Simple and efficient synthesis of chiral amino alcohols with an amino acid-based skeleton

Sodium bis(2-methoxyethoxy)aluminum hydride, NaAlH₂(OCH₂CH₂OCH₃)₂, commercially known as Vitride® or Red-Al®, enables rapid synthesis of pure optically active N-protected amino alcohols and peptide alcohols in very high yields. The method is very simple and attractive, as it does not require an additional step of N-protected amino acid derivatization and proceeds without the loss of enantiomeric homogeneity.     

Nucleophilic substitution at C-2 of S-alkylated 2-thiocytidines by cysteine and lysine : A new method for specific covalent linking of peptides to nucleic acids

S-Alkylated 2-thiocytidine can be substituted at C-2 by nucleophilic agents. This reaction has been investigated with model compounds as well as with tRNA using the amino acids cysteine and lysine in order to develop a new affinity label linking covalently tRNA and a protein. Reaction with N-protected cysteine gives 2-S-alkyl-pyrimidines, while unprotected cysteine yields an N-alkyl-pyrimidine, after intramolecular substitution. With the -amino group of lysine a fast replacement at C-2 is observed, leading to an unstable 2-N-alkyl-pyrimidine. All products have been characterized both chemically and spectroscopically.     

Simple and efficient synthesis of chiral amino alcohols with an amino acid-based skeleton

Sodium bis(2-methoxyethoxy)aluminum hydride, NaAlH₂(OCH₂CH₂OCH₃)₂, commercially known as Vitride® or Red-Al®, enables rapid synthesis of pure optically active N-protected amino alcohols and peptide alcohols in very high yields. The method is very simple and attractive, as it does not require an additional step of N-protected amino acid derivatization and proceeds without the loss of enantiomeric homogeneity.     

Synthesis,characterization and carbonic anhydrase inhibitory activity of novel benzothiazole derivatives

N-protected amino acids were reacted with substituted benzothiazoles to give the corresponding N-protected amino acid-benzothiazole conjugates (60–89%). Their structures were confirmed by proton nuclear magnetic resonance (¹H NMR), carbon-13 nuclear magnetic resonance (¹³C NMR), IR and elemental analysis. Their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activities were determined against two cytosolic human isoforms (hCA I and hCA II), one membrane-associated (hCA IV) and one transmembrane (hCA XII) enzyme by a stopped-flow CO₂ hydrase assay method. The new compounds showed rather weak, micromolar inhibitory activity against most of these enzymes.     

Targeting the polyamine biosynthetic enzymes: a promising approach to therapy of African sleeping sickness, Chagas’ disease, and leishmaniasis

Summary. Trypanosomatids depend on spermidine for growth and survival. Consequently, enzymes involved in spermidine synthesis and utilization, i.e. arginase, ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (AdoMetDC), spermidine synthase, trypanothione synthetase (TryS), and trypanothione reductase (TryR), are promising targets for drug development. The ODC inhibitor α-difluoromethylornithine (DFMO) is about to become a first-line drug against human late-stage gambiense sleeping sickness. Another ODC inhibitor, 3-aminooxy-1-aminopropane (APA), is considerably more effective than DFMO against Leishmania promastigotes and amastigotes multiplying in macrophages. AdoMetDC inhibitors can cure animals infected with isolates from patients with rhodesiense sleeping sickness and leishmaniasis, but have not been tested on humans. The antiparasitic effects of inhibitors of polyamine and trypanothione formation, reviewed here, emphasize the relevance of these enzymes as drug targets. By taking advantage of the differences in enzyme structure between parasite and host, it should be possible to design new drugs that can selectively kill the parasites.     

