A new strategy for the stereoselective synthesis of unnatural α-amino acids

A new method for the synthesis of racemic non-proteinogenic α-amino acids has been developed, which involves (i) hetero-Diels-Alder addition of ethyl 2-nitrosoacrylate to electron rich alkenes such as enol ethers, enamines and allylsilanes, (ii) NaCNBH₃ reduction of the CN bond in the oxazines thus generated, the stereochemistry of the products being controlled by epimerisation of the thermodynamically less stable isomer to the more stable one, (iii) protection of the N-H group as N-Boc and (iv) finally, N-O bond cleavage of both free and protected products to give proline or bis-homoserine derivatives, respectively. An example with concomitant reduction of the carboxylate group, resulting in the formation of the respective amino alcohol is reported. Applying this methodology to a homochiral enol ether, the protected parent d-proline was prepared in enantiomerically pure form, whereas the asymmetric synthesis of the respective bis-homoserine was unsuccessful.     

A modular synthesis of dithiocarbamate pendant unnatural α-amino acids

Unnatural α-amino acids containing dithiocarbamate side chains were synthesized by a one-pot reaction of in situ generated dithiocarbamate anions with sulfamidates. A wide range of these anions participated in the highly regio- and stereo-selective ring opening of sulfamidates to produce the corresponding dithiocarbamate pendant α-amino acids in high yields.     

Diphenylparabanic acid as a synthon for the synthesis of α-diketones and α-ketocarboxylic acids

Diphenylparabanic acid was found to react with >2 equiv of organolithiums at -78 °C to effectively give the corresponding symmetrical α-diketones. However, upon treatment with 1 equiv of organolithium, the parabanic acid gave mainly 5-substituted 5-hydroxyimidazolidine-2,4-diones. On the other hand, Grignard reagents were less reactive toward the parabanic acid at low temperature, and selectively gave the corresponding 5-hydroxyimidazolidine-2,4-diones even if more than 1 equiv of the reagents was used. A tandem process in which the parabanic acid was first reacted with a Grignard reagent and then reacted in one-pot with an organolithium effectively gave the unsymmetrical α-diketone. 5-Substituted 5-hydroxyimidazolidine-2,4-diones were useful as versatile precursors for preparing α-ketocarboxylic acids as well as unsymmetrical α-diketones.     

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 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.     

Facile synthesis of α-hydroxy carboxylic acids from the corresponding α-amino acids

An effective and improved procedure is developed for the synthesis of α-hydroxy carboxylic acids by treatment of the corresponding protonated α-amino acid with tert-butyl nitrite in 1,4-dioxane–water. The amino moiety must be protonated and located α to a carboxylic acid function in order to undergo initial diazotization and successive hydroxylation, since neither β-amino acids nor acid derivatives such as esters and amides undergo hydroxylations. The method is successfully applied for the synthesis of 18 proteinogenic amino acids.     

Asymmetric synthesis of allylic secondary alcohols: a new general approach for the preparation of α-amino acids

A new general approach for the synthesis of optically active α-amino acids has been developed. The key steps involve a ruthenium catalysed cross-coupling reaction to give a range of α,β-unsaturated ketones, which were then reduced to allylic secondary alcohols in the presence of a chiral CBS oxazaborolidine. A thermal Overman rearrangement was used to prepare a series of allylic trichloroacetimidates and these were converted under standard conditions to the target α-amino acids in good overall yields.     

Synthesis of unnatural N-glycosyl α-amino acids via Petasis reaction

A convenient and efficient protocol for the synthesis of unnatural N-glycosyl a-amino acids was developed.Condensation of 1,3,4,6-tetra-O-actyl-β-D-glucosamine hydrochloride,alkenyl boronic acid,and glyoxylic acid was achieved in CH_2C1_2 to give the derivatives of 2-(N-glycosyl)aminobut-3-enoic acid which may find applications in glycobiology research and medicinal chemistry.     

Stereo- and regio-selective one-pot synthesis of triazole-based unnatural amino acids and β-amino triazoles

Synthesis of triazole based unnatural amino acids and β-amino triazoles has been described via a stereo and regioselective one-pot multi-component reaction of sulfamidates, sodium azide, and alkynes under MW conditions. The developed method is applicable to a broad substrate scope and has significant potential for the synthesis of unnatural amino acids with a triazole side chain.     

Meldrum's acid — A reagent for the synthesis of unsaturated γ-lactones and Β-acylacrylic acids

The thermal cyclization of 2,2-dimethyl-5-(2-aryl-2-oxoethyl)-1,3-dioxan-4,6-diones forms 5-aryl-, butenolides. Regioselective chlorination of 2, 2-dimethyl-5-[2-aryl(alkyl)-2-oxoethyl]-1,3-dioxane-4,6-diones by SO₂Cl₂ gives the 5-chloro derivatives; these are cleaved by aqueous AcOH to the E--acylacrylic acids, which are synthones for unsaturated -lactones.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 5, pp.1212–1214, May, 1991.     

