title: Organic chemistry. Strain-release amination.
abstract: To optimize drug candidates, modern medicinal chemists are increasingly turning to an unconventional structural motif: small, strained ring systems. However, the difficulty of introducing substituents such as bicyclo[1.1.1]pentanes, azetidines, or cyclobutanes often outweighs the challenge of synthesizing the parent scaffold itself. Thus, there is an urgent need for general methods to rapidly and directly append such groups onto core scaffolds. Here we report a general strategy to harness the embedded potential energy of effectively spring-loaded C-C and C-N bonds with the most oft-encountered nucleophiles in pharmaceutical chemistry, amines. Strain-release amination can diversify a range of substrates with a multitude of desirable bioisosteres at both the early and late stages of a synthesis. The technique has also been applied to peptide labeling and bioconjugation.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
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, CA 92037, USA.
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, CA 92037, USA.
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, CA 92037, USA.
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, CA 92037, USA.
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, CA 92037, USA.
authors.forename: Liher
authors.initials: L
authors.lastname: Prieto
authors.affiliation: Chemical Research and Development, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA.
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, CA 92121, USA.
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, CA 92121, USA.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Gallego
authors.affiliation: Department of Chemistry, La Jolla Laboratories, Pfizer Inc., 10770 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Neal W
authors.initials: NW
authors.lastname: Sach
authors.affiliation: Department of Chemistry, La Jolla Laboratories, Pfizer Inc., 10770 Science Center Drive, San Diego, CA 92121, USA.
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, CA 92121, USA.
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, CA 92121, USA.
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, CA 92037, USA. pbaran@scripps.edu.
authors.forename: Phil S
authors.initials: PS
authors.lastname: Baran
mesh_terms: D000586:Amination; D060326:Chemistry Techniques, Synthetic; D002626:Chemistry, Pharmaceutical; D010455:Peptides / Q000138:chemical synthesis*; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis*
chemical_list: D010455:Peptides; D004364:Pharmaceutical Preparations
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