ORGANIC
LETTERS
2002
Vol. 4, No. 8
1307-1310
Total Synthesis of Hectochlorin
Jeannie R. P. Cetusic,* Frederick R. Green III, Paul R. Graupner, and
M. Paige Oliver
DiscoVery Research, Dow AgroSciences LLC, Indianapolis, Indiana 46268
Received January 22, 2002
ABSTRACT
Hectochlorin (1) is a marine natural product with significant fungicidal activity. A synthesis effort was initiated to develop a flexible route to
hectochlorin which would allow access to analogues with potentially improved activity and/or attributes relative to the natural product. A
successful total synthesis of hectochlorin is described.
Hectochlorin (1) is a novel, natural fungicide isolated from
Lyngbya majuscula, a cyanobacterium collected in Hector
Bay, Jamaica. It has recently been fully characterized,1 and
it was found to be active against a number of pathogens in
our crop disease screens. A synthesis program was initiated
to develop a convergent route to hectochlorin and its
analogues. A successful total synthesis of hectochlorin is
described herein.
The thiazole subunit 3 was prepared in two steps from
2-bromo-4-carboethoxythiazole (4, Scheme 2).3 A Negishi
reaction was used to install the isobutylene group in 5,4 and
a Sharpless catalytic asymmetric dihydroxylation of the
alkene provided the vicinal diol 3.5 The S configuration of
the asymmetric center in 3 was assigned on the basis of a
modified Mosher’s ester analysis.6
The next task was to differentially protect 3 to give two
thiazole coupling precursors. A p-methoxybenzylidene acetal
Retrosynthetically, hectochlorin disconnects to two less
complex subunits: the aldol subunit, 2, and the thiazole
subunit, 3 (Scheme 1). The synthesis of (2R,3S)-2 is
published,2 and an analogous approach incorporating inver-
sion of the hydroxy group is all that is necessary to access
(2S,3S)-2. The thiazole segments in hectochlorin can both
be derived from subunit 3. The forward synthesis requires
the generation and coupling of two suitably protected thiazole
precursors to give a bis-thiazole, introduction of the aldol
subunit, and finally cyclization to afford hectochlorin.
Scheme 1. Retrosynthesis of Hectochlorin
(1) Structure and Absolute Stereochemitry of Hectochlorin, a Potent
Stimulator of Actin Assembly. Marquez, B. L.; Watts, K. S.; Yokochi, A.;
Roberts, M. A.; Verdier-Pinard, P.; Jimenez, J. I.; Hamel, E.; Scheuer, P.
J.; Gerwick, W. H. Submitted.
(2) Sone, H.; Kondo, T.; Kiryu, M.; Ishiwata, H.; Ojika, M.; Yamada,
K. J. Org. Chem. 1995, 60, 4774-4781.
10.1021/ol025604h CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/21/2002