Catalytic enantioselective synthesis of glutamic acid derivatives via tandem conjugate addition-elimination of activated allylic acetates under chiral PTC conditions

A new, general, and practical procedure for the asymmetric synthesis of 4-alkylidenyl glutamic acid derivatives via a catalytic enantioselective tandem conjugate addition-elimination on allylic acetates under chiral phase-transfer conditions is reported. A variety of structural types of allylic acetates have been reacted with the benzophenone imine of glycine tert-butyl ester to give the products in good to excellent yields and enantioselectivities (63-92% yield, 80-97% ee, 8 cases).     

Enantioselective synthesis of (S)-4-methyleneglutamic acid via tandem conjugate addition-elimination under phase-transfer catalytic conditions

An efficient enantioselective synthetic method for (S)-4-methyleneglutamic acid is reported. Phase-transfer catalytic conjugate addition-elimination of the benzophenone imine of glycine tert-butyl ester in the presence of chiral Cinchona-derived catalysts give the corresponding conjugated addition products (>99% ee), which could be hydrolyzed to chiral (S)-4-methyleneglutamic acid.     

Co-catalyst enhancement of enantioselective PTC Michael additions involving glycine imines

In this Letter we demonstrate that the use of 2,4,6-trimethylphenol (mesitol) as a co-catalyst facilitates highly enantioselective addition of benzophenone glycine imine tert-butyl ester to a range of Michael acceptors.     

Substituent effect of binaphthyl-modified spiro-type chiral phase-transfer catalysts

Binaphthyl-modified spiro-type phase-transfer catalysts possessing 4,4′-diaryl substituents are shown to exhibit high asymmetric induction in asymmetric benzylation of benzophenone imine glycine tert-butyl ester under phase-transfer conditions.     

Convenient preparation of highly active phase-transfer catalyst for catalytic asymmetric synthesis of α-alkyl- and α,α-dialkyl-α-amino acids: application to the short asymmetric synthesis of BIRT-377

A highly active phase-transfer catalyst was conveniently prepared from the known, easily available (S)-4,5,6,4′,5′,6′-hexamethoxybiphenyldicarboxylic acid. This catalyst 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.     

Immobilization of catalysts derived from Cinchona alkaloids on modified poly(ethylene glycol)

The straightforward immobilization of some derivatives of Cinchona alkaloids on modified poly(ethylene glycol)s is reported. The compounds, obtained by simple reactions exploiting different sites for the attachment of the alkaloids to the polymer, were tested as catalysts in the enantioselective benzylation of the benzophenone imine of glycine t-butyl ester (ee up to 64%) and in the conjugate addition of thiophenol to cyclohexenone (ee 22%). The observed stereoselectivities were compared to those obtained either with the unsupported catalysts or with the catalysts immobilized on different polymeric matrixes. The influence of the poly(ethylene glycol) moieties on the catalytic activity is discussed.     

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.     

Catalytic asymmetric Mannich reactions of glycine derivatives with imines. A new approach to optically active alpha,beta-diamino acid derivatives

Imines of glycine alkyl esters react with imines in a diastereo- and highly enantioselective Mannich reaction in the presence of chiral copper(I) complexes as the catalyst to give optically active alpha,beta-diamino acid derivatives. A series of imines of glycine esters derived from glycine and aromatic carbonyl compounds has been screened as substrates for the Mannich reaction with different imines in the presence of various combinations of metal salts and chiral ligands. The benzophenone imine of glycine esters was found to react with N-protected imines in a diastereoselective fashion giving functionalized alpha,beta-diamino acid esters with excellent enantioselectivities. The most effective chiral catalysts are chiral copper(I) complexes having phosphino-oxazoline (P,N)-ligands, and among these ligands, those derived from (1R,2S)-dihydroxy-1,2,3,4-tetrahydronaphthalene gave the best results. The scope of this new catalytic asymmetric reaction of the benzophenone imine glycine esters is demonstrated for the reaction with different N-protected-C-aryl and C-alkyl imines giving the Mannich adducts with excellent optical purity. Furthermore, the synthetic aspects of the reaction are presented by converting the Mannich adducts into alpha,beta-diamino acid derivatives. The relative and absolute configuration of the Mannich adduct have been determined and based on the stereochemical outcome of the reaction a tetrahedral chiral-copper(I)-imino glycine alkyl ester intermediate is proposed. In this intermediate the Re-face of the benzophenone imine glycine ester is shielded by the chiral ligand leaving the Si-face available for approach of the Si-face of the imine. A series of semiempirical calculations has been performed to support the structure of the tetrahedral chiral-copper(I) complex and to account for the influence of the substituents in the chiral phosphino-oxazoline ligands.     

