Asymmetric synthesis of the chlorocyclopropane-containing callipeltoside A side chain.

Article abstract of DOI:10.1021/ol0155182

[reaction: see text] The callipeltoside A chlorocyclopropyl-containing dienyne side chain has been synthesized in nine steps and 33% overall yield from commercially available 1,2,5,6-O-dicyclohexylidene-D-mannitol. The key steps in the synthesis are a hig

Full text of DOI:10.1021/ol0155182

ORGANIC
LETTERS
2001
Vol. 3, No. 4
503-505
Asymmetric Synthesis of the
Chlorocyclopropane-Containing
Callipeltoside A Side Chain
David A. Evans* and Jason D. Burch
Department of Chemistry & Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
eVans@chemistry.harVard.edu
Received January 5, 2001
ABSTRACT
The callipeltoside A chlorocyclopropyl-containing dienyne side chain has been synthesized in nine steps and 33% overall yield from commercially
available 1,2,5,6-O-dicyclohexylidene-D-mannitol. The key steps in the synthesis are a highly diastereoselective cyclopropanation of a vinyl
chloride allylic ether and a Suzuki cross-coupling to complete the carbon framework.
During the course of screening marine organisms for the
identification of new antitumor and antiviral agents, Minale
and co-workers isolated the active constituent, callipeltoside
A (1, Figure 1), from the marine sponge Callipelta sp. This
new macrolide was found to display antitumor activity, as
well as in vitro protection of HIV infected cells.1 Callipel-
toside A contains a highly functionalized deoxyamino sugar
(callipeltose) and a dienyne-trans-chlorocyclopropane side
chain appended to a polyketide-derived 14-membered mac-
rolactone. The stereochemical assignment of 1 was made on
the basis of extensive NMR spectroscopic studies. At the
present time, the principal stereochemical ambiguity yet to
be addressed is associated with the absolute stereochemical
relationships associated with the pendant cyclopropane ring.
The unique structure and biological activity of callipeltoside
A has stimulated efforts directed toward a synthesis and
ultimate stereochemical assignment of this natural product.2
In this Letter we describe a practical asymmetric synthesis
of the chlorocyclopropane-containing dienyne side chain.
Scheme 1 illustrates the general synthetic strategy that is
being pursued in the assemblage of callipeltoside A. Because
of the stereochemical ambiguity associated with the dienyne
side chain, our objectives are to be able to readily access
either C15-C22 side chain enantiomer which might be
appended to the glycosylated macrolactone through an (E)-
selective Horner-Emmons coupling of phosphonate 4 with
the lactone subunit 3.3 Dibromoolefin 5 serves as a suitable
precursor to phosphonate 4 using either a Stille4 or a Suzuki5
coupling/elimination sequence. The chlorocyclopropane 5
(1) (a) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.; Roussakis,
C. J. Am. Chem. Soc. 1996, 118, 11085-11088. (b) Zampella, A.; D’Auria,
M. V.; Minale, L.; Debitus, C. Tetrahedron 1997, 53, 3243-3248.
(2) (a) Smith, G. R.; Finley, J. J.; IV.; Giuliano, R. M. Carbohydr. Res.
1998, 308, 223-227. (b) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 169-
171. (c) Vela´zquez, F.; Olivo, H. F. Org. Lett. 2000, 2, 1931-1933. (d)
Olivo, H. F.; Vela´zquez, F.; Trevisan, H. C. Org. Lett. 2000, 2, 4055-
4058.
Figure 1.
10.1021/ol0155182 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/31/2001

