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 [*] Dr.