Protected Building Blocks Research Articles

Sphingolipid Synthesis via Olefin Cross Metathesis: Preparation of a Differentially Protected Building Block and Application to the Synthesis of D‐erythro‐Ceramide.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Sphingolipid synthesis via olefin cross metathesis: preparation of a differentially protected building block and application to the synthesis of D-erythro-ceramide.

The sphingolipid backbone is readily assembled by E-selective olefin cross metathesis of a suitable building block.

Synthesis and DNA binding properties of dioxime–peptide nucleic acids

Peptide nucleic acids (PNAs) C- or N-modified with dioxime ligands were prepared by solid-phase synthesis using iron(II)-clathrochelates as protected dioxime building blocks. These PNA bind complementary DNA sequence specifically, though with much reduced affinity in comparison with nonmodified PNA. The dioxime–PNA conjugates bind Cu 2+ and Ni 2+ at μM concentration.

Synthesis of Iduronic Acid Building Blocks for the Modular Assembly of Glycosaminoglycans

The modular synthesis of glycosaminoglycans requires straightforward methods for the production of large quantities of protected uronic acid building blocks. In particular, the preparation of fully differentiated iduronic acids has proven particularly challenging. An efficient route to methyl 3-O-benzyl-1,2-O-isopropylidene-alpha-l-idopyranosiduronate 6 from diacetone glucose in nine steps and 36% overall yield is described. Idopyranosiduronate 6 is useful as a glycosyl acceptor and as an intermediate that may be further elaborated into iduronic acid trichloroacetimidate glycosyl donors for the assembly of glycosaminoglycan structures as illustrated here.

Oligomerization of a rhamnanic trisaccharide repeating unit of O-chain polysaccharides from phytopathogenic bacteria

An efficient synthesis of a protected trisaccharide building block α- l-Rha(1→3)-α- l-Rha(1→2)-α- l-Rha related to the structure of many lipopolysaccharide O-chains from phytopathogenic bacteria has been developed. The protecting group pattern consisting of benzoyl, benzyl and chloroacetyl groups facilitated the use of the trisaccharide building block in the synthesis of two higher oligomers, an oligorhamnosyl hexasaccharide and a nonasaccharide.

An Orthogonally Protected alpha,alpha-bis(aminomethyl)-beta-alanine building block for the construction of glycoconjugates on a solid support.

Synthetic glycoclusters are extensively used as mimetics of naturally occurring, multivalent carbohydrate ligands in various glycobiological applications. Their preparation, however, is far from trivial, and it still is a limiting factor in the study of carbohydrate binding. We herein report the synthesis of an orthogonally protected building block, N-Alloc-N'-Boc-N' '-Fmoc-alpha,alpha-bis(aminomethyl)-beta-alanine (1), and its use in the preparation of triantennary peptide glycoclusters (21-24) on a solid support. The assembly of the clusters involves removal of the amino protections of the solid-supported branching unit 1 in the order Fmoc, Boc, and Alloc, and subsequent coupling of peracetylated O-(glycopyranosyl)-N-Fmoc-L-serine pentafluorophenyl esters (galactose, glucose, mannose, and ribose) to each amino group exposed.

ChemInform Abstract: A Convenient Multigram Preparation of Functionalized 2‐Azido‐2‐deoxy‐D‐mannose as a Useful Orthogonally Protected Building Block for Oligosaccharide Synthesis.

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Synthesis of a hexasaccharide fragment of the capsular polysaccharide of Streptococcus pneumoniae type 3

In the framework of the development of a new generation of neoglycoconjugate vaccines against Streptococcus pneumoniae, the synthesis is described of a spacer-containing hexasaccharide fragment related to the capsular polysaccharide of S. pneumoniae type 3. Hexasaccharide β-D-GlcpA-(1[Formula: see text]4)-β-D-Glcp-(1[Formula: see text]3)-β-D-GlcpA-(1[Formula: see text]4)-β-D- Glcp-(1[Formula: see text]3)-β-D-GlcpA-(1[Formula: see text]4)-β-D-Glcp-(1[Formula: see text]O-(CH2)3NH2) (1), comprised of three repeating units, was synthesized via a blockwise strategy employing suitably protected disaccharide building blocks. Carboxylic groups were introduced by selective oxidation with TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) in the last reaction steps. Deprotection afforded target hexasaccharide 1.Key words: oligosaccharide synthesis, Streptococcus pneumoniae type 3, TEMPO oxidation.

