Ir-catalyzed asymmetric allylic amination using chiral diaminophosphine oxides

An Ir-catalyzed asymmetric allylic amination using chiral diaminophosphine oxide is described. Asymmetric allylic amination of terminal allylic carbonates proceeded in the presence of 2 mol % of Ir catalyst, 2 mol % of chiral diaminophosphine oxide, 5 mol % of NaPF₆, and BSA, affording the chiral branched allylic amines in up to 95% ee.     

Palladium(II)-catalyzed 1,4-addition of arylboronic acids to β-arylenals for enantioselective syntheses of 3,3-diarylalkanals: a short synthesis of (+)-(R)-CDP 840

1,4-Addition of arylboronic acid to trans-β-arylenals proceeded smoothly in acetone-water (10/1) at 10-25 °C in the presence of [Pd(S,S-chiraphos)(PhCN)₂](SbF₆)₂ (0.5 mol %), AgX (X = BF₄, SbF₆, 10 mol %) and aqueous 42% HBF₄ to afford optically active 3,3-diarylalkanals with high enantioselectivities in a range of 86-97% ee. The protocol provided a method for short-step synthesis of optically active (+)-(R)-CDP 840.     

Catalytic and asymmetric Friedel-Crafts alkylation of indoles with nitroacrylates. Application to the synthesis of tryptophan analogues

An asymmetric Friedel-Crafts alkylation of indoles with nitroacrylates catalyzed by chiral (4R,5S)-DiPh-BOX (L1)-Cu(OTf)₂ complex (10 mol %) has been developed. The reactions provide tryptophan nitro-precursors in moderate diastereoselectivities (anti/syn up to 72:28) and good to excellent enantioselectivities (up to 99% ee). The alkylation products could be easily reduced to optically active tryptophan analogues with Zn/H⁺.     

An FeCl3-catalyzed highly C3-selective Friedel-Crafts alkylation of indoles with alcohols

The FeCl₃-catalyzed C3-selective Friedel-Crafts alkylation of indoles using allylic, benzylic and propargylic alcohols has been developed. The reaction was performed in the presence of a catalytic amount of inexpensive anhydrous FeCl₃ (10 mol %) in nitromethane under mild conditions. This method can also be used for the alkylation of pyrrole.     

Inverse electron demand asymmetric cycloadditions of cyclic carbonyl ylides catalyzed by chiral Lewis acids—Scope and limitations of diazo and olefinic substrates

High enantioselectivities (94-96% ee) were obtained for the inverse electron-demand 1,3-dipolar cycloadditions between cyclohexyl vinyl ether and 2-benzopyrylium-4-olate generated via Rh₂(OAc)₄-catalyzed decomposition of o-methoxycarbonyl-α-diazoacetophenone. The reactions were effectively catalyzed by Eu(OTf)₃, Ho(OTf)₃, or Gd(OTf)₃ complexes (10 mol %) of chiral 2,6-bis[(4S,5S)-4,5-diphenyl-2-oxazolinyl]pyridine. The reactions with the other electron-rich dipolarophiles such as allyl alcohol, 2,3-dihydrofuran, and butyl-tert-butyldimethylsilylketene acetal showed moderate enanantioselectivities (60-73% ee). Good to high enantioselectivities (73-97% ee) were also obtained for the cycloadditions between 3-acyl-2-benzopyrylium-4-olates, generated from methyl 2-(2-diazo-1,3-dioxoalkyl)benzoates and butyl or cyclohexyl vinyl ethers, in the presence of binaphthyldiimine (BINIM)-Ni(II) complexes (10 mol %). Under similar conditions, the reaction between methyl 2-(2-diazo-1,3-dioxohexyl)benzoate and 2,3-dihydrofuran was highly endo-selective, and moderately enantioselective (70% ee). For the BINIM-Ni(II)-catalyzed reactions of cyclohexyl vinyl ether, the use of an epoxyindanone as the 3-acyl-2-benzopyrylium-4-olate precursor revealed that the chiral Lewis acid can function as a catalyst for asymmetric induction. The scope of the cyclic carbonyl ylides was extended to those generated from 1-diazo-2,5-pentanedione derivatives, which were reacted with butyl or TBS vinyl ether and catalyzed using the (4S,5S)-Pybox-4,5-Ph₂-Lu(OTf)₃ complex to give good levels of asymmetric inductions (75-84% ee).     

InBr3 as a versatile and highly efficient catalyst for the synthesis of 3-allyl- and 3-benzylindoles

Indoles undergo smooth alkylation with allylic and benzylic alcohols in the presence of 10 mol % of InBr₃ under mild conditions to produce 3-allyl- and 3-benzyl indoles, respectively, in excellent yields and with high selectivity. This is the first example of the alkylation of indoles with benzylic alcohols using InBr₃ as an acid catalyst.     

