Diels-Alder reactions of 3-(1H-tetrazol-5-yl)-nitrosoalkenes: synthesis of functionalized 5-(substituted)-1H-tetrazoles

A general route to 1,2-oxazines and open chain oximes bearing a 1H-tetrazolyl substituent via Diels-Alder reaction of 3-(tetrazol-5-yl)-nitrosoalkenes is reported. It was also demonstrated that reduction of these adducts followed by deprotection of the tetrazolyl group give 5-(1-aminoalkyl)-1H-tetrazoles, α-amino acid analogues.     

Fluoridolysis of 5,6-epoxy carbohydrates: application to the synthesis of 5-fluoro lactosamine and isolactosamine glycosides

The synthesis of 6-selenophenyl derivatives of β-1,3 and β-1,4 disaccharides has been explored for the purpose of extending our epoxide fluoridolysis methodology to the synthesis of 5-fluoro analogues of N-acetyl isolactosamine (isoLacNAc, lacto-N-biose) and N-acetyl lactosamine (LacNAc) glycosides. Successful synthesis of the C-6 selenium-containing disaccharides was achieved via Lewis acid-mediated donor and acceptor substrates, the latter containing a selectively protected C-6 hydroxyl group for ultimate conversion to the desired 6-selenophenyl disaccharides. In contrast, the use of selenium-containing acceptor substrates under a variety of conditions failed to yield the desired selenium-containing disaccharides. Oxidation of the 6-selenophenyl derivatives to the corresponding selenoxides followed by thermal elimination yielded the exocyclic olefins, which were converted to the 5,6-epoxides. Epoxide fluoridolysis yielded the desired target compounds, 5-fluoro β-octyl glycoside analogues of type 1 and type 2 glycans. The newly synthesized fluorine-containing disaccharides have potential application as fucosyltransferase substrates, both for mechanistic studies and in the chemoenzymatic synthesis of fluorine-containing oligosaccharides.     

(2S,5R/2R,5S)-Aminoethylpipecolyl aepip-aegPNA chimera: synthesis and duplex/triplex stability

This article reports the design and facile synthesis of novel chiral six-membered PNA analogues (2S,5R/2R,5S)-1-(N-Boc-aminoethyl)-5-(thymin-1-yl)pipecolic acid, aepipPNA IV that upon incorporation into standard aegPNA sequences effected stabilization of complexes with complementary target DNA. Substitution of aegPNA unit by the designed monomer at the C-terminus was more effective than substitution at N-terminus. The stabilizing behaviour improved with degree of substitution and was found to be dependent on their relative positions in the sequence. The six-membered piperidine ring in the design may freeze the rigid chair conformations and the relative stereochemistry of the substituents may in effect direct the complex formation with DNA/RNA by sequence-specific nucleobase recognition. In the present aepipPNA analogues, the l-trans stereochemical disposition of the substituents seems to lead to the favorable pre-organization of the PNA oligomers for complex formation with DNA. The results reported here further expand the repertoire of cyclic PNA analogues.     

3′-Amino-5′-carboxymethyl-3′,5′-dideoxy nucleosides for the synthesis of fully amide-linked RNA mimics

A convenient protocol is developed for the synthesis of 3′-[N-(fluorenylmethoxycarbonyl)-amino]-5′-carboxymethyl derivatives of all four natural ribonucleosides from cheap chiral pool compound glucose. Synthesis of fully amide-linked RNA analogues of small oligonucleotides containing, for the first time, all four nucleoside amino acids using standard solid phase Fmoc-chemistry is described.     

A catalyst free synthesis of 8, 9, 11-trihalo-5H-benzofuro[3,2-c]carbazol-10-ols

8, 9, 11-Trichloro-5H-benzofuro[3,2-c]carbazol-10-ol analogues have been synthesized by treating 2,3-dihydro-1H-carbazol-4(9H)-one with chloranil/fluoranil without any catalyst and is found to be applicable across a range of carbazolone substrates. A possible mechanism has been proposed.     

An asymmetric approach to 5-O-carbamoyl-2-epi-polyoxamic acid and the total synthesis of 2′′-epi-polyoxin J

A stereospecific synthetic approach to 5-O-carbamoyl-2-epi-polyoxamic acid has been developed. The asymmetric nucleophilic addition of 2-lithiofuran to a tert-butanesulfinyl imine was employed as the key step to construct the C-2 stereocenter and 2′′-epi-polyoxin J has been synthesized for the first time. Significantly, the synthesis provides a facile method for the large scale and stereoselective preparation of 5-O-carbamoyl-2-epi-polyoxamic acid and some related diastereoisomers of polyoxins and its analogues because of its simple operation, excellent yield, and high stereoselectivity. This will be convenient for research of the polyoxins’ structure–activity relationship and to search for more potent and effective anticandidal agents.     

