonracemic borane
(+)-IpcBH2,14 the preference of stereoisomers could be
inverted to favor the (17S,18S) configuration of 18 but with
only a 2:1 diastereomer ratio. However, formation of the silyl
ether 17 substantially changed the conformation (based on
1H NMR observations), and the hydroboration-oxidation of
17 with BH3-THF afforded a separable 3.8:1 mixture of
Scheme 4. Cross-Coupling of Module 3 with 13 Leading to the Aflastatin C9-C27 Degradation Product (2)
Org. Lett., Vol. 10, No. 9, 2008
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C17-C19 diols favoring 18 (the TBS ether was lost under
the basic oxidation conditions). The structures of our
synthetic materials were confirmed by formation of the
pentaacetonide 2, agreeing with the reported spectroscopic
and physical data for this compound obtained by oxidative
degradation of aflastatin A.2
our construction of the aflastatin C9-C27 degradation
product 2. The successful and high-yielding union of epoxide
3 and alkyne 13 to provide internal alkyne 14 represents the
most complex structure prepared to date by this type of
transformation.
In conclusion, we have demonstrated the efficacy of
alkyne-epoxide cross-couplings in the synthesis of structur-
ally complex and stereochemically rich polypropionates in
Acknowledgment. We thank Profs. Shohei Sakuda and
Hiromachi Nagasawa (University of Tokyo) for stimulating
conversations on this topic and for sharing original spectral
data for compound 2. We also acknowledge the initial
contributions of Ms. Mary H. Davidson (Emory University)
in the preparation of module 5.
(10) (a) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391. (b)
Eis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem. Soc. 1984, 106, 3693.
(11) (a) Tamao, K.; Maeda, K.; Tanaka, T.; Ito, Y. Tetrahedron Lett.
1988, 29, 6955. (b) Marshall, J. A.; Yanik, M. M. Org. Lett. 2000, 2, 2173.
(12) Evans, A. B.; Knight, D. W. Tetrahedron Lett. 2001, 42, 6947.
The corresponding transformation with BF3-OEt2 proceeded in much lower
yield and was not highly reproducible.
Supporting Information Available: Detailed experimen-
tal procedures and characterization for all synthetic com-
pounds and spectral comparisons of synthetic 2 with naturally
derived material. This material is available free of charge
via the Internet at http://pubs.acs.org.
(13) (a) Gulea, M.; Lo´pez-Romero, J. M.; Fensterbank, L.; Malacria,
M. Org. Lett. 2000, 2, 2591. For the corresponding reaction with alkenes,
see: (b) Stork, G.; Sofia, M. J. J. Am. Chem. Soc. 1986, 108, 6826. (c)
Koreeda, M.; Hamann, L. G. J. Am. Chem. Soc. 1990, 112, 8175.
(14) Brown, H. C.; Jadhav, P. K.; Mandal, A. K. J. Org. Chem. 1993,
58, 3703.
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