U-4C-3CR versus U-5C-4CR and stereochemical outcomes using suitable bicyclic β-amino acid derivatives as bifunctional components in the Ugi reaction

Intramolecular Ugi reactions with bicyclic β-amino acids have been performed and the effects of the configuration and N-alkylation have been studied. We have proven that preferential ring contraction or nucleophilic attack by the solvent depend not only on the presence of N-alkylation but also on the relative disposition of the carboxyl group and the amine. Excellent results in terms of stereoselectivity have been obtained in the case of N-alkyl-3-exo-amino-7-oxabicyclo[2.2.1]-2-endo-carboxylic acids.     

N-Dmc protected amino acid aglycones: versatile hydrogenolysis stable acceptors for O-glycosylation

N^α-(4,4-Dimethyl-2,6-dioxocyclohexylidenemethylene) (Dmc) protected l-serine, l-threonine and l-homoserine have been prepared as tert-butyl esters in excellent yields. These hydrogenolysis stable acceptors underwent efficient α-O-glycosylation with an l-fucopyranosyl bromide donor and also allowed convenient protecting group manipulations to ultimately deliver novel glycoamino acid building blocks suitable for Fmoc based solid-phase glycopeptide synthesis.     

Uncatalyzed solventless Diels-Alder reaction of 2-amino-3-nitroacrylate: synthesis of new epimeric 2-amino-3-nitro-norbornene- and norbornane-2-carboxylic acids

A highly diastereoselective Diels-Alder reaction between cyclopentadiene and ethyl (Z)-2-N-Boc-amino-3-nitroacrylate in neat conditions affords the ethyl 2-t-butoxycarbonylamino-3-endo-nitro-bicyclo[2.2.1]hept-5-ene-2-exo-carboxylate: a new constrained carbocyclic amino acid. Catalytic hydrogenation of this cycloadduct gave the corresponding reduced norbornane derivative. A preliminary investigation into the chemistry of these two amino acids was performed. In particular, the epimerization to their corresponding 3-exo-nitro compounds by treatment both with acid and base was studied. From this study, valuable information on the endo/exo process at the C-3 carbon atom, as well as on the stability of the different stereomers, was obtained. The stability is closely related to the presence or the absence of the double bond in the ring and to the substitution pattern. Finally, deprotection of the amino acid function has been performed.     

Synthesis of γ-fluoro-α-amino acids by Claisen rearrangement

A series of N-protected glycine and alanine esters 4-7 of different fluorinated allylic alcohols 1 was prepared using the dicyclohexylcarbodiimide/dimethylaminopyridine method. All fluorinated esters of this type failed to react in an esterenolate Claisen rearrangement under the general conditions of the Kazmaier variant of this rearrangement. Change of the solvent from tetrahydrofuran to the less coordinating diethyl ether enabled the rearrangement of N-Boc-protected glycine esters 4a-c of 2-fluoroalken-3-ols 1a-c to form N-Boc-2-amino-4-fluoroalk-4-enecarboxylic acids 8a-c, while the rearrangement failed with N-Boc-alanine esters and all amino acid esters of 2-fluoroallylic alcohol (1e). This might be due to competing deprotonation of the position β to fluorine. Similarly to the esters 4a-c, the TFA-protected glycine esters 5a-c of 2-fluoroalken-3-ols 1a-c were rearranged. Deprotection of the Boc or the TFA group under salt-free conditions yielded the free amino acids 11a-c, which might be seen as mimics for N-alkylasparagines a group of lipoproteins.     

