Highly Enantioselective Phase‐Transfer Catalytic α‐Alkylation of α‐tert‐Butoxycarbonyllactams: Construction of β‐Quaternary Chiral Pyrrolidine and Piperidine Systems

A new enantioselective α‐alkylation of α‐tert‐butoxycarbonyllactams for the construction of β‐quaternary chiral pyrrolidine and piperidine core systems is reported. α‐Alkylations of N‐methyl‐α‐tert‐butoxycarbonylbutyrolactam and N‐diphenylmethyl‐α‐tert‐butoxycarbonylvalerolactam under phase‐transfer catalytic conditions (solid potassium hydroxide, toluene, −40 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐3,3′,5,5′‐tetrahydro‐2,6‐bis(3,4,5‐trifluorophenyl)‐4,4′‐spirobi[4H‐dinaphth[2,1‐c:1′,2′‐e]azepinium] bromide [(S,S)‐NAS Br] (5 mol%) afforded the corresponding α‐alkyl‐α‐tert‐butoxycarbonyllactams in very high chemical (up to 99%) and optical yields (up to 98% ee). Our new catalytic systems provide attractive synthetic methods for pyrrolidine‐ and piperidine‐based alkaloids and chiral intermediates with β‐quaternary carbon centers.     

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.     

Highly Diastereoselective Synthesis of 2,6‐Di[1‐(2‐alkylaziridin‐1‐yl)alkyl]pyridines,Useful Ligands in Palladium‐Catalyzed Asymmetric Allylic Alkylation

C₂‐Symmetrical, enantiopure 2,6‐di[1‐(1‐aziridinyl)alkyl]pyridines (DIAZAPs) were prepared by a high‐yielding, three‐step sequence starting from 2,6‐pyridinedicarbaldehyde and (S)‐valinol or (S)‐phenylglycinol. The new compounds were tested as ligands in palladium‐catalyzed allylation of carbanions in different solvents. Almost quantitative yield and up to 99 % enantiomeric excess were obtained in the reactions of the enolates derived from malonate, phenyl‐ and benzylmalonate dimethyl esters with 1,3‐diphenyl‐2‐propenyl ethyl carbonate.     

Ruthenium‐Catalyzed Asymmetric Hydrogenation of β‐Keto‐ enamines: An Efficient Approach to Chiral γ‐Amino Alcohols

A highly efficient and enantioselective hydrogenation of unprotected β‐ketoenamines catalyzed with ruthenium(II) dichloro{(S)‐(−)‐2,2′‐bis[di(3,5‐xylyl)phosphino]‐1,1′‐binaphthyl}[(2S)‐(+)‐1,1‐bis(4‐methoxyphenyl)‐3‐methyl‐1,2‐butanediamine] {Ru[(S)‐xylbinap][(S)‐daipen]Cl₂} has been successfully developed. This methodology provides a straightforward access to free γ‐secondary amino alcohols, which are key building blocks for a variety of pharmaceuticals and natural products, with high yields (>99%) and excellent enantioselectivities (up to 99% ee) in all cases.     

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.

     

Stereoselective Lewis Base‐Catalyzed Asymmetric Hydrosilylation of α‐Acetamido‐β‐enamino Esters: Straightforward Approach for the Construction of α,β‐Diamino Acid Derivatives

The Lewis base‐organocatalyzed asymmetric hydrosilylation of α‐acetamido‐β‐enamino esters was investigated. Among various chiral Lewis base catalysts, a novel catalyst derived from L ‐serine was found to be the most efficient one which can promote the reaction to afford a series of α,β‐diamino acid derivatives with high yields (up to 99%), excellent enantioselectivities (up to 98% ee) and moderate diastereoselectivities (up to 80:20 dr). The absolute configuration of one of the products was determined by the X‐ray crystallographic analysis. In addition, the mechanism and the transition state of the reaction were proposed.     

One‐Step Catalytic Enantioselective α‐Quaternary 5‐Hydroxyproline Synthesis: An Asymmetric Entry to Highly Functionalized α‐Quaternary Proline Derivatives

The highly enantioselective cascade reaction between N‐protected α‐cyanoglycine esters and α,β‐unsaturated aldehydes is disclosed. The reaction represents a one‐step entry to polysubstituted 5‐hydroxyproline derivatives having a quaternary α‐stereocenter generally in high yields with up to >95:5 dr and 99:1 er. It is also a direct catalytic two‐step entry to functionalized α‐quaternary proline derivatives.     

Phase‐Transfer‐Catalyzed Olefin Isomerization/α‐Alkylation of α‐Alkynylcrotonates as a Route for 1,4‐Enynes

The phase‐transfer‐catalyzed alkylation of α‐alkynylcrotonates was developed as a means to provide 1,4‐enynes deconjugated by an all‐carbon quaternary center. Extension to the asymmetric version using the chiral phase‐transfer catalyst (S)‐ 3 provided the alkylated compounds with up to 87% ee.     

Highly Enantioselective Allylation of Aromatic α‐Keto Phosphonates Catalyzed by Chiral N,N′‐Dioxide‐Indium(III) Complexes

The ramipril derivative N,N′‐dioxide 3g ‐indium(III) complex was found to be an efficient catalyst for the allylation of the aromatic α‐keto phosphonates. The corresponding α‐hydroxy phosphonates were obtained with high yields (up to 98 %) and high enantioselectivities (up to 91 % ee). A bifunctional catalyst system was described with an N‐oxide as Lewis base activating tetraallyltin and indium as Lewis acid activating aromatic α‐keto phosphonates. A possible catalytic cycle has been proposed to explain the mechanism of the reaction.     

