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.     

Synthesis and resolution of new paramagnetic α-amino acids

New, paramagnetic unnatural α-amino acids were synthesized by the O'Donnell method. In the new amino acids nitroxide is condensed with thiophene, benzene, and tetrahydroisoquinoline ring, or linked through a methylene, benzyl or propargyl spacer. Some of the racemic paramagnetic α-amino acid esters described earlier or in this work were resolved by fractional crystallization of diastereomeric salts. Another approach for optically active paramagnetic amino acids is the modification of S-tyrosine derivatives with Pd-catalyzed cross-coupling reactions with paramagnetic acetylene and with a paramagnetic boronic acid.     

Visible-Light-Driven Three-Component Reaction of Unactivated Alkenes Enables Access to Monofluoro γ-Amino Acids

A strategy for the synthesis of diverse protected α-monofluoro-γ-amino acid derivatives has been developed. This reaction assembles a simple enamide, quinoxalin-2(1H)-one, and diethyl 2-bromo-2-fluoromalonate through a three-component reaction driven by visible light. The advantages of this protocol include the simplicity of its operation, mild conditions, high functional group tolerance, and applicability to a wide variety of substrates. The synthesis of this fluorine-containing amino acid derivative has significant value for potential applications in medicinal chemistry and chemical biology.     

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.     

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.     

Highly Stereoselective Aldol Reactions by Memory of Chirality: Synthesis of Quaternary β-Hydroxy α-Amino Acids

We describe here an asymmetric aldol reaction based on the principle of Memory of Chirality. From α-amino acids such as leucine and methionine, we have synthesized in two steps quaternary α-amino acid derivatives with high diastereoselectivity and enantioselectivity, using the chirality of the initial α-amino acid as the only chirality source. Furthermore, we were able to determine the relative and absolute configurations of the aldol products thanks to crystallographic structures and thus showed that the relative configuration depended on the aldehyde employed. We proposed a stereoselectivity explanation and obtained also quaternary β-hydroxy α-amino acids after acidic hydrolysis.     

Retention of chirality of 5-membered alicyclic α-amino acids bearing N-(2-phenyl)benzoyl group in photoinduced decarboxylative intermolecular radical addition to acrylonitrile

Photoinduced decarboxylative radical additions of 5-membered alicyclic α-amino acids bearing a (2-phenyl)benzoyl protective group to acrylonitrile under mild organic photoredox catalysis conditions furnished γ-amino acid derivatives with high retention of chirality via the memory of chirality (MOC) strategy. The retention of chirality in the photoinduced decarboxylation was strongly dependent on the structure of the alicyclic α-amino acids and alkenes. To the best of our knowledge, this is the first example of the decarboxylative intermolecular radical addition to alkenes with retention of chirality at the position of radical generation using the MOC strategy.     

Amphiphilic allylation of arylidene-1,3-oxazol-5(4H)-one using bis-π-allylpalladium complexes: an approach to synthesis of cyclohexyl and cyclohexenyl α-amino acids

An efficient method for synthesis of cyclohexyl and cyclohexenyl α-amino acids via palladium-catalyzed three-component assemblies followed by ring-closing metathesis (RCM) is described. The present catalytic reaction is successfully extended to substituted benzylidene azlactones 2a-j RCH=(1,3-oxazole): R = alkyl or aryl. The amphiphilic bis-allylation of these substrates has been achieved by replacing toxic allylstannanes with allyltrifluoroborate and the reaction proceeded smoothly to afford the corresponding 1,7-diene derivatives 3a-j in acceptable to good yields. RCM of the resulting octadienes using the first generation Grubbs catalyst gave easy access to stereodefined substituted cyclohexene derivatives 7-11 in high yields. Acid hydrolysis of the oxazolone ring of 7-10 gave protected amino acids 12-16. Debenzoylation of 13 and 15 afforded 1-amino-6-aryl-cyclohex-3-enecarboxylic acids 17 and 18 in excellent yields, respectively. Moreover, catalytic reduction of 13 gave the corresponding cyclohexane derivative 19 which could be debenzoylated to give 1-amino-2-phenylcyclohexene-1-carboxylic acid (20). The structures of compounds 9, 12 and 13 were confirmed by X-ray structural analysis. It is an excellent method for creating a wide range of cyclic α,α-disubstituted α-amino acids.     

