Butyldimethylsilyl ethers of iodine-catalysed solvolysis products of long-chain epoxides

Epoxides of methyl esters of elaidic and oleic acids were allowed to react with methanol, ethanol, n-propanol, iso-propanol and n-butanol, in the presence of iodine, to give the corresponding alkoxyhydroxy methyl esters. Ethyl elaidate epoxide gave a hydroxymethoxy methyl ester when treated with boron trifluoride in methanol but the ethyl ester group was not attacked with iodine as catalyst. Mass spectra of the alkoxyhydroxy esters contained strong peaks which demonstrated the location in the chain of the original epoxide ring. Iodine also catalysed the addition of water to methyl elaidate or oleate, giving erythro- and threo-9,10-dihydroxyoctadecanoates, respectively. The alkoxyhydroxy esters were quantitatively converted to t-butyldimethylsilyl ethers by reaction with t-butyldimethylchlorosilane/imidazole/dimethylformamide reagent at 100°C but the dihydroxyoctadecanoates were not completely derivatised. Mass spectra of all the t-butyldimethylsilyl ether derivatives contained intense fragments allowing the molecular weights and the positions of the ether functions to be easily determined.     

Intramolecular cyclization of pentose and hexose dithioacetals

The intramolecular cyclization of O-tosyl derivatives of dithioacetals of d-ribose, d-arabinose, and d-glucose was investigated. p-Toluenesulfonylation of d-glucose diethyl dithioacetal gave 3,6-anhydro-d-glucose diethyl dithioacetal. Variously substituted 5-O-tosyl-d-glucose dibenzyl dithioacetals gave derivatives of either 2,5-anhydro-l-idose dibenzyl dithioacetal, benzyl 1,5-dithio-l-idopyranoside, or l-idose dibenzyl dithioacetal. Likewise, 4-O-tosyl-d-glucose dibenzyl dithioacetal derivatives gave benzyl 1,4-dithio-d-galactofuranoside derivatives.     

Synthetic Approaches to a Mononucleotide Prodrug of Cytarabine

Synthetic pathways to a mononucleotide prodrug of cytarabine (Ara-C) bearing S-pivaloyl-2-thioethyl (tBuSATE) groups, as biolabile phosphate protections, are reported. Using a common phosphoramidite approach, two different kinds of nucleoside protecting groups have been investigated. During this study, we observed an intermolecular migration of the Boc protecting group in the course of the tert-butyldimethylsilyl ether cleavage using tetrabutyl ammonium fluoride.     

Use of t-butyldimethylsilyl cyanoacetate for preparation of α-cyano ketones

The synthesis of t-butyldimethylsilyl cyanoacetate and the reactions of its anion with acyl donors are described. The reagent was found to be the method of choice for the syntheses of α-cyano ketone substrate analogues for carboxypeptidase A. These compounds have been shown to be potent mechanism-based inactivators for the enzyme.     

Nucleosides and Nucleotides. 192. Toward the Total Synthesis of Cyclic ADP-Carbocyclic-Ribose. Formation of the Intramolecular Pyrophosphate Linkage by a Conformation-Restriction Strategy in a Syn-form Using a Halogen Substitution at the 8-Position of the Adenine Ring

Abstract

The synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was investigated. Construction of the 18-membered backbone structure was successfully achieved by condensation of the two phosphate groups of 19, possibly due to restriction of the conformation of the substrate in a syn-form using an 8-chloro substituent at the adenine moiety. SN2 reactions between an optically active carbocyclic unit 8, which was constructed by a previously developed method, and 8-bromo-N ⁶-trichloroacetyl-2′,3′-O-isopropylideneadenosine 9c gave N-1-carbocyclic derivative, which was deprotected to give 5′,5′-diol derivatives 18. When 18 was treated with POCl₃ in PO(OEt)₃, the bromo group at the 8-position was replaced to give N-1-carbocyclic-8-chloroadenosine 5′,5′-diphosphate derivative 19 in 43% yield. Treatment of 19 with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride gave the desired intramolecular condensation product 20 in 10% yield. This is the first chemical construction of the 18-membered backbone structure containing an intramolecular pyrophosphate linkage of a cADPR-related compound with an adenine base.     

