Noncovalent Interactions in Organocatalysis and the Prospect of Computational Catalyst Design

• Published in: Accounts of chemical research 2016-05, Vol.49 (5), p.1061-1069
• Main Authors: Wheeler, Steven E, Seguin, Trevor J, Guan, Yanfei, Doney, Analise C
• Format: Article
• Language: English
• ISSN: 0001-4842; 1520-4898
• DOI: 10.1021/acs.accounts.6b00096

Noncovalent interactions are ubiquitous in organic systems, and can play decisive roles in the outcome of asymmetric organocatalytic reactions. Their prevalence, combined with the often subtle line separating favorable dispersion interactions from unfavorable steric interactions, often complicates the identification of the particular noncovalent interactions responsible for stereoselectivity. Ultimately, the stereoselectivity of most organocatalytic reactions hinges on the balance of both favorable and unfavorable noncovalent interactions in the stereocontrolling transition state (TS). In this Account, we provide an overview of our attempts to understand the role of noncovalent interactions in organocatalyzed reactions and to develop new computational tools for organocatalyst design. Following a brief discussion of noncovalent interactions involving aromatic rings and the associated challenges capturing these effects computationally, we summarize two examples of chiral phosphoric acid catalyzed reactions in which noncovalent interactions play pivotal, although somewhat unexpected, roles. In the first, List’s catalytic asymmetric Fischer indole reaction, we show that both π-stacking and CH/π interactions of the substrate with the 3,3′-aryl groups of the catalyst impact the stability of the stereocontrolling TS. However, these noncovalent interactions oppose each other, with π-stacking interactions stabilizing the TS leading to one enantiomer and CH/π interactions preferentially stabilizing the competing TS. Ultimately, the CH/π interactions dominate and, when combined with hydrogen bonding interactions, lead to preferential formation of the observed product. In the second example, a series of phosphoric acid catalyzed asymmetric ring openings of meso-epoxides, we show that noncovalent interactions of the substrates with the 3,3′-aryl groups of the catalyst play only an indirect role in stereoselectivity. Instead, the stereoselectivity of these reactions are driven by the electrostatic stabilization of a fleeting partial positive charge in the SN2-like transition state by the chiral electrostatic environment of the phosphoric acid catalyst. Next, we describe our studies of bipyridine N-oxide and N,N′-dioxide catalyzed alkylation reactions. Based on several examples, we demonstrate that there are many potential arrangements of ligands around a hexacoordinate silicon in the stereocontrolling TS, and one must consider all of these in order to identify the lowes