Homologations of organic molecules that add a carbon atom to the substrate are useful in drug discovery to access compounds with improved properties that otherwise present a synthetic challenge. Carboxylic acids are present in many bioactive molecules and are widely available building blocks for chemical synthesis, yet their direct homologation is unknown. This valuable transformation currently necessitates implementation of multistep processes that require the use of carboxylic acid derivatives rather than the native substrates, and commonly involves highly reactive and toxic reagents. Herein, we report the first one-step homologation directly from native carboxylic acids using a novel, bench-stable (1-phosphoryl)vinyl sulfonate reagent under mild conditions. This strategy was applied to a wide range of aliphatic carboxylic acid building blocks and biologically relevant complex molecules to access an array of ester, amide, and carboxylic acid homologues in a single step. The (1-phosphoryl)vinyl sulfonate reagent participates in complementary homologation protocols featuring either radical-chain transfer or organic photoredox catalysis and introduces a new synthon, the distonic acylium radical, for molecular diversification. We anticipate this strategy, which addresses a long-standing challenge in organic synthesis, will expedite drug discovery by enabling the rapid synthesis of diversified homologues.

中文翻译：

---

使用自由基-极性联合试剂进行羧酸的同源分析


在底物上添加碳原子的有机分子的同系物在药物发现中很有用，以获得具有改进特性的化合物，否则会带来合成挑战。羧酸存在于许多生物活性分子中，是广泛可用的化学合成结构单元，但它们的直接同源性尚不清楚。这种有价值的转变目前需要实施多步骤工艺，这些工艺需要使用羧酸衍生物而不是天然底物，并且通常涉及高反应性和毒性试剂。在此，我们报道了在温和条件下使用新型、台式稳定（1-磷酸基）乙烯基磺酸盐试剂直接从天然羧酸进行的第一个一步同源反应。该策略应用于各种脂肪族羧酸结构单元和生物学相关的复杂分子，以一步获得一系列酯、酰胺和羧酸同系物。（1-磷酸基）乙烯基磺酸盐试剂参与以自由基链转移或有机光氧化还原催化为特征的互补同源方案，并引入了一种新的合成子，即二氧酰基自由基，用于分子多样化。我们预计这一策略解决了有机合成中长期存在的挑战，将通过实现多样化同系物的快速合成来加速药物发现。