First enantioselective synthesis of the novel antiinfective TAN-1057A via its aminomethyl-substituted dihydropyrimidinone heterocycle

Enantiomerically pure N²-Z-N²-MeAsnOH [(S)-14], prepared in 8 steps (23% overall yield) from asparaginic acid, was first subjected to a Hofmann degradation with PhI(OCOCF₃)₂ yielding (S)-N²-Z-N²-methyl-2,3-diaminopropanoic acid [N²-Z-N²-Me-L-A₂pr, (S)-15], and this in turn was protected to give N²-Z-N³-Boc-N²-Me-L-A₂pr [(S)-17]. Condensation of (S)-17 with HNC(SMe)NHCONH₂ followed by removal of the tert-butoxycarbonyl protecting group, cyclization and hydrogenolytic removal of the Z-group gave the heterocycle of TAN-1057A [(S)-1] with an e.e. of 87 in 36% yield [from (S)-14]. Coupling of (S)-1 with (S)-tris-Z-β-homoarginine (20a) in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and iPr₂NEt in N,N-dimethylacetamide followed by hydrogenolysis afforded the most active A-diastereomer of the natural antibiotic TAN-1057 in 52% yield (from (S)-1 and 20a). Similarly, starting from (S)-1, a single diastereomer of the potent, less toxic TAN-1057A analogue 22b with a β-lysine side chain has been prepared. All described synthetic steps do not require column chromatography for purification of the products.     

Synthesis and complexation properties towards amino acids of mono-substituted p-sulphonato-calix-[n]-arenes

A series of mono-hydroxy functionalised calix-[n]-arenes, and p-sulphonato-calix-[n]-arenes where n=4, 6 and 8, have been synthesised, with the pendant functions being ethoxycarbonyl methoxy group, 2-carboxy methoxy group, 2-amido methoxy group or 2-amino ethoxy group. With calix-[4]-arene and calix-[6]-arenes the compounds are obtained in good yield by treatment of the relevant p-H-calix-[n]-arene with a suitable metal carbonate, as a weak base, in the presence of one equivalent of the corresponding alkyl bromide. However in the case of calix-[8]-arene, the extremely low solubility of p-H-calix-[8]-arene prevented its use and p-tBu-calix-[8]-arene was used in the monosubstitution reactions. The corresponding sulphonate derivatives were prepared in the case of the 2-carboxy methoxy group, 2-amido methoxy group and 2-amino ethoxy group systems, either by sulphonation of the para-H derivatives or by ipso-sulphonation of the tert-butyl derivatives. The complexation properties of the water-soluble p-sulphonato-derivatives with regard to 11 amino acids have been studied by ¹H NMR titration experiments. The obtained association constants show a 1:1 stoichiometry. The presence of a pendant group at the lower rim of calix strongly modifies the observed association constant as compared to the parent p-sulphonato-calix-[n]-arenes. While generally, the cationic amino acids lysine and arginine bind strongly to all the derivatives, the binding of other amino acids is dependant on the nature of the pendant functions, in particular pendant arm-lateral chain function leads to strong binding with aspartic acid, serine and tryptophan.     

Interaction between N-phosphoryl-α, β- and γ-amino acids and nucleosides

The reactions of four different N-(O,O′-diisopropyl) phosphoamino acids (DIPP-aa),such as N-phosphoryl-L-α-alanine (DIPP- L-α-Ala),N-phosphoryl-D-α-alanine (DIPP-D-α-Ala),N-phosphoryl-β-alanine (DIPP-β-Ala) and N-phosphoryl-γ-amino butyric acid (DIPP-γ-Aba),and four nucleosides,adenosine (A),guanosine (G),cytidinc (C) and uridine (U),were studied by electrospray ionization tandem mass spectrometry (ESI-MS/MS) and HPLC/ESI-MS.DIPP-L-α-Ala and DIPP-D-α-Ala produced the same phosphorylated nucleosidcs,dinucleotidcs and phosphoroligopeptide.However,DIPP-β-Ala and DIPP-γ-Aba gave no relevant products.     