Ketoreductases in the synthesis of valuable chiral intermediates: application in the synthesis of α-hydroxy β-amino and β-hydroxy γ-amino acids

A general method for the synthesis of β-alkyl α-hydroxy β-amino and α- and γ-alkyl substituted β-hydroxy-γ-amino acids is described. The synthesis of all three classes of amino acids proceeds through a common chiral alcohol intermediate that is generated from a pro-chiral ketone diester via the action of a nicotinamide-dependent ketoreductase. Regioselective chemical or enzymatic hydrolysis followed by rearrangement under Hofmann or Curtius conditions gives the final amino acid products. High yields of single diastereomers of the final amino acids are obtained. Amino acids with both natural and unnatural alkyl substituents can be accessed using this methodology.     

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.     

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.     

A new method for the preparation of functionalized unnatural α-H-α-amino acid derivatives

A new method for the preparation of α-H-α-amino acids is reported based on the α-alkylation of iminoacetic acid esters or amides. These imines are readily available by the reaction of glyoxylic acid esters with branched primary amines. The subsequent reaction with methanolic ammonia gave the corresponding iminoacetic acid amides. α-Alkylation of these imines with various electrophiles under basic conditions, followed by an acidic hydrolysis, gave α-amino acids, esters, or amides in up to 93% yield. α-Alkylation under chiral PTC conditions resulted in mono-alkylated amino acids with 90% ee.     

Sulphur in the Strategy of Natural Products Synthesis

Abstract

Syntheses of secondary metabolites of α-and β-mercapto aminoacids are described. The strategy in the first class of compounds consists of using N-hydroxy-α-amino acid derivatives as intermediates and of converting them into α-functionalized, in particular thiol-substituted amino acids; as examples serve syntheses in the gliotoxin and sporidesmin series. In the second class of compounds the cycloaddition products of indole derivatives, having sulfide substituents, and nitroso olefins are transformed into indole alkaloids, in particular tryptathionins, by rearrangement and further reactions. The antitumor agent sparsomycin has been synthesized via an amino sultine and its stereospecific nucleophilic ring opening. Bioassays done with this compound and sixteen of its structural analogs gave insight in the structural features that are required for sparsomycin's antitumor activity.     

新型富勒烯α-氨基酸的合成及其纳米颗粒水悬液的制备

通过1,3-偶极环加成反应合成中间体N-取代的3,4-富勒烯吡咯烷, 利用α-氨基与α-羧基均被保护的天冬氨酸或谷氨酸的非α-羧基与中间体N-取代的3,4-富勒烯吡咯烷衍生物的活化羟基进行缩合反应, 产物脱保护后得到了2种新的α-富勒烯氨基酸: 富勒烯天冬氨酸和富勒烯谷氨酸. 采用MALDI-TOF质谱、红外光谱、紫外-可见光谱和1H NMR 等方法对它们进行了结构表征. 采用有机溶剂交换法, 制备富勒烯氨基酸纳米颗粒水悬液, 并进行了电镜和表面zeta-电位分析, 结果表明, 此水悬液体系稳定, 颗粒形态大小均一, 在生物医学领域中具有潜在的应用前景.     

Synthesis of novel fullerene α-amino acid conjugates

Aspartic acid and glutamic acid with protected α-amino and α-carboxyl groups had been used to react with the activated hydroxyl group of N-substituted 3,4-fullero pyrrolidine. The products were deprotected, affording two monofuUerene α-amino acids, monofullerene aspartic acid （mFas） and monofullerene glutamic acid （mFgu）. Then a bifullerene glutamic acid conjugate （bFguC） was synthesized by reaction of mFgu containing protected amino group with N-substituted 3,4-fullero pyrrolidine.     

Asymmetric β-Methylation of l- and d-α-Amino Acids by a Self-Contained Enzyme Cascade

This report describes a modular enzyme-catalyzed cascade reaction that transforms l - or d -α-amino acids to β-methyl-α-amino acids. In this process an α-amino acid transaminase, an α-keto acid methyltransferase, and a halide methyltransferase cooperate in two orthogonal reaction cycles that mediate product formation and regeneration of the cofactor pyridoxal-5′-phosphate and the co-substrate S-adenosylmethionine. The only stoichiometric reagents consumed in this process are the unprotected l - or d -α-amino acid and methyl iodide.     

