title: Asymmetric Synthesis of the Major Metabolite of a Calcitonin Gene-Related Peptide Receptor Antagonist and Mechanism of Epoxide Hydrogenolysis.
abstract: An asymmetric synthesis of the major metabolite of the calcitonin gene-related peptide recepotor antagonist BMS-846372 is presented. The variously substituted cyclohepta[b]pyridine ring system represents an underexplored ring system and showed some unexpected chemistry. Reactivities of epoxide and ketone functional groups on the cycloheptane ring were extensively controlled by a remote bulky TIPS group. The rate difference of the hydrogenolysis between two diastereomeric epoxide intermediates shed some light on the mechanism of epoxide hydrogenolysis, and further, deuterium labeling studies revealed more mechanistic details on this well-known chemical transformation for the first time.
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06443, United States.
authors.forename: Guanglin
authors.identifier: 0000-0002-9465-3330
authors.initials: G
authors.lastname: Luo
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06443, United States.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06443, United States.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Conway
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06443, United States.
authors.forename: Walter
authors.initials: W
authors.lastname: Kostich
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06443, United States.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Johnson
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06443, United States.
authors.forename: Alicia
authors.initials: A
authors.lastname: Ng
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06443, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Bristol-Myers Squibb Research & Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06443, United States.
authors.forename: Gene M
authors.initials: GM
authors.lastname: Dubowchik
mesh_terms: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004852:Epoxy Compounds / Q000737:chemistry*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006868:Hydrolysis; D013057:Spectrum Analysis / Q000379:methods
chemical_list: C576963:BMS-846372; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004852:Epoxy Compounds; D006576:Heterocyclic Compounds, 4 or More Rings