Most bioactive chemicals are chiral, including pharmaceuticals in development and those currently being prescribed. Process chemists have only recently begun to regularly incorporate asymmetric catalytic reactions into pharmaceutical process design. Asymmetric organocatalytic reactions have the potential to provide safer, more cost-effective, and environmentally benign routes to pharmaceuticals. However, enabling the application of asymmetric organocatalytic reactions to industrial pharmaceutical processes is a challenging task. Without a reasonable mechanistic picture of how a particular asymmetric conversion is achieved, it is difficult to predict how such a reaction will behave when scaled up to production or applied to the synthesis of lead compound analogs. Most asymmetric catalytic conversions are poorly understood. Few asymmetric catalytic procedures are considered reliable enough for pharmaceutical production. The dearth of mechanistic information pertinent to these reactions is largely the result of improper mechanistic tools. The project proposed here leverages several mechanistic tools developed in our laboratory to understand, at a very detailed and quantitative level, how asymmetric organocatalytic reactions work. Specifically, the work proposed here aims to understand asymmetric organocatalytic aldol reactions. In general, aldol reactions are effective reactions in key steps of proposed pharmaceutical syntheses. A key example of the effectiveness of aldol reactions is their prominent use in the synthesis of epothilones, a general class of anticancer therapeutics that are currently in clinical testing. Examples of promising drug candidates in this class are: Patupilone, KOS-862, ZK-EPO, BMS-310705, and KOS-1584. Asymmetric organocatalytic aldol reactions have many reaction steps. The most important steps in these reactions are the rate-determining step and the product-determining step. The former determines how rapidly the reaction proceeds, while the latter determines how effective the reaction is at inducing asymmetry in the desired product. The key to understanding a given reaction step is knowing the transition structure. Kinetic isotope effects (KIEs) are perhaps the most direct and practical method for developing models of the transition structure. However, current KIE methodologies are insensitive to the symmetry breaking event that is inherent in asymmetric reactions. We have developed 2H and 13C KIE methodologies that utilize molecular symmetry to probe asymmetric transition structures for both the rate- and product- determining steps. Our preliminary data suggest that, for the most well-known variant of the asymmetric organocatalytic aldol reaction, the rate- and product-determining steps are different. If these findings are validated, they will radically change our current picture of this class of reactions and provide crucial information that will be essential to the development of better organocatalysts.
Improved asymmetric organocatalysts could reduce the costs of both pharmaceutical discovery and production, thus making new and existing treatments more cost effective and, therefore, accessible. Before existing catalysts can be improved upon in a rational and systematic fashion, the mechanisms of these chemical reactions must be understood. The studies described in this proposal leverage new mechanistic methodologies developed in our laboratory to unravel the mechanisms of an important subclass of asymmetric organocatalytic reactions.
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