Highly Enantioselective Michael Addition of α‐Substituted Cyano Ketones to β,γ‐Unsaturated α‐Keto Esters using Bifunctional Thiourea‐Tertiary Amine Catalysts: An Easy Access to Chiral Dihydropyrans

An asymmetric Michael addition of α‐substituted cyano ketones to β,γ‐unsaturated α‐keto esters to form chiral dihydropyrans catalyzed by a series of α‐amino acid‐derived thiourea‐tertiary amines is presented. A novel tyrosine‐derived thiourea catalyst was identified as the optimal catalyst providing the desired product in 91–95% yields and with 90–96% ee at a low catalyst loading of 2.0 mol%. The utility of the reaction was exemplified by facile conversion of the dihydropyran product into pharmaceutically useful dihydropyridine.     

Chiral N,N′‐Dioxide–Yttrium Triflate Complexes‐Catalyzed Asymmetric Aldol Cyclization of α‐Keto Esters with α‐Isothiocyanato Imide

A highly effective aldol cyclization of α‐isothiocyanato imide to both β,γ‐unsaturated α‐keto esters and aryl‐substituted α‐keto esters has been developed. A chiral N,N′‐dioxide–yttrium triflate complex was used as the catalyst. A series of cyclic thiocarbamates bearing chiral quaternary stereocenters was synthesized in good to high yields, excellent diastereo‐ (up to 25:1 dr) and enantioselectivities (up to 99 % ee). In addition, the reaction could be carried out on a gram‐scale, and other functionalized derivatives are also conveniently transformed. Interestingly, a discrepancy of diastereoselection was observed between the reactions of β,γ‐unsaturated α‐keto esters and aryl‐substituted α‐keto esters. Moreover, a substrate dependency of non‐linear effects was observed in this reaction. On the basis of the experimental results and the absolute configuration of the products, possible catalytic models have been proposed to explain the origin of the asymmetric process.

     

In Situ Formed Bifunctional Primary Amine‐Imine Catalyst: Application to the Construction of Chiral Tertiary Alcohols through Asymmetric Aldol‐Type Reaction

An in situ formation method to obtain chiral bifunctional primary amine‐imine catalysts from the C₂‐symmetric chiral diimines has been developed. The efficiency of this method in the construction of chiral tertiary alcohols which are valuable pharmaceutical intermediates is proved by its application to the asymmetric aldol‐type reaction of cyclic ketones with other activated ketone compounds as the enamine acceptors, i.e., β,γ‐unsaturated α‐keto esters and isatins. In general, good to excellent diastereoselectivities and enantioselectivities (up to 96/4 dr, 96% ee for β,γ‐unsaturated α‐keto esters and up to 91/9 dr, 94% ee for isatins) were obtained. The active primary amine‐imine catalylst and enamine intermediate in the reaction process could be demonstrated by ESI‐MS analysis.     

The Synthesis of trans‐Perhydroindolic Acids and their Application in Asymmetric Domino Reactions of Aldehyde Esters with β,γ‐Unsaturated α‐Keto Esters

(2S,3aR,7aS)‐Perhydroindolic acid, the key intermediate in the synthesis of trandolapril, and its trans‐isomers, were readily prepared. These proline‐like molecules are unique in that they contain a rigid bicyclic structure, with two hydrogen atoms trans to each other at the bridgehead carbon atoms. These molecules were used successfully as chiral organocatalysts in asymmetric domino Michael addition/cyclization reactions of aldehyde esters with β,γ‐unsaturated α‐keto esters. They proved to have excellent catalytic behavior, allowing for the synthesis of multi‐substituted, enantiomerically enriched hemiacetal esters. Under optimal conditions (using 10 mol% catalyst loading), a series of β,γ‐unsaturated α‐keto esters was examined with up to 99% de, ee and yield, respectively. Additionally, the enantiomerically enriched hemiacetal esters could be readily transformed into their corresponding bioactive pyrano[2,3‐b]pyrans (possessing a multi‐substituted bicyclic backbone).     

Highly Enantioselective Michael Addition of Cyclic 1,3‐Dicarbonyl Compounds to β,γ‐Unsaturated α‐Keto Esters

A highly enantioselective Michael addition of cyclic 1,3‐dicarbonyl compounds to β,γ‐unsaturated α‐keto esters catalyzed by amino acid‐derived thiourea‐tertiary‐amine catalysts is presented. Using 5 mol% of a novel tyrosine‐derived thiourea catalyst, a series of chiral coumarin derivatives were obtained in excellent yields (up to 99%) and with up to 96% ee under very mild conditions within a short reaction time.     