adopted. Homologation of unpurified 10 using Ohira’s
reagent 128 yielded alkyne 11 in 94% yield. The one-pot
hydroboration/chlorination sequence developed by Masuda9
was then employed to afford vinyl chloride (+)-8 in 70%
yield as a single olefin isomer (>20:1).
Scheme 1
Vinyl chloride (+)-8 proved resistant to Simmons-Smith
cyclopropanation. Less than 15% conversion was observed
using either the Furukawa10 or Denmark11 reaction variants.
These failures prompted investigation of the highly activated
conditions developed by Shi, in which Et2Zn is premixed
with 1 equiv of trifluoroacetic acid prior to the addition of
1 equiv of CH2I2.12 This dramatically enhanced carbenoid
delivered chlorocyclopropane 13 as a single diastereomer
(>50:1)13 in 82% yield (Scheme 3). This result illustrates
Scheme 3
would arise from a diastereoselective cyclopropanation of
vinyl chloride 8.
While the Takai reaction6 of glyceraldehyde cyclohexyl-
idene ketal 107 was initially investigated to afford vinyl
chloride (+)-8, the reaction exhibited modest selectivity (87:
13) and yields (Scheme 2). Significantly, the olefin isomers
Reaction conditions: (a) Et2Zn, CF3COOH, CH2I2, CH2Cl2, rt;
(b) Dowex resin, MeOH, rt; (c) Pb(OAc)4, K2CO3, CH2Cl2, rt; (d)
PPh3, CBr4, CH2Cl2, rt.
Scheme 2
that the Shi conditions can be used for directed cyclopro-
panations of electron-deficient olefins.
Removal of the cyclohexylidene protecting group initially
proved difficult due to reketalization during in vacuo
concentration. However, washing the methanolic reaction
solution with hexanes prior to concentration removed the
cyclohexanone dimethyl ketal and allowed the isolation of
diol 14 in 84% yield (Scheme 3). Diol 14 was converted to
the desired dibromide (-)-5 in two steps (Scheme 3). Diol
cleavage with potassium carbonate-buffered lead tetraacetate
afforded the volatile aldehyde 16 which was treated with 5
equiv of the Corey-Fuchs reagent14 without purification to
Reaction conditions: (a) KIO4, KHCO3, THF/H2O, rt; (b) CrCl2,
CHCl3, THF, 70 °C; (c) 12, K2CO3, MeOH, rt; (d) (i) Thexyl2BH,
-15 to 0 °C, THF, (ii) CuCl2, H2O, HMPA, THF, 0 to 70 °C.
(6) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408-
7410.
(7) Aldehyde 10 was prepared by the method of: Schmid, C.; Bradley,
D. A. Synthesis 1992, 587-590.
(8) (a) Ohira, S. Synth. Commun. 1989, 19, 561-564. (b) Mu¨ller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521-522.
(9) Masuda, Y.; Hoshi, M.; Arase, A. J. Chem. Soc., Perkin Trans. 1
1992, 2725-2726.
(10) Furukawa, J.; Kawabata, N.; Nishimura. J. Tetrahedron 1968, 24,
53-58.
(11) Denmark, S.; O′Connor, S. P. J. Org. Chem. 1997, 62, 3390-3401.
(12) Yang, Z.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39, 8621-
8624.
(13) The diastereoselectivity was verified by independent synthesis of a
mixture of cyclopropane diastereomers, which were distinguishable by gas
chromatography (see Supporting Information).
were not readily separated by chromatography. As an
alternative, an improved two-step stereospecific route was
(3) (a) Nicolaou, K. C.; Zipkin, R. E.; Dolle, R. E.; Harris, B. D. J. Am.
Chem. Soc. 1984, 106, 3548-3551. (b) Nicolaou, K. C.; Chung, Y. S.;
Hernandez, P. E.; Taffer, I. M.; Zipkin, R. E. Tetrahedron Lett. 1986, 27,
1881-1882. (c) Nicolaou K. C.; Webber, S. E. Chem. Commun. 1986,
1816-1817.
(4) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873-8879.
(5) (a) Roush, W. R.; Moriarty, K. J.; Brown, B. B. Tetrahedron Lett.
1990, 31, 6509-6512. (b) Frank, S. A.; Chen, H.; Kunz, R. K.; Schnad-
erbeck, M. J.; Roush, W. R. Org. Lett. 2000, 2, 2691-2694.
(14) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 23, 3769-3772.
504
Org. Lett., Vol. 3, No. 4, 2001

Scheme 4
Scheme 5
Reaction conditions: (a) Pd(PPh3)4, TlOEt, THF/H2O, rt; (b)
DBU, MePh, 110 °C.
In summary, a highly stereoselective synthesis of the
enantiopure side chain of callipeltoside A has been completed
in nine steps and 33% overall yield from commercially
available 1,2,5,6-di-O-cyclohexylidene-D-mannitol. This syn-
thesis is amenable to the preparation of both enantiomers of
the side chain, using ent-10, which is available by periodate
cleavage of 5,6-O-cyclohexylidene-L-gulono-1,4-lactone.17
The total synthesis of callipeltoside A will be reported in
due course.
Reaction conditions: (a) p-BrC6H4COCl, pyr, CH2Cl2, 0 °C.
afford (-)-5 in 94% overall yield. The relative and absolute
stereochemistry of the cyclopropane was verified by single-
crystal X-ray crystallographic analysis of the derived p-
bromobenzoate 15 (Scheme 4).
Conversion of dibromide (-)-5 to the desired enyne
alcohol 17 using the Stille coupling/elimination conditions
developed by Shen4 was initially attempted with vinylstan-
nanes 6a and 6b. This sequence produced the desired enynes
in low yield (<50%), and chromatographic removal of tin
byproducts proved problematic. A sequential coupling and
elimination using the Roush modification of the Suzuki
coupling5 was pursued as an alternate coupling strategy.
Coupling of dibromide (-)-5 with vinylboronic acid 715 in
the presence of Pd(PPh3)4 and thallium ethoxide afforded
the dienol 18 in 85% yield (Scheme 5). The side chain
synthesis was completed using a DBU-induced elimination16
to produce enyne alcohol 17 in 91% yield.
Acknowledgment. Support has been provided by the
National Institutes of Health (GM 33327-16) and Merck. The
authors gratefully acknowledge Prof. Andre´ Charette for
useful discussions and C. Wade Downey for the X-ray crystal
structure determination of 15.
Supporting Information Available: Experimental pro-
cedures and characterization of compounds (-)-5, (+)-8, 11,
13, 14, 17, and 18; synthesis and GC separation of a
diastereomeric mixture of 13; X-ray crystallographic data
for 15. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Roush, W. R.; Champoux, J. A.; Peterson, B. C. Tetrahedron Lett.
1996, 37, 8989-8992. The authors thank Prof. William Roush and Dr. Scott
Frank for providing the experimental details for the preparation of 7.
(16) Nakamura, T.; Namiki, M.; Ono, K. Chem. Pharm. Bull. 1987, 35,
2635-2645.
OL0155182
(17) The conversion of 5,6-O-pentylidene-L-gulono-1,4-lactone to L-
glyceraldehyde pentylidene ketal is known; see ref 7.
Org. Lett., Vol. 3, No. 4, 2001
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