Highly efficient polymer supported phase-transfer catalysts containing hydrogen bond inducing functional groups

Merrifield resin supported cinchona ammonium salts bearing 2′-fluorobenzene, 2′-cyanobenzene and 2′-N-oxypyridine groups were prepared and applied to the phase-transfer catalytic alkylation of N-(diphenylmethylene)glycine tert-butyl ester for the enantioselective synthesis of α-amino acids (76-96% ee).     

The synthesis and applications of asymmetric phase-transfer catalysts derived from isomannide and isosorbide

We report herein the synthesis of various derivatives of isomannide and isosorbide. Alkylation on N-(diphenylmethylene)glycine tert-butyl ester show the new catalysts to be effective phase-transfer catalysts with moderately good enantioselectivity. The effect of exo and endo substituents on the enantioselectivity of alkylation reaction have also been studied.     

Fluoroalkyl substituted (Z)-dehydro α-amino ester as a building block for the fluorine-containing cyclopropyl α-amino esters and dihydrooxazole

Multi-functionalized β-trifluoromethyl and β-difluoromethyl substituted (Z)-α,β-dehydro α-amino esters have been successfully prepared from N-protected fluorinated threonine ester. Applications of this new fluorine-containing building block to the synthesis of biologically important fluorinated cylcopropyl α-amino esters and dihydrooxazole ester have also been reported.     

Preparation of an electrophilic glycine cation equivalent and its reaction with heteroatom nucleophiles

A variety of heteroatom substituted Schiff base amino esters 4 - 7 are prepared either from the benzophenone imine of glycine ethyl ester (3) or by reaction of acetate 4 with heteroatom nucleophiles.     

Synthesis of a C3-symmetric macrocycle with alternating sugar amino acid and tyrosine residues

A C₃-symmetric macrocycle with alternating sugar amino acid and tyrosine residues was synthesized in seven steps from tyrosine tert-butyl ester and a sugar amino acid precursor derived from D-glucosamine. An Fmoc-protected D-glucosamine derivative was oxidized at C-6 to give the sugar amino acid, which was immediately coupled to tyrosine tert-butyl ester to produce an orthogonally protected building block. This building block was subsequently elongated to the trimer via the dimer, and finally cyclized to give the C₃-symmetric macrocycle.     

Solid-phase synthesis and utilization of side-chain reactive unnatural amino acids

Alkylation of the benzophenone imine of glycine Wang resin with α,ω-dihaloalkanes yielded valuable reactive intermediates. These racemic ω-chloro or ω-bromo intermediates were converted to α-amino acids containing diverse side-chain functionalities (e.g. ω-chlorides, nitriles, and thioethers), proline and its ring homologs, and 1-aminocycloalkanecarboxylic acid derivatives.     

1,4-Diazobicyclo[2.2.2]octane-catalyzed coupling of aldehydes and activated double bonds. Part 3. A short ans practical synthesis of mikanecic acid (4-vinyl-1-cyclohexene-1,4-dicarboxylic acid)

The title dicarboxylic acid 1d has been prepared in 24% overall yield via, 1,4-diazabicyclo[2.2.2]octane (DABCO)-catalyzed coupling of ethanal and tert-butyl propenoate ( 3 ) to 4 , S_N2′-reaction to tert-butyl (Z)-2-romomethyl-2-butenoate ( 5a ), dehydrobrominatin to tert-butyl 2-methylidene-3-butenoate ( 2c ), dimerizatoin to di-tert-butyl 4-vinyl-1-cyclohexene-1,4-dicarboxylate ( 1c ) and acidic ester cleavage. Acidic cleavage of easily obtainable 5a affords (Z)-2-bromomethyl-2-butenoic acid ( 5a ) in 68% yield with respect to ethanal.     

An efficient synthesis of tert-butyl ethers/esters of alcohols/amino acids using methyl tert-butyl ether

A facile synthesis of a wide variety of tert-butyl ethers and tert-butyl ester derivatives under mild conditions is described. Alcohols etherified with tert-butyl methyl ether as tert-butyl source and solvent, in the presence of sulfuric acid. Many amino acid tert-butyl esters have been synthesized by this procedure. The reaction is simple, inexpensive, easily scaled up, and proceeds without observable racemization. A green method was developed for the deprotection of this group using Amberlite resin IR 120-H as catalyst.     

