Stereoselective enzymatic synthesis of monoglucosyl-myo-inositols with in vivo anti-inflammatory activity

The monoglucosyl-inositols α-d-glucopyranosyl-(1→4)-4d-myo-inositol 3 and α-d-glucopyranosyl-(1→1)-1d-myo-inositol 4 were synthesized by a combined enzymatic transglucosylation and hydrolysis strategy, using cyclodextrin glucosyl transferase (CGTase) from Thermoanaerobacter sp., followed by hydrolysis with Aspergillus niger glucoamylase. The glucosides were separated by preparative HPLC and fully characterized by extensive 1D and 2D NMR studies. The structure of the regioisomer 4 was confirmed by X-ray crystallography of its perbenzoylated derivative 4a. Both isomers demonstrated in vivo anti-inflammatory activity at comparative levels to corticosterone on mouse ear oedema induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) and in rat hind paw oedema induced by carrageenan.     

Derives 14-hydroxyles de la vincadifformine et de la vincamine

Hydroboration-oxidation of tabersonine 1 yielded as major product 14 β-hydroxy vincadifformine 9b, which was correlated with 14 β-hydroxy N(1)-methyl 2β-H, 16β-H dihydro vincadifformine 6b (previously prepared and characterised), and 14α-hydroxy vincadifformine 9a as minor product. The regio- and stereoselectivity of hydroboration-oxidation were interpreted. 9a and 9b were respectively oxidised and rearranged to the corresponding 14-hydroxy vincamines 13a and 13b. The coupling constants of H(14) on the NMR of the acetyl derivatives of 9a, 9b, 13a and 13b are consistent with an inversion of N(4) during the rearrangement leading from the vincadifformine to the vincamine skeleton.     

A short route to the phthalideisoquinolines and the 13-hydroxylated protoberberines

CrO₃ oxidation of 2′-hydroxymethylpapaverine (2) yields the aromatic phthalideisoquinoline 3. Catalytic reduction of 3 gives the erythro-norphthalideisoquinoline 7 and the threo analog 9. Respective N-methylation furnishes the erythro-phthalideisoquinoline 8, and the threo isomer 10. The nor compounds 7 and 9 can be converted in hydroxylic base to the lactam alcohols 11 and 12, respectively; but 12 tends to dehydrate to the oxyprotoberberine 15. LAH reduction of 11 and 12 affords in turn the 13-hydroxyprotoberberines 13 and 14. Three fractors affect the conformation of the phthalideisoquinolines, namely the relative stereochemistry at C-1 and C-9, substitution on nitrogen, and substitution at C-8.     

Synthese totale de la (±) negamycine

A total synthesis of (±) negamycine 1 has been achieved in 14 steps from the acrolein dimer 6, which possesses the same carbon skeleton as the key intermediate lactone 4. Treatment of 2-acetoxymethyl 3,4-dihydro[2H]pyran 8, obtained from 6, with lead tetracetate gave the allylic hemiketal 15, which was converted into the corresponding anomeric methyl ethers 23. Hydroxylation of the double bond of 23 with mercuric acetate, occurred selectively at the γ-position and the resulting isomeric alcohols 24 were isolated as their dimesylates 25a and 25b. Condensation of sodium azide with the (trans-derivative 25a resulted in the formation of the cis-diazide 26a by inversion of configuration at C₃. Hydrogenation of 26a followed by acetylation of the intermediate diamine gave the cis-diamide 28 having the required stereochemistry. Oxidation of the corresponding hemiketal 29 by means of silver silicate yielded the diacetamido-lactone 4, which was then hydrolysed into (±) δ-hydroxy β-lysine 2 by refluxing aqueous HCl. Under the conditions required to protect the amino-groups as benzylcarbamates, the lactone 30 was produced. However, 30 gave directly the hydrazine 36 by condensation with benzyl N-methyl-hydrazinoacetate in refluxing acetonitrile m the presence of SiO₂. Finally (±) negamycine was obtained by hydrogenolysis of the protecting groups of 36. The antibacterial activities of the racemic antibiotic have been compared, in vitro and in vivo, with those of the natural product and with gentamicine C.     

