Synthesis of the C1-C13 fragment of leucascandrolide A.

Article abstract of DOI:10.1021/ol991345t

[reaction: see text] The synthesis of the C1-C13 fragment 3 of leucascandrolide A has been completed utilizing a stereoselective and regioselective reductive cleavage of a highly functionalized spiroketal to incorporate the cis-2,6-disubstituted tetrahydropyan. The spiroketal was constructed by addition of a lithiated pyrone 5 to aldehyde 6.

Full text of DOI:10.1021/ol991345t

ORGANIC
LETTERS
2000
Vol. 2, No. 5
597-599
Synthesis of the C1−C13 Fragment of
Leucascandrolide A
Michael T. Crimmins,* Charlotte A. Carroll, and Bryan W. King
Venable and Kenan Laboratories of Chemistry, The UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599-3290
crimmins@email.unc.edu
Received December 14, 1999
ABSTRACT
The synthesis of the C1−C13 fragment 3 of leucascandrolide A has been completed utilizing a stereoselective and regioselective reductive
cleavage of a highly functionalized spiroketal to incorporate the cis-2,6-disubstituted tetrahydropyan. The spiroketal was constructed by addition
of a lithiated pyrone 5 to aldehyde 6.
Leucascandrolide A (1) was isolated from the calcareous
sponge Leucascandra caVeolata collected from the Coral Sea
off the coast of New Caladonia. The gross structure and
relative stereochemistry were assigned on the basis of
extensive two-dimensional NMR experiments, and the
absolute configuration was assigned by Mosher’s method
using the Mosher ester of the C5 hydroxyl. Leucascandrolide
A displayed significant cytotoxicity in vitro (IC50 ) 0.05
and 0.25 µg/mL with KB and P388 cells, respectively) as
well as very strong inhibition of Candida albicans, a
pathogenic yeast that attacks AIDS patients.1
The unusual macrolide structure, combined with its novel
biological activity, prompted us to investigate the total
synthesis of leucascandrolide A. The strategy for the total
synthesis of leucascandrolide A is illustrated in Figure 1.
Leucascandrolide A (1) would be derived from a macrolac-
tonization of the seco acid 2 with a subsequent attachment
of the ester at the C5 hydroxyl. The seco acid 2 would be
derived from tetrahydropyran 3 by formation of the C13-
C14 bond through an alkylation of a C13 iodide derived from
3 with an appropriate C14-C22 nucleophilic fragment or a
similar strategy. Tetrahydropyran 3 would be revealed
through a chelation-controlled, stereoselective reductive
Figure 1. Retrosynthesis of Leucascandrolide A.
cleavage of spiroketal 4 according to our recently developed
protocol.2 Spiroketal 4 can be prepared from addition of
metalated pyrone 5 to aldehyde 6 and subsequent spiro-
cyclization.3 We report here the implementation of this
(1) Ambrosio, M. D.; Guerriero, A.; Debitus, C.; Pietra, F. HelV. Chim.
Acta 1996, 79, 51-59.
10.1021/ol991345t CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/03/2000

