Facile entry to the zaragozic acids. Asymmetric total synthesis of 6,7-dideoxysqualestatin H5

Full text of DOI:10.1021/jo981684k

7592
J . Org. Chem. 1998, 63, 7592-7593
F a cile En tr y to th e Za r a gozic Acid s.
Asym m etr ic Tota l Syn th esis of
6,7-Did eoxysqu a lesta tin H5
Stephen F. Martin* and Satoru Naito1
Department of Chemistry and Biochemistry, The University of
Texas, Austin, Texas 78712
Received August 20, 1998
The zaragozic acids2 and the squalestatins3 constitute a
novel family of fungal metabolites that exhibit extraordinary
potency as inhibitors of squalene synthase, as antifungal
agents, and as inhibitors of farnesyl protein transferase.4
The unusual structure of these highly functionalized metab-
olites coupled with their promising biological activitities,
especially their potential as leads for hypercholesterolemic
therapy, have inspired numerous efforts directed toward
their synthesis. Consequent to these efforts, a variety of
approaches to the central 2,8-dioxabicyclo[3.2.1]octane core
have been recorded,5 and several total syntheses of zaragozic
acid A (squalestatin S1) (1) and zaragozic acid C (2) have
been reported.6,7 Despite these elegant successes, we were
attracted to the considerable challenge of devising a more
concise and general approach to members of the zaragozic
acid family. In this context, we targeted the bicyclic lactone
10 as a potentially versatile gateway because it contains the
requisite absolute chiralty at C(3)-C(5) as well as appropri-
ate functional handles for introducing the remaining sub-
stituents and side chains of the zaragozic acids. We
envisaged that this compact intermediate might be as-
sembled via the intramolecular vinylogous aldol reaction of
the 5-substituted-2-furoate 9 (Scheme 1).8 We now report
the implementation of such a cyclization as a key step in a
concise synthesis of 6,7-dideoxysqualestatin H5 (3).3c
As the point of departure en route to the pivotal vinylo-
gous aldol reaction, dimethyl D-tartrate was converted to the
monoprotected derivative 5 (69%).9,10 Selective reduction of
the ester R to the free hydroxyl group in 5 was best achieved
using borane-dimethyl sulfide complex in the presence of
catalytic sodium borohydride,10 although under the best
conditions an inseparable mixture (4:1) of the 1,2- and 1,3-
diols was obtained. Fortunately, protection of the primary
alcohols as their tert-butyldiphenylsilyl ethers (TBDPS) led
to a mixture from which 6 was isolated by chromatography
in 50% overall yield. Esterification of 6 with the known acid
7, which is available in three steps from commercially
available 5-bromo-2-furancarboxylic acid,11 proceeded in 96%
yield to give 8. Removal of the tetrahydropyranyl protecting
group12 followed by oxidation of the intermediate alcohol
with Dess-Martin periodinane13 gave 9 (94% overall yield).
The key cyclization of 9 via an intramolecular vinylogous
aldol reaction was now at hand, and after some experimen-
tation, we found that this transformation proceeded most
efficiently in the presence of 3 equiv of TiCl4 (CH2Cl2, 0 °C
f rt, 2 h) to give 10 in 40% yield. Less than 5% of the other
three diastereomeric adducts were obtained under these
conditions, whereas use of other Lewis acids such as ZnCl2,
ZnBr2, SnCl4, BF3‚OEt2, and TMS-OTf either returned
starting material or complex mixtures containing other
diastereomeric adducts. Interestingly, the presence of the
phenylthio group on the furan ring was critical to the success
of this reaction, as the cyclization of the corresponding
methoxyfuran furnished mixtures containing comparable
quantities of each of the four possible adducts. Reduction
of the double bond followed by protection of the tertiary
hydroxyl group gave 11 (75% overall yield); the structure of
11 was confirmed by X-ray analysis.
(1) On leave from Sankyo Co., Ltd., Tokyo, J apan.
(2) (a) Dufresne, C.; Wilson, K. E.; Zink, D.; Smith, J .; Bergstrom, J . D.;
Kurtz, M.; Rew, D.; Nallin, M.; J enkins, R. et al. Tetrahedron 1992, 48,
10221. (b) Bergstrom, J . D.; Kurtz, M. M.; Rew, D. J .; Amend, A. M.; Karkas,
J . D.; Bostedor, R. G.; Bansal, V. S.; Dufresne, C.; VanMiddlesworth, F. L.
et al. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 80. (c) Tanimoto, T.; Hamano,
K.; Onodera, K.; Hosoya, T.; Kakusaka, M.; Hirayama, T.; Shimada, Y.;
Koga, T.; Tsujita, Y. J . Antibiot. 1997, 50, 390.
