Concise syntheses of GB22, GB13, and himgaline by cross-coupling and complete reduction.

Neuroactive metabolites from the bark of Galbulimima belgraveana occur in variable distributions among trees and are not easily accessible through chemical synthesis because of elaborate bond networks and dense stereochemistry. Previous syntheses of complex congeners such as himgaline have relied on iterative, stepwise installation of multiple methine stereocenters. We decreased the synthetic burden of himgaline chemical space to nearly one-third of the prior best (7 to 9 versus 19 to 31 steps) by cross-coupling high fraction aromatic building blocks (high Fsp2) followed by complete, stereoselective reduction to high fraction sp3 products (high Fsp3). This short entry into Galbulimima alkaloid space should facilitate extensive chemical exploration and biological interrogation.

Synthesis of psychotropic alkaloids from Galbulimima.

Efficient syntheses of valuable natural products open gateways from kind learning environments to wicked worlds, where long-term, interdisciplinary research questions can be asked and answered. In this Perspective, we discuss the Galbulimima (GB) alkaloids, metabolites of a rainforest canopy tree that exhibit potent but poorly understood effects in humans, including accounts of hallucination. Recent syntheses from our group have opened up GB alkaloid chemical space for investigation by way of new cross-coupling reactions and gram-scale target production. Although natural product synthesis can be challenging, its objective is obvious. Realization of long-term, enabling goals will be a circuitous journey at the interface of chemistry, pharmacology and neuroscience-a potent mix to foster discovery in the coming century.

Scope and mechanistic investigations of Pd-catalyzed coupling/cyclizations and cycloisomerizations of allenyl malonates.

Pd-catalyzed transformations of allenyl malonates provide convenient access to functionalized carbocycles, but the influence of the ligand, solvent, base, and reaction conditions on the mechanism, regioselectivity, and product outcome of the cyclization are not well-understood. Additionally, from the perspective of synthetic utility, access to either fully substituted or enantioenriched cyclopentane building blocks has not yet been achieved. This work describes how targeted changes to the reaction conditions enable predictable control over the mechanism of Pd-catalyzed allene cross-coupling/cyclization and cycloisomerization, irrespective of the allene substitution pattern. Both enantioenriched cyclopropanes and cyclopentenes can be obtained through axis-to-center chirality transfer from the allene precursor at room temperature, which is not possible using reported Pd-catalyzed methods that result in racemization of the allene. Finally, the ability to divert the reactivity of the allenyl malonate from cross-coupling/cyclization to cycloisomerization by a simple switch of the ligand on Pd from a bidentate phosphine to an electron-poor triphenylphosphite is demonstrated.

Stereodivergent Metal-Catalyzed Allene Cycloisomerizations.

Metal-catalyzed allene cycloisomerizations provide rapid entry into five-membered carbocyclic frameworks, a common motif in natural products and pharmaceuticals. While both Au(I) and Pd(0)-catalyzed allene cycloisomerizations give 5-endo-dig cyclization, Pd prefers the syn diastereomer in contrast to the anti isomer observed with Au. The change in stereoselectivity is proposed to arise from buildup of A1,3 strain during the key carbopalladation step to furnish the cycloisomerized products in moderate to good dr with yields comparable to Au(I) catalysts.