5-Trihydroxypropyl-dihydrouracil derivatives as precursors of 1-azasugars: application to the stereoselective synthesis of d-galacto-isofagomine

A new route for the synthesis of isofagomine analogues has been carried out by using as precursors enantiopure 5-trihydroxypropyl-dihydrouracil derivatives obtained from aldol-type addition of 1,3-dibenzyl-dihydrouracil to isopropylidene-protected glyceraldehyde. The synthesis of d-galacto-isofagomine is reported.     

Stereoselective synthesis and moulting activity of 2,3-diepi-20-hydroxyecdysone and 2,3-diepi-5α-20-hydroxyecdysone

The ecdysteroid analogues 2,3-diepi-20-hydroxyecdysone and 2,3-diepi-5α-20-hydroxyecdysone have been synthesized from the readily available ecdysteroid, 20-hydroxyecdysone, and moulting activity has been determined using the Musca bioassay. As expected, the 2,3-diepi-analogue was less active than the parent ecdysteroid, 20-hydroxyecdysone. However, the 2,3-diepi-5α-analogue, which was expected to be inactive in the assay, exhibited moulting activity though it was approximately 1.5-fold less active than its 5β-analogue. The activity of the 5α-analogue could possibly result from the ability of this compound to bind to the ecdysteroid receptor. Alternatively, a possible in vivo C-5 epimerization of the 2,3-diepi-5α-analogue to the corresponding 5β-analogue could account for its activity.     

Synthesis of difluorinated carbocyclic analogues of 5-deoxypentofuranoses and 1-amino-5-deoxypentofuranoses: en route to fluorinated carbanucleosides

The synthesis of difluorinated carbocyclic analogues of 5-deoxypentofuranoses and 1-amino-5-deoxypentofuranoses is described. The sequence involves an addition of PhSeCF₂TMS to carbohydrate-derived aldehydes or their corresponding tert-butanesulfinylimines followed by a radical cyclization. Optimized conditions for the PhSeCF₂TMS addition to α-chiral aldehydes have been disclosed and its unusual diastereoselectivity is discussed. Application of the sequence using Ellman's auxiliary allows a more direct access to 1-aminopentose analogues with a complete control of the pseudo-anomeric center configuration.     

Microwave-assisted synthesis of N-glycolylneuraminic acid derivatives

A rapid, efficient and scalable synthesis of biologically-relevant N-glycolylneuraminic acid derivatives from the natural N-acetyl (Neu5Ac) precursors has been developed. Microwave irradiation provides accelerated de-N-acetylation compared to more traditional methods, with optimised NaOH-promoted de-N-acetylation in only 15 min. The prepared amines were readily re-N-acylated to afford the corresponding N-glycolyl (Neu5Gc) analogues.     

Chimeric peptide nucleic acids incorporating (2S,5R)-aminoethyl pipecolyl units: synthesis and DNA binding studies

The design and facile synthesis of a novel chiral six-membered PNA analogue (2S,5R )-1-(N-Boc-aminoethyl)-5-(thymin-1-yl)pipecolic acid, aepipPNA, that upon incorporation into PNA sequences effected stabilization of complexes with target complementary DNA. This is the first example where a six membered-PNA is shown to be capable of forming stable complexes with DNA and further expands the repertoire of cyclic PNA analogues.     

Investigation,optimization and synthesis of sulfamoyloxy-linked aminoacyl-AMP analogues

Aminoacyl-tRNA synthetases (aaRSs) constitute a family of enzymes that transfer amino acids to their corresponding tRNA molecules to form aminoacyl-tRNAs and have been validated as potential drug targets. Sulfamoyloxy-linked aminoacyl-AMP analogues are potent inhibitors of aaRSs. In this article, we report the synthesis of several new sulfamoyl analogues of aa-AMP that up to now have been difficult or even impossible to prepare with current synthetic strategies. The developed synthetic strategy relies on performing the synthesis under neutral conditions followed by global deprotection using catalytic hydrogenation affording the desired 5′-O-(N-aminoacyl)sulfamoyladenosine compounds.     

Regioselective synthesis of 5-trifluoromethyl-1,2,3-triazole nucleoside analogues via TBS-directed 1,3-dipolar cycloaddition reaction

Herein described was a straightforward method for the highly regioselective synthesis of 5-trifluoromethyl-1,2,3-triazole nucleoside analogues, which featured the utilization of tert-butyldimethylsilyl (TBDMS) group as the directing group in the 1,3-dipolar cycloaddition reactions. 4-tert-Butyldimethylsilyl-5-trifluoromethyl-1,2,3-triazole nucleoside analogues were generated as the only cycloaddition products in moderate yields (15-79%) via the treatment of glycosyl azides with 3,3,3-trifluoro-1-tert-butyldimethylsilylpropyne 1 in toluene at 85 °C. Removal of TBS groups in these triazole cycloadducts with tetrabutylammonium fluoride (TBAF) smoothly afforded the various 5-trifluoromethyl-1,5-disubstituted 1,2,3-triazole nucleoside analogues in good yields (40-88%).     

