Extended applications and potential limitations of ring-fused 2,3-oxazolidinone thioglycosides in glycoconjugate synthesis

The utility of ring-fused 2,3-oxazolidinone derivatives of 2-amino-2-deoxy-thioglycosides in the synthesis of glycopeptide intermediates and building blocks for the synthesis of heparan sulfate oligosaccharides is reported. These unique ring-fused monosaccharides afford a novel and efficient route to alpha-O-linked 2-amino-2-deoxy amino acid derivatives and heparan sulfate oligosaccharide intermediates.     

Hofmann rearrangement of primary carboxamides and cyclic imides using DCDMH and application to the synthesis of gabapentin and its potential peptide prodrugs

Two protocols for the efficient transformation of aromatic as well as aliphatic primary carboxamides to the corresponding carbamates and aromatic as well as aliphatic cyclic imides to the corresponding anthranilic acid derivatives & amino acid derivatives, respectively, are described. We also developed a novel methodology to the multigram scale synthesis of gabapentin and (S)-pregabalin. The gabapentin methyl carbamate was converted to novel potential peptide prodrugs of gabapentin.     

Novel ester linked glycosyl amino acids: convenient building blocks for the synthesis of glycopeptide libraries

The completely orthogonally protected aspartic acid derivative FmocAsp(OBn)O^tBu is readily synthesized on a large scale. Deprotection of the β-carboxylic acid allows coupling to various sugar derivatives via free hydroxyl groups to produce novel glycosyl amino acids. Subsequent deprotection of either the α-acid or nitrogen is achieved cleanly to allow elaboration into an oligopeptide, whilst selective deprotection of PMB protected sugar hydroxyls is also readily achievable. Such novel glycosyl amino acid building blocks may be useful for the combinatorial synthesis of novel glycopeptide libraries.     

The concept of internal solubilization in peptide synthesis: ethylene glycol-based protecting groups

A novel, ethylene glycol-based protecting group is designed and synthesized for use in solid phase peptide synthesis. Ether and ester type protected amino acids are prepared. The acid stability of the new protecting group showed complete Fmoc/t-Bu compatibility. The new derivatives are tested in solid phase peptide synthesis, with a ‘difficult’ sequence to examine the disruption of peptide aggregation.     

A novel one-pot pseudo-four-component isocyanide-based reaction: an unexpected approach for the synthesis of tetrahydrodiisoindoloquinoxalines and tetrahydrobenzodiisoindoloquinoxalines

A novel isocyanide based one-pot pseudo-four-component strategy for the synthesis of tetrahydrodiisoindoloquinoxaline and tetrahydrobenzodiisoindoloquinoxaline derivatives via the reaction of 1,2-diamines, 2-formylbenzoic acid, and an isocyanide at room temperature in good yields without using any catalyst and activation, is described.     

Syntheses of spiro[cyclopropane-1,3′-oxindole]-2-carboxylic acid and cyclopropa[c]quinoline-7b-carboxylic acid and their derivatives

The synthesis of spiro[cyclopropane-1,3′-oxindole]-2-carboxylic acid, including novel 3-(2- and 3-pyridyl)-substituted analogues and the novel cyclopropa[c]quinoline-7b-carboxylic acid and their ester and amide derivatives is described. These syntheses involve diastereoselective cyclopropanation reactions of methyl 2-(2-nitrophenyl)acrylate and (3E)-(pyridin-2-ylmethylene)- and (3E)-(pyridin-3-ylmethylene)-1,3-dihydro-2H-indol-2-one with ethyl (dimethyl sulfuranylidene) acetate (EDSA). The synthesis of methyl cyclopropa[c]quinoline-7b-carboxylate involves a regioselective reductive cyclization of a nitro-diester precursor. The relative stereochemistry of key compounds has been determined by single-crystal X-ray structural analysis.     

Synthetic studies of decursivine derivatives: preparation of key indole alkaloids via α-hydroxyalkylation

2-Hydroxyacetyl indole modified at C-3 position was prepared with an eye to developing a total synthesis of decursivine derivatives (decursivine, serotobenine, moschaminindolol, and flavumindole). The indole was prepared through a sequence of oxalyl chloride introduction at C-3 position of indole and acid chloride reduction with tributyltin hydride. In addition, we report a novel synthesis of fully functionalized Uhle's ketone via ortho-selective α-hydroxyalkylation.     

