Total synthesis of callipeltoside A

Article abstract of DOI:10.1021/ol0480325

(Chemical Equation Presented) A convergent total synthesis of cytotoxic marine macrolide callipeltoside A is described. The synthesis highlights two stereoselective [4 + 2] annulations for the preparation of associated pyran rings.

Full text of DOI:10.1021/ol0480325

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4383-4385
Total Synthesis of Callipeltoside A
Hongbing Huang and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and
Library DeVelopment, 590 Commonwealth AVenue, Boston UniVersity,
Boston, Massachusetts 02215
panek@chem.bu.edu
Received September 27, 2004
ABSTRACT
A convergent total synthesis of cytotoxic marine macrolide callipeltoside A is described. The synthesis highlights two stereoselective [4
2] annulations for the preparation of associated pyran rings.
+
Callipeltoside A is the first member of a family of novel
glycosidic macrolides isolated in 1996 from the shallow
Scheme 1. Retrosynthetic Analysis of Callipeltoside A
water lithistid sponge, Callipelta sp., collected in the waters
off the east coast of New Caledonia.1 It is found to exhibit
moderate cytotoxic activity against NSCLC-N6 and P388
cell lines.1 Intriguing structural features of callipeltoside A
include a hydroxylated hemiacetal pyran ring embedded in
a 14-membered macrolactone, which is connected to a trans-
chlorocyclopropane via a conjugated dienyne linkage. At-
tached to the macrolactone is a unique deoxyamino sugar
callipeltose (Scheme 1). The initial structure assignment of
callipeltoside A disclosed the relative stereochemical rela-
tionship of callipeltose to the macrolactone; however, the
relative stereochemistry of the chlorocyclopropyl side chain
to the rest of the molecule and the absolute stereochemistry
of callipeltoside A remained unresolved. The novel structure
of callipeltoside A, together with its stereochemical ambi-
total syntheses reported by Trost3a and Evans3b established
the absolute configuration of natural callipeltoside A as illu-
strated in Scheme 1.3 In this communication, we report a
convergent total synthesis of callipeltoside A based on the
guities and its intriguing biological activity, has prompted
considerable interest from the synthetic community.2 Recent
(1) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.; Roussakis,
C. J. Am. Chem. Soc. 1996, 118, 11085-11088.
(2) For synthetic efforts towards callipeltoside aglycon, see: (a) Hoye,
T. R.; Zhao, H. Org. Lett. 1999, 1, 169-171. (b) Velazquez, F.; Olivo, H.
F. Org. Lett. 2000, 2, 1931-1933. (c) Olivo, H. F.; Velazquez, F.; Trevisan,
H. C. Org. Lett. 2000, 2, 4055-4058. (d) Paterson, I.; Davies, R. D. M.;
Marquez, R. Angew. Chem., Int. Ed. 2001, 40, 603-607. (e) Romero-Ortega,
M.; Colby, D. A.; Olivo, H. F. Tetrahedron Lett. 2002, 43, 6439-6441.
(3) Total synthesis: (a) Trost, B. M.; Dirat, O.; Gunzner, J. L. Angew.
Chem., Int. Ed. 2002, 41, 841-843. (b) Evans, D. A.; Hu, E.; Burch, J. D.;
Jaeschke, G. J. Am. Chem. Soc. 2002, 124, 5654-5655. (c) Paterson, I.;
Davies, R. D. M.; Heimann, A. C.; Marquez, R.; Meyer, A. Org. Lett. 2003,
5, 4477-4480.
10.1021/ol0480325 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/16/2004

