Chiral Ugi-Type Amines: Practical Synthesis, Ligand Development, and Asymmetric Catalysis

Ugi’s amine has become one type of privileged chiral skeleton for chiral ligand design bearing central/planar chirality, and such ligands have exhibited tremendous success in various asymmetric catalysis. However, the current access to enantiopure Ugi’s amine is quite tedious and relies heavily on optical resolution, which impedes its practical applications, to some extent. Herein, we present a facile asymmetric synthesis of enantioenriched Ugi-type amines bearing a long-carbon chain through Ir-catalyzed cascade allylation/2-aza-Cope rearrangement, followed by amino exchange and Pd/C-catalyzed one-pot hydrogenation/reductive amination. The protocol could be readily scaled up, and it has been conducted in 20-g-scale asymmetric synthesis of (S)-Ugi-type amine from commercially available reagents, in >99% ee and >70% overall yield in four steps with one short silica gel-plug purification. (S,Rp)-PPFA-type and (S,Rp)-Josiphos-type ligands, readily prepared from the achieved Ugi-type amine, exhibited higher or comparable asymmetric induction and catalytic efficacy in several Cu­(I)-catalyzed asymmetric reactions, which indicated great potential of the applications of the readily accessible Ugi-type amines in ligand/catalyst design.乌吉胺（Ugi’s amine）已成为兼具中心/平面手性的手性配体设计领域一类优势手性骨架，此类配体在各类不对称催化反应中已取得巨大成功。然而，当前获取对映纯乌吉胺的方法仍较为繁琐，且高度依赖光学拆分，这在一定程度上限制了其实际应用。在此，我们报道了一种简便的不对称合成方法，可制备带有长碳链的对映富集乌吉类胺：先通过铱（Ir）催化的级联烯丙基化/2-氮杂-Cope重排反应，再依次经氨基交换与钯碳（Pd/C）催化的一锅法氢化/还原胺化过程。该合成策略可轻松放大制备，我们已利用市售原料，通过四步反应、仅需一次短硅胶柱快速纯化，以对映体过量值（ee）>99%、总收率>70%的结果，实现了20克级规模的(S)-乌吉类胺不对称合成。从所得乌吉类胺可便捷制备(S,Rp)-PPFA型与(S,Rp)-Josiphos型配体，此类配体在数种一价铜（Cu(I)）催化的不对称反应中展现出更优或相当的不对称诱导效果与催化效能，这表明易获取的乌吉类胺在配体/催化剂设计中具备巨大的应用潜力。