Enantiomerically Enriched Bicyclic Hydroxamic Acids in One Step from α-Aminohydroxamic Acids and Keto Acids via Cyclocondensation

New enantiomerically enriched bicyclic hydroxamic acids, 1-hydroxy-dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones, have been synthesized by the cyclocondensation of L-α-aminohydroxamic acids with keto acids in a highly chemo- and stereoselective manner. The cis configuration between the amino acid side chain and the methyl group at C7a in 1H-pyrrolo[1,2-a]imidazole-2,5-dione was unambiguously established by X-ray crystallographic analysis. This method could also be applied to the cyclocondensation with o-formylbenzoic acid, giving a tricyclic hydroxamic acid in a good yield.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Determination of five nucleosides by LC‐MS/MS and the application of the method to quantify N6‐methyladenosine level in liver messenger ribonucleic acid of an acetaminophen‐induced hepatotoxicity mouse model

Ribonucleic acid N⁶‐methyladenosine methylation plays an important role in a variety of biological processes and diseases. Acetaminophen‐induced hepatotoxicity is one of the major challenges faced by clinicians. To date, the link between N⁶‐methyladenosine and acetaminophen‐induced hepatotoxicity has not been studied. In this study, a simple ultra high performance liquid chromatography with tandem mass spectrometry method was developed for the simultaneous determination of five nucleosides (adenosine, uridine, cytidine, guanosine, and N⁶‐methyladenosine) in messenger ribonucleic acid. After enzymatic digestion of messenger ribonucleic acid, the nucleosides sample was separated on an Acquity UPLC column with gradient elution using methanol and 0.02% formic acid water, and detected by a Qtrap 4500 mass spectrometer with an electrospray ionization mode. The method was validated over the concentration ranges of 4–800 ng/mL for adenosine, uridine, cytidine, and guanosine and 0.1–20 ng/mL for N⁶‐methyladenosine. It was successfully applied to the determination of N⁶‐methyladenosine levels in liver messenger ribonucleic acid in an acetaminophen‐induced hepatotoxicity mouse model and a control group. This study offers a method for the determination of nucleoside contents in epigenetic studies and constitutes the first step toward the investigation of ribonucleic acid methylation in acetaminophen‐induced hepatotoxicity, which will facilitate the elucidation of its mechanism.     

Synthesis and ligation ability of mono-aminooxy-functionalized dendrigraft poly-l-lysine (DGL)

A bifunctional tetraethylene glycol (TEG) linker was prepared and used as an initiator for the synthesis of the first two generations of dendrigraft poly-l-lysines (DGL). The key steps involved the desymmetrization of TEG by introduction of an amine group after activation of a terminal hydroxyl group and of a conveniently protected aminooxy functionality at the other end. Initiation of l-lysine N-carboxyanhydride polymerization by the terminal amine yielded generations 1 and 2 of DGL in which a subsequent functionalization of the aminooxy group by ligation with entities bearing an aldehyde group turned out to be feasible.     

New strategies for the synthesis of heteroannulated 2-pyridinones, substituted 2-quinolinones and coumarins from dehydroamino acid derivatives

Several heteroannulated pyridinones were prepared from the methyl esters of N-Boc-β,β-diheteroaryldehydroalanines by treatment with acetic acid. The latter were obtained by a bis-Suzuki coupling of a β,β-dibromodehydroalanine with heteroarylboronate compounds. The products were obtained in good yields and the cyclization reaction involves the nucleophilic attack of one of the heteroaromatic rings on the carbonyl of the Boc group. The scope of this reaction was extended to the Z-isomer of N-Boc-β-heteroaryldehydrophenylalanines to give 4-phenylpyridinones. A tandem Suzuki coupling-cyclization protocol was developed for the synthesis of 2-quinolinones and coumarins. Thus, β-brominated dehydroamino acids were reacted with 2-(pinacolboronate)aniline or phenol in a one-pot Suzuki coupling followed by lactamization or lactonization to give the corresponding 3-amino-2-quinolinones or 3-aminocoumarins in good to high yields. This type of strategy was also applied to the synthesis of 2-quinolinones and coumarins linked in position-3 to amino acids, using as starting materials brominated dehydropeptides.     

Chiron based synthesis of isocoumarins: reactivity of α-substituted carboxylic acids

The asymmetric synthesis of a novel (S)-isocoumarin has been attempted in a single step by the coupling of homophthalic acid with (S)-N-protected amino acids and α-chloroacids at high temperature by exploiting a chiral pool methodology. The coupling of homophthalic acid with N-protected (S)-amino acids gave exclusion of the carboxyl/alkyl group. However, coupling of homophthalic acid with α-chloroacids afforded asymmetric isocoumarins in high yield.     

