Synthetic enantiopure aziridinomitosenes: preparation, reactivity, and DNA alkylation studies.
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.
Vedejs
Edwin
E
Departments of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA. edved@umich.edu
Naidu
B N
BN
Klapars
Artis
A
Warner
Don L
DL
Li
Ven-shun
VS
Na
Younghwa
Y
Kohn
Harold
H
D000478:Alkylation / Q000187:drug effects; D001388:Aziridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism*; D008937:Mitomycins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism
D001388:Aziridines; D008937:Mitomycins; C046001:mitosene; D004247:DNA