Catalytic Enantioselective Addition of Aryl, Heteroaryl, and Alkenyl Halides to Aliphatic Aldehydes

Cobalt complexes of chiral Josiphos catalyzed enantioselective addition of aryl, heteroaryl, and alkenyl halides to a wide range of linear and branched aliphatic aldehydes, without using directing groups. The new method was easily scalable with low loadings of cobalt catalysts, and its synthetic utility was demonstrated in concise synthesis of chiral carbinols that are key motifs of drugs or synthetic precursors. The cobalt catalyst also provided high diastereoselectivity in the addition of chiral amino aldehydes. Mechanistic studies suggest cationic complexes of aryl-cobalt(II) act as active species for asymmetric insertion. Lewis acidic titanium alkoxides assist ionization of aryl-cobalt halides to form cationic complexes. The lowest-energy transition states for insertion are stabilized by π-π stacking between the migrating aryl ring and P-phenyl ring of Josiphos.