A simple method for the oxidation of α-amino acid esters to α-oximino esters

Magnesium bis(monoperoxyphthalate) hexahydrate (MMPP) was found to be an effective reagent for the oxidation of various α-amino acid esters to the corresponding α-oximino acid esters. This transformation could be completed under mild conditions within 2.5 h using 1.1 equiv of MMPP in THF. Clean oximino esters were obtained after quenching and extracting the reaction from sodium thiosulfate solution. The O-phosphorylated derivative of 2-oximinoglutarate exhibited slow binding inhibitory potency for the metallopeptidase prostate-specific membrane antigen (PSMA) with an IC₅₀ value of 58 nM.     

Synthesis of α-amino ketone hydrochlorides via chemoselective hydrogenation of α-nitro ketones

Chemoselective hydrogenation of various α-nitro ketones was accomplished with 5% Pt sulfide on carbon as a catalyst to afford α-amino ketone hydrochlorides in good yields.     

Non-phosgene route to unsymmetrical ureas from N-Cbz-α-amino acid amides

A convenient method toward the synthesis of α-amino acid-derived unsymmetrical ureas 2 is described herein. This route involves an interesting rearrangement of amides of N-Cbz-α-amino acids 1, which presumably entails the intermediacy of hydantoins that is followed by hydrolysis to afford unsymmetrical ureas 2 in quantitative yields and high purity.     

Enantioselective nickel-catalyzed conjugate addition of dialkylzinc to chalcones using chiral α-amino amides

A series of α-amino amides derived from natural amino acids (alanine, valine, phenylalanine, isoleucine, and phenylglycine) have been synthesized and fully characterized. Their Ni(II) complexes prepared from Ni(acac)₂ catalyze the enantioselective conjugate addition of diethylzinc to chalcones in high yields and in good enantioselectivities (up to 84%). The side chain of the amino acid and the substituents in the amide nitrogen govern the enantioselectivity of the catalytic process.     

Chiral magnesium BINOL phosphate-catalyzed phosphination of imines: access to enantioenriched α-amino phosphine oxides

A new method to synthesize chiral α-amino phosphine oxides is reported. The reaction combines N-substituted imines and diphenylphosphine oxide and is catalyzed by a chiral magnesium phosphate salt. A wide variety of aliphatic and aromatic aldimines substituted by electron-neutral benzhydryl or dibenzocycloheptene groups were excellent substrates for the addition reaction. The dibenzocycloheptene protected imines afforded improved enantioselectivity in the resulting products. Substituted diphenylphosphine oxide nucleophiles also showed good reactivity.     

Ligand-free CuI-catalyzed selective C–N coupling of aliphatic amino group of α-amino acid amides with ortho-dihaloarenes

Many synthetic methods of racemic N-aryl (including N-(2-haloaryl)) α-amino acid amides have been reported, but there are only a few for eutomers and none for inactivated halo(hetero)arenes. Selective C–N coupling of aliphatic amino group of α-amino acid amides is a direct and valuable method, but still unresolved. Here we disclose a simple and cheap ligand-free CuI-catalyzed selective synthesis of chiral N-(2-halo(hetero)aryl) amino acid amides without obvious racemization. A rational mechanism is proposed.     

Oligomers of β-amino acid bearing non-planar amides form ordered structures

In this report, we explore the feasibility of using bicyclic chiral β-amino acids, (1R,2R,4S)- and (1S,2S,4R)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid (R-Ah2c and S-Ah2c, respectively), to prepare novel peptides with unique properties. Facile cis-trans isomerization of the non-planar amide bonds of these β-amino acids should result in great flexibility of the backbone structure of β-peptides containing them. Indeed, oligomers of these amino acids showed thermostability and characteristic CD absorptions, which were not concentration-dependent, suggesting that the oligomers remained monomeric. The results indicated the formation of self-organized monomeric structures with chain-length-dependent stabilization. Energy calculations suggested that the peptides can take helical structures in which the energy barriers to cis-trans isomerization are greater for the central amide bonds than for the terminal amides.     

Synthesis of leucine-enkephalin analogs containing α-amino squaric acid

Novel Leu-enkephalin analogs 10a-c in which the Tyr¹, Gly², or Gly³ residue of Leu-enkephalin 9 was replaced with α-amino squaric acid analog Sq-Tyr 8b or Sq-Gly 8a were synthesized starting from 14 or 18. Conformational analysis of 10a-c together with its model compound 26 and their opioid receptor binding activity were evaluated.     

