Total synthesis of cystothiazoles A and B

Article abstract of DOI:10.1021/ol048893d

(Chemical Equation Presented) Convergent enantioselective syntheses of the antifungal agents cystothiazoles A and B are described. The routes feature an asymmetric crotylation using a propargylic dicobalt hexacarbonyl complex, which provided enhanced diastereoselectivity over the uncomplexed propargylic acetal. The bisthiazole fragment was united with the side chain through a Stille cross-coupling of a terminal (E)-vinylstannane with a 4-trifloyl-substituted thiazole.

Full text of DOI:10.1021/ol048893d

ORGANIC
LETTERS
2
004
Vol. 6, No. 18
083-3085
Total Synthesis of Cystothiazoles
A and B
3
Jian Shao and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and
Library DeVelopment, Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
panek@chem.bu.edu
Received June 11, 2004
ABSTRACT
Convergent enantioselective syntheses of the antifungal agents cystothiazoles A and B are described. The routes feature an asymmetric
crotylation using a propargylic dicobalt hexacarbonyl complex, which provided enhanced diastereoselectivity over the uncomplexed propargylic
acetal. The bisthiazole fragment was united with the side chain through a Stille cross-coupling of a terminal (E)-vinylstannane with a 4-trifloyl-
substituted thiazole.
In 1998, Sakagami and co-workers reported the isolation of
cystothiazoles A and B from a culture broth of the myxo-
bacterium, Cystobacter fuscus. Cystothiazoles A and B have
Our retrosynthetic strategy is illustrated in Scheme 1. The
target molecules could be divided into two subunits, C -C
fragment 4 and bisthiazole fragment 5, which will be coupled
1
7
1
demonstrated potent antifungal activity against a wide range
of fungi. These agents, however, show little or no effect on
inhibition of bacterial growth. Although these compounds
are structurally related to the known antibiotic myxothiazole,
cystothiazole A is more active against fungi and less
cytotoxic.
at a late stage via a Stille cross-coupling reaction. The
C
1
-C fragment could be obtained from the â-ketoester 6,
7
which was ultimately derived from a crotylsilane addition
to the dicobalt hexacarbonyl complex 10. The bisthiazole
fragment 5 was synthesized by a regioselective Stille cross-
coupling reaction with the 2,4-bistrifloyl thiazole 7 and
2
4
Earlier reports have documented the independent total
4-bromothiazole 8.
3
synthesis of cystothiazoles A, B, C, E and G. In this paper,
In our preliminary studies, it was found that the direct
we describe convergent enantioselective syntheses of cys-
tothiazoles A and B.
crotylation between silane (S)-9 and the 3-(trimethylsilyl)
(1) (a) Ojika, M.; Suzuki, Y.; Tsukamoto, A.; Sakagami, Y.; Fudou, R.;
Yoshimura, T.; Yamanaka, S. J. Antibiot. 1998, 51, 275-281. (b) Suzuki,
Y.; Ojika, M.; Sakagami, Y.; Fudou, R.; Yamanka, S. Tetrahedron 1998,
5
4, 11399-11404.
2) (a) Gerth, K.; Irschik, H.; Reichenbach, H.; Trowitzsch, W. J. Antibiot.
980, 33, 1474-1479. (b) Trowitzsh, W.; Reifenstahl, G.; Wray, W.; Gerth,
(
1
K. J. Antibiot. 1980, 33, 1480-1490.
3) (a) Williams, D.; Patnaik, S.; Clark, M. J. Org. Chem. 2001, 66,
463-8469. (b) Kato, K.; Nishimura, A.; Yamamoto, Y.; Akita, H.
(
8
Tetrahedron Lett. 2002, 43, 643-645. (c) Kato, K.; Sasaki, T.; Takayama
H.; Akita, H. Tetrahedron 2003, 59, 2679-2685. (d) DeRoy, P.; Charette,
A. Org. Lett. 2003, 5, 4163-4165. (e) Bach, T.; Heuser, S. Angew. Chem.,
Int. Ed. 2001, 40, 3184-3185. (f) Sasaki, T.; Kato, K.; Akita, H. Chem.
Pharm. Bull. 2004, 52, 770-771. (g) Akita, H.; Sasaki, T.; Kato K.; Suzuki
Y.; Kondo, K.; Sakagami, Y.; Ojika, M.; Fudou R.; Yamanaka, S.
Tetrahedron 2004, 60, 4735-4738.
(
4) Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485-
2
488.
1
0.1021/ol048893d CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/30/2004

