Total synthesis of the acetyl CoA carboxylase allosteric inhibitor soraphen A and the development of new catalytic methods using palladium, iridium and rhodium

Metal catalysis with palladium, iridium, and rhodium has provided a lexicon of synthetic transformations extensively utilized in the construction of complex molecules. The total synthesis of soraphen A, a type 1 polyketide allosteric inhibitor of Acetyl-CoA carboxylase, was completed in 11 steps (LLS), less than half the previously required steps. The synthesis maximizes convergency by exploiting the catalytic reactivity of transition metals to facilitate five asymmetric processes and four carbon-carbon bond formations. A key strategic element involves the development of a new synthetic method: a palladium-AntPhos catalyst directed diastereoselective hydrogenolysis of allylic carbonates to reveal a terminal olefin for successive olefin cross-metathesis. The development of palladium-catalyzed hydrogenolysis of allylic compounds, current asymmetric methods, and their application in the total synthesis of complex natural products will be described. In addition, an iridium-catalyzed enantioselective allylation of indoles and various azoles to access products with complete N- and branched-regioselectivity and a rhodium-catalyzed reductive coupling-internal redox isomerization of vinyl triflates and aldehydes to furnish ketones were developed.