Convenient Synthesis of 2′-Deoxy-2-fluoroadenosine from 2-Fluoroadenine

Abstract

A convenient synthesis of 2′-deoxy-2-fluoroadenosine from commercially available 2-fluoroadenine is described. The coupling reaction of silylated 2-fluoroadenine with phenyl 3,5-bis[O-(t-butyldimethylsilyl)]-2-deoxy-1-thio-D-erythro-pentofuranoside gave the corresponding 2-fluoro-2′-deoxyadenosine derivative (α/β =1:1) in good yield. The α- and β-anomers were separated by chromatography, and then desilylated to give compounds 1a and 1b.     

Crystal state conformation of three model monomer units for the β-bend ribbon structure

The molecular and crystal structures of three compounds, representing the repeating units of the β-bend ribbon (an approximate 3₁₀-helix, with an intramolecular hydrogen-bonding donor every two residues), have been determined by x-ray diffraction. They are Boc-Aib-Hib-NHBzl, Z-Aib-Hib-NHBzl, and Z-L -Hyp-Aib-NHMe (Aib, α-aminoisobutyric acid; Bzl, benzyl; Boc, t-butyloxycarbonyl; Hyp, hydroxyproline Hib, α-hydroxyisobutyric acid; Z, benzyloxycarbonyl). The two former compounds are folded in a β-bend conformation: type III (III′) for Boc-Aib-Hib-NHBzl, while type II (II′) for the Z analogue. Conversely, the structure of Z-L -Hyp-Aib-NHMe, although not far from a type II β-bend, is partially open.     

Self-association of N-protected α-amino acids. Optically active and racemic N-tert-butyloxycarbonyl-alanine

The ir absorption and x-ray diffraction analysis of N-tert-butyloxycarbonyl-DL -alanine (t-Boc-DL -Ala-OH) in the solid state has revealed a new mode of self-association for a N-urethanyl-α-amino acid, i.e., ribbons of hydrogen-bonded cyclic dimers formed through the —COOH groups. In contrast to the recemate, a water molecule, incorporated into the crystal of the chiral t-Boc-D -Ala-OH, alters in part that hydrogen-bonding scheme. In the two independent molecules of the unit cell of the optically active alanine derivative, as in that of the racemic derivative: (i) the conformation of the —CONH group is trans, also a new observation for a N-urethanyl-α-amino acid, and (ii) the overall conformation is quasi-extended. These findings exclude the occurrence of an oxy-C₇ peptide conformation. In solvents of high polarity, strongly solvated species predominate, as shown by ir absorption spectroscopy. In deuterochloroform nonassociated and associated species occur simultaneously. No differences were observed between the optically active and racemic derivatives. The type of self-association near saturation seems to differ, at least in part, from that found in the anhydrous racemic compound in the crystal state.     

Inversion of 310-helix screw sense in a (D-αMe)Leu homotetrapeptide induced by a guest D-(αMe)val residue

The terminally blocked tetrapeptide pBrBz-[D -(αMe)Leu]₂-D -(αMe)Val-D -(αMe)Leu-OtBu is folded in the crystal state in a left-handed 3₁₀-helical structure stabilized by two consecutive 1 ← 4 C?O ?H? N intramolecular H-bonds, as determined by X-ray diffraction analysis. A CD study strongly supports the view that this conformation is also that largely prevailing in MeOH solution. A comparison with the published conformation of pBrBz-[D -(αMe)Leu]₄-OtBu indicates that incorporation of a single internal β-branched (αMe)Val guest residue into the host homo-tetrapeptide from the γ-branched (αMe)Leu residue is responsible for a dramatic structural perturbation, i.e. an inversion of the 3₁₀ screw sense from right to left-handed.     

