Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity

• Published in: Journal of the American Chemical Society Vol. 139; no. 8; pp. 3209 - 3226
• Main Authors: Lopchuk, Justin M, Fjelbye, Kasper, Kawamata, Yu, Malins, Lara R, Pan, Chung-Mao, Gianatassio, Ryan, Wang, Jie, Prieto, Liher, Bradow, James, Brandt, Thomas A, Collins, Michael R, Elleraas, Jeff, Ewanicki, Jason, Farrell, William, Fadeyi, Olugbeminiyi O, Gallego, Gary M, Mousseau, James J, Oliver, Robert, Sach, Neal W, Smith, Jason K, Spangler, Jillian E, Zhu, Huichin, Zhu, Jinjiang, Baran, Phil S
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.03.2017; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; UNCATALYZED ALDOL ADDITIONS; CHEMICAL PROTEIN MODIFICATION; SMALL-RING PROPELLANES; NUCLEOPHILIC-SUBSTITUTION; AZETIDINE DERIVATIVES; EFFICIENT SYNTHESIS; FREE CLICK CHEMISTRY; TRIPLE REUPTAKE INHIBITORS; REDUCTIVE AMINATION; CONJUGATE ADDITION
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.6b13229

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.