Highly Efficient Asymmetric Three‐Component Vinylogous Mannich Reaction Catalyzed by a Chiral Scandium(III)‐ N,N′‐Dioxide Complex

The asymmetric three‐component vinylogous Mannich reaction of an acyclic silyl dienol ester, an aldehyde and 2‐aminophenol was accomplished using a chiral N,N′‐dioxide‐scandium(III) complex as the catalyst. A variety of aldehydes were found to be suitable substrates for the reaction and the desired δ‐amino‐α,β‐unsaturated esters were obtained in 90–99% yields with good to excellent enantioselectivities (up to >99% ee) and complete regioselectivities. Moreover, the simple experimental procedures were air‐tolerant and convenient. The present catalytic process provides the potential for large‐scale syntheses of the chiral δ‐amino‐α,β‐unsaturated esters.     

A Simple Approach to Unsymmetric Atropoisomeric Bipyridine N,N′‐Dioxides and Their Application in Enantioselective Allylation of Aldehydes

The [2+2+2] cyclotrimerization of 1‐isoquinolinyl‐1,7‐octadiyne with benzonitrile catalyzed by CpCo(CO)₂ opened a new pathway for a synthesis of unsymmetrical axially chiral bipyridine N,N′‐dioxides. The N,N′‐dioxide 3a was found to be highly catalytically active and enantioselective for the asymmetric allylation of aldehydes with allyltrichlorosilane. The allylation took place with even 1 % of the catalyst with an enantioselectivity up to 87 % ee.     

Enantioselective Construction of Cyclic Indolyl α‐Amino Esters via a Friedel–Crafts Alkylation Reaction

An enantioselective Friedel–Crafts alkylation reaction of indoles with cyclic N‐sulfonyl ketimino esters was developed. Under the optimized conditions using a chiral copper(II) triflate‐bisoxazoline complex as the catalyst, a range of N‐sulfonyl ketimino ester derivatives and indoles reacted smoothly to afford indole‐containing chiral cyclic α‐amino esters bearing tetrasubstituted α‐stereogenic centers [3‐ethoxycarbonyl‐3‐(3‐indolyl)‐2,3‐dihydrobenzo[d]isothiazole 1,1‐dioxides] in excellent yields and with high enantioselectivities (up to 99% ee). Pyrrole and N,N‐dimethylaniline were also investigated as aromatic substrates to afford the corresponding products with good results. An asymmetric induction model was then proposed on the basis of the observed absolute configuration of the product 3‐ethoxycarbonyl‐3‐(5‐bromo‐3‐indolyl)‐2,3‐dihydrobenzo[d]isothiazole 1,1‐dioxide. Synthetic transformations to convert the products into cyclic chiral N‐sulfonamido alcohols and the deprotection of the sulfonamides were performed. This study provides an efficient approach to chiral α‐tetrasubstituted indolic α‐amino acids as potential building blocks for peptides and biologically active molecules.

     

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.     

Asymmetric Strecker Reaction of Ketoimines Catalyzed by a Novel Chiral Bifunctional N,N′‐Dioxide

A novel bifunctional N,N′‐dioxide derived from L ‐prolinamide was employed to catalyze the enantioselective Strecker reaction of a range of N‐tosyl ketoimines, and an effective additive was used to improve the reactivity (up to 99 % yield) as well as the enantioselectivity (up to 91 % ee). In addition, a rational transition state was proposed to elucidate the origin of chiral induction in which an S‐adduct was produced.     

Simple Chiral Diaminobinaphthyl Dilithium Salts for Intramolecular Catalytic Asymmetric Hydroamination of Amino‐1,3‐dienes

Simple and easily accessible chiral lithium amide salts are reported as efficient (pre)catalysts for the diastereo‐ [up to (E:Z)=92:8] and enantioselective [up to 72% ee (E)] hydroamination/cyclisation of conjugated primary aminodienes. These chiral lithium salts are straightforwardly prepared by in situ combination of an N‐substituted (R)‐(+)‐1,1′‐binaphthyl‐2,2′‐diamine ligand and a commercial methyllithium solution. Information on the solid‐state structure of these salts was obtained by X‐ray analysis of a single crystal.     