A P-chiral bisdiamidophosphite ligand with a 1,4:3,6-dianhydro-d-mannite backbone and its application in asymmetric catalysis

A novel readily available P,P-bidentate diamidophosphite ligand with P^∗-stereocentres is prepared from an inexpensive C₂-symmetric 1,4:3,6-dianhydro-d-mannite. By using this efficient ligand, up to 98% ee is achieved in Pd-catalysed asymmetric allylic alkylation, up to 92% ee in Pd-catalysed asymmetric allylic amination and up to 87% ee in Rh-catalysed asymmetric hydrogenation. The influence of the precatalyst, substrate and solvent on the enantioselectivity is discussed.     

Bis-paracyclophane N-heterocyclic carbene-ruthenium catalyzed asymmetric ketone hydrosilylation

New chiral bis-paracyclophane N-heterocyclic carbene (NHC) ligands 1-3 have been explored for ruthenium catalyzed asymmetric hydrosilylation of ketones using diphenylsilane to give enantioenriched alcohols. These ligands provide for efficient asymmetric reduction in the presence of silver(I) triflate (1 mol %) at room temperature with high reactivity and selectivity. Acetophenone 4 was reduced with 1 mol % catalyst in 96% isolated yield, 97% ee. Following removal of the silyl ether, various alcohols 5 were obtained from aromatic ketones in high yield and selectivity.     

Achiral β-amino alcohols as efficient ligands for the ruthenium-catalysed asymmetric transfer hydrogenation of sulfinylimines

Some achiral β-amino alcohols have been shown as efficient ligands for the ruthenium-catalysed asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)imines in isopropanol. The ruthenium complex prepared from [RuCl₂(p-cymene)]₂ (2.5 mol %) and 2-amino-2-methyl-1-propanol (5 mol %) leads to α-branched chiral primary amines with very high optical purities (up to 98% ee) by the diastereoselective reduction of the imines followed by removal of the sulfinyl group under mild acidic conditions. Short reaction times (2-3 h) were needed to complete the reduction reactions when they were performed at 50 °C.     

Convenient preparation of chiral phase-transfer catalysts with conformationally fixed biphenyl core for catalytic asymmetric synthesis of α-alkyl- and α,α-dialkyl-α-amino acids: application to the short asymmetric synthesis of BIRT-377

Chiral phase-transfer catalysts (S)-1a, (S)-1b, and (S)-2 with conformationally fixed biphenyl cores were conveniently prepared from the known, easily available (S)-6,6′-dimethylbiphenyl-2,2′-diol 3 and (S)-4,5,6,4′,5′,6′-hexamethoxybiphenyl-2,2′-dicarboxylic acid 14, respectively, in five steps. The catalysts, (S)-1a and (S)-1b are readily applicable to asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester with excellent enantioselectivity. In particular, catalyst (S)-1b was found to exhibit the unique temperature effect on the enantioselectivity, and asymmetric alkylation of glycine derivatives at room temperature gave higher enantiomeric excess than that at 0 °C. In addition, the catalyst (S)-2 exhibited the high catalytic performance (0.01-1 mol %) in the asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester and N-(p-chlorophenylmethylene)alanine tert-butyl ester compared to the existing chiral phase-transfer catalysts, thereby allowing to realize a general and useful procedure for highly practical enantioselective synthesis of structurally diverse natural and unnatural α-alkyl-α-amino acids as well as α,α-dialkyl-α-amino acids. This approach is successfully applied to the short asymmetric synthesis of cell adhesion BIRT-377.     

Asymmetric cyano-ethoxycarbonylation of aldehydes catalyzed by self-assembled titanium catalyst

A new self-assembled catalyst based on titanium complex has been developed for the effective enantioselective cyano-ethoxycarbonylation of aldehydes. The self-assembled catalyst was readily prepared from (R)-3,3′-bis((methyl((S)-1-phenylethyl)amino)methyl)-1,1′-binaphthyl-2,2′-diol (1h), N-((1S,2R)-2-hydroxy-1,2-diphenylethyl)acetamide (2b), and tetraisopropyl titanate (Ti(OiPr)₄). A variety of aromatic aldehydes, aliphatic aldehydes, and α,β-unsaturated aldehydes were found to be suitable substrates in the presence of the self-assembled titanium catalyst (5 mol % 1h, 5 mol % 2b, and 5 mol % Ti(OiPr)₄). The desired cyanohydrin ethyl carbonates were afforded with high isolated yields (up to 95%) and moderate to good enantioselectivities (up to 92% ee) under mild conditions (at −15 °C). A possible catalytic cycle based on the experimental observation was proposed.     

Highly enantioselective Michael addition of isobutyraldehyde to nitroalkenes

The asymmetric catalytic Michael reaction between isobutyraldehyde and nitroalkanes with chiral primary amine thiourea organocatalysts was described. In the presence of 10 mol % of 1-((1R,2R)-2-amino-1,2-diphenylethyl)-3-benzylthiourea, the desired products were achieved in excellent enantioselectivity (up to>99% ee) with up to 98% yield.     

