13 20員環マクロラクタム抗生物質ビセニスタチンの立体化学と全合成研究(口頭発表の部)

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Vicenistatin (1) is an antitumor antibiotic, isolated from Streptomyces sp. HC-34, having a novel structure including a 20-membered macrocyclic lactam and aminosugar (vicenisamine: 2). Among other characteristic features is its significant activity especially against human leukemia and human colon carcinoma. Synthetic studies have now been launched to analyze essential chemical features in expressing biological activities and to further develop novel compounds useful in cancer chemotherapy. The absolute stereochemistry of the aglycon part was first determined by synthetic approach. Relevant MTPA ester derivatives of two fragments (aminoalcohol and triol), which include the chiral center C18 and the C6-C7 portion, respectively, were degradatively derived from natural vicenistatin, and compared with the respective synthetic specimen prepared from the known compounds by stereochemically defined chemistry. The absolute configuration was determined to be 6S, 7S, 18S. Total synthesis of vicenistatin was the next issue. We envisioned that the final macrocyclization should be either by macrolactamization (path A) or an intramolecular Wittig-Horner reacton (path B). The crucial precursors were respectively synthesized convergently from two major components. One fragment was synthesized from cyclopropyl methyl ketone and the other amino fragment from (S)-citronellol. Two key reactions were involved, that is, the Suzuki's coupling allowed to connect these two components and the subsequent Evans' asymmetric aldol reaction to construct the remaining two vicinal chiral centers. We were successful in the final cyclization (path A) to construct the whole skeleton of the aglycon. The aminosugar part (vicenisamine) is essential in expressing biological activities as well, and its synthesis and derivatization is naturally important. Our route starting from a known chiral epoxyalcohol obtained by Sharpless' asymmetric epoxidation involved two key reactions: intramolecular epoxide opening promoted by Lewis acid and Brown's asymmetric allylation.
天然有機化合物討論会の論文
1997-07-20

13 20員環マクロラクタム抗生物質ビセニスタチンの立体化学と全合成研究(口頭発表の部)

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