Catalytic Asymmetric Inverse‐Electron‐Demand (IED) [4+2] Cycloaddition of Salicylaldimines: Preparation of Optically Active 4‐Aminobenzopyran Derivatives

The catalytic asymmetric inverse‐electron‐demand (IED) [4+2] cycloaddition of various salicylaldehyde‐derived N‐arylimines with electron‐rich alkenes in the presence of chiral BINOL‐derived phosphoric acid catalysts has been studied with the aim of obtaining optically active 4‐aminobenzopyran derivatives. Dienophiles such as 2,3‐dihydro‐2H‐furan, benzyl N‐vinylcarbamate and 2‐vinylindole have been employed.     

Iron‐Catalyzed Highly Enantioselective Reduction of Aromatic Ketones with Chiral P2N4‐Type Macrocycles

Novel P₂N₄‐donors containing chiral 22‐membered macrocyclic ligands have been synthesized and the structures have been determined by an X‐ray diffraction study. The catalytic systems in situ generated from triiron dodecarbonyl, Fe₃(CO)₁₂, and the chiral macrocyclic ligand exhibited high activity (TOF up to 1940 h⁻¹) and excellent enantioselectivity with up to 99% ee in the asymmetric transfer hydrogenation of various aromatic ketones.     

Chiral Bis(N‐arylamino)phosphine‐oxazolines: Synthesis and Application in Asymmetric Catalysis

N‐Arylation or N‐alkylation of chiral 1,2‐diamines followed by ring closure with phosphorus trichloride (PCl₃) and subsequent coupling with an oxazoline alcohol resulted in a new class of N,P ligands. The corresponding iridium tetrakis[3,5‐bis(trifluormethyl)phenyl]borate (BAr_F) complexes were found to be efficient catalysts for the enantioselective hydrogenation of unfunctionalized olefins and α,β‐unsaturated carboxylic esters.     

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.     

Cationic Carboxylato Complexes of Dirhodium(II) with Oxo Thioethers: Catalysts for Silane Alcoholysis under Homogeneous and Liquid‐Liquid Biphasic Conditions

A set of cationic dirhodium(II) complexes with oxo thioethers was prepared and employed as catalysts for the silane alcoholysis reaction. The complexes were found to be highly active under homogeneous conditions, both in the absence and in the presence of a solvent, including coordinating solvents such as N,N‐dimethylformamide; the catalysts could be conveniently employed in concentrations as low as 0.01 mol %, and a maximum TON of 30000 was recorded after 24 h. The same catalysts were also employed under liquid‐liquid biphasic conditions with an ionic liquid as the catalyst‐containing phase: comparable catalytic activity was observed under these conditions, and the catalyst‐containing phase could be recovered and recycled. A chiral cationic dirhodium(II) complex was also prepared in the frame of this work; kinetic resolution of a racemic alcohol was attempted with this catalyst, unfortunately without success.     

Tandem Copper‐Catalyzed N‐Arylation–Condensation and van Leusen Reaction: Synthesis of 1,4‐Benzodiazepines and Imidazobenzodiazepines (ImBDs)

A straightforward, tandem, copper‐catalyzed N‐arylation–condensation has been developed using chiral cyclic 1,2‐diamines and ortho‐haloaryl aldehydes or ketones. The corresponding chiral tricyclic 1,4‐benzodiazepines were synthesized in high yields. Subsequently, the 1,4‐diazepines have been converted to a new class of tetracyclic N‐fused imidazobenzodiazepines (ImBDs) using the van Leusen reaction. A one‐pot sequential strategy has also been demonstrated for the synthesis of ImBDs. The synthetic utility of 1,4‐benzodiazepines and ImBDs is described.

     

Chiral Bis(N‐sulfonylamino)phosphine‐ and TADDOL‐Phosphite‐Oxazoline Ligands: Synthesis and Application in Asymmetric Catalysis

A series of N,P‐ligands has been prepared, containing a chiral oxazoline ring and as a second chiral unit a bis(N‐sulfonylamino)phosphine group embedded in a diazaphospholidine ring or a cyclic phosphite group derived from TADDOL. These modular ligands are readily synthesized from chiral amino alcohols and chiral 1,2‐diamines or TADDOLs. Palladium and iridium complexes derived from these ligands were found to be efficient catalysts for enantioselective allylic alkylation and olefin hydrogenation, respectively.     

