Palladium-catalyzed reactions and their application to the total synthesis of plakortone B and analogs

The palladium-catalyzed alkoxycarbonylation reaction is an important reaction in organic synthesis for the selective formation of oxygen-containing heterocycles. The mechanism of this reaction has recently been questioned, and so a conformation of this mechanism has been achieved by the use of X-ray diffraction analysis of a derivative of the major tetrahydropyran product. In order to increase the scope of the reaction, especially with respect to the formation of tetrahydrofurans, a survey of ligand effects on the selectivity of these reactions has been performed. It has been shown that modest diastereoselectivities can be achieved for the formation of tetrahydrofurans when the cyclizations are performed in the presence of (-)-sparteine and also in the absence of chloride ion.; The scope of the palladium-catalyzed hydrostannylation of alkynes has also been extended to include reaction of highly hindered substrates by the use of hexane as solvent to minimize competitive dimerization of tributyltin hydride. Regioselective hydrostannylation can be achieved by using the directing effect of oxygen-containing groups (either ethers or esters) in the propargylic position.; The two palladium-catalyzed reactions described above have been utilized in an asymmetric total synthesis of the natural furanolactone Plakortone B, along with three other related compounds. The plakortone family has shown an ability to activate Ca2+ uptake via the sarcoplasmic reticulum Ca2+ ATPase, a process linked to heart regulation. These convergent syntheses show the efficacy of the palladium-catalyzed alkoxycarbonylation reaction, and constitute the most complex cases performed to date, with as many as three competing olefins present in the structure. Also, the synthetic pathway allowed for a number of analogs of the plakortones to be created rapidly from a common intermediate.