Asymmetric Synthesis of Quaternary Hydantoins via a Palladium-Catalyzed Aza-Heck Cyclization

An asymmetric, palladium-catalyzed aza-Heck cyclization to prepare enantioenriched 5,5-disubstituted hydantoins (quaternary hydantoins), which are medicinally important compounds but are classically challenging to prepare, is reported. The required substrates can be prepared readily from α,β-unsaturated amides in a single operation, and aza-Heck cyclization provides a wide range of topologically complex, highly substituted, pharmaceutically relevant hydantoins. The capacity of this method to impact the synthesis of drug substances is demonstrated by the first asymmetric synthesis of the anticonvulsant (R)-mephenytoin.本研究报道了一种不对称钯催化氮杂Heck（aza-Heck）环化反应，用于制备对映富集的5,5-二取代乙内酰脲（季碳乙内酰脲）。该类化合物虽具有重要药用价值，但传统合成方法颇具挑战性。所需反应底物可通过α,β-不饱和酰胺经一步操作便捷制备，该氮杂Heck环化反应可得到一系列拓扑结构复杂、高度取代且与药学研究相关的乙内酰脲类化合物。本研究通过抗惊厥药(R)-美芬妥英的首例不对称合成，验证了该方法在药物合成中的应用潜力。