In an organic setting, the intramolecular cyclizations of bis-propargyl radicals have long represented a daunting task, given a low regioselectivity, involvement of different termini of propargyl triads, and lack of mechanistic tools that could be used for controlling the stereoselectivity of carbon-carbon bond formation. The coordination with a transition metal, such as cobalt, provides significant advantages, from precluding acetylene-allene rearrangements to stabilizing intermediate cations, to increasing bulkiness of propargyl triads, to introducing angularity into linear acetylenic moieties, and to stereodirecting converging propargyl radicals. Novel methods for stereoselective synthesis of cyclopentanes, tetrahydrofurans, indanes, pyrrolidines, cyclohexanes, and tetralins employing, as a key step, cobalt-assisted radical cyclizations were developed. The requisite bis-dicobalthexacarbonyl complexes of 1,8/9-nona/decadiyne-3,7/8-diols, synthesized from the respective acid chlorides or carboxylic acids in four-to-five steps, were cyclized (HBF4/Zn) via isolable bis-cations and transient bis-radicals. The cyclization mode was dependent upon the ring size and substituents at the acetylenic termini (1,3-steric induction), affording mono and fused, carbo-(C5,C6) and heterocycles(C5) with excellent cis- and trans-stereoselectivities (up to 100%). The impact of the tether rigidity upon the ring configuration, kinetic vs thermodynamic control, and prospects for targeted synthesis of methamphetamine analogs, as well as linear and angularly fused estrogen mimics will be presented.

Stereoselective synthesis of mono and fused, carbo- and heterocyclic compounds via cobalt-assisted radical cyclizations

2019 Fall National Meeting

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