Piotrowski David W, Kamlet Adam S, Dechert-Schmitt Anne-Marie R, Yan Jiangli, Brandt Thomas A, Xiao Jun, Wei Liuqing, Barrila Mark T
Worldwide Medicinal Chemistry, Pfizer, Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
Chemical Research and Development, Pfizer, Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
J Am Chem Soc. 2016 Apr 13;138(14):4818-23. doi: 10.1021/jacs.6b00207. Epub 2016 Mar 30.
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.
我们报道了一种模块化的三组分动态动力学拆分（DKR）反应，该反应可得到对映体富集的、由唑类和醛类衍生的半胺酯。这种新颖且可扩展的反应可通过对平衡的唑 - 醛加合物进行封端（例如酰化），以区域选择性的方式合成有价值的取代唑类。使用脯氨醇衍生的DMAP催化剂作为手性路易斯碱，能够以高化学产率和高对映体过量获得产物。该DKR反应在多公斤规模上进行，以制备一种用于领先临床候选药物的四唑前药片段，该片段的合成面临巨大挑战。
