Convenient methods for the synthesis of highly functionalized and naturally occurring chiral allenes

A convenient two step procedure to access highly functionalized chiral allenes using chiral N-methylcamphanyl piperazine derivatives is described. In this transformation, chiral propargylamines are obtained in 79–96% yields with up to 99:1 dr by the CuBr catalyzed reactions of chiral piperazine derivatives with 1-alkynes and aldehydes containing functional groups, which are converted into chiral allenes in the presence of zinc bromide, affording the chiral allenes in 59–85% yields and with up to 99% ee. The antifungal agent Sapium japonicum and an allene precursor intermediate for the synthesis of the pheromone of the male dried bean beetle 15 are obtained in 72–78% yields and with up to 98% ee following this methodology.     

Enantioselective synthesis of 2-amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitriles using squaramide as the catalyst

The organocatalyzed enantioselective synthesis of a series of chiral 2-amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitriles was achieved using bifunctional squaramides as the catalysts. The tandem Michael addition–cyclization reaction of cyclohexane-1,3-diones and benzylidenemalononitriles gave the corresponding products in excellent yields (up to 99%) and moderate to good enantioselectivities (up to 83% ee). This investigation provides an efficient and useful process for the synthesis of chiral 2-amino-4H-chromenes.     

Chiral thiophosphoramide catalyzed asymmetric aryl transfer reactions for the synthesis of functional diarylmethanols

In this investigation, chiral thiophosphoramide 3d was easily prepared from chiral (1R,2R)-1,2-diphenylethylenediamine and then applied as an efficient chiral ligand in the catalytic asymmetric arylation reactions of various aromatic aldehydes. The corresponding diarylmethanol products were produced with good to excellent yields (up to 98%) and enantioselectivities (up to 94%). The recovery of chiral ligand 3d could be as high as 96%.     

Novel C2-symmetric bisoxazolines with a chiral trans-(2R,3R)-diphenylcyclopropane backbone: preparation and application in several enantioselective catalytic reactions

Various chiral bisoxazoline ligands with a chiral trans-(2R,3R)-diphenylcyclopropane backbone have been efficiently synthesized (five examples). These chiral ligands were tested and compared in palladium(0)-catalysed enantioselective allylic alkylations (up to 97% ee), copper(I)-catalysed enantioselective cyclopropanations (up to 89% ee) and aziridinations (up to 90% ee). We observed that the presence of a stereogenic centre on the oxazoline moiety is mandatory in order to obtain acceptable enantioselectivities.     

Asymmetric synthesis of 3-substituted indole derivatives containing tetrahydrothiophene via cascade sulfa-Michael/Michael additions catalyzed by a chiral squaramide catalyst

The organocatalyzed enantioselective cascade sulfa-Michael/Michael addition reaction of (E)-3-mercapto-2-butenoic acid esters to (E)-3-aryl-2-(indol-3-ylcarbonyl)acrylonitriles has been developed. This process was promoted by a chiral squaramide catalyst to afford chiral 3-substituted indole derivatives containing tetrahydrothiophene with three contiguous stereocenters in excellent diastereoselectivities (up to >20:1 dr) with moderate to good yields and enantioselectivities (up to 93%, 89% ee).     

Enantioselective hydrosilylation of ketimines with trichlorosilane promoted by chiral N-picolinoylaminoalcohols

Enantioselective hydrosilylation of N-aryl and N-benzyl ketimines with trichlorosilane catalyzed by readily accessible chiral N-picolinoylaminoalcohols proceeded smoothly furnishing chiral secondary amines in good yields (up to 93%) and moderate to excellent enantioselectivities (up to 95% ee).     

Asymmetric synthesis of β-aryl-β-trifluoromethyl-β-aminoarones via Mannich-type reactions of ketone enolates with chiral aryl CF3-substituted N-tert-butanesulfinyl ketimines

A method for the preparation of chiral β-aryl-β-trifluoromethyl-β-aminoarones has been developed involving the Mannich-type reactions of ketone-derivative enolates with chiral aryl CF₃-substituted N-tert-butanesulfinyl ketimines. This method tolerates a wide of aromatic ketones, giving the products in moderate to excellent yields (up to 91%) with good diastereoselectiveties (up to 93:7 dr). Acidic cleavage of the tert-butanesulfinyl group gave optically pure β-aryl-β-trifluoromethyl-β-aminoarones in excellent yields (up to 98%), which can be further transformed into CF₃-substituted aziridine derivatives.     

