Synthetic Enantiopure Aziridinomitosenes:  Preparation, Reactivity, and DNA Alkylation Studies

• Published in: Journal of the American Chemical Society Vol. 125; no. 51; pp. 15796 - 15806
• Main Authors: Vedejs, Edwin, Naidu, B. N, Klapars, Artis, Warner, Don L, Li, Ven-shun, Na, Younghwa, Kohn, Harold
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.12.2003; Amer Chemical Soc
• Subjects: Alkylation - drug effects; Aziridines - chemical synthesis; Aziridines - chemistry; Aziridines - pharmacology; Chemistry; Chemistry, Multidisciplinary; DNA - drug effects; DNA - metabolism; Mitomycins - chemical synthesis; Mitomycins - chemistry; Mitomycins - pharmacology; Physical Sciences; Science & Technology; Stereoisomerism; SECONDARY ALCOHOLS; ANTITUMOR AGENTS; OXAZOLIUM SALTS; DESS-MARTIN PERIODINANE; CROSS-LINKING AGENTS; ASYMMETRIC-SYNTHESIS; 4-OXAZOLINE ROUTE; STABILIZED AZOMETHINE YLIDES; MITOMYCIN-C; AMINO-PROTECTING GROUP
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja030452m

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.