Amine Organocatalysis of Remote, Chemoselective C(sp3)-H Hydroxylation.

We introduce an organocatalytic approach for oxaziridinium-mediated C-H hydroxylation that employs secondary amines as catalysts. We also demonstrate the advantages of this operationally simple catalytic strategy for achieving high yielding and highly selective remote hydroxylation of compounds bearing oxidation-sensitive functional groups such as alcohols, ethers, carbamates, and amides. By employing hexafluoroisopropanol as the solvent in the absence of water, a proposed hydrogen bonding effect leads to, among other advantages, as high as ≥99:1 chemoselectivity for remote aliphatic hydroxylation of 2° alcohols, an otherwise unsolved synthetic challenge normally complicated by substantial amounts of alcohol oxidation. Initial studies of the reaction mechanism indicate the formation of an oxaziridinium salt as the active oxidant, and a C-H oxidation step that proceeds in a stereospecific manner via concerted insertion or hydrogen atom transfer/radical rebound. Furthermore, preliminary results indicate that site selectivity can be affected by amine catalyst structure. In the long term, we anticipate that this will enable new strategies for catalyst control of selectivity based on the abundance of catalytic scaffolds that have proliferated over the last twenty years as a result of Nobel Prize-winning discoveries.

Radical-Polar Crossover Annulation: A Platform for Accessing Polycyclic Cyclopropanes.

Photoredox-mediated radical/polar crossover (RPC) processes provide unique solutions to challenging annulations. Herein, we describe an approach to the cyclopropanation of olefins that are embedded within bicyclic scaffolds. Whereas these systems are notoriously recalcitrant toward classical cyclopropanation approaches, RPC cyclopropanation can be executed with ease, leading to polycarbocyclic and polyheterocyclic cyclopropanes. The cyclopropanation proceeds through a photoredox-enabled Giese-type radical addition followed by an intramolecular anionic substitution reaction on a neopentyl leaving group.

Access to a Catalytically Generated Umpolung Reagent through the Use of Cu-Catalyzed Reductive Coupling of Ketones and Allenes for the Synthesis of Chiral Vicinal Aminoalcohol Synthons.

We report the development of a stereoselective method for the allylation of ketones utilizing N-substituted allyl equivalents generated from a chiral allenamide. By employing N-heterocyclic carbenes as ligands for the Cu catalyst, good branched selectivity can be obtained with high diastereocontrol. This methodology allows access to a catalytically generated, polarity-reversed (umpolung) allyl nucleophile to enable the preparation of chiral 1,2-aminoalcohol synthons containing a dissonant functional group relationship.