This project focuses on the development of a semi-rational approach for discovery/invention of new catalytic reactions largely based upon catalysis by complexes of ruthenium. Transformations that previously were unknown or quite difficult not only may become feasible but will be performed with high atom economy. The use of two separate transition metal catalyzed reactions occurring in the presence of each other either concurrently or consecutively will also be examined. Thus, in one pot, combining up to four components can lead to important synthetic building blocks. The extraordinarily broad range of stable oxidation states of ruthenium may impart reactivity where it did previously exist. Use of allenes in place of alkynes in these reaction schemes opens the prospect of alkene/alkyne/aldehyde 3-component coupling cyclizations. Special attention will be paid to comparing and contrasting rhodium vs. ruthenium catalysis of [5+2] cycloadditions. Ruthenium promoted additions of nucleophiles to alkyne offer a number of significant outcomes, including the addition of water, offering a novel synthesis of ruthenium enolates. A new strategy involving a [3+2+1] multicomponent coupling to generate pyridines, an extremely important class of heterocycles found in many biologically important targets, will be examined. Catalytic redox isomerization will be developed as an atom economic way to adjust oxidation levels. Intercepting the intermediates in the process provides opportunities for rapid increase of molecular complexity by multicomponent coupling protocols.
With the support of this award from the Organic and Macromolecular Chemistry Program, Professor Barry Trost, of the Department of Chemistry at the Stanford University, is developing new methods to catalyze selective and efficient organic reactions. The need of increasingly complex organic molecules for a myriad of applications ranging from biology to material science heightens the need for increased sophistication in organic synthesis. Increasingly, it is no longer a question of whether a target can be synthesized, but rather how. Practical syntheses, whether total or partial, derive from the existence of the basic set of synthetic reactions. The limitations of that base set cripples our ability to broadly solve the problems of complex synthesis. The goal of this program is to enhance synthetic efficiency for the synthesis of complex molecules by increasing the basic set of synthetically useful reactions. Selectivity (chemo-, regio-, diastereo-, and enantio-) has been the prevailing issue to date. Limitations of raw materials and environmental concerns require attention to an equally important but frequently overlooked issue - atom economy, i.e., the development of reactions in which, to the greatest extent possible, any stoichiometric by-products are minimized and, in the ideal case, eliminated so that the product is the sum of the reactants with any additional reagent being required only catalytically.
