Biocatalytic and synthetic routes for the preparation of valuable products

Oxidation reactions are challenging in organic chemistry. Selectivity of the oxidation products and the hazardous chemical waste generated are the major issues. Methods that exert lesser environmental impact while keeping the efficiency of the transformation are highly sought. Microbial oxidations have been recognized as a valuable benign strategy to prepare oxidized products. These microbial oxidations are carried out in aqueous solutions and mild reaction conditions. Certain microorganisms can perform selective oxidations such as hydroxylation, Baeyer-Villiger oxidation, and sulfoxidation. Important discoveries were made during efforts to selectively effect microbial transformations of unactivated carbon position within organic molecules. Different microbial activities were found in Beauveria bassiana. A new aromatic Baeyer-Villiger activity in B. bassiana transformed N-piperidinyl acetophenone, followed by hydrolysis of the resulting phenyl acetyl ester, to 4-piperidinyl phenol in 42% yield. This aromatic Baeyer-Villiger activity opened an opportunity when the substrate contains functionalities sensitive to chemical Baeyer-Villiger oxidation conditions. Methods for asymmetric microbial sulfoxidation and direct microbial amidation of a carboxylic acid were developed. B. bassiana performed a sulfoxidation of beta-sulfanyl carboxylic acid providing the (S)-sulfoxide in a remarkable 89% yield and 99% ee. The bacterium Bacillus subtilis carried out a direct amidation of the (S)-sulfoxide to produce (S)-modafinil in good yield. Thus, one chemical and two selective microbial reactions were employed in the preparation of the novel non-addictive psychostimulant modafinil. Modafinil is under clinical studies for new applications such as Attention-Deficit Hyperactivity Disorder (ADHD), anti-convulsant activity, and cocaine and methamphetamine addiction treatment. A new thiazolidinethione chiral auxiliary was conveniently prepared from indene in 54% overall yield on multigram scale. This indene-based thiazolidinethione imide proved effective in delivering 2 propionate aldol products (87-92%, 94:6-98:2 dr) and acetate aldol products (90-98% yield, 91:9-98:2 dr) in high yields and high diastereoselectivities. High selectivities were also observed in the acetate aldol reaction with chiral aldehydes. The syn-acetate aldol products were obtained with high yields and high diastereoselectivities (84-86% yield, 96:4-99:1 dr). This new indene-based thiazolidinethione proved to be cost-efficient when compared with thiazolidinethione chiral auxiliaries developed for the acetate aldol reactions. Microbial and chemical reactions were successfully combined to prepare useful compounds.