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.

     

Highly Enantioselective Organocatalyzed Construction of Quaternary Carbon Centers via Cross‐Aldol Reaction of Ketones in Water

The asymmetric construction of quaternary carbon centers via cross‐aldol reactions of ketones with β,γ‐unsaturated keto esters catalyzed by 4‐(tert‐butyldiphenylsilyloxy)‐pyrrolidine‐2‐carboxylic acid in water is described. The adducts bearing two adjacent chiral centers were obtained in high yields, mostly up to 99% ee, and with high diastereoselectivities. The corresponding polyfunctional products could also be easily transformed to useful lactones with three chiral centers.     

Rhodium‐Catalyzed Addition of α‐Keto Acid Chlorides with Terminal Alkynes

The addition reaction of α‐keto acid chlorides with terminal alkynes proceeds in the presence of (acetylacetonato)dicarbonylrhodium used as catalyst to afford synthetically versatile (Z)‐γ‐chloro‐α‐oxo‐β,γ‐unsaturated ketones regio‐ and stereoselectively.     

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.

     

N,N′‐Dioxide‐Magnesium Ditriflate Complex‐Catalyzed Asymmetric α‐Hydroxylation of β‐Keto Esters and β‐Keto Amides

The highly catalytic asymmetric α‐hydroxylation of 1‐tetralone‐derived β‐keto esters and β‐keto amides using tert‐butyl hydroperoxide (TBHP) as the oxidant was realized by a chiral N,N′‐dioxide‐magnesium ditriflate [Mg(OTf)₂] complex. A series of corresponding chiral α‐hydroxy dicarbonyl compounds was obtained in excellent yields (up to 99%) with excellent enantioselectivities (up to 98% ee). The products were easily transformed into useful building blocks and the precursor of daunomycin was achieved in an asymmetric catalytic way for the first time.     

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.

     

A Convenient Ruthenium‐Catalysed α‐Methylation of Carbonyl Compounds using Methanol

An efficient ruthenium catalyst is reported, for the first time, to catalyse the α‐methylation of ketones and esters using methanol as a green methylating agent. The in situ generated catalyst from the complexes [RuCp*Cl₂]₂ or [RuCp*Cl₂]_n with dpePhos provided up to quantitative yields in the presence of only 20 mol% of lithium tert‐butoxide (LiO‐t‐Bu) as a base. Regioselective mono‐ or multi‐methylation could be effectively controlled by temperature. This catalyst system was also effective for the one‐pot sequential α‐alkylation–α‐methylation of methyl ketones and conjugate reduction–α‐methylation of α,β‐unsaturated ketones to synthesise α‐branched ketones. An application of the α‐methylation of esters using the ruthenium catalyst was demonstrated for an alternative catalytic synthesis of Ketoprofen.

     

Synthesis of Valuable Chiral Intermediates by Isolated Ketoreductases: Application in the Synthesis of α‐Alkyl‐β‐hydroxy Ketones and 1,3‐Diols

Regio‐ and stereoselective reductions of α‐substituted 1,3‐diketones to the corresponding β‐keto alcohols or 1,3‐diols by using commercially available ketoreductases (KREDs) are described. A number of α‐monoalkyl‐ or dialkyl‐substituted symmetrical as well as non‐symmetrical diketones were reduced in high optical purities and chemical yields, in one or two enzymatic reduction steps. In most cases, two or even three out of the four possible diastereomers of α‐alkyl‐β‐keto alcohols were synthesized by using different enzymes, and in two examples both ketones were reduced to the 1,3‐diol. By replacing the α‐alkyl substituent with the OAc group, 1‐keto‐2,3‐diols, as well as 1,2,3‐triols were synthesized in high optical purities. These enzymatic reactions provide a simple, highly stereoselective and quantitative method for the synthesis of different diastereomers of valuable chiral synthons from non‐chiral, easily accessible 1,3‐diketones.     

