Copper-Catalyzed Asymmetric Hydroamination: A Unified Strategy for the Synthesis of Chiral β-Amino Acid and Its Derivatives

Abstract

Catalytic asymmetric aza-Michael represents one of the most convenient and atom-economical approaches for the rapid construction of biologically active chiral β-amino acid frameworks. However, the direct enantioselective addition of nitrogen-based nucleophiles to intrinsically low reactivity of α,βunsaturated carboxylic acid, ester, and amide, as well as simple α,β-unsaturated nitrile, remains a long-standing challenge. Herein, we report a unified Cu-catalyzed asymmetric reversal hydroamination, capable of direct preparation of a series of β-amino acid, ester, amide, and nitrile in a highly regio-and enantioselective manner, without the requirement of traditional preinstallation of stoichiometric quantities of auxiliaries.

Asymmetric hydroamination with far fewer chiral species than copper centers achieved by tuning the structure of supramolecular helical catalysts

“…The asymmetric Cu–H promoted hydroamination of alkenes 55–57 is performed efficiently by a relatively narrow number of chiral diphosphine ligands, 58–83 with particularly strong effects exerted by substituents located on the aryl rings attached to the phosphorus atom. 84,85 In addition to BTA ligands, BTA P H and BTA P Me , previously investigated in the copper-catalysed hydrosilylation of acetophenone derivatives, 51,52,54 it appears desirable to investigate more electron poor ligands as it may facilitate the hydrocupration step of the catalytic cycle.…”

Catalytic Asymmetric Hydroalkylation of α,β-Unsaturated Amides Enabled by Regio-Reversed and Enantiodifferentiating syn-Hydronickellation

“…Previously, when electron-deficient alkenes such as β-alkyl-α,β-unsaturated carbonyl compounds were used in hydrocupration reactions, an α-copper intermediate was produced in a manner consistent with the electronic requirements which limited the subsequent functionalization to the α-position (Figure b, left). , To overcome the electronic effect and reverse the classical regioselectivity of hydrometalation, we questioned if the coordination effect of a certain metal hydride with a carbonyl group could predominate and whether the stereoselectivity could be simultaneously controlled. − In such a case, a wide range of structurally diverse, enantiopure β-functionalized carbonyl compounds could be obtained (Figure b, right). As shown in Figure c, we speculated that the amide group could serve as a good directing group for an appropriately ligated NiH species to undergo a regio-reversed syn -hydronickellation and then form a five-membered nickellacycle. − In terms of enantiomeric control, such a hydrometalation step with an appropriate chiral ligand could be enantioselective producing enantioenriched β-alkylnickel intermediates, which could undergo subsequent stereospecific cross-coupling with alkyl iodides to produce the enantioenriched β-alkylation product .…”

Enantioselective copper-catalysed cascade hydroboration and hydroallylation of alkynes to access chiral homoallylic boronates

“…6d). Based on these control experiments and the present related literature, [51][52][53][57][58][59][60][61][62][63][65][66][67][68] a proposed mechanistic picture for this cascade asymmetric hydroboration and hydroallylation of alkynes was shown in Fig. 6e.…”