Ermanis Kristaps, Hsiao Yin-Ting, Kaya Uğur, Jeuken Alan, Clarke Paul A
Department of Chemistry , University of York , Heslington , York , North Yorkshire YO10 5DD , UK . Email:
Chem Sci. 2017 Jan 1;8(1):482-490. doi: 10.1039/c6sc03478k. Epub 2016 Aug 30.
The origins of the stereodivergence in the thioester oxy-Michael cyclization for the formation of 4-hydroxy-2,6-- or 2,6--substituted tetrahydropyran rings under different conditions was investigated both computationally and experimentally. Synthetic studies showed that the 4-hydroxyl group was essential for stereodivergence. When the 4-hydroxyl group was present, TBAF-mediated conditions gave the 2,6--tetrahydropyran and trifluoroacetic acid-mediated conditions gave the 2,6--tetrahydropyran. This stereodivergence vanished when the hydroxyl group was removed or protected. Computational studies revealed that: (i) the trifluoroacetic acid catalysed formation of 2,6--tetrahydropyrans was mediated by a trifluoroacetate-hydroxonium bridge and proceeded a chair-like transition state; (ii) the TBAF-mediated formation of 2,6--tetrahydropyrans proceeded a boat-like transition state, where the 4-hydroxyl group formed a crucial hydrogen bond to the cyclizing alkoxide; (iii) both reactions are under kinetic control. The utility of this stereodivergent approach for the formation of 4-hydroxy-2,6-substituted tetrahydropyran rings has been demonstrated by the total syntheses of the anti-osteoporotic natural products diospongin A and B.
通过计算和实验研究了在不同条件下硫酯氧-Michael环化反应中立体发散的起源，该反应用于形成4-羟基-2,6-或2,6-取代的四氢吡喃环。合成研究表明，4-羟基对于立体发散至关重要。当存在4-羟基时，TBAF介导的条件下生成2,6-四氢吡喃，而三氟乙酸介导的条件下生成2,6-四氢吡喃。当羟基被去除或保护时，这种立体发散消失。计算研究表明：（i）三氟乙酸催化形成2,6-四氢吡喃是由三氟乙酸根-羟基鎓桥介导的，并通过椅式过渡态进行；（ii）TBAF介导的2,6-四氢吡喃的形成通过船式过渡态进行，其中4-羟基与环化醇盐形成关键的氢键；（iii）两个反应均受动力学控制。抗骨质疏松天然产物薯蓣皂苷A和B的全合成证明了这种立体发散方法在形成4-羟基-2,6-取代的四氢吡喃环中的实用性。
