Regio- and Diastereoselective and Enantiospecific Metal-Free C(sp(3) )-H Arylation: Facile Access to Optically Active 5-Aryl 2,5-Disubstituted Pyrrolidines.

Abstract

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 sp(3) 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(≠) G=25.6 kcal mol(-1) .

• Authors: Surajit Haldar, Subhra Kanti Roy, Bholanath Maity, Debasis Koley, Chandan K Jana
• Journal: Chemistry (Weinheim an der Bergstrasse, Germany) (Chemistry) Vol. 21 Issue 43 Pg. 15290-8 (Oct 19 2015) ISSN: 1521-3765 [Electronic] Germany
• PMID: 26471443 (Publication Type: Journal Article)
• Copyright: © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.