Enantioselective Copper-Catalysed Allylic Alkylation of Cinnamyl Chlorides by Grignard Reagents using Chiral Phosphine-Phosphite Ligands

The copper( I)-catalysed S(N)2'-type allylic substitution of E-3-aryl-allyl chlorides (cinnamyl chlorides) using Grignard reagents represents a powerful method for the synthesis ol compounds carrying a benzylic stereocentre. By screening a small library of modular chiral phosphine-phosphite ligands a new copper(I)-based catalyst system was identified which allows the performance of such reactions with exceptional high degrees of regio- and enantioselectivity. Best results were obtained using TADDOL-derived hgands (3 mol%), copper(I) bromide.di-methyl sulfide ((CuBrSMe2)-S-center dot) (2 5 mol%) and methyl tert-butyl ether (MTBE) as a solvent. Various (1-alkyl-allyl)benzene derivatives were prepared with up to 99% ee (GC) in isolated yields of up to 99% In most cases the product contained less than 3% of the linear regizioisomer (except for ortho-substituted substrates). Both electron-rich and electron-deficient cinnamyl chlorides were successfully employed The absolute configuration of the products was assigned by comparison of experimental and calculated CD spectra. The substrates were prepared from the corresponding alcohols by reaction with thionyl chloride. Initially formed mixtures of regioisomeric allyllc chlorides were homogenised by treatment with CuBr SMe2 (2.5 mol%) in the presence of triphenyl phosphine (PPh3) (3 mol%) in MTBE at low temperature to give the pure linear isomers In reactions with methylmagnesium bromide (MeMgBr) an ortho-chphenylphosphanyl-arylphosphite ligand with an additional phenyl substituent in ortho'-position at the aryl backbone proved to be superior. In contrast, best results were obtained in the case of higher alkyl Grignard reagents (such as ethyl-, n-butyl-, isopropyl-. and 3-butenylmagnesium bromides) with a related ligand carrying an isopropyl substituent in ortho'-position. The method was tested on a multimmol scale and is suited for application in natural product synthesis.