Catalyst–Substrate\nPairings for Carbocyclic\nand Heterocyclic Systems in Atroposelective Quinazolinone Synthesis

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