Mitomycin skeleton

The intramolecular cycloaddition of munchnone intermediates (derived from the cyclodehydration of A-acyl amino acids) with 1,3-dipolarophiles was employed to construct the mitomycin skeleton. Thus, heating alkynyl acids 23 with acetic anhydride forms the intermediates 24 which undergo cyclization with loss of carbon dioxide to afford the 4-oxo-tetrahydroindoles 25 <96TL2887>... 

Lim and Sulikowski (84) explored the intramolecular C-H insertion in 119 alpha to the nitrogen atom as a rapid entry to the mitomycin skeleton and the antitumor agent FR-900482. Rhodium(II) based catalysts provide nearly racemic products. Bis(oxazoline) (55b) affords highest selectivities in this system and chloroform was found to be the optimal solvent, Eq. 71. The authors note that the reaction is somewhat capricious. 

More recently Franck et a/.331 prepared the pyrrolo[l,2-a]indolyl anion (247) by a similar method as part of a total synthesis of the mitomycin antibiotics (Section VI,A) Alkylation of (247) with methyl chloromethyl ether followed by photooxidation gave a product 248 with the basic mitomycin skeleton. 

Free radical reactions. A-(ft)-Iodoalkyl)pyrroles and indoles cyclize in the presence of H202-FeS04 in DMSO under ultrasonic irradiation. The method is useful for the synthesis of mitomycin skeleton and (-l-monomorine. ... 

Figure 11.4 Carbohydrate precursors to the carbon skeleton of mitomycin C.

These discoveries generated a lot of effort over the successive 25 years in the preparation of especially designed drug delivery systems for the controlled release of radioactive progesterone [654], colchicine [656], naproxen [657,673, 674], mitomycin C [675-677], inulin [678], trimethoprin [657], succinylsul-fathiazole [657], ethacrynic acid [653], and steroids [633], regardless of whether these drugs are physically trapped in polyphosphazene matrices, or chemically bonded to the polymer skeleton. 

Aromatic azapentalenes have not been found naturally, though an imidazo[4,5-d]imidazole derivative has been implicated in the prebiotic synthesis of purines130 74 (see also Section III,A,l,d). Saturated derivatives occur fairly widely the Senecio alkaloids contain the reduced pyrrolol l,2-a]pyrrole (pyrrolizidine) skeleton,487 and the alkaloid withasomnine is a derivative of pyrrolo[ l,2-6]pyrazole.374,488 The mitomycin antibiotics mentioned earlier in this review (Sections III,B,l,f and III,B,5) contain the pyrrolol l,2-a]indole ring,166,331 and the recently reported fungal metabolite sporidesmin is a saturated derivative of pyrrolo[2,3-6]indole.489... 

Mitomycin A, 1, is a natural product which shows potent antibiotic and antitumor activity, and has been the subject of extensive synthetic studies. French workers have described a simple procedure for one-pot preparation of the tricyclic skeleton of the mitomycins. Thus, simply mixing and stirring a solution of nitrosobenzene and (E,E)-hexa-2,4-dienal in absolute ethanol at... 

Streptovaridns and Mitomycins.—Consideration of the structures deduced for metabolites with the streptovaricin skeleton which lack in particular the extensive oxygenation of say streptovaricin D, has allowed a reasonable sequence of events for streptovaricin biosynthesis to be proposed. (The streptovaridns belong to the class of ansamydns. For earlier reviews on ansamycin biosynthesis see ref. 5, p. 52, and ref. 6, p. 45.)... 

Since CHEC-I appeared in 1984, several reviews on specific fused (5,5,6) heterocycles have been published. A review on pyrrolo[l,2-a]indoles has appeared in which the different synthetic approaches leading to this particular heterocyclic assembly have been systematized <86RTC199>. Special interest of the authors in the five most important strategies leading to the pyrrolo[l,2-ajindole skeleton has been shown, of which the greater part is related to the synthesis of the mitomycins, alkaloid-type antibiotics with antitumor activity. The literature cited covered the period from 1978 to the end of 1985. 

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>. 

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... 

Another common ring-expansion mechanism is that of intramolecular nucleophilic displacement, and three examples published in 1980 will suffice to illustrate the scope of the reaction. Mitomycin C has the benzo[/]pyrroIo[l,2-a]indole-5,8-dione skeleton (474) and Ohta has approached this skeleton via the construction of an eight-membered ring (473), followed by transannular cyclization (Scheme 71). 

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