Erik J. Alexanian , University of North Carolina (Chapel Hill)
The development of fundamentally new complexity-increasing reactions is a paramount goal of modern organic synthesis, as chemists strive to develop step-economical or "greener" syntheses of complex targets. Transition-metal-catalyzed cycloadditions of simple p-systems are examples of powerful synthetic transformations capable of directly constructing diverse cyclic structures from readily available starting materials. In particular, multicomponent [m+n+o]-type cycloadditions offer the potential for the rapid generation of molecular complexity through the formation of multiple s-bonds and sp3-hybridized stereocenters in a single reaction step. We have initiated the development of new classes of complexity-generating transition-metal-catalyzed [2+2+2] cycloadditions of easily accessible p-systems delivering complex carbocycles for applications in chemical synthesis.
Our studies have begun with the development of a rhodium-catalyzed [2+2+2] cycloaddition of ene-allenes with allene p-systems (Figure 1). This reaction delivers synthetically valuable carbocycles and constructs up to four contiguous stereogenic centers in a single step with high stereoselectivity. The trans-hydrindane framework readily accessed via this cycloaddition is a core structure in many bioactive small molecules, yet still presents a formidable synthetic challenge. Substitution of reaction p-components leads to a variety of bicyclic compounds, including structures containing all-carbon quaternary centers. Preliminary studies have also indicated the potential for a catalytic asymmetric variant of the ene-allene-allene [2+2+2]. The development of a general, highly enantioselective process is a focus of ongoing studies.
Catalytic [2+2+2] cycloadditions which are capable of forging multiple bonds and sp3 stereocenters are rare, despite the impressive synthetic potential of such processes. These complexity-generating reactions construct important classes of fused carbocycles with levels of efficiency unmatched by current synthetic protocols, providing fundamentally new strategic choices for the rapid construction of stereochemically-dense carbocycles, including those present in many classes of bioactive, complex natural products and small molecules. We would like to thank the ACS PRF for their generous support of this project.