Mitosane synthesis

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 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). 

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. ... 

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>. 

Miller and coworkers demonstrated a successful application of a peptide-catalysed kinetic resolution in the total synthesis of (-)-mitosane, which is a key intermediate for mitomycin C synthesis. A pentapeptide was found to effect kinetic resolution via acylation of a racemic alcohol with a A ei of 27. ° To expand the scope of applications of peptide catalysts to substrates lacking additional hydrogen-bond donors and acceptors, the group of Miller initiated a screening of a peptide library containing potential catalysts (resin bound. 

Interest in the synthesis of the mitomycins has resulted in a variety of procedures for the preparation of pyrrolo-indoles and related structures. Now Ban and his colleagues have reported a biomimetic route to the mitosane skeleton which involves a novel retro-aldol type of ring-opening reaction followed by a trans-annular cyclization (Scheme 102). A mitosane-like compound is available via... 

Investigations of the biosynthesis of the mitomycins are obviously very scanty. Until a research group becomes interested in such studies from an academic point of view, the biogenesis of these unique compounds will continue to remain obscure. It seems fairly certain, at this time, that methylation will prove to be a primary reaction of importance in the terminal steps of mitomycin synthesis. The reactions involved in the transfer of methyl group to the appropriate reactive location of mitosane can be altered and impeded by ethionine. This observation coupled with the fact that extent of ethionine inhibition may be influenced by providing the appropriate concentration of methionine under proper conditions. 

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