Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei 230026, China.
Center for Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, Hefei 230026, China.
J Am Chem Soc. 2021 Dec 8;143(48):20454-20461. doi: 10.1021/jacs.1c10721. Epub 2021 Nov 24.
Asymmetric functionalization of the C(sp)-H bond is an attractive yet challenging strategy to achieve versatile bond-forming events, enabling the precise assembly of molecular complexity with minimal manipulation of functional groups. Here, we report an asymmetric C(sp)-H/C(sp)-H umpolung coupling of -allylimine and coordinating α-aryl carbonyls by using chiral phosphoramidite-palladium catalysis. A wide variety of α-heteroaryl ketones and 2-acylimidazoles are nicely tolerated to open a convenient and tunable avenue for efficient synthesis of enantioenriched β-amino-γ,δ-unsaturated carbonyl derivatives with high levels of regio- and stereoselectivities, capable of providing a key intermediate for asymmetric synthesis of Focalin. This protocol showcases an umpolung reactivity of the -allylimines through a concerted proton and two-electron transfer process to cleave the allylic C-H bond, effectively complementing established methodology for allylic C-H functionalization. An inner-sphere allylation pathway for both α-heteroaryl carbonyls and 2-acylimidazoles to attack the π-allylpalladium species is suggested by computational studies and experimental facts, wherein the nitrogen coordination to the palladium center enables the preference of branched regioselectivity.
C(sp)-H 键的不对称功能化是一种很有吸引力但具有挑战性的策略，可以实现多种键形成事件，通过最小限度地官能团操作，实现分子复杂性的精确组装。在这里，我们报告了通过手性膦酰胺-钯催化，-烯丙基亚胺和配位的α-芳基羰基的不对称 C(sp)-H/C(sp)-H 反转偶联。各种α-杂芳基酮和 2-酰基咪唑都可以很好地耐受，为高效合成具有高区域和立体选择性的对映体富集的β-氨基-γ,δ-不饱和羰基衍生物开辟了一条方便且可调的途径，能够为不对称合成 Focalin 提供关键中间体。该方案通过协同质子和两电子转移过程展示了-烯丙基亚胺的反转反应性，有效地补充了已建立的烯丙基 C-H 功能化方法。计算研究和实验事实表明，对于两种α-杂芳基羰基和 2-酰基咪唑，都存在一个内球烯丙基化途径来攻击π-烯丙基钯物种，其中氮与钯中心的配位使支化区域选择性成为可能。
