title: Regio- and Enantioselective Synthesis of Azole Hemiaminal Esters by Lewis Base Catalyzed Dynamic Kinetic Resolution.
abstract: 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.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer, Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: David W
authors.initials: DW
authors.lastname: Piotrowski
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer, Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Kamlet
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer, Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Anne-Marie R
authors.initials: AM
authors.lastname: Dechert-Schmitt
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer, Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jiangli
authors.initials: J
authors.lastname: Yan
authors.affiliation: Chemical Research and Development, Pfizer, Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Brandt
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer, Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer, Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Liuqing
authors.initials: L
authors.lastname: Wei
authors.affiliation: Chemical Research and Development, Pfizer, Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Barrila
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000476:Alkanesulfonates / Q000138:chemical synthesis / Q000737:chemistry; D001393:Azoles / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D058115:Lewis Bases / Q000737:chemistry*; D013237:Stereoisomerism; D013777:Tetrazoles
chemical_list: D000447:Aldehydes; D000476:Alkanesulfonates; D001393:Azoles; D004952:Esters; D058115:Lewis Bases; D013777:Tetrazoles