Development of a novel nucleoside analogue with S-type sugar conformation: 2′-deoxy-trans-3′,4′-bridged nucleic acids

Two novel trans-3′,4′-bridged nucleic acid (trans-3′,4′-BNA) monomers, one with a 3,5,8-trioxabicyclo[5.3.0]decane structure and the other with a 4,7-dioxabicyclo[4.3.0]nonane structure, were successfully synthesized from thymidine. The locked trans-fused ring structures of the nucleoside analogues were confirmed by X-ray crystallography, which also indicated that their furanose rings had a typical S-type conformation involving C_2′-endo or C_3′-exo sugar puckering, respectively, and the same ring conformation as that observed in the B-type helical structure of the DNA duplex.     

A novel synthetic route for the total synthesis of (±)-uleine

In this study, a new synthetic route for the total synthesis of (±)-uleine is described. The important step in the synthesis of this alkaloid consists of an intramolecular cyclization of the D ring of the azocino[4,3-b]indole skeleton. Reduction of (N-methyl){3-β-ethyl-4-oxo-2,3,4,9-tetrahydrospiro[1H-carbazole-1,2′(1,3)dithiolane]-2-yl}-2-acetamide with borane yielded the corresponding (N-methyl){3-β-ethyl-4-hydroxy-2,3,4,9-tetrahydrospiro[1H-carbazole-1,2′(1,3)dithiolane]-2-yl}-2-acetamide, which underwent acid-catalyzed ring closure to produce azocino[4,3-b]indole core. Finally, the synthesis of (±)-uleine was completed through several steps from the azocino[4,3-b]indole core.     

Synthesis of 2′-O,3′-O bicyclic adenosine analogues using ring closing metathesis

The synthesis of 2′-O,3′-O bicyclic adenosine derivatives is presented as the first examples of a new family of 13-membered ring bicyclic nucleoside analogues. Cyclisation was achieved through ring closing metathesis (RCM) on a diene intermediate using Grubbs’ catalyst. The Z and E isomers were purified and characterised.     

6,7,14,15-Tetrahydro[1,5]diazocino[1,2-a:6,5-a′]diindole. Synthesis of a novel pentacyclic ring system

In search of new lead structures for potent allosteric enhancers of antagonist binding to muscarinic M₂ receptors, the first representative of a novel heterocyclic ring system, 6,7,14,15-tetrahydro[1,5]diazocino[1,2-a:6,5-a′]diindole, has been synthesized. The new pentacyclic ring skeleton is obtained from [3-(2-dibenzylaminoethyl)indol-2-yl]-acetic acid methyl ester in three steps.     

A new synthesis of potent antitumor saponin OSW-1 via Wittig rearrangement

OSW-1 and its analogues in which thiophene ring was introduced at the side chain were synthesized employing Wittig rearrangement of 17E(20)-ethylidene-16α-(4′-methyl-2′-thienyl)methyloxy steroid. The synthesis required nine steps from the known 17E(20)-ethylidene-16α-hydroxy steroid in 15.6% overall yield.     

Synthesis of new condensed nitrogen heterocyclic systems

A cotarnine alkaloid-based synthesis was developed for new heptacyclic condensed diisoquinolines via the double intramolecular pseudosalt bis[1,3]dioxolo[4,5-g;4′,5′-g′][1,3,4]oxadiazolo[2,3-a;5,4-a′]diisoquinoline 6. Substitution of the central O atom in 6 by C, S, or N nucleophiles afforded the first representatives of the new ring systems bis[1,3]dioxolo[4,5-g:4,5-g′]pyrazolo[3,2-a:5,1-a′]diisoquinoline (7a-d), bis[1,3]dioxolo[4,5-g:4,5-g′][1,3,4]thiadiazolo[2,3-a:5,4-a′]diisoquinoline (8), and bis[1,3]dioxolo[4,5-g:4,5-g′][1,2,4]triazolo[3,2-a:5,1-a′]diisoquinoline (9a-d) under simple reaction conditions.     

First synthesis of 4-aminopyrido[2′,3′:4,5]furo[3,2-d]pyrimidines

This Letter describes for the first time the synthesis of pyrido[2′,3′:4,5]furo[3,2-d]pyrimidines substituted by a primary or secondary amino group on position 4 of the pyrimidine ring. Application of microwave irradiation technology allowed fast and convenient procedures.     

Synthesis of benzannulated spiroacetals using chiral gold–phosphine complexes and chiral anions

The development of an asymmetric gold-catalysed dihydroalkoxylation strategy for the synthesis of the 3′H-spiro[chroman-2,1′-isobenzofuran] spiroacetal ring system 5 is described. Spiroacetal was generated in up to 87:13 enantiomeric ratio using chiral gold–phosphine complexes and chiral silver phosphate Ag(S)-TRIP.     

