Efficient stereochemical relay en route to leucascandrolide A.

Article abstract of DOI:10.1021/ol015514x

[structure: see text]. A complete relay of the initial stereochemical information is central to the efficient and highly stereocontrolled construction of the C1-C15 fragment of the marine macrolide leucascandrolide A. Cyclic silane 3, assembled via Pt-cat

Full text of DOI:10.1021/ol015514x

ORGANIC
LETTERS
2001
Vol. 3, No. 5
755-758
Efficient Stereochemical Relay en Route
to Leucascandrolide A
Sergey A. Kozmin
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
skozmin@uchicago.edu
Received January 4, 2001
ABSTRACT
A complete relay of the initial stereochemical information is central to the efficient and highly stereocontrolled construction of the C −C
1
15
fragment of the marine macrolide leucascandrolide A. Cyclic silane 3, assembled via Pt-catalyzed hydrosilylation, was designed to serve as
a temporary template for the installation of the C12 stereogenic center. The strategy features a highly convergent C −C11 bond construction
10
via 1,5-anti-selective aldol reaction and rapid assembly of the trisubstituted pyran subunit via Prins desymmetrization.
Efficient assembly of diverse stereochemical arrays contain-
ing multiple stereogenic centers plays a pivotal role in target-
oriented synthesis. Advances in asymmetric synthesis in-
volving the use of external chiral controllers (i.e., auxiliaries,
reagents or catalysts) have simplified solutions of many
challenging stereochemical puzzles.1 However, creation of
new chiral elements by means of internal asymmetric
induction utilizing substrate-based diastereochemical relay
often represents a more direct and efficient approach.2 The
ideal scenario entails formation of all asymmetric centers of
the target compound starting from a single stereogenic point
without any additional external chirality being used in the
assembly process.2d
isolated by Pietra et al. from a new genus of calcareous
sponges, Leucascandra caVeolata (Scheme 1).3,4 Due to the
difficulty in isolating leucascandrolide A, combined with the
presently unknown biogenetic origin,5 an efficient chemical
synthesis of this macrolide would provide an ideal approach
for its efficient production for further pharmacological
evaluation.6 Herein, I present a convergent, highly stereo-
controlled assembly of the C1-C15 fragment (2) representing
the central portion of leucascandrolide A and incorporating
six of the requisite stereogenic centers.
Retrosynthetically, subtarget 2 was envisioned to derive
from hydroxy ketone 4 via a series of diastereo- and
chemoselective transformations involving reduction of the
Aiming at the development of an efficient and practical
strategy featuring a complete acyclic stereochemical relay,
we recently initiated a program aimed at the synthesis of
leucascandrolide A (1), a highly bioactive marine macrolide
(3) (a) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. HelV. Chim.
Acta 1996, 79, 51-60. (b) For isolation of leucascandrolide B, see:
D’Ambrosio, M.; Tato`, M.; Pocsfalvi, G.; Debitus, C.; Pietra, F. HelV. Chim.
Acta 1999, 82, 347-353.
(4) For a recent total synthesis of leucascandrolide A, see: (a) Horn-
berger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000,
122, 12894-12895. For another synthetic approach, see: (b) Crimmins,
M. T.; Carroll, C. A.; King, B. W. Org. Lett. 2000, 2, 597-599. (c)
Vakalopoulos, A.; Hoffmann, H. M. R. Org. Lett. 2001, 3, 177-180.
(5) Several lines of evidence presently suggest that leucascandrolide A
may originate from the microbial organism present in L. caVeolata.
(6) In preliminary in vitro studies, leucascandrolide A displayed potent
cytotoxicity against KB and P388 tumor cell lines (IC50 50 ng/mL and 0.25
µg/mL respectively), as well as strong inhibition of Candida albicans.
(1) (a) Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New
York, 1984. (b) Ager, D. J.; East, M. B. Asymmetric Synthetic Methodology;
CRC Press: Boca Raton, 1996. (c) Hayashi, T.; Tomioka, K.; Yonemitsu,
O. Asymmetric Synthesis; Kodansha: Tokyo, 1998.
(2) (a) Bartlett, P. A. Tetrahedron 1980, 36, 3-72. (b) Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-1370. (c) Mengel, A.;
Reiser, O. Chem. ReV. 1999, 99, 1191-1223. (d) Smith, A. B., III; Empfield,
J. R. Chem. Pharm. Bull. 1999, 47, 1671-1678.
10.1021/ol015514x CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/16/2001

