Prior to our work in this area Kelly et al had already
described an elegant synthesis of dimethyl sulfomycinamate
that used palladium-catalyzed coupling reactions for target
construction.16 Our new approach, which will be discussed
shortly, complements this earlier work. It avoids the use of
palladium catalysts and constructs the heterocyclic compo-
nents from acyclic precursors.
lithium and reacted with chlorotrimethylsilane to provide
5-(trimethylsilyl)thiazole 11 in 80% yield. This then permit-
ted lithiation at the 2-methyl substituent (Scheme 4).
Scheme 4. Synthesis of Oxazole-Thiazole-Pyridine Domain
14
Our synthetic plan for accessing dimethyl sulfomycinamate
(1) hoped to establish pyridine 2 by the Bohlmann-Rahtz
reaction17 of methyl oxobutynoate 4 with a suitable enamine
3, already bearing the thiazole substituent (-R) (Scheme 2).
Scheme 2. Dimethyl Sulfomycinamate (1) Disconnective
Scheme
We have previously developed mild methods for affecting
this transformation and have demonstrated their utility for
constructing the pyridine core of a range of thiopeptide
targets.18
Starting from 2-methacrylamide (5), oxazole 7 was pro-
duced in excellent yield via a two-step modified Hantzsch
reaction with ethyl bromopyruvate. Hydrolysis with lithium
hydroxide in methanol-water and subsequent generation of
the Weinreb amide 9 was accomplished by reacting acid 8
with ethyl chloroformate and treating the mixed anhydride
with N-methoxymethylamine hydrochloride (Scheme 3).
Subsequent reaction of 11 with n-butyllithium and condensa-
tion with Weinreb amide 9 provided Claisen condensation
product 12 as a mixture of tautomers. Although successful,
the efficiency of this transformation proved to be highly
unreliable and varied with scale. Moreover all efforts to
improve the reaction through the use of alternative conditions
failed to increase the yield of enol 12 above 45%.
Subsequent reaction of 12 with tetrabutylammonium
fluoride protodesilylated the 5-position and gave thiazole 13
in good yield. Conventional attempts to form enamine 3a
(5) Boeck, L. D.; Favret, M. E.; Wetzel, R. W. J. Antibiot. 1992, 45,
1278.
(6) Liesch, J. M.; Rinehart, K. L., Jr. J. Am. Chem. Soc. 1977, 99, 1645.
(7) Lau, R. C. M.; Rinehart, K. L., Jr. J. Antibiot. 1994, 47, 1467.
(8) Yun, B.-S.; Hidaka, T.; Furihata, K.; Seto, H. J. Antibiot. 1994, 47,
969.
Scheme 3. Synthesis of 2-(2-Propenyl)oxazoles 7, 8, and 9
(9) Kumar, E. K. S. V.; Kenia, J.; Mukhopadhyay, T.; Nadkarni, S. R.
J. Nat. Prod. 1999, 62, 1562.
(10) Yun, B.-S.; Seto, H. Biosci. Biotech. Biochem. 1995, 59, 876.
(11) Yun, B.-S.; Hidaka, T.; Furihata, K.; Seto, H. J. Antibiot. 1994, 47,
510.
(12) Rodriguez, J. C.; Gonza´lez Holgado, G.; Santamaria Sa´nchez, R.
I.; Canedo, L. M. J. Antibiot. 2002, 55, 391.
(13) Yun, B.-S.; Hidaka, T.; Furihata, K.; Seto, H. J. Antibiot. 1994, 47,
1541.
(14) Yun, B.-S.; Hidaka, T.; Furihata, K.; Seto, H. Tetrahedron 1994,
50, 11659.
(15) Matsumoto, M.; Kawamura, Y.; Yasuda, Y.; Tanimoto, T.; Mat-
sumoto, K.; Yoshida, T.; Shoji, J. J. Antiobiot. 1989, 42, 1465.
(16) Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4623.
(17) Bohlmann, F.; Rahtz, D. Chem. Ber. 1957, 90, 2265.
(18) Bagley, M. C.; Dale, J. W.; Bower, J. Synlett 2001, 1149.
(19) Produced by the reduction of ethyl 2-methylthiazole-4-carboxylate
with LiAlH4 followed by reaction with 2-(trimethylsilyl)ethoxymethyl
chloride (SEM-Cl).
Readily available 2-methyl-4-[2-(trimethylsilyl)ethoxy-
methoxymethyl]thiazole (10)19 was deprotonated with n-butyl-
4422
Org. Lett., Vol. 5, No. 23, 2003