A Priori Theoretical Prediction of Selectivity in Asymmetric Catalysis: Design of Chiral Catalysts by Using Quantum Molecular Interaction Fields

Abstract

Much effort has been devoted toward the development of asymmetric catalysts for the synthesis of chiral compounds in pure form.[1] Despite this body of work, the science of asymmetric catalysis remains far from exact, and the process of finding a new catalyst usually requires a large investment of manpower and funding. Therefore, a major goal is the development of more efficient methods for identifying highly selective asymmetric catalysts. In terms of computational methods, the calculation of ground state and transition state energies [2] for metal catalysts is promising.[3] Even so, a detailed knowledge of the reaction mechanism is needed, and many variables must be evaluated requiring extensive time, effort, and resources. This communication illustrates the first example of rapid quantitative structure-selectivity relationship (QSSR) calculations being used to predict the enantioselectivities of new chiral catalysts. Subsequent synthesis and assessment of the new chiral catalysts in the asymmetric addition of Et 2 Zn to benzaldehyde (Scheme 1) revealed that the QSSR calculations forecast the experimental results with a high degree of fidelity.In a prior report [4] we determined that grid-based QSSR methods [5] derived from quantum mechanical molecular interaction fields can be used to generate statistically valid models that correlate enantioselectivities in the addition of Et 2 Zn to PhCHO with catalyst geometries obtained from transition structures. The true test of this method lies in predicting the selectivity of catalysts with ligands that have not been tested and for which the experimental results cannot be easily anticipated based on previous results. To this end, we designed P1, a cyclohexane with trans amino and hydroxy

Direct Asymmetric Amination of α-Branched Cyclic Ketones Catalyzed by a Chiral Phosphoric Acid

“…2 Additionally, β -amino alcohols, which are derivatives of α -amino cyclic ketones, are widely used as chiral ligands in asymmetric catalysis. 3 The past decade has witnessed the development of direct asymmetric α -amination of carbonyl compounds as a useful method for the preparation of chiral amine-containing structures. 4 Despite these advances, the majority of reported reactions rely on activated carbonyl compounds, such as 1,3-dicarbonyls, 2-oxindoles, α -cyanoacetates, and other reactive substrates.…”

A mathematical expression for the enantioselectivity and thermodynamic factors in the conformational equilibrium of catalysts in the addition of diethylzinc to benzaldehyde

“…The replacement of the axial Ha with a larger phenyl substituent results in a further increase in enantioselectivity from 59% ee to 94% ee (ligand 10 vs 14b). 15 Likewise, another method for enhancing the diastereofacial selectivity of 11 is to substitute the axial hydrogen atom Hb in 11 with a bulky R 00 group, to give chiral catalyst 13. Indeed, experiments for the asymmetric addition of diethylzinc to benzaldehyde revealed that the chiral ligand 15 exhibits very high enantioselectivity (up to 98% ee).…”

An Index for Characterization of Natural and Non-Natural Amino Acids for Peptidomimetics

“…More importantly, computational screening methods strive to illustrate structural, dynamic, and binding information at an atomic level, making it necessary for the better understanding of sequence-structure-activity relationship and design principles for peptides mimetics. The QSAR is currently an important contributor to rational design of drugs, materials, catalysts, and proteins/peptides with desirable activities and functions [13]–[17]. The underlying hypothetical principle of QSAR models is to define mathematical relationships between a set of molecular descriptors and a given activity (chemical, physical, or biological activity) as an end point, to predict the activity of unknown ligands [18]–[29].…”