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In this Communication, we describe the construction of chiral α,β-unsaturated δ-lactams, widely used as pharmacophores, in high yields and excellent enantioselectivities using an oxidative relay Heck arylation reaction. This strategy also allows facile access to 7- substituted α,β-unsaturated ε-lactam products and δ- lactams containing a tetrasubstituted nitrogen-bearing stereocenter. [ABSTRACT FROM AUTHOR]

A highly efficient Ru-catalyzed asymmetric hydrogenation of α,β-unsaturated γ-lactams has been developed by using a C 2 -symmetric ruthenocenyl phosphine-oxazoline as the chiral ligand. This method achieves the enantioselective synthesis of chiral β-substituted γ-lactams in high yields and with excellent enantioselectivities (up to 99% yield with 99% ee). Mechanistic studies based on detailed control experiments and computational investigation revealed that the cationic Ru-complex acts as the active catalytic species; the protonation process of the oxa-π-allyl-Ru complex, which is formed by the migratory insertion of the C=C double bond to the Ru-H bond (the stereocontrolling step) followed by an isomerization process, is the rate-determining step, and the existence of PPh 3 is crucial for the highly efficient catalytic behavior. The protocol provides a straightforward and practical pathway for the synthesis of key intermediates for several chiral drugs and bioactive compounds, particularly for the 150 kg-scale industrial production of Brivaracetam, an antiepileptic drug that shows 13-fold more potent binding to the synaptic vesicle protein 2A compared with the well-known Levetiracetam.

An efficient iridium-catalyzed enantioselective hydrogenation of 2-alkylidene 1,4-benzoxazin-3-ones using our developed i Pr-BiphPHOX as a ligand is reported. This method showed good functional group compatibility and delivered the corresponding reduced products in excellent yields (up to 99%) with excellent enantioselectivities (up to 99% ee). The reaction proceeded very well on a gram scale with low catalyst loadings (0.1 mol %), providing the product with no erosion in enantioselectivity. Additionally, three bioactive molecules can be easily obtained from the reduced products.

Chiral γ-lactams have been synthesized in excellent yields and enantioselectivities (up to 99% yield and 96% ee) from easily accessible racemic γ-hydroxy γ-lactams via an iridium-phosphoramidite catalyzed asymmetric hydrogenation. The reaction was designed based on insight into the reaction mechanism demonstrated in previous work and can be carried out at a reduced catalyst loading of 0.1 mol % on a gram scale. Several potential bioactive compounds can be synthesized from the reduced products. Mechanistic studies indicated that the reduced products were obtained via the hydrogenation of the N-acyliminium cations, generated from γ-hydroxy γ-lactams.

An efficient asymmetric hydrogenation of β,γ-unsaturated γ-lactams using an iridium-phosphoramidite complex is reported. The chiral γ-lactams were obtained in excellent yields and enantioselectivities (up to 99% yield and 99% ee). The mechanistic studies indicated that the reduced products were obtained via the hydrogenation of the N-acyliminium cations, generated from β,γ-unsaturated γ-lactams, which was verified by 1 H NMR analysis. The reaction was carried out at a reduced catalyst loading of 0.1 mol %, and the reduced products can be transformed to two potential bioactive compounds. A new route is provided for the synthesis of chiral γ-lactams.

A Pd-catalyzed asymmetric allylic substitution with 1,3-dithianes as acyl anion equivalents has been developed in high yields and excellent enantioselectivities. The reaction was performed on a gram scale, and the corresponding alkylated products were conveniently converted into several biologically active products. This work provides an alternative strategy utilizing electrophilic carbonyl compounds as nucleophilic species in a Pd-catalyzed allylic substitution.