The Use of Microorganisms and Enzymes in the Total Syntheses of Natural Products with a Medicinal Interest
Horacio F. Olivo
Medicinal and Natural Products Chemistry
The University of Iowa, Iowa City, IA 52242
Microorganisms have been employed for the regio- and stereoselective hydroxylation of unfunctionalized carbons, a reaction extremely difficult to emulate by conventional chemical means (e.g., the microbial hydroxylation of C-11 of progesterone for the syntheses of glucocorticoids). Inspired by this reaction, our research group has been interested in employing microorganisms for different types of oxidative reactions, which have allowed us to shorten the number of steps in the syntheses of medicinally important molecules.
We have employed whole cell microorganisms possessing oxidative enzymes to stereoselectively hydroxylate unfunctionalized carbons in a 7-azanorbornane for the synthesis of the alkaloid epibatidine, a poisonous frog alkaloid with extremely potent analgesic properties and different mode of action. We have also employed microorganisms for the stereoselective sulfoxidation and amidation in the synthesis of modafinil, a unique CNS stimulant devoid of any addiction liability approved for the treatment of narcolepsy. The syntheses of (S)-modafinil was accomplished in three steps (one chemical and two microbial) and rac-modafinil in only two steps (one chemical and one microbial). We have employed lipases for the perhydrolysis of ethyl acetate and oxidation of indene in the synthesis of a new and extremely useful chiral auxiliary.
This presentation will showcase the utility of microorganisms in synthesis and the use of enzymes in green chemistry.
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