Solution-phase synthesis of a thiazoyl-substituted indolyl library via Suzuki cross-coupling.

The application of parallel synthesis to generate combinatorial libraries as an efficient means of creating pharmaceutical “drug-like leads” has gained considerable interest.1,2 By accelerating the synthesis and screening of an ever larger number of synthetic analogues, combinatorial chemistry has greatly impacted the drug discovery process.3 Despite this success, compounds originating from natural sources still play a major role in drug therapy. One of the topics of current combinatorial chemistry is to design small molecule libraries based on natural products as templates.4 Camalexins (1a-1c), which was produced as phytoalexins in the leaves of Camelina satiVa (Cruciferae) in response to infection by the fungus Alternaria brassicae, was elucidated to be (3′-indolyl)-2-thiazoles.5 The naturally occurring BE 10988 (2), an inhibitor of topoisomerase, was shown to be a thiazole-substituted indolequinone.6 Several syntheses of analogues of these two natural products were introduced, from a Grignard reaction of substituted indoles and 2-bromothiazole,7 with a Hantzsch reaction as the key step,8 or by photocyclization of substituted (indol-1-yl)thioureas.9 The thiazole and benzothiazole derivatives of indole have been found to exhibit antimicrobial7 and cytotoxic activities.8 Our efforts for the synthesis and biological activity studies of bis(indolyl)thiazoles also developed new antitumor agents.10 Biaryl bond construction using the Suzuki reaction is attractive because both solution-11 and solid-phase12 reaction conditions are documented. The boric acid byproducts of the Suzuki coupling process are essentially nontoxic, which is of particular importance in library synthesis. In our efforts to search for novel antitumor agents, we have synthesized bisindole alkaloids utilizing Suzuki coupling as the key step.13 As a part of our ongoing study in building libraries for pharmaceutical drug discovery,14 we designed some analogues of camalexins mainly by introducing diversities in the thiazole moiety. Herein, we report a solution-phase synthesis of a thiazoyl-substituted indolyl library using Suzuki cross-