Synthesis of the Aziridinomitosene Skeleton by Application of Guanidinium Ylide‐Mediated Aziridination

Abstract

An aziridinomitosene skeleton, a basic core of mitomycin antibiotics, was straightforwardly prepared from N-(p-toluenesulfonyl)indole-2-carboxaldehyde in 16% overall yield by successive reactions of guanidinium ylide-mediated aziridination, InCl 3 -catalyzed epimerization of trans-3-(indol-2-yl)aziridine-2-carboxylate, leading to the cis-derivative, and dehydrative cyclization.Introduction. -Mitomycins are antibiotics isolated from Streptomyces species [1], and mitomycin C, among them, has clinically been used as an anticancer drug [2]. Aziridinopyrroloindole, composed of a 6-5-5-3 ring system, is the core skeleton of mitomycin antibiotics and is generally called as either aziridinomitosane or aziridinomitosene depending upon the saturation of the indole unit. Many groups have attempted at the synthesis of mitomycin antibiotics due to their interesting biological activities, and Kishi and co-workers [3], and Fukuyama and Yang [4] have skillfully achieved total syntheses of natural mitomycins. Although various synthetic approaches to aziridinomitosane [5] and aziridinomitosene [6] skeletons have also been examined, the use of bond connection between C(3) and N(4) (cf. the atom numbering of aziridinomitosene in Scheme 1) in the final construction of the ring system has never been reported to the best of our knowledge. We have established a unique guanidinium ylide-mediated aziridination reaction of an aromatic [7] [8] or unsaturated [9] aldehyde, in which trans-3-(indol-2-yl)aziridine-2-carboxylate (trans-2; Scheme 1) could be obtained, when indole-2-carboxaldehyde (1; Scheme 1) is used as an aldehyde source. Herein, we describe a straightforward construction of a model aziridinomitosene skeleton from 3-(indol-2-yl)aziridine-2-carboxylate.Results and Discussion. -Our synthetic strategy toward the aziridinomitosene skeleton 3 or 4 is outlined in Scheme 1, in which three reactions are combined: i) Scheme 2. Trials for Aziridination of Ethyl 2-Formyl-1H-indole-3-carboxylate 7 Scheme 3. Aziridination of (Silyloxy)methyl-Substituted 1H-Indole-2-aldehydes and Trials for Epimerization of the trans-Aziridines Formed

Recent Advances in the Stereoselective Synthesis of Aziridines

“…Experimental evidence from a Hammet-plot supports the proposed models. A nice application of this methodology is the straightforward preparation of aziridinomitosene precursor 284 , a basic core of mitomycin antibiotics, realized by cyclization of cis -3-(1 H -indol-2-yl)­aziridine-2-carboxylate prepared by guanidinium ylide-mediated aziridination of 1 H -indole-2-carboxaldehyde (Scheme ) …”