Convergent and streamlined synthesis of 6-etherified imidazo[1,2-b]pyridazine-2-amine derivatives possessing VEGFR-2 kinase inhibitory activity

A convergent and streamlined synthesis of selective vascular endothelial growth factor receptor (VEGFR) 2 kinase inhibitors has been achieved using a synthetic strategy based on an S_NAr reaction of 6-chloroimidazo[1,2-b]pyridazine with phenols in the final step. For the synthesis of 6-chloroimidazo[1,2-b]pyridazine, a one-pot reaction using 3-amino-6-chloropyridazine, cyclopropanecarboxamide, and bromoacetyl bromide was developed. The phenols were easily prepared by chemoselective acylation of 3-aminophenols with pyrazole carboxylic acids, and an efficient and high-yielding synthesis of N-ethylpyrazole was also developed. The S_NAr reaction of 6-chloroimidazo[1,2-b]pyridazine with phenols in DMSO in the presence of cesium carbonate successfully proceeded at 100–110 °C to give the target products in good yields. This new chromatography-free process will be not only useful for the further bulk supply of these compounds but also applicable to the synthesis of other compounds containing the 6-etherified imidazo[1,2-b]pyridazin-2-amine core.     

Convenient preparation of chiral phase-transfer catalysts with conformationally fixed biphenyl core for catalytic asymmetric synthesis of α-alkyl- and α,α-dialkyl-α-amino acids: application to the short asymmetric synthesis of BIRT-377

Chiral phase-transfer catalysts (S)-1a, (S)-1b, and (S)-2 with conformationally fixed biphenyl cores were conveniently prepared from the known, easily available (S)-6,6′-dimethylbiphenyl-2,2′-diol 3 and (S)-4,5,6,4′,5′,6′-hexamethoxybiphenyl-2,2′-dicarboxylic acid 14, respectively, in five steps. The catalysts, (S)-1a and (S)-1b are readily applicable to asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester with excellent enantioselectivity. In particular, catalyst (S)-1b was found to exhibit the unique temperature effect on the enantioselectivity, and asymmetric alkylation of glycine derivatives at room temperature gave higher enantiomeric excess than that at 0 °C. In addition, the catalyst (S)-2 exhibited the high catalytic performance (0.01-1 mol %) in the asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester and N-(p-chlorophenylmethylene)alanine tert-butyl ester compared to the existing chiral phase-transfer catalysts, thereby allowing to realize a general and useful procedure for highly practical enantioselective synthesis of structurally diverse natural and unnatural α-alkyl-α-amino acids as well as α,α-dialkyl-α-amino acids. This approach is successfully applied to the short asymmetric synthesis of cell adhesion BIRT-377.     

Reactions of trimethylsilyl fluorosulfonyldifluoroacetate with purine and pyrimidine nucleosides

Difluorocarbene, generated from trimethylsilyl fluorosulfonyldifluoroacetate (TFDA), reacts with the uridine and adenosine substrates preferentially at the enolizable amide moiety of the uracil ring and the 6-amino group of the purine ring. 2′,3′-Di-O-benzoyl-3′-deoxy-3′-methyleneuridine reacts with TFDA to produce 4-O-difluoromethyl product derived from an insertion of difluorocarbene into the 4-hydroxyl group of the enolizable uracil ring. Reaction of the difluorocarbene with the adenosine substrates having the unprotected 6-amino group in the purine ring produced the 6-N-difluoromethyl derivative, while reaction with 6-N-benzoyl protected adenosine analogues gave the difluoromethyl ether product derived from the insertion of difluorocarbene into the enol form of the 6-benzamido group. Treatment of the 6-N-phthaloyl protected adenosine analogues with TFDA resulted in the unexpected one-pot conversion of the imidazole ring of the purine into the corresponding N-difluoromethylthiourea derivatives. Treatment of the suitably protected pyrimidine and purine nucleosides bearing an exomethylene group at carbons 2′, 3′ or 4′ of the sugar rings with TFDA afforded the corresponding spirodifluorocyclopropyl analogues but in low yields.     