Comparison of the isomeric α-amino acyl adenylates and amino acid phosphoramidates of adenosine by electrospray ionization tandem mass spectrometry

The isomeric α-amino acyl adenylates and amino acid phosphoramidates of adenosine were synthesized and analyzed in detail by electrospray ionization tandem mass spectrometry (ESI-MS(n)). In ESI-MS/MS of α-amino acyl adenylates, the novel rearrangement ion [cAMP-H](-) observed as the most intense signal was formed through the pentacoordinate phosphorus intermediate with a six-membered ring by nucleophilic attack of the 3'-hydroxyl group on the phosphorus atom. In contrast, for the amino acid phosphoramidate of adenosine, the phosphorus atom could be attacked not only by the carboxylic group to form the cyclic aminoacyl phosphoramidates (CAPAs), but also by the nitrogen atom on the nucleobase leading to intramolecular phosphoryl group migration. It was found that the sodium ion having multidentate binding ability played an essential role in this characteristic rearrangement. The proposed mechanisms were supported by the MS/MS study, deuterium-labeled experiments, high-resolution tandem mass spectrometry and moderate calculations at the B3LYP/6-31G* level. The characteristic fragmentation patterns of α-amino acyl phosphates and amino acid phosphoramidates allows identification of stereoisomers when either the phosphorylation is at the N-terminus or C-terminus of amino acids.     

Stereoselective Synthesis of Unsaturated and Functionalized l-NHBoc Amino Acids, Using Wittig Reaction under Mild Phase-Transfer Conditions

The stereoselective synthesis of a new amino acid phosphonium salt was described by quaternization of melting triphenylphosphine with the γ-iodo NHBoc-amino ester, derived from l-aspartic acid. The deprotection of the carboxylic acid function to afford the phosphonium salt with a free carboxylic acid group was achieved by a palladium-catalyzed desallylation reaction. This phosphonium salt was used in the Wittig reaction with aromatic or aliphatic aldehydes and trifluoroacetophenone, under solid-liquid phase-transfer conditions in chlorobenzene and in the presence of K(3)PO(4) as weak base, to afford the corresponding unsaturated amino acids without racemization. Thus, the reaction with substituted aldehydes allows to graft various functionalized groups on the lateral chain of the amino acid, such as trifluoromethyl, cyano, nitro, ferrocenyl, boronato, or azido. In addition, the reaction of the amino acid Wittig reagent with α,β-unsaturated aldehydes leads to amino acids bearing a diene on the lateral chain. Finally, this amino acid phosphonium salt appears to be a new powerful tool for the preparation of unsaturated and non-proteinogenic α-amino acids, directly usable for the synthesis of customized peptides.     

含α-氨基酸配位体的手性聚甲基丙烯酸酯的合成

本文讨论了聚甲基丙烯酸缩水甘油酯同α-氨基酸的功能基化反应。实验结果表明,此反应操作简便、条件温和,易于制备含α-氨基酸的手性高聚物。利用与铜(Ⅱ)离子络合的含L-脯氨酸聚甲基丙烯酸酯为固定相,在柱色谱上拆分D·L-苯丙氨酸,能够把D和L型完全拆分开,且D型先于L型流出柱子。     

Über einen neuartigen synthetischen Zugang zu β,γ-ungesättigten α-Aminocarbonsäuren

A New Synthetic Route to β,α-Unsaturated α-Amino Acids A versatile new synthetic pathway for the preparation of βγ-unsaturated α-amino acids ( 1 ) is presented. Cu(I)-catalyzed addition of ethyl isocyanoacetate ( 2 ) to α-chloro carbonyl compounds ( 3 ) gives 5-chloroalkyl-2-oxazolin-4-carboxylates ( 4 ) in high yields. A reductive elimination on 4 by means of zinc yields the N-formyl derivatives of βγ-unsaturated α-amino carboxylates ( 5 ), which on acid hydrolysis lead to the free amino acids 1 . The five different βγ-dehydro-α-amono acids 1b-1f have been prepared by this method.