Propargyloxycarbonyl as a protecting group for the side chains of serine, threonine and tyrosine

Propargyloxycarbonyl group is used as a protecting group for the hydroxyl groups of serine, threonine and tyrosine. The propargyloxycarbonyl derivatives of these hydroxy amino acids are stable to acidic and basic reagents commonly employed in peptide synthesis. The deprotection of the O-Poc derivatives using tetrathiomolybdate does not affect commonly used protecting groups such as N-Boc, N-Cbz, N-Fmoc, methyl and benzyl esters. The di-and tripeptides synthesized using O-Poc derivatives of serine, threonine and tyrosine are stable, isolable compounds and give the hydroxy peptides in good yields when treated with tetrathiomolybdate.     

Solid-phase synthesis of O-sulfated glycopeptide by the benzyl-protected glycan strategy

To expand the repertoire of our benzyl-protection strategy for solid-phase glycopeptide synthesis, an O-sulfated glycopeptide was chosen as the synthetic target. Trisaccharyl serine derivatives (Galβ1-4-GlcNAcβ1-2-Manα1-3-Ser) carrying (4-methoxyphenyl)methyl (MPM) groups at either 3-O or 6-O of the Gal residue were prepared through three stereoselective glycosylations. Cleavage of MPM followed by reaction with Me₃N·SO₃ efficiently afforded 3-O- and 6-O-sulfo-glycoserines, respectively. A preliminary debenzylation study using the sulfated glycoserines revealed that the sulfate groups persisted under ‘low-acidity TfOH’ conditions, when using a limited amount of TfOH and extending the reaction period. The 3-O-sulfo-glycoserine was then introduced into an icosapeptide modeled after an α-dystroglycan fragment by a combination of automated and manual solid-phase peptide synthesis procedures. The synthesized glycopeptide was successfully debenzylated by the low-acidity TfOH cocktail with slight damage to the sulfate functionality.     

A stereocontrolled construction of 2-azido-2-deoxy-1,2-cis-α-galactosidic linkages utilizing 2-azido-4,6-O-benzylidene-2-deoxygalactopyranosyl diphenyl phosphates: stereoselective synthesis of mucin core 5 and core 7 structures

TMSOTf-promoted glycosidation of 2-azido-4,6-O-benzylidene-2-deoxygalactosyl diphenyl phosphates with fluorenylmethoxycarbonyl (Fmoc)-protected serine and threonine derivatives in THF/Et₂O (1:1) gave glycosyl amino acids in high yields and with excellent levels of α-selectivity (α/β=94:6–95:5). The synthetic utility of the present glycosidation method was demonstrated by a stereoselective synthesis of mucin-type glycopeptide core 5 and core 7 building blocks, which are suitable for Fmoc-based solid-phase synthesis of O-glycopeptides.     

Sulfuric acid immobilized on silica: an efficient reusable catalyst for the synthesis of O-isopropylidene sugar derivatives

Sulfuric acid immobilized on silica proved to be an efficient catalyst for the synthesis of O-isopropylidene sugar derivatives from reducing sugars. The method is very simple and economic for large-scale synthesis in which the catalyst is recovered and reused several times. Reactions with d-glucose, d-galactose, d-mannose, l-rhamnose, l-arabinose, d-xylose and l-sorbose led to the formation of the corresponding thermodynamically stable di-O- and/or mono-O-isopropylidene derivatives in good to excellent yields.     

N-Benzyloxycarbonylation of amines in the ionic liquid [TPA][l-Pro] as an efficient reaction medium

An efficient method for the N-benzyloxycarbonylation of amines is described. The reaction of amines with Cbz-Cl in the ionic liquid [TPA][l-Pro] afforded the corresponding N-Cbz derivatives in excellent yields. The method is versatile for the preparation of a wide variety of N-Cbz derivatives of aliphatic and aromatic amines.     