Stereoselective synthesis of new glycooxathiecinone using vic-cyclic thionocarbonate haloalkylation and ring closing metathesis as key steps

Herein, we describe the first glycoconjugate macrocyclic thiolcarbonate namely (Z)-10(S)-[3′-O-acetyl-1′,2′-O-isopropylidene-4′-deoxy-d-erythrofuranose]-4,7,9-trihydro-10H-8-thia-1,3-oxathiecin-2-one (17a) using a strategy based on two key steps synthesis: (i) a haloalkylation of vic-diol via their cyclic thionocarbonate derivatives; (ii) a macrocyclisation using ring closing metathesis reaction. Detailed here is a newly developed extension of vic-diol halogenation via the cyclic thionocarbonate function but using a range of alkyl halides other than the customarily used MeI. For example, with 1,2-O-isopropylidene-5,6-O-thionocarbonate-d-glucose (1) and allyl bromide, the 5-allylthiolcarbonate-6-bromo-6-deoxy-d-glucose derivative 6 was obtained in good yield. The later submitted to 6-allythioetherification and ring closing metathesis (RCM) with Grubbs second generation gave stereoselectively the target oxathiecinone 17a in 75% yield for the RCM step.     

Novel fluoro-substituted benzo- and benzothieno fused pyrano[2,3-c]pyrazol-4(1H)-ones

A straightforward, two-step synthesis of fluoro substituted chromeno[2,3-c]pyrazol- and [1]benzothieno[2′,3′:5,6]pyrano[2,3-c]pyrazol-4(1H)-ones, respectively, is presented. Hence, treatment of 1-substituted or 1,3-disubstituted 2-pyrazolin-5-ones with fluoro substituted 2-fluorobenzoyl chlorides or 3-chloro-6-fluoro-1-benzothiophene-2-carbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane gave the corresponding 4-aroylpyrazol-5-ols, which were cyclized into the fused ring systems. 5-Fluorochromeno[2,3-c]pyrazol-4(1H)-one was obtained upon treatment of the 1-(4-methoxybenzyl) protected congener with trifluoroacetic acid. Treatment of 5-fluorochromeno[2,3-c]pyrazol-4(1H)-ones with methylhydrazine afforded novel tetracyclic ring systems such as 2-methyl-7-phenyl-2,7-dihydropyrazolo[4′,3′:5,6]pyrano[4,3,2-cd]indazole. Detailed NMR spectroscopic investigations (¹H, ¹³C, ¹⁵N, ¹⁹F) with the obtained compounds were undertaken.     

Highly diastereoselective chemoenzymatic synthesis of (2′R)- and (2′S)-2′-deoxy[2′-H]guanosines

In an effort to develop an efficient synthetic method of highly diastereoselective (2′R)- and (2′S)-2′-deoxy[2′-²H]guanosines, chemoenzymatic conversion was investigated. The synthesis of (2′R > 98% de)-2′-deoxy[2′-²H]guanosine was achieved by biological transdeoxyribosylation using (2′R > 98% de)-2′-deoxy[2′-²H]uridine, 2,6-diaminopurine, and Enterobacter aerogenes AJ-11125, followed by treatment with adenosine deaminase. (2′S > 98% de)-2′-Deoxy[2′-²H]guanosine was synthesized from (2′S > 98% de)-2′-deoxy[2′-²H]uridine and 2,6-diaminopurine using thymidine phosphorylase and purine nucleoside phosphorylase instead of E. aerogenes AJ-11125.     

Synthesis of a series of novel 2′,3′-dideoxy-6′,6′-difluoro-3′-thionucleosides

A series of novel 2′,3′-dideoxy-6′,6′-difluoro-3′-thionucleosides 1a-d, analogues of 3TC that has high biological activities against HIV and HBV, have been synthesized from the gem-difluorohomoallyl amine 7 in a straightforward fashion. Our synthesis featured the construction of thiofuranose skeleton through ring closure of key intermediates and installation of pyrimidine ring with amino group in compounds 13a,b.     

Convergent syntheses of carbon-13 labeled midazolam and 1′-hydroxymidazolam

For the purpose of drug interaction studies, the stable-isotope labeled [¹³C₃]midazolam and its metabolite, 1′-hydroxy-[¹³C₃]midazolam were synthesized in four and five steps in overall yields of 25.5% and 14.2%, from 7-chloro-5-(2-fluorophenyl)-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepine, respectively, by a convergent synthesis, in which a key imidazoline ring formation was achieved by the facile reaction of [¹³C]2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine with varying ethyl imidate hydrochlorides. The scrambling of C-3 and C-4 labeling in intermediate diamine, and consequently in the final products, as well as the formation of a Δ^4,5 isomer of 1′-hydroxy-[¹³C₃]midazolam was observed and explained.     

