A novel strategy for the stereoselective construction of all-carbon quaternary centers on acyclic molecules using a two-step tandem process is reported. The first step involves an intramolecular and stereoselective atom transfer radical cyclization reaction from an allyl or vinyl subunit attached on a silyloxy, serving as a tether, to a tertiary radical alpha to an ester. A subsequent mild acidic elimination leads stereoselectively to a quaternary center bearing an allyl or a vinyl in high yield.

Reported herein is an experimental and theoretical study that elucidates why silylated nucleobase additions to acyclic α-alkoxythiacarbenium intermediates proceed with high 1,2-syn stereocontrol (anti-Felkin-Anh), which is opposite to what would be expected with corresponding activated aldehydes. The acyclic thioaminals formed undergo intramolecular cyclizations to provide nucleoside analogues with anticancer and antiviral properties. The factors influencing the selectivity of the substitution reaction have been examined thoroughly. Halothioether species initially form, ionize in the presence (low dielectric media) or absence (higher dielectric media) of the nucleophile, and react through SN2-like transition structures (TS A and D), where the α-alkoxy group is gauche to the thioether moiety. An important, and perhaps counterintuitive, observation in this work was that calculations done in the gas phase or low dielectric media (toluene) are essential to locate the product- and rate-determining transition structures (C-N bond formation) that allow the most reasonable prediction of selectivity and isotope effects for more polar solvents (THF, MeCN). The ΔΔG(⧧) (G(TSA-TSD)) obtained in silico are consistent with the preferential formation of 1,2-syn product and with the trends of stereocontrol displayed by 2,3-anti and 2,3-syn α,β-bis-alkoxydithioacetals.

Hydroxycarboxylic acids (ether carboxylic acids) and esters P 0280 Stereoselective Quaternary Center Construction via Atom-Transfer Radical Cyclization Using Silicon Tethers on Acyclic Precursors. -Radical allylation and vinylation proceeds with complete formation of 2,3-syn-alcohols tolerating aliphatic and aromatic substituents and various protecting groups. -(DUPLESSIS, M.; WALTZ, M.-E.; BENCHEQROUN, M.; CARDINAL-DAVID*, B.; GUINDON, Y.; Org. Lett. 11 (2009) 14, 3148-3151; Inst. Rech. Clin. Montreal, Montreal, Que. H2W 1R7, Can.; Eng.) -R. Steudel 52-062

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