Nickel-Catalyzed Enantioselective Hydrophosphinylation of 2‑Azadienes to Access Enantioenriched α‑Aminophosphine Oxides

The practical synthesis of C-stereogenic α-aminophosphine
oxides, which exhibit a wide range of applications in medicinal chemistry,
biochemistry, material science, and asymmetric catalysis, represents
an unmet need. Herein, a Ni/(S,S)-BenzP* catalyst system is developed for asymmetric synthesis of
branched α-aminophosphine oxides through an enantioselective
Markovnikov addition of H-phosphine oxides to 2-azadienes. A variety
of readily available 2-azadienes and H-phosphine oxides undergo hydrophosphinylation
with high enantioselectivities (up to 99%) and good yields (up to
96%). These products can be readily hydrolyzed to afford synthetically
valuable chiral α-aminophosphine oxides, which are key building
blocks for the synthesis of bioactive compounds (such as phospholeucine
synthesized herein), organocatalysts, and ligands. Mechanistic studies
suggest a hydrofunctionalization process.

含碳立体中心的α-氨基膦氧化物（α-aminophosphine oxides）在药物化学、生物化学、材料科学及不对称催化领域拥有广泛应用，但其实用化合成方法仍存在未被满足的需求。本研究开发了一种镍/(S,S)-BenzP*催化剂体系，通过H-膦氧化物对2-氮杂二烯的对映选择性马氏加成（Markovnikov）反应，实现支链型α-氨基膦氧化物的不对称合成。多种易得的2-氮杂二烯与H-膦氧化物可发生氢膦酰化反应，该反应表现出优异的对映选择性（最高可达99%）与良好的收率（最高可达96%）。所得产物可经简便水解得到具有合成价值的手性α-氨基膦氧化物，这类化合物是合成生物活性分子（如本文中合成的膦亮氨酸（phospholeucine））、有机催化剂及配体的关键合成砌块。机理研究表明该反应遵循氢官能化过程。