Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
J Am Chem Soc. 2023 Sep 27;145(38):20951-20958. doi: 10.1021/jacs.3c06423. Epub 2023 Sep 12.
α,β-Dehydrogenation of aliphatic acids has been realized through both enolate and β-C-H metalation pathways. However, the synthesis of isolated β,γ-unsaturated aliphatic acids via dehydrogenation has not been achieved to date. Herein, we report the ligand-enabled β,γ-dehydrogenation of abundant and inexpensive free aliphatic acids, which provides a new synthetic disconnection as well as a versatile platform for the downstream functionalization of complex molecules at remote γ-sites. A variety of free aliphatic acids, including acyclic and cyclic systems with ring sizes from five-membered to macrocyclic, undergo efficient dehydrogenation. Notably, this protocol features good chemoselectivity in the presence of more accessible α-C-H bonds and excellent regioselectivity in fused bicyclic scaffolds. The utility of this protocol has been demonstrated by the late-stage functionalization of a series of bioactive terpene natural products at the γ-sites. Further functionalization of the β,γ-double bond allows for the installation of covalent warheads, including epoxides, aziridines, and β-lactones, into complex natural product scaffolds, which are valuable for targeted covalent drug discovery.
通过烯醇化物和β-C-H 金属化两种途径，实现了脂肪酸的α,β-脱氢。然而，迄今为止，通过脱氢合成孤立的β,γ-不饱和脂肪酸尚未实现。在此，我们报告了配体促进的丰富且廉价的游离脂肪酸的β,γ-脱氢，这为复杂分子在远程γ位的下游官能化提供了新的合成断裂点和多功能平台。各种游离脂肪酸，包括具有从五元环到大环的环大小的环状和非环状体系，都经历了有效的脱氢。值得注意的是，该方案在存在更易接近的α-C-H 键时具有良好的化学选择性，并且在稠合双环支架中具有优异的区域选择性。该方案的实用性已通过在一系列生物活性萜类天然产物的γ位进行后期官能化得到证明。β,γ-双键的进一步官能化允许将共价弹头（包括环氧化物、氮丙啶和β-内酰胺）安装到复杂的天然产物支架中，这对于靶向共价药物发现非常有价值。