An efficient synthesis of chiral terminal 1,2-diamines using an enantiomerically pure [1-(1′R)-methylbenzyl]aziridine-2-yl]methanol

Enantiomerically pure terminal 1,2-diamines, which can serve as precursors for the synthesis of many biologically important compounds, were synthesized efficiently from a commercially available chiral [1-(1′R)-methylbenzyl]aziridine-2-yl]methanol. Various enantiomerically pure 2-vinylaziridines were prepared by Wittig reactions from aziridine-2-carboxaldehyde and the corresponding phosphonium salts. The C(2)-N bond of the vinyl substituted aziridine ring was regioselectively cleaved by azidotrimethylsilane (TMSN₃). The azido group and the double bond were reduced successively to give the target compounds in high yields.     

1,n-Diamines. Part 3: Microwave-assisted synthesis of N-acyl-N′-arylhexahydropyrimidines and hexahydro-1,3-diazepines

In this Letter we present a method for the synthesis of N-acyl-N′-arylhexahydropyrimidines 1, by ring closure of N-acyl-N′-aryl-1,3-propanediamines 3 with formaldehyde. Cyclodehydrations were performed in aqueous medium under microwave irradiation, and led to high yields of the desired compounds in remarkably short reaction times. The method also allowed for the synthesis of hitherto unreported N-acyl-N′-arylhexahydro-1,3-diazepines 2. The acyclic tetramethylenic precursors 4 were synthesized by selective functionalization of N-arylputrescines.     

6,7,14,15-Tetrahydro-15aH-azocino[1,2-a:6,5-b′]diindole. Synthesis of a novel pentacyclic ring system

In search of new lead structures for potent allosteric enhancers of antagonist binding to muscarinic M₂ receptors, a novel heterocyclic ring system, 6,7,14,15-tetrahydro-15aH-azocino[1,2-a:6,5-b′]diindole, has been synthesized. The new ring skeleton was obtained from indol-2-yl-acetic acid in three steps.     

Spiro[1H-azulenium-1,9′-fluorene] perchlorate. Intramolecular charge-transfer interaction between orthogonally arranged units of the azulenium cation and fluorene

Spiro[1H-azulenium-1,9′-fluorene] (3) perchlorate was synthesized in five steps starting from fluorenone and trimethylsilyl enol ether of 1-acetylcycloheptatriene. The pK_R+ value of 3 was determined to be 7.8. A characteristic absorption band of 3 in acetonitrile was observed at 430 nm, which shows a bathochromic shift in dichloromethane, indicating the first example of the intramolecular charge-transfer interaction between orthogonally arranged units of an azulenium ion having a tropylium ion ring and fluorene having two benzene rings.     

First synthesis and absolute configuration of a β-farnesene-trimethoxystyrene conjugate isolated from Pachypodanthium confine

(E)-1-[3′-(4″,8″-Dimethylnona-3″,7″-dienyl)cyclohex-3′-enyl]-2,4,5-trimethoxybenzene (1), a β-farnesene-trimethoxystyrene conjugate, was isolated from Pachypodanthium confine. Its first synthesis was accomplished, and absolute configuration was determined to be R.     

A novel,chemoselective one-pot procedure for the preparation of 3H-spiro[isobenzofuran-1,2′-pyrrole]-3,3′(1′H)-dione derivatives via oxidative cleavage of 3a,8b-dihydroxyindeno[1,2-b]pyrroles

A one-pot, efficient and chemoselective procedure for the synthesis of new 3H-spiro[isobenzofuran-1,2′-pyrrole]-3,3′(1′H)-dione derivatives has been developed which involves room temperature oxidative cleavage of 3a,8b-dihydroxyindeno[1,2-b]pyrroles themselves synthesized from the reaction of ninhydrin and enaminones in 30% ethanol. A reasonable mechanism is proposed for the oxidation reaction based on the results of this study and our previous related work.     

An efficient and versatile synthesis of GlcNAcstatins—potent and selective O-GlcNAcase inhibitors built on the tetrahydroimidazo[1,2-a]pyridine scaffold

We report a novel approach to the synthesis of GlcNAcstatins—members of an emerging family of potent and selective inhibitors of peptidyl O-GlcNAc hydrolase build upon tetrahydroimidazo[1,2-a]pyridine scaffold. Making use of a streamlined synthetic sequence featuring de novo synthesis of imidazoles from glyoxal, ammonia and aldehydes, a properly functionalised linear GlcNAcstatin precursor has been efficiently prepared starting from methyl 3,4-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-α-d-mannopyranoside. Subsequent ring closure of the linear precursor in an intramolecular S_N2 process furnished the key fused d-mannose-imidazole GlcNAcstatin precursor in excellent yield. Finally, a sequence of transformations of this key intermediate granted expeditious access to a variety of the target compounds bearing a C(2)-phenethyl group and a range of N(8) acyl substituents. The versatility of the new approach stems from an appropriate choice of a set of acid labile permanent protecting groups on the monosaccharide starting material. Application was demonstrated by the synthesis of GlcNAcstatins containing polyunsaturated and thiol-containing amido substituents.