Enantioselective, Noncovalent, Substrate-Directable Heck-Matsuda and Oxidative Heck Arylations of Unactivated Five-Membered Carbocyclic Olefins.

Highly diastereo- and enantioselective, noncovalent, substrate-directable Heck desymmetrizations of cyclopentenyl olefins containing hydroxymethyl and carboxylate functional groups are presented. These conformationally unbiased cyclic olefins underwent effective arylations in yields of up to 97 %, diastereoselectivity up to >20:1, and enantiomeric excesses of up to 99 %. Noncovalent directing effects were shown to be prevalent in both Heck-Matsuda and oxidative Heck reactions, allowing the preferential formation of cis-substituted aryl cyclopentenes containing two stereocenters, including quaternary stereocenters. These results further validate the internal out-of-coordination-sphere ion-dipole interaction concept directing the reaction diastereoselectivity to the cis-Heck product. This approach is complementary to existing methods using bis-phosphine monoxide ligands to give the opposite trans-diastereoisomer. The applicability of the method is showcased by the straightforward synthesis of a potent phosphodiesterase 4 inhibitor in a diastereo- and enantioselective manner. The reaction is operationally simple and has broad scope with regard to the nature of the arenediazonium salt and boronic acid employed. The mechanism and origin of stereoselectivity were investigated with control experiments and DFT calculations that fully supported the stabilizing internal out-of-coordination-sphere ion-dipole interaction between the resident functional group and cationic palladium.

Intermolecular Noncovalent Hydroxy-Directed Enantioselective Heck Desymmetrization of Cyclopentenol: Computationally Driven Synthesis of Highly Functionalized cis-4-Arylcyclopentenol Scaffolds.

New computationally driven protocols for the Heck desymmetrization of 3-cyclopenten-1-ol with aryldiazonium tetrafluoroborates were developed. These new conditions furnished remarkable product selectivity originating from a resident hydroxyl group and the critical choice of the reaction solvent. Mechanistic insights gleaned from theoretical calculations of the putative transition states predicted toluene as an adequate solvent choice to attain high enantioselectivity by strengthening the noncovalent interaction of the substrate hydroxyl group and the chiral cationic palladium catalyst. Laboratory experiments validated the theoretical predictions, and by employing 2% MeOH/toluene as solvent, the Heck-Matsuda reaction provided exclusively the cis-4-arylcyclopentenols 3a-l in good to excellent yields in enantiomeric excesses up to 99%. The performance of the new PyOx ligand (S)-4-tert-butyl-2-(3,5-dichloropyridin-2-yl)-4,5-dihydrooxazole was also successfully evaluated in the Heck-Matsuda desymmetrization of 3-cyclopenten-1-ol. The synthetic potential of these highly functionalized cis-4-arylcyclopentenols is illustrated by a gold-catalyzed synthesis of cyclopenta[b]benzofuran skeletons.