Asymmetric synthesis of cyclic alpha-amino phosphonates using masked oxo sulfinimines (N-sulfinyl imines)

Five-, six-, and seven-membered cyclic alpha-amino phosphonates, amino acid surrogates, are prepared in enantiomerically pure form via the highly diastereomeric addition of metal phosphonates to masked oxo sulfinimines. Hydrolysis of the resulting masked oxo alpha-amino phosphonates followed by reduction of the intermediate cyclic imino phosphonates affords the title compounds in good yield.     

Methyl 2-((succinimidooxy)carbonyl)benzoate (MSB): a new,efficient reagent for N-phthaloylation of amino acid and peptide derivatives

A new, efficient, and readily available reagent, methyl 2-((succinimidooxy)carbonyl)benzoate (MSB), for N-phthaloylation of amino acids and amino acid derivatives is described. The phthaloylation procedure is simple and racemization-free and gives excellent results with alpha-amino acids, alpha-amino alcohols, dipeptides, alpha-amino carboxamides, and alpha-amino esters.     

Synthesis of enantiopure omega-functionalized C15 alpha-amino carboxylates

An efficient route for the synthesis of enantiopure omega-hydroxy, omega-carboxy, omega-oxo, and omega-amino alpha-amino acids and bis-alpha-amino acids was developed. The synthesis of omega-trityloxy delta,epsilon-unsaturated alpha-amino acids was based on the Wittig reaction of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-oxopentanoate with omega-trityloxy alkylidene triphenylphosphoranes. After hydrogenation, the omega-hydroxy alpha-amino acid was used as starting material for the synthesis of other omega-functionalized alpha-amino acids. The length of the side chain of alpha-amino acids or bis-alpha-amino acids depends on the starting alkanediol or dibromide used to prepare the phosphoranes.     

Analysis of amino acids as formamidene butyl esters by electrospray ionization tandem mass spectrometry.

Amino acid formamidene butyl esters are optimally prepared by heating amino acids with dimethylformamide dimethylacetal (DMF-DMA) for 2 minutes at 65 degrees C and then with n-butanol/hydrogen chloride for 15 minutes at 65 degrees C. The formamidene butyl esters of simple alpha-amino acids and beta-amino acids afford between 1.1 and 20 times the signal intensity of the corresponding butyl esters during electrospray ionization tandem mass spectral analysis. Complex alpha-amino acids, such as ornithine, arginine and citrulline, and gamma-amino acids are better analyzed as butyl esters. Secondary alpha-amino acids, such as proline and sarcosine, give a mixture of two iminium salts with the DMF-DMA derivatization method. A derivative incorporating two molecules of the amino acid predominates at higher derivatization temperatures. Contrary to a previous report, N-formylamino acids were not detected. The presence of secondary amino acids in amino acid mixtures, derivatized as formamidene butyl esters, affords derivatives that incorporate two different amino acids. The new formamidene butylation method is unlikely to replace the butylation procedure used by neonatal blood spot screening programs for amino acid disorders, since a much poorer response was obtained with formamidene butyl esters of arginine and citrulline, important in the diagnosis of arginase deficiency and citrullinaemia.     

Facile N-derivatization of alpha-amino esters and amides via benzotriazolylmethyl derivatives

Alpha-(N-substituted amino)esters were prepared in a two-step procedure from available unsubstituted alpha-amino esters. alpha-Amino esters are first converted into the corresponding N-benzotriazolylmethyl derivatives; in the second step, the benzotriazole group is substituted by various nucleophiles with or without the presence of a Lewis acid to give substituted alpha-amino esters in high overall yield under mild conditions with no signs of racemization. Boc-protected amino acids were converted into alpha-amino amides; subsequent deprotection allowed the conversion into N-substituted derivatives analogously to the alpha-amino esters, without racemization in high yields under mild conditions.     

Analogs of alicyclic alpha-amino acids--effect of ring size and side chain on tumor accumulation

We studied the tumor-localizing characteristics of alicyclic alpha-amino acid analogs (a-j) without alpha-hydrogen, because of the selective affinity of synthetic nonmetabolizing amino acids such as 1-aminocyclopentanecarboxylic acid (ACPC) and alpha-aminoisobutyric acid alpha-AIB) to tumor tissues. Ten different alicyclic alpha-amino acids (a-j) were labeled with 14C using a modified Bücherer synthesis for amino acids. The tissue distributions and whole-body autoradiographic study of these 14C-labeled alicyclic alpha-amino acid analogs (a-j) were investigated in mice bearing Ehrlich tumor. These results showed that the tumor uptakes and tumor to tissue concentration ratios increased with decreasing ringsize in homologous series (8- through 4-membered ring systems) and alicyclic alpha-amino acid analogs containing 3- or 4-methyl group had the higher tumor to tissue concentration ratios. On the other hand, alicyclic alpha-amino acid analogs containing 2-methyl group and 4-phenyl group showed the lower tumor uptakes and the lower tumor to tissue concentration ratios. These results suggest that the small ringsize alicyclic alpha-amino acid analogs containing 3-methyl group such as 3-methyl-1-aminocyclopentanecarboxylic acid (3-MeACPC) may be effective for the early detection of tumors.     

