Copper(I)-catalyzed asymmetric alkene aziridination mediated by PhI(OAc)2: a facile one-pot procedure

A facile one-pot procedure for copper-catalyzed PhI(OAc)₂-mediated asymmetric alkene aziridination had been developed. Commercially available PhI(OAc)₂ and sulfonamides were used to generate the nitrene precursors (PhINR) in situ for olefin aziridination. This one-pot procedure had been optimized using 4-nitrobenzenesulfonamide as the nitrene source. With 5 mol % of the chiral copper catalyst, these conditions afforded 94% yield of the isolated product with 75% ee. We had also developed a simple and rapid method to monitor the rate of this one-pot aziridination.     

Catalytic enantioselective fluorination of α-cyano acetates catalyzed by chiral palladium complexes

The catalytic enantioselective electrophilic fluorination promoted chiral palladium complexes is described. Treatment of α-cyano acetates with N-fluorobenzenesulfonimide as the fluorine source under mild reaction conditions afforded the corresponding α-cyano α-fluoro acetates in high yields with excellent enantiomeric excesses (85-99% ee).     

Catalytic asymmetric aziridination of α,β-unsaturated aldehydes

The development, scope, and application of the highly enantioselective organocatalytic aziridination of α,β-unsaturated aldehydes is presented. The aminocatalytic azirdination of α,β-unsaturated aldehydes enables the asymmetric formation of β-formyl aziridines with up to >19:1 d.r. and 99% ee. The aminocatalytic aziridination of α-monosubstituted enals gives access to terminal α-substituted-α-formyl aziridines in high yields and up to 99% ee. In the case of the organocatalytic aziridination of disubstituted α,β-unsaturated aldehydes, the transformations were highly diastereo- and enantioselective and give nearly enantiomerically pure β-formyl-functionalized aziridine products (99% ee). A highly enantioselective one-pot cascade sequence based on the combination of asymmetric amine and N-heterocyclic carbene catalysis (AHCC) is also disclosed. This one-pot three-component co-catalytic transformation between α,β-unsaturated aldehydes, hydroxylamine derivatives, and alcohols gives the corresponding N-tert-butoxycarbonyl and N-carbobenzyloxy-protected β-amino acid esters with ee values ranging from 92-99%. The mechanisms and stereochemistry of all these catalytic transformations are also discussed.     

Catalytic enantioselective conjugate addition of aromatic amines to fumarate derivatives: asymmetric synthesis of aspartic acid derivatives

The catalytic enantioselective conjugate addition of aromatic amines to fumarate derivatives promoted by chiral palladium complexes is described. Treatment of aniline derivatives with fumaryl pyrrolidinone as Michael acceptor under mild reaction conditions afforded the corresponding chiral aspartic acid derivatives with excellent enantiomeric excesses (83–96% ee).     

Asymmetric aziridination: a new entry to optically active non-N-protected aziridines

A newly designed robust Ru(salen)(CO) complex 3 was found to catalyze asymmetric aziridination using azide compounds carrying p-nitrobenzenesulfonyl and 2-(trimethylsilyl)ethanesulfonyl (SES) groups, which are easily removable N-protecting groups under mild conditions, as a nitrene precursor in a highly enantioselective manner. In particular, the reactions with SES azide showed excellent enantioselectivity greater than 90% ee, except for one example.     

Rigid backbone 1,8-anthracene-linked bis-oxazolines (AnBOXes): design,synthesis, application and characteristics in catalytic asymmetric aziridination