Synthese de derives de la purpurosamine C,composant de la gentamicine C1a

The synthesis of derivatives of purpurosaimine C and epi-purpurosamine C is described, from methyl 2,3,4,6-tetra-O?-methylsulphonyl-α-d-galacto and glucopyranosides 2 and 3 by reaction with azide ion to give diazides 4 and 5, transformed in a series of reactions via epoxides 6 and 7 into the corresponding olefines 16 and 17, thermal rearrangement to give diazides 18 and 19, which were transformed into the methyl glycosides 27 and 29 and mercaptolysis with ethanethiol followed by N-acetylation, gave 2,6-diacetamido-2,3,4,6-tetradeoxy-d-erythro-hexose diethyl dithioacetal 30 (identical with authentic 30 prepared from gentamicin C_1a)and 2,6-diacetamido-2,3,4,6-tetradeoxy-d- threo-hexose diethyl dithioacetal 31, an enantiomer of a mercaptolysis product of dihydrosisomicin.     

Enantiospecific synthesis of a glycoside of d-epi-purpurosamine

2-Propyl d-epi-purpurosaminide dihydrochloride 14 and its di-N-acetylated derivative 15 were synthesized by an enantiospecific sequence which involves the 2-propyl 6-O-acetyl-3,4-dideoxy-α-d-erythro-hex-3-enopyranosid-2-ulose 2 as the key precursor. The first approach through the saturated diol 4, prepared by reduction of the enone system of 2, was unsuccessful as the C-2 position of 2,6-di-O-sulfonyl derivatives 5 and 6 resisted substitution by azide. Therefore, an alternative sequence starting from the allylic alcohol 3, also derived from 2, was developed. In this case, the 2,6-di-O-tosyl derivative 9 gave the expected 2,6-diazide 10 with additional unwanted rearrangement of the double bond to the 2-propyl 4,6-diazido-2,3,4,6-tetradeoxy-α-d-threo-hex-2-enopyranoside 11 isomer. However, the ditriflate derivative 13, analogous to 9, underwent substitution to afford the diazide 10 in good yield. Upon reduction of the azide functions and saturation of the double bond of 10 by catalytic hydrogenation under acidic conditions, the dihydrochloride salt 14 was obtained as a crystalline product (43% overall yield from 3).     

Syntheses totales et etudes de lignanes biologiquement actifs—6: Syntheses totales de la (±)-iso-β-peltatine et de ses analogues

2-Benzyloxypiperonal 15, a key intermediate in our synthesis of (±)- iso - β - peltatin 7, was obtained by bromination of 4 - hydroxy - 1,3 - benzodioxole 12, followed by treatment with (i) excess n-BuLi,o li]N-methylformanilide, li]HCl/H₂O, and li]benzyl chloride/K₂CO₃. The aromatic aldehydes 15 and 6 were subsequently transformed into the corresponding β - (2 - alkoxy 3,4 - methylenedioxybenzyl) -γ- butyrolactones 19 and 29, respectively. α-Hydroxyalkylation of 19 with 3,4,5-trimethoxybenzaldehyde 20, followed by cyclisation and hydrogenolysis afforded (±)- iso -β- peltatin 7 in good yield. Similarly, α-hydroxyalkylation of 29 with 20 and syringaldehyde 21, followed by cyclisation, afforded good yields of (±)- iso -β- peltatin O-methyl ether 5 and (±)-iso-α- peltatin O-methyl ether 8, respectively.     

Alcaloides steroidiques—CLXIV : Isomerisation en presence d'une base ou d'un acide d'oxazirannes steroidiques derives de la conanine

Isomerisation into an imino-carbinol or a nitrone is the first step in the hydrolysis of an oxazirane. This isomerisation, studied on three steroidal compounds lead to the following results: compound 6, bearing cis-oriented 18H and oxazirane ring, gives rise only to the nitrone 13. Compound 1 which bears trans 18H may isomerise either into the imino-carbinol 5 or into the nitrone 11 (11 is quantitatively obtained in acidic conditions with minimum basic catalysis). The case of compound 7 which isomerises whatever the conditions into the α hydroxylated imino-ether 8 shows the influence of structural factors which enhance the mobility of the 18H.     

1,3-Dipolar cycloaddition of a nitrone derived from (S)-malic acid to α,β-unsaturated δ-lactones

1,3-Dipolar cycloaddition of nitrone 7 to α,β-unsaturated δ-lactones: non-chiral 2, racemic mixture 3/3ent, d-glycero 3 and d-threo 15 proceeds with high stereoselectivity in the case of 2 and 15, and with a significant kinetic resolution in the case of the racemate 3/3ent. The endo approach of reactants was not observed. CD-spectroscopy proved an attractive tool for determination of the absolute configuration of cycloadducts.     

