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N-iodosuccinimide/triflic acid mediated one-pot two-step glycosylation of ethyl 2,3,4-tri-O-benzyl-1-thio-α-L-rhamnopyranoside (8) with phenyl 3,4-O-(2,3-dimethoxybutane-2,3-diyl)-1-thio-α-L-rhamnopyranoside (10b) and phenacyl (R)-3-hydroxydecanoate (13) gave rhamnolipid 17. The latter was transformed in five steps into the title compound 2. Esterification of 2 with diazomethane resulted into the corresponding methyl ester derivative 1.

A stereoselective synthesis of a chiral PNA analogue containing an ornithine based backbone is described. In this approach each elongation cycle consists of two individual coupling steps: i.e. extension of the free δ-amino function in the growing chain by a TOPPipU mediated coupling with Fmoc-Orn(Boc)-OH, and subsequent acylation of a free α-amine with thymin-1-ylacetic acid. Thyminyl decamers were prepared following this strategy and hybridization experiments indicated that they formed stable complexes with cRNA.

The spacer-containing tetrameric arabinogalactans 1−3, suitable for CCRC-M7 epitope characterization, are readily accessible by ZnCl2-assisted stepwise elongation of 11-methoxycarbonylundecanol 9 with the 1,2-anhydrogalactose building unit 6. NIS/cat. TfOH-mediated glycosylation of the newly formed 2-OH, 2′-OH, or 2′′-OH function in the β-(16)-galactoside backbone with the 1-thioarabinofuranoside donor 8, followed by deprotection, provided the target tetramers in high overall yield.

Three new potential ligands for the IP 3 receptor ( i.e. compounds 5–7 ) were prepared by Sonogashira coupling of propargyl 2- O -acetyl-5- O -benzyl-3- O -(3,4-di- O -acetyl-2,6-di- O -benzyl-α- d - glycopyranosyl)-β- d -ribofuranoside ( 15 ) with iodobenzene, 1,2-diiodobenzene and 1,2,4,5-tetraiodobenzene, followed by deacetylation, phosphorylation and deprotection. © 1997 Elsevier Science Ltd.

Ring-opening of an α-1,2-epoxide function in sugars with lithium alkynyl derivatives in the presence of zinc chloride proceeds with retention of configuration to afford α-C-(alkynyl)-glycosides in reasonable yields. © 1997 Elsevier Science Ltd.

Novel mono- and difarnesylated triphosphonates (i.e. 2 and 7) and the corresponding cyclic derivatives (i.e. 3 and 8) were synthesised and tested on inhibitory potential and specificity for the enzymes squalene synthase and protein:farnesyl transferase. The IC50 values of these new derivatives are in the range of 1–60 μM concentration.

A synthesis is presented of the cyclic trimeric d-oligonucleotide 3′-isopropylphosphate I, comprising one formacetal and two (3′ → 5′)-internucleosidic phosphodiester bonds. The ester linkages connect d-guanosine with the 3′ and 5′ ends of thymidine and 5-hydroxymethyl-2′-deoxyuridine-3′-isopropylphosphate (HMDUpiPr), respectively. The 5′-end of the thymidine unit is anchored via the formacetal bond to the allylic hydroxyl group of HMDUpiPr. The cyclic arrangement of the three d-nucleosides in I mimics, as based on molecular modeling, the key structural features of the conformationally constrained T7pG8pT9p-domain of the thrombin-binding DNA aptamer d(G1G2T3T4G5G6 T 7 G 8 T 9 G10G11T12T13G14G15). Biological evaluation showed that compound I did not exhibit anti-thrombin activity.

Automated chemical synthesis of PNA and PNA-DNA chimera on a DNA synthesizer using the monomethoxytrityl/acyl protecting group strategy is described.

A versatile synthetic route to compound 2 - an analog of the naturally occurring bacteriocin Agrocin 84 is described.