A series of rigid backbone 1,8-anthracene-linked bis-oxazolines (AnBOXes) have been designed, synthesized, and evaluated in the catalytic asymmetric aziridination with [N-(p-toluenesulfonyl)imino]phenyliodinane (PhINTs) as a nitrene source. The results indicate that highly enantioselective aziridination of chalcones catalyzed by an AnBOX and CuOTf complex with up to >99% ee and the opposite enantioselectivity, compared with the ligands of Evans et al., can be achieved. The enantioselectivity is substituent dependent with respect to chalcones. Chalcones with electron-donating substituents show higher enantioselectivities due to the stronger Lewis basicity of the oxygen of their carbonyl groups than those with electron-withdrawing substituents. The results also indicate that the coordination between the oxygen of the carbonyl group in chalcones and the ether group in alkenes with the copper in the catalyst is essential for high enantioselectivity, while the π–π stacking interaction between two reactants plays an importantly additional role for high enantioselectivity in asymmetric aziridination. An excellent backbone-controlled stereoselectivity was observed for the AnBOX ligands in asymmetric aziridination, as this will provide very important information for designing novel ligands.     

Asymmetric carbonyl-ene reaction catalyzed by chiral N,N'-dioxide-nickel(II) complex: remarkably broad substrate scope

Highly enantioselective carbonyl-ene reaction of glyoxal derivatives and glyoxylate with various alkenes was accomplished using a novel nickel(II)-N,N'-dioxide complex under mild conditions, which facilitated the asymmetric synthesis of biologically interesting alpha-hydroxy carbonyl compounds. Various aromatic, aliphatic, and heteroaromatic glyoxal derivatives, as well as glyoxylate, could be tolerated in this system and afforded the corresponding adducts in excellent enantioselectivities (97->99% ee) with high yields. Moreover, the catalyst loading could even be decreased to 1 mol%, while the enantioselectivity was basically maintained.     

Cobalt-catalyzed efficient aziridination of alkenes

[reaction: see text]. Cobalt porphyrins are capable of catalyzing the aziridination of alkenes with bromamine-T as the nitrene source. Among cobalt complexes of different porphyrins, Co(TDClPP) is an effective catalyst that can aziridinate a wide variety of alkenes. The catalytic system can operate at room temperature in a one-pot fashion with alkenes as limiting reagents, forming the desired N-sulfonylated aziridine derivatives in high to excellent yields with NaBr as the byproduct.     

Enantioselective organocatalytic Michael-hemiketalization catalyzed by a trans-bifunctional indane thiourea catalyst

An efficient, convenient and enantioselective Michael-hemiketalization reaction has been developed for the synthesis of naphthoquinones. In this work, a novel trans-bifunctional indane thiourea catalyst has been reported to promote this process to afford high yields (up to 99%) and high to excellent enantiomeric excesses (90-98% ee).     

Catalytic Enantioselective Double Carbopalladation/C−H Functionalization with Statistical Amplification of Product Enantiopurity: A Convertible Linker Approach

Combining a catalytic enantioselective reaction with dimerization in a single operation is an efficient way to upgrade the enantiomeric excesses (ee ) of the product. Palladium‐catalyzed reaction of N ‐(2‐iodophenyl)‐N ‐methyl methacrylamide derivatives with oxadiazole afforded, by a double enantioselective carbopalladation/intermolecular heteroarene C−H alkylation sequence, homodimers in good yields with excellent ee values. The dimer was subsequently elaborated to the monomer in which the linker (oxadiazole) was incorporated into the target product.     

Asymmetric catalytic aziridination of dihydronaphthalenes for the preparation of substituted 2-aminotetralins

An enantioselective synthesis of substituted 2-aminotetralins from dihydronaphthalenes in four steps is described. The key step is the Jacobsen’s (diimine)copper-catalyzed asymmetric aziridination of dihydronaphthalenes to the respective aziridines in 33-82% yields and 60-87% enantiomeric excess. The enantioselectivity and the yield were dependent on the properties of the nitrene precursor. pTsNIPh appeared in general to give better results than pNsNIPh. Aziridines were ring-opened in the benzylic position by catalytic hydrogenolysis in quantitative yields, and deprotected in two steps to the respective 2-aminotetralins in 66-85% yields. The synthesis of (S)-2-aminotetralin (>98% ee) and (S)-2-amino-7-methoxytetralin (56% ee) were accomplished in 30 and 52% overall yields, respectively.     

