16 TMC-95Aの全合成(口頭発表の部)

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TMC-95A (1) was isolated as a potent proteasome inhibitor. The structural features of 1 are the axially-chiral biaryl bond in the macrocycle, the highy oxidized tryptophan moiety, the (Z)-propenylamide and the 3-methyl-2-oxopentanoic acid side chain. Here we present the efficient, stereoselective total synthesis of 1. (Z)-selective Mizoroki-Heck reaction of 9, which was derived from D-serine, afforded the oxindole 10. The diastereoselective epoxidation of 10, followed by 6-endo epoxide ring-opening reaction, installed the C6 and C7 stereocenters to give 13. Then, the removal of carbamate group from 15 under Gassman's conditions was accompanied by concomitant loss of the acetonide to produce 16. Finally, 16 was transformed to 19 through regeneration of the oxindole structure. Suzuki coupling reaction between 19 and 31 afforded the biaryl 32. After the introduction of the L-asparagine derivative, the lactamization produced the macrocyclic framework 34 in high yield. Then, 34 was coverted to 39 through 6 steps. On treatment of β-hydroxycarboxylic acid 39 under Mitsunobu conditions, the decarboxylative anti-elimination proceeded smoothly to yield the isomerically pure (Z)-propenylamide 41. Deprotection of 41 and selective oxidation of the C35-alcohol of 42 gave MOM-protected TMC-95A 43. The C7 alcohol was temporarily protected as its chroloacetyl ester 44 to suppress the side reaction that involved the propenylamide. Exposure of 45 to 1N HCl-THF and then saturated aqueous NaHCO_3 in one pot afforeded fully synthetic TMC-95A (1), of which phisical data are identical to those of the natural product.
天然有機化合物討論会の論文
2003-09-01

16 TMC-95Aの全合成(口頭発表の部)

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