Facile Synthesis of <Emphasis Type="Italic">N</Emphasis>-protected Amino Acid Esters Assisted by Microwave Irradiation

A highly efficient and safe methodology for synthesis of various N-protected amino acid ethyl esters have been established in this study. This methodology employs orthoesters as both esterification reagent and solvent for protected amino acids. The reactions were carried out under microwave irradiation in neutral conditions for only 2 min, resulting in highly pure crude products in most cases. This strategy works with a variety of N-protecting groups, such as acid labile protecting group: BOC and tBu; base labile protecting group: Fmoc; hydrogenation labile protecting group: Z and Na/NH₃ labile protecting group: Tos, thus providing facile access to numerous valuable building blocks for solid phase synthesis. Further reduction of the crude protected amino acid ethyl ester by sodium borohydride under mild conditions led to the corresponding protected β-amino alcohols with excellent yield, as demonstrated by three examples.     

Photoanalogues of the Initiation Substrates of the RNA Polymerase II, 5‐Azido‐2‐Nitrobenzoyl Derivatives of the ATP γ‐Amidophosphate: The Possible Photoinduced Degradation of the Functional Group to an N‐Arylhydroxylamine

Photoanlogues of the initiation substrates of the RNA polymerase II, N₃Ar‐ NH(CH₂)_nNHpppA where N₃Ar is 5‐azido‐2‐nitrobenzoyl group (n = 2 or 4) were synthesized, allowing the preparation of photoreactive oligonucleotides in situ by RNA polymerase II for application as photolabels. Photolysis of p‐nitro‐substituted aromatic azide in aqueous medium was investigated. Using the azoxy‐coupling reaction it was possible to determine whether a nitrene or p‐nitrophenyl hydroxylamine azoxy compound is the trappable intermediate that is generated at ambient temperature in aqueous solution.     

Aminooxy analogues of spermine and their monoacetyl derivatives

Convenient methods of synthesis of 1-aminooxy-3,8-diaza-11-aminoundecane, its earlier unknown N ¹-and N ¹¹-acetyl derivatives, and also 1,10-bis(aminooxy)-3,8-diazadecane are suggested. It is shown that it is possible to selectively delete the acid-labile ethoxyethylidene protection of aminooxy group by hydrosulfates in the presence of N-tert-butyloxycarbonyl group.     

The use of N-urethane-protected N-carboxyanhydrides (UNCAs) in amino acid and peptide synthesis

N-Urethane-protected N-carboxyanhydrides (UNCAs) are very reactives. They have been successfully used in peptide synthesis, in both solution and solid phase. We have demonstrated that UNCAs are interesting starting materials for the synthesis of various amino acid derivatives. Chemoselective reduction of UNCAs with sodium borohydride led the corresponding N-protected β amino alcohols. Reaction of UNCAs with Meldrum's acid, followed by cyclisation, yielded enantiomerially pure tetramic acid derivatives. Diastereoselective reduction of tetramic acid derivatives produced (4S,5S)-N-alkoxycarbonyl-4-hydroxy-5-alkylpyrrolidin-2-ones derived from amino acids, which after hydrolysis yielded statine and statine analogues. Tetramic acid derivatives could also be obtained by reaction of UNCAs with benzyl ethyl followed by hydrogenolytic deprotection and decarboxylation. UNCAs also reacted with phosphoranes to produce the ketophosphorane in excellent yields. Subsequent oxidation with oxone or with [bis(acetoxy)-iodol]-benzene produced vicinal tricarbonyl derivatives. These reactions usually proceeded smoothly and with high yields.     

Enantiopure β<Superscript>3</Superscript>-amino acids-2,2-d<Subscript>2</Subscript> via homologation of proteinogenic α-amino acids

Summary. A procedure for the synthesis of enantiopure β³-amino acids from proteinogenic α-amino acids, developed by our group a few years ago, has been modified to enable the production of C-2 fully deuterated, C-protected β³-amino acids and, even more important, the synthesis of valuable deuterium labelled N(Boc)-protected chiral synthons, such as 2-aminoalcohols, 2-aminoiodides, and β³-amino nitriles.     