Enantioselective α-chlorination of β-oxo esters catalyzed by chiral diterpenoid alkaloid derivatives

Easily accessible diterpenoid alkaloid derivatives have been used as organocatalysts in the enantioselective α-chlorination of β-oxo esters. The treatment of β-oxo esters with N-chlorophthalimide (NCP) as a chlorine source under mild reaction conditions afforded the corresponding α-chlorinated β-oxo esters in excellent yields (up to 98%) and with moderate enantioselectivities (up to 68% ee) in 30 min.     

Catalytic, highly enantioselective Friedel-Crafts reactions of aromatic and heteroaromatic compounds to trifluoropyruvate. A simple approach for the formation of optically active aromatic and heteroaromatic hydroxy trifluoromethyl esters.

A new catalytic enantioselective synthetic method for the formation of optically active aromatic and heteroaromatic hydroxy-trifluoromethyl ethyl esters is presented. This catalytic enantioselective Friedel-Crafts reaction of trifluoromethyl pyruvate with aromatic and heteroaromatic compounds is catalyzed by a chiral bisoxazoline copper(II) complex and proceeds in good yield and with high enantiomeric excess. For a series of substituted indoles, the corresponding 3-substituted hydroxy-trifluoromethyl ethyl esters are formed in up to 93% yield and 94% ee. Pyrrole and 2-substituted pyrroles also react with trifluoromethyl pyruvate in a highly enantioselective aromatic electrophilic reaction and up to 93% ee and good yields are obtained. Furanes and thiophenes give the corresponding 2-hydroxy-trifluoromethyl ethyl esters in high enantiomeric excess; however, the yields of the products are only moderate. Various types of aromatic compounds react in this catalytic reaction with trifluoromethyl pyruvate to give the aromatic electrophilic addition product in good yield. To obtain high enantiomeric excess (> 80% ee) it is necessary that aromatic amines are protected with sterically demanding protecting groups such as benzyl or allyl. This prevents coordination of the amine nitrogen atom to the catalyst, as aromatic amines having a N,N-dimethyl group probably coordinate to the catalyst, leading to a significant reduction of the enantioselective properties of the catalyst. On the basis of the experimental results and the absolute configuration of the formed chiral center, the mechanism for the catalytic enantioselective Friedel-Crafts reaction is discussed.     

Palladium(II)-catalyzed enantioselective synthesis of 2-vinyl oxygen heterocycles

2-Vinylchromanes (1), 2-vinyl-1,4-benzodioxanes (2), and 2,3-dihydro-2-vinyl-2H-1,4-benzoxazines (3) can be prepared in high yields (90-98%) and excellent enantiomeric purities (87-98% ee) by [COP-OAc](2)-catalyzed cyclization of phenolic (E)-allylic trichloroacetimidate precursors. Deuterium-labeling and computational experiments are consistent with these cyclization reactions taking place by an anti-oxypalladation/syn-deoxypalladation mechanism. 2-Vinylchromanes can also be prepared in good yields and high enantiomeric purities from analogous (E)-allylic acetate precursors, which constitutes the first report that acetate is a competent leaving group in COP-catalyzed enantioselective S(N)2' substitution reactions.     

Rational tuning chelate size of bis-oxazoline ligands to improve enantioselectivity in the asymmetric aziridination of chalcones

[reaction: see text] Chalcones were asymmetrically aziridinated with [N-(p-toluenesulfonyl)imino]phenyliodinane (PhI=NTs) as a nitrene source under catalysis of CuOTf and a series of cyclohexane-linked bis-oxazolines (cHBOXes), which are chelate size rationally tuned bis-oxazolines. The results indicate that highly enantioselective aziridination of chalcones with up to >99% ee have been achieved under catalysis of (S,S)-1,2-bis[(S)-(4-phenyl)oxazolin-2-yl]cyclohexane, which is the most-matched stereoisomer among cyclohexane-linked bis-oxazolines. It was also found that the enantioselectivity is not substituent-dependent with respect to chalcones in the present case, unlike with 1,8-anthracene-linked bis-oxazolines (AnBOXes).     

