Transition State Models for Understanding the Origin of Chiral Induction in Asymmetric Catalysis.

Abstract

In asymmetric catalysis, a chiral catalyst bearing chiral center(s) is employed to impart chirality to developing stereogenic center(s). A rich and diverse set of chiral catalysts is now available in the repertoire of synthetic organic chemistry. The most recent trends point to the emergence of axially chiral catalysts based on binaphthyl motifs, in particular, BINOL-derived phosphoric acids and phosphoramidites. More fascinating ideas took shape in the form of cooperative multicatalysis wherein organo- and transition-metal catalysts are made to work in concert. At the heart of all such manifestations of asymmetric catalysis, classical or contemporary, is the stereodetermining transition state, which holds a perennial control over the stereochemical outcome of the catalytic process. Delving one step deeper, one would find that the origin of the stereoselectivity is delicately dependent on the relative stabilization of one transition state, responsible for the formation of the predominant stereoisomer, over the other transition state for the minor stereoisomer. The most frequently used working hypothesis to rationalize the experimentally observed stereoselectivity places an undue emphasis on steric factors and tends to regard the same as the origin of facial discrimination between the prochiral faces of the reacting partners. In light of the increasing number of asymmetric catalysts that rely on hydrogen bonding as well as other weak non-covalent interactions, it is important to take cognizance of the involvement of such interactions in the sterocontrolling transition states. Modern density functional theories offer a pragmatic and effective way to capture non-covalent interactions in transition states. Aided by the availability of such improved computational tools, it is quite timely that the molecular origin of stereoselectivity is subjected to more intelligible analysis. In this Account, we describe interesting molecular insights into the stereocontrolling transition states of five reaction types, three of which provide access to chiral quaternary carbon atoms. While each reaction has its own utility and interest, the focus of our research has been on the mechanism and the origin of the enantio- and diastereoselectivity. In all of the examples, such as asymmetric diamination, sulfoxidation, allylation, and Wacker-type ring expansion, the role played by non-covalent interactions in the stereocontrolling transition states has been identified as crucial. The transfer of the chiral information from the chiral catalyst to the product is identified as taking place through a series of non-covalent interactions between the catalyst and a given position/orientation of the substrate in the chiral environment offered by the axially chiral catalyst. The molecular insights enunciated herein allude to abundant opportunities for rational modifications of the present generation of catalysts and the choice of substrates in these as well as related families of reactions. It is our intent to propose that the domain of asymmetric catalysis could enjoy additional benefits by having knowledge of the vital stereoelectronic interactions in the stereocontrolling transition states.