Deacylation studies on furanose triesters using an immobilized lipase: synthesis of a key precursor for bicyclonucleosides

Lipozyme TL IM immobilized on silica catalyses the deacylation of 4-C-acyloxymethyl-3,5-di-O-acyl-1,2-O-(1-methylethylidene)-beta-L-threo-pentofuranose to form 3,5-di-O-acyl-4-C-hydroxymethyl-1,2-O-(1-methylethylidene)-alpha-d-xylo-pentofuranose in a highly selective and efficient manner.     

Convergent synthesis of polyhalogenated quinoline C-nucleosides as potential antiviral agents

2,5,6-Trichloro-1-(beta-d-ribofuranosyl)benzimidazole (TCRB) and 2-bromo-5,6-dichloro-1-(beta-d-ribofuranosyl)benzimidazole (BDCRB) are benzimidazole nucleosides that exhibit strong and selective anti-HCMV activity. We proposed to synthesize 2-halo-6,7-dichloro-4-(beta-d-ribofuranosyl)quinolines as 6 + 6 bicyclic analogues of TCRB. The synthesis used Wittig reactions in two key steps. The first Wittig reaction coupled a fully functionalized benzene with a ribofuranose derivative to provide (Z)-6-O-(tert-butyldimethylsilyl)-1-(4,5-dichloro-2-nitrophenyl)-1,2-dideoxy-3,4-O-isopropylidene-d-allo-1-enitol (5) as the basic skeleton for the target compounds. The following electrophile-mediated intramolecular cyclization of the cis-alkene (5) was found to afford (1S,2S)-2,5-anhydro-1-bromo-6-O-(tert-butyldimethylsilyl)-1-deoxy-1-(4,5-dichloro-2-nitrophenyl)-3,4-O-isopropylidene-d-allitol (8) as the major product. This alpha-stereoselectivity was contrary to the literature precedence. A double-bond isomerization was established to be the cause of the unexpected stereochemistry. The bromo group of 8 was displaced by a hydroxyl group. Oxidation of the hydroxy group and the reduction of a phenylnitro group provided (2S)-1-(2-amino-4,5-dichