Computer-aided design of chiral ligands. part 2. Functionality mapping as a method to identify stereocontrol elements for asymmetric reactions

A computational method to determine the energetically favorable positions of functional groups with respect to the transition states of stereoselective reactions based on force field energy minimization is presented. The parameters of this functionality mapping, the characteristics of the target transition states, and the features of the probe structures are outlined. Our method was found to reproduce the positions of the stereodiscriminating fragments for some known chiral ligands including the Masamune dimethylborolane, dimenthylborane, the Corey stien reagent, the Roush allylboronate tartrates, and the secondary amine Diels-Alder catalysts described by MacMillan. Functionality mapping can be used to better understand the specific interactions in the transition states leading to the products by providing a quantitative measure of the stabilization/destabilization afforded by the different ligand components via nonbonded interactions. The method can determine if a chiral ligand imparts the observed selectivity by stabilizing one reaction pathway, by destabilizing a reaction pathway, or by a combination of both. Orientational as well as positional information about potential functional groups is readily obtained. In addition to its utility as an analytical tool, functionality mapping can be used to explore starting points for the design of new chiral ligands.