Short synthesis of new salacinol analogues and their evaluation as glycosidase inhibitors

Versatile synthesis of some analogues of the naturally-occurring α-glucosidase inhibitor salacinol (1), involving thioanhydro alditol moieties with erythro, d,l-threo, xylo, ribo, d-arabino and d-manno configurations is described. Nucleophilic attack at the least-hindered carbon atom of an l- or d-protected erythritol cyclic sulfate by the thioanhydro alditol sulfur atom yielded the desired zwitterionic compounds. In addition, the preparation of the cyclic sulfates of 2,4-O-benzylidene-d-erythritol and 2,4-O-isopropylidene-l-erythritol was improved. Enzyme inhibition tests showed that most of the new compounds were weak but specific inhibitors, while good inhibitory activity was found for a six-membered ring analogue (β-glucosidase: K_i=16 μM).     

Synthesis of d-gluco-, l-ido-, d-galacto-, and l-altro-configured glycaro-1,5-lactams from tartaric acid

The d-gluco-, l-ido-, d-galacto-, and l-altro-configured glycaro-1,5-lactams 1-4 were prepared from the known tartaric anhydride 5 via the aldehyde 6. These lactams are known (1) or potential (2-4) inhibitors of β-d-glucuronidases and α-l-iduronidases. Olefination of 6 to the (E)- and (Z)-alkenes 7 or 8, followed by reagent or substrate controlled dihydroxylation, lactonization, azidation, reduction, and deprotection led in 10 steps and in overall yields of 11-20% to the title lactams.     

Stereochimie de la cycloaddition sur les ethers butadienyliques d'alcools chiraux. Derives en 4 et 6 de glucosides perbenzylés

Two partially protected derivatives of α-D-glucose with one free OH group function, benzyl 2,3,6-tri-O--α-D-glucopyranoside 2 and benzyl-2,3,4-tri-$\text{O}$-benzyl-α-D-glucopyranoside 4 were prepared. Base-catalysed addition of the diyne-diol 5 onto these sugars gave trans-cis mixtures of enynyl ethers, 6 and 8 from compound 2, and 7 and 9 from compound 4. Catalytic partial hydrogenation gave the corresponding butadienyl ethers 10 and 12 from 6 and 8, and 11 and 13 from 7 and 9. All trans-cis mixtures obtained could be readily separated by fractionnal crystallisation or column chromatography, thus making for the first time pure trans and cis enynyl ethers readily available in quantity. The cycloaddition of butyl glyoxylate onto the trans dienes led to mixtures of dia-stereoisomeric, dihydropyrannyl ethers, 14 (β-L) 18 (α-D) and 22 (β-D) from diene 10, and 16 (β-L), 20 (α-D) and 24 (β-D) from diene 11. Configurations were ascribed by the use of already described methods. This study brings to a number of five all examined reactions of cycloaddition onto butadienyl ethers of chiral alcohols. In each case a strong preference is observed for one of the faces of the prochiral butadienyl ether, but no great preference for the endo path of cycloaddition.     

An efficient approach to d-threo-3-hydroxyaspartic acid for the synthesis of novel l-threo-oxazolines as selective blockers of glutamate reversed uptake

An efficient, stereoselective synthetic strategy to d-threo-3-hydroxyaspartic acid was developed. Starting from l-(2S,3S)-N-benzoyl-3-hydroxyaspartic acid dimethyl ester by a Deoxo-fluor-catalyzed cyclization reaction, an inversion of configuration at the β-center (erythro isomer), was observed. A base-induced epimerization reaction led to the d-trans-isomer, which was hydrolyzed to give d-threo-3-hydroxyaspartic acid with excellent stereoselectivity and overall yield. Starting from d-threo-3-hydroxyaspartic acid, l-threo-oxazolines can be stereoselectively synthesized.     

Fragmentation of carbohydrate anomeric alkoxyl radicals. Synthesis of highly functionalized chiral vinyl sulfones

The reaction of derivatives of 3-acetyl-d-glucal, 3-acetyl-l-rhamnal, 3-acetyl-d-galactal, and 3-acetyl-d-lactal with sodium benzenesulfinate in acid medium catalyzed by HgSO₄ afforded diastereoisomeric mixtures of the corresponding 2,3-dideoxy-3-(phenylsulfonyl)-hexopyranoses through a Ferrier rearrangement. The anomeric alkoxyl radical fragmentation of these γ-hydroxy sulfones using the system (diacetoxyiodo)benzene and iodine gave vinyl sulfones with structures of 1,2-dideoxy-4-O-formyl-2-(phenylsulfonyl)-pent-1-enitol and configurations d-erythro, l-erythro, and d-threo at the two stereogenic centers.     