Immobilized penicillin-G acylase mediated removal of the N-phenylacetyl protective group in ethanolamine phosphates 7 and 9 furnished compounds 8 and 10, respectively. Deblocking of N-phenylacetyl-protected ethanolamine phosphate heptosyl disaccharide 22, a protected spacer-containing fragment of the inner-core lipopolysaccharide region of Neisseria meningitidis, immunotype L3 was readily accomplished with penicillin-G acylase, yielding target dimer 2. Disaccharide 22 was accessible by elongation of ethyl 1-thio-L-glycero-α-D-manno-heptopyranosyl donor 13 with acceptor 14 under the influence of N-iodosuccinimide/triflic acid. Protective group manipulations, phosphorylation with the reagent 2-cyanoethyl 2-(phenylacetylamino)ethyl N,N-diisopropylphosphoramidite (5) and deprotection furnished LD-Hepp dimer 22.

Adenophostin A analog 4 was prepared via trimethylsilyl trifluoromethanesulfonate (TMSOTf)-assisted glycosylation of (S)-6-N-diphenylacetyl-9-(2-tert-butyldiphenylsilyloxy-1-hydroxyprop-3-yl)-adenine (11) with trichloroacetimidate donor 12 to give dimer 13. Protective group manipulations on 13 followed by phosphitylation with N,N-diisopropyl-bis-[2-(methylsulfonyl)ethyl] phosphoramidite (17) and in situ oxidation gave, after deprotection, (2S)-9-1-(α-D-glucopyranosyloxy 3,4-bisphosphate)-2-monophosphate-prop-3-yl-adenine (4). Condensation of phosphoryloxymethyl-adenosine 25 with d -arabinitol derivative 21 under the agency of TMSOTf afforded methylene acetal 26. Protective group manipulations (→ 32), phosphorylation, and deprotection yielded 3′-O-( d -arabinitol -4-O- methylene 2,3-bisphosphate)-adenosine 2′-monophosphate (5), a methylene acetal-containing analog of adenophostin A.

Glycosylation of ethyl 3,4,6- tri -O- acetyl -2-O- benzyl-1-thio - α β - d -glucopyranoside (6) with tert-butyldiphenylsilylglycol (7) or 1,2-di-O-p-methoxybenzyl-sn-glycerol (16) under the agency of N-iodosuccinimide/triflic acid afforded α-glucosides 8 and 17, respectively. Protective group manipulations (8 → 10 and 17 → 20) and acetolysis of the methylthiomethyl functions yielded 2-O-(3,4,6- tri -O- acetyl -2-O- benzyl -α- d -glucopyranosyl )-1-O- acetoxymethylglycol (11) and 3-O(3,4,6- tri -O- acetyl -2-O- benzyl -α- d -glucopyranosyl )-2-O- acetoxymethyl -1-O-tert- bytyldiphenylsilyl -sn- glycerol (21). Vorbruggen condensation with silylated 6-N-benzoyladenine (22), subsequent protective group manipulations on 23 and 29 followed by phosphorylation furnished, after purification, homogeneous glycol-based adenophostin A analog 4 and glycerol-based analog 5.

An automated online solid-phase synthesis of Ac-cac ct T∗GG TC t∗ac ct-Gly-OH1 using standard DNA and appropriately protected PNA building blocks (2–5) is described. This chimera forms stable duplexes with complementary DNA and RNA.

Structurally well defined di- and tri-antennary lysine-based galactose- and N-acetylgalactosamine-containing ligands for the hepatic asialoglycoprotein receptor (ASGP-R) could be assembled on a solid support, using a combined Fmoc/Alloc protecting group strategy for the amino functions of lysine. This methodology allowed easy introduction of spacers, the length of which could be readily accommodated for optimal binding to the ASGP-R.

Derivatization of the octadecathymidylate derivative 18 (T18 ODN) containing a free amine function with sulfo-SIAB® gave the corresponding iodoacetyl ODN 21. Conjugation of the latter with the thiol-containing pentasaccharide 17c gave pentasaccharide–ODN conjugate III, which exhibited anti-Xa and antithrombin activities of 173 U mg-1 and 5 U mg-1, respectively.

