Investigation of Diastereoselective Acyclic α‑Alkoxydithioacetal Substitutions Involving Thiacarbenium Intermediates

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⧧ (GTSA–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.