The impact of carbon tether rigidity and 1,3-steric induction upon the stereoselectivity of C-C bond formation was probed in cobalt-mediated radical cyclization reactions of bis-propargyl alcohols. The metal core offers several synthetic advantages, from precluding acetylene-allene rearrangements to stabilizing intermediate cations, increasing bulkiness and angularity of propargyl triads, and stereodirecting converging propargyl radicals. The requisite bis-dicobalthexacarbonyl complexes of 1,9-decadiyne-3,8-diols were synthesized from adipoyl chloride (four steps) or phenylene dicarboxylic acid (five steps). Relative chromatographic mobilities, and thus separability of diastereomeric diols, were dependent upon the topology of the molecule, the nature of substituents at the acetylenic termini, as well as rigidity of the carbon tether. Diastereomeric diols, with a phenyl group as a rigid tether, were independently cyclized (1.HBF4; 2. Zn) to stereoselectively yield cis-tetralins (cis- 98-100%), wherein the bulky cobalt-alkyne units occupy axial and equatorial positions of the fused carbocycles. The said stereochemical outcome stands in sharp contrast with cyclizations of 1,9-decadiyne-3,8-diols containing a flexible carbon tether (trans- 90-100%). A 1,3-steric induction by TMS-group was proven to be an efficient tool in intramolecular cyclizations, forming exclusively trans-isomers and directing cobalt-alkyne units into axial positions of the newly formed six-membered rings. The results on conformational analysis, relative thermodynamic stabilities of geometric isomers, low-temperature NMR data on intermediate bis-propargyl cations, and hydration-cyclization algorithms converting 1,2-diethynyl moieties to fused cyclopentenone rings will be presented. This project provides access to linearly fused polycarbocycles and paves the way for targeted synthesis of novel estrogen mimics and estrogen receptor modulators.

Carbon-carbon bond formation in intramolecular setting: Cobalt-mediated stereoselective synthesis of cyclohexanes and tetralins

255th National Meeting (2018)

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