Diastereoselective syntheses of 2-amino propargyl alcohols. Chiral building blocks for enantiopure amino γ-lactones and 5-hydroxy-piperidinone derivatives

α-Dibenzylamino aldehydes, derived from the corresponding natural α-amino acids, react with metal acetylides to yield anti-amino propargyl alcohols in good yield and diastereomeric excess. syn Amino alcohols are prepared from the anti diastereoisomers and all of them are elaborated in few steps to enantiopure amino lactones and hydroxy-piperidin-2-ones.     

A novel synthesis of cyclic α-amino aldehydes, amino alcohols, and α-amino acid methyl esters from cyclic ketones through sulfinylaziridines

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from cyclic ketones and chloromethyl p-tolyl sulfoxide in three steps in good yields, with N-lithio arylamines gave sulfinylaziridines in high yields. On treatment with N-lithio aniline or N-lithio p-chloroaniline, the sulfinylaziridines gave α-amino aldehydes in high yields. The α-amino aldehydes were converted to amino alcohols and α-amino acid methyl esters in moderate to good yields. This procedure offers an efficient method for synthesis of cyclic α-quaternary α-amino aldehydes, amino alcohols, and α-amino acid derivatives from cyclic ketones.     

Synthesis of crosslinked poly(α-amino acids) with various functional groups

The esterification of the carboxyl group in copoly(γ-benzyl-L -glutamyl-L -glutamic acid) was carried out using N-hydroxysuccinimide and dicyclohexylcarbodimide to yield the activated site for the coupling reaction with amino compounds. The α-helix stability of the reactive copolymer thus obtained is remarkably affected in the presence of succinimide ring. This copolymer was proved to react nearly completely with amino alcohols such as 2-aminoethanol, 3-aminopropanol, and diethanolamine. The copoly(N⁵-hydroxyalkyl-L -glutamine) thus prepared is insoluble in water, since the benzyl ester remains in this copolymer. The copoly(α-amino acids) having another functional group were also prepared using aminoalkylsilane. Crosslinked poly(α-amino acids) were prepared by the reaction of the reactive copolymer with a low-molecular-weight polymer of PBLG having one amino group on each end of its main chain which was obtained from the corresponding NCA using p-diaminobenzene as an initiator. Another crosslinked polymer was prepared using an alkyl diamine such as 1,6-diaminohexane or 1,12-diaminododecane as a crosslinking reagent. The crosslinked copoly(α-amino acids) bearing the activated site are able to further react with various compounds having amino groups.     

Cyclodextrins as chiral stationary phases in capillary gas chromatography. Part II: Heptakis(3-O-acetyl-2,6-di-O-pentyl)-ß-cyclodextrin

Heptakis (3-O-acetyl-2,6-di-O-pentyl)-ß-cyclodextrin is used as a chiral stationary phase in capillary gas chromatography. High enantioselectivity towards trifluoro-acetylated α and β-chiral amines, amino alcohols, α- and β-amino acid esters, and cyclic trans-diols is observed. In contrast to chiral polysiloxane phases, where hydrogen bonding interaction is essential for enantiomer separation, in cyclodextrins inclusion properties contribute to enantioselectivity. This can be concluded from the separation of N-alkylated amino compounds. The new chiral stationary phase exhibits a wide operating temperature range and is stable above 200°C.     

N Reactivity vs. O reactivity in aqueous chlorination

Nitrogenated compounds react with hypochlorous acid yielding N-chloro compounds. In principle, α-amino acids chlorination may take place on the oxygen of the carboxylic group or on the nitrogen of the amino group. In this framework, we discuss the different reactivities of nitrogen and oxygen towards chlorine, and come to the conclusion that the nitrogen is the preferred reaction site in α-amino acids chlorination. © 1994 John Wiley & Sons, Inc.     

1,3-Dipolar cycloadditions of nitrile oxides with 4-carbethoxymethyleno-4,5,6,7-tetrahydro-6,6-dimethylbenzo[c][1,2,5]oxadiazole

The (E)- and (Z)-α,β-unsaturated esters, 3 and 4 are prepared by applying a Wittig reaction on the ketone 1. Stable nitrile oxides are added to the stable (E)-isomer 3 resulting to the formation of the spiro-derivatives 7 , whereas with the unstable nitrile oxides a second stereoisomer 8 is also formed. Mesitonitrile oxide reacts also with the ketone 1 to give the spiro-cycloadduct 10. The assignment of regio-isomers 7 was deduced from their spectral data as well as from some molecular orbital considerations.     

Sur les esters activés III. Nouvelle synthèse des dioxo-2,5-pipérazines et étude de leurs propriétés chimiques

By reacting an α-amino acid N-carboxyanhydride with an amidoxime the dioxopiperazine derived from the parent amino acid is formed in quantitative yield. In this way the dioxopiperazine of glutamic acid, which is not otherwise accessible, has been prepared.     

