Catalyst–Substrate Pairings for Carbocyclic and Heterocyclic Systems in Atroposelective Quinazolinone Synthesis
Year: 2024
Type: article
Abstract: 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 (CPA) catalyst, ( R )-TCYP, mediated these processes with up to 98:2 enantiomeric ratio (er) and up to 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 this instance, 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 ( R )-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 non-covalent interactions that operate to deliver high enantioselectivity.
Source: ACS Catalysis
Authors: Melody C. Guo, Scott J. Miller
Institution: Yale University
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W4404132148