Enantioselective Construction of Acyclic Quaternary Carbon Stereocenters: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully Substituted Amide Enolates.

We report a divergent and modular protocol for the preparation of acyclic molecular frameworks containing newly created quaternary carbon stereocenters. Central to this approach is a sequence composed of a (1) regioselective and -retentive preparation of allyloxycarbonyl-trapped fully substituted stereodefined amide enolates and of a (2) enantioselective palladium-catalyzed decarboxylative allylic alkylation reaction using a novel bisphosphine ligand.

An Efficient Protocol for the Palladium-catalyzed Asymmetric Decarboxylative Allylic Alkylation Using Low Palladium Concentrations and a Palladium(II) Precatalyst.

Enantioselective catalytic allylic alkylation for the synthesis of 2-alkyl-2-allylcycloalkanones and 3,3-disubstituted pyrrolidinones, piperidinones and piperazinones has been previously reported by our laboratory. The efficient construction of chiral all-carbon quaternary centers by allylic alkylation was previously achieved with a catalyst derived in situ from zero valent palladium sources and chiral phosphinooxazoline (PHOX) ligands. We now report an improved reaction protocol with broad applicability among different substrate classes in industry-compatible reaction media using loadings of palladium(II) acetate as low as 0.075 mol % and the readily available chiral PHOX ligands. The novel and highly efficient procedure enables facile scale-up of the reaction in an economical and sustainable fashion.

Expanding insight into asymmetric palladium-catalyzed allylic alkylation of N-heterocyclic molecules and cyclic ketones.

Eeny, meeny, miny ... enaminones! Lactams and imides have been shown to consistently provide enantioselectivities substantially higher than other substrate classes previously investigated in the palladium-catalyzed asymmetric decarboxylative allylic alkylation. Several new substrates have been designed to probe the contributions of electronic, steric, and stereoelectronic factors that distinguish the lactam/imide series as superior alkylation substrates (see scheme). These studies culminated in marked improvements on carbocyclic allylic alkylation substrates.

Probing Trends in Enantioinduction via Substrate Design: Palladium-Catalyzed Decarboxylative Allylic Alkylation of α-Enaminones.

Herein, we report the palladium-catalyzed decarboxylative asymmetric allylic alkylation of α-enaminones. In addition to serving as valuable synthetic building blocks, we exploit the α-enaminone scaffold and its derivatives as probes to highlight structural and electronic factors that govern enantioselectivity in this asymmetric alkylation reaction. Utilizing the (S)-t-BuPHOX ligand in a variety of nonpolar solvents, the alkylated products are obtained in up to 99% yield and 99% enantiomeric excess.

Oxidative Fragmentations and Skeletal Rearrangements of Oxindole Derivatives.

An oxidative sequence for the conversion of oxindoles to structurally distinct heterocyclic scaffolds and aniline derivatives is disclosed by the combination of a copper-catalyzed C-H peroxidation and subsequent base-mediated fragmentation reaction. In contrast to classic enzymatic (i.e., kynurenine pathway) and biomimetic methods (i.e., Witkop-Winterfeldt oxidation) for oxidative indole cleavage, this protocol allows for the incorporation of external nucleophiles. The new transformation displays broad functional group tolerance and is applicable to tryptophan derivatives, opening potential new avenues for postsynthetic modification of polypeptides, bioconjugation, and unnatural amino acid synthesis.

Exceedingly Efficient Synthesis of (±)-Grandifloracin and Acylated Analogues.

A highly efficient regio- and stereoselective total synthesis of (±)-grandifloracin via a tandem dearomative epoxidation/spontaneous Diels-Alder cyclodimerization from salicylic acid in only four steps is reported. The synthetic route allows for late-stage diversification of the core structure to give ready access to analogues of this promising agent against pancreatic cancer.