The impact of β‐azido(or 1‐piperidinyl)methylamino acids in position 2 or 3 on biological activity and conformation of dermorphin analogues

The synthesis of new dermorphin analogues is described. The (R)‐alanine or phenylalanine residues of natural dermorphin were substituted by the corresponding α‐methyl‐β‐azidoalanine or α‐benzyl‐β‐azido(1‐piperidinyl)alanine residues. The potency and selectivity of the new analogues were evaluated by a competitive receptor binding assay in rat brain using [³H]DAMGO (a μ ligand) and [³H]DELT (a δ ligand). The most active analogue in this series, Tyr‐(R)‐Ala‐(R)‐α‐benzyl‐β‐azidoAla‐Gly‐Tyr‐Pro‐Ser‐NH₂ and its epimer were analysed by ¹H and ¹³C NMR spectroscopy and restrained molecular dynamics simulations. The dominant conformation of the investigated peptides depended on the absolute configuration around C^α in the α‐benzyl‐β‐azidoAla residue in position 3. The (R) configuration led to the formation of a type I β‐turn, whilst switching to the (S) configuration gave rise to an inverse β‐turn of type I′, followed by the formation of a very short β‐sheet. The selectivity of Tyr‐(R)‐Ala‐(R) and (S)‐α‐benzyl‐β‐azidoAla‐Gly‐Tyr‐Pro‐Ser‐NH₂ was shown to be very similar; nevertheless, the two analogues exhibited different conformational preferences. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.     

Binding of alcohols to the peptide CO group of poly-L-proline in the I and II conformation. II. Binding constants from infrared measurements in solution

Trifluoroethanol, benzyl alcohol, and n-butanol bind to the peptide and acelyl CO groups of poly-O-acetyl-L -hydroxyproline in dichloromethane via hydrogen bonds. The binding aflinity decreases from trifhioroelhanol to n-buitanol. For the acelyl CO groups the binding does not depend on the conformation of the polymer but for the peptide CO groups the binding constants are larger by a factor of two to five time when it is in the helix II conformation (all peptide bonds trans) than when it assumes the helix I conformation (all peptide bonds cis). This preference is explained by the higher accessibility of the peptide CO groups in the II helix. The small additional energy which results from the preferential binding is sufficient, to induce a complete I → II transition because of the very high cooperativily of the system. The quantitative dependence of the equilibrium constant s for the propagation step of the transition on solvent composition (ratio of trifluoroethanol or benzyl alcohol to n-butanol) is derived from the binding data. It agrees satisfactorily with the empirical relation obtained from a best fit to transition curves of Ganseret al. The I ? II conversion of poly-L -proline is therefore an example of a conformational transition whose solvent dependence can be explained by a binding mechanism.     

Conformational studies of peptides: Crystal and molecular structures of L-3,4-dehydroproline and its t-butoxycarbonyl and acetyl amide derivatives

The crystal structures of L -3,4-dehydroproline, t-butoxycarbonyl-L -3,4-dehydroproline amide, and acetyl-L -3,4-dehydroproline amide have been determined. L -3,4-Dehydroproline is orthorhombic with a = 16.756, b = 5.870, c = 5.275 Å, and Z = 4; t-butoxycarbonyl-L -3,4-dehydroproline amide is orthorhombic with a = 6.448, b = 8.602, c = 21.710 Å, and Z = 4; acetyl-L -3,4-dehydroproline amide is monoclinic with a = 4.788, b = 10.880, c = 7.785 Å, β = 105.25°, and Z = 2. The final R value for the L -3,4-dehydroproline is 0.046 based on 529 reflections; for t-butoxycarbonyl-L -3,4-dehydroproline amide, 0.050 based on 792 reflections; and for acetyl-L -3,4-dehydroproline amide, 0.058 based on 632 reflections. The structures clearly establish that the free amino acid exists in the zwitterionic form in the crystalline state. The molecular conformations of the t-Boc and acetyl derivatives consist of two planes: one involving the primary amide and the other the remaining atoms of the molecule. The acetyl-L -3,4-dehydroproline amide contains a tertiary amide bond in the cis conformation. To the best of our knowledge, this is the first example of a cis bond in an acetyl derivative of an amino acid or peptide. At variance with the previously reported proline amides, which present ? and ψ values corresponding to those of a right-handed α-helical conformation (conformation A), the t-Boc and acetyl derivatives both have ? and ψ values corresponding to a collagenlike conformation (conformation F).     