Pyrrolidine N-alkylphosphonates and related nucleotide analogues: synthesis and stereochemistry

N-Phosphonoalkyl-trans-3,4-dihydroxypyrrolidine derivatives were synthesized and exploited as synthons for the preparation of hydroxypyrrolidine nucleoside phosphonic acids, the 3′-deoxynucleoside 5′-phosphate analogues. Simultaneously, an alternative route, the N-phosphoalkylation of the preformed pyrrolidine nucleosides employing Mannich- and Michael-type reactions, was investigated to obtain desired nucleotide analogues. In contrast to the latter approach, the former resulted in the formation of two diastereoisomers very likely due to the existence of two possible S_N2 transition states during a nucleophilic displacement. The stereochemistry of the prepared nucleotide analogues was studied by NMR spectroscopy.     

Single- and double-chained truncated jaspine B analogues: asymmetric synthesis, biological evaluation and theoretical study of an unexpected 5-endo-dig process

An optimized synthesis of jaspine B analogues bearing an n-octyl or a p-fluorophenethyl lipophilic appendage was developed. Key to the approach was the use of acetylenic nucleophiles for the stereocontrolled introduction of the side chain and the implementation of a novel cyclization procedure to build the tetrahydrofuran ring. Three N-substituted amine or amide derivatives were also accessed. The biological activity of these four jaspine B analogues was shown to strongly depend on the nature of both the N-substituent and the aliphatic moiety connected to the tetrahydrofuran ring. Gratifyingly, the truncated jaspine B derivative proved to be a pro-apoptotic inhibitor of the conversion of ceramide into sphingomyelin. Finally, the efficient formation of a fused bis-furan derivative according to a 5-endo-dig process was observed under saponification conditions. On the basis of a theoretical study, a mechanistic pathway was delineated highlighting the Lewis acidity of the K⁺ ion as the driving force for this transformation in a strongly alkaline medium.     

Preparation of 6-chloropyrazolo[3,4-b]pyridine-5-carbaldehydes by Vilsmeier-Haack reaction and its use in the synthesis of heterocyclic chalcones and dipyrazolopyridines

Novel 6-chloropyrazolo[3,4-b]pyridine-5-carbaldehydes 5 have been synthesized from the 4,5-dihydropyrazolo[3,4-b]pyridine-6-ones 4 via Vilsmeier-Haack reaction. Further treatment of carbaldehydes 5 with acetophenones 6 and hydrazine hydrate afforded chalcone analogues 7 and dipyrazolo[3,4-b:4′,3′-e]pyridines 8, respectively.     

Stereoselective transformation of pyrazinones into substituted analogues of cis-5-amino-6-oxo-2-piperidinemethanol and cis-5-amino-2-piperidinemethanol

Various analogues of cis-5-amino-6-oxo-2-piperidinemethanol and cis-5-amino-2-piperidinemethanol have been prepared via Diels-Alder reaction of substituted pyrazinones with ethene followed by acid methanolysis of the bridged lactam adducts. Further reduction of the resulting methyl 2-piperidinecarboxylate ester compounds led to the corresponding 2-piperidinemethanol products that were converted into potential SP antagonists.     

An extended scope synthesis of an artificial safranine cofactor

Safranines hold great promise as artificial flavin-like electron transfer cofactors with tunable properties. We have previously reported the stepwise synthesis of a safranine analogue, p-methoxy safranine. We now report an improved synthetic pathway which enables the synthesis of safranine analogues containing electron donating phenyl substituents. Low potential safranine analogues were synthesized that extend the range of two electron midpoint reduction potentials to 249 mV, or 11.4 kcal/mol. NMR analysis of the safranine series demonstrates that the ¹⁵N chemical shift at the N(5) position correlates with the two-electron reduction midpoint potential.     

In situ alcohol oxidation-Wittig reactions using N-methoxy-N-methyl-2-(triphenylphosphoranylidine)acetamide: application to the synthesis of a novel analogue of 5-oxo-eicosatetraenoic acid

Benzylic, allylic, propargylic and unactivated alcohols can be oxidised with activated manganese dioxide in the presence of N-methoxy-N-methyl-2-(triphenylphosphoranylidine)acetamide to generate directly the corresponding α,β-unsaturated Weinreb amides. Elaboration of the resulting Weinreb amides is also described, in particular as part of a new route to analogues of the arachidonic acid metabolite 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid.     

Asymmetric de novo synthesis of fluorinated d-glucitol and d-mannitol analogues

A highly efficient anti-S_E2′ electrophilic fluorination of enantioenriched allylsilanes a subsequent dihydroxylation of the resulting allylic fluorides were used as key steps for the synthesis of three fluorinated carbohydrate analogues, 1,5-di-O-benzyl-2-deoxy-2-fluoro-d-glucitol, 2,6-di-O-benzyl-5-deoxy-5-fluoro-l-glucitol and 1,5-di-O-benzyl-2-deoxy-2-fluoro-d-mannitol. A new catalytic asymmetric route to 1-benzyloxy-4-trimethylsilyl-but-3-yn-2-ol, a common precursor to two advanced allylsilanes, is also described featuring a Noyori asymmetric transfer hydrogenation reaction.