strategy for the preparation of the C1-C13 fragment 3 which
contains six of the eight stereogenic centers of leucascan-
drolide A.
Scheme 2
The synthesis of fragment 3 began with the preparation
of aldehyde 6 as illustrated in Scheme 1. The known alcohol
Scheme 1
84 was prepared by alkylation of the titanium enolate of
propionyl oxazolidinone 7 with chloromethylbenzyl ether5
followed by reductive removal of the auxiliary6 (95%
overall). The primary alcohol was oxidized under Swern7
conditions, and the resultant aldehyde was exposed to the
well-documented chelation-controlled, Lewis acid mediated
addition of allylsilanes to aldehydes8 to provide the anti
alcohol 9 as the major diastereomer (83% overall; 89:11 dr).9
After chromatographic separation, the major diastereomer
was protected as its p-methoxybenzyl ether and the terminal
olefin was cleaved to the desired aldehyde 6 under Lemeiux-
Johnson conditions.
Conversion of aldehyde 6 to the required spiroenone 13
was accomplished according to our established protocol10
(see Scheme 2). Metalation of pyrone 511 at -78 °C followed
by addition of aldehyde 6 resulted in formation of hydroxy-
pyrone 10 in 84% yield as a 1:1 mixture of diastereomers.
The mixture was carried forward in anticipation of using the
spiroketal as a template in a stereoselective reduction to
control the C9 stereocenter. The secondary alcohol was
treated with t-BuMe2SiOTf to give silyl ether 11 in high
yield. Removal of the p-methoxybenzyl ether with DDQ12
(pH 7 buffer, CH2Cl2) produced alcohol 12, which upon
exposure to trifluoroacetic acid in benzene resulted in the
formation of a 1:1 thermodynamic mixture of spiroenone
13 and pyrone 12. Starting pyrone 12 and spiroenone 13 were
easily separable by flash chromatography, and resubjection
of pyrone 12 to the reaction conditions ultimately provided
spiroenone 13 in 80% yield after three recycles. Copper-
catalyzed addition of vinylmagnesium bromide to enone 13
Scheme 3
(2) Crimmins, M. T.; Rafferty, S. W. Tetrahedron Lett. 1996, 37, 5649-
5652.
(3) Crimmins, M. T.; Washburn, D. G.; Katz, J. D.; Zawacki, F. J.
Tetrahedron Lett. 1998, 39, 3439-3442. Crimmins, M. T.; Washburn, D.
G. Tetrahedron Lett. 1998, 39, 7487-7490.
(4) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J.
Am. Chem. Soc. 1990, 112, 5290-5313.
(5) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T.
J. Am. Chem. Soc. 1990, 112, 8215-8216.
(6) Prashad, M.; Har, D.; Kim, H. Y.; Repic, O. Tetrahedron Lett. 1998,
39, 7067-7070.
(7) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(8) Reetz, M. T.; Kesseler, K.; Jung, A. Tetrahedron Lett. 1984, 25, 729-
732. Kiyooka, S.-I.; Heathcock, C. H. Tetrahedron Lett. 1983, 24, 4765-
4768.
(9) All new compounds were characterized by 1H and 13C NMR, IR,
and optical rotation. Yields are for isolated, chromatographically purified
products.
(10) Zawacki, F. J.; Crimmins, M. T. Tetrahedron Lett. 1996, 37, 6499-
6502.
(11) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021-3028.
598
Org. Lett., Vol. 2, No. 5, 2000

to establish the C3 stereocenter resulted in 78% yield of
spiroketal 14 with excellent stereocontrol (95:5 dr). The
selective equatorial addition appears to be controlled by steric
shielding of the substituent at C11 of the spiroketal (leucas-
candrolide A numbering).13 Reduction of the C5 ketone with
L-Selectride14 provided axial alcohol 15 in high yield as a
single detectable isomer at C5. Protection of alcohol 15 (KH,
THF, BnBr) gave benzyl ether 16 in excellent yield (Scheme
3), and the C9 stereocenter was established in an oxidation-
reduction sequence using the spiroketal as a template for
stereocontrol. Removal of the TBS ether with n-Bu4NF
followed by Jones oxidation of the C9 alcohol gave ketone
17. The ketone was reduced with sammarium iodide in the
presence of 2-propanol as described by Evans,14 producing
exclusively the equatorial alcohol 18. Alcohol 18 was
subsequently protected as a triisopropylsilyl ether to give
spiroketal 4, leaving only the incorporation of the C7
stereogenic center to be completed. To this end, chelation-
controlled reductive cleavage of the spiroketal was investi-
gated. Exposure of spiroketal 4 to AlCl3-Et3SiH14 at -78
°C afforded cis-2,6-disubstituted tetrahydropyran 3 as a
single, detectable isomer. Bidentate coordination of the C13
benzyl and the C11 spiroketal oxygen to the metal center
allows selective activation of the C11 oxygen-anomeric
carbon bond. Subsequent reduction of the resulting oxa-
carbenium ion results in axial approach of the hydride to
give tetrahydropyran 3.
The synthesis of the C1-C13 fragment of leucascandrolide
A has been accomplished using a metalated pyrone addition
to a â-alkoxy aldehyde to construct the key spiroketal
intermediate. The spiroketal serves as a rigid template,
allowing the stereocontrol of the C5 and C9 hydroxyl groups
through stereoselective ketone reductions. Finally, the che-
lation-controlled, stereoselective and regioselective reductive
cleavage of the spiroketal anomeric center incorporates the
required cis-2,6-disubstituted tetrahydropyran. Completion
of the synthesis of leucascandrolide A from the C1-C13
fragment 3 is currently in progress.
(12) Crimmins, M. T.; Al-awar, R. S.; Vallin, I. M.; O’Mahony, R.;
Hollis, W. G., Jr.; Bankaitis-Davis, D. M.; Lever, J. G. J. Am. Chem. Soc.
1996, 119, 7513-7528.
(13) Claffey, M. M.; Heathcock, C. H. J. Org. Chem. 1996, 61, 7646-
7647.
(14) Evans D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J.
Am. Chem. Soc. 1990, 112, 7001-7031.
Acknowledgment. This research was supported by a
grant from the National Institutes of Health (NCI) (CA63572).
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