合成对映体纯的氮丙啶米托蒽醌类化合物：制备、反应性及DNA烷基化研究。

Synthetic enantiopure aziridinomitosenes: preparation, reactivity, and DNA alkylation studies.

作者信息

Vedejs Edwin, Naidu B N, Klapars Artis, Warner Don L, Li Ven-shun, Na Younghwa, Kohn Harold

机构信息

Departments of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.

出版信息

J Am Chem Soc. 2003 Dec 24;125(51):15796-806. doi: 10.1021/ja030452m.

DOI:10.1021/ja030452m

PMID:14677970

Abstract

An enantiocontrolled route to aziridinomitosenes had been developed from l-serine methyl ester hydrochloride. The tetracyclic target ring system was assembled by an internal azomethine ylide cycloaddition reaction based on silver ion-assisted intramolecular oxazole alkylation and cyanide-induced ylide generation via a labile oxazoline intermediate (62 to 66). Other key steps include reductive detritylation of 26, methylation of the N-H aziridine 56, oxidation of the sensitive cyclohexenedione 68 to quinone 70, and carbamoylation using Fmoc-NCO. Although the aziridinomitosene tetracycle is sensitive, a range of protecting group manipulations and redox chemistry can be performed if suitable precautions are taken. A study of DNA alkylation by the first C-6,C-7-unsubstituted aziridinomitosene 11a has been carried out, and evidence for DNA cross-link formation involving nucleophilic addition to the quinone subunit is described.

摘要

已从L-丝氨酸甲酯盐酸盐开发出一种对映体控制的氮丙啶米托蒽醌类化合物的合成路线。四环目标环系通过基于银离子辅助分子内恶唑烷基化和氰化物诱导的叶立德生成的分子内偶氮甲碱叶立德环加成反应组装而成，该反应通过不稳定的恶唑啉中间体（62至66）进行。其他关键步骤包括26的还原脱三苯甲基、氮丙啶56的N-H甲基化、敏感的环己二烯酮68氧化为醌70以及使用Fmoc-NCO进行氨甲酰化。尽管氮丙啶米托蒽醌四环化合物很敏感，但如果采取适当的预防措施，仍可进行一系列保护基操作和氧化还原化学反应。已对首个C-6、C-7未取代的氮丙啶米托蒽醌11a的DNA烷基化进行了研究，并描述了涉及亲核加成到醌亚基的DNA交联形成的证据。