Ru-Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated γ-Lactams.

A highly efficient Ru-catalyzed asymmetric hydrogenation of α,β-unsaturated γ-lactams has been developed by using a -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 is crucial for the highly efficient catalytic behavior.

Iridium-Catalyzed Asymmetric Hydroarylation of Unactivated Alkenes with Heterobiaryls: Simultaneous Construction of Axial and Central Chirality.

There are only a few examples being reported for the simultaneous control of central chirality and axial chirality because it is more challenging. Herein, we report an iridium-catalyzed asymmetric hydroarylation of unactivated alkenes with heterobiaryls to simultaneously construct axial and central chirality. The reaction showed a broad substrate scope and delivered the products with satisfactory results.

Iridium-Catalyzed Asymmetric Hydrogenation of Unfunctionalized Cycloalkenes to Access Chiral 2-Aryl Tetralins.

The transition-metal catalyzed asymmetric hydrogenation of unfunctionalized alkenes is challenging. Herein, we report an efficient iridium-catalyzed asymmetric hydrogenation of unfunctionalized cycloalkenes, delivering chiral 2-aryl tetralins in excellent yields and with moderate to excellent enantioselectivities. The reaction can be performed on a gram-scale with a low catalyst loading (S/C = 1000), and the reduced product was obtained without erosion of the enantioselectivity.

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.

Iridium-Catalyzed Remote Site-Switchable Hydroarylation of Alkenes Controlled by Ligands.

An iridium-catalyzed remote site-switchable hydroarylation of alkenes was reported, delivering the products functionalized at the subterminal methylene and terminal methyl positions on an alkyl chain controlled by two different ligands, respectively, in good yields and with good to excellent site-selectivities. The catalytic system showed good functional group tolerance and a broad substrate scope, including unactivated and activated alkenes. More importantly, the regioconvergent transformations of mixtures of isomeric alkenes were also successfully realized.

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.

Axis-Unfixed Biphenylphosphine-Oxazoline Ligands: Design and Applications in Asymmetric Catalytic Reactions.

The design and synthesis of chiral ligands plays an important role in asymmetric catalytic reactions. Over the past decades, various types of chiral phosphine-oxazolines (PHOX ligands) have been developed and have greatly advanced the field of asymmetric catalysis. Novel chiral PHOX ligand with an axis-unfixed biphenyl backbone, developed by our group, have shown interesting coordination behavior and excellent chiral inducing ability in various transition-metal-catalyzed asymmetric reactions.

Synergistic Li/Li Bimetallic System for the Asymmetric Synthesis of Antituberculosis Drug TBAJ-587.

TBAJ-587, an analogue of the antituberculosis drug bedaquiline (BDQ), bearing a diarylquinoline skeleton retains the high bacterial potency, is less toxic, and has a better pharmacokinetic profile than the parent molecule, which has entered phase I clinical trials. In contrast to its fascinating bioactivity, however, the highly efficient synthesis of this molecule is still an unsolved challenge. Herein, the first asymmetric synthesis of TBAJ-587 based on a synergistic Li/Li bimetallic system is reported.

Iridium-Catalyzed 1,3-Rearrangement of Allylic Alcohols.

The allylic alcohol structural motif is prevalent in many important molecules and valuable building blocks. The rearrangement reaction is one of the most important transformations, however there are only a few reports for the 1,3-rearrangement of allylic alcohols. Herein, a 1,3-rearrangement of allylic alcohols catalyzed by an Ir(III) dihydride complex is described.

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 C═C 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.

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-2-benzo[][1,4]oxazocines, affording enantiomerically enriched 3,4-dihydro-2-1,4-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).

Synthesis of Chiral 2-Substituted 1,4-Benzoxazin-3-ones via Iridium-Catalyzed Enantioselective Hydrogenation of Benzoxazinones.

An efficient iridium-catalyzed enantioselective hydrogenation of 2-alkylidene 1,4-benzoxazin-3-ones using our developed 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.

Enantioselective Synthesis of γ-Functionalized Cyclopentenones and δ-Functionalized Cycloheptenones Utilizing a Redox-Relay Heck Strategy.

