ja1060966_si_003.cif (21.54 kB)

Synthesis of P-Stereogenic Compounds via Kinetic Deprotonation and Dynamic Thermodynamic Resolution of Phosphine Sulfides: Opposite Sense of Induction Using (−)-Sparteine

Download (21.54 kB)
posted on 06.10.2010, 00:00 by Jonathan J. Gammon, Viktoria H. Gessner, Greg R. Barker, Johan Granander, Adrian C. Whitwood, Carsten Strohmann, Peter O’Brien, Brian Kelly
A systematic study of the asymmetric deprotonation of a dimethyl-substituted phosphine sulfide using organolithium bases in the presence of (−)-sparteine has been carried out. Use of nBuLi and (−)-sparteine in Et2O at −78 °C gave trapped adducts in ∼88:12 er via a kinetically controlled process that was successfully predicted using a computational approach at the B3LYP/6-31+G(d) level. This initial kinetic enantioselectivity could be enhanced up to 97:3 er by trapping the lithiated intermediate with a prochiral electrophile (e.g., pivaldehyde or tBuPCl2). In addition, it was found that the RP and SP stereoisomers of the lithiated methylphosphine sulfide could interconvert at temperatures above 0 °C. Such interconversion is unprecedented and differs from the configurational instability of organolithiums that are stereogenic at a lithiated carbon atom. The major, thermodynamically preferred diastereomeric (−)-sparteine-complexed lithated phosphine sulfide was investigated by X-ray crystallography and computational methods at the B3LYP/6-31+G(d) level. Through the interconversion of the RP and SP stereoisomers of the lithiated methylphosphine sulfide, a novel dynamic thermodynamic resolution of a racemic lithiated phosphine sulfide has been developed. Thus, the phosphine sulfide was lithiated with nBuLi, and then (−)-sparteine was added. After equilibration at 0 °C for 3 h, electrophilic trapping generated an adduct in 81:19 er with the configuration opposite to that obtained under kinetic control. Thus, the methodology provides access to P-stereogenic compounds with the opposite sense of induction using (−)-sparteine as the ligand simply by changing the reaction conditions (kinetic or thermodynamic control).