Evolution of a Short and Stereocontrolled Synthesis of (+)-7,20-Diisocyanoadociane.

A full account of the development of a concise and highly stereoselective synthesis of (+)-7,20-diisocyanoadociane (DICA)─a structurally complex isocyanoditerpene with potent antiplasmodial activity─is described. The strategy that evolved relies on the rapid construction of unsaturated tricyclic precursors designed to undergo stereocontrolled Birch reductions and a subsequent "bay ring" formation to generate the isocycloamphilectane core. This report is divided into three sections: (1) a description of the initial strategy and the results that focused our efforts on a single route to the DICA core, (2) a discussion of the precise choreography needed to enable a first-generation formal synthesis of (±)-DICA, and (3) the execution of a 13-step second-generation synthesis of (+)-DICA that builds on important lessons learned from the first-generation effort.

Concise Synthesis of the Antiplasmodial Isocyanoterpene 7,20-Diisocyanoadociane.

The flagship member of the antiplasmodial isocyanoterpenes, 7,20-diisocyanoadociane (DICA), was synthesized from dehydrocryptone in 10 steps, and in 13 steps from commercially available material. Our previous formal synthesis was reengineered, leveraging only productive transformations to deliver DICA in fewer than half the number of steps of our original effort. Important contributions, in addition to the particularly concise strategy, include a solution to the problem of axial nucleophilic methylation of a late-stage cyclohexanone, and the first selective synthesis and antiplasmodial evaluation of the DICA stereoisomer with both isonitriles equatorial.

Catalytic Synthesis of Indolines by Hydrogen Atom Transfer to Cobalt(III)-Carbene Radicals.

We report a new method for the synthesis of indolines from o-aminobenzylidine N-tosylhydrazones proceeding through a cobalt(III)-carbene radical intermediate. This methodology employs the use of inexpensive commercially available reagents and allows for the transformation of easily derivatized benzaldehyde-derived precursors to functionalized indoline products. This transformation takes advantage of the known propensity of radicals to undergo rapid intramolecular 1,5-hydrogen atom transfer (1,5-HAT) to form more stabilized radical intermediates. Computational investigations using density functional theory identify remarkably low barriers for 1,5-HAT and subsequent radical rebound displacement, providing support for the proposed mechanism. We explore the effect of a variety of nitrogen substituents, and highlight the importance of adequate resonance stabilization of radical intermediates to the success of the transformation. Furthermore, we evaluate the steric and electronic effects of substituents on the aniline ring. This transformation is the first reported example of the synthesis of nitrogen-containing heterocycles from cobalt(III)-carbene radical precursors.

Computational and experimental investigations of the formal dyotropic rearrangements of Himbert arene/allene cycloadducts.

The fascinating intramolecular arene/allene cycloaddition discovered by Himbert affords dearomatized, polycyclic intermediates with sufficient strain energy to drive rearrangement processes of the newly formed ring system. We disclose a detailed examination of a thermally induced stepwise dyotropic skeletal rearrangement of these cycloadducts, a reaction also first described by Himbert. We offer computational evidence for a two-stage mechanism for this formal dyotropic rearrangement and provide rationalizations for the significant substitution-dependent rate differences observed in experiments. These investigations led to the development of a Lewis-acid-catalyzed rearrangement of precursors that were unreactive under simple thermal instigation. The isolation of the product of an "interrupted" rearrangement under Lewis acidic conditions provides further support for the proposed stepwise mechanism. Computational results also matched experiments in terms of regiochemical preferences in unsymmetrical rearrangement precursors and explained why lactam O-, S-, and C-heterologues do not easily undergo this rearrangement.

Direct stereospecific amination of alkyl and aryl pinacol boronates.

The direct amination of alkyl and aryl pinacol boronates is accomplished with lithiated methoxyamine. This reaction directly provides aliphatic and aromatic amines, stereospecifically, and without preactivation of the boronate substrate.