NMR studies of the free and DNA-bound states of the lac represser headpiece show that formation of the hinge helix requires protein–protein interactions and occurs only when the represser binds to the full lac operator.

A convenient route to the preparation of 4-methoxy-1-oxido-pyridine-2-methyl N-2-(4,4′-dimethoxytrityloxy)ethyl-N-thymin-1-yl-aminomethylphosphonate (1a, T∗) and the corresponding N4-benzoylcytosin-1-yl derivative 1b (C∗) is reported. These PPNA monomers proved to be suitable building blocks in a solid-support synthesis of the tetradecameric fragment (C∗T∗T∗T∗C∗T∗T∗T∗T∗C∗T∗C∗T∗)dT.

This paper deals with the crystal structure of d(CG)3-spermidine complex. The DNA fragment, d(CG)3, was crystallized with N-(2-amino-propyl)-1,4-diamino-butane, PA(34), spermidine. The results of its X-ray crystallographic analysis showed many intermolecular contacts between d(CG)3 and spermidine, but the binding mode of spermidine to the d(CG)3 molecule is different from that of the d(CG)3 and N-(2-amino-ethyl)-1,4-diamino-butane [PA(24)]complex: a spermidine molecule bound to the d(CG)3 and its symmetrically related neighboring d(CG)3 molecules through the water molecules with hydrogen bonds, while one PA(24) molecule connected directly to one d(CG)3 molecule, but not to its neighboring d(CD)3 molecule. In the crystal, the d(CG)3 molecule was the left-handed Z-form, and three magnesium cations and a sodium cation were observed around the d(CG)3 moiety with different binding modes from the case of the d(CG)3-PA(24) complex.

The properly protected ethyl 1-thio-abequopyranoside 11 and ethyl 1-thio-tyvelo-pyranoside 26 were prepared by a sequence of reactions, the key step of which was the regioselective hydride-mediated ring-opening of the cyclic sulfate function in compounds 8 and 18. Iodonium ion-assisted glycosylation of allyl mannopyranoside 30 with the individual ethyl 3,6-dideoxy- 1-thio-D-hexopyranoside donors 11 and 26 furnished, after deprotection, the respective allyl 3-O-(α-D-abequopyranosyl)-α-D-mannopyranoside 1 and allyl 3-O-(α-D-tyvelopyranosyl)-α-D-mannopyranoside 2.

The preparation of the spacer-containing trimers 2, 3-aminopropyl 3-O-[4-O-Me-3-O-(4-N-D,L-lactoyl-3-O-Me-β-D-Quip)-α-L-Rhap]-α-L-Rhap, derivatives of the antigenic determinant of the glycopeptidolipid from Mycobacterium avium serotype 12, are described. Thus, iodonium ion-mediated glycosylation of the spacer-containing acceptor 7 with ethyl 1-thio-rhamnopyranoside donor 10, followed by selective deprotection of the p-methoxybenzyl group of thus obtained 19 gave bis-rhamnopyranoside acceptor 20. Elongation of 20 with ethyl 4-azido-1-thio-β-D-quinovopyranoside 18 and subsequent reduction of the azido function in 21 led to trimer 22. The amino group in 22 was coupled with both D- and L-lactic acid to give, after removal of the protective groups, trimers 2.