Dendritic Chiral Phosphine Lewis Bases‐Catalyzed Asymmetric Aza‐Morita–Baylis–Hillman Reaction of N‐Sulfonated Imines with Activated Olefins

A series of polyether dendritic chiral phosphine Lewis bases was synthesized, and successfully applied to the asymmetric aza‐Morita–Baylis–Hillman reaction of N‐sulfonated imines (N‐arylmethylidene‐4‐methylbenzenesulfonamides) with methyl vinyl ketone (MVK), ethyl vinyl ketone (EVK), and acrolein to give the adducts in good to excellent yields along with up to 97 % ee, which are more effective than our previously reported original chiral phosphine Lewis bases. In addition, the dendrimer‐supported chiral phosphine Lewis bases can be easily recovered and reused.     

Storable and Air‐Stable Zirconium Complex‐Catalyzed Highly Enantioselective Darzens Reaction of Diazoacetamide with Aldehydes

An asymmetric Darzens reaction of aldehydes with diazo‐N,N‐dimethylacetamide ( 3 ) catalyzd by an air‐stable and storable chiral zirconium Lewis acid catalyst, which is formed from 3,3′‐diiodobinaphthol and tetrabutoxyzirconium, gives solely the cis‐glycidic amides in high yields with excellent enantioselectivity (up to 97% yield, >99% ee).     

Asymmetric Ring Opening of meso‐Epoxides with Aromatic Amines Catalyzed by a New Proline‐Based N,N′‐Dioxide‐Indium Tris(triflate) Complex

The catalytic asymmetric ring opening of meso‐epoxides with aromatic amines was achieved using a new proline‐based N,N′‐dioxide‐indium tris(triflate) complex in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee) under mild conditions. The coordination ability of N,N′‐dioxide 1c was investigated by X‐ray and NMR analysis. A plausible seven‐coordinate transition state model was proposed. The chiral N,N′‐dioxides surveyed were synthesized from proline through only three conventional steps. The procedure could be run on a gram‐scale without any loss of enantioselectivity. This protocol provides a highly practical and useful tool for the bulky preparation of optically pure β‐amino alcohols.     

A Mixed Ligand Approach for the Asymmetric Hydrogenation of 2‐Substituted Pyridinium Salts

Herein we describe a new methodology for the asymmetric hydrogenation (AH) of 2‐substituted pyridinium salts. An iridium catalyst based on a mixture of a chiral monodentate phosphoramidite and an achiral phosphine was shown to hydrogenate N‐benzyl‐2‐arylpyiridinium bromides to the corresponding N‐benzyl‐2‐arylpiperidines with full conversion and good enantioselectivity. The mechanism of the reaction under optimized conditions was investigated via kinetic measurements and isotopic labeling experiments. Our study suggests that the hydrogenation starts with a 1,4‐hydride addition and that the enantiodiscriminating step involves the reduction of an iminium intermediate.

     

(−)‐Sparteine‐Mediated Directed ortho‐Metalation of N‐Cumyl‐N‐ethylferrocenecarboxamide. Versatile Routes to Functionalized Planar Chiral Ferrocenecarboxamides,Amines, Esters and Phosphines

N‐Cumyl‐N‐ethylferrocenecarboxamide 5 provides planar chiral carboxamides 6 in high yield and % ee via (−)‐sparteine‐mediated directed ortho‐metalation. Mild decumylation affords secondary amides 7 , which serve as intermediates for a convenient and general route to the venerable Ugi planar chiral ferrocenylamines 13 and as versatile precursors for the preparation of novel chiral ferrocenes 15 and 20 . The chiral TMS‐ferrocenyl derivative 7c is used to prepare the enantiomeric (S)‐ 7f , circumventing the lack of availability of (+)‐sparteine.     

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.     

Fully Enzymatic Resolution of Chiral Amines: Acylation and Deacylation in the Presence of Candida antarctica Lipase B

A fully enzymatic methodology for the resolution of chiral amines has been demonstrated. Candida antarctica lipase B (CaLB)‐catalyzed acylation with N‐methyl‐ and N‐phenylglycine, as well as analogues having the general formula R¹ X CH₂CO₂R² (R¹=Me, Ph; X=O, S) afforded the corresponding enantioenriched amides, which were subsequently enzymatically hydrolyzed. Surprisingly, CaLB also proved to be the catalyst of choice for this latter step. The heteroatom in the acyl donor profoundly influences both the enzymatic acylation and deacylation; the O‐substituted reagents performed best with regard to enantioselectivity as well as reaction rate in synthesis and hydrolysis.