Electrocatalytic Synthesis of Essential Amino Acids from Nitric Oxide Using Atomically Dispersed Fe on N-doped Carbon

How to transfer industrial exhaust gases of nitrogen oxides into high-values product is significantly important and challenging. Herein, we demonstrate an innovative method for artificial synthesis of essential α-amino acids from nitric oxide (NO) by reacting with α-keto acids through electrocatalytic process with atomically dispersed Fe supported on N-doped carbon matrix (AD-Fe/NC) as the catalyst. A yield of valine with 32.1 μmol mg_cat⁻¹ is delivered at −0.6 V vs. reversible hydrogen electrode, corresponding a selectivity of 11.3 %. In situ X-ray absorption fine structure and synchrotron radiation infrared spectroscopy analyses show that NO as nitrogen source converted to hydroxylamine that promptly nucleophilic attacked on the electrophilic carbon center of α-keto acid to form oxime and subsequent reductive hydrogenation occurred on the way to amino acid. Over 6 kinds of α-amino acids have been successfully synthesized and gaseous nitrogen source can be also replaced by liquid nitrogen source (NO₃⁻). Our findings not only provide a creative method for converting nitrogen oxides into high-valued products, which is of epoch-making significance towards artificial synthesis of amino acids, but also benefit in deploying near-zero-emission technologies for global environmental and economic development.     

Efficient synthesis of fluorinated α- and β-amino nitriles from fluoroalkylated α,β-unsaturated imines

A simple and efficient synthesis of fluoroalkylated α-amino nitrile (4) derivatives by regioselective 1,2-addition of trimethylsilyl cyanide to fluoroalkylated α,β-unsaturated imines (1) is described. Fluoroalkylated β-amino nitriles (7) are also prepared by regioselective 1,2-addition of α-carbanions derived from acetonitrile to fluoroalkylated α,β-unsaturated imines (1). Fluoroalkylated α-(4) and β-amino nitriles (7) are also prepared through an ‘one pot’ procedure by reaction of enaminophosphonate 2 with BuLi, addition of aldehydes and subsequent addition of either trimethylsilyl cyanide or α-carbanion derived from acetonitrile. Basic hydrolysis of α-(4) and β-amino nitriles (7) gives fluoroalkylated α-(5) and β-amino acids (8).     

Oxidation of α-oxo-oximes to nitrile oxides with hypervalent iodine reagents

Upon reaction with PhI(OAc)(2), α-oxo-aldoximes are oxidized to α-oxo-nitrile oxides, while α-oxo-ketoximes are converted into nitrile oxides via the oxidative cleavage of the carbonyl-imino σ bond. The nitrile oxides thus formed were trapped with norbornene or styrene in good yield. α,α'-Dioxo-ketoximes react less efficiently.     

Palladium-Catalyzed Carbo-Oxygenation of Propargylic Amines using in Situ Tether Formation

1,2-Amino alcohols and α-aminocarbonyls are frequently found in natural products, drugs, chiral auxiliaries, and catalysts. This work reports a new method for the palladium-catalyzed oxyalkynylation and oxyarylation of propargylic amines. The reaction is perfectly regioselective based on the in situ introduction of a hemiacetal tether derived from trifluoroacetaldehyde. cis-Selective carbo-oxygenation was achieved for terminal alkynes, whereas internal alkynes gave trans-carbo-oxygenation products. The obtained enol ethers could be easily transformed into 1,2-amino alcohols or α-amino ketones using hydrogenation or hydrolysis, respectively.     

Copper/DIPEA-catalyzed, aldehyde-induced tandem decarboxylation-coupling of natural α-amino acids and phosphites or secondary phosphine oxides

A copper/DIPEA-catalyzed, aldehyde-induced intermolecular decarboxylative coupling reaction of natural α-amino acids and phosphites or secondary phosphine oxides was developed. In this process, a series of potentially useful ligands for organic synthesis and biologically important unnatural amino acid derivatives (tertiary amino phosphorus compounds) were obtained.     

Les β-cétonitriles groupes protecteurs de la fonction amine. Préparation d'amino-alcools

β-Ketonitrile-Derived Protecting Groups of the Amino Function. Synthesis of Amino Alcohols The amino group of natural L -amino acid esters is protected by condensation with 2-oxocyclopentanenitrile ( 1 ) or 2-formyl-2-phenylacetonitrile ( 10 ). Only the ester group of the formed cyanoenamino esters 2 and 11 reacts with nucleophilic reagents such as organometallics (RMgX, RLi), borohydrides, or metal amides, whereas the cyanoenamino group is unchanged (Schemes 1 and 2). Cyanoenamino alcohols obtained by reduction of cyanoenamino esters 2 are hydrolyzed under acidic conditions to amino alcohols with retention of the configuration of the starting amino acid. This sequence of reactions allows to prepare derivatives of L -tyrosinol from (?)-L -tyrosine (see, e.g., Scheme 4). Cyanoenamino esters 11 are readily methylated at the N-atom to give N-methylated cyanoenamino esters (Scheme 3). This property is exploited on the way of a multistep procedure to obtain N-methylated amino alcohols homologous to natural (?)-(1R,2S)-ephedrine.     