Asymmetric Henry reaction catalyzed by a chiral Cu(II) complex: a facile enantioselective synthesis of (S)-2-nitro-1-arylethanols

A catalytic asymmetric Henry reaction has been developed using a novel chiral Cu(II) complex derived from (R)-2-(diphenylmethanol)-l-(2-pyridylmethyl)pyrrolidine and copper(II) acetate in ethanol under mild conditions. The corresponding chiral 2-nitro-1-arylethanol derivatives were obtained in high yields with moderate to good enantiomeric excess (up to 86% ee). The results indicate that the coordination of a metal atom to the nitrogen of the pyridine ring is essential in determining the stereochemistry of the process.     

Chiral iminophosphorane catalyzed asymmetric Henry reaction of α,β-alkynyl ketoesters

α,β-Alkynyl ketoesters were introduced to the enantioselective Henry reaction (nitroaldol condensation) with nitromethane catalyzed by tartaric acid derived chiral iminophosphoranes. As such, a variety of optically active β-nitro-substituted tertiary alcohols bearing alkyne moieties were obtained in good to excellent yields (42%-99%) and moderate to good level of enantiomeric excess (up to 87% ee).     

Highly enantioselective Mannich reactions of imines with tert-butyl acetoacetate catalyzed by squaramide organocatalyst

Highly enantioselective Mannich reactions of imines bearing a benzothiazole moiety with tert-butyl acetoacetate, catalyzed by a cinchona-based squaramide organocatalyst have been developed. The corresponding benzothiazole β-keto ester derivatives were obtained in high yields (up to 99%) and with excellent enantioselectivities (up to 98% ee).     

Catalytic, enantioselective [4 + 2]-cycloadditions of ketene enolates and o-quinones: efficient entry to chiral, alpha-oxygenated carboxylic acid derivatives

We report catalytic, enantioselective [4 + 2]-cycloadditions of o-quinones with ketene enolates (derived from readily available acid chlorides) using cinchona alkaloid derivatives as catalysts to produce products in high enantiomeric excess (ee) and good to excellent yields. The thermodynamic driving force for these reactions is due in part to the restoration of aromaticity to the products. The resulting chiral, bicycloadducts can be synthetically manipulated in a variety of useful ways, for example to provide a flexible synthesis of alpha-oxygenated carboxylic acid derivatives.     

A convenient synthesis of optically active 5,5-disubstituted 4-amino- and 4-hydroxy-2(5H)-furanones from (S)-ketone cyanohydrins

(S)-Ketone cyanohydrins (S)-2 are accessible by enantioselective HCN addition to ketones 1 by using hydroxynitrile lyase from Manihot esculenta ((S)-MeHNL) as a biocatalyst. Acylation of (S)-2 gave the corresponding (S)-acyloxynitriles (S)-3, which can be cyclized by LHMDS to give 5,5-disubstituted (S)-4-amino-2(5H)-furanones (S)-4 and (S)-5. Different substituents (H. Me, OBn, OH) in the 3-position of the furanones were introduced by selecting the appropriate acylating agent, which in the case of benzyloxyacetyl chloride led to the novel structure type of 4-amino-3-hydroxyfuranones (S)-5. For the synthesis of 5,5-disubstituted (S)-tetronic acids (S)-8, ketone cyanohydrins (S)-2 were first transformed into the corresponding 2-hydroxy esters (S)-6. Acylation of (S)-6 gave 2-acyloxy esters (S)-7, which, by treatment with LHMDS or LDA, afforded tetronic acids (S)-8 in high yields and enantiomeric excesses. By debenzylation of benzyloxy acetoxy derivatives (S)-8e,f, the new vitamin C analogues (S)-9a,b were generated. All the described tetronic acid and aminofuranone derivatives were obtained in good chemical yields and without racemization with respect to the starting cyanohydrins (S)-2. In many cases the enantiomeric purity could be enriched by simple recrystallization (e.g. (S)-4a from 69% ee to > 99% ee).