Synthesis of a hexasaccharide that relates to the arabinogalactan epitope

A hexasaccharide derivative of the arabinogalactan epitope, methyl β- d-galactopyranosyl-(1→6)-[α- l-arabinofuranosyl-(1→3)]-β- d-galactopyranosyl-(1→6)-β- d-galactopyranosyl-(1→6)-[α- l-arabinofuranosyl-(1→3)]-α- d-galactopyranoside, was synthesized efficiently using a 3+3 strategy. The key step is the preparation of the trisaccharide donor, isopropyl 2,3,4,6-tetra- O-benzoyl-β- d-galactopyranosyl-(1→6)-[2,3,5-tri- O-benzoyl-α- l-arabinofuranosyl-(1→3)]-2,4-di- O-benzoyl-1-thio-β- d-galactopyranoside, from isopropyl 1-thio-β- d-galactopyranoside using a one-pot synthesis of a 3,6-differentially protected building block.

Synthesis and thermodynamic studies of oligonucleotides containing the two isomers of thymine glycol.

Thymine glycol is a major type of base damage, which is formed in DNA by reactive oxygen species. I describe the synthesis of oligonucleotides containing the 5S isomer of thymine glycol, which was not obtained by the oxidation of the oligonucleotides. Before the 5S isomer was synthesized, a building block without the protection of the tertiary hydroxy function at the C5 position of thymine glycol was tested by the use of the previously reported 5R isomer. In the presence of imidazole, migration of the silyl group between the C5 and C6 positions was observed, while the result of the oligonucleotide synthesis was identical to the case of the fully protected building block. Therefore, oligonucleotides containing the (5S)-thymine glycol were synthesized with the disilylated building block. In contrast to the 5R derivative, two products were detected in the HPLC analysis of the crude mixture after deprotection. Analysis by matrix-assisted laser-desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry revealed that the larger peak was the desired oligonucleotide, and it was found that the by-product was completely degraded by a short treatment with ammonium hydroxide at room temperature. I also report the application of oligonucleotides containing each isomer of thymine glycol to thermodynamic analyses of base-pair formation. The thermodynamic parameters obtained for the duplexes containing either the (5R)- or (5S)-thymine glycol indicated that the thymine glycol cannot form a base-pair with any nucleobase, regardless of the configuration at the C5 position.

N-Terminal peptide aldehydes as electrophiles in combinatorial solid phase synthesis of novel peptide isosteres.

N-Terminal peptide aldehydes were synthesized on a solid support and utilized as electrophiles in nucleophilic reactions in order to furnish novel and diverse peptide isosteres. The aldehyde moiety of the peptide was synthesized by coupling a protected aldehyde building block to the peptide and deprotecting it quantitatively in less than 3 min. It was found that protection of the two succeeding amide nitrogens was necessary in order to avoid reaction between the aldehyde and backbone amides. The N-terminal peptide aldehydes were successfully reacted in the following way: (a) reductive amination with a large variety of amines, leading to N-alkyl-gamma-aminobutyric peptide isosteres positioned centrally in the peptide; (b) reductive amination with amino esters, leading to N-terminal 2,5-diketopiperazine peptides; (c) Horner-Wadsworth-Emmons olefination, leading to unsaturated peptide isosteres positioned centrally in the peptide; and (d) Pictet-Spengler condensations, leading to tetrahydro-beta-carbolines either positioned centrally in a peptide or fused with a diketopiperazine ring in the N-terminus of the peptide.

Synthesis of tumor associated sialyl-T-glycopeptides and their immunogenicity.