Application of negative-ion chemical ionization isotope dilution gas chromatography—mass spectrometry to single-dose bioavailability studies of mefloquine

An electron-capture negative-ion chemical ionization gas chromatographic—mass spectrometric assay for mefloquine, an antimalarial drug used in the treatment of drug-resistant Plasmodium falciparum malaria, is described. The method, developed in support of bioavailability studies involving the co-administration of different tableted formulations of the drug and an aqueous solution of its ¹³C₃-labeled analog, enables quantification of both dosage forms. Quantitative analysis of extracted plasma samples was performed on the O-tert.-butyldimethylsilyl (t-BDMS) derivative of the drug by selected-ion monitoring, using a VG Trio 2000 quadrupole mass spectrometer and monitoring the [M — t-BDMSOH]^−√ ions of the analytes. The method, incorporating [²H₆]mefloquine as an internal standard, demonstrated good accuracy and precision over the 1–200 ng ml⁻¹ range, with correlation coefficients greater than 0.990 for all standard curves and a detection level of 50 fg on-column. Replicate analysis of plasma samples over a 90-day period exhibited a mean intra-day and inter-day variation of less than 4.5% and 5.5%, respectively. The high stability and sensitivity of the assay, combined with the inherent selectivity of mass spectrometric detection, make the method well-suited for such studies.     

Protecting Groups Transfer: Unusual Method of Removal of Tr and Tbdms Groups by Transetherification

The triphenylmethyl (Tr) group undergoes a transfer (transetherification or disproportionation) between the molecules of 5′-O-Tr-2′-deoxynucleosides in a process mediated by anhydrous sulfates of Cu⁺², Fe⁺², or Ni⁺² to yield mixtures of 3′,5′-bis-O-Tr and 3′-O-Tr products. If phenylmethanol is present in a reaction medium, detritylation results with concomitant formation of phenylmethyl triphenylmethyl ether. The behavior of t-butyldimethylsilyl (TBDMS) group in 5′-O-TBDMS-2′-deoxynucleosides is exactly the same. Such type of transetherifications was not observed before for the O-Tr and O-TBDMS groups.     

Determination of ergosterol in organic dust by gas chromatography-mass spectrometry

A gas chromatographic-mass spectrometric method was developed for the determination of ergosterol in organic dust. Samples were hydrolyzed under alkaline conditions, and the hydrolysate was extracted, purified on a silica-gel column, and subjected to derivatization. The limit of detection of the trimethylsilyl ether derivative of ergosterol was approximately 10 pg and that of the tert.-butyldimethylsilyl ether derivative was approximately 20 pg (injected amounts). House dust contained 6–45 μg ergosterol/g and iar from a pig barn contained 0.2–0.3 ng ergosterol/ liter. The proposed method can be used as a complement or alternative to microscopy and culturing for measuring fungal biomass in air-borne organic dust.     

Defect peptide chemistry: Perturbations in the structure of a homopentapeptide induced by a guest residue interrupting side-chain regularity

The fully blocked pentapeptide Tfa-(Deg)₂-L -Abu-(Deg)₂-OtBu (Tfa:triflouroacetyl; Deg: C^α,α-diethylglycine; OtBu: tert-butoxy) adopts in the crystal state a regular, right-handed 3₁₀-helical structure stabilized by three N ? H …? O ? C intramolecular 1 ← 4 (or C₁₀) H bonds, as determined by an x-ray diffraction analysis. However, a Fourier transform ir absorption and ¹H-nmr study strongly supports the view that in deuterochloroform solution the four Deg residues at both termini of the peptide main chain are involved in successive, fully extended C₅ forms. A comparison with the stable, fully developed, multiple C₅ conformation of Tfa-(Deg)₅-OtBu indicates that incorporation of an Abu guest residue, interrupting the side-chain uniformity of the host (Deg)₅ homopeptide, while altering only marginally the conformation in a solvent of low polarity, is responsible for a dramatic perturbation of the crystal-state structure. © 1994 John Wiley & Sons, Inc.     

A Simple and Regioselective Synthesis of 13C-Methyl-Labeled Thymedine

Abstract

A convenient and efficient procedure for the synthesis of ¹³C methyl-labeled thymidine by way of lithiation of t-butyldimethylsilyl protected 2′-deoxyuridine is described.     

