Catalyst–Substrate Pairings for Carbocyclic and Heterocyclic Systems in Atroposelective Quinazolinone Synthesis

Asymmetric catalytic reaction development depends critically on the matching of an appropriate catalytic scaffold with a substrate of interest. In many cases, a catalyst will be discovered to be quite selective for a given substrate, and that same catalyst is then evaluated for its scope with respect to alterations of the substrate. In the context of a catalytic atroposelective cyclocondensation, we discovered that a chiral phosphoric acid catalyst (CPA), (<i>R</i>)-TCYP, mediated these processes with up to 98:2 enantiomeric ratio (er) and in 95% yield. Yet, when the same reaction was attempted in the presence of a basic nitrogen heteroatom within the substrate, enantioselectivity was significantly reduced (73:27 er). In these instances, a different catalyst scaffold based on phosphothreonine (pThr), while ineffective for the carbocyclic substrate (53:47 er), was found to be quite selective (90:10 er) for its pyridyl analog. Mechanistic studies exploring this divergence in reactivity unveiled that the 8-carbocyclic substrate (using (<i>R</i>)-TCYP) displayed a positive nonlinear effect (NLE), whereas the 8-heterocyclic substrate (using a pThr-based catalyst) displayed no NLE at all. The mechanistic distinctions between these two scenarios suggest significant differences in the nature of the noncovalent interactions that operate to deliver high enantioselectivity.