Chemistry - A European Journal p. 15290 - 15298 (2015)
Update date:2022-08-17
Topics:
Haldar, Surajit
Roy, Subhra Kanti
Maity, Bholanath
Koley, Debasis
Jana, Chandan K.
Optically active 5-aryl 2,5-disubstituted pyrrolidines are the principal structural moiety of many bioactive compounds including natural products and catalysts for asymmetric synthesis. A highly regio- and diastereoselective and enantiospecific method for direct C-H arylation of aliphatic amine has been developed. Structurally diverse enantiopure arylated pyrrolidines were synthesized from commercially available starting materials, through a single-step three-component reaction under metal- and oxidant-free conditions. Furthermore, the complex analogous structure of CCK antagonist RP 66803 and angiotensin-converting enzyme inhibitors was easily constructed using the synthesized arylated pyrrolidine derivative. Detailed theoretical calculations (M06-2X/TZVPP/SMD//M06-2X/6-31+G(d,p) level) were also carried to investigate the mechanism and high level of stereocontrol involved in this direct sp3 C-H arylation reaction. Preference for a given regio- and stereoselectivity in the arylated product can be explained through elucidation of the mechanism for dehydration, generating azomethine ylide, and for the final re-aromatization step. The calculated energies reveals that the re-aromatization step is essentially rate determining, accompanying an activation barrier of Δ≠GSL=25.6 kcal mol-1. On arylated note: A novel, regio- and diastereoselective and enantiospecific direct C-H arylation reaction has been developed whereby enantiopure arylated pyrrolidines are synthesized in a single operation under metal- and oxidant-free conditions, starting from commercially available materials. The mechanistic pathway that results in high stereoselectivity is studied by using DFT.
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