Synthesis of a 2-acetamido-5-amino-2,5-dideoxy- -xylopyranosyl derivative

2-Acetamido-5-amino-2,5-dideoxy- -xylopyranosyl hydrogensulfite (11) has been synthesized from benzyl 2-(benzyloxycarbonylamino)-2-deoxy-5,6-O-isopro-pylidene-β- -glucofuranoside (1). O-Deisopropylidenation of 1 gave the triol 2, which was converted, via oxidative cleavage at C-5-C-6 and subsequent reduction, into the related benzyl β- -xylofuranoside derivative (3). Catalytic reduction of benzyl 2-(benzyloxycarbonylamino)-2-deoxy-5-O-tosyl-β- -xylofuranoside, derived from 3 by selective tosylation, and subsequent N-acetylation, afforded benzyl 2-acetamido-2-deoxy-5-O-tosyl-β- -xylofuranoside, which was treated with sodium azide to give the corresponding 5-azido derivative (6). (Tetrahydropyran-2-yl)ation of the product formed by hydrolysis of 6 gave 2-acetamido-5-azido-2,5-dideoxy-1,3- di-O-(tetrahydropyran-2-yl)- -xylofuranose (9). Treatment of 2-acetamido-5-amino-2,5-dideoxy-1,3-di-O-(tetrahydropyran-2-yl)- -xylofuranose, derived from 9 by reduction, with sulfur dioxide in water gave 11. Hydrogenation of 6 and subsequent acetylation yielded 3-acetamido-4,5-diacetoxy-1-acetyl-xylo-piperidine. Evidence in support of the structures assigned to the new derivatives is presented.     

Synthesis of 1,5-Anhydro-D-Mannitol Nucleosides with a Purine Base Moeety

Abstract

D-Mannitol nucleosides with a purine base moiety have been conveniently synthesized strating from 1,5-anhydro-4,6-O-benzylidene-D-glucitol. The 3-OH function of 1,5-anhydro-4,6-O-benzylidene-D-glucitol was selectively protected with t-butyldimethylsilyl group and subsequently converted to the corresponding 0-triflate derivative for the introduction of the nucleobase moietes. These nucleoside derivatives were transformed to 1,5-Anhydro-6-O-MMTr-2-(N⁶-benzoyladenin-9-yl)-2-deoxy-3-O-TBDMS-D-mannitol and 1,5-Anhydro-6-O-MMTr-2-(N²-isobutyryl-guanin-9-yl)-2-deoxy-3-O-TBDMS-D-mannitol, useful as the building blocks for oligonucleotide synthesis. Also, the synthesis of the corresponding fully deprotected anhydrohexitol nucleosides were achieved for evaluation of antiviral activity test.     

Glycosylation reactions — present status future directions

A short review of the present status of glycosylation reactions is presented. The reactivity of both proven and newer glycosylation methods are briefly discussed. Emphasis is placed on the control of stereochemistry and regiochemistry. As well, the identification and avoidance of side reactions is covered. Polymer-supported synthesis of oligosaccharides is noted as a promising direction for eliminating some of the problems associated with purification. It is suggested that a better understanding of the mechanism of glycosylation reactions is necessary for future improvements to stereoselectivity and regioselectivity. A key advance would be methods for enhancing the reactivity of weakly nucleophilic hydroxyls.Abbreviations BF₃ OEt₂ boron trifluoride diethyl ether complex - TMSOTf trimethylsilyl trifluorometh-anesulfonate - NIS NBS N-iodosuccinimide andN-bromosuccinimide - TfOH trifluoromethanesulfonic acid or triflic acid - AgOTf CuOTf₂ silver triflate and copper(II)triflate - Tf₂O triflic anhydride - IDCP iodonium dicollidine perchlorate - TEP triethyl phosphite - HfCp₂Cl₂ hafnium dicyclopentadienyl dichloride - Ac acetyl - Bz benzoyl - Bn benzyl - Ph phenyl - Me methyl - Et ethyl - Bu₄NOTf tetrabutylammonium triflate - Ph₂IOTf diphenyliodinium triflate - PhSeNPhth N-(phenylseleno)phthalimide - Pent 4-pentenyl - TCI trichloroactemidyl - TBDPS t-butyl diphenylsilyl - DTBP 2,6-di-t-butylpyridine - Tr trityl or triphenylmethyl Dedicated to Professor J.J. Krepinsky on the occasion of his 60th birthday