Diastereomeric separation of α-amino acid derivatives using a chiral carbodiimide

N,N′-Bis[(S)-1-phenylethyl]carbodiimide (1) was found to be an efficient chiral derivatizing agent for the diastereomeric separation of 2-N-benzyloxycarbonylamino acids (2). Diastereomeric acylureas prepared from 1 and 2 showed a large chromatographic selectivity (α). Their capacity factors and selectivity depend on the carbon chain length of the α-alkyl substituents of acylureas.     

One-pot synthesis of bromodifluoroacetimidoyl halides and its Suzuki coupling reactions with aryl boronic acids

N-aryl bromodifluoroacetimidoyl halides were prepared by the reaction of bromodifluoroacetic acid, triphenyl phosphine, p-arylaniline and triethylamine in tetrachloromethane in good yields. Palladium-catalyzed cross-coupling reaction of N-aryl bromodifluoroimidoyl iodide with arylboronic acids was realized to afford bromodifuoromethyl ketimine in good yields.     

Enamines of 3-acyltetramic acids from β-enamino amides and amino acids

A novel approach for the synthesis of enamine derivatives of N-protected 3-acyltetramic acids is described. The synthetic procedure relies on α-C-acylation of β-enamino amides with N-protected α-amino acids and subsequent cyclisation of the obtained intermediates in refluxing TFA. The tetramic derivatives are obtained with very good enantiopurity (e.r. ≥95:5). Ring-enlarged analogues (piperidine-2,4-diones) can also be obtained from β-amino acids.     

Chemoselective detection and discrimination of carbonyl‐containing compounds in metabolite mixtures by 1H‐detected 15N nuclear magnetic resonance

NMR spectra of mixtures of metabolites extracted from cells or tissues are extremely complex, reflecting the large number of compounds that are present over a wide range of concentrations. Although multidimensional NMR can greatly improve resolution as well as improve reliability of compound assignments, lower abundance metabolites often remain hidden. We have developed a carbonyl‐selective aminooxy probe that specifically reacts with free keto and aldehyde functions, but not carboxylates. By incorporating ¹⁵N in the aminooxy functional group, ¹⁵N‐edited NMR was used to select exclusively those metabolites that contain a free carbonyl function while all other metabolites are rejected. Here, we demonstrate that the chemical shifts of the aminooxy adducts of ketones and aldehydes are very different, which can be used to discriminate between aldoses and ketoses, for example. Utilizing the 2‐bond or 3‐bond ¹⁵N‐¹H couplings, the ¹⁵N‐edited NMR analysis was optimized first with authentic standards and then applied to an extract of the lung adenocarcinoma cell line A549. More than 30 carbonyl‐containing compounds at NMR‐detectable levels, six of which we have assigned by reference to our database. As the aminooxy probe contains a permanently charged quaternary ammonium group, the adducts are also optimized for detection by mass spectrometry. Thus, this sample preparation technique provides a better link between the two structural determination tools, thereby paving the way to faster and more reliable identification of both known and unknown metabolites directly in crude biological extracts. Copyright © 2015 John Wiley & Sons, Ltd.     

Features of switchable multicomponent heterocyclizations of salicylic aldehydes and 5-aminopyrazoles with pyruvic acids and antimicrobial activity of the reaction products

Three-component reactions of 5-aminopyrazoles and salicylic aldehydes with pyruvic acids were studied. The method of tuning of the selectivity of the heterocyclizations allowing to change its direction by variation of the reaction parameters was worked out. The treatment involving pyruvic acid can be selectively directed to the formation to either 3-aryl-10,11-dihydro-4,10-methano-pyrazolo[4,3-c][1,5]benzoxazocine-4-carboxylic acids or 3,6-diarylpyrazolo[3,4-b]pyridine-4-carboxylic acids, while the reaction involving arylpyruvic acid leads only to 7-hydroxy-2,5,6-triaryl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrimidine-7-carboxylic acids. Antimicrobial activity of the compounds obtained was also studied: Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus) were found sensitive to the substances tested, however, only in the highest concentration.