Glycosylation of 1,2-O- isopropylidene -5-O-tert- butyldiphenylsilyl -α- d -ribofuranose (8) with ethyl 3,4,6- tri -O- acetyl -2-O- benzyl-1-thio -α/β- d -glucopyranoside (7) under the agency of N-iodosuccinimide and trifluoromethanesulfonic acid afforded α-linked dimer 10 in 95% yield. Acetylation of 13, obtained after hydrogenation of 10 followed by pivaloylation of 11 (→ 12) and deacetonation, yielded penta-acetate 14. Vorbruggen-type condensation of 14 with bis-trimethylsilyl 6-N-benzoyladenine (9) gave adenosyl glucoside 17. Deacetylation of 17 resulted in migration of the pivaloyl group from the 2″-OH to the 3″-OH of the glucosyl moiety (→ 18), giving access, after phosphorylation and deprotection, to adenophostin A analog 4 containing two (2″–4″)-cis oriented phosphate groups. Vorbruggen-type condensation of 9 with 16, obtained by deacetonation of 10 and subsequent acetylation, gave adenosyl glucoside 22. Protective group manipulations followed by phosphorylation furnished, after deprotection, homogeneous adenophostin A (2) in a high overall yield.

Two procedures are described towards the assembly of the tyramine spacer-containing tetramer 5, a derivative of the phenolic glycolipid of Mycobacterium kansasii serovar I. First, iodonium ion-mediated glycosylation of trimeric acceptor 2a with d -rhamnopyranoside donor 10 gave fully protected tetramer 17. Selective removal of the chloroacetyl group of 17, subsequent deoxygenation and removal of the protective groups, led to target 5. The potential occurrence of double stereodifferentiation (DSD) was examined by condensation of l -fucopyranoside model acceptor 14 with both the enantiomeric rhamnopyranoside donors 10 and 13. The second procedure involves elongation of trimeric acceptor 2b with 6-deoxy- d -glucopyranoside 28. Desulfurisation of the resulting tetrameric fragment 36 followed by hydrogenation of 37 gave 38, the phenylacetyl (PhAc) of which was enzymatically removed to yield target tetramer 5.

DNA three-way junctions (TWJs) containing unpaired residues at the branch point can adopt a conformation in which one helix is stacked upon another, forming a coaxial, quasicontinuous double helix. As in four-way junctions (FWJs), two conformers with different stacking arrangements between the arms are possible. However, in both types of structures a markedly strong preference for one conformer has been observed. To investigate the basis for this preference, in particular the influence of the stacking proclivity of the base-pairs at the centre of the junction, two linear oligomers (36 nucleotides), TWJ1 and TWJ2, differing only in one base-pair (G.C versus C.G, respectively) at the branch point, were designed and chemically synthesized. Each one is expected to fold into a stable three-way junction, containing two unpaired thymidine bases at the junction region and two arms capped with a hairpin loop. The data obtained from 1H and 31P-NMR spectroscopy confirm that both oligomers are present as stable three-way junctions. In both TWJs two of the helical arms stack preferentially upon each other. However, the stacking arrangement is similar in both molecules. From this it is deduced that purine-purine stacking across the junction cannot be considered as a major factor that determines the preferred stacking arrangement.

The solid phase assembly of alkylphosphonylated peptides 3a,b using the readily available new phosphonylating reagents p-methoxybenzyl N,N-diisopropylaminomethylphosphonamidite (9a) and its octyl analogue (9c) is described.

Carbenoid species generated from ethyl diazoacetate and catalytic Rh 2 (OAc) 4 react smoothly and with a high degree of stereoselectivity with glycals resulting in the predominant formation of doubly branched adducts containing an α- exo -orientated ethyl cyclopanecarboxylate moiety.

The synthesis of two diastereoisomeric pyranopyran sugar amino acids, starting from (+)-D-3,4,6-tri-O-benzylglucal, is described. The key reaction sequence towards the bicyclic structure entails Petasis olefination followed by ring closing metathesis.

The bifunctional platinum compound, [(trans-PtCI(NH)3)2)2(H2N(CH2)4NH2)]2+, forms a stable adduct with the self-complementary DNA oligomer CATGCATG, with the two platinum atoms coordinated at the N7 positions of the two symmetrical G4 nucleotides. The NMR-derived structure shows that the DNA octamer forms a novel hairpin structure with the platinated G4 residue adopting a syn conformation and the guanine base in the minor groove. Two such hairpins stack end-over-end and are linked together by the butanediamine tether to form a dumbbell structure. Such unusual structural distortion is different from that of the anticancer drug cisplatin-DNA adduct and may provide clues to explain the distinct biological activities of the two compounds.

