Mitosanes

The antitumor activity displayed by the mitosanes and many synthetic aziridines stems from their ability to act as alkylating agents which chemically modify (crosslink) DNA. For this reason, a large number have been screened for antitumor activity, the mechanism of which has been the subject of considerable research effort <75CJC289l). An excellent account of the broad spectrum of biological properties of a multitude of compounds containing the aziridinyl moiety has been published [Pg.93]

A number of genes can be assigned roles in tailoring of the mitosane core... 

By screening in solution Miller et al. identified the pentapeptide 32 as a catalyst for kinetic resolution of the alcohol roc-33 (selectivity factor 27, Scheme 12.17). roc-33 was an intermediate in their synthesis of enantiomerically pure mitosane 34 [37]. 

A variety of common electrophiles can be used in conjunction with deprotonation of the benzylic position of complexed aUcylbenzenes. This includes alkyl iodides, aldehydes, ketones, and epoxides. Mitosanes can be prepared by deprotonation of the tricyclic complex (52) followed by addition of oxirane (Scheme 92). Depending on the substituent on the complexed aromatic ring, both regio-and stereoselective benzylic alkylations are observed. For example, deprotonation and alkylation of the benzylic position meta to the dimethylamino group of (53) is exclusively observed (Scheme 93). 

A total synthesis of ( + )-mitomycins via isomitomycin A is described (87JA7881), and from a mitomycin rearrangement albomitomycin A and isomitomycin A were formed from mitomycin A (87JA7224). Amidine derivatives were prepared from mitomycin C and formamide acetals. These, when treated with amines, afforded the corresponding 7-N-substituted mitosanes (87JOC5601). 

These intramolecular ring-openings have been utilized in stereospecific syntheses of necine bases and mitosanes. ... 

The mitosane A -oxide derivative (57) is similarly converted into the pyrroloindole derivative (58) in high yield upon reaction with acetic anhydride in chloroform (equation 17). The corresponding reaction of the 1,2-diacetoxy derivative (59) is more complex, however, as there is no directing functionality to orient the reaction (Scheme 11). One of the reaction products (62) is viewed as being formed via intermediates (60) and (61). If this mechanistic rationale is correct then the transformation of (59) to (62) represents a new manifestation of the Polonovski reaction. 

The antitumor activity displayed by the mitosans and many synthetic aziridines stems from their ability to act as alkylating agents which chemically modify (crosslink) DNA. For this reason, a... 

This intramolecular reaction proved to be very useful for the synthesis of a number of pyr-rolizidine-based natural products including trachelanthamidine, isoretronecanol, di-hydroxyheliotridane, and mitosane derivatives. ... 

Intramolecular Reformatski reaction yields suitably substituted benzopyrrolizidines. Thus from (220), the mitosane (221) was obtained <85LA1398>. 

Functionalization of mitosenes has been studied thoroughly <85LA1413, 85LA1422,88LA381,89LA239, 90MI801-01 >. The Dotz reaction (84AG(E)587> offers a simple and versatile route to mitosanes. 

An extensive review on the synthesis of pyrrolo[l,2-a]indoles has appeared of which the greater part is dedicated to the representatives with the mitosane skeleton <86RTC199>. 

The different approaches to the synthesis of the pyrrolo[l,2-a]indoles have been summarized in an excellent review, of which the greater part is dedicated to the preparation of 2,3,9,9a-tetrahydro-5,8-dioxo-l/f-pyrrolo[l,2-a]indole, the mitosane basic skeleton of mitomycins. In 1993, an overview appeared on the total syntheses of mitomycins, in which the different approaches to the mitomycin ring system have been discussed <93MI 836-0l>. These approaches can be divided into five pathways as depicted in Scheme 24 <86RTC199>. 

---