Chiral Amino Diol Derivatives as New Modular Organocatalysts for the Enantioselective α‐Chlorination of Cyclic β‐Keto Esters

Highly modular chiral amino diol derivatives have been used as organocatalysts in the enantioselective α‐chlorination of cyclic β‐keto esters. Optimization of the catalyst structure and the reaction conditions has allowed the synthesis of optically active α‐chlorinated products with high enantioselectivities (up to 96% ee) using inexpensive commercially available N‐chlorosuccinimide (NCS) as the chlorine source under mild conditions.     

Synthesis of γ‐Fluoro‐α, β‐unsaturated Carboxylic Esters from Saturated α‐Fluoro Aldehydes

γ‐Fluoro‐α, β‐unsaturated carboxylic esters 7a, 7b and 7d and 4‐fluoro‐4‐phenylbut‐3‐enoic ester ( 8 ) are obtained by two alternative pathways from 2‐fluoro aldehydes 5a—d , either by Horner—Wadsworth—Emmons reaction or by Wittig reaction. The aldehydes 5a—d are prepared by Swern oxidation of the corresponding fluorohydrins 4a—d . These are available from α‐olefins by bromofluorination, bromineby‐acetate replacement and subsequent hydrolysis.     

Access to Both Enantiomers of α‐Chloro‐β‐keto Esters with a Single Chiral Ligand: Highly Efficient Enantioselective Chlorination of Cyclic β‐Keto Esters Catalyzed by Chiral Copper(II) and Zinc(II) Complexes of a Spiro‐2,2′‐bischroman‐Based Bisoxazoline Ligand

The spiro‐2,2′‐bichroman‐based chiral bisoxazoline ligands (SPANbox) were found to be highly efficient in copper(II)‐ and zinc(II)‐catalyzed asymmetric chlorinations of cyclic β‐keto esters with N‐chlorosuccinimide (NCS) as the chlorination reagent, to give the corresponding α‐chloro‐β‐keto esters in excellent yields in 5–30 min with ee values up to 97%. The copper(II) triflate and zinc(II) triflate complexes of a single SPANbox ligand demonstrated complementary results to each other with respect to the enantioselection, affording both antipodes of the chlorinated product enantiomers with good to excellent optical purities.     

Efficient Synthesis of β,γ‐Alkynyl α‐Amino Acid Derivatives by Ag(I)‐Catalyzed Alkynylation of α‐Imino Esters

The first catalytic synthesis of β,γ‐alkynyl α‐amino acid derivatives was achieved by direct addition of terminal alkynes to α‐imino esters in the presence of an Ag(I) salt under mild reaction conditions.     

Organocatalytic Highly Enantioselective Synthesis of β‐Formyl‐α‐hydroxyphosphonates

The cross‐aldol reaction between enolizable aldehydes and α‐ketophosphonates was achieved for the first time by using 9‐amino‐9‐deoxy‐epi‐quinine as the catalyst. β‐Formyl‐α‐hydroxyphosphonates were obtained in high to excellent enantioselectivities. The reaction works especially well with acetaldehyde, which is a tough substrate for organocatalyzed cross‐aldol reactions. The products were demonstrated to have anticancer activities.     

Ruthenium(II)‐Catalyzed Regioselective Synthesis of Allyl Ketones from Alkynes and their Silver(I)‐Catalyzed Hydroarylation into γ‐Functionalized Ketones

The regioselective synthesis of β,γ‐unsaturated ketones from terminal alkynes is achieved by cooperative action of tris(acetonitrile)pentamethylcyclopentadieneruthenium hexafluorophosphate [Cp*Ru(NCMe)₃⁺ PF₆⁻] and para‐toluenesulfonic acid catalysts. These allyl ketones undergo direct regioselective hydroarylation/Friedel–Crafts reaction to introduce an electron‐rich aryl group at the γ‐position in the presence of ligand‐free silver triflate (AgOTf) catalyst. Both catalytic reactions take place with atom economy and provide an alternative to the synthesis of a variety of allyl ketones and γ‐arylated ketones.     

Highly Enantioselective Iridium‐Catalyzed Hydrogenation of Trisubstituted Olefins, α,β‐Unsaturated Ketones and Imines with Chiral Benzylic Substituted P,N Ligands

The benzylic substituted P,N ligands, diphosphinobenzyloxazolines, showed their high catalytic activity as well as asymmetric induction in the iridium‐catalyzed asymmetric hydrogenation of unfunctionalized alkenes, α,β‐unsaturated esters, allyl alcohols, α,β‐unsaturated ketones, and imines, providing the corresponding chiral products in high ee with high conversion.