Sulfuric acid immobilized on silica: an efficient reusable catalyst for selective hydrolysis of the terminal O-isopropylidene group of sugar derivatives

Sulfuric acid immobilized on silica proved to be an efficient catalyst for selective hydrolysis of the terminal O-isopropylidene group of sugar derivatives. The method is very simple and economic for large-scale synthesis in which the catalyst is recovered and reused for several runs. Reactions with di-O-isopropylidene derivatives of d-glucose, d-mannose, d-fructose and l-sorbose led to the formation of the corresponding mono-O-isopropylidene derivatives in good to excellent yields.     

Regioselective synthesis of O- and O-cyclopyrimidine nucleoside analogues

Regioselective synthesis of two new series of cyclonucleoside analogues from the 1,2-carbonucleoside of uracil 1a: O²,7′-cyclonucleosides (3a-c) and O⁶,7′-cyclonucleosides (4a-c), analogues of pyrimidine (cyclohexane derivatives) is reported. Synthesis of O²-cyclonucleoside analogues was performed by activation of the hydroxymethyl group of carbocyclic moiety and using the carbonyl group at position 2 of the heterocyclic base as a nucleophile. Synthesis of O⁶-cyclonucleoside analogues was achieved by nucleophilic attack of the 7′-hydroxyl group on the electron-deficient 6-position and subsequently dehydrohalogenation in basic conditions.     

Synthesis of cyclic peptides via O-N-acyl migration

We describe here a novel and convenient synthesis of head-to-tail cyclic peptide avoiding racemization. Linear depsipeptides including a serine residue as the key element for ester bond formation and acyl transfer were synthesized on 2-chlorotrityl chloride resin. After cleavage from the resin, intramolecular head-to-tail cyclization was performed in solution by C-terminal activation of urethane protected O-acyl serine residue. After removal of the N^α-serine protecting group, the final step consisted in O-N-acyl migration reaction on the ‘switch’ or ‘click’ element to restore native cyclic peptides.     

A high yielding, one-pot synthesis of O,S-dialkyl dithiocarbonates from alcohols using Mitsunobu’s reagent

A novel Mitsunobu-based protocol has been developed for the synthesis of O,S-dialkyl dithiocarbonates from a variety of primary, secondary and tertiary alcohols using carbon disulfide, in good to excellent yields. This protocol is mild and efficient compared to other reported methods.     

An unexpected migration of O-silyl group under Mitsunobu reaction conditions

A 1,4 O→O silyl migration followed by nucleophilic substitution with phthalimide was observed under Mitsunobu reaction conditions. This one step secondary alcohol protection and primary alcohol substitution with N-nucleophiles was extended to a variety of 2-hydroxyethyl trialkylsilylether derivatives. A possible mechanism has been postulated based on the pK_a values of the alcohol and nucleophile. The present one-pot silyl migration and substitution reaction might find application in the stereoselective synthesis of novel iminosugar derived anti diabetic agents.     

Radiation-induced destruction of hydroxyl-containing amino acids and dipeptides

The yields of molecular products resulting from radiolysis of hydroxyl-containing amino acids and dipeptides under various conditions were determined. The possibility of a new radiation-induced destruction pathway has been shown for serine and threonine, as well as for the dipeptides having residues of these amino acids at the N-terminal part of the respective molecule. This process includes formation of N-centered radicals from the starting molecules followed by their decomposition with elimination of side substituents. On radiolysis, serine and threonine were also shown to undergo free-radical destruction to form acetaldehyde and acetone, respectively. A mechanism has been proposed including consecutive stages of fragmentation of α-hydroxyl-containing carbon-centered radicals with elimination of ammonia and decomposition of the secondary radicals with elimination of CO₂. The yields of CO₂ obtained on radiolysis of serine and threonine were significantly higher (except for solutions at pH 12) than those for alanine and valine, which have no hydroxyl groups in their structures. The obtained data indicate that the hydroxyl-containing amino acids occupy a special place among other amino acids as regards the variety of radiation-induced reactions which they may undergo due to their structural features.     

Microwave-assisted,regioselective one-pot synthesis of quinolines and bis-quinolines catalyzed by Bi(III) immobilized on triazine dendrimer stabilized magnetic nanoparticles

Fe₃O₄-TDSN-Bi(III) was utilized as an efficient and reusable catalyst for the regioselective one-pot synthesis of quinoline derivatives from arylamines, arylaldehydes and methyl propiolate under microwave irradiation and solvent-free conditions. Also, bis-quinolines were obtained in high yields from dialdehydes or diamines. Atom-economy, high to excellent yields, easy work-up, as well as simple catalyst recovery and reusability are the key features of this procedure.     