Rapid identification of enantioselective ketone reductions using targeted microbial libraries

A collection of about 300 microbes was surveyed for the ability to generate chiral secondary alcohols by enantioselective reduction of a series of alkyl aryl ketones. Microbial cultures demonstrating utility in reducing model ketones were arrayed in multi-well plates and used to rapidly identify specific organisms capable of producing chiral alcohols used as intermediates in the synthesis of several drug candidates. Approximately 60 cultures were shown to selectively reduce various ketones providing both the R and S enantiomers of the corresponding alcohols in 92-99% ee with yields up to 95% at 1-4 g/L. An alternative approach to chiral alcohols based on selective microbial oxidation of racemic alcohols is also reported. This study provides a useful reference for generating chiral alcohols by selective microbial bioconversion.     

Enantioselective Friedel–Crafts alkylation of indoles with β,γ-unsaturated α-ketoesters catalyzed by new squaramide-linked bisoxazoline–Zn(OTf)2 complexes

Enantioselective Friedel–Crafts alkylation reactions of indoles with β,γ-unsaturated α-ketoesters catalyzed by novel chiral C₂-symmetric squaramide-linked bisoxazoline–Zn(OTf)₂ complexes were investigated. The corresponding indole ketoesters were obtained in good to excellent yields (up to 98%) and with high enantioselectivities (up to 94% ee). This is the first report on the use of chiral squaramide-linked bisoxazoline SQBOX in a catalytic enanitioselective Friedel–Crafts alkylation reaction.     

Organocatalytic asymmetric [3 + 3] annulation of isatin N,N'-cyclic azomethine imines with enals: Efficient approach to functionalized spiro N-heterocyclic oxindoles

An unprecedented chiral secondary amine-catalyzed [3 + 3] annulation of isatin N,N'-cyclic azomethine imines with α,β-unsaturated aldehydes was developed. This strategy allowed the construction of structurally novel spiro N-heterocyclic oxindole derivatives in good yields (up to 91%) and good to excellent enantioselectivities (up to >99% ee), albeit with modest diastereoselectivities (up to 3.1:1 dr).     

Chirality control in the enantioselective arylation of aromatic aldehydes catalyzed by cis-(1R,2S)-2-benzamidocyclohexanecarboxylic acid derived 1,3-aminoalcohols

A series of chiral 1,3-aminoalcohols derived from cis-(1R,2S)-2-benzamidocyclohexanecarboxylic acid were synthesized and applied to the enantioselective arylation of aromatic aldehydes. The reactions exhibited good yields (up to 90%) and moderate to high enantioselectivities (up to 99%). Not only the enantioselectivity but also the stereochemistry of the product were controlled by the substituent effect of the chiral ligands.     

Facile synthesis of chiral 2-amino-4-(indol-3-yl)-4H-chromene derivatives using thiourea as the catalyst

The enantioselective Friedel–Crafts alkylation of indoles with iminochromenes catalyzed by a bifunctional thiourea organocatalyst was investigated. This reaction afforded chiral functionalized 2-amino-4-(indol-3-yl)-4H-chromenes in good yields (up to 87% yield) and with moderate to good enantioselectivities (up to 86% ee).     

Enantioselectivity switch controlled by N,N′-di- or N,N,N′,N′-tetra-substituted chiral thiophosphorodiamide ligands,structural relatives of thioureas,in catalytic additions of diethylzinc to aldehydes

We have developed a series of new chiral thiophosphorodiamide ligands derived from (1R,2R)-(+)-1,2-diphenylethylenediamine, which are the structural relatives of thioureas. An investigation into their catalytic properties in asymmetric additions of diethylzinc to aldehydes has shown that N,N,N′,N′-tetra-substituted chiral thiophosphorodiamides can give (R)-secondary alcohols with up to 98% yield and 98% ee, while N,N′-di-substituted chiral thiophosphorodiamides give (S)-secondary alcohols with up to 99% yield and 97% ee values. The enantioselectivity switch is highly efficient with a broad substrate scope. We have also proposed hypothetical reaction pathways, which result in an enantioselectivity switch.     

