Enantioselective Alkylation Research Articles

Organocatalytic Enantioselective Vinylogous Allylic Alkylation between β,γ‐Unsaturated Pyrazoleamides and MBH Carbonates

AbstractThe direct asymmetric vinylogous allylic alkylation is an efficient method to construct chiral 1,5‐diene compounds. In this work, acyclic unsaturated amides are used as a nucleophile for enantioselective vinylogous allylic alkylation. With 10 mol % of chiral tertiary amine C11, the enantioselective vinylogous allylic alkylation between β,γ‐unsaturated pyrazoleamides and Morita‐Baylis‐Hillman carbonates is achieved, affording optically active multifunctional chiral 1,5‐dienes in moderate‐to‐excellent yields (74–99 %) with good‐to‐excellent enantioselectivities (67–94 % ee).

Catalytic Enantioselective Friedel–Crafts Allenylation

AbstractThe first enantioselective Friedel‐Crafts (FC) allenylation reaction for the creation of central chirality is developed under cooperative Ir(I)/(phosphoramidite,olefin) and Lewis acid catalysis. This enantioconvergent reaction utilizes racemic allenylic alcohol as the electrophile and shows compatibility with a variety of electron‐rich arenes and heteroarenes. The resulting highly enantioenriched (up to >99.5 : 0.5 e.r.) 1,1‐disubstituted allenylic methanes, bearing a benzylic carbon stereocenter, are obtained with complete regiocontrol – both on (hetero)arenes as well as on the allenylic fragment. This protocol allows for the enantioselective formal introduction of a 4‐carbon alkyl chain into (hetero)arenes, along with the creation of a benzylic stereocenter. Judicious synthetic elaborations not only lead to formal enantioselective FC alkylation products of less electron‐rich arenes but also of substituted arenes in ortho‐ and even meta‐selective fashion. An intramolecular version of this FC allenylation is shown to proceed with promising enantioselectivity under the same catalytic conditions. Mechanistic studies revealed the involvement of dynamic kinetic asymmetric transformation (DyKAT) of racemic allenylic alcohols in this reaction.

Catalytic Enantioselective Friedel-Crafts Allenylation.

The first enantioselective Friedel-Crafts (FC) allenylation reaction for the creation of central chirality is developed under cooperative Ir(I)/(phosphoramidite,olefin) and Lewis acid catalysis. This enantioconvergent reaction utilizes racemic allenylic alcohol as the electrophile and shows compatibility with a variety of electron-rich arenes and heteroarenes. The resulting highly enantioenriched (up to >99.5 : 0.5 e.r.) 1,1-disubstituted allenylic methanes, bearing a benzylic carbon stereocenter, are obtained with complete regiocontrol - both on (hetero)arenes as well as on the allenylic fragment. This protocol allows for the enantioselective formal introduction of a 4-carbon alkyl chain into (hetero)arenes, along with the creation of a benzylic stereocenter. Judicious synthetic elaborations not only lead to formal enantioselective FC alkylation products of less electron-rich arenes but also of substituted arenes in ortho- and even meta-selective fashion. An intramolecular version of this FC allenylation is shown to proceed with promising enantioselectivity under the same catalytic conditions. Mechanistic studies revealed the involvement of dynamic kinetic asymmetric transformation (DyKAT) of racemic allenylic alcohols in this reaction.

Enantioselective S-Alkylation of Sulfenamides by Phase-Transfer Catalysis.

A general phase-transfer catalyst (PTC) mediated enantioselective alkylation of N-acylsulfenamides is reported. Essential to achieving high selectivity was the use of the triethylacetyl sulfenamide protecting group along with aqueous KOH as the base under biphasic aqueous conditions to enable the reaction to be performed at -40 °C. With these key parameters, enantiomeric ratios up to 97.5 : 2.5 at the newly generated chiral sulfur center were achieved with an inexpensive cinchona alkaloid derived PTC. Broad scope and excellent functional group compatibility was observed for a variety of S-(hetero)aryl and branched and unbranched S-alkyl sulfenamides. Moreover, to achieve high selectivity for the opposite enantiomer, a pseudoenantiomeric catalyst was designed and synthesized from inexpensive cinchonidine. Given that sulfoximines are a bioactive pharmacophore of ever-increasing interest, selected product sulfilimines were oxidized to the corresponding sulfoximines with subsequent reductive cleavage affording the free-NH sulfoximines in high yields. The utility of the disclosed method was further demonstrated by the efficient asymmetric synthesis of atuveciclib, a phase I clinical candidate for which only chiral HPLC separation had previously been reported for isolation of the desired (R)-sulfoximine stereoisomer.

