Chiral vinyl halide coupling reaction

A Pd(ll) catalyst system with an oxazoline ligand 44 has been described that allows the desymmetrization of meso-Z-alkyl-2-propargylcyclohexane-l,3-diols in an asymmetric cyclization-carbonylation reaction. The products which contain a chiral quaternary carbon were obtained in excellent yields with high ee s (Scheme 56) <2006T9988>. 7-Hydroxy terminal <2005JOC3099> and internal <2006TL2793> alkenes can be converted to tetrahydrofurans by Pd(0)-catalyzed carboetherification reactions combined with a coupling of aryl or vinyl halides. 

The transformation that has come to be known as the Heck reaction is broadly defined as the palladium(O)-mediated coupling of an aryl or vinyl halide or triflate with an alkene. The basic mechanism for the Heck reaction of aryl halides or trifiates (as outlined in more detail in the Key Chemistry), involves initial oxidative addition of the chiral palladium(O) catalyst to afford a a-arylpalladium(II) complex. Coordination of an alkene and subsequent carbon-carbon bond formation by syn insertion provide a a-alkylpalladium(II) intermediate, which readily undergoes P-hydride elimination to release the alkene product. Finally, the hydridopalladium(II) complex has to be converted into the active palladium(O) catalyst to complete the catalytic cycle. 

Cross coupling between an aryl halide and an activated alkyl halide, catalysed by the nickel system, is achieved by controlling the rate of addition of the alkyl halide to the reaction mixture. When the aryl halide is present in excess, it reacts preferentially with the Ni(o) intermediate whereas the Ni(l) intermediate reacts more rapidly with an activated alkyl halide. Thus continuous slow addition of the alkyl halide to the electrochemical cell already charged with the aryl halide ensures that the alkyl-aryl coupled compound becomes the major product. Activated alkyl halides include benzyl chloride, a-chloroketones, a-chloroesters and amides, a-chloro-nitriles and vinyl chlorides [202, 203, 204], Asymmetric induction during the coupling step occurs with over 90 % distereomeric excess from reactions with amides such as 62, derived from enantiomerically pure (-)-ephedrine, even when 62 is a mixture of diastereoisomcrs prepared from a racemic a-chloroacid. Metiha-nolysis of the amide product affords the chiral ester 63 and chiral ephedrine is recoverable [205]. 

Organozincs generated under similar conditions have been shown to add to optically active vinyl phosphine oxides with retention of configuration at phosphorus [63] (Scheme 8). In this case a 1 1 zinc/copper couple was employed to activate the zinc. The one-pot reaction proceeded best with tertiary or secondary alkyl halides. The resulting phosphine oxides are used as chiral ligands for catalysts in asymmetric synthesis and were previously only available by reaction with the analogous cuprate [147] since conjugate addition of simple alkyl halides normally results in polymerisation. 

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