Improved synthesis and low-temperature performance of a series of saturated α-branched fatty acids

Five saturated α-branched fatty acids, also known as Guerbet acids, including α-propylhexyl acid (G ₁ ), α-butylhexyl acid (G ₂ ), α-propyloctyl acid (G ₃ ), α-butyloctyl acid (G ₄ ), and α-hexyloctyl acid (G ₅ ), were synthesized in high yields by four-step reaction. Colorless, almost odorless, and oily products were obtained with high purity, whose structures were confirmed by GC, ¹H/¹³C NMR, and ESI–MS characterization. G ₁ , G ₃ , and G ₄ had pour points lower than ?60 °C, while G ₂ and G ₅ showed higher pour points (?42 °C and 6 °C, respectively) because of their molecular symmetry. Considering the low-temperature properties, G ₁ , G ₃ , G ₄ , and even G ₂ held great potential applications in the lubricant and oilfield.     

A stereoselective synthesis of an α-substituted α-amino acid as a substructure for the construction of myriocin

A synthetic route to the protected quaternary α-amino acid 2 with a hydroxylated side chain has been achieved. The key transformations are the diastereoselective substrate-controlled epoxidation of allylic alcohol 4; a highly stereoselective oxidation–reduction protocol, and the excellent regioselective isomerization of the oxazolidinone ring to give an oxazinanone skeleton in derivative 3. The carboxylic acid 2 obtained represents the polar substructure, which is present in myriocin 1.     

The preparation and alkylation of a butanedione-derived chiral glycine equivalent and its use for the synthesis of α-amino acids and α,α-disubstituted amino acids

A benzyloxycarbonyl protected glycine equivalent 2 has been prepared in enantiopure form and has been used in the synthesis of both α-substituted amino acids and α,α-disubstituted amino acids. The process involved deprotonation to form the corresponding enolates which underwent stereoselective alkylation with various electrophiles and upon hydrolysis gave the corresponding amino acid derivatives as enantiomerically pure products.     

Absolute asymmetric synthesis of tertiary α-amino acids

Frozen: the spontaneous crystallization of an achiral compound in a chiral conformation is used as the unique source of chirality in an absolute asymmetric synthesis of tertiary amino acids. The dynamic axial chirality of tertiary aromatic amides is frozen in a crystal and is responsible for the stereoselectivity of the deprotonation/alkylation. α-Amino acid derivatives are synthesized in up to 96 % ee.     

Carbocyclic α-amino acids: asymmetric Strecker synthesis of a series of 2-alkylated 1-aminocyclopentanecarboxylic acids

A series of 12 carbocyclic α-amino acids has been prepared from four different racemic 2-alkylated cyclopentanones and (R)-1-phenylethylamine as the chiral auxiliary by means of an asymmetric Strecker synthesis. The stereoselectivity was influenced by solvent, temperature and size of the substituent at the 2-position of the cyclopentanones. For the methyl and ethyl substituted amino acids all four possible stereoisomers could be obtained, whereas for the isopropyl and tertiary butyl compounds an unexpected side reaction prohibited the isolation of the cis configured amino acids. The 1,3-induction mechanism observed for the kinetically controlled α-amino nitrile formation in the 2-methyl and 2-ethyl series was overlayed by a 1,2-induction in the respective 2-isopropyl and 2-tertiary butyl series.     

Enantiopure synthesis of side chain-modified α-amino acids and 5-cis-alkylprolines

A short, concise synthesis of enantiopure, side chain-modified α-amino acids such as 4-oxo-L-norvaline, 6-oxo-L-homonorleucine, and 5-cis-alkyl prolines is described. Knoevenagel condensation of l-aminocarboxylate-derived β-ketoesters with aldehydes followed by reductive decarboxylation results in unnatural α-amino acids in good yield. A fluorescent amino acid is synthesized using a similar protocol. These studies show that aminocarboxylate-derived β-ketoesters are very useful intermediates and the method employed is both general and practical for the preparation of γ(δ)-oxo α-amino acids and alkylprolines.     

New polymer-supported chiral phase-transfer catalysts in the asymmetric synthesis of α-amino acids: the role of a spacer

Polymer-supported cinchona alkaloid salts with different spacers were used as phase-transfer catalysts in the asymmetric C-alkylation of N-diphenyl methylene glycine tert-butyl ester. Various catalysts and alkylation conditions were studied, the best result being 81% e.e. with cinchoninium iodide bound to polystyrene with a four-carbon spacer.