Copper(0) Nanoparticles in Click Chemistry: Synthesis of 3,5‐Disubstituted Isoxazoles

An efficient procedure for the synthesis of 3,5‐disubstituted isoxazoles via [3 + 2] cycloaddition reaction of in situ generated nitrile oxides with acetylenes employing readily preparable copper(0) nanoparticles is described. A variety of in situ generated nitrile oxide and acetylenic substrates were engaged in the study and found to undergo cyclization in short duration affording respective isoxazoles in excellent yield. Several amino acid‐derived isoxazoles were also prepared in high yield. Consistent activity of the recovered catalyst was found to be almost same up to three cycles.     

Enantio- and Site-Selective α-Fluorination of N-Acyl 3,5-Dimethylpyrazoles Catalyzed by Chiral π–CuII Complexes

Catalytic enantioselective α-fluorination reactions of carbonyl compounds are among the most powerful and efficient synthetic methods for constructing optically active α-fluorinated carbonyl compounds. Nevertheless, α-fluorination of α-nonbranched carboxylic acid derivatives is still a big challenge because of relatively high pK_a values of their α-hydrogen atoms and difficulty of subsequent synthetic transformation without epimerization. Herein we show that chiral copper(II) complexes of 3-(2-naphthyl)-l -alanine-derived amides are highly effective catalysts for the enantio- and site-selective α-fluorination of N-(α-arylacetyl) and N-(α-alkylacetyl) 3,5-dimethylpyrazoles. The substrate scope of the transformation is very broad (25 examples including a quaternary α-fluorinated α-amino acid derivative). α-Fluorinated products were converted into the corresponding esters, secondary amides, tertiary amides, ketones, and alcohols with almost no epimerization in high yield.     

Highly functionalised organolithium and organoboron reagents for the preparation of enantiomerically pure α-amino acids

Homochiral, highly functionalised organolithium reagents derived from l-serine have been generated and reacted with electrophiles. The novel enantiomerically pure adducts thus obtained were then converted, through β-amino alcohols, into novel non-proteinogenic α-amino acids. The methodology also made available a novel boronic acid which was then employed as a Suzuki cross-coupling partner, elaborating a new pathway to phenylalanine analogues.     

α-Amino acids as acid components in the Passerini reaction: influence of N-protection on the yield and stereoselectivity

The Passerini reaction offers an easy access to depsipeptides, when both acid and isocyanide are derived from α-amino acids. However, racemisation of isocyanides derived from α-amino acid esters severely limits their use in the Passerini reaction. In order to overcome this limitation, a study on the influence of the α-amino acid N-protecting group on the yield and diastereoisomeric ratio of the product of the Passerini reaction was performed. Six different protecting groups were tested. Their influence turns out to be crucial and is not constant when the amino acid is changed. After optimisation, the Passerini reaction products with cyclohexanone as the carbonyl component were obtained with 99% yield and >98% de.     

Aziridines derived from amino acids as synthons in pseudopeptide synthesis

The reactivity of the Z-protected aziridine derived from aspartic acid has been studied with various N- and O-nucleophiles. The optimized reaction conditions allow quick and easy access to 1, 2-diamines or amino alcohols. In the case of opening with N-nucleophiles, very good regioselectivity was observed. Use of an α-amino ester as the nucleophile yielded a methyleneamino pseudodipeptide.     

Bisorthoesters as polymer intermediates. I. Synthesis of bisorthoesters

Derivatives of three types of bisorthoesters, hexaalkyl orthoisophthalates, hexaalkyl orthoterephthalates, and hexaethyl orthooxalate, were synthesized. The orthoesters of isophthalic and terephthalic acid were prepared from α, α, α, α′, α′, α′ -hexachloro-m-xylene or hexachloro-p-xylene, respectively. It was found more advantageous to prepare initially the hexamethyl orthoesters by reacting the hexachloro compounds with sodium methoxide in methanol either at the boiling point of methanol or under pressure at temperatures up to 200°C. Transesterification with higher alcohols, for example, ethanol or propanol, with the aid of molecular sieves gave the higher bisorthoesters in high yield and high purity. Attempts to synthesize orthoisophthalates and orthoterephthalates of higher alcohols directly from the hexachloroxylenes and alkoxides of higher alcohols gave only low yields of impure products. The Pinner synthesis of the bisorthoesters from the corresponding dinitriles was also ineffective. The ease of purification of hexa-n-propyl orthoisophthalate and orthoterephthalate makes these orthoesters the favored candidates for use in polymer syntheses. Hexaethyl orthooxalate was prepared in a three-step synthesis from triethyl orthoformate by a convenient, but low yield reaction. All bisorthoesters were purified to give compounds which were monomer grade materials free of normal esters.     

The preparation of selenium-containing aromatic and heterocyclic C-substituted α-amino acetic acid derivatives of potential biomedical application

Model selenium-containing aromatic and heterocyclic C-substituted α-amino acid compounds have been synthesized as potential biomedical organ scanning application (external imaging) agents. The synthesis is based on the amidoalkylation of aromatic and heterocyclic compounds with α-hydroxyglyoxylic acid-primary amide adducts (2). The procedure is simple and straightforward, the overall yields are good, and the method appears to be of general use for the preparation of a wide variety of selenium-containing amino acids (4).