P-25 2種のルートによる天然型(+)-デュオカルマイシンSAの全合成(ポスター発表の部)

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概要

• 論文の詳細を見る

• Duocarmycin SA (1) is a representative member of a new class of exceptionally potent antitumor antibiotics which carry CPI (cyclopropa[c]pyrrolo[3,2-e]indole) subunit as the common pharmacophore. Because of its relative stability, compared to structurally related CC-1065 (2) and duocarmycin A (3), the synthetic investigation of 1 is particularly attractive. Previously we reported a 12-step synthesis of (±)-1, in which the pharmacophore A was constructed from tetrahydroquinolinol derivative C instead of the conventionally used precursor B. We describe herein two advanced synthesis routes for natural (+)-duocarmycin SA (1) by way of the type C intermediate, (S)-5. The first route, involving an optical resolution, realized an enantioselective synthesis of (+)-1 as follows. According to our report, 4 was transformed to 15 which was then led to (±)-6. HPLC separation of (R)-O-methylmandelate of (±)-6 was found to be readily attainable and optically pure (S)-6 and (R)-6 were obtained. The reported procedures were applied to (S)-5 derived from (S)-6 to complete a total synthesis of (+)-duocarmycin SA (1). An optical inversion of the unnatural enantiomer (R)-6 to (S)-6 was easily achieved by the Mitsunobu reaction with acetic acid and subsequent methanolysis of 22. The second route, adopting L-malic acid as a chiral source, is the first example of an asymmetric synthesis without optical resolution of the duocarmycins and its related substances. Ketoester 31 prepared from L-diethyl malate was condensed with 32 to yield 33. The crucial indole cyclization reaction from 33 was achieved in 54% yield with 2-ethyl-2-methyl-1,3-dioxane and BF_3・OEt_2, providing an indole derivative 34. Curtius reaction of 37 derived from 34 followed by methanolysis gave a carbamate 38, whose benzyl ether was cleaved with BBr_3 to yield primary alcohol 40 selectively. Piperidine ring formation from 40 was easily effected with DEAD and Ph_3P to provide 44, and its protecting groups were successively cleaved to afford the above mentioned (S)-5. This study established the absolute structure of (+)-1 as shown.

• 天然有機化合物討論会の論文
• 1995-09-01

著者

• 夏目 充隆

  乙卯研究所

• 夏目 充隆

  Research Foundation Itsuu Laboratory

• 村竹 英昭

  Res. Foundation Itsuu Lab. Tokyo Jpn

• 村竹 英昭

  乙卯研

• 安倍 乙子

  乙卯研

• 松村 直茂

  乙卯研

• 松村 直茂

  Research Foundation Itsuu Laboratory

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