Nickel/Photoredox-Catalyzed Asymmetric Three-Component Cross-Coupling To Access Enantioenriched 1,1-Diaryl(heteroaryl)alkanes.

An enantioselective 1,2-dicarbofunctionalization of vinyl (hetero)arenes with alkyl bromides and aryl bromides through nickel/photoredox catalysis is described. This three-component enantioselective domino alkyl arylation of vinyl (hetero)arenes could generate a diverse array of enantioenriched 1,1-diaryl(heteroaryl)alkanes with good to excellent yields (up to 88%) and high enantioselectivities (up to 99% ee). This transformation could proceed well under mild conditions with excellent chemo- and regioselectivity due to the avoidance of the use of air- and moisture-sensitive organometallic reagents and stoichiometric metal reductants. Mechanistic studies suggested that the alkyl radical is generated via NiI species or photocatalyst.

Nickel-Catalyzed Enantioselective Alkylation of Primary Phosphines.

Functional molecules derived from stereogenic phosphorus centers have important applications in the discovery of drugs and agrochemicals. They are also widely utilized as chiral ligands or organocatalysts for diverse asymmetric transformations. However, access to P-stereogenic motifs has always been regarded as a highly challenging yet desirable goal in organic synthesis. The development of general and practical methods for the stereoselective construction of synthetically versatile P(III)-stereogenic phosphines is particularly appealing but remains elusive. Herein, we describe a nickel-catalyzed asymmetric alkylation of primary phosphines with alkyl halides for the synthesis of P-stereogenic secondary phosphine-boranes with high enantioselectivity and broad substrate scope. The resulting optically active secondary phosphine-boranes allow for further stereospecific transformations, thereby establishing a modular and efficient platform for the diversity-oriented construction of P-stereogenic phosphine compounds.

Synthesis of chiral sulfilimines by organocatalytic enantioselective sulfur alkylation of sulfenamides.

Sulfilimines are versatile synthetic intermediates and important moieties in bioactive molecules. However, their applications in drug discovery are underexplored, and efficient asymmetric synthetic methods are highly desirable. Here, we report a transition metal-free pentanidium-catalyzed sulfur alkylation of sulfenamides with exclusive chemoselectivity over nitrogen and high enantioselectivity. The reaction conditions were mild, and a wide range of enantioenriched aryl and alkyl sulfilimines were obtained. The synthetic utility and practicability of this robust protocol were further demonstrated through gram-scale reactions and late-stage functionalization of drugs.

Enantioselective S‐Alkylation of Sulfenamides by Phase‐Transfer Catalysis

AbstractA general phase‐transfer catalyst (PTC) mediated enantioselective alkylation of N‐acylsulfenamides is reported. Essential to achieving high selectivity was the use of the triethylacetyl sulfenamide protecting group along with aqueous KOH as the base under biphasic aqueous conditions to enable the reaction to be performed at −40 °C. With these key parameters, enantiomeric ratios up to 97.5 : 2.5 at the newly generated chiral sulfur center were achieved with an inexpensive cinchona alkaloid derived PTC. Broad scope and excellent functional group compatibility was observed for a variety of S‐(hetero)aryl and branched and unbranched S‐alkyl sulfenamides. Moreover, to achieve high selectivity for the opposite enantiomer, a pseudoenantiomeric catalyst was designed and synthesized from inexpensive cinchonidine. Given that sulfoximines are a bioactive pharmacophore of ever‐increasing interest, selected product sulfilimines were oxidized to the corresponding sulfoximines with subsequent reductive cleavage affording the free‐NH sulfoximines in high yields. The utility of the disclosed method was further demonstrated by the efficient asymmetric synthesis of atuveciclib, a phase I clinical candidate for which only chiral HPLC separation had previously been reported for isolation of the desired (R)‐sulfoximine stereoisomer.

