Protected Α-amino Acids Research Articles

Nickel-Catalyzed Multicomponent Coupling: Synthesis of α-Chiral Ketones by Reductive Hydrocarbonylation of Alkenes.

A nickel-catalyzed, multicomponent regio- and enantioselective coupling via sequential hydroformylation and carbonylation from readily available starting materials has been developed. This modular multicomponent hydrofunctionalization strategy enables the straightforward reductive hydrocarbonylation of a broad range of unactivated alkenes to produce a wide variety of unsymmetrical dialkyl ketones bearing a functionalized α-stereocenter, including enantioenriched chiral α-aryl ketones and α-amino ketones. It uses chiral bisoxazoline as a ligand, silane as a reductant, chloroformate as a safe CO source, and a racemic secondary benzyl chloride or an N-hydroxyphthalimide (NHP) ester of a protected α-amino acid as the alkylation reagent. The benign nature of this process renders this method suitable for late-stage functionalization of complex molecules.

The Asymmetric Synthesis of Amines via Nickel-Catalyzed Enantioconvergent Substitution Reactions.

Chiral dialkyl carbinamines are important in fields such as organic chemistry, pharmaceutical chemistry, and biochemistry, serving for example as bioactive molecules, chiral ligands, and chiral catalysts. Unfortunately, most catalytic asymmetric methods for synthesizing dialkyl carbinamines do not provide general access to amines wherein the two alkyl groups are of similar size (e.g., CH2R versus CH2R1). Herein, we report two mild methods for the catalytic enantioconvergent synthesis of protected dialkyl carbinamines, both of which use a chiral nickel catalyst to couple an alkylzinc reagent (1.1-1.2 equiv) with a racemic partner, specifically, an α-phthalimido alkyl chloride or an N-hydroxyphthalimide (NHP) ester of a protected α-amino acid. The methods are versatile, providing dialkyl carbinamine derivatives that bear an array of functional groups. For couplings of NHP esters, we further describe a one-pot variant wherein the NHP ester is generated in situ, allowing the generation of enantioenriched protected dialkyl carbinamines in one step from commercially available amino acid derivatives; we demonstrate the utility of this method by applying it to the efficient catalytic enantioselective synthesis of a range of interesting target molecules.

Synthesis of protected α-amino acids via decarboxylation amination from malonate derivatives.

A general and efficient strategy for the synthesis of protected α-amino acids is reported. The method uses malonate derivatives as the starting materials and Cs2CO3 as a base at 60 degrees, giving α-amino acid derivatives in moderate yields by releasing CO2. This methodology shows broad substrate scope (primary and secondary acids), excellent functional group tolerance and high efficiency to give the desired products under mild reaction conditions. It also allows the construction of β and γ-amino acids and other unnatural products.

Peptide and Pseudopeptide Bond Synthesis in Phosphorus Dipeptide Analogs.

Peptide analogs modified with a phosphorus-based moiety (phosphonate, phosphonamidate, or phosphinate) have emerged as invaluable tools in fundamental and medicinal, mechanistic, and inhibitory studies of proteolytic enzymes and other catalytic proteins that process the amino acids and peptides. The first stages of the chemical synthesis of these compounds frequently involve formation of peptide or pseudopeptide bond between a suitably protected α-amino acid and an α-aminoalkyl phosphorus derivative. These preparative protocols are distinct from conventional solution and solid-phase peptide syntheses that have become routine and automatized. In the following chapter, we describe in details the methods and techniques utilized to perform this nonstandard coupling and to obtain P-terminal dipeptidyl phosphonates and pseudodipeptides containing the internal phosphonamidate or phosphinate linkages. Methods of products' purification, the deprotection conditions, and stability issues are also presented and discussed.

Removal of Aminoquinoline Auxiliary from Protected α-Amino Acids

Key words aminoquinoline auxiliary - iodoxybenzoic acid - deprotection - oxidation - phthaloyl amino acids - C–N bond cleavage

Synthesis of Acetaminophen Analogues Containing α-Amino Acids and Fatty Acids for Inhibiting Hepatotoxicity

Acetaminophen is a popular antipyretic analgesic medicine that has weaker anti-inflammatory properties and lower incidence of side effects than nonsteroidal anti-inflammatory drugs (NSAIDs). However, acetaminophen causes hepatotoxicity due to the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI). We have obtained acetaminophen analogues in 57–99% yields by using aniline derivatives with protected α-amino acids and fatty acids via the corresponding mixed carbonic carboxylic anhydrides in aqueous MeCN. We have also succeeded in synthesizing AM404 analogues in 76–97% yields, which are expected to be promising candidates for reducing hepatotoxicity.

Synthesis of 1,3,4-oxadiazole derivatives from α-amino acid and acyl hydrazides under thermal heating or microwave irradiation conditions

A series of new 2,5-disubstituted 1,3,4-oxadiazoles was synthesized under conventional thermal heating and microwave irradiation conditions through the reaction of acyl hydrazides with N- protected α-amino acid in presence of a small amount of POCl3. Heterocycles were obtained in moderate to good yields and in relatively short reaction times.