from methyl acetate. The resulting mixture of diastereomeric
alcohols 15 was subjected to an oxidation using PCC to form
the â-ketoester 6 in 85% yield (6:1 ketone/enol form
Scheme 1. Retrosynthesis
1
determined by H NMR). â-Ketoester 6 was treated with
trimethyl orthoformate in the presence of catalytic sulfuric
acid to form the desired (E)-â-methoxyacrylate 16 in 86%
1
7
yield (E:Z ) 7:1 as determined by H NMR). The E
geometry was assigned by measurement of NOE for the
olefin proton and the methoxy group. After deprotection by
2 3
K CO in methanol, the alkyne 17 was subjected to the Pd-
catalyzed hydrostannylation. â-(E) regioselective product 4
was achieved in 84% yield (R:â-(E):â-(Z) ) 1:7:0 as
1
8
determined by H NMR relative to the MeO group).
The bisthiazole fragments 5a and 5b were derived from
three different thiazoles as illustrated in Schemes 4 and 5.
Scheme 3
propargyl dimethyl acetal 11 produced the homoallylic ether
in high yield (> 80%); however, it did so without useful
selectivity (syn/anti ) 2:1). To get around this problem, a
5
propargylic dicobalt complex was used to add steric bulk
to the acetal, which we hoped would create a sufficient
energy difference between the competing diastereotopic
transition states during the crotylation. Gratifyingly, reaction
of silane (S)-9 with the cobalt complexed acetal 10 resulted
in a significant enhancement of diastereoselectivity (syn/anti
>
10:1), affording the homoallylic ether in 86% yield
6
(Scheme 2). The removal of the dicobalt complex of 13
Scheme 2
Accordingly, 4-bromo-2-isopropyl-thiazole 8a was obtained
by a regioselective Negishi cross-coupling reaction from the
9
10
dibromide 18 in 72% yield. As predicted, the reaction
occurred at the most electron-deficient position of the
heterocycle. The synthesis of the 4-bromo-2-(isopropyl-tert-
butyldimethylsilyloxy)-thiazole 8b involved a bromine-
lithium exchange, followed by the addition of anhydrous
acetone, followed by treatment of the derived secondary
(
5) (a) Schreiber, S. L.; Klimas, M. T.; Sammakia, T. J. Am. Chem. Soc.
1
987, 109, 5749-5759. (b) Jamison, T. F.; Shambayati, S.; Crowe, W. E.;
Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353-4363.
was achieved using trimethylamine N-oxide in MeOH. The
cleavage of the olefin by ozonolysis gave the aldehyde 14
in 68% yield, which is volatile and prone to decomposition
at room temperature. This material was submitted to low-
temperature condensation with the lithium enolate derived
(
(
(
(
6) Sui, M.; Panek, J. S. Org. Lett. 2001, 3, 2439-2442.
7) Poirier, J. M.; Hennequin, L. Tetrahedron 1989, 45, 4191-4202.
8) Smith, A. B.; Ott, G. R. J. Am. Chem. Soc. 1998, 120, 3935-3948.
9) Reynaud, P.; Robba, M.; Moreau, R. C. Bull. Soc. Chim. Fr. 1962,
1
735-1738.
(10) Bach, T.; Heuser, S. J. Org. Chem. 2002, 67, 5789-5795.
3084
Org. Lett., Vol. 6, No. 18, 2004

with Bu
to the Stille cross-coupling reaction with the ditriflate 7 using
Pd(PPh as a catalyst, dioxane as a solvent, and the addition
equiv of LiCl. The reactions were achieved in 72 and 68%
3
SnCl. The crude stannane was submitted directly
Scheme 4
3 4
)
3
4
,11
yields when R ) H or OTBS, respectively.
Identical
conditions were employed for the construction of the
bisthiazole fragments in the final Stille cross-coupling
reaction. Cystothiazole A (1) could be synthesized directly
from the coupling of the C
fragment 5a in 85% yield. After the Stille cross-coupling of
the C -C fragment 4 and bisthiazole fragment 5b (72%
1
7
-C fragment 4 and bisthiazole
1
7
yield), a final deprotection step using TBAF gave cystothia-
zole B (2) in 98% yield.
In summary, convergent enantioselective syntheses of the
antifungal agents cystothiazoles A and B have been achieved.
Cystothiazole A was synthesized in 12 linear steps and 15%
overall yield, and cystothiazole B was synthesized in 13
linear steps and 13% overall yield. Key features of the
synthesis include high levels of selectivity in the crotylation
using a propargylic dicobalt hexacarbonyl complex to
establish the syn-homoallylic ether of the side chain. The
bisthiazole fragment was coupled to the left-hand side chain
using a Stille cross-coupling. On balance, the asymmetric
crotylation methodology, together with transition metal-
mediated cross-coupling reaction, offers a promising and
efficient approach to these natural products.
Scheme 5
Acknowledgment. We acknowledge Professor Sakagami
and Professor Ojika (Nagoya University) for authentic
samples of cystothiazoles A and B. We thank Mr. Qibin Su
and Neil Langille (Boston University) for helpful discussions.
Financial support was obtained from the NIH-GM55740.
J.S.P. is grateful to Johnson & Johnson, Merck Co., Amgen,
Inc., Novartis, Pfizer, and GSK for financial support.
Supporting Information Available: General experimen-
tal procedures, including spectroscopic and analytical data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
alcohol with TBSOTf and 2,6-lutidine, and gave the silyl-
protected bromothiazole 8b in 98% yield.
The bisthiazole fragments of 1 and 2 were formed through
Stille cross-coupling reactions. The required 4-tributylstan-
nylthiazoles 19a and 19b were prepared from the bromide
by bromine-lithium exchange and the subsequent quench
OL048893D
(11) Arcadi, A.; Attanasi, O. A.; Guidi, B.; Rossi, E.; Santeusanio, S.
Eur. J. Org. Chem. 1999, 3117-3126.
Org. Lett., Vol. 6, No. 18, 2004
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