Novel stereoselective synthesis of 2,3-dihydro-1H-benzo[f]chromen-3-amine derivatives through a one-pot three-component reaction

A short and stereoselective novel synthesis of benzo[f]chromen-3-amine derivatives in good yields, through a three-component aromatic Betti type reaction under solvent free conditions is reported. The spontaneous reaction occurs in the absence of acid catalysts. The use of chiral 1-phenylethylamine or α,β-unsaturated aldehydes allowed us to prepare enantiopure benzo[f]chromen-3-amine derivatives with good stereoselectivity. Conformational analysis compared with the ¹H NMR data of the products obtained, allowed us to the determine the absolute configuration, which was also confirmed by X-ray analysis.     

A four-component, one-pot synthesis of highly substituted 1,4-dihydro-1,8-naphthyridine-3-carboxamides

A new, one-pot, four-component reaction for the synthesis of a novel class of highly substituted 1,4-dihydro-1,8-naphthyridine-3-carboxamide derivatives starting from readily available inputs including aliphatic or aromatic amines, diketene, aromatic aldehydes, and 2-aminopyridines in the presence of a catalytic amount of p-toluenesulfonic acid under mild reaction conditions and in good yields at ambient temperature is described.     

Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes. Part VI: Synthesis and incorporation of the novel polyhydroxylated 5-aminocyclopent-1-enecarboxylic acids into peptides

The first total synthesis of enantiopure methyl (3aR,4S,5S,6R,6aS)-4-benzyloxycarbonylamino-6-hydroxy-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxole-5-carboxylate has been carried out according to our recent novel strategy for the transformation of nitrohexofuranoses into cyclopentylamines. This approach is based on an intramolecular cyclization that leads to 2-oxabicyclo[2.2.1]heptane derivatives. E1cb elimination of the methoxy substituent was observed when attempting to incorporate these β-amino acid into peptides. As a result, the synthesis and incorporation of the first polyhydroxylated 5-aminocyclopent-1-enecarboxylic acid into peptides were developed.     

A novel type of acyclic nucleoside phosphonates derived from 2-(phosphonomethoxy)propanoic acid

A convenient and efficient synthesis of a novel class of acyclic nucleoside phosphonates derived from 2-(phosphonomethoxy)propanoic acid has been developed. The key step of the synthesis is the optimized oxidation of the 3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) analogues to the corresponding 2′-carboxy-PME (CPME) derivatives using the TEMPO/NaClO₂/NaClO oxidizing system. Although (S)-3-(adenin-9-yl)-2-(phosphonomethoxy)propanoic acid ((S)-CPMEA) has been designed as a compound with potential anti-HIV activity, none of the newly prepared CPME analogues exhibited any antiviral activity.     

Polymeric catalyst for the synthesis of new pyrido[2,3-b]indoles

A new and efficient method has been developed for the one-pot synthesis of novel 2,9-dihydro-2-oxo-4-aryl-1H-pyrido[2,3-b]indole-3-carbonitrile derivatives by condensation of substituted (triethoxymethyl)arene, 1-methyl-1H-indol-2-ol and cyanoacetamide in the presence of a catalytic amount of crosslinked poly(2-acrylamido-2-methyl propane sulfonic acid) (AMPS) as an efficient and heterogeneous catalyst. This polymeric solid acid catalyst is stable and can be easily recovered and reused without significant change in its activity.     

Synthesis of racemic and enantiomeric 3-pyrrolidinyl derivatives of nucleobases

The synthesis of novel 3-pyrrolidinyl derivatives of nucleobases is described. Starting from malic acid, we improved the synthesis of both racemic and optically active N-benzyl-3-hydroxypyrrolidine-2,5-diones, which were transformed in four steps into N-tert-butyloxycarbonyl-3-mesyloxypyrrolidines, the key synthons for the alkylation of purine and pyrimidine nucleobases. Alkylations of cesium salts of purines and sodium salts of pyrimidines with N-tert-butyloxycarbonyl-3-mesyloxypyrrolidines proceeded smoothly, giving high yields of 9-substituted purine derivatives and moderate yields of 1-substituted pyrimidine derivatives. Using (S)-N-tert-butyloxycarbonyl-3-mesyloxypyrrolidine as the same intermediate for the synthesis of both enantiomeric N-Boc-3-pyrrolidinyladenines, and considering the results obtained on chiral HPLC analysis of the products, we proved that nucleophilic displacement of the mesyloxy group proceeded with inversion and not with retention of the configuration. Prepared compounds were tested for cytostatic and antiviral properties, but no significant activity was found.     

