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.

本研究报道了一项实验与理论结合的系统性研究，阐明了向无环α-烷氧基硫鎓离子中间体（acyclic α-alkoxythiacarbenium intermediates）中加入甲硅烷基化核碱基（silylated nucleobase）时，为何会表现出高度的1,2-顺式立体控制（1,2-syn stereocontrol）——即遵循反费尔金-安（anti-Felkin–Anh）规则，这与对应活化醛（activated aldehydes）所预期的立体选择性完全相悖。所生成的无环硫胺缩醛（acyclic thioaminals）可发生分子内环化（intramolecular cyclizations）反应，得到兼具抗癌与抗病毒活性的核苷类似物（nucleoside analogues）。本研究对影响该取代反应（substitution reaction）选择性的各类因素开展了全面考察：反应首先生成卤代硫醚物种（Halothioether species），随后在亲核试剂（nucleophile）存在的低介电介质（dielectric media）中，或无亲核试剂的高介电介质中发生解离，并通过类SN2过渡态（SN2-like transition structures，TS A与D）完成反应，此时α-烷氧基基团与硫醚部分（thioether moiety）处于邻位交叉构象。本研究中一项重要且颇具反直觉性的发现是：在气相（gas phase）或低介电介质甲苯（toluene）中进行的量子化学计算，是定位碳氮键形成（C–N bond formation）过程的产物决速与速率决速过渡态（product- and rate-determining transition structures）的必要前提——这类过渡态可对四氢呋喃（THF）、乙腈（MeCN）等极性溶剂（polar solvents）中的反应选择性与同位素效应（isotope effects）做出最为合理的预测。通过计算机模拟（in silico）得到的过渡态吉布斯自由能差（ΔΔG⧧，GTSA–TSD），与1,2-顺式产物的优先生成，以及2,3-反式和2,3-顺式α,β-双烷氧基二硫缩醛（2,3-anti and 2,3-syn α,β-bis-alkoxydithioacetals）所展现的立体控制趋势完全一致。