Mitomycin precursors

The most functionalized mitomycin precursor was synthesized by Dong and Jeminez <1999JOC2520> in a racemic form, starting from indolic anion 266 and vinylsulfonium salts (route a) they also explored a diastereoselective version of this synthesis by using enantiopure vinylsulfonium salts, which gave low asymmetric induction <2001TA999>. 

A convenient and inexpensive method to transform electron rich aromatic aldehydes to phenols," or a,p-unsaturated aldehydes to vinyl formates, utilizes 30% hydrogen peroxide catdyzed by bis(n-nitro-phenyl) diselenide. A two-step formylation/MCPBA oxidation procedure (Scheme 25) was utilized by Kishi and coworkers in the 100 g scale conversion of 2,6-dimethoxytoluene to the mitomycin precursor (76). An organic peroxy acid was not required for the conversion of 9-formyl-6-methylellipticine (77) to... 

The photo-Fries rearrangement has been used in various synthetic reactions. A recent application concerned the synthesis of the mitomycin precursor (148) in high yield from the lactone (147). Finally, reference is made to the efficient photochemical deconjugation of piperidine esters (149) to the endocyclic isomers (150), presumably by a photoenolization reaction. ... 

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

A number of mitomycin analogues have been prepared by precursor-directed biosynthesis [104]. A range of amines were fed to S. caespitosus, and novel derivatives of mitomycin C (type I analogues) and mitomycin B (type II analogues) were identified and in some cases (42-46 and 52-56 Scheme 11.4) isolated and characterized. Antibiotic and antitumor activities were comparable to those of mitomycin C, with the type I analogues more active than the type II analogues. 

Neither shikimic acid66 nor its methyl ester, nor dehydroquinic acid,65 were precursors of mitomycin, so it is likely that deviation to mitomycin biosynthesis occurs from DAHP (150) via, it has been suggested,65 (151), as shown in Scheme 12. 

Shikimic acid (144), or a close relative, has been deduced to be the source of a C7N unit (shown with heavy bonding) common to the antibiotics mitomycin (147)128 129 and rifamycin S (148) 129-131 a similar unit is also apparent in strep-tovaricin D (149). Shikimic acid is a proven precursor for bacterial phenazines which are arguably constructed from two related C7N units132 (for further research on these metabolites, see below). 

Although cataract surgery is a potential precursor to bullous keratopathy, there are many other causes. Fuchs endothelial dystrophy, infection, trauma, retained foreign body, posterior polymorphous dystrophy, chronic uveitis, chronically elevated intraocular pressure (lOP), and vitreous touch are all known causes of bullous keratopathy. Other less common causes of bullous keratopathy include corneal thermal injury secondary to carbon dioxide laser skin resurfacing, air bag trauma, the use of topical dorzolamide hydrochloride in glaucoma patients with endothelial compromise, and use of mitomycin C during trabeculectomy surgery. 

Both citrulline (156) and arginine (157) serve as effident precursors for mitomy-dns (155). An efficient incorporation of L-[NH2CO- N, C]dtrulline with high retention of both labels as doubly labelled mitomycin rather than a mixture of singly labelled species establishes an intact incorporation of this precursor. Moreover, dtrulline is not converted into arginine (157) or urea prior to incorporation since this would have resulted in a loss of half the N by interchange with the N in either compound. 

Fig. 8. Mitomycin analogs produced by feeding various amine precursors.

K. 3 which is reduced by Raney nickel to. K cd conversion of the keto group at hv "imcdiate precursor to ( )-mitomycin... 

The syntheses described below afforded pyrrolo[l,2-a]indoles that are not direct precursors to mitosenes. Nevertheless, they are important because they contain strategies or techniques that might be valuable to subsequent preparations of mitomycin analogs. 

From this result, it was confirmed that 3-amino-5-hydroxybenzoic acid was the direct biosynthetic precursor of the w-CyN unit of porfiromycin. Because of its chemical structure, it might be thought that tryptophan could be involved in the biosynthesis of the mitomycins, like those alkaloids possessing an indole nucleus, whereas in fact the mitomycins were biosynthesized from an m-CyN unit and a D-glucosamine moiety. 

Richards and coworkers ° ° concluded that the precursor should be 3-amino-5-hydroxybenzoic acid (Fig. 33). They synthesized this compound in labeled form and demonstrated its efficient and specific incorporation into the major classes of antibiotics containing a CyN unit, rifamycin, mitomycin and the ansamitosins (Fig. 33). From our own laboratory, we can add two additional compounds, naphtho-mycin (Fig. 34) and ansatrienin (Fig. 35), to these examples. Both of these compounds, as the spectra show, are efficiently and specifically labeled from 3-amino-5-hydroxy-[carboxy- C]benzoic acid. Studies by Hornemann s... 

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