title: Investigation of diastereoselective acyclic α-alkoxydithioacetal substitutions involving thiacarbenium intermediates.
abstract: 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.
authors.affiliation: Bio-Organic Chemistry Laboratory, Institut de Recherches Cliniques de Montréal (IRCM) , Montréal, Québec, H2W 1R7, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Prévost
authors.forename: Starr
authors.initials: S
authors.lastname: Dostie
authors.forename: Marie-Ève
authors.initials: MÈ
authors.lastname: Waltz
authors.forename: Yvan
authors.initials: Y
authors.lastname: Guindon
mesh_terms: D000080:Acetals / Q000737:chemistry*; D000447:Aldehydes / Q000737:chemistry*; D015394:Molecular Structure; D013237:Stereoisomerism; D013440:Sulfides / Q000737:chemistry*; D014050:Toluene
chemical_list: D000080:Acetals; D000447:Aldehydes; D013440:Sulfides; D014050:Toluene