Metal-Hydride C-C Cross-Coupling of Alkenes Through a Double Outer-Sphere Mechanism.

This Synopsis covers recent reports of metal-catalyzed alkene functionalizations that likely involve iterative outer-sphere reactions in which the substrate reacts directly with a metal ligand instead of with the metal center itself. Traditional metal hydride-catalyzed alkene functionalizations involve this latter pathway whereby the alkene forms part of the metal ligand sphere (i.e. an inner-sphere reaction). In contrast, alkenes do not ligate the metal in so-called outer-sphere reactions and instead react with a metal ligand. These transformations have proved crucial for the synthesis of high fraction sp3 (Fsp3) targets, especially in hindered fragment couplings of relevance to natural product space.

Carbon quaternization of redox active esters and olefins by decarboxylative coupling.

The synthesis of quaternary carbons often requires numerous steps and complex conditions or harsh reagents that act on heavily engineered substrates. This is largely a consequence of conventional polar-bond retrosynthetic disconnections that in turn require multiple functional group interconversions, redox manipulations, and protecting group chemistry. Here, we report a simple catalyst and reductant combination that converts two types of feedstock chemicals, carboxylic acids and olefins, into tetrasubstituted carbons through quaternization of radical intermediates. An iron porphyrin catalyst activates each substrate by electron transfer or hydrogen atom transfer, and then combines the fragments using a bimolecular homolytic substitution (SH2) reaction. This cross-coupling reduces the synthetic burden to procure numerous quaternary carbon---containing products from simple chemical feedstocks.

A Route to Potent, Selective, and Biased Salvinorin Chemical Space.

The salvinorins serve as templates for next generation analgesics, antipruritics, and dissociative hallucinogens via selective and potent agonism of the kappa-opioid receptor (KOR). In contrast to most opioids, the salvinorins lack basic amines and bind with high affinity and selectivity via complex polyoxygenated scaffolds that have frustrated deep-seated modification by synthesis. Here we describe a short asymmetric synthesis that relies on a sterically confined organocatalyst to dissociate acidity from reactivity and effect Robinson annulation of an unactivated nucleophile/unstable electrophile pair. Combined with a cobalt-catalyzed polarized diene-alkyne cycloaddition, the route allows divergent access to a focused library of salvinorins. We appraise the synthesis by its generation of multiple analogs that exceed the potency, selectivity, stability, and functional bias of salvinorin A itself.

Prying open a Thiele cage: discovery of an unprecedented extended pinacol rearrangement.

The first extended pinacol rearrangement across an sp3-sp3 bond is reported. The reaction appears to be both stereo- and regio-specific, and results in an extremely rare example of cage opening for a 1,3-bishomocubane structure derived from Thiele's ester.