Enantioselective, Palladium-Catalyzed α-Arylation of N -Boc Pyrrolidine: In Situ React IR Spectroscopic Monitoring, Scope, and Synthetic Applications

Department of Chemistry, University of York, Heslington, York YO10 5DD, UK.
The Journal of Organic Chemistry (Impact Factor: 4.72). 06/2011; 76(15):5936-53. DOI: 10.1021/jo2011347
Source: PubMed


A comprehensive study of the enantioselective Pd-catalyzed α-arylation of N-Boc pyrrolidine has been carried out. The protocol involves deprotonation of N-Boc pyrrolidine using s-BuLi/(-)-sparteine in TBME or Et(2)O at -78 °C, transmetalation with ZnCl(2) and Negishi coupling using Pd(OAc)(2), t-Bu(3)P-HBF(4) and the aryl bromide. This paper reports several new features including in situ React IR spectroscopic monitoring of the process; use of (-)-sparteine and the (+)-sparteine surrogate to access products with opposite configuration; development of a catalytic asymmetric lithiation-Negishi coupling reaction; extension to a wide range of heteroaromatic bromides; total synthesis of (R)-crispine A, (S)-nicotine and (S)-SIB-1508Y via short synthetic routes; and examples of α-vinylation of N-Boc pyrrolidine using vinyl bromides exemplified by the total synthesis of naturally occurring (+)-maackiamine (thus establishing its configuration as (R)). In this way, the full scope and limitations of the methodology are delineated.

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