Scheme 1
Scheme 2
(PPTS, toluene, 110 °C), furnishing the Prins cyclization
precursor 8 in 92% yield (Scheme 2). Treatment of vinyl-
ogous ester 8 with TFA12 at 5 °C followed by basic
hydrolysis of the trifluoroacetate resulted in formation of the
all-cis tetrahydropyran 9 in 77% yield.13 Equatorial disposi-
tion of substituents was rigorously established at this stage
by a combination of DQF COSY and NOESY experiments.
The highly stereocontrolled construction of three stereogenic
centers in a single step is illustrative of the power of Prins
desymmetrization tactics for the assembly of polysubstituted
tetrahydropyrans. Acid-catalyzed benzylation of alcohol
9 (BnOC(NH)CCl3, TfOH (cat.), CH2Cl2-cyclohexane)14
then afforded ketone 6, completing construction of the
first aldol coupling partner in three steps and 50% overall
yield.
Preparation of aldehyde 5, the second aldol component,
was similarly accomplished in three steps (Scheme 3).
C9-carbonyl and hydrosilylation of the C12-methylene. The
resulting silacycle 3 was designed to reveal advanced
fragment 2 upon cleavage of the C-Si and O-Si linkages.
Highly convergent disconnection of ketone 4 at C10-C11
furnished the corresponding aldol coupling partners 5 and
6. According to the precedent recently provided by Paterson7
and Evans,8 boron-enolate mediated aldolization was ex-
pected to deliver the desired anti-stereochemical relationship
between the newly created C11-hydroxyl and C7-alkoxy
group. Aldehyde 5 would be rapidly assembled via an
alkylation-formylation sequence (vide infra). Construction
of ketone 6, incorporating an all-cis trisubstituted tetrahy-
dropyran subunit, would entail a highly diastereoselective
Prins cyclization.9
Scheme 3
Conversion of acetaldehyde to the corresponding cyclohexyl
imine, followed by lithiation15 and alkylation with 2,3-
dibromopropene (10), afforded aldehyde 11 in 74% yield.16
Acetalization (ethylene glycol, TsOH) and formylation via
metal-halogen exchange, followed by addition of dimeth-
ylformamide, furnished aldehyde 5 in 38% overall yield for
the three steps.
Assembly of ketone 6 began with vinylogous transesteri-
fication10 of 4-methoxy-3-butenone with heptadienol 711
(7) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996,
37, 8585-8588.
(8) (a) Evans, D. A.; Coleman, P. J.; Coˆte´, B. J. Org. Chem. 1997, 62,
788-789. (b) Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Coˆte´, B.; Dias,
L. C.; Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55, 8671-8726.
(c) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc.
2000, 122, 10033-10046.
(9) For reviews and leading references, see: (a) Adams, D. R.; Bhatnagar,
S. P. Synthesis 1977, 661-672. (b) Snider, B. B. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon
Press: New York, 1991; Vol. 2, pp 527-561. (c) Yang, J.; Viswanathan,
G. S.; Li, C. J. Tetrahedron Lett. 1999, 40, 1627-1630. (d) Cloninger, M.;
Overman, L. E. J. Am. Chem. Soc. 1999, 121, 1092-1093. (e) Rychnovsky,
S. D.; Thomas, C. R. Org. Lett. 2000, 2, 1217-1219.
(10) Danishefsky, S. J.; Bednarski, M.; Izawa, T.; Maring, C. J. Org.
Chem. 1984, 49, 2290-2292.
(11) Available from Aldrich Chemical Co.
(12) Nussbaumer, C.; Frater, G. HelV. Chim. Acta 1987, 70, 396-401.
(13) A minor amount (7%) of the C5 diastereomer was also isolated.
(14) Widmer, U. Synthesis 1987, 568-570.
(15) Le Borgne, J. F. J. Organomet. Chem. 1976, 122, 129-137.
(16) Barnhart, R. W.; Wang, X.; Noheda, P.; Bergens, S. H.; Whelan, J.
Bosnich, B. J. Am. Chem. Soc. 1994, 116, 1821-1830.
756
Org. Lett., Vol. 3, No. 5, 2001