Influence of Amino Acid Stereocenters on the Formation of Bicyclic N,O-Acetals

In recent years, our group has reported the highly diastereoselective acid-catalyzed N,O-acetalization/intramolecular transcarbamoylation cascade of reactions between protected α-amino acid derivatives (Ser and Thr) and tetramethoxyalkanes. The resulting oligocyclic N,O-acetals have been used as excellent chiral building blocks for asymmetric transformations such as diastereoselective alkylation of the α-position. We now evaluate the scope of the reaction with related non-natural α-amino acid derivatives. A combined experimental and theoretical study reveals the key influence of the α-carbon substitution (serine versus α-methylserine) and the relative configuration of α-/β-carbons (threonine versus allo-threonine) in the thermodynamic stability of the products and, as a consequence, the stereochemical outcome of the reaction. Notably, the complete diastereoselectivity achieved with natural amino acid precursors is completely lost with their non-natural analogues.

Base-promoted diastereoselective addition of nitromethane and nitroethane to N-tert-butylsulfinyl imines: synthesis of N-protected α-amino acids and amino ketones

The reaction of N-tert-butylsulfinyl imines with nitromethane or nitroethane in the presence of NaHCO3 under solvent-free reaction conditions gave β-nitro amine derivatives with reasonable levels of diastereoselectivity. Enantioenriched N-tert-butylsulfinyl protected α-amino acids or α-amino ketones are accessible upon oxidation of the adducts derived from nitromethane or nitroethane, respectively.

Chiral Ar-BINMOL-derived salan as fluorescent sensor for recognition of CuCl and cascade discrimination of α-amino acids

It was found that the chiral salan compound derived from chiral Ar-BINMOL could serve as a fluorescent turn-on sensor for CuCl salt and the corresponding salan–copper(II) complex can work as a fluorescent sensor for the selective recognition and discrimination of protected α-amino acids with considerable selectivity.

A One-Pot Procedure for the Preparation ofN-9-Fluorenylmethyloxycarbonyl-α-amino Diazoketones from α-Amino Acids

The study describes a new "one-pot" route to the synthesis of N-9-fluorenylmethyloxycarbonyl (Fmoc) α-amino diazoketones. The procedure was tested on a series of commercially available free or side-chain protected α-amino acids employed as precursors. The conversion into the title compounds was achieved by masking and activating the α-amino acids with a single reagent, namely, 9-fluorenylmethyl chloroformate (Fmoc-Cl). The resulting N-protected mixed anhydrides were reacted with diazomethane to lead to the α-amino diazoketones, which were isolated by flash column chromatography in very good to excellent overall yields. The versatility of the procedure was verified on lipophilic α-amino acids and further demonstrated by the preparation of N-Fmoc-α-amino diazoketones also from α-amino acids containing side-chain masking groups, which are orthogonal to the Fmoc one. The results confirmed that tert-butyloxycarbonyl (Boc), tert-butyl ((t)Bu), and 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), three acid-labile protecting groups mostly adopted in the solution and solid-phase peptide synthesis, are compatible to the adopted reaction conditions. In all cases, the formation of the corresponding C-methyl ester of the starting amino acid was not observed. Moreover, the proposed method respects the chirality of the starting α-amino acids. No racemization occurred when the procedure was applied to the synthesis of the respective N-Fmoc-protected α-amino diazoketones from L-isoleucine and L-threonine and to the preparation of a diastereomeric pair of N-Fmoc-protected dipeptidyl diazoketones.

Synthesis and Reactivity of N-Alkyl Carbamoylimidazoles: Development of N-Methyl Carbamoylimidazole as a Methyl Isocyanate Equivalent

A high-yielding synthesis of N-methyl carbamoylimidazole from 1,1-carbonyldiimidazole (CDI) and MeNH(3)Cl is described. The product is a crystalline, readily storable, water-stable compound that reacts as a methyl isocyanate (MIC) substitute. Reaction of N-methyl carbamoylimidazole in the presence of a base such as triethylamine occurs with nucleophiles such as amines, protected and unprotected amino acids, thiols and alcohols. The product N-methylureas, carbamates and thiocarbamates are obtained in good to excellent yields, with reactions occurring in either organic solvents or water. The protocol for the synthesis of N-methyl carbamoylimidazole is both scalable and general, occurring in quantitative yield at scales ranging from 300 mg to 20 g. The success of this method relies upon the reaction of CDI with the ammonium salt rather than the free amine, resulting in a significant improvement in the yield of N-methyl carbamoylimidazole. The reaction presumably involves a proton transfer from MeNH(3)Cl to the CDI, which results in the release of MeNH(2) with simultaneous activation of the CDI as its protonated form. Other primary ammonium hydrochloride salts, including protected α-amino acid salts, give excellent yields of the corresponding N-alkyl carbamoylimidazoles and serve as alkyl isocyanate surrogates. The resultant N-alkyl carbamoylimidazoles can be converted to ureas in high yields without the formation of intermediary isocyanates.