use of chiral organosilane methodology developed in our
laboratories.
Scheme 2
Our retrosynthetic analysis of callipeltoside A led to three
subunits 3-5. The tetrahydropyran-containing subunits 3 and
4 were thought to be obtained from dihydropyrans that were
available from formal [4 + 2] annulations of chiral orga-
nosilanes recently reported from our laboratories.4a,b In the
synthetic direction, union of 4 and 5 via a Julia-Kocienski
olefination5 precedes macrocyclization. It was envisioned that
the anti stereochemical relationship at the C8 and C9 in 6
would be established utilizing a chelation-controlled anti
crotylation, and the trans-chlorocyclopropane could be
accessed by an asymmetric Simmons-Smith reaction.
Synthesis of intermediate 6 was initiated by an anti-
selective condensation of the R-benzyloxyacetaldehyde 8
with silane (S)-9. In the presence of SnCl4, the reaction
provided tetrahydrofuran 10 in 87% yield (trans/cis
>30:1).6 Upon treatment with SbCl5, tetrahydrofuran 10
underwent E2-type elimination, providing an anti homoallylic
alcohol. This intermediate was converted to aldehyde 11 with
a two-step sequence in 92% yield.
Under previously optimized conditions,4a the annulation
of 11 and organosilane 12 provided dihydropyran 6 with high
diastereoselectivity; however, a significant amount of un-
desired dihydropyran 13 was also obtained. We suspected
that the generation of 13 was associated with the â-elimina-
tion of aldehyde 11. Gratifyingly, the use of TfOH afforded
6 in 85% yield as a single diastereomer. Despite our pre-
vious success on the stereoselective epoxidation of a similar
pyran system giving the epoxide cis to the adjacent methyl
group,7 epoxidation of dihydropyran 6 under various con-
ditions resulted in low selectivities that were circumvented
by an oxidation/hydride reduction sequence. Epoxidation
using m-CPBA was followed by epoxide ring opening
(K2CO3/MeOH), and oxidation of the resulting alcohol (PDC)
afforded enone 14. The C5 stereocenter was installed by 1,2-
reduction of the enone under Luche’s conditions.8 Protection
of the emerging alcohol as a TBS ether was followed by
one-carbon homologation of the methyl ester 15. In that
regard, an Arndt-Eistert reaction provided the homologated
methyl ester 16 in good yield. Debenzylation (H2/Pd-C) and
oxidation of the primary alcohol (PDC) completed the
preparation of aldehyde 4. The synthesis of subunit 5 utilizes
a stereoselective Horner-Emmons olefination and a Stille
coupling reaction to install the (E,E)-dienyne moiety. The
construction of 5 began with an asymmetric Simmons-Smith
reaction of allylic alcohol 17. The use of Charette’s (S,S)-
dioxoborolane ligand provided the cyclopropyl alcohol 18
in 97% ee.9 Oxidation to the aldehyde followed by dibro-
moolefination afforded vinyldibromide 19. Stille coupling
between 19 and vinylstannane 20 under conditions developed
by Shen and Wang gave enyne 21 in moderate yield.10 The
allylic alcohol was converted to phosphonate 22 in a straight-
forward manner. The Horner-Emmons reaction between
phosphonate 22 and aldehyde 23 resulted in exclusive
(E)-olefin formation providing (E,E)-dienyne 24 in 89%
yield.11 Deprotection of TBDPS silyl ether followed by a
Mitsunobu reaction and oxidation of the intermediate sulfide
gave sulfone 25. The preparation of 5 was completed after
protecting group manipulation. With the synthesis of subunits
4 and 5 completed, conditions for their union were investi-
gated. It was found that sulfone 5 was a very sensitive
substrate in the Julia-Kociensky olefination. Reliable condi-
tions were developed using THF as the solvent and LiHMDS
as the base. The use of a more polar solvent (DME, DMF)
and other bases (KHMDS, NaHMDS) led only to the de-
composition of the sulfone. After deprotection of the eth-
oxyethyl ether (PPTS, MeOH), the alcohol 26 was obtained
in 20% overall yield. After hydrolysis of the methyl ester to
the seco acid, the crucial macrolactonization was undertaken
using Yamaguchi conditions.12 The reaction provided a 1:1
mixture of dihydropyran containing lactone 27 and the
(4) (a) Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 9836-
9837. (b) We have reported the synthesis of methyl-L-callipeltose: Huang,
H.; Panek, J. S. Org. Lett. 2003, 5, 1991-1993. For other syntheses of
callipeltose, see: (c) Smith, G. R.; Finley, J. J., IV; Giuliano, R. M.
Carbohydr. Res. 1998, 308, 223-237. (d) Gurjar, M. K.; Reddy, R.
Carbohydrate Lett. 1998, 3, 169-172. (e) Pihko, A. J.; Nicolaou, K. C.;
Koskinen, A. M. P. Tetrahedron: Asymmetry 2001, 12, 937-942. (f) Evans,
D. A.; Hu, E.; Tedrow, J. S. Org. Lett. 2001, 3, 3133-3136. (g) Trost, B.
M.; Gunzner, J. L.; Dirat, O.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124,
10396-10415.
(5) Blakemore, P. R.; Cole, W. J.; Kociensky, P. J.; Morley, A. Synlett
1998, 26-28.
(6) Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 26, 9868-9870.
(7) Huang, H.; Panek, J. S. Org. Lett. 2001, 3, 1693-1696.
(8) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454-
5459.
(9) (a) Charette A. B.; Juteau, H. J. Am. Chem. Soc. 1994, 116, 2651-
2652. (b) Charette A. B.; Prescott, S.; Brochu, C. J. Org. Chem. 1995, 60,
1081-1083.
(10) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873-8879.
(11) Nicolaou, K. C.; Zipkin, R. E.; Dolle, R. E.; Harris B. D. J. Am.
Chem. Soc. 1984, 106, 3548-3551.
4384
Org. Lett., Vol. 6, No. 23, 2004

Scheme 3
Scheme 4
desired lactone 28 in 90% yield. Gratifyingly, the dihydro-
pyran 27 was converted to lactol in quantitative yield by
treating with a catalytic amount of triphenylphosphine
hydrogen bromide and water.13 The aglycon was obtained
in 85% yield after deprotecting TBS silyl ether. Lactone 28
was also transformed to aglycon 2 by a two-step sequence:
TBS deprotection (TBAF) and hydrolysis of the methyl lactol
ether (cat. PPTS, H2O/CH3CN). The total synthesis of
callipeltoside A was completed by a Schmidt glycosidation,4g,14
followed by deprotection (TBAF/AcOH) of N-TBS protect-
ing group. The analytical data were fully consistent in all
aspects with those reported for natural callipeltoside A. In
conclusion, a convergent enantioselective synthesis of cal-
lipeltoside A has been completed with a longest linear se-
quence of 25 steps. Our approach highlights an enantiose-
lective [4 + 2] annulation to assemble dihydropyrans suitably
functionalized for complex molecule synthesis. Further ex-
periments aimed at the development of the scope of the
annulation are currently under investigation.
Acknowledgment. Financial support was obtained from
NIGMS (GM56304). J.S.P. is grateful to Johnson & Johnson,
Merck Co., Novartis, Pfizer, and GlaxoSmith Kline for
financial support of our programs.
Supporting Information Available: General experimen-
tal procedures, including spectroscopic and analytical data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0480325
(12) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993.
(13) Bolitt, B.; Mioskowiski, C.; Lee, S.; Falck, J. R. J. Org. Chem.
1990, 55, 5812-5813.
(14) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980, 19,
731-732.
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