A chemoselective Reformatsky–Negishi approach to α-haloaryl esters

A practical synthesis of α-haloaryl esters has been achieved via a chemoselective Negishi coupling of poly-halogenated aromatics and Reformatsky reagents in the presence of catalytic Pd(dba)₂ and Xantphos. This chemistry tolerates a variety of aryl halides and was successfully applied to the synthesis of Ibuprofen. The α-haloaryl ester products, exemplified by ethyl 2-(4-bromo-2-chlorophenyl)acetate (3a), can be further functionalized via palladium or copper catalysis to afford an array of α-aryl esters.     

Visible-light-mediated direct access to α-ketoamides by dealkylative amidation of tertiary amines with benzoylformic acids

A visible-light induced direct amidation of benzoylformic acids with tertiary amines has been explored. Tertiary amines underwent N-dealkylative amidation with α-keto acid in the presence of [Ir{dFCF₃ppy}₂(bpy)]PF₆ and Cs₂CO₃, affording the corresponding α-ketoamides in good yields under mild conditions. This transformation exhibits a wide substrate scope and provides a facile synthetic approach to α-ketoamides.     

Multicomponent reaction design: a one-pot route to substituted di-O-acylglyceric acid amides from α-diazoketones

A four-component assembly of substituted di-O-acylglyceric acid amides has been developed from α-diazoketones. The process involves copper-catalyzed reaction of the α-diazoketone with a carboxylic acid, and subsequent Passerini condensation of the in situ formed α-acyloxyketone.     

Direct asymmetric synthesis of α-deuterated α-amino acid derivatives from the parent α-amino acids via memory of chirality

A method for asymmeyric α-deuteration of α-amino acid derivatives has been developed by a memory of chirality (MOC) strategy. The α-deuterated α-amino acid derivatives with 88–93% D were obtained in 60–98% ee in retention of the configuration (7 examples). The characterisrtic feature of the present procedure is that asymmeric induction was achieved by employing the parent amino acid derivatives as a sole source of chirality without the use of any external chiral souces.     

A reasonably stereospecific multistep conversion of Boc-protected α-amino acids to Phth-protected β-amino acids

A method for the synthesis of β³-amino acids starting from α-amino acids is described. This conversion can be effected by an eight-step procedure which involves the transformation of the carboxylic group into an alkyne followed by a selenium-mediated conversion of the carbon-carbon triple bond to a Se-phenyl selenocarboxylate intermediate. The reactive Se-phenyl selenocarboxylate intermediates can be trapped with water, alcohols or the amine of an amino acid derivative to give β³-amino acids, β³-amino esters or mixed peptides, respectively. The whole transformations of the carboxylic group into an alkyne and of the alkyne group into β³-amino acids may not require purification of the intermediate products but a work-up and isolation procedure of crude materials.     

A comparative study of the multicomponent Ugi reactions of an oxabicycloheptene-based β-amino acid in water and in methanol

Di-exo-3-amino-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid 1, five aldehydes and two isocyanides were reacted both in methanol and in water to prepare a 10-membered β-lactam library via a Ugi-4-centre-3-component reaction. The yields were found to be similar in water and methanol. The diastereoselectivities of the aqueous reactions were similar, though in a few cases higher than those in methanol. The benefits of water are the facile isolation of the precipitated product and the shorter reaction time.     

An organocatalyzed facile and rapid access to α-hydroxy and α-amino phosphonates under conventional/ultrasound technique

In the present work, successful implementation of ultrasound irradiation for the rapid synthesis of α-hydroxy and α-amino phosphonates under solvent-free conditions is demonstrated. Use of a novel catalyst (i.e., camphor sulfonic acid) in combination with ultrasound technique is reported for the first time. Comparative study for the synthesis of α-hydroxy and α-amino phosphonates using conventional as well as ultrasonication method is discussed.     

Photodecarboxylative additions of N-protected α-amino acids to N-methylphthalimide

Photoreactions involving N,N-dimethylated α-amino acid salts and N-methylphthalimide are dominated by photoreduction and acetone trapping. Only, N-phenyl glycinate underwent photodecarboxylative addition in a moderate yield of 30%. In contrast, N-acylated α-amino acid salts readily gave addition products in fair to high yields of 20-95%. Comparison experiments with N,N-dimethylacetamide and amino-/amido-containing phthalimides revealed the origin of the crucial electron-transfer step and the reactivity order NR₃ »  ? RCONR₂ was established.     

Salts of α-cyanoacrylic acid with sterically hindered tertiary amines

Syntheses are reported for representatives of a new class of derivatives of -cyanoacrylic acid, namely, its salts with brucine, tert-butyldimethylamine, and diisopropylmethylamine.A. N. Nesmeyanov Institute of Organometallic Compounds, Russian Academy of Sciences, 117813 Moscow. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 1, pp. 212–214, January, 1992.