Total Synthesis of Hectochlorin

Article abstract of DOI:10.1021/ol025604h

(Equation Presented) 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 a

Full text of DOI:10.1021/ol025604h

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
jrpcetusic@dow.com
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

Scheme 2
Scheme 4
was chosen to protect the diol because it could be removed
using neutral conditions which would not concomitantly
remove the secondary acetate. The ethyl ester was then
hydrolyzed in high yield to provide the carboxylic acid
coupling precursor 7 (Scheme 3).
Scheme 3
The coupling of 7 and 9 was performed using dicyclo-
hexylcarbodiimide (DCC) with a catalytic amount of 4-(dim-
ethylamino)pyridine (DMAP), giving the coupled product
10 in low yield (Scheme 4). Treatment of 10 with CAN not
only removed the benzylidene acetal but oxidatively cleaved
the resulting diol to give the aldehyde 11. As it turned out,
the benzylidene acetal could be removed from the coupled
product under acidic conditions to give diol 12 in good yield
without adversely affecting the acetate.
Armed with the information that acidic conditions would
not harm the acetate, an isopropylidene acetal was chosen
to replace the benzylidene acetal. It was hoped that replace-
ment of the acid-labile stereocenter present in the benzylidene
acetal with an achiral acetonide would simplify the isolation
of coupled products and possibly boost the yield. The
isopropylidene acetal was installed in 3 under standard
conditions (Scheme 5). The ethyl ester was then removed to
For the tertiary alcohol coupling piece, the ethyl ester in
3 was transesterified to the allyl ester 8 using lanthanum-
(III) isopropoxide as the catalyst.7 The allyl ester is the
protecting group of choice for the acid, as it will be removed
late in the synthesis using mild conditions which should be
compatible with the other esters in the molecule. The acetate
was then installed selectively on the secondary alcohol,
leaving the tertiary alcohol of 9 available for coupling to
the acid in 7.
Scheme 5
(3) Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4623-4633.
(4) Campbell, J. B., Jr.; Firor, J. W.; Davenport, T. W. Synth. Commun.
1989, 19, 2265-2272.
(5) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
(6) Ohtani, I.; Takenori, K.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092-4096. A detailed description of the modified Mosher
analysis of 3 is included in the Supporting Information.
(7) Okano, T.; Miyamoto, K.; Kiji, J. Chem. Lett. 1995, 246.
provide the new carboxylic acid coupling partner 13.
Although use of the isopropylidene acetal protecting group
in place of the benzylidene acetal led to a higher yield of
coupled product (14, Scheme 6), removal of the isopropy-
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Org. Lett., Vol. 4, No. 8, 2002

Scheme 6
Scheme 8
lidene acetal required much more forcing conditions than
did removal of the benzylidene acetal. However, the two-
step yield for the sequence using the isopropylidene acetal
(40%) was significantly higher than that for the sequence
utilizing the benzylidene acetal (∼24%), so the former route
was utilized to make several hundred milligrams of 12 for
coupling to aldol subunits.
The preparation of the aldol subunit 2 is shown in Scheme
7. 5,5-Dichlorohexanal2,8 was reacted with the boron enolate
of (S)-(+)-4-benzyl-3-propionyl-2-oxazolidinone in an Evans
asymmetric aldol reaction9 resulting in a 69% yield of
(2S,3R)-15 in >95% de.10 The secondary hydroxy group in
15 was inverted using Mitsunobu conditions to give a 57%
yield of the inverted p-nitrobenzoate ester 16.11 Conditions
for hydrolysis of the chiral auxiliary also effected removal
of the p-nitrobenzoate ester. The secondary alcohol was then
protected as its tert-butyldimethylsilyl (TBS) ether. Silylation
of the free acid also occurred, so the reaction mixture was
subjected to potassium carbonate in methanol in order to
remove the resulting silyl ester. This sequence was performed
in one pot, providing the desired aldol coupling piece 2 in
72% yield.
Scheme 7
Coupling of aldol subunit 2 with the bis-thiazole diol 12
to produce the linear triester 17 proceeded smoothly using
the same DCC/DMAP conditions employed earlier in the
synthesis (Scheme 8). The allyl ester and TBS protecting
groups were removed under standard conditions, and the
(8) Villieras, J.; Perriot, P.; Normant, J. F. Bull. Soc. Chim. Fr. 1979,
765-768.
(9) Evans, D. A.; Rieger, D. L.; Jones, T. K.; Kaldor, S. W. J. Org.
Chem. 1990, 55, 6260-6268.
1
(10) The de for 15 could be estimated from the 600 MHz H NMR of
the mixture.
(11) The success of the inversion was confirmed by comparing coupling
constants of key protons in inverted benzoate 16 to those of the noninverted
benzoate prepared directly from 15. Details are provided in the Supporting
Information.
Org. Lett., Vol. 4, No. 8, 2002
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seco-acid 18 was subjected to Keck macrolactonization
conditions.12 The use of DMAP‚HCl as a buffer in this
reaction was critical to its success.13 Hectochlorin was
isolated in 59% yield and was spectroscopically identical to
natural hectochlorin. The optical rotation for the synthetic
material ([R]20D ) -12.5) was slightly less than that of the
natural product ([R]20D ) -14.9) which most likely reflects
the fact that some of the antipode is present.
Hectochlorin is a fungicidal natural product which dem-
onstrated activity on pathogens in crop disease screens. A
synthetic route to hectochlorin was devised and carried out,
and this methodology has been applied to the synthesis of
analogues. The synthesis and activity of these analogues will
be reported in due course.
Acknowledgment. The authors would like to thank
Professor Bill Gerwick and Dr. Brian Marquez for supplying
initial samples of and spectroscopic data for hectochlorin.
Supporting Information Available: Experimental pro-
cedures and characterization of compounds 3, 13, 9, 12, 2,
17, and 1. Additionally, a detailed description of the modified
Mosher ester analysis of 3, NMR data supporting the
inversion of (2S,3R)-16 to (2S,3S)-16, and a 1H NMR
comparison of natural and synthetic hectochlorin. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J.
Am. Chem. Soc. 1990, 112, 7001-7031.
(13) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394-2395.
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