The chemistry of zerumbone. Part 3: Stereospecific creation of five stereogenic centers by double Sharpless oxidation

The Sharpless asymmetric epoxidation was applied to zerumbol 2 in order to introduce chirality into the readily available achiral sesquiterpene zerumbone 1. Single bisepoxides (+)-3 and (−)-3 were obtained in nearly 100% enantiomeric purity, characterized as the unexpected all erythro configuration by X-ray analysis.     

Synthese de C-nucleosides—IX : Purines substituees en position 8 par le desoxy-2 ribose

Benzyl 2-deoxy-3,5-di-O-p-toluyl-d-erythro-pentofuranosyl thioformimidate 3, prepared from nitrile 1, reacts with α-aminocyanoacetic acid derivatives to yield C-imidazole nucleosides which are further cyclized into purines. The 6-mercapto purine 2 is obtained in two different ways.     

Synthesis and properties of a novel nucleoside derivative possessing a 2,3,5,6-tetraazabenzo[cd]azulene skeleton

We describe herein the synthesis and properties of the novel nucleoside derivative, 4,7-diamino-2-(2-deoxy-β-d-erythro-pentofuranosyl)-2,6-dihydro-7H-2,3,5,6-tetraazabenzo[cd]azulene (1). The palladium catalyzed cross-coupling reaction of 2,4-diamino-5-iodo-7-(2-deoxy-β-d-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine (9) with acrylonitrile afforded 2,4-diamino-5-[(E)-1-cyano-2-ethenyl]-7-(2-deoxy-β-d-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine (10) in 77% yield, which was treated with NaOMe in MeOH in the presence of NaSPh to give the desired 1 in 64% yield. Whereas 1 was stable in concentrated ammonia at room temperature, it was gradually hydrolyzed in water to give 4-amino-2-(2-deoxy-β-d-erythro-pentofuranosyl)-2,6-dihydro-7H-2,3,5,6-tetraazabenzo[cd]azulen-7-one (12). Density functional calculations indicated that 12 was 20 kcal/mol more thermodynamically stable than 1 in a model study.     

Enantiopure erythro- and threo-1-aryl-1-[2-pyrrolidyl]-methanols: synthesis from l-proline

Enantiopure (1R,2S)-erythro- and (1S,2S)-threo-isomers of four new aryl-pyrrolidyl alcohols 5aH, 5aMe, 5bH and 5bMe have been obtained in five steps from (−)-(S)-proline and fully characterized. The oxidation of alcohol 8 into aldehyde 9 was the most difficult step and racemization occurs during Swern oxidation but this difficulty can be overcome by using SO₃/pyridine as oxidant. Diastereomer I of the protected amino alcohol 10a crystallized and was shown to be the (1R,2S)-erythro-isomer (e-10a-I) using X-ray crystallography. Therefore the (1R,2S)-erythro structure was assigned to all compounds obtained from e-10a-I, and, as a consequence, the (1S,2S)-threo structure was assigned to diastereomers II.     

Highly efficient stereoselective synthesis of d-erythro-sphingosine and d-lyxo-phytosphingosine

Starting from a single suitable functionalised epoxide, a highly efficient stereoselective synthesis of d-erythro-sphingosine and d-lyxo-phytosphingosine is described. The approach allows the formal preparation of all stereoisomers of these sphingoid structures.     

Steric constraints against [3,3]-sigmatropic rearrangement of allylic azides. A convenient approach to β-l-4-aminopent-2-enoglyceropyranosides

Starting from alkyl α-d-4-O-methanesulphonylpent-2-enoglyceropyranosides 13a–c, nucleophilic substitution carried out with polymer-supported azide ion led to regioisomeric mixtures of the azides 14a–c and 15a–c. An analogous result, due to a [3,3]-sigmatropic rearrangement, was observed starting from methyl α-d-hex-2-enoerythropyranoside derivatives 6a and 6b. On the contrary, starting from alkyl β-d-4-O-methanesulphonylpent-2-enoglyceropyranosides 21a–c, azides 22a–c were exclusively obtained, and subsequently converted into the corresponding amino derivatives 23a–c. The behaviour of β-anomers 21a–c was ascribed to steric interactions in the cyclic transition state, as supported by ab initio calculations.