Stereoselective Synthesis of Ribonucleoside 3′,5′-Cyclic Methyl(phenyl)phosphonates and Phosphonothioates

Abstract

Monophosphonylation of 2′-protected ribonucleosides (i.e. 2′-O-THP-uridine and 2′-O-THP-N ⁶-levulinoyl-adenosine) with the bifunctional reagents bis[(6-trifluoromethyl)benzotriazol-1-yl] methyl(phenyl)phosphonates or the analogous phosphonothioates, and subsequent addition of N-methylimidazole, gave the chirally pure 3′,5′-cyclic methyl(phenyl)phosphonate or phosphonothioate derivatives, respectively. Deblocking of the fully protected compounds yielded, as evidenced by X-ray analysis, the corresponding pure Sp-diastereoisomers.     

Synthesis of α-trifluoromethyl α-amino acids with aromatic, heteroaromatic and ferrocenyl subunits in the side chain

Summary. 5-Benzyloxy-4-trifluoromethyl-1,3-oxazoles, obtained from 5-fluoro-4-trifluoromethyloxazoles and benzyl alcohols, are capable for rearrangements. A 1,3 shift of a benzyl group is the key step of a new general route toward α-trifluoromethyl substituted aromatic and heteroaromatic amino acids, demonstrating that 5-fluoro-4-trifluoromethyl-1,3-oxazole is a synthetic Tfm-Gly equivalent. On reaction with benzpinacol partially fluorinated oxazoles are transformed into bis(trifluoromethyl) substituted 2,5-diamino adipic acid and N-benzoyl-2-benzhydryl-3,3,3-trifluoroalanine.     

Synthesis of α-carboxyphosphinopeptides derived from norleucine

In the present study, we describe in detail the synthesis of a relatively rare class of phosphorus compounds, α-carboxyphosphinopeptides. We prepared several norleucine-derived α-carboxyphosphinic pseudopeptides of the general formula Nle-Ψ[PO(OH)]-Gly. These compounds could have important applications as transition state-mimicking inhibitors for methionine or leucine aminopeptidases or other enzymes. For the preparation of the key α-carboxyphosphinate protected precursors, we investigated, compared and improved two different synthetic methods described in literature: the Arbuzov reaction of a silylated N-protected phosphinic acid with a bromoacetate ester and the nucleophilic addition of a mixed O-methyl S-phenyl N-protected phosphonic acid or a methyl N-protected phosphonochloridate with tert-butyl lithioacetate. We also prepared two N-Fmoc protected synthons, Fmoc-Nle-Ψ[PO(OH)]-Gly-COOH and Fmoc-Nle-Ψ[PO(OAd)]-Gly-COOH, and demonstrated that these precursors are suitable building blocks for the solid-phase synthesis of α-carboxyphosphinopeptides.     

MICROWAVE ASSISTED HIGH YIELDING PREPARATION OF N-PROTECTED 2′-DEOXYRIBONUCLEOSIDES USEFUL FOR OLIGONUCLEOTIDE SYNTHESIS

ABSTRACT

A rapid and high yielding method for the synthesis of precursors of synthons for DNA synthesis, N-protected 2′-deoxyribonucleosides is described, which occur under mild conditions using microwave irradiation. The desired material, N-protected nucleosides, was obtained in 93–96% yield in few minutes. The final products were then characterized by ¹H-NMR and MALDI-TOF and compared with the standard samples. The method is amenable to small to moderate scale of synthesis.     

The biological and biochemical properties of L-canaline, a naturally occurring structural analogue of L-ornithine.

Many leguminous plants synthesize L-canavanine and sequester this nitrogen-rich, non-protein amino acid in the seed (1,2). Arginase-mediated hydrolytic cleavage of L-canavanine, in a manner analogous to L-ornithine and urea formation from L-arginine, produces urea and L-canaline (3,4). The resulting canaline is distinctive in being the only naturally occurring amino acid which possesses the aminooxy group (Fig. 1). Canaline decomposes in several organic solvents employed for its analysis by partition and ion-exchange chromatography (5,6) but the important question of the overall stability of this substituted hydroxylamine has not been investigated.     

