Asymmetric Synthesis of Spirocyclic β‐Lactams through Copper‐Catalyzed Kinugasa/Michael Domino Reactions

Abstract

The first copper-catalyzed highly chemo-, regio-, diastereo-, and enantioselective Kinugasa/Michael domino reaction for the desymmetrization of prochiral cyclohexadienones is described. In the presence of a chiral copper catalyst, alkyne-tethered cyclohexadienones couple with nitrones to generate the chiral spirocyclic lactams with excellent stereoselectivity (up to 97 % ee, >20:1 dr). The new method provides direct access to versatile highly functionalized spirocyclic β-lactams possessing four contiguous stereocenters, including one quaternary and one tetra-substituted stereocenter.

Copper(I)‐Catalyzed Asymmetric Interrupted Kinugasa Reaction: Synthesis of α‐Thiofunctional Chiral β‐Lactams

“…In 1995, the first catalytic reaction of terminal alkynes and nitrones was developd by Miura et al [9b] . Recently, the asymmetric catalytic Kinugasa reaction was realized by the Fu group and others, and provides a catalytic enantioselective synthesis of β‐lactams from readily available starting materials [9c–j] . However these reactions can only produce a 3,4‐disubstituted product ( K ).…”

“…Very recently, Enders et al. developed an intermolecualr Kinugasa reaction followed by intramolecular desymmetric Michael addition, providing spiro polycyclic β‐lactams [9j] . The complete three‐component intermolecular sequence involving the Kinugasa reaction has not been reported to date.…”

The Use of Domino Reactions for the Synthesis of Chiral Rings

“…In the same year, an asymmetric synthesis of spirocyclic lactams 169 was reported by Enders and co-workers using copper catalysis. 49 Indeed, cyclohexadienones 167 reacted with nitrones 168 in the presence of Cu(OTf) 2 and chiral bisoxazoline ligand 166 as the catalyst system to give domino products 169 in high enantioselectivities (82-97% ee), good diastereoselectivities (72 to >90% de) and moderate to excellent yields (55-94%) through consecutive Kinugasa and Michael reactions (Scheme 46).…”

Enhanced stability of highly-dispersed copper catalyst supported by hierarchically porous carbon for long term selective hydrogenation

“…Thus, plenty of works have been focused on the exploration of Cu-based catalysts, including the synthesis method, the modification of catalytic performance and so on [24]. As for synthetic strategies, the wildly used methods are ion exchange [26], wet impregnation [27], and deposition precipitation [7,8,10] and so on, which are mainly belonged to aqueous precursor solutions methods. For example, Wang have prepared Cu/TiO2 catalysts by deposition-precipitation with urea (DPu), and found that DPu time has a great effect on the structure of TiO2 supported Cu species, e.g., Cu2(OH)3NO3 and CuO for DPu of 3 and 20 h, and results in a T100% at 75 and 90 °C, respectively, under a constant Cu loading.…”