Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Nat Chem. 2012 Dec;4(12):996-1003. doi: 10.1038/nchem.1495.
Site-selective functionalizations of complex small molecules can generate targeted derivatives with exceptional step efficiency, but general strategies for maximizing selectivity in this context are rare. Here, we report that site-selectivity can be tuned by simply modifying the electronic nature of the reagents. A Hammett analysis is consistent with linking this phenomenon to the Hammond postulate: electronic tuning to a more product-like transition state amplifies site-discriminating interactions between a reagent and its substrate. This strategy transformed a minimally site-selective acylation reaction into a highly selective and thus preparatively useful one. Electronic tuning of both an acylpyridinium donor and its carboxylate counterion further promoted site-divergent functionalizations. With these advances, we achieve a range of modifications to just one of the many hydroxyl groups appended to the ion channel-forming natural product amphotericin B. Thus, electronic tuning of reagents represents an effective strategy for discovering and optimizing site-selective functionalization reactions.
复杂小分子的位点选择性功能化可以生成具有卓越步骤效率的靶向衍生物，但在这种情况下，最大化选择性的一般策略很少见。在这里，我们报告说，通过简单地修饰试剂的电子性质，可以调整位点选择性。哈米特分析与哈蒙德假设一致：电子调谐到更类似于产物的过渡态，放大了试剂与其底物之间的位点区分相互作用。这种策略将一种最小位点选择性的酰化反应转化为高度选择性的，因此具有制备实用性的反应。酰基吡啶鎓供体及其羧酸根抗衡离子的电子调谐进一步促进了位点发散的功能化。有了这些进展，我们实现了对离子通道形成天然产物两性霉素 B 上附加的许多羟基之一的多种修饰。因此，试剂的电子调谐代表了发现和优化位点选择性功能化反应的有效策略。
