清华大学齐湘兵团队报道了脂肪族氧化还原活性酯与宝石级硼锆茂烷的对映选择性脱羧C(sp³)-C(sp³)交叉偶联。相关研究成果发表在2024年9月17日出版的国际知名学术期刊《美国化学会杂志》。

羧酸的不对称脱羧交叉偶联是合成药物化学和材料科学中，必不可少的手性结构单元的有力方法。尽管它们具有潜力，但通过由现成的脂肪酸和温和的有机金属试剂，进行不对称脱羧C(sp³)-C(sp³)交叉偶联仍具有挑战性。

该文中，研究人员提出了一种可见光诱导的镍催化的对映收敛C(sp³)-C(sp³)交叉偶联的，非活化的伯胺脂肪酸NHPI酯与宝石-硼氮二茂烷，制备了多种有价值的手性烷基硼构建块。

该方法具有广泛的底物范围、高官能团耐受性，以及对复杂药物分子和天然产物进行后期修饰的能力，具有高对映选择性，展示了其合成潜力。

机理研究表明，镍催化的对映收敛自由基交叉偶联途径，其中氧化还原活性酯的初级自由基，是通过Zr_III物种的单电子还原产生的。这代表了在没有光催化剂的情况下，对映选择性自由基C(sp³)-C(sp³)交叉偶联的一个前所未有的例子。

附：英文原文

Title: Enantioselective Decarboxylative C(sp3)-C(sp3) Cross-Coupling of Aliphatic Redox-Active Esters with gem-Borazirconocene Alkanes

Author: Jing Wang, Songlin Bai, Chao Yang, Xiangbing Qi

Issue&Volume: September 17, 2024

Abstract: Asymmetric decarboxylative cross-couplings of carboxylic acids are powerful methods for synthesizing chiral building blocks essential in medicinal chemistry and material science. Despite their potential, creating versatile chiral alkylboron derivatives through asymmetric decarboxylative C(sp3)-C(sp3) cross-coupling from readily available primary aliphatic acids and mild organometallic reagents remains challenging. In this study, we present a visible light-induced Ni-catalyzed enantioconvergent C(sp3)-C(sp3) cross-coupling of unactivated primary aliphatic acid NHPI esters with gem-borazirconocene alkanes, producing a diverse array of valuable chiral alkylboron building blocks. The method boasts a broad substrate scope, high functional group tolerance, and the ability for late-stage modification of complex drug molecules and natural products with high enantioselectivity, showcasing its synthetic potential. Mechanistic investigations suggest a nickel-catalyzed enantioconvergent radical cross-coupling pathway, wherein the primary radical from a redox-active ester is generated through single-electron reduction with ZrIII species. This represents an unprecedented example of enantioselective radical C(sp3)-C(sp3) cross-coupling in the absence of photocatalysts.

DOI: 10.1021/jacs.4c09245

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c09245