(3) (a) Sidebottom, P. J .; Highcock, R. M.; Lane, S. J .; Procopiou, P. A.;
Watson, N. S. J . Antibiot. 1992, 45, 648. (b) Hasumi, K.; Tachikawa, K.;
Sakai, K.; Murakawa, S.; Yoshikawa, S.; Kumazawa, S.; Endo, A. J . Antibiot.
1993, 46, 689. (c) Blows, W. M.; Foster, G.; Lane, S. J .; Noble, D.; Pielcey,
J . E.; Sidebottom, P. J .; Webb, G. J . Antibiot. 1994, 47, 740.
(4) For reviews, see: (a) Bergstrom, J . D.; Dufresne, C.; Bills, G. F.;
Nallin-Omstead, M.; Byrne, K. Annu. Rev. Microbiol. 1995, 49, 607. (b)
Nadin, A.; Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 1622.
(5) For some recent examples, see: (a) Kraus, G. A.; Maeda, H. J . Org.
Chem. 1995, 60, 2. (b) Hodgson, D. M.; Bailey, J . M.; Harrison T.
Tetrahedron Lett. 1996, 37, 4623. (c) Freeman-Cook, K. D.; Halcomb, R. L.
Tetrahedron Lett. 1996, 37, 4883. (d) Xu, Y.; J ohnson, C. R. Tetrahedron
Lett. 1997, 38, 1117. (e) Paterson, I.; Fessner, K.; Finlay, M.; Raymond V.
Tetrahedron Lett. 1997, 38, 4301. (f) Ito, H.; Matsumoto, M.; Yoshizawa,
T.; Takao, K.; Kobayashi, S. Tetrahedron Lett. 1997, 38, 9009. (g) Hegde,
S. G.; Myles, D. C. Tetrahedron 1997, 53, 11179. (h) Brogan, J . B.; Zercher,
C. K. Tetrahedron Lett. 1998, 39, 1691. (i) Mann, R. K.; Parsons, J . G.;
Rizzacasa, M. A. J . Chem. Soc. Perkin Trans. 1 1998, 1283.
The requisite (C1) side chain of 3 was prepared according
to a straightforward sequence of reactions consisting of four
(6) (a) Nicolaou, K. C.; Nadin, A.; Leresche, J . E.; Yue, E. W.; La Greca,
S. Angew. Chem.; Int. Ed. Engl. 1994, 33, 2190. (b) Nicolaou, K. C.; Yue, E.
W.; La Greca, S.; Nadin, A.; Yang.; Z.; Leresche.; J . E.; Tsuri T.; Naniwa,
Y.; De Riccardis, F. Eur. J . Chem. 1995, 1, 467. (c) Stoermer, D.; Caron, S.;
Heathcock, C. H. J . Org. Chem. 1996, 61, 9115. (d) Caron, S.; Stoermer, D.;
Mapp, A. K.; Heathcock, C. H. J . Org. Chem.. 1996, 61, 9126.
(7) (a) Carreira, E. M.; Du Bois, J . J . Am. Chem. Soc. 1994, 116, 10825-
6. J . Am. Chem. Soc. 1995, 117, 8106. (b) Evans, D. A.; Barrow, J . C.;
Leighton, J . L.; Robichaud, A. J .; Sefkow, M. J . Am. Chem. Soc. 1994, 116,
12111. (c) Sato, H.; Nakamura, S.; Watanabe, N.; Hashimoto, S. Synlett
1997, 451. (d) Armstrong, A.; J ones, L. H.; Barsanti, P. A. Tetrahedron Lett.
1998, 39, 3337.
(9) The structure assigned to each compound was in accord with its
spectral (1H and 13C NMR, IR, MS) characteristics. Analytical samples of
new compounds were obtained by distillation, recrystallization, or prepara-
tive HPLC and gave satisfactory combustion analysis (C, H) and/or
identification by high-resolution mass spectrometry. Yields are based on
purified materials.
(10) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T. Tetra-
hedron 1992, 48, 4067.
(11) Cella, J . A. J . Org. Chem. 1988, 53, 2099.