Synthesis of optically active 2-fluoroalk-1-en-3-yl esters and chirality transfer in their Claisen-type rearrangements

A series of enantioenriched long chain 2-fluoroalk-1-en-3-ols 1 has been prepared by lipase-catalyzed resolution of the racemic compounds synthesized from terminal alkenes. The lipase of Candida antarctica was shown to be the most efficient one in terms of enantioselectivity. Transesterification of the fluorinated allylic alcohols 1 was superior over the hydrolysis in a phosphate buffer of the corresponding acetates 2. Lipase-catalyzed acetylation of allylic alcohols 1 in organic medium gave (S)-(−)-3-acetoxy-2-fluoroalk-1-enes of chain lengths C₁₀, C₁₆ and C₁₈ with 68-89% yield and 92-96% ee, while the remaining (R)-(+)-2-fluoroalk-1-en-3-ols were isolated with 54-96% yield and 72-86% ee. The absolute configuration was assigned by comparison of measured and calculated CD-spectra, and unambiguously by ¹H and ¹⁹F NMR spectroscopy using a modified Mosher's method. From the optically active fluorinated allylic alcohols 1 corresponding esters 2 such as propionates, 3,3,3-trifluoropropionates and Boc-glycinates were synthesized. These compounds were rearranged to 2-substituted 4-fluoroalk-4-enecarboxylic acids 3 applying modified conditions of the [3,3]-sigmatropic Ireland-Claisen rearrangement. While a complete chirality transfer from C-3 of the allylic esters to C-2 of the carboxylic acids or 2-amino acids, respectively, occurred in rearrangements of the propionates and Boc-glycinates, racemic 2-(trifluoromethyl)alk-4-enecarboxylic acids were formed from the allylic trifluoropropionates. The configurational lability of the latter products is caused by the strongly acidic proton in α-position to the trifluoromethyl and the carboxyl groups under the basic rearrangement conditions.     

Polymeric chiral phase-transfer catalysts derived from cinchona alkaloids for enantioselective synthesis of α-amino acids

A series of dimeric/trimeric chiral quaternary ammonium salts derived from cinchona alkaloids were designed as efficient and practical chiral phase-transfer catalysts (PTCs). Presented are the details on the development of the dimeric PTCs for the synthesis of optically active α-amino acid derivatives and the optimization of the reaction variables suitable for the dimeric PTCs. The 1,3-phenyl- and the 2,7-naphthyl-linked dimeric PTCs showed excellent catalytic capability on the reactivity and enantioselectivity in the catalytic phase-transfer alkylation of N-(diphenylmethylene)glycine tert-butyl ester (1). A variety of α-amino acid derivatives were obtained with high enantiopurities using the dimeric PTCs, especially the 2,7-naphthyl-dimer 41, in a very practical manner.     

A general approach to l-tyrosine porphyrins

A novel and general approach has been developed to prepare l-tyrosine-containing porphyrins. The key intermediates, 2-tert-butoxycarbonylamino-3-(3-formyl-4-hexyloxy-phenyl)-propionic acid hexyl ester and 2-tert-butoxycarbonylamino-3-(3-formyl-4-methoxy-phenyl)-propionic acid methyl ester, were prepared by the Reimer-Tiemann reaction of Boc-protected l-tyrosine, which was followed by esterification and alkylation of the phenol hydroxide. A number of novel chiral l-tyrosine porphyrins were obtained from the reactions of 2-tert-butoxycarbonylamino-3-(3-formyl-4-alkoxy-phenyl)-propionic acid ester with different dipyrrolylmethanes and the reaction of 5-(4-trifluoromethylphenyl)pyrromethane afforded the highest yield. The tyrosine porphyrins could be readily deprotected to afford the corresponding diacid or diamine derivatives.     

Synthesis of 2-Substituted and 2,3-Disubstituted Quinazolin-4-ones Containing a Sterically Hindered Phenol Residue

A series of 2-substituted and 2,3-disubstituted quinazolin-4-ones containing a 3,5-di(tert-butyl)-4-hydroxyphenyl group has been synthesized. They were prepared by the condensation of carboxylic acid imino ester hydrochlorides containing the indicated fragment with ethyl anthranilate and also by the reaction of azomethines, N-acylhydrazones, or the 4-phenylthiosemicarbazone of 3,5-di(tert-butyl)-4-hydroxybenzaldehyde with 2-methyl-4H-2,1-benzoxazin-4-one.