Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
Nat Commun. 2022 Sep 3;13(1):5200. doi: 10.1038/s41467-022-32851-7.
The direct modification of naturally occurring chiral amino acids to their amino ketone analogs is a significant synthetic challenge. Here, an efficient and robust cross-coupling reaction between chiral amino acid chlorides and unactivated C(sp)-H hydrocarbons is achieved by a mechanistically designed Ni/Ir photoredox catalysis. This reaction, which proceeds under mild conditions, enables modular access to a wide variety of chiral amino ketones that retain the stereochemistry of the starting amino acids. In-depth mechanistic analysis reveals that the strategic generation of an N-acyllutidinium intermediate is critical for the success of this reaction. The barrierless reduction of the N-acyllutidinium intermediate facilitates the delivery of chiral amino ketones with retention of stereochemistry. This pathway avoids the formation of a detrimental nickel intermediate, which could be responsible for undesirable decarbonylation and transmetalation reactions that limit the utility of previously reported methods.
将天然手性氨基酸直接修饰成它们的氨基酮类似物是一个重大的合成挑战。在这里，通过一种经过机制设计的 Ni/Ir 光氧化还原催化，实现了手性氨基酸氯化物与非活化 C(sp)-H 烃之间的高效、稳健的交叉偶联反应。该反应在温和条件下进行，能够模块化地获得保留起始氨基酸立体化学的各种手性氨基酮。深入的机理分析表明，策略性地生成 N-酰基六氢吡啶鎓中间体对于该反应的成功至关重要。N-酰基六氢吡啶鎓中间体的无势垒还原促进了手性氨基酮的传递，保留了立体化学。该途径避免了形成有害的镍中间体，这可能是导致以前报道的方法中出现不必要的脱羧和转金属反应的原因，这些反应限制了它们的实用性。
