ORGANIC
LETTERS
2006
Vol. 8, No. 3
475-478
Total Synthesis of (+)-Lasonolide A
Tomoyuki Yoshimura, Fumika Yakushiji, Shingo Kondo, Xiaofeng Wu,
Mitsuru Shindo, and Kozo Shishido*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokushima,
1-78 Sho-machi, Tokushima 770-8505, Japan
Received November 15, 2005
ABSTRACT
An enantiocontrolled total synthesis of (
+)-lasonolide A has been accomplished by using the sequential cross metathesis and macrolactonization
for the key assembly of the 20-membered polyene macrolide core of the natural product.
(+)-Lasonolide A (1) was isolated from an extract of the
shallow water Caribbean marine sponge, Forcepia sp., by
McConnell.1 This compound was discovered to inhibit the
in vitro proliferation of A-549 human lung carcinoma cells
as well as cell adhesion in a newly developed whole cell
assay that detects signal transduction agents. Because of the
intriguing structural features, notable biological profiles, and
limited availability, lasonolide A represents an attractive
target for total synthesis. Several synthetic studies2 have been
reported, and to date, two total syntheses have been com-
municated.3 In this communication, we report a novel strategy
toward the synthesis of (+)-lasonolide A that is characterized
by an efficient assembly of the 20-membered polyene
macrolide core through sequential cross metathesis4 and
macrolactonization.
Our synthetic strategy was based on the retrosynthetic
degradation of 1 into the three segments 2-4. Because
the introduction of the C26-C35 side chain by Wittig
reaction3a,b of the ylide generated from 4 in the final stage
of the total synthesis has been established,3 the assembly
of the 20-membered polyene macrolide core should be
crucial. We envisioned that it would be constructed by a
sequence consisting of the cross metathesis between the
C5-C172f and C18-C25 segments (2 and 3), carbon
chain elongation, and macrolactonization. The key segment
3 would be addressed from a chiral building block 55 by
taking advantage of the convex nature of the molecule
for the stereochemical control of the C21 and C22, particu-
larly of the C22 quaternary center, on the pyran ring (Figure
1).
(1) Horton, P. A.; Koehn, F. E.; Longley, R. E.; McConnell, O. J. J.
Am. Chem. Soc. 1994, 116, 6015.
(2) (a) Gurjar, M. K.; Kumar, P.; Rao, B. V. Tetrahedron Lett. 1996,
37, 8617. (b) Nowakowski, M.; Hoffmann, H. M. R. Tetrahedron Lett. 1997,
38, 1001. (c) Gurjar, M. K.; Chakrabarti, A.; Rao, B. V.; Kumar, P.
Tetrahedron Lett. 1997, 38, 8617. (d) Misske, A. M.; Hoffmann, M. R. H.
Chem.-Eur. J. 2000, 6, 3313. (e) Hart, D. J.; Patterson, S.; Unch, J. P.
Synlett 2003, 1334. (f) Deba, T.; Yakushiji, F.; Shindo, M.; Shishido, K.
Synlett 2003, 1500. (g) Yoshimura, T.; Bando, T.; Shindo, M.; Shishido,
K. Tetrahedron Lett. 2004, 45, 9241. (h) Dalgard, J. E.; Rychnovsky, S. D.
Org. Lett. 2005, 7, 1589.
(3) (a) Lee, E.; Song, H. Y.; Kang, J. W.; Kim, D. S.; Jung, C.-K.; Joo,
J. M. J. Am. Chem. Soc. 2002, 124, 384. (b) Song, H. Y.; Joo, J. M.; Kang,
J. W.; Kim, D. S.; Jung, C. K.; Kwak, H. S.; Rark, J. H.; Lee, E.; Hong, C.
Y.; Jeong, S. W.; Jeon, K.; Rark, J. H. J. Org. Chem. 2003, 68, 8080. (c)
Kang, S. H.; Kang, S. Y.; Kim, C. M.; Choi, H. W.; Jun, H. S.; Lee, B. M.;
Park, C. M.; Jeong, J. W. Angew. Chem., Int. Ed. 2003, 42, 4779. (d) Kang,
S. H.; Kang, S. Y.; Choi, H. W.; Kim, C. K.; Jun, H. S.; Youn, J. H.
Synthesis 2004, 1102.
The synthesis of the C5-C17 segment (2) was initiated
with the introduction of the skipped triene appendage at C11
of the lactone 6, which was prepared diastereoselectively
(4) Recent review on the cross metathesis: Connone, S. J.; Blechert, S.
Angew. Chem., Int. Ed. 2003, 42, 1900.
(5) Takeuchi, M.; Taniguchi, T.; Ogasawara, K. Synthesis 1999, 341.
10.1021/ol0527678 CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/14/2006