16 スピロケタールの選択的還元反応を利用したトウトマイシンの合成研究(口頭発表の部)

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Tautomycin (1) was first isolated in 1987 by Isono and co-workers and the full stereostructure was established recently. This compound is a potent inhibitor of protein phosphatases type 1 and type 2A. Here we describe the synthetic studies of 1. Synthesis of the C1-C10 segment. We applied the newly developed methodology for the synthesis of this segment. This methodology involves the selective spiroketal formation using thermodynamic equilibration and its regio- and stereoselective reduction. These reaction proceeds in high selectivity, and the reduction product 15A was leaded to the aldehyde 8 in 8 steps. Synthesis of the C11-C18 segment. Starting from methyl (S)-3-hydroxy-2-methylpropionate, the aldehyde 26 was prepared without any loss of the optical activity. This aldehyde was then treated with tributylcrotylstannane in the presence of BF_3・OEt_2 to afford 27 with moderate selectivity. The adduct 27 was further converted to the sulfone 7 in 4 steps. Synthesis of the C21-C26 segment. Optically active epoxyalcohol 29, which was obtained in 3 steps from isobutyraldehyde, was subjected to titanium(IV)-mediated ring opening reaction to yield 30 in good selectivity. Introduction of the C22 chiral centre to the olefin 32 was achieved by the diastereoselective osmylation. The desired epoxide 3 was synthesized successively with the inversion at the C22 stereocentre. Synthesis of the dialkylmaleic anhydride segment. The chirality at C3' position was introduced successfully by Sharpless's asymmetric dihydroxylation. The diol 36 was converted to diethyl dialkylmaleate 38 via the ketoester 37. Synthesis of the degradation product corresponding to C1-C18. The lithium salt of 7 was coupled with 8, and the alcohol portion was successively oxidized to give the ketosulfone 39 in good overall yield. After the phenylsulfonyl group was removed, the spiroketal moiety was selectively constructed by the deprotection sequence of the hydroxyl groups The silyl eher 40 was further leaded to 6, which was identical with the degradation product of 1 in all respects. On the other hand, the epoxyalcohol 41 was synthesized through asymmetric crotylboration and epoxydation. We now undertake the coupling of the remaining segments and complete the total synthesis of 1.
天然有機化合物討論会の論文
1993-09-10

16 スピロケタールの選択的還元反応を利用したトウトマイシンの合成研究(口頭発表の部)

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