Palladium-catalyzed asymmetric trimethylenemethane cycloaddition [electronic resource] : development and application to the synthesis of highly substituted carbocycles and heterocycles

The development of new methods for chemical synthesis is motivated by the desire to add efficient chemo-, regio-, diastereo-, and enantioselective reactions to the repository of transformations available to researchers. In addition to reaction development, a primary goal of methodology research is to fundamentally understand chemical reactivity. This understanding provides the impetus for further discovery, inevitably allowing for the rapid synthesis of complex molecules as well as the development of industrially feasible processes. The research described herein discusses method development and seeks to place it within this context. Cycloaddition reactions have been widely used in organic synthesis since initial accounts of the Diels-Alder reaction were reported over 80 years ago. These reactions can proceed by either stepwise or concerted processes, can be thermally or photochemically initiated, metal catalyzed or non-metal catalyzed, but one unifying feature of this reaction class is the ability to quickly assemble a complex molecular architecture. A method for the synthesis of cyclopentane rings was disclosed by the Trost group in 1979 through the controlled generation of trimethylenemethane (TMM), a three-carbon dipole capable of participating in a palladium-catalyzed stepwise cycloaddition. Over the ensuing 20 years, this procedure was expanded to other five-membered rings, including pyrrolidines and tetrahydrofurans. It was generalized to include [4+3] and [6+3] cycloadditions in addition to the initial [3+2] reaction. However, only minimal advances were made in the establishment of a catalytic, asymmetric variant of the reaction, which would have enormous value in that chiral variants of the above molecules could be prepared. A protocol for the enantioselective TMM reaction was developed and is described herein. The synthesis of novel phosphoramidite ligands was critical in this effort, and the preparation and reactivity of these ligands is detailed. The evolution of the ligand design, commencing with acyclic amine-derived phosphoramidites and leading to cyclic azetidine and pyrrolidine structures is discussed. The initial conditions used to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of alkene acceptors, providing the desired cyclopentanes with high levels of enantioselectivity. The donor scope was also explored and various substituted systems were tolerated, including one bearing a nitrile moiety and a one bearing a propiolate function. These were reactive with unsaturated acylpyrroles, giving the product cyclopentane rings bearing three stereocenters in high enantioselectivity and complete diastereoselectivity. The nitrile donor was reactive with methyleneoxindoles, providing products containing up to three adjacent stereocenters, two being all-carbon quaternary. Furthermore, ligand controlled diastereoselection was seen. The methodology was further applied to the synthesis of heterocycles. The parent donor successfully reacted with N-aryl and N-Boc imines. A nitrile donor was found to react with a series of N-Tosyl imines, giving the pyrrolidines in high yield. Multiple regioisomers were formed and reaction conditions were developed to favor each product. In the case of N-Tosyl ketimines, the desired cycloadducts containing tetrasubstituted centers were prepared with nearly complete enantio- and diastereoselectivity. The protecting group could be removed to afford a synthetically versatile compound with several handles for further elaboration. Conditions were also developed to perform an enantioselective TMM reaction with aldehydes, giving the desired tetrahydrofurans in moderate to good enantioselectivity. Finally, an asymmetric [4+3] cycloaddition utilizing ortho-quinone methides was successfully performed in an effort to prepare oxepanes. Taken collectively, these results demonstrate that the palladium-phosphoramidite catalyst system represents a versatile method for the rapid assembly of complex molecular architectures from simple starting materials via cycloaddition.

Keywords: Chemistry
Advisor: Trost Barry M. primary advisor. Thesis advisor
Huestis Wray advisor. Thesis advisor
Kool Eric T. advisor. Thesis advisor