Catalytic Enantioselective Synthesis of α‐Arylaminocyclobutanones

A catalytic enantioselective synthesis of α‐arylaminocyclobutanones from racemic α‐hydroxycyclobutanone and a selection of N‐alkylanilines has been established, via a tandem condensation/keto‐enol tautomerization process reminiscent of the Amadori and Heyns rearrangements.

     

Altering the Substrate Specificity of Reductase CgKR1 from Candida glabrata by Protein Engineering for Bioreduction of Aromatic α‐Keto Esters

A versatile keto ester reductase CgKR1, exhibiting a broad substrate spectrum, was obtained from Candida glabrata by genome data mining. It showed the highest activity toward an aliphatic β‐keto ester, ethyl 4‐chloro‐3‐oxobutanoate (COBE), but much lower activity toward bulkier α‐keto esters with an aromatic group, such as methyl ortho‐chlorobenzoylformate (CBFM) and ethyl 2‐oxo‐4‐phenylbutyrate (OPBE). By rational design of the active pocket, the substrate specificity of the reductase was significantly altered and this tailor‐made reductase showed a much higher activity toward aromatic α‐keto esters (∼7‐fold increase in k_cat/K_m toward CBFM) and lower activity toward aliphatic keto esters (∼12‐fold decrease in k_cat/K_m toward COBE). Meanwhile, the thermostability of the reductase was enhanced by a consensus approach. Such improvements may yield practical catalysts for the asymmetric bioreduction of these aromatic α‐keto esters

     

Selective Debromination and α‐Hydroxylation of α‐Bromo Ketones Using Hantzsch Esters as Photoreductants

Two transformations initiated by photoinduced one‐electron transfer to α‐bromo ketones have been demonstrated. Hantzsch esters donate one electron to α‐bromo ketones under photoirradiation, promoting reductive debromination. Subsequent reactions of the resulting radical species of the ketones with molecular oxygen and Hantzsch esters lead to α‐hydroxylation or debromination, respectively. The relative dominance of the two pathways depends profoundly on the reaction conditions, including solvent, O₂ levels, and the concentration of the Hantzsch esters. The synthetic protocols feature advantages because they require the environmentally benign sources, molecular oxygen and visible light.

     

Oxygen‐Involved Oxidative Deacetylation of α‐Substituted β‐Acetyl Amides – Synthesis of α‐Keto Amides

α‐Substituted β‐acetyl amides could undergo C C bond cleavage to form α‐keto amides when treated with copper(II) chloride (CuCl₂) and boron trifluoride diethyl etherate (BF₃⋅OEt₂) under an oxygen atmosphere. The yield can be increased by the addition of tert‐butyl hydroperoxide which alone can also effect the reaction. The reaction provides a new protocol for the synthesis of α‐keto amides.

     

Asymmetric Organocatalytic Cascade Michael/Hemiketalization/Retro‐Aldol Reaction of 2‐[(E)‐2‐Nitrovinyl]phenols with 2,4‐Dioxo‐4‐arylbutanoates: A Convenient Access to Chiral α‐Keto Esters

An unprecedented organocatalytic enantioselective cascade Michael/hemiketalization/retro‐aldol reaction of 2‐[(E)‐2‐nitrovinyl]phenols and 2,4‐dioxo‐4‐arylbutanoates is described. With a bifunctional squaramide catalyst incorporating (1R,2R)‐1,2‐diphenylethane‐1,2‐diamine, the reactions afford products in 75–99% yields with 80–98% ee. This process provides an enantioselective pathway for the synthesis of chiral α‐keto esters, precursors of 3‐arylproline derivatives, δ‐amino α‐keto acids or cyclic α‐keto lactams.

     

Iron Chloride‐Catalyzed Three‐Component Domino Sequences: Syntheses of Functionalized α‐Oxy‐N‐acylhemiaminals and α‐Oxyimides

The iron(III) chloride‐multicatalyzed dioxygenation of enamides with TEMPO in the presence of alcohols has been developed. This multicomponent domino process affords efficient new strategies for the synthesis of α‐oxy‐N‐acylhemiaminals or α‐oxyimides in good to excellent yields under mild conditions.

     

Copper‐Catalyzed Oxidative α‐Alkylation of α‐Amino Carbonyl Compounds with Ethers via Dual C(sp3)‐H Oxidative Cross‐ Coupling

A novel copper‐catalyzed oxidative alkylation of α‐amino carbonyl compounds with ethers has been established for the selective synthesis of α‐etherized α‐amino carbonyl compounds. This oxidative alkylation is achieved by dual C(sp³) H bond oxidative cross‐coupling, and its scope is expanded to α‐amino ketones, α‐amino esters and α‐amino amides.