In this report, the desymmetrization of cyclic enones under relay Heck conditions with an array of aryl boronic acids, alkenyl triflates and indole derivatives is described. This method grants facile access to diverse γ-functionalized cyclopentenones and δ-functionalized cycloheptenones. Using this approach, a formal synthesis of ()-baclofen was completed in high yield and excellent enantioselectivity.

Catalytic Asymmetric Synthesis of the anti-COVID-19 Drug Remdesivir.

The catalytic asymmetric synthesis of the anti-COVID-19 drug Remdesivir has been realized by the coupling of the P-racemic phosphoryl chloride with protected nucleoside GS441524. The chiral bicyclic imidazole catalyst used is crucial for the dynamic kinetic asymmetric transformation (DyKAT) to proceed smoothly with high reactivity and excellent stereoselectivity (96 % conv., 22:1 S :R ).

Enantioselective construction of remote tertiary carbon-fluorine bonds.

The carbon-fluorine bond engenders distinctive physicochemical properties and significant changes to general reactivity. The development of catalytic, enantioselective methods to set stereocentres that contain a benzylic C-F bond is a rapidly evolving goal in synthetic chemistry. Although there have been notable advances that enable the construction of secondary stereocentres that contain both a C-F and a C-H bond on the same carbon, significantly fewer strategies are defined to access stereocentres that incorporate a tertiary C-F bond, especially those remote from pre-existing activating groups.

Palladium-Catalyzed Enantioselective Alkenylation of Enelactams Using a Relay Heck Strategy.

In this report, a palladium-catalyzed redox-relay Heck process to access optically active alkenylated α,β-unsaturated lactams is described. Under mild reaction conditions, electron-deficient alkenyl triflates and electron-rich alkenyl iodonium salts undergo enantioselective and site-selective coupling with enelactams to deliver the products in high yields and excellent enantioselectivities. Furthermore, the products allow facile access to natural products such as (+)-calvine and (+)-2-epicalvine in addition to the bioactive molecule aza-goniothalamin.

Pd-catalyzed asymmetric allylic substitution cascade using α-(pyridin-1-yl)-acetamides formed as nucleophiles.

A Pd-catalyzed asymmetric allylic substitution cascade reaction, using α-(pyridin-1-yl)-acetamides (formed ) as nucleophiles, has been developed, generating chiral piperidine-containing amino acid derivatives a one-pot procedure in high yields and with up to 96% ee. The products can be easily converted into potential bioactive compounds, unnatural chiral amino acids and dipeptides.

Enantioselective C2-Alkylation of Indoles through a Redox-Relay Heck Reaction of 2-Indole Triflates.

A palladium-catalyzed enantioselective redox-relay Heck reaction of 2-indole triflates and disubstituted alkenes is reported. This process combines readily available indole triflates with a variety of alkenes to afford a range of indole derivatives bearing a stereocenter adjacent to C2. Enantioselectivity is achieved through use of a simple pyridine-oxazoline ligand.

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.

Synthesis of Chiral γ-Lactams via in Situ Elimination/Iridium-Catalyzed Asymmetric Hydrogenation of Racemic γ-Hydroxy γ-Lactams.

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.

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 H NMR analysis.

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.

Iridium-catalyzed allyl-allyl cross-coupling of allylic carbonates with (E)-1,3-diarylpropenes.

An efficient Ir-catalyzed allyl-allyl cross-coupling reaction of allylic carbonates with (E)-1,3-diarylpropenes was developed to form linear allylated products, 1,5-dienes, regioselectively in excellent yields and with high turnover numbers (up to 2000 S/Ir).

Synthesis of the scalarane sesterterpenoid 16-deacetoxy-12-epi-scalarafuranacetate.

The marine natural product 16-deacetoxy-12-epi-scalarafuranacetate, isolated from Spongua officinalis , was synthesized in 18 linear steps, starting from (-)-sclareol, with high stereoselectivity and an overall yield of 6.1%. The intermediate 16-deacetoxy-12-epi-scalarafuran could be easily transformed into a series of natural scalarane sesterterpenoids in a few steps.