Regio- and Enantioselective Synthesis of Azole Hemiaminal Esters by Lewis Base Catalyzed Dynamic Kinetic Resolution
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- 作者：David W. Piotrowski ; Adam S. Kamlet ; Anne-Marie R. Dechert-Schmitt ; Jiangli Yan ; Thomas A. Brandt ; Jun Xiao ; Liuqing Wei ; Mark T. Barrila
- 刊名：Journal of the American Chemical Society
- 出版年：2016
- 出版时间：April 13, 2016
- 年：2016
- 卷：138
- 期：14
- 页码：4818-4823
- 全文大小：480K
- 年卷期：0
- ISSN：1520-5126
文摘
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.