Scheme 4
Generation of the dicyclohexylboron enolate from ketone
facile formation of silacycle 16 (dr 85:15). Importantly, no
products resulting from competing olefin isomerization were
detected. Stereochemical assignment of 16, initially based
on the precedent by Tamao,20 was achieved by conversion
to the known lactone 1821 involving protodesilylation (TBAF,
DMF)22 and acid-catalyzed acetal hydrolysis, followed by
oxidation of the resulting lactol to the lactone (Br2, NaOAc,
AcOH-H2O).23
6 followed by addition of aldehyde 5 (-78 °C, ether)7
efficiently accomplished the union of these aldol reaction
partners, furnishing hydroxy ketone 4 as a single diastere-
omer (Scheme 4). Apart from the high convergency, this
operation delivered the requisite stereochemistry of the newly
created C11 alcohol as a result of efficient 1,5-anti stereo-
chemical induction by the C7-alkoxy group.7,8
Diastereoselective ketone reduction [SmI2 (30 mol %),
CH3CHO, THF]17 cleanly established the C9-stereogenic
center (92% yield, dr >95:5). Methylation (MeOTf, 2,6-di-
tert-butylpyridine),18 followed by removal of the acetate with
LiAlH4, gave allylic alcohol 14 in 86% yield.
The validation of the projected late-stage hydrosilylation
was initially achieved in a model study summarized in
Scheme 5. Conversion of alcohol 1519 into the corresponding
Having established a reliable hydrosilylation protocol,
attention was focused on conversion of alcohol 14 to
subtarget 2 (Scheme 4). Silylation [(Me2HSi)2NH, CHCl3,
15 min), followed by addition of H2PtCl6 (0.5 mol %),
resulted in diastereoselective formation of silacycle 3 (dr 87:
13) without detectable hydrosilylation of the terminal olefin.
Protodesilylation was then achieved using TBAF (DMF, 70
°C, 15 min)22 to give the fully elaborated C1-C15 fragment
(2) of leucascandrolide A.
The stereochemical outcome of the intramolecular hy-
drosilylation of alcohols 14 and 15 resulting in predominant
formation of anti-diastereomeric products 2 and 17, respec-
tively, is in agreement with erythro selectivity previously
observed by Tamao.20 If hydroplatination is assumed to be
a stereochemistry-determining step,20c examination of the
diastereomeric transition structures C and D (Scheme 6)
provides a rationale for the observed selectivity. Indeed,
transition state D is expected to be higher in energy due to
the unfavorable nonbonding interaction between R1 and R2
resulting in significant A1,2-strain. Therefore, formation of
Scheme 5
(20) (a) Tamao, K.; Nakajima, T.; Sumiiya, R.; Arai, H.; Higuchi, N.;
Ito, Y. J. Am. Chem. Soc. 1986, 108, 6090-6093. (b) Tamao, K.; Yamauchi,
T.; Ito, Y. Chem Lett. 1987, 171-174. (c) Tamao, K.; Nakagawa, Y.; Ito,
Y. Organometallics 1993, 12, 2297-2308. Also, see: (d) Bergens, S. H.;
Noheda, P.; Whelan, J.; Bosnich, B. J. Am. Chem. Soc. 1992, 114, 2121-
2128. (e) Bergens, S. H.; Noheda, P.; Whelan, J.; Bosnich, B. J. Am. Chem.
Soc. 1992, 114, 2128-2135.
silyl ether using tetramethyldisilazane, followed by treatment
with H2PtCl6 (0.3 mol %) in benzene at 50 °C, resulted in
(17) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447-
6449.
(18) Walba, D. M.; Thurmes, W. H.; Haltiwanger, R. C. J. Org. Chem.
1988, 53, 1046-1056.
(19) This compound was prepared in one step by addition of n-BuLi to
aldehyde 5 (87% yield).
(21) Collum, D. B.; Mohamadi, F.; Hallock, J. S. J. Am. Chem. Soc.
1983, 105, 6882-6889.
(22) Hale, M. R.; Hoveyda, A. H. J. Org. Chem. 1992, 57, 1643-1645.
(23) Kocienski, P. J.; Street, S. D. A.; Yeates, C.; Campbell, S. F. J.
Chem. Soc., Perkin Trans. 1987, 2171-2181.
Org. Lett., Vol. 3, No. 5, 2001
757

Scheme 6
the cis-disubstituted cyclic silane E, as the major product,
development of new stereoselective transformations, are
currently under active investigation and will be reported in
due course.
proceeds through transition state C involving diastereose-
lective delivery of hydride from the re-face. Final cleavage
of the O-Si and C-Si bonds reveals the observed anti-
alcohol G.
Acknowledgment. This work was supported by the
In summary, the assembly of C1-C15 fragment 2 of
leucascandrolide A (1) has been achieved in nine steps and
11% overall yield. The six requisite stereogenic centers were
assembled via a stereochemical relay featuring a series of
highly diastereoselective processes including Prins desym-
metrization, aldol condensation, and Pt-catalyzed hydrosi-
lylation. Completion of the synthesis of leucascandrolide A,
along with further applications of cyclic silanes for the
University of Chicago.
Supporting Information Available: Complete experi-
mental procedures and spectral characterization of all new
compounds. This material is available free of charge at
http://pubs.acs.org.
OL015514X
758
Org. Lett., Vol. 3, No. 5, 2001