title: The Synthesis of Methyl-Substituted Spirocyclic Piperidine-Azetidine (2,7-Diazaspiro[3.5]nonane) and Spirocyclic Piperidine-Pyrrolidine (2,8-Diazaspiro[4.5]decane) Ring Systems.
abstract: The synthesis of a series of pharmaceutically important N-protected methyl-substituted spirocyclic piperidine-azetidine (2,7-diazaspiro[3.5]nonane) and spirocyclic piperidine-pyrrolidine (2,8-diazaspiro[4.5]decane) ring systems was developed. These motifs contain two differentiated sites (protected secondary amines) to allow for further functionalization via reductive amination, amidation, or other chemistry. The methyl-substituted spiroazetidine ring systems were accessed using nitrile lithiation/alkylation chemistry while the methyl-substituted spiropyrrolidines were synthesized by 1,4-addition reactions with nitroalkanes, followed by reduction and cyclization. These conditions were then scaled for the synthesis of 1-methyl spirocyclic piperidine-pyrrolidine with a classical resolution of the product using a tartaric acid derivative to isolate a single enantiomer.
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Smith
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Shawn
authors.initials: S
authors.lastname: Cabral
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Kung
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Rose
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: James A
authors.initials: JA
authors.lastname: Southers
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Carmen N
authors.initials: CN
authors.lastname: García-Irizarry
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Damon
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Bagley
authors.affiliation: Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Griffith