P-6 Tubulysin類の合成研究(ポスター発表の部)
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Tubulysins (1a-e), a family of antimitotic agents isolated from the myxobacterial strains Archangium gephyra and Angiococous disciformis, possess potent cell growth inhibitor activity exceeding that of vinblastine. Therefore, tubulysins have attracted considerable attention as leads for the development of new anticancer agents. We report herein efficient methods for the synthesis of tubulysins that would provide convenient access to synthetic analogues. Tubulysin D (1b) is composed of four amino acid fragments, N-methyl-D pipecolic acid (D-Mep), L-isoleucine (L-Ile), tubuvaline (Tuv), and tubuphenylalanine (Tup) (Fig. 2). We especially focused on stereoselective synthesis of Tuv and Tup. The highly stereoselective synthesis of Tuv-methyl ester was accomplished by 1,3-dipolar cycloaddition of nitron 6 and acrylic acid derivatives 7 as a key step (Scheme 2-4). Synthesis of Tup involved an aldol reaction of boron enolate of (S)-4-isopropyl-3-propionyl-2-oxazolidinone with aldehyde 12, readily prepared from phenylalanine, follwed by Barton deoxygenation under radical conditions. With the Tuv and Tup in hand, we have accomplished a synthesis of tubulysin D (1b) by employing Ellman's sequence. We have succeeded in exploring a novel synthetic route to Tuv and Tup. These syntheses may be applied to other analogues required for investigation of the structure-activity relationship. Novel tubulysins analogues unavailable from natural resources are expected to be found in future.
- 2008-09-01
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