Palladium-Catalyzed Enantioselective Relay Heck Arylation of Enelactams: Accessing α,β-Unsaturated δ‑Lactams

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

Iridium-Catalyzed Asymmetric Hydrogenation of β,γ-Unsaturated γ‑Lactams: Scope and Mechanistic Studies

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 1H 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

Iridium-Catalyzed Asymmetric Hydrogenation of β,γ-Unsaturated γ‑Lactams: Scope and Mechanistic Studies

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 <i>N</i>-acyliminium cations, generated from β,γ-unsaturated γ-lactams, which was verified by ¹H 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

Nickel-Catalyzed Hydroamination and Hydroalkoxylation of Enelactams with Unactivated Amines and Alcohols

Nickel-catalyzed hydroamination and hydroalkoxylation of enelactams with unactivated amines and alcohols are reported. This method showed good functional group tolerance and delivered the corresponding hydrofunctionalized products in good to excellent yields (≤98%). Furthermore, an intramolecular hydroalkoxylation of an enelactam was also realized, giving a cyclization product in a good yield. Mechanistic studies indicated that tBuI acts as a hydride donor and radical precursor, which is crucial for the success of the reaction

Iridium-Catalyzed Double Asymmetric Hydrogenation of 2,5-Dialkylienecyclopentanones for the Synthesis of Chiral Cyclopentanones

Herein, we report an efficient iridium-catalyzed double asymmetric hydrogenation of 2,5-dialkylienecyclopentanones, delivering the chiral 2,5-disubstituted cyclopentanones in excellent yields and stereoselectivities. The results of the kinetic experiments and control experiments indicated that the two CC bonds were hydrogenated in a stepwise manner and the second stereocenter was synergistically controlled by the chiral catalyst and the chirality of monohydrogenated product. The hydrogenated products can be prepared on a gram-scale and are easily derivatized

Nickel-Catalyzed Remote C(sp³)–N/O Bond Formation of Alkenes with Unactivated Amines and Alcohols

Transition metal-catalyzed remote hydrofunctionalization of alkenes is an efficient method to realize C(sp3)–H functionalization. However, remote hydrofunctionalization of alkenes with unactivated amines and alcohols has not been successfully developed to date. Herein, we report an efficient nickel-catalyzed remote hydroamination and hydroetherification of alkenes with unactivated amines and alcohols, accessing a series of gem-diamine and N,O-acetal derivatives in good to high yields (up to 93%) and exclusive regioselectivities. The mechanistic investigations and DFT computations indicated that the use of 2-iodo-2-methylpropane (tBuI) as both a mild hydride source and radical precursor was essential to afford the remote functionalized products. This research work provides an efficient method to install an amino or alkoxyl group at the C(sp3)–H position that is far from the double bond of alkenes

Iridium-Catalyzed 1,3-Rearrangement of Allylic Ethers

The 1,3-rearrangement of allylic derivatives has rarely been reported, except for allylic alcohols. Herein, we describe an iridium-catalyzed 1,3-rearrangement of readily available allylic ethers to access the difficultly prepared allylic ethers with a large steric hindrance. The developed method shows a broad substrate scope and could be used in the late-stage modification of several natural products. In addition, a possible reaction pathway is also provided on the basis of the control experiments

1,3-Dithianes as Acyl Anion Equivalents in Pd-Catalyzed Asymmetric Allylic Substitution

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

Pd(II)-Catalyzed Enantioselective Ring-Contraction for the Construction of 1,4-Benzoxazines

Enantioselective ring-contraction reactions have not been widely reported. We have developed an enantioselective ring contraction of 5,6-dihydro-2H-benzo­[b]­[1,4]­oxazocines, affording enantiomerically enriched 3,4-dihydro-2H-1,4-benzoxazine derivatives as single regioisomers. An acidic additive is necessary in order to obtain the products with good yields and enantiomeric ratios (up to 93% yield, 98:2 er). The reaction was successfully performed on a gram scale, and the products can be derivatized easily

Asymmetric Hydrogenation of Tetrasubstituted α,β-Unsaturated Ketones: Access to Chiral 2‑Substituted Cyclopentyl Aryl Ketones

Asymmetric hydrogenation of tetrasubstituted alkenes is an important but challenging research topic. Herein, we report an efficient iridium-catalyzed asymmetric hydrogenation of tetrasubstituted α,β-unsaturated ketones for the synthesis of chiral 2-substituted cyclopentyl aryl ketones, an important chiral structural motif for the preparation of chiral pharmaceuticals and bioactive molecules. The reaction proceeded very well with good functional group compatibility and delivered the hydrogenated products in high yields and stereoselectivities (up to 99% yield, >20:1 dr and 99% ee). In addition, the reaction could be carried out on a gram-scale, and all four stereoisomers of the hydrogenated products bearing two contiguous stereocenters were obtained. Furthermore, the hydrogenated product can be transformed into the ERβ agonist Erteberel, and the reaction pathway was also studied via deuterium-labelling experiments