title: The effect of additives on the zinc carbenoid-mediated cyclopropanation of a dihydropyrrole.
abstract: The synthesis of a key intermediate in the preparation of oral antidiabetic drug Saxagliptin is discussed with an emphasis on the challenges posed by the cyclopropanation of a dihydropyrrole. Kinetic studies on the cyclopropanation show an induction period that is consistent with a change in the structure of the carbenoid reagent during the course of the reaction. This mechanistic transition is associated with an underlying Schlenk equilibrium that favors the formation of monoalkylzinc carbenoid IZnCH2I relative to dialkylzinc carbenoid Zn(CH2I)2, which is responsible for the initiation of the cyclopropanation. The factors influencing reaction rates and diastereoselectivities are discussed with the aid of DFT computational studies. The rate accelerations observed in the presence of Brønsted acid-type additives correlate with the minimization of the undesired induction period and offer insights for the development of a robust process.
authors.affiliation: Chemical Development, Bristol-Myers Squibb Company , One Squibb Drive, New Brunswick, New Jersey 0890, United States.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ramirez
authors.forename: Vu Chi
authors.initials: VC
authors.lastname: Truc
authors.forename: Michael
authors.initials: M
authors.lastname: Lawler
authors.forename: Yun K
authors.initials: YK
authors.lastname: Ye
authors.forename: Jianji
authors.initials: J
authors.lastname: Wang
authors.forename: Chenchi
authors.initials: C
authors.lastname: Wang
authors.forename: Steven
authors.initials: S
authors.lastname: Chen
authors.forename: Thomas
authors.initials: T
authors.lastname: Laporte
authors.forename: Nian
authors.initials: N
authors.lastname: Liu
authors.forename: Sergei
authors.initials: S
authors.lastname: Kolotuchin
authors.forename: Scott
authors.initials: S
authors.lastname: Jones
authors.forename: Shailendra
authors.initials: S
authors.lastname: Bordawekar
authors.forename: Srinivas
authors.initials: S
authors.lastname: Tummala
authors.forename: Robert E
authors.initials: RE
authors.lastname: Waltermire
authors.forename: David
authors.initials: D
authors.lastname: Kronenthal
mesh_terms: D003500:Cyclization; D003521:Cyclopropanes / Q000737:chemistry*; D007700:Kinetics; D011758:Pyrroles / Q000737:chemistry*; D011789:Quantum Theory; D013237:Stereoisomerism; D015032:Zinc / Q000737:chemistry*
chemical_list: D003521:Cyclopropanes; D011758:Pyrroles; D015032:Zinc