Enantioselective Alkylation of Ketones In Flow

Enantioselective Alkylation of Ketones In Flow

Enantioselective Friedel-Crafts alkylation of 1,3,5-trimethoxybenzene with trans-β-nitrostyrenes catalysed by [Cp*Rh{(R)-Prophos}(H2O)][SbF6]2 (Prophos = propane-1,2-diyl-bis(diphenylphosphane)

The aqua complex (SRh,RC)-[Cp*Rh{(R)-Prophos}(H2O)][SbF6]2 (Prophos = propane-1,2-diyl-bis(diphenylphosphane) catalyses the asymmetric Friedel-Crafts (FC) alkylation of 1,3,5-trimethoxybenzene with trans-β-nitrostyrenes. Only the monoalkylated adduct was obtained in all cases with enantioselectivities of up to 93/7 e.r. Solution NMR measurements have allowed us to detect and characterise catalytic intermediates such as metal-trans-β-nitrostyrene and metal‑aci-nitro complexes, as well as free aci‑nitro compound. Based on these studies, a Michael-type Friedel-Crafts mechanism is proposed.

En Route to Enantioenriched Quaternary Stereocenters via Lewis Base/Palladium Cooperative Catalysis

AbstractThe prevalence of quaternary stereogenic centers in bioactive molecules coupled with innate challenges associated with their enantioselective preparation continues to provide powerful impetus for the development of catalytic asymmetric methods capable of their construction. Herein, we describe a cooperative isothiourea Lewis base‐palladium catalyst system that enables the enantioselective alkylation of α‐substituted‐α‐cyano esters with allyl methanesulfonate. While the levels of enantioselection are modest, this study represents the first time we have successfully constructed quaternary‐substituted stereogenic centers using this Lewis base‐palladium cooperative catalysis scheme. Further, this strategy constitutes a departure from ligand‐based enantiocontrol and suggests that, when using acidic pro‐nucleophiles, the development of protocols where Lewis base catalysis can outcompete direct deprotonation might be within reach.

Catalytic Enantioselective Propargylation of Pyrazolones by Amide-Based Phase-Transfer Catalysts.

In this paper, we developed a highly enantioselective alkylation of 4-substituted pyrazolones catalyzed by phase-transfer catalysis. Cheap halohydrocarbons were employed as electrophilic alkylationg agents, and propargyl, allyl, and benzyl products with all-carbon quaternary stereocenters were afforded with excellent enantioselectivities and good yields. We found that the unique structures of the catalyst (hydrogen bond donors of the C-9 hydroxyl group and amide group, the triphenyl at the NH-position) were important for good enantioselectivity. Furthermore, chiral propargyl products could be easily connected to azide molecules by click cycloaddition, which offers unique opportunities to obtain structurally diverse chiral pyrazolones.

Asymmetric Paired Electrolysis: Enantioselective Alkylation of Sulfonylimines via C(sp3)-H Functionalization.

Enantioselective transformation of ubiquitous C(sp3)-H bonds into three-dimensional chiral scaffolds is of longstanding interest to synthetic chemists. Herein, an asymmetric paired electrolysis enables a highly efficient and sustainable approach to the enantioselective alkylation of sulfonylimines via C(sp3)-H functionalization. In this protocol, anodic oxidation for benzylic radical formation and Lewis acid-catalyzed sulfonylimine reduction on the cathode were seamlessly cross-coupled (up to 88 % yield). Enantioenriched chiral amines containing a tetrasubstituted carbon stereocenter are accessed with high enantioselectivity (up to 96 % ee). Mechanistic studies suggest that the amine generated in situ could serve as a base to deprotonate phenols and decrease the oxidation potential of the reaction, allowing phenols with lower potentials to be preferentially oxidized.