A simple and efficient FeCl3-catalyzed direct alkylation of active methylene compounds with benzylic and allylic alcohols under mild conditions

A highly efficient FeCl₃-catalyzed alkylation of various active methylene compounds with various benzylic or allylic alcohols under mild conditions has been developed. The reaction was carried out in the presence of a catalytic amount of anhydrous FeCl₃ (10 mol %) under reflux in methylene chloride. High to excellent yields were obtained.     

π-Allyl palladium approach toward the diazabicyclo[3.2.1]octane core of the naphthyridinomycin alkaloids

A novel and efficient protocol for the synthesis of the 3,8-diazabicyclo[3.2.1]octane system found in the naphthyridinomycin, dnacin, and tetrazomine families of alkaloids is described. The key transformation involves an intramolecular palladium-catalyzed allylic alkylation. The cyclization proceeds smoothly under mild conditions (20 mol % Pd₂dba₃, 1.5 equiv DBU, 65 °C, THF, 20 min) to afford 3,8-diazabicyclo[3.2.1]octanes in excellent yields (94-98%).     

Kinetic resolution of 5-substituted cycloalkenones by peptidic amidophosphane-copper-catalyzed asymmetric conjugate addition of dialkylzinc

Asymmetric conjugate alkylation reaction of racemic 5-substituted cyclohexenones with dialkylzinc reagents was catalyzed by 2-5 mol % of dipeptidic amidophosphane-Cu(MeCN)₄BF₄ in toluene at 0 °C for 20 min to recover enantioenriched starting 5-substituted cyclohexenones with 88-98% ee in 28-41% yield along with trans major 3-alkylated 5-substituted cyclohexanones with 81-90% ee in 53-60% yield. Complete consumption of starting racemic 5-TMS-cyclohexenone by treating with diethylzinc under the catalytic asymmetric reaction conditions gave trans major 85:15 mixture of trans- and cis-3-ethyl-5-TMS-cyclohexanones with 15% ee (for trans) in 83% combined yield, indicating that the conformation-controlled trans-alkylation of cyclohexenone prevails over chiral catalyst-controlled enantiofacial differentiation.     

Pd-catalyzed enantioselective synthesis of quaternary α-amino acid derivatives using a phenylalanine-derived P-chirogenic diaminophosphine oxide

A Pd-catalyzed enantioselective synthesis of quaternary α-amino acid derivatives using a phenylalanine-derived P-chirogenic diaminophosphine oxide is described. Asymmetric allylic substitution using acyclic β-keto esters with a nitrogen functional group at the α-carbon as prochiral nucleophiles proceeded in the presence of 5 mol % of Pd catalyst, 10 mol % of chiral diaminophosphine oxide 1j, BSA, and appropriate additives, affording the corresponding quaternary α-amino acid derivatives in excellent yield and in up to 92% ee.     

Chiral terpene auxiliaries. Part 1: Highly enantioselective reduction of ketones with borane catalyzed by an oxazaborolidine derived from (−)-β-pinene

(1R,2S,3R,5R)-3-Amino-6,6-dimethyl-2-hydroxybicyclo[3.1.1]heptane was synthesized in three steps from (−)-β-pinene. It was used for the in situ generation of a B-methoxy-oxazaborolidine catalyst for the asymmetric reduction of alkyl-aryl ketones with borane-dimethyl sulfide complex. In the presence of 3 mol % of the catalyst, the product alcohols were obtained in high yields and with enantiomeric excesses in the range of 93-98%.     

Palladium-catalyzed asymmetric allylic substitution using novel phosphino-ester (PHEST) ligands with 1,1′-binaphthyl skeleton

The asymmetric allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate 1 with dimethyl malonate 2a proceeded smoothly in the presence of lithium acetate, BSA (N,O-bis(trimethylsilyl)acetamide), [Pd(η³-C₃H₅)Cl]₂, and the chiral ligand (R)-i-Pr₂N-PHEST (R)-5a to give the allylic alkylation product (R)-3a in 89% yield with 99% ee. Furthermore, the asymmetric allylic amination of 1 with potassium phthalimide 2c has been carried out using the same ligand to give the allylic amination product (S)-3c in 10% yield with 66% ee.     

Highly enantioselective addition of linear alkyl alkynes to linear aldehydes

It is discovered that the use of biscyclohexylamine (Cy₂NH) as an additive can greatly enhance the enantioselectivity for the reaction of linear alkyl alkynes with linear aldehydes. The combination of (S)-BINOL (20 mol %), Cy₂NH (5 mol %), ZnEt₂ (2 equiv), and Ti(OⁱPr)₄ (0.5 equiv) catalyzes the reaction at room temperature in diethyl ether solution with 81-89% ee and 57-77% yield.     

Pd-catalyzed asymmetric allylic alkylation with nitromethane using a chiral diaminophosphine oxide: (S,RP)-Ph-DIAPHOX. Enantioselective synthesis of (R)-preclamol and (R)-baclofen

A Pd-catalyzed asymmetric allylic alkylation with nitromethane using an aspartic acid-derived P-chirogenic diaminophosphine oxide [(S,R_P)-Ph-DIAPHOX] is described. This method was successfully applied to enantioselective synthesis of (R)-preclamol and (R)-baclofen.