Synthesis of 2′-Modified Oligonucleotides Containing Aldehyde or Ethylenediamine Groups

Abstract

Oligonucleotides carrying 2′-aldehyde groups were synthesized and coupled to peptides containing an N-terminal cysteine, aminooxy or hydrazide group to give peptide-oligonucleotide conjugates in good yield. The synthesis of a novel phosphoramidite reagent for the incorporation of 2′-O-(2,3-diaminopropyl)uridine into oligonucleotides was also described. Resultant 2′-diaminooligonucleotides may be useful intermediates in further peptide conjugation studies.     

New Atropisomeric Amino Alcohol Ligands for Enantioselective Addition of Diethylzinc to Aldehydes

Efficient synthesis of several new atropisomeric amino alcohols having 1‐phenyl‐1H‐pyrrole skeleton are reported. Steric arrangements of the products were confirmed by a single‐crystal X‐ray measurement. The consequences of the size of the N‐substituents on enantioinduction were examined by employing the enantioselective catalytic addition of diethylzinc to a series of substituted benzaldehydes (yields 91–97%, up to 85% enantiomeric excess). The special effect of the ortho methoxy group of the substrate on the enantioinduction is also interpreted. Chirality 27:216–222, 2015. © 2014 Wiley Periodicals, Inc.     

Condensation reactions catalyzed by α-N-acetylgalactosaminidase from Aspergillus niger yielding α-N-acetylgalactosaminides

Abstract

Extracellular α-N-acetylgalactosaminidase from Aspergillus niger catalyzed glycosylation yielding a series of 2-acetamido-2-deoxy-α-D-galactobiosides using 2-acetamido-2-deoxy-D-galactopyranose as a glycosyl donor. The isomers α-D-GalpNAc-(1→6)-D-GalpNAc, α-D-GalpNAc-(1→3)-D-GalpNAc and α-D-GalpNAc-(1→6)-D-GalfNAc were isolated and spectrally characterized. The purified enzyme was further used for the glycosylation of free amino acids (serine and threonine) and their N-(tert-butoxycarbonyl)-protected analogs to synthesize the Tn antigen (GalpNAc-α-O-Ser/Thr) and its N-(tert-butoxycarbonyl)-protected derivatives.     

Synthesis and carbonic anhydrase inhibitory properties of amino acid – coumarin/quinolinone conjugates incorporating glycine,alanine and phenylalanine moieties

N-Protected amino acids (Gly, Ala and Phe) were reacted with amino substituted coumarin and quinolinone derivatives, leading to the corresponding N-protected amino acid–coumarin/quinolinone conjugates. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was assessed against various human (h) isoforms, such as hCA I, hCA II, hCA IV and hCA XII. The quinolinone conjugates were inactive as enzyme inhibitors, whereas the coumarins were ineffective hCA I/II inhibitors (K_Is?>?50?μM) but were submicromolar hCA IV and XII inhibitors, with inhibition constants ranging between 92?nM and 1.19?μM for hCA IV, and between 0.11 and 0.79?μM for hCA XII. These coumarin derivatives, as many others reported earlier, thus show an interesting selective inhibitory profile for the membrane-bound over the cytosolic CA isoforms.     

Chemoenzymic Synthesis of Pα-Methyl Deoxynucleoside Triphosphates

Abstract

5′-O-(methylphosphonyl)-N-(phenylacetyl)-2 ′-deoxycytidine, deoxyadenosine and deoxyguanosine were pyrophosphorylated and the resulting N-protected P α-methyl nucleoside triphosphates were deblocked by treatment with penicillin amidase at pH 7.8, 25°C to give P α-methyl nucleoside triphosphates.