Sialyl-T-glycopeptides were synthesized by solid-phase techniques, using a PEGA resin as the solid support. An appropriately protected building block containing alpha-Neu5Ac-(2 --> 3)-beta-Gal-(1 --> 3)-alpha-GalN3-(1-->) attached to Fmoc-Thr/Ser-OPfp was employed in a solid phase glycopeptide assembly of a 10-mer glycopeptide, using a general Fmoc/OPfp-ester strategy. Reduction of the azido group of the GalN3 residue was effected on solid-phase, using DTT and DBU. After acidolytic cleavage from the resin, the methyl ester of the sialic acid residue and acetyl groups were removed with 30% NaOMe/MeOH in MeOH and water pH 14, at -30 degrees C for 2 h. At this low temperature, the highly basic conditions did not result in any detectable beta-elimination. However, one O-acetyl group, located at the 2-position of the Gal was resistant to hydrolysis. To remove this remaining acetyl group, reaction with hydrazine hydrate in CHCl3 and MeOH at room temperature for 2.5 h was successful. The two target sequences of sialyl-T-glycopeptides were obtained in good yield. In contrast to the the analogs carrying the T-antigen, the Sial-T-glycopeptides were nonimmunogenic, supporting the idea that the sialylation is a method of circumventing the recognition by the immune system.

Sequence Selectivity of 3-Hydroxypyrrole/Pyrrole Ring Pairings in the DNA Minor Groove

Hairpin polyamides containing the aromatic amino acids 3-hydroxypyrrole (Hp), pyrrole (Py), and imidazole (Im) are capable of discriminating all four Watson−Crick base pairs in the DNA minor groove according to a set of pairing rules. Equilibrium association constants for four eight-ring hairpins containing all four pairings of Hp and Py at a single common position (ImImXPy-γ-ImYPyPy-β-Dp, where X/Y is Py/Py, Py/Hp, Hp/Py, and Hp/Hp) were determined at four DNA sites, 5‘-TGGTCA-3‘, 5‘-TGGACA-3‘, 5‘-TGGCCA-3‘, and 5‘-TGGGCA-3‘, to study the relative binding affinities of the 16 possible complexes. The protected 3-hydroxypyrrole amino acid building block, 3-methoxypyrrole, is prepared on a 50 g scale, and the solid-phase synthesis of hydroxypyrrole−imidazole−pyrrole polyamides is described. Quantitative DNase I footprint titrations demonstrate that a Py/Py pair is partially degenerate for A•T and T•A, but disfavors G•C and C•G base pairs by 53- and 17-fold, respectively. An Hp/Py pair placed opposite T•A binds at least 20-fold more tightly than when placed opposite A•T, G•C, and C•G base pairs. The Py/Hp pair selectively binds A•T with 11-fold higher affinity over T•A and with ≥30-fold selectivity relative to G•C and C•G. An Hp/Hp pairing is disfavored opposite all four base pairs, potentially limiting certain slipped motifs available to unlinked dimers in the minor groove. This study serves to guide the design of second-generation polyamides for DNA recognition.

Efficient enantioselective synthesis of a β-hydroxyepoxide building block for the construction of macrocyclic natural products

The synthesis of a protected β-hydroxyepoxide macrolide building block in seven steps from commerically available ( R )-3-hydroxybutyric acid methyl ester in 68% overall yield is described. Graphic

Synthesis and Biological Evaluation of a Backbone‐Modified Phytoalexin Elicitor

AbstractTwo suitably protected building blocks (11 and 33) for the preparation of amide‐linked heptaglucoside mimetic 2, an analogue of the naturally occurring phytoalexin elicitor 1a, were readily accessible by glycal chemistry. Sequential elongation of terminal glucuronide 21 with laminaribiosyl hemiaminal 33 and anomeric amine 11 by EDC/HOBt‐catalyzed condensation and two‐step conversion of the C6‐OTr moiety into the corresponding carboxylate function afforded homogeneous carbopeptoid 2 in high overall yield. It was found that replacement of the acetal linkages by the more rigid amide bonds destroys the phytoalexin‐elicitor activity.

Synthesis of Polyamide Nucleic Acids (Pnas), Pna /Dna-Chimeras and Phosphonic Ester Nucleic Acids (Phonas)

The synthesis of polyamide nucleic acids (PNAs) and derivatives thereof by different synthetic routes is described. The first strategy makes use of 9-Fluorenylmethoxycarbonyl (Fmoc)/monomethoxytrityl (Mmt) protected building blocks, whereas the second approach involves the use of Mmt/acyl protected monomers, which allows the preparation of PNADNA chimera. Additionally, a block coupling strategy is presented for the synthesis of novel phosphonic ester nucleic acids (PHONAs).

