Tetrazoles are valuable moieties that are often used as carboxylic acid isosteres. However, the polar nature of tetrazoles can lead to bioactive molecules with low permeability, sometimes necessitating the use of prodrugs. Hemiaminal ester tetrazole prodrugs can be made by unselective alkylation to afford mixtures of the 1,5- and 2,5-disubstituted tetrazole products. Some substituted hemiaminal esters have further mixture complexity through introduction of a new stereogenic center. Although an isomeric mixture of prodrugs will ultimately be cleaved in vivo to the same parent compound, the relative rates of cleavage of the isomers will likely differ, and the inability to control them can hinder identification of the final crystalline solid form. We have developed an organocatalytic dynamic kinetic resolution to obtain enantiomerically enriched aminals derived from azoles, aldehydes, and acylating reagents. The novel three-component scalable reaction employs a chiral DMAP derivative and is highly modular, allowing for rapid SAR exploration and optimization of pharmacokinetic properties of tetrazole prodrugs.

Regio- and enantioselective synthesis of azole hemiaminal esters by Lewis-base-catalyzed dynamic kinetic resolution

251st National Meeting (2016)

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