Effect of the residual silanol group protection on the liquid chromatographic resolution of racemic primary amino compounds on a chiral stationary phase based on optically active (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6

A liquid chromatographic chiral stationary phase (CSP) based on (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6, which has been utilized in the resolution of alpha-amino acids, amines and amino alcohols, was treated with excess of n-octyltriethoxysilane to prepare a new improved CSP. The residual silanol groups of the original CSP were protected by n-octyl groups in the new CSP. The chiral recognition ability of the new CSP was superior to that of the original CSP in the resolution of alpha-amino acids, amines and amino alcohols. Retention factors (k1) for the resolution of alpha-amino acids were lower on the new CSP than on the original CSP while those for the resolution of amines and amino alcohols were higher on the new CSP than on the original CSP. The improved chiral recognition ability of the new CSP and the retention behaviors of the two enantiomers on the new CSP have been rationalized to stem from the removal of the non-enantioselective interactions between the analytes and the residual silanol groups of the original CSP and the improved lipophilicity of the CSP.     

Review: derivatization in mass spectrometry-6. Formation of mixed derivatives of polyfunctional compounds

The review describes chemical transformations of multifunctional compounds (amino acids and peptides, amino alcohols, amino thiols, hydroxy acids, oxo acids, oxo alcohols, compounds containing simultaneously three or more different groups etc.) by using step-wise or one-step modification or protection of functional groups. Some chemical aspects of mixed derivatization performed for improving the physical-chemical properties and mass spectral characteristics are discussed. Application of mixed derivatization to qualitative and quantitative analysis of various multifunctional compounds mainly in biological fluids and other matrices by gas chromatography/mass spectrometry in electron ionization, chemical ionization, negative-ion chemical ionization and selected ion monitoring modes is considered.     

螯合金属离子亲和色谱法分离α-氨基酸和肽

 以ＳｅｐｈａｄｅｘＧ１０为基质螯合二价铜离子的亲和色谱法分离α－氨基酸和肽，使之得以完全分离。对分离过程的原理进行了讨论。     

New chiral crown ether stationary phase for the liquid chromatographic resolution of alpha-amino acid enantiomers

A new chiral stationary phase (CSP) for the liquid chromatographic separation of enantiomers was prepared by bonding a novel enantiopure (diphenyl-substituted 1,1'-binaphthyl) crown ether to 5 microm silica gel. The resulting CSP was applied to the separation of the enantiomers of various natural and unnatural alpha-amino acids. All alpha-amino acids tested were resolved very well on the new CSP, with the exception of proline, which does not contain a primary amino group. The resolution of alpha-amino acid enantiomers on this new CSP was found to be dependent on the type and amounts of organic and acidic modifiers, and on column temperature.     

Applications of the sulfinimine-mediated asymmetric strecker synthesis to the synthesis of alpha-alkyl alpha-amino acids

Addition of Et(2)AlCN and i-PrOH to ketosulfinimines (N-sulfinyl imines) affords corresponding alpha-alkyl alpha-amino nitriles in moderate to good yields. The diastereoselectivity is largely dependent on the E/Z isomer ratio of the ketosulfinimine. Hydrolysis of the diastereomerically pure amino nitriles affords enantiopure alpha-alkyl alpha-amino acids in moderate to good yields.     

Asymmetric 1,4-addition of oxazolones to nitroalkenes by bifunctional cinchona alkaloid thiourea organocatalysts: synthesis of alpha,alpha-disubstituted alpha-amino acids

An easy and simple synthetic approach to optically active alpha,alpha-quaternary alpha-amino acids using asymmetric organocatalysis is presented. The addition of oxazolones to nitroalkenes catalyzed by thiourea cinchona derivatives provides the corresponding alpha,alpha-quaternary alpha-amino acid derivatives with good yields, excellent diastereoselectivities (up to 98 % dr), and from moderate to good enantioselectivities (up to 92 % ee). The reaction can be performed on a large scale. The optically active oxazolone-nitroalkene addition products can be opened in a one-pot reaction to the corresponding ester-amide derivatives. Additional transformations are also presented, such as the synthesis of amino esters, amino acids, and transformation into 3,4-disubstituted pyrrolidin-2-ones.     

A highly enantioselective amino acid-catalyzed route to functionalized alpha-amino acids

The development of syntheses providing enantiomerically pure alpha-amino acids has intrigued generations of chemists and been the subject of intense research. This report describes a general approach to functionalized alpha-amino acids based on catalytic asymmetric synthesis. Proline catalyzed Mannich-type reactions of N-PMP-protected alpha-imino ethyl glyoxylate with a variety of unmodified ketones to provide functionalized alpha-amino acids in high yields with excellent regio-, diastereo-, and enantioselectivities. Study of seven examples yielded six with product ee values of > or = 99%. In reactions involving ketone donors where diastereoisomeric products could be formed, two adjacent stereogenic centers were created simultaneously upon carbon-carbon bond formation with complete syn-stereocontrol. Significantly, this methodology utilizes readily available and rather inexpensive starting materials, does not require any preactivation of substrates or metal ion assistance, and can be carried out on a gram scale under operationally simple reaction conditions. The keto-functionality present in the products provides a particularly attractive site for versatile modifications. This study compliments and extends our bioorganic approach to asymmetric synthesis to a versatile synthon class. Given that we have shown that a variety of optically active amino acids can be synthesized with proline catalysis, where an L-amino acid begets other L-amino acids, our results may stimulate thoughts concerning prebiotic syntheses of optically active amino acids based on this route.     

