Asymmetric Dual-Catalytic Cascade by Chiral N‑Heterocyclic Carbene and Quinuclidine: Mechanism and Origin of Enantioselectivity in Benzofuranone Formation

• Published in: ACS catalysis Vol. 5; no. 3; pp. 1596 - 1603
• Main Authors: Reddi, Yernaidu, Sunoj, Raghavan B
• Format: Journal Article
• Language: English
• Published: American Chemical Society 06.03.2015
• Subjects: reaction mechanism; Stetter reaction; asymmetric catalysis; transition state; dual catalysis; noncovalent interactions; N-heterocyclic carbenes
• ISSN: 2155-5435; 2155-5435
• DOI: 10.1021/cs502006x

Contemporary literature offers a number of interesting examples for asymmetric multicatalytic reactions using chiral N-heterocyclic carbenes (NHCs) in conjunction with other catalysts. One of the very recent examples demonstrated a convenient strategy toward realizing chiral benzofuranones from salicylaldehyde and dimethyl acetylenedicarboxylate (DMAD). In this article, we report the mechanism and insights on the origin of asymmetric induction as obtained through a comprehensive density functional theory (M06-2X and mPW1K) investigation. Different likely catalyst–substrate combinations as well as the timing/sequence of activation of different substrates are carefully examined so as to identify the most preferred pathway. In the lowest energy path, the activation of DMAD by quinuclidine occurs first; the resulting zwitterionic intermediate then undergoes a Michael addition with a salicylate ion to yield a salicylate–DMAD adduct, which, in turn, is intercepted by the chiral NHC. In the next crucial step, an enantioselective C–C bond formation via an intramolecular Stetter reaction furnishes the benzofuranone framework bearing a chiral carbon atom. Two transition state models, with and without an explicitly bound catechol (an additive employed in the reaction that resulted in enhanced enantioselectivity), are considered. A distinct energetic advantage, of the order of 3.4 kcal/mol, for the addition of the re face of the Breslow intermediate (derived from the chiral NHC and the salicylate–DMAD adduct) to the re face of the dimethyl maleate moiety is noticed in the stereocontrolling C–C bond formation step. The Gibbs free energy difference between the diastereomeric transition states for (re,re) and (re,si) modes of addition is traced to the differential nonbonding interactions (O–H···π, lone pair (lp)···π, and C–H···O). The predicted enantioselectivity is in good agreement with the experimental observations.