     

Construction of 2,3,4,7‐Tetrahydro‐1,2,4,5‐oxatriazepines via [4+3] Cycloadditions of α‐Halogeno Hydrazones with Nitrones

In the presence of sodium carbonate, the [4+3] cycloadditions of α‐halogeno hydrazones with nitrones were performed efficiently, and affording 2,3,4,7‐tetrahydro‐1,2,4,5‐oxatriazepines in moderate to high yields.

     

Friedel–Crafts Reaction of Indoles with Isatin‐Derived β,γ‐Unsaturated α‐Keto Esters Using a BINOL‐Derived Bisoxazoline (BOX)/Copper(II) Complex as Catalyst

Several chiral BINOL‐derived bisoxazoline (BOX)/copper(II) complexes were synthesized and evaluated as catalysts for the Friedel–Crafts reaction of indoles with isatin‐derived β,γ‐unsaturated α‐keto esters. The resulting bis‐indole products bearing a quaternary stereocenter were obtained in excellent yields and enantioselectivities. Additionally, the desired products were practically transformed to α‐amino esters, α‐hydroxy esters and α‐keto amides. It is noteworthy that this catalytic procedure was conducted with a catalyst loading of 0.5 mol% without any discernible decrease in the reactivity or enantioselectivity.

     

Asymmetric α‐Hydroxylation of β‐Indanone Esters and β‐Indanone Amides Catalyzed by C‐2′ Substituted Cinchona Alkaloid Derivatives

The highly catalytic asymmetric α‐hydroxylation of β‐indanone esters and β‐indanone amides using peroxide as the oxidant was realized with a new C‐2′ substituted Cinchona alkaloid derivatives. The two enantiomers of α‐hydroxy‐β‐indanone esters could be obtained by simply changing the oxidant. This protocol allows a convenient access to the corresponding α‐hydroxy‐β‐indanone esters and α‐hydroxy‐β‐indanone amides with up to 99% yield and 98% ee.

     

Four‐Electron Electrocyclic Ring‐Opening/Intermolecular [4+2] Cycloadditions of α‐Hydroxycyclobutenones: Stereoselective Synthesis of Multiple Substituted δ‐Lactams

A four‐electron electrocyclic ring‐opening/intermolecular [4+2] cycloaddition of α‐hydroxycyclobutenones is reported. The reaction represents the first example for the intermolecular cycloaddition of the extensively studied enol‐ketene intermediate, and provides a new synthetic route to multiply substituted δ‐lactams in high stereoselectivity.

     

Enantioselective Protonation by Aza‐Michael Reaction between Pyrazoles and α‐Substituted Vinyl Ketones

An enantioselective protonation by means of chiral scandium complex‐catalyzed aza‐Michael reaction was realized. A series of α‐aryl‐substituted vinyl ketones reacted with pyrazoles smoothly, affording the corresponding enantiomerically enriched pyrazole derivatives with excellent results (up to 99% yield, 94% ee). Water and hydrogen chloride were found to accelerate the protonation process.

     

Enantioselective α‐Alkylation of Benzylideneamino tert‐Butyl Malonates by Phase‐Transfer Catalysis

A new enantioselective synthetic method for the synthesis of α,α‐dialkylmalonates with a quaternary carbon center was developed via α‐alkylation of prochiral malonates by phase‐transfer catalysis (PTC). Asymmetric α‐alkylation of benzylideneamino tert‐butyl α‐methylmalonates under phase‐transfer catalytic conditions in the presence of (S,S)‐3,4,5‐trifluorophenyl‐NAS bromide afforded the corresponding α,α‐dialkylmalonates in high yields (up to 97%) with excellent enantioselectivities (up to 98% ee). The products were then selectively hydrolyzed to chiral malonic monoacids under basic, acidic, or catalytic hydrogenation conditions.

     

Highly Regio‐ and Diastereoselective Addition of Organolithium Reagents to Chiral Fluoroalkyl α,β‐Unsaturated N‐tert‐Butanesulfinyl Ketimines: A General and Efficient Access to α‐Tertiary Fluoroalkyl Allylic Amines and α‐Fluoroalkyl α‐Amino Acids

Highly regio‐ and diastereoselective 1,2‐addition of organolithium reagents to chiral fluoroalkyl α,β‐unsaturated N‐tert‐butanesulfinyl ketimines was developed, providing a general and efficient method for the asymmetric synthesis of structurally diverse α‐tertiary fluoroalkyl allylic amines in high yields and with excellent diastereoselectivities (dr up to>99:1). The synthetic application of the method was demonstrated by the rapid and convenient preparation of challenging α‐fluoroalkyl α‐amino acids with α‐tetrasubstituted carbon.

