Palladium catalyzed asymmetric allylic alkylation (AAA) of prochiral nucleophiles: Efforts toward the synthesis of erinacine A

Asymmetric alkylation of simple ketone enolates to generate quaternary chiral centers was investigated. The complex generated from palladium(0) and a chiral ligand synthesized from 1,2-diaminocyclohexane and 2-diphenylphosphinobenzoic acid catalyzed the alkylation and gave the quaternary substituted products with excellent enantioselectivity. Lithium enolates of 2-alkylcycloalkanones and potassium enolates of 2-arylcycloalkanones gave the best results. For α-aryl ketones, a naphthyl derived chiral ligand was required for good enantioselectivity.; The palladium catalyzed AAA of cyclic 1,2-diketones was examined. The corresponding O-alkylated products were obtained in excellent regio- and enantioselectivity. Acyclic and cyclic allylic carbonates as well as vinyl epoxides functioned well as electrophiles. Claisen rearrangement of the allylic enol ethers using catalytic HoFOD transferred the stereochemistry from oxygen to carbon with outstanding chirality transfer and complete diastereoselectivity. This two step AAA/Claisen protocol constitutes a second approach toward synthesizing α-quaternary substituted cycloalkanones.; Application of the palladium catalyzed AAA to the synthesis of barbituric acid derivatives was explored. Palladium catalyzed AAA using prochiral electrophiles allowed for the synthesis of cyclopentobarbital and pentobarbital in 91% and 81% ee respectively. Palladium catalyzed AAA of prochiral nucleophiles to give enantioenriched barbiturates proved more difficult and gave the corresponding alkylated products in poor ee (37%).; The erinacines present formidable synthetic targets due to their 5,6,7-tricyclic ring system, oxidation state, and quaternary chiral centers. Efforts were directed toward the total synthesis of erinacine A, a potent stimulator of nerve growth factor synthesis. All of the stereocenters were set from an enantioenriched α-quaternary substituted cyclopentanone which was itself a product of the palladium catalyzed AAA of a prochiral ketone enolate. The six membered ring was constructed with a palladium catalyzed reductive diyne cyclization while the seven membered ring was formed in a palladium catalyzed [4+3] TMM reaction. The TMM cycloaddition gave the tricyclic core of erinacine A in just thirteen steps. The second quaternary chiral center was set by an intramolecular Stork radical cyclization. An advanced intermediate was ultimately constructed which possessed all of the carbon atoms of erinacine A. Adjustment of the oxidation state remains to be completed.