Several suitable building blocks for the construction of the phytoalexin elicitor α-methyl-32, 34-di-β-D-glucopyranosylgentiopentaoside (2) were readily accessible by oxidative coupling of glucals. Block coupling of trimeric phenylseleno- and ethylthioglucosyl donors 17 and 18 with tetrasaccharide 16 in the presence of the thiophilic promoter N-iodosuccinimide and catalytic trifluoromethanesulfonic acid furnished the desired heptaglucan 2 in high overall yield.

The inhibitory potency of farnesyl pyrophosphate analogues was investigated on two farnesyl pyrophosphate-consuming enzymes: squalene synthase, a secondary regulation site in the cholesterol synthesis pathway, and protein: farnesyl transferase, which plays a role in the function of Ras-proteins. For the transferase determination a rapid in vitro assay, using Sepharose-bound Ras-peptides, was developed. The distinct farnesyl pyrophosphate analogues showed a different order of potency in the inhibition of these two enzymes. Using the farnesyl transferase assay with pre-p21 Ha-ras as substrate the same result was obtained. The difference observed in the in vitro assays was also reflected in the inhibition of cholesterol synthesis, protein prenylation in general and Ha-ras farnesylation in Rat-1.Hras13 cells, a rat flbroblast cell line that overproduces human p21 Ha-ras . This work shows that farnesyl pyrophosphate analogues can be developed for specific inhibition of different processes such as cholesterol synthesis and protein prenylation.

Addition of [(dimethylphenylsilyl)methyl]magnesium chloride to 6-benzylimino-6-deoxy-1,2;3,4-di- O -isopropylidene-α- D -galactopyranose mediated by Ce(III)Cl 3 or CuI/BF 3 ·Et 2 O proceeds with complete syn - or anti -diastereoselectivity, respectively, to afford highly chiral precursors of destomic acid or lincosamine.

The syntheses of two amino acid based phosphodiester linkage-containing cryptands (30 and 44) as well as diphosphorylated macrocycles (28, 29, 32 and 33) are described. Boc-L-Ser(Bn)-OH and/or Boc-D-Ser(Bn)-OH were used for the construction of the precursors for the diphosphitylation and macrocyclization by phosphitylation. The carboxylic acid groups were connected with a diethylene glycol unit and the amino functionalities were linked using (ethylenedioxy)diacetic acid, oxydiacetic acid, or an isophthalic acid derivative. The LD-cryptands 30 and 44 were obtained after phosphitylation of the precursors 12 and 16, respectively, confining (ethylenedioxy)acetic acid or an isophthalic acid derivative as a bottom-spacer, using 4-chlorobenzyl phosphorodichlorodite followed by oxidation and hydrogenolysis. Phosphitylation of the precursors containing (ethylenedioxy)acetic acid or oxydiacetic acid as bottom-spacres 11-14, using bis(4-chlorobenzyl) N,N-diisopropylphosphoramidite and subsequent oxidation resulted in the corresponding diphosphorylated macrocycles 28,29,32 and 33

Intramolecular peptide synthesis could be achieved using tetrahydrophthalazine ( 1 ) as template. Peptide bond formation proceeded via the N-acyl-N′α-aminoacylhydrazine-rearrangement. The feasibility of the approach is illustrated by the synthesis of the protected tripeptide Z-Val-Gly-Ala-OMe ( 8 ).