Enantio- and chemoselective differentiation of protected α-amino acids and β-homoamino acids with a single copper(II) host.

The association between an achiral copper(II)-containing host 1 and chiral carboxylates has been expanded beyond previous studies to new chiral carboxylate guests, both α-amino acids and β-homoamino acids. The observed exciton-coupled circular dichroism (ECCD) signals for the enantiomers of each carboxylate were equal and opposite, and these signals differed in size and shape between the individual amino acids. Linear discriminant analysis (LDA) was applied as a statistical analysis technique to differentiate the amino acids, both enantioselectively and chemoselectively, giving the absolute configuration and identity of the amino acid. The identity of each of the α-amino acids and β-homoamino acids were determined independently by LDA, and then the two were considered together. Each of these analyses showed good differentiation of the amino acid guests with the use of only one host molecule.

A functionalized enol lactone containing a protected α-amino acid

The crystal structure of N-(3,9-dimethyl-4-phenyl-2,5-dioxo-3,4-dihydro-2H,5H-pyrano[3,2-c]chromen-3-yl)-N-methylbenzamide methanol monosolvate, C28H23NO5·CH3OH, has been determined at room temperature by X-ray diffraction. Structural parameters are discussed with reference to ab initio calculations.

ChemInform Abstract: Preparation of Enantiomerically Pure Protected Unsaturated α-Amino Acids from a New Serine Derived Zinc-Copper Reagent.

Treatment of the iodoalanine derived zinc reagent 1 with Knochel's soluble copper salt (CuCN·2LiCl) allows the preparation of a reactive copper reagent 2 which couples in moderate to good yield with allyl halides to give protected unsaturated α-amino acids in a single step from easily available precursors.

ChemInform Abstract: Catalytic Asymmetric Hydrogenation of 1-Aza-2-cycloalkene-2-carboxylates Catalyzed by a trans-Chelating Chiral Diphosphine PhTRAP-Rhodium Complex.

Abstract A rhodium complex coordinated with a trans -chelating chiral diphosphine (S,S)-(R,R) -PhTRAP was an effective catalyst for asymmetric hydrogenation of N -acyl-1-aza-2-cycloalkene-2-carboxylates, which gave the corresponding protected cyclic α-amino acids with 73–97% ee.

ChemInform Abstract: Phase Transfer Catalysis: Some Recent Applications in Organic Synthesis

Abstract A survey dealing with the use of anhydrous potassium carbonate as an efficient base for promoting organic reactions under solid–liquid phase transfer catalysis (SL-PTC) conditions is reported. In particular, the generation in situ of trifluoro- and trichloroacetamidide, and reactions of these azaanions with 2-bromocarboxylic esters and epoxides, affording protected α-amino acids and β-amido alcohols, respectively, are described. The reduction of allylic nitroderivatives with CS 2 to oximes or nitriles under SL- and liquid–liquid PTC (LL-PTC) is also presented. Finally, new preparation methods and a study of the reactivity of quaternary onium fluorides, hydrogendifluorides and dihydrogentrifluorides, together with the use of dihydrogentrifluorides as hydrofluorinating agents under SL-PTC conditions, are reported.

Site-Selective Methylation of Nβ-Nosyl Hydrazides of N-Nosyl Protected α-Amino Acids

The methylation reaction of N(beta)-nosyl hydrazides of N-nosyl protected alpha-amino acids by using diazomethane shows a controlled regiochemical trend and makes it possible to obtain the corresponding products methylated at specific positions depending on the amount of diazomethane used. The observed selectivity is closely connected with the different acidity of sulfonyl hydrazide, sulfonamide, and acyl hydrazine protons present in the analyzed substrates. The reactivity order of these three diverse reactive sites is supported by theoretical calculations. The hydrazine derivatives considered in this work belong to a class of compounds with interesting biological activity and of great interest in organic synthesis.

A simple approach for the synthesis of new pyrimidinyl α-amino acids

A simple synthetic method for the preparation of optically active pyrimidinyl α-amino acids is presented. A nucleophilic ipso-substitution reaction between 2-(benzylsulfonyl)-4-isopropoxypyrimidines and a nucleophilic side chain of several protected natural α-amino acids is investigated to obtain new pyrimidin-2-yl α-amino acids. A detailed optimisation study of this reaction is discussed. Moreover, the selective O-alkylation of 2-(benzylsulfanyl)-4(3H)pyrimidinones with a hydroxylic side chain of some natural α-amino acids under Mitsunobu conditions is studied as a method to prepare new pyrimidin-4-yl α-aminoesters.

Enzymatic synthesis of carnosine derivatives catalysed by Burkholderia cepacia lipase

A new enzymatic synthesis of α,β-dipeptides has been developed with particular focus on the preparation of carnosine (β-alanyl-α-histidine) and analogues. The lipase PS-D from Burkholderia cepacia has been used as a catalyst for the formation of the peptide bond starting from a β-lactam and a protected α-amino acid.