Catalysis of an S2 pathway by geometric preorganization.

Bimolecular nucleophilic substitution (S2) mechanisms occupy a central place in the historical development and teaching of the field of organic chemistry. Despite the importance of S2 pathways in synthesis, catalytic control of ionic S2 pathways is rare and notably uncommon even in biocatalysis, reflecting the fact that any electrostatic interaction between a catalyst and the reacting ion pair necessarily stabilizes its charge and, by extension, reduces polar reactivity. Nucleophilic halogenase enzymes navigate this tradeoff by desolvating and positioning the halide nucleophile precisely on the S2 trajectory, using geometric preorganization to compensate for the attenuation of nucleophilicity. Here we show that a small-molecule (646 Da) hydrogen-bond-donor catalyst accelerates the S2 step of an enantioselective Michaelis-Arbuzov reaction by recapitulating the geometric preorganization principle used by enzymes. Mechanistic and computational investigations show that the hydrogen-bond donor diminishes the reactivity of the chloride nucleophile yet accelerates the rate-determining dealkylation step by reorganizing both the phosphonium cation and the chloride anion into a geometry that is primed to enter the S2 transition state. This new enantioselective Arbuzov reaction affords highly enantioselective access to an array of H-phosphinates, which are in turn versatile P-stereogenic building blocks amenable to myriad derivatizations. This work constitutes, to our knowledge, the first demonstration of catalytic enantiocontrol of the phosphonium dealkylation step, establishing a new platform for the synthesis of P-stereogenic compounds.