Regio- and Enantioselective Synthesis of Azole Hemiaminal Esters by Lewis Base Catalyzed Dynamic Kinetic Resolution

We report a modular three-component dynamic kinetic resolution (DKR) that affords enantiomerically enriched hemiaminal esters derived from azoles and aldehydes. The novel and scalable reaction can be used to synthesize valuable substituted azoles in a regioselective manner by capping (e.g., acylatio...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2016-04, Vol.138 (14), p.4818-4823
Main Authors: Piotrowski, David W, Kamlet, Adam S, Dechert-Schmitt, Anne-Marie R, Yan, Jiangli, Brandt, Thomas A, Xiao, Jun, Wei, Liuqing, Barrila, Mark T
Format: Article
Language:English
Subjects:
Aldehydes - chemistry
Alkanesulfonates - chemical synthesis
Alkanesulfonates - chemistry
Azoles - chemical synthesis
Azoles - chemistry
Catalysis
Esters - chemical synthesis
Esters - chemistry
Kinetics
Lewis Bases - chemistry
Stereoisomerism
Tetrazoles
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Summary:We report a modular three-component dynamic kinetic resolution (DKR) that affords enantiomerically enriched hemiaminal esters derived from azoles and aldehydes. The novel and scalable reaction can be used to synthesize valuable substituted azoles in a regioselective manner by capping (e.g., acylation) of the equilibrating azole-aldehyde adduct. With the use of a prolinol-derived DMAP catalyst as the chiral Lewis base, the products can be obtained in high chemical yield and with high enantiomeric excess. The DKR was performed on a multikilogram scale to produce a tetrazole prodrug fragment for a leading clinical candidate that posed formidable synthesis challenges.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.6b00207