(12) Ogawa, Y.; Shibasaki, M. Tetrahedron Lett. 1984, 25, 663.
(13) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b) Meyer,
S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549.
(8) For a review, see: Casiraghi, G.; Rassu, G. Synthesis 1995, 607.
10.1021/jo981684k CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/06/1998

Communications
J . Org. Chem., Vol. 63, No. 22, 1998 7593
Sch em e 1
Sch em e 3
(1:2.5) of the desired bicyclic ketal 17 (25% yield) together
with a mixture (ca. 1:1, 65%) of epimeric methyl ketals that
have been tentatively identified as 18. Obtention of this
mixture was somewhat surprising inasmuch as all other
acid-catalyzed transformations leading to zaragozic acids A
and C reportedly delivered exclusively the desired 2,8-
dioxabicyclo[3.2.1]octane core.6,7 On the other hand, in
various model studies directed toward the zaragozic acids,
mixtures of isomeric ketals have been reported.5b,d,e,g Thus,
the presence of the hydroxyl groups at C(6) and C(7) in
synthetic intermediates may play an important role in
dictating the thermodynamic course of these transketaliza-
tions. In any event, the mixture of 17 and 18 was readily
separable by chromatography, and the undesired ketals 18
could be reequilibrated upon exposure to methanolic acid
to give additional quantities of 17. Oxidation of the primary
alcohol function of 17 to the corresponding carboxyl group18
and hydrolysis of the methyl esters gave synthetic 3 (62%
Sch em e 2
1
overall yield), which gave H and 13C NMR spectra identical
with those of an authentic sample.19
The total asymmetric synthesis of the natural product 6,7-
dideoxysqualestatin H5 (3) has been completed by a concise
approach in which the longest linear sequence is 14 steps.
The synthesis highlights a novel strategy for assembling the
core of the zaragozic acids and provides a compelling
example of the power and versatility of intramolecular
vinylogous aldol reactions in organic synthesis.
steps from the known aldehyde 12 (>95% ee) (Scheme 2).14
Thus, isopropenylmagnesium bromide added to 12 without
epimerization of the stereocenter bearing the methyl group
to give 13 as a mixture (ca. 1:1) of epimers (75%).15
Compound 13 was then converted in two steps (81% overall
yield) to the allyl bromide 14, which was alkylated with the
potassium salt of methyl phenyl sulfone to give the mono-
alkylated product 15 (89% yield).16
Coupling the C(1) side chain with the spiro bicyclic
subunit 11 was then achieved by selective addition of the
dianion of the sulfone 15 to the less hindered lactone moiety
of 11 to give, following reductive desulfonylation,17 the
hemiketal 16 in 73% overall yield (Scheme 3). Treatment
of 16 with methanolic acid led to an equilibrium mixture
Ack n ow led gm en t. We thank the National Institutes
of Health and The Robert A. Welch Foundation for their
generous support of this research. We are grateful to the
Sankyo Co., Ltd. (Tokyo, J apan) for financial support. We
also thank Drs. Spiros Liras and Philip R. Kym for
conducting key model studies that led to development of
the successful strategy documented herein.
Su p p or tin g In for m a tion Ava ila ble: Complete experimental
procedures and characterization (1H and 13C NMR and IR spectra
and mass spectral data) (9 pages).
(14) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J . L. J . Am. Chem.
Soc. 1994, 116, 9361.
J O981684K
(15) The optical purity of 13 (>95% ee) was established by degradation
(NaIO4, RuO2‚xH2O) to the carboxylic acid derivative of 12 and NMR
analysis of its methyl (S)-(+)-mandelate derivative. See: Tyrrel, E.; Tsang,
M. W. H.; Skinner, G. A.; Fawcett, J . Tetrahedron 1996, 62, 9841.
(16) Pine, S. H.; Shen, G.; Bautista, J .; Sutton, C., J r.; Yamada, W.;
Apodaca, L. J . Org. Chem. 1990, 55, 2234.
(18) Xu, Z.; J ohannes, C. W.; Houri, A. F.; La, D. S.; Cogan, D. A.;
Hofilena, G. E.; Hoveyda, A. H. J . Am. Chem. Soc. 1997, 119, 10302.
(19) We thank Dr. Philip J . Sidebottom (GlaxoWellcome, UK) for 1H and
13C NMR spectra of authentic 6,7-dideoxysqualestatin H5.
(17) Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1965, 87, 1345.