Design and synthesis of new carbohydrate-lithocholic acid conjugates linked via 1,2,3-triazole rings

In this work, we report the synthesis of a novel carbohydrate-lithocholic acid conjugate linked through of 1,2,3-triazole rings and its derivatives in good to excellent yields. The conjugate was synthesized via copper-catalyzed azide?alkyne cycloaddition (CuAAC) from methyl 4,6-O-benzylidene-2,3-di-O-propargyl-α-d-glucopyranoside and methyl 3-azidolithocholate. The structures of all new compounds were properly characterized by infrared (IR), high-resolution mass spectroscopy (HRMS) and one- and two-dimensional nuclear magnetic resonance (NMR).     

Synthesis and NMR elucidation of novel amino acid cavitand derivatives

The synthesis of seven novel protected amino acid cavitands is reported. All have four pendant n-undecyl chains and ‘headgroups’ connected by a two-carbon spacer at four positions on the aromatic rings. The amino acids employed are glycine, alanine, phenylalanine, leucine, proline, tryptophan, serine, glutamine and lysine. The structures of the compounds were elucidated using one- and two-dimensional NMR techniques, which verified that all tetra-substituted cavitands have symmetrical C_4v conformation. This is the first example of a complete study for amino acid cavitand derivatives.     

An efficient synthesis of 5-aminolaevulinic acid (ALA)-containing peptides for use in photodynamic therapy

An efficient and cost-effective procedure has been devised for the preparation of urethane-protected 5-aminolaevulinic acid (5-ALA) dipeptide ester derivatives which avoids problems associated with the instability of 5-ALA under basic conditions. The procedure is also applicable to the direct synthesis of N-(α)-acetyl amino acid-ALA dipeptides in high enantiomeric purity as potential novel prodrugs for photodynamic therapy (PDT).     

Use of nanoporous Na+-montmorillonite sulfonic acid (SANM) as an eco-benign, efficient and reusable solid acid catalyst for the one-pot synthesis of 14-aryl-14-H-dibenzo[a,j]xanthenes and 1,8-dioxo-dodecahydroxanthene derivatives

Nanoporous Na⁺-montmorillonite sulfonic acid was found to be an efficient and green catalyst for the synthesis of various 14-aryl-14H-dibenzo[a,j]xanthenes and 1,8-dioxo-dodecahydroxanthene derivatives by the reaction of aldehydes with 2-naphthol and 1,3-cyclohexanedione, respectively. This novel synthetic method has the advantages of high yields, short reaction times and recyclability of the catalyst, simplicity and easy workup compared to the conventional methods reported in the literature.     

The study of the interaction between chitosan and 2,2-bis(hydroxymethyl)propionic acid during solid-phase synthesis

New polymer salts and N-acetylated chitosan derivatives are prepared in an extruder by the method of solid-phase synthesis via the interaction of chitosan and 2,2-bis(hydroxymethyl)propionic acid. The effect of the initial component ratio and temperature on the yield and structure of the target products is studied. Joint deformation of solid components at room temperature is found to cause the quantitative formation of salt bonds between carboxylic groups of the acid and amino groups of chitosan. At elevated temperatures of synthesis, the corresponding acetylated derivatives with a degree of substitution of amino groups varying from 0.16 to 0.43 are prepared. The relaxation and phase transitions in the polymer salts and acetylated chitosan derivatives and their sorptional activity are studied. The films prepared from aqueous solutions of the new salt modification of chitosan are characterized by a homogeneous structure and improved mechanical characteristics relative to those of the films based on chitosan acetates. An additional thermal treatment of the products of the solid-phase synthesis leads to the formation of crosslinked and water-swollen materials that can be used for the development of novel polymeric chitosan-based membranes and sorbents.     

A new bicyclic proline-mimetic amino acid

A new constrained bicyclic α-amino acid proline-mimetic was developed. The synthesis was achieved starting from derivatives of the chiral pool, thus allowing to prepare analogues of either l- or d-proline by choosing appropriate stereoisomers of serine and α,β-isopropylidene-glycerol derivatives. The scaffolds were prepared as N-Fmoc-amino acid suitable for solid-phase peptide synthesis.     

Synthesis of new 3,3-dimethoxyazetidine-2-carboxylic acid derivatives

Cyclization of γ-amino-α-bromocarboxylic esters resulted in an efficient synthesis of new 3,3-dimethoxyazetidine-2-carboxylates, that is, methyl N-t-butyl-3,3-dimethoxyazetidine-2-carboxylic ester and 3,3-dimethoxyazetidine-2-carboxylic acid, or 3-bromo-4,4-dimethoxypyrrolidin-2-ones, depending on the substituent at nitrogen. Reduction of the 3,3-dimethoxyazetidine-2-carboxylates gave the corresponding 3,3-dimethoxy-2-(hydroxymethyl)azetidines. These novel cyclic amino acid derivatives, available on multigram scale, have a suitably protected carbonyl function at the 3-position, which enables further functionalization.