Enantioselective Total Synthesis of (-)-Himalensine A via a Palladium and 4-Hydroxyproline Co-catalyzed Desymmetrization of Vinyl-bromide-tethered Cyclohexanones.

Herein, we describe the convergent enantioselective total synthesis of himalensine A in 18 steps, enabled by a highly enantio- and diastereoselective construction of the morphan core via a palladium/hydroxy proline co-catalyzed desymmetrization of vinyl-bromide-tethered cyclohexanones. The reaction pathway was illuminated by density functional theory calculations, which support an intramolecular Heck reaction of an in situ-generated enamine intermediate, where exquisite enantioselectivity arises from intramolecular carboxylate coordination to the vinyl palladium species in the rate- and enantio-determining carbopalladation steps. The reaction tolerates diverse N-derivatives, all-carbon quaternary centers, and trisubstituted olefins, providing access to molecular scaffolds found in a range of complex natural products. Following large-scale preparation of a key substrate and installation of a ß-substituted enone moiety, the rapid construction of himalensine A was achieved using a highly convergent strategy based on an amide coupling/Michael addition/allylation/ring-closing metathesis sequence which allowed the introduction of three of the five rings in only three synthetic steps (after telescoping). Moreover, our strategy provides a new enantioselective access to a known tetracyclic late-stage intermediate that has been used previously in the synthesis of many Daphniphyllum alkaloids.

Enantioselective Silver-Catalyzed Cascade Synthesis of Fused Lactone and Lactam Oxazolines.

A new and highly stereoselective cascade reaction between isocyanoacetate esters and α-hydroxy and α-amino ketones has been developed. A cinchona alkaloid derived aminophosphine/silver(I) catalyst complex promoted the reaction and enabled the ready synthesis of fused bicyclic γ-lactone and γ-lactam oxazolines with high enantiocontrol (up to 99% ee).

Access to a Guanacastepene and Cortistatin-Related Skeleton via Ethynyl Lactone Ireland-Claisen Rearrangement and Transannular (4 + 3)-Cycloaddition of an Azatrimethylenemethane Diyl.

Heating a 2,5-furanocyclic (2-azidoethyl)allene initiates a cascade reaction comprising azide-allene cycloaddition, loss of nitrogen, and azatrimethylenemethane (ATMM) diyl-furan transannular (4 + 3)-cycloaddition. The major product of this reaction contains the pentacyclic core common to guanacastepenes D and H and radianspenes J-L; in addition, the central oxa-bridged cycloheptene ring, flanked by two carbocyclic rings, is structurally related to the ABC-ring system found in the cortistatins. This is the first reported synthetic application of a "free" (nonconjugated) ATMM. The cyclization precursors were prepared via the first reported examples of the Ireland-Claisen rearrangement of an ethynyl lactone.