Highly Enantioselective Epoxidation of α,β‐Unsaturated Ketones Catalyzed by Primary‐Secondary Diamines

The asymmetric epoxidation of α,β‐unsaturated ketones has been achieved by using functional and readily accessible primary‐secondary diamines as the catalysts, giving the useful alkyl epoxy products with good yields and high enantioselectivities (up to 99% ee).     

Asymmetric Synthesis of β‐Substituted α‐Methylenebutyro‐ lactones via TRIP‐Catalyzed Allylation: Mechanistic Studies and Application to the Synthesis of (S)‐(−)‐Hydroxymatairesinol

Asymmetric allylation of (hetero)aromatic aldehydes by a zinc(II)‐allylbutyrolactone species catalyzed by a chiral BINOL‐type phosphoric acid gave β‐substituted α‐methylenebutyrolactones in 68 to >99% ee and 52–91% isolated yield. DFT studies on the intermediate Zn²⁺‐complex – crucial for chiral induction – suggest a six‐membered ring intermediate, which allows the phosphoric acid moiety to activate the aldehyde. The methodology was applied to the synthesis of the antitumour natural product (S)‐(−)‐hydroxymatairesinol.

     

Catalytic Asymmetric Hydrogenation of α‐Arylcyclohexanones and Total Synthesis of (−)‐α‐Lycorane

An efficient catalytic asymmetric hydrogenation of racemic α‐arylcyclohexanones with an ethylene ketal group at the 5‐position of the cyclohexane ring via dynamic kinetic resolution has been developed, giving chiral α‐arylcyclohexanols with two contiguous stereocenters with up to 99% ee and >99:1 cis/trans‐selectivity. Using this highly efficient asymmetric hydrogenation reaction as a key step, (−)‐α‐lycorane was synthesized in 19.6% overall yield over 13 steps from commercially available starting material.     

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 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.

     

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.     

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.

     

Organocatalytic Asymmetric Sulfa‐Michael Addition to α,β‐Unsaturated Ketones

The highly enantioselective organocatalytic sulfa‐Michael addition to α,β‐unsaturated ketones has been accomplished using benzyl and tert‐butyl mercaptans as the sulfur‐centered nucleophiles. Optically active products are obtained in high yields and good to excellent stereocontrol (up to 96 % ee) from a large variety of enones. Central to these studies has been the use of the catalytic primary amine salt A , derived from 9‐amino‐(9‐deoxy)‐epi‐hydroquinine and D ‐N‐Boc‐phenylglycine, in which both the cation and the anion are chiral, that exhibits high reactivity and selectivity for iminium ion catalysis with enones.     

Bis(3,5‐dimethylphenyl)‐(S)‐pyrrolidin‐2‐ylmethanol: an Improved Organocatalyst for the Asymmetric Epoxidation of α,β‐Enones

The asymmetric epoxidation of α,β‐enones by the readily available bis(3,5‐dimethylphenyl)‐(S)‐pyrrolidin‐2‐ylmethanol and tert‐butyl hydroperoxide (TBHP) is described. Stereoelectronic substitution on the aryl moiety of diaryl‐2‐pyrrolidinemethanols was found to significantly affect the efficiency with respect to the previously reported (S)‐diphenyl‐2‐pyrrolidinemethanol. Improved reactivity and enantioselectivity were achieved with bis(3,5‐dimethylphenyl)‐(S)‐pyrrolidin‐2‐ylmethanol at reduced catalyst loading (20 mol %) with ees up to 94% for chalcone epoxides under mild reaction conditions, whereas (S)‐diphenyl‐2‐pyrrolidinemethanol afforded a maximum ee of 80%. Interestingly, the methodology is applicable to the epoxidation of more challenging aliphatic or enolizable enones with good control of the asymmetric induction (up to 87% ee).     

Imidazolium Ion‐Tagged Proline Organocatalyst for α‐Aminoxylation of Aldehydes and Ketones in Ionic Liquids

A novel imidazolium ion‐tagged L ‐proline catalyst has been developed. The asymmetric α‐aminoxylation of aldehydes and ketones with excellent enantioselectivities, up to 99% ee, and high yields in ionic liquids has been achieved. The system can be easily recycled and reused for at least six times without significant loss of yields and enantioselectivity.     

Enantioselective Synthesis of Chiral β‐Aryloxy Alcohols by Ruthenium‐Catalyzed Ketone Hydrogenation via Dynamic Kinetic Resolution (DKR)

A highly efficient enantioselective synthesis of chiral β‐aryloxy alcohols by the {RuCl₂[(S)‐SDP][(R,R)‐DPEN]} [(S_a,R,R)‐ 1a ; SDP=7,7′‐bis(diarylphosphino)‐1,1′‐spirobiindane; DPEN=trans‐1,2‐diphenylethylenediamine] complex‐catalyzed asymmetric hydrogenation of racemic α‐aryloxydialkyl ketones via dynamic kinetic resolution (DKR) has been developed. Enantioselectivities of up to 99% ee with good to high cis/anti‐selectivities (up to>99:1) were achieved.