Reactivity and Enantioselectivity in NHC Organocatalysis Provide Evidence for the Complex Role of Modifications at the Secondary Sphere.

Secondary-sphere interactions are often harnessed to control reactivity and selectivity in organometallic and enzymatic catalysis. Yet, such strategies have only recently been explicitly applied in the context of organocatalytic systems. Although increased stability, reproducibility, and selectivity were obtained in previous work using this approach, the precise mechanistic pathway promoted by secondary-sphere modification in organocatalysis remained unclear. Herein, we report a comprehensive mechanistic study on the origin of the unique reactivity patterns and stereocontrol observed with boronic acids (BAs) as secondary-sphere modifiers of N-heterocyclic carbene (NHC) organocatalysts. Kinetic experiments revealed partial order in catalyst upon the addition of BA and unusual preactivation behavior, indicating the presence of stable off-cycle catalyst aggregation and BA-base adducts. These hypotheses were supported both by computations and by a series of NMR and nonlinear effect experiments. Furthermore, computations indicated a rate-limiting, water-assisted hydrogen atom transfer mechanism. This finding led to a considerable enhancement in the experimental reaction rate while maintaining excellent enantioselectivity by adding catalytic amounts of water. Finally, computations and racemization experiments uncovered an uncommon Curtin-Hammett-controlled enantioselectivity in the presence of secondary-sphere modifiers.

Metal-Free Multicomponent Strategy for Amidine Synthesis.

Amidines are a ubiquitous class of bioactive compounds found in a wide variety of natural products; thus, efficient strategies for their preparation are in great demand. Specifically, their common structural core decorated with three substituents sets amidines as perfect candidates for multicomponent synthesis. Herein, we present a highly modular metal-free multicomponent strategy for the synthesis of sulfonyl amidines. This work was focused on selecting readily accessible reagents to facilitate the in situ formation of enamines by the addition of amines to ketones. These components were coupled with azides to provide a broad reaction scope with respect to all three coupling partners. Aromatic and aliphatic amines and ketones were tolerated under our reaction conditions. Likewise, the presence of a methyl group on the ketone was critical to reactivity, which was leveraged for the design of a highly regioselective reaction with aliphatic ketones. A biologically active compound was successfully synthesized in one step, demonstrating the practical utility of our methodology. Finally, the postulated mechanism was investigated and supported both experimentally and by means of a multivariate statistical model.

Unravelling mechanistic features of organocatalysis with in situ modifications at the secondary sphere.

Secondary-sphere interactions serve a fundamental role in controlling the reactivity and selectivity of organometallic and enzymatic catalysts. However, there is a dearth of studies that explicitly incorporate secondary-sphere modifiers into organocatalytic systems. In this work, we introduce an approach for the in situ systematic modification of organocatalysts in their secondary sphere through dynamic covalent binding under the reaction conditions. As a proof-of-concept, we applied boronic acids as secondary-sphere modifiers of N-heterocyclic carbenes that contained a hydroxy handle. The bound system formed in the reaction mixture catalysed the enantioselective benzoin condensations of a challenging substrate class that contains electron-withdrawing groups. Linear regression coupled with data visualization served to pinpoint the divergent origins of enantioselectivity for different substrates and decision tree algorithms served to formulate selection criteria for the appropriate secondary-sphere modifiers. The combination of this highly modular catalytic approach with machine-learning techniques provided mechanistic insights and guided the streamlined optimization process of a gram-scale reaction at low organocatalyst loading.