Mitosene

Alkylation reactions by the iminium methide species are well known in the mitomycin and mitosene literature 4,49,51-53 and are largely responsible for the cytotoxicity/antitumor activity of these compounds. As illustrated in Scheme 7.8, the electron-rich hydroquinone intermediate can also be attacked by the iminium ion resulting in either head-to-head or head-to-tail coupling. The head-to-head coupling illustrated in Scheme 7.8 is followed by a loss of formaldehyde to afford the coupled hydroquinone species that oxidizes to the head-to-head dimer upon aerobic workup. Analogous dimerization processes have been documented in the indole literature, 54-56 while the head-to-tail mechanism is unreported. In order to... 

Scheme 7.11 shows the product structures resulting from the dithionite reduction of a simplified version of WV-15. The symmetric sulfite diester was extracted from the reaction mixture with methylene chloride. The isolation and characterization of the sulfite diester confirmed that this species can form in dithionite reductive activation reactions and provided the chemical shift for the 10a-13C center of a mitosene sulfite ester (49.37 ppm). The aqueous fraction of the reaction contained the mitosene sulfonate and trace amounts of Bunte salt, based on their 13C chemical shifts. 

The above studies show that dithionite reduction of mitosenes results in the formation of lOa-sulfite esters as well as sulfonates. The presence of the excellent sulfite-leaving group at the mitosene 1 Oa-position suggests that alkylation reactions at this position could still occur. The subsequent sulfite to sulfonate rearrangement results in loss of alkylation capability by this position. 

SCHEME 7.11 Dithionite reduction of a mitosene bearing an acetate-leaving group at the 10a position (a simplified WV-15 analogue). The I3C labels are designated with asterisks ( ). 

Ouyang, A. Skibo, E. B. The iminium ion chemistry of mitosene DNA alkylating agents, enriched 13C-NMR studies. Biochemistry 2000, 39, 5817-5830. 

Edstrom has utilized the carbonylation variation to engineer new routes to 3-substituted 4-hydroxyindoles, indolequinones, and mitosene analogs [113, 114]. For example, triflate 155 is converted to methyl ester 156 in high yield [114]. Subsequent oxidation affords indole 157. 

It has been known for sometime that 2-(2-bromoanilino)enones undergo Heck-type cyclizations to form indoles and carbazoles. Thus, Kibayashi reported the synthesis of 4-keto-l,2,3,4-tetrahydrocarbazoles in this manner [362], and Rapoport employed this reaction (296 to 297) to achieve an improved synthesis of 7-methoxymitosene [363]. A series of related mitosene analogs has been crafted using Pd chemistry by Michael and co-workers [364], They found that P(o-tol)3 was far superior to PPh3 in conjunction with Pd(OAc)2. 

Michael et al. <2001TL7513> described a Heck cyclization of 154 to form functionalized mitosene 155 which was further transformed into tetracyclic compound (route b). Also Lee et al. <1999JOC4224> described a synthesis in... 

In an interesting approach to the mitosenes, Danishefsky showed that treatment of 1 with mercuric acetate in THF containing sodium bicarbonate leads directly to the indole derivative 2 in over 50% yield. 

The mode of antitumor action of 60 is activated in vivo by bioreduction of the hydroxylamine moiety (Scheme 9) leading to the ring-expanded product, azocinone 61, which upon cyclization furnishes the mitosene-like 62 <1997T10229>. 

Scheme 13. Indole radical intermediacy in the total synthesis of a mitosene...

The results from this preliminary study demonstrated the reality of effecting the regioselective oxidative functionalization of simple 8-oxo-l//-pyrrolo[l,2-a]indoles as a function of the electronics of the C-9 ring substituent. Access to the C-l-substituted ethers 89a-c and tetrahydro-3//-pyrrolo[l,2-a]indole 86 allows for an entry into the mitosenes that was not previously possible.68... 

An efficient and economical new approach toward the synthesis of 7-aminoaziridinomitosenes, as represented by compound 96, has been developed in less than 15 total operations from commercially available chemicals. Overall our scheme represents the second total synthesis of a fully functionalized aziridinomitosene. At one stage, new insights into the mechanistic details involving the reaction of l,2-epoxypyrrolo[l,2-c]indoles with nucleophiles are provided. Notably, the route presented has the advantage of accessing both the aziridine and 7-amino substituents in deprotected form. Further application of this synthetic approach to additional C-9-substituted mitosenes can be anticipated. 

For examples of ring-modified mitosene or mitomycin analogues, see K6hler,... 

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