Asymmetric Paired Electrolysis: Enantioselective Alkylation of Sulfonylimines via C(sp3)−H Functionalization

AbstractEnantioselective transformation of ubiquitous C(sp3)−H bonds into three‐dimensional chiral scaffolds is of longstanding interest to synthetic chemists. Herein, an asymmetric paired electrolysis enables a highly efficient and sustainable approach to the enantioselective alkylation of sulfonylimines via C(sp3)−H functionalization. In this protocol, anodic oxidation for benzylic radical formation and Lewis acid‐catalyzed sulfonylimine reduction on the cathode were seamlessly cross‐coupled (up to 88 % yield). Enantioenriched chiral amines containing a tetrasubstituted carbon stereocenter are accessed with high enantioselectivity (up to 96 % ee). Mechanistic studies suggest that the amine generated in situ could serve as a base to deprotonate phenols and decrease the oxidation potential of the reaction, allowing phenols with lower potentials to be preferentially oxidized.

Nickel- and Photocatalytic Enantioselective Alkylation of α-Amino C(sp3)–H Bonds

Nickel- and Photocatalytic Enantioselective Alkylation of α-Amino C(sp3)–H Bonds

Unconventional Ligand‐to‐Catalyst Ratio for the Distal C−C Bond Formation via C−H Activation and Chain‐Walking

AbstractA mechanism‐navigated enantioselective alkylation of an indole C2 C−H bond with an internal alkene was developed. Under the unconventional ligand‐to‐metal catalyst ratio, a moderate enantiomeric ratio (er), ranging from 70:30 to 88:12, was achieved with our original ligand. We propose that chain‐walking and bond formation are mechanistically independent and suggest that hydridoiridium generated from the C−H source does not play a role in the chain‐walking process.

Enantioselective alkyl–alkyl coupling by Ni-catalysed asymmetric cross-hydrodimerization of alkenes

Enantioselective alkyl–alkyl coupling by Ni-catalysed asymmetric cross-hydrodimerization of alkenes

Visible-Light-Promoted Enantioselective Acylation and Alkylation of Aldimines Enabled by 9-Fluorenone Electron-Shuttle Catalysis.

Chiral acyclic α-tertiary amino ketones are widely present in various natural products and pharmaceuticals; however, the direct synthesis of this pharmacophore through a robust strategy still presents significant challenges. The emerging photocatalysis provides a powerful approach to construct chemical bonds that are difficult to form via a traditional two-electron pathway. Herein, we developed visible-light-induced chiral Lewis acid-catalyzed highly enantioselective acylation/alkylation of aldimines enabled by cooperative FLN (9-fluorenone) electron-shuttle catalysis via radical addition. An array of α-tertiary amino ketones, β-amino alcohols, and chiral amines were achieved with high yields and good to excellent stereocontrol (87 examples, up to 84% yield, 96% ee). These products can be easily transformed into valuable and bioactive skeletons. Extensive control experiments, detailed mechanism studies, and density functional theory calculations elucidated the reaction process and highlighted the crucial role played by FLN.

Enantioselective alkylation of α-amino C(sp3)−H bonds via photoredox and nickel catalysis

Enantioselective alkylation of α-amino C(sp3)−H bonds via photoredox and nickel catalysis

Phosphine-Catalyzed Asymmetric Allylic Alkylation of Isoxazol-5(4H)-ones with Morita-Baylis-Hillman Carbonates

Aims: Phosphine-catalyzed asymmetric allylic alkylation of isoxazol-5(4H)-ones with achiral Morita-Baylis-Hillman (MBH) carbonates has been developed. A series of isoxazol-5(4H)- ones bearing all-carbon quaternary stereocenters were obtained in 55-96% yield with 75-90% ee. Gram-scale reaction and further transformation of allylation products were conducted to demonstrate the synthetic practicability. Methods: Under Ar atmosphere, the mixture of isoxazol-5-one 1 (0.1 mmol), MBH carbonate 2 (0.12 mmol, 1.2 equiv), catalyst P5 (10 mol%), and 4Å MS (10 mg) in toluene (1 mL) was stirred at 0 oC for 24 h. The solvent was removed under vacuum, and the residue was purified by flash chromatography (petroleum ether/ethyl acetate = 3/1) to provide product 3. Result and Conclusion: We developed an efficient and enantioselective allylic alkylation of isoxazol- 5(4H)-ones with achiral MBH carbonates in the presence of chiral phosphine catalyst. A broad range of isoxazol-5(4H)-ones bearing all-carbon quaternary stereocenters were prepared with high efficiency and enantioselectivity. Importantly, the organocatalytic δ-stereocontrol of MBH carbonates was achieved via the synthetic strategy.