9-BBN as a convenient protecting group in functionalisation of hydroxylysine

9-BBN was used for regioselective protection of the α-amino and α-carboxyl groups of (5R)-5-hydroxy-l-lysine. The resulting 9-BBN complex was then employed in transformations such as N-Cbz protection, azido transfer, O-glycosylation, and O-silylation. Further manipulations led to improved methods for preparation of hydroxylysine and galactosylated hydroxylysine building blocks, suitable for direct use in peptide synthesis under standard Fmoc conditions.     

A versatile radical based approach to O-alkylated hydroxylamines and oximes

O-Alkylhydroxylamines, often used for the preparation of bioconjugates, can be readily obtained by radical addition to suitable O-alkenylhydroxylamine derivatives. In the case of N-Boc-O-allylhydroxylamine, the addition is unexpectedly followed by elimination resulting in an overall allylation of the radical species.     

Preparation and reactivity of an O,O-chelating silsesquioxane-palladium complex

An incompletely condensed silsesquioxane containing trisilanol (c-C₅H₉)₇Si₇O₉(OH)₃ reacts with [PdI₂(bpy)] (bpy = 2,2′-bipyridine) in the presence of Ag₂O to produce a palladium complex with an O,O-chelating silsesquioxanate ligand, [Pd{O₁₁Si₇(c-C₅H₉)₇(OH)}(bpy)] (1). The reaction of Ph₂SiClH with 1 in 2:1 ratio causes disilylations of the silsesquioxanate ligand, forming [PdCl₂(bpy)]. Addition of p-cresol to a solution of 1 yields the trisilanol and [Pd(OC₆H₄CH₃-p)₂(bpy)].     

Unprecedented formation of stable ketene-N,O-acetals and their rearrangement under basic conditions

Treatment of 2,4-disubstituted glutaryl dichlorides with benzimidic acid ethyl ester hydrochloride in the presence of triethylamine did not give the expected bis(acylbenzimidates), but delivered O-acyl-N-ethoxybenzylidene-ketene-N,O-acetals in good to excellent yields. These compounds, which are stable to moisture and chromatography on silica gel, underwent an unprecedented rearrangement to cyclic enamides under stronger basic conditions. A mechanism for this rearrangement is proposed.     

A novel method for regioselective ring-opening reduction of 4,6-O-benzylidene hexopyranoside derivatives using CoCl2 and BH3·THF

A novel and facile reductive ring-opening reaction for 4,6-O-benzylidene acetal derivatives of hexopyranosides using CoCl₂/BH₃·THF gave the corresponding 4-O-benzyl-6-OH derivatives selectively in good yields. This convenient method should allow large-scale synthesis at low cost.     

First regioselective iodocyclization of O-allylselenocarbamates

4-Alkyl-2-imino-1,3-oxaselenolanes were prepared in good yields with high regioselectivity under mild conditions by the reaction of selenocarbamates with I₂ or NIS. The resulting 4-alkyl-2-imino-1,3-oxaselenolanes on dehydrohalogenation gave 4-alkylidene-2-imino-1,3-oxaselenolanes. The formation of the (Z)- or (E)-isomer of 4-alkylidene-2-imino-1,3-oxaselenolanes, strongly depends on the configuration of the double bond of O-allylselenocarbamates.     

Tandem Sulfonylation/Cyclization of Vinyl Azides with Aryldiazonium Tetrafluoroborates and SO2

An efficient and facile strategy for the synthesis of 6-(sulfonylmethyl)phenanthridines and its derivatives has been developed via tandem sulfonylation cyclization of vinyl azides under mild conditions in the absence of any catalysts and additives. The reaction simply utilizes easily accessible and cheap K₂S₂O₅ as the sulfur dioxide source, delivering functionalized phenanthridines in moderate to excellent yields with operational simplicity and gram-scale synthesis, as well as good functional-group tolerance.     

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.