39(D-9) ステバステリン類の全合成研究(口頭発表の部)

抄録

Stevastelins are novel cyclic depsipeptides isolated from a culture broth of penicillium, and reported to show a potent immunosuppressive activity. Herein we describe the total synthesis and structure confirmation of stevastelins B (1) and B3 (3), and the synthesis and structure revision of stevastelin C3 (2). For a synthesis of the fatty acid precursor 13 with four contiguous chiral centers in stevastelins, we chose L-quebrachitol (5), an optically active cyclitol obtained in large quantities from the serum of the rubber tree, as the starting material. Stereo- and regioselective introduction of two methyl groups into 5 gave ketone 6, which was converted into 13 by regioselective Baeyer-Villiger reaction, followed by introduction of an alkyl group. Stepwise introduction of the peptide moiety into 13 gave an amino carboxylic acid, whose macrolactamization under the Shioiri's conditions successfully gave macrocycle 19. Removal of the O-benzyl group in 19, followed by selective O-acetylation furnished stevastelin B (1). For a synthesis of stevastelins C3 (3) and B3 (4), cyclization precursor 21 was prepared from 13. Macrolactamization of the derived amino carboxylic acid by Shioiri's procedure effectively constructed the 13-membered cyclic structure. Deprotection of the O-benzyl group gave the proposed structure of stevastelin C3 (3). Selective O-acetylation furnished stevastelin B3 (4). Although synthetic stevastelin B3 (4) was identical with the natural product, synthetic stevastelin C3 (3) was not, implying that the proposed structure of stevastelin C3 (3) might be incorrect. Spectral analysis and degradation study of natural stevastelin C3 suggested thate the natural product should be a 5-deoxy derivative of the proposed structure. To confirm the structure of the natural product, 5-deoxy diol (22) was synthesized from 13. Introduction of the peptide, followed by macrolactamization and deprotection gave macrocycle (24), whose spectral data were found to be fully identical with those of natural stevastelin C3. On the basis of this synthesis, it was revealed that the structure of stevastelin C3 is not 3 but should be revised to 24.