Highly efficient chiral copper Schiff-base catalyst for asymmetric cyclopropanation of 2,5-dimethyl-2,4-hexadiene

A remarkable increase in catalytic activity is found for the asymmetric cyclopropanation of 2,5-dimethyl-2,4-hexadiene with diazoacetate by use of the chiral copper Schiff-base complexes, which are derived from substituted salicylaldehydes, chiral aminoalcohols, and copper acetate monohydrate. Furthermore, a combination of a chiral copper Schiff-base with a Lewis acid showed an increase in yield (up to 90%) and in enantioselectivity (up to 90% ee) for the asymmetric cyclopropanation of the diene with t-butyl diazoacetate at 20 °C.     

Highly enantioselective construction of CF3-bearing all-carbon quaternary stereocenters: Chiral spiro-fused bisoxazoline ligands with 1,1'-binaphthyl sidearm for asymmetric Michael-type Friedel-Crafts reaction

A novel class of chiral spiro-fused bisoxazoline ligands possessing a deep chiral pocket was prepared.The developed ligands have been employed in the nickel-catalyzed highly enantioselective Michael-type Friedel-Crafts reaction, affording the products bearing a trifluoromethylated all-carbon quaternary stereocenter with moderate to excellent yields（up to 99%） and good to excellent enantioselectivies（up to> 99.9% ee）. Moreover, a proposed model of chiral pocket revealed that the attack of indo...     

Highly enantioselective addition of diethylzinc to N-diphenylphosphinylimines using dendritic chiral ligands with hydrocarbon backbones

Chiral dendrimers bearing three or six chiral β-amino alcohols on the hyperbranched hydrocarbon chain-ends act as efficient chiral ligands for the enantioselective addition of diethylzinc to N-diphenylphosphinylimines to afford enantiomerically enriched N-diphenylphosphinylamines with up to 94% e.e.     

Synthesis of chiral quaternary fluorinated cyclic sulfamidates via palladium-catalyzed arylation with arylboronic acids

An enantioselective palladium-catalyzed arylation of fluorinated cyclic N-sulfonyl ketimines with arylboronic acids is described. This methodology provides an efficient and convenient route to chiral quaternary fluorinated cyclic sulfamidates in high yields with up to 99% ee.     

Use of rhodium complexes with amphiphilic and nonamphiphilic ligands for the preparation of chiral α-aminophosphonic acid esters by hydrogenation in micellar media

Several kinds of micelle forming amphiphiles were tested in the asymmetric hydrogenation of the prochiral dialkyl 1-benzamido-2-phenyl-ethenephosphonates in aqueous media. The chiral catalytic system [Rh(cod)₂]BF₄/BPPM or amphiphilized PPM proved to be suitable for the hydrogenation reaction affording enantiomeric excesses up to 99%. A chiral induction is possible to a certain extent (up to 11% ee) by selected chiral amphiphiles in the presence of achiral rhodium catalysts.     

Enantioselective Michael addition of 3-ethyl carboxylate substituted pyrazolones to 5-alkenyl thiazolones catalyzed by squaramide organocatalyst

Asymmetric Michael addition between 3-ethyl carboxylate substituted pyrazolones and 5-alkenylthiazolones catalyzed by a series of chiral bifunctional hydrogen bonding organocatalysts was investigated. Good yields (up to 96%) and excellent enantioselectivities (up to 99% ee) were achieved by using a squaramide containing piperidine group derived from (1S, 2S)-cyclohexanediamine. This strategy provides facile access to a diverse library of thiazole-pyrazolone derivatives with potential bioactivity.     

Diastereodifferentiating photodimerization of alkyl 2-naphthoates with chiral auxiliaries

Photodimerization of alkyl 2-naphthoates with chiral auxiliaries resulted in cubane-like anti head-to-head photodimers in 93% yield and with up to 59% diastereomeric excess. After removal of the chiral auxiliaries enantiomers of cubane-like photodimer of 2-naphthalene carboxylic acid were obtained in 80% yield.