Synthesis of trans/cis‐3,4‐Disubstituted 1,2,3,4‐Tetrahydroisoquinolines by Nucleophilic Acyl Substitution of Homophthalic Anhydride with Aldimines

The reaction of the functionalized N‐protected imines 3 and 7 containing either the chloromethyl or ethyl ester moieties, respectively, attached to the imine carbon with homophthalic anhydride 2 afforded cis/tran‐3‐subsituted‐1‐oxo‐1,2,3,4‐tetrahydroisoquinoline‐4‐caboxylic acids appropriate for further synthetic elaboration.     

Asymmetric cyclization via memory of chirality: a concise access to cyclic amino acids with a quaternary stereocenter

N-(omega-Bromoalkyl)-amino acid derivatives, readily prepared from natural alpha-amino acids, gave cyclic amino acids with a quaternary stereocenter by treatment with potassium hexamethyldisilazaide in DMF. The chirality of parent amino acids was almost completely preserved during an enolate-formation and cyclization process, giving aza-cyclic amino acids in up to 98% ee in retention of configuration. This method is applicable to the asymmetric synthesis of azetidine, pyrrolidine, piperidine, and azepane derivatives. The asymmetric cyclization seems to proceed via an axially chiral enolate intermediate and not through a concerted SEi process.     

Formation and stability of peptide enolates in aqueous solution

Second-order rate constants k(DO) (M(-1) s(-1)) were determined in D(2)O for deprotonation of the N-terminal alpha-amino carbon of glycylglycine and glycylglycylglycine zwitterions, the internal alpha-amino carbon of the glycylglycylglycine anion, and the acetyl methyl group and the alpha-amino carbon of the N-acetylglycine anion and N-acetylglycinamide by deuterioxide ion. The data were used to estimate values of k(HO) (M(-1) s(-1)) for proton transfer from these carbon acids to hydroxide ion in H(2)O. Values of the pK(a) for these carbon acids ranging from 23.9 to 30.8 were obtained by interpolation or extrapolation of good linear correlations between log k(HO) and carbon acid pK(a) established in earlier work for deprotonation of related neutral and cationic alpha-carbonyl carbon acids. The alpha-amino carbon at a N-protonated N-terminus of a peptide or protein is estimated to undergo deprotonation about 130-fold faster than the alpha-amino carbon at the corresponding internal amino acid residue. The value of k(HO) for deprotonation of the N-terminal alpha-amino carbon of the glycylglycylglycine zwitterion (pK(a) = 25.1) is similar to that for deprotonation of the more acidic ketone acetone (pK(a) = 19.3), as a result of a lower Marcus intrinsic barrier to deprotonation of cationic alpha-carbonyl carbon acids. The cationic NH(3)(+) group is generally more strongly electron-withdrawing than the neutral NHAc group, but the alpha-NH(3)(+) and the alpha-NHAc substituents result in very similar decreases in the pK(a) of several alpha-carbonyl carbon acids.     

Synthesis of a sulfahydantoin library

A five-step solid-phase synthesis of sulfahydantoins from alpha-amino acids and aldehydes was developed. The synthetic method allows the use of hindered amino acids, including Val, Phg, and Aib, and use of aromatic aldehydes substituted with electron-withdrawing and -donating groups. Some limitations were encountered with amino acids with reactive side chains. A small but diverse library of compounds was produced for biological testing.     

Highly efficient stereoconservative amidation and deamidation of alpha-amino acids

[reaction: see text] An overall stereoconservative protection and deprotection method of amino and carboxyl groups is presented. N-Phthaloyl N'-alkyl secondary amides of alpha-amino acids can be generated from corresponding N-phthaloyl amino acids by coupling reaction of N-alkylamines using mixed anhydride method. These secondary amides can be transformed by thermal rearrangement of intermediate nitrosoamides to O-alkyl esters with retention of configuration and excellent yields.     

Stereoinversion of beta- and gamma-substituted alpha-amino acids using a chemo-enzymatic oxidation-reduction procedure

Both D- and L-beta- and gamma-substituted alpha-amino acids can be interconverted to their respective L- and D- diastereoisomers by treatment with an enantioselective amino acid oxidase and a chemical reducing agent.     

Synthesis of cyclopropene alpha-amino acids via enantioselective desymmetrization

[reaction: see text] The preparation of cyclopropene alpha-amino acids via the enantioselective desymmetrization of cyclopropene bis-carboxylic acid derivatives is described. The amino acids are stable to harsh reaction conditions, and a derivative has been incorporated into a tripeptide using conventional methods for peptide synthesis.