A Study of Exocyclic Radical Reductions of Polysubstituted Tetrahydropyrans

Exocyclic
radical reductions were thoroughly investigated in the
context of the synthesis of polysubstituted tetrahydropyrans, which
are found in numerous macrolides. The radical precursors studied herein
were generated by tandem cycloetherification and iodoetherification
reactions or, alternatively, by semicyclic acetals substitutions.
DFT calculations (BHandHLYP/TZVP) performed at the transition-state
level for the hydrogen radical delivery are in good accordance with
the experimental data and enabled the identification of important
conformational factors that govern the selectivities obtained. This
study demonstrates that both the preferred reactive conformation of
the radical and steric interactions with the incoming hydride have
to be considered in order to fully rationalize the levels of diastereoselection
generated in acyclic free-radical processes.

本研究围绕多取代四氢吡喃（polysubstituted tetrahydropyrans）的合成场景，系统深入地开展了环外自由基还原反应的探究，此类结构广泛存在于各类大环内酯类化合物（macrolides）中。本文所研究的自由基前体（radical precursors）可通过串联环醚化与碘醚化反应制得，亦可通过半环缩醛取代反应（semicyclic acetals substitutions）合成。针对氢自由基传递过程在过渡态势能水平下开展的密度泛函理论（Density Functional Theory, DFT）计算（BHandHLYP/TZVP）结果与实验数据高度吻合，借此明确了主导反应选择性的关键构象因素。本研究表明，若要完整合理化无环自由基反应过程（acyclic free-radical processes）中生成的非对映选择性水平，需同时兼顾自由基的优势反应构象（preferred reactive conformation）与进攻性氢自由基（incoming hydride）之间的空间位阻相互作用。