Part A. Rhodium chemzymes: Michaelis-Menten kinetics in dirhodium (II) carboxylate-catalyzed carbenoid reactions; Part B. Solution-phase high-throughput synthesis of an illudin analogue library

The concept of chemzyme has been put forward by Corey in describing oxazaborolidine catalysts. Since then, a number of chemzyme examples have been studied. Rhodium (II)-catalyzed decomposition of diazocompounds has been widely used in organic synthesis and many studies have been focused on its applicability in chemical and stereo selectivity. It is believed that the intermediates in these reactions are rhodium carbenoids. Our lab first carried out a preliminary study (Pirrung, M. C.; Morehead, A. T. J. Am. Chem. Soc. 1996, 118, 8162–3) demonstrating that the kinetics of the decomposition of diazo carbonyl compounds obeys the classic Michaelis-Menten equation-saturation kinetics. In this study, we systematically studied how the structures of rhodium catalysts, the local environment of the diazocompounds, and the reaction media (solvents and added inhibitors) affect the two key parameters of saturation kinetics, K_m and k_cat. From these parameters, we analyzed the factors that affect the two key steps in these carbenoid transformations, which are the association of the diazocompound to the rhodium catalyst to form a complex and the breakdown of this complex to give the rhodium carbenoid. Interestingly, the possibility of the involvement of the backbonding from the rhodium to the carbenic carbon was discussed based on a series of inhibitor studies.; Although the total synthesis of natural products has achieved great success, much less efforts have been endeavored in the combinatorial synthesis of natural products. We successfully constructed an illudin analogue library in a high-throughput manner. The illudin family has been found to include potentially useful antitumor agents, however, their extreme toxicity has resulted in a low therapeutic index. We adopted the Kinder-Padwa synthesis of illudin M that features a rhodium-mediated carbonyl ylide cycloaddition in our library synthesis. Our modular synthesis of the library enabled us to introduce the chemical diversity during the building block preparation stage. The carbonyl ylide cycloaddition has been optimized to best suit the needs of high-throughput synthesis and a thiophenol resin was utilized in the efficient removal of the excess enones in the reaction. This solution-phase high-throughput synthesis has rendered a 7 x 7 x 1 library containing 119 compounds including stereoisomers.