Bioreductive alkylation process

For over 35 years, the quinone methide species has been invoked as a reactive intermediate in bioreductive alkylation and in other biological processes.8 29 Generally, there is only circumstantial evidence that the quinone methide species forms in solution. Conceivably, the O-protonated quinone methide (i.e., the hydroquinone carbocation) could be the electrophilic species. If so, bioreductive alkylation may simply be an SN1 reaction. Also, there are questions concerning the mechanism of quinone methide... 

Another class of DNA alkylating agents, the Mitomycins, proved to be most promising in clinical trials. Among these, mitomycin C, shown in Fig. 6.1, exhibits significant anti-tumor activity. Its mechanism of activation consists of a complex bioreductive process. The first step is the reduction to hydroquinone, followed by a loss of methanol. This reaction fa-... 

The indolequinone moiety is of interest (i) as the activating nucleus of aziridine alkylating substituents and/or alkylating functionality through an iminium derivative produced in a C-3 elimination process [115-118], and (ii) as a vehicle for oxygen-sensitive, bioreductively-activated drug delivery [119,120] (see below). 

Alkyl-4-oxy-3,4-dihydroisocoumarins are enantioselectively prepared by oxylactonization ofo-(alk-l-enyl)benzoates promoted by the in situ-generated chiral lactate-based hypervalent iodine(III) catalysts (13EJ07128). Chemoenzymatic synthesis of 3,4-dialkyl-3,4-dihydroisocoumarins involves one-pot dynamic kinetic reductive resolution processes catalyzed by E. co/i/alcohol desidrogenase. This strategy consists in the bioreduction of various racemic ketones to the corresponding enantiopure alcohols followed by intramolecular acidic cyclization (Scheme 71) (130L3872). 

Enzymes with different stereochemical preferences for 3-oxo esters and 2-alkyl 3-0X0 esters have been isolated [57,62,63,68]. They are NADPH-dependent enzymes and are able to catalyze the reduction of oxo esters of different type. However, they are not available for enzyme-catalyzed reaction in substitution of the whole-cell catalyst. Synthetic applications make use of whole-cell biocatalysts. Valuable intermediates in synthesis are keto esters possessing additional functionality. Thus 5 -4-chloro-3-hydroxybutanoic acid 33 (Scheme 12) has been obtained by reduction with suspended cells from cultures of G. candidum. The compound is the intermediate in the synthesis of the cholesterol antagonist 34. In the biotransformation process a reaction yield of 95% and optical purity of 96% were obtained at 10 g/L. The optical purity was increased to 99% by heat treatment of cell suspensions prior to conducting the bioreduction [69]. 

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