     

Copper‐Mediated 1,2‐Difunctionalization of Styrenes with Sodium Arylsulfinates and tert‐Butyl Nitrite: Facile Access to α‐Sulfonylethanone Oximes

A new copper‐mediated synthesis of α‐sulfonylethanone oximes from styrenes, sodium arylsulfinates and tert‐butyl nitrite (t‐BuONO; TBN) is presented. This intermolecular three‐component method enables the one‐step formation of C N and C S bonds under mild conditions, and represents a new, straightforward approach to α‐sulfonylethanone oximes.

     

Gold(I)‐Catalyzed Tandem Reaction of γ‐Amino‐Substituted Propargylic Esters to Pyrrolines and its Application in the Formal Synthesis of (±)‐Aphanorphine

An effective synthesis of structurally diverse pyrroline derivatives has been accomplished by a gold(I)‐catalyzed tandem 1,3‐acyloxy rearrangement/intramolecular azacylization reaction of γ‐amino‐substituted propargylic esters in good to excellent chemical yields (52–98%). The reaction proceeds under extremely mild conditions and has also demonstrated its potential in a concise formal synthesis of (±)‐aphanorphine with a catalyst loading as low as 0.5 mol% to provide the key intermediate 5‐(4‐methoxybenzyl)‐1‐tosyl‐2,5‐dihydro‐1H‐pyrrol‐3‐yl pivalate on a gram scale.

     

Acid‐Controlled Chemodivergent Synthesis of Three Differently Substituted Quinolines via Site Selective Coupling of ortho‐ Aminoaryl Ketones with α‐Enolic Dithioesters

A straightforward approach for the chemodivergent synthesis of quinolines is described through site‐selective coupling of ortho‐aminoaryl ketones with α‐enolic dithioesters (DTEs) under solvent‐free conditions. The operationally and user‐simple one‐pot methodology is based on the trifunctional nature of DTEs. Both the carbonyl and the thiocarbonyl moiety in α‐enolic dithioesters were employed for the efficient construction of three differently substituted quinolines in a chemoselective manner simply by variation of an easy to handle acid catalyst.

     

Iron‐Catalyzed Regioselective Oxo‐ and Hydroxy‐Phthalimidation of Styrenes: Access to α‐Hydroxyphthalimide Ketones

This paper describes the aerobic oxidation of styrenes catalyzed by iron(III) chloride (FeCl₃) to form β‐keto‐N‐alkoxyphthalimides in fair to good yields. This oxidative process employs mild conditions with green and atom efficient dioxygen (O₂) as the oxidant.

     

Potassium Phosphate‐Catalyzed Chemoselective Reduction of α‐Keto Amides: Route to Synthesize Passerini Adducts and 3‐Phenyloxindoles

A chemoselective reduction of α‐keto amides to biologically important α‐hydroxy amides (mandelamides) by polymethylhydrosiloxane (PMHS) using 5 mol% potassium phosphate (K₃PO₄) as catalyst has been developed. This transition metal‐free protocol discloses excellent chemoselectivity for the ketone reduction of α‐keto amides in the presence of other reducible functionalities like ketone, nitro, halides, nitrile and amide. Also, the chemoselectively reduced α‐hydroxy amide has been derivatized to isocyanide‐free Passerini adducts. The N‐alkyl‐α‐hydroxy amides have been successfully converted to 3‐phenyloxindole derivatives by treatment with methanesulfonyl cholride and triethylamine.

     

One‐Pot Quinine‐Catalyzed Synthesis of α‐Chiral γ‐Keto Esters: Enantioenriched Precursors of cis‐α,γ‐Substituted‐γ‐Butyrolactones

A highly enantioselective one‐pot synthesis of important building blocks, α‐chiral γ‐keto esters, has been developed by combining a quinine‐catalyzed Michael addition of malononitrile to trans‐enones followed by magnesium monoperoxyphthalate (MMPP) oxidation. These synthons proved to be useful reagents for a simple access to challenging cis‐α,γ‐disubstituted γ‐butyrolactones in good diastereoselectivity and high enantiocontrol.