Cycloadditions via TMM-PdL2 intermediates: New strategies for total synthesis and asymmetric induction

ORGN 268

Barry Trost, bmtrost@stanford.edu, Department of Chemistry, Stanford University, Stanford, CA 94305
The generation of metal complexed trimethylenemethane intermediates in a catalytic cycle provides entry into the formation of 5 (via [3+2]), 6 (via [3+3], 7 (via [4+3]) and 9 (via [6+3]) membered rings, both all carbon as well as heterocyclic. A novel version of this process involves use of a conjunctive reagent wherein the departing carboxylate group initially carboxylates the TMM-PdL2 as well as effect cycloaddition. The power of this method to simplify the total synthesis of complex biologically active targets is illustrated in a concise total synthesis of the complex heptacyclic marcfortines (and potentially the related paraherquamides), natural products isolated from Penicillium species and possessing potent anthelmintic acitivity. To make this synthesis asymmetric, the development of asymmetric Pd catalysts for these cycloadditions is required. The great difficulty in this task stems from the fact that the acceptor partner approaches the TMM on the face opposite from where the Pd, and thus the chiral environment, resides (i.e. the bond forming events occur outside the coordination sphere of the metal). Efforts to design suitable ligands have begun and are leading to quite promising results.