The synthesis of three cyclic phosphopeptides, which contain a phosphodiester linkage, is described. Starting from either Boc-L-Ser(OBn)-OH or Boc-L-Thr(OBn)-OH, three precursors for the macrocyclization by phosphitylation were prepared. After phosphitylation, using 4-chlorobenzyl bis(N,N-diisopropylamino)phosphinite or 4-chlorobenzyl dichlorophosphinite, subsequent oxidation and hydrogenolysis the cyclic phosphopeptides 18-20 were obtained. The solution conformation of cyclic phosphopeptide 18 was studied by NMR spectroscopy and restrained molecular dynamics calculations

This paper describes the synthesis of O-phosphorothioylserine, -threonine, and -tyrosine by sulfurization of the intermediate phosphite triester using phenylacetyl disulfide. Several deprotection procedures were investigated to find the optimal conditions necessary for obtaining the deprotected phosphorothioate amino acids. This method could then be extended to the preparation of O-phosphorothioylserine- and -threonine-containing pentapeptides on a solid phase. After completion of the synthesis of the peptides on the solid support, the amino acid residue containing the free hydroxyl function was phosphitylated using N,N-diisopropylbis(4-chlorobenzyl)phosphoramidite and subsequently sulfurized using phenylacetyl disulfide. Silylitic cleavage of the protecting groups, using thiophenol and m-cresol as scavengers, gave the pure deprotected phosphorothioylated peptides . The corresponding phosphopeptides were obtained when the phosphitylated peptides attached to the solid support were oxidized instead of sulfurized using tert-butylhydroperoxyde

Reaction of deoxynucleoside 3'-O-(methylthiomethyl) acetals 1 with N-iodosuccinimide (NIS) and dibutyl phosphate furnished the corresponding 3'-O-(dibutoxyphosphoryloxy)methyl acetals 6. Condensation of the latter with appropriately protected deoxynucleoside acceptors 3, in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf), afforded in most cases the (3'→5') methylene acetal linked d(B 1Λ B 2 ) dimers 4. In addition, TMSOTf-promoted coupling of donor 6 (B 1 =C Bz ) with 3'-O-(methylthiomethyl)thymidine (8) yielded dimer 9. Reaction of 9 with NIS and dibutyl phosphate gave dimer 10, which was applied successfully in the TMSOTf-assisted fusion with acceptor 3 (B 2 =C Bz and A Bz ), to afford the corresponding trimers d(C Λ T Λ C) 11 and d(C Λ T Λ A) 12

A convenient route towards the synthesis of peptides containing the methylphosphinamide moiety as a novel transition-state isostere of the amide bond hydrolysis is described. The key step being the coupling of a methylphosphinic chloride with an amino acid or peptide protected at the C-terminus. A proper choice of the amino protecting group appeared to be essential.

A versatile route of synthesis of phosphorus oxide and phosphorus borane templates starting from the bifunctional phosphorylating agent bis(diisopropylamino)ethynylphosphine is presented. Ring-closing enyne metathesis using 4,5-dihydro-imidazol-2-ylidene ruthenium benzylidene complex 3 on these types of substrates led to the formation of mono- and bicyclic phosphorus heterocycles.

The syntheses of azaMan-beta-(1-->6)-C-Glc (4), azaGlc-beta-(1-->6)-C-Glc (5), and azaGal-beta-(1-->6)-C-Glc (6) based upon double reductive amination of acetylenic carbohydrate-derived diketones is described. The required diketones are obtained by addition of the acetylenic sugar anion derived from dibromoolefin 7 to benzyl-protected mannopyranolactone, glucopyranolactone, or galactopyranolactone, followed by reduction of the ketose and oxidation of the resulting diol. Ensuing double reductive amination and hydrogenolysis affords the target compounds in reasonable to good yields. Enzyme inhibition tests show that neither of the three compounds 4, 5, and 6 inhibit beta-glycosidases, while moderate to good inhibitory activities were found on alpha-glycosidases, the most active being 6 (alpha-galactosidase: K-i = 0.092 mu M).

A general approach towards the construction of highly functionalised pyranopyran and pyranofuran systems via Grubbs [Ru] catalysed ring-closing metatheses of neighbouring vinyl-O-allyl and vinyl-O-propargyl functions on monosaccharide scaffolds is described.