Force-modulated and strain-dependent stereoselectivity of copper-catalyzed reductive coupling

Force coupled to the dihedral angle of a macrocyclic biaryl bisphosphine ligand modulates the stereoselectivity of the copper-catalyzed reductive coupling of 2-vinyl pyridine with acetophenone to form 1-phenyl-2-(pyridin-2-yl)butan-2-ol (1) as a mixture of the (2S,3S)/(2R,3R) (1a) and (2R,3S)/(2S,3R) (1b) diastereomers. Across a ∼280 pN range of extension forces, the diastereomeric ratio (1a : 1b) decreases from 2.7 : 1 to 1.7 : 1 and the enantiomeric ratios of 1a and 1b decrease from 5.60 to 2.37 and 7.23 to 1.93, respectively. DFT calculations support a model for the observed force-dependent stereoselectivity of reductive coupling in which the competing transition states are differentially destabilized by the applied tensile force. The degree of destabilization corresponds to the magnitude of the nuclear motions along the coupled vector of applied force that occur on moving from the ground state to the transition state. The stereoselectivity of reductive coupling is likewise modulated in the bulk by compressing elastomeric polyacrylate gels containing crosslinked [(R)-Biphep]Cu active sites. The diastereomeric ratio (1a : 1b) decreases from 1.9 to 1.7 : 1 and the enantiomeric ratios of 1a and 1b decrease from 2.88 to 2.58 and 2.77 to 2.48, respectively, when the support is compressed by 50% in a single dimension. Stereoselectivity returns to basal levels when the polymer is relaxed. Control experiments employing polymers containing mechanically-decoupled [(R)-Biphep]Cu active sites support the mechanical origin of the strain dependent stereoselectivity of reductive coupling.