Novel polyamide based nucleic acid analogs-synthesis of oligomers and RNA-binding properties

The synthesis of novel polyamide based nucleic acid analogs incorporating monomer units of type I – III has been accomplished using solid-phase strategies based on N δ-Fmoc protected building blocks. An oligomer composed of monomer units I exhibited weak, but sequence-specific RNA binding. Improved RNA-binding affinity was observed for analogs incorporating building blocks of type III with 2-(R) stereochemistry, but not in the case of the 2-(S) isomers.

Utilization of some non coded amino acids as isosters of peptide building blocks

In our study on non coded amino acids and their utilization in peptide chemistry we synthesized methylene-thio (CH2-S) and methyleneoxy (CH2-O) group containing amino acids and pseudodipeptides which could be used as building blocks for the construction of peptide hormone analogues. The (CH2-S) isoster of peptide bond exhibits increased flexibility, lipophility and resistance to proteolytic enzymes. This group exhibits similar properties as the isosteric disulfide bond in the side chain of cystine residue. The (CH2-O) isoster is moreover similar in its geometry to extended conformation of peptide bond. As a consequence, the changed profile of biological activities could be expected for peptide hormone analogues containing such isosteric moiety. The (CH2-S) isosters of the peptide bond were prepared by alkylation of thiolates of 2-mercaptocarboxylic acids, the disulfide bond by alkylation of cysteine or homocysteine. The (CH2-O) isosters were prepared by (AcO)4Rh2 catalyzed addition of carbenes of alkyl diazocarboxylates to N-protected aminoalcohols. Pseudodipeptides H-Leu-ψ(CH2-S)-Gly-NH2 and H-Leu-ψ(CH2-O)-Gly-NH2 were introduced into the C-terminal part of the oxytocin molecule using solution methods of peptide chemistry. Both inserted isosteric bonds were resistant against proteolytic degradation, the first one was found to decrease an enzymic cleavage of the distant Tyr(2)-Ile(3) bond in the corresponding analogue, too. The (CH2-S) isosters of the disulfide bond containing an orthogonal protection of theirα-amino (Fmoc) andα-(OAll, OH) orω-(OBu(+), OH) carboxylic groups were applied in the solid phase synthesis of the aminoterminal 1-deamino-15-pentadecapeptide of endothelin-I which represents a strong vasoactive agent. The solid phase synthesis was carried out by the step-wise protocol on the Rink or Merrifield type resin using orthogonally protected carba cystine building blocks.

The 1,1- dianisyl-2,2,2-trichloroethyl group as 2′-hydroxyl protection of ribonucleotides

The 1,1-dianisyl-2,2,2-trichloroethyl group (DATE, 1) was introduced as a new 2′-hydroxyl protecting group of ribonucleotides. The usefulness of DATE as a 2′-OH protection was demonstrated in the solid phase synthesis of a dinucleotide by the phosphoramidite method. Starting from 2′-O-DATE-uridine ( 5), a suitable protected building block 7 was thus prepared and condensed in a conventional DNA synthesizer with the unprotected 5′-hydroxyl group of thymidine bound to a support via the 3′-hydroxy group. The resulting chimeric dinucleotide was cleaved from the support and the protecting groups were removed to yield 8. Cleavage of DATE was performed by means of lithium cobalt(I)phthalocyanine smoothly and quantitatively without any by-product formation

ChemInform Abstract: SYNTHESIS OF A TEICHOIC ACID FRAGMENT OF BACILLUS SUBTILIS USING A MODIFIED PHOSPHOTRIESTER APPROACH

AbstractDie Synthese der Titelverbindung (Vb) wird nach eine modifizierten Phosphotriesterverfahren unter Verwendung der ‐ aus der Vorstufe (Ia) mit den Phosphorylierungsreagenzien (II) erhältlich ‐ Bausteine (Ib)‐(Id) durchgeführt: Das (Ib)/(Ic)‐Kondensationsprodukt (IIIa) wird mit Isopentylnitrit/Py/Essigsäure in (IIIb) übergeführt, das dann mit (Id) kondensiert wird [→(IVa)].