title: Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity.
abstract: Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their lead compounds. Too often, however, the difficulty of installing these fragments surpasses the challenges posed even by the construction of the parent drug scaffold. This full account describes the development and application of a general strategy where spring-loaded, strained C-C and C-N bonds react with amines to allow for the "any-stage" installation of small, strained ring systems. In addition to the functionalization of small building blocks and late-stage intermediates, the methodology has been applied to bioconjugation and peptide labeling. For the first time, the stereospecific strain-release "cyclopentylation" of amines, alcohols, thiols, carboxylic acids, and other heteroatoms is introduced. This report describes the development, synthesis, scope of reaction, bioconjugation, and synthetic comparisons of four new chiral "cyclopentylation" reagents.
authors.affiliation: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Lopchuk
authors.affiliation: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Kasper
authors.initials: K
authors.lastname: Fjelbye
authors.affiliation: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kawamata
authors.affiliation: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Lara R
authors.initials: LR
authors.lastname: Malins
authors.affiliation: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Chung-Mao
authors.initials: CM
authors.lastname: Pan
authors.affiliation: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Gianatassio
authors.affiliation: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Liher
authors.initials: L
authors.lastname: Prieto
authors.affiliation: Pfizer Worldwide Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: James
authors.initials: J
authors.lastname: Bradow
authors.affiliation: Pfizer Worldwide Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Brandt
authors.affiliation: Department of Chemistry, La Jolla Laboratories, Pfizer Inc. , 10770 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Collins
authors.affiliation: Department of Chemistry, La Jolla Laboratories, Pfizer Inc. , 10770 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Jeff
authors.initials: J
authors.lastname: Elleraas
authors.affiliation: Department of Chemistry, La Jolla Laboratories, Pfizer Inc. , 10770 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Ewanicki
authors.affiliation: Department of Chemistry, La Jolla Laboratories, Pfizer Inc. , 10770 Science Center Drive, San Diego, California 92121, United States.
authors.forename: William
authors.initials: W
authors.lastname: Farrell
authors.affiliation: Pfizer Worldwide Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Olugbeminiyi O
authors.initials: OO
authors.lastname: Fadeyi
authors.affiliation: Department of Chemistry, La Jolla Laboratories, Pfizer Inc. , 10770 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Gallego
authors.affiliation: Pfizer Worldwide Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: James J
authors.initials: JJ
authors.lastname: Mousseau
authors.affiliation: Pfizer Worldwide Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Oliver
authors.affiliation: Department of Chemistry, La Jolla Laboratories, Pfizer Inc. , 10770 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Neal W
authors.initials: NW
authors.lastname: Sach
authors.affiliation: Pfizer Worldwide Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Smith
authors.affiliation: Department of Chemistry, La Jolla Laboratories, Pfizer Inc. , 10770 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Jillian E
authors.initials: JE
authors.lastname: Spangler
authors.affiliation: Department of Chemistry, La Jolla Laboratories, Pfizer Inc. , 10770 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Huichin
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Chemistry, La Jolla Laboratories, Pfizer Inc. , 10770 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Jinjiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Phil S
authors.identifier: 0000-0001-9193-9053
authors.initials: PS
authors.lastname: Baran
mesh_terms: D000438:Alcohols / Q000138:chemical synthesis / Q000737:chemistry*; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry*; D015394:Molecular Structure; D013237:Stereoisomerism; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D000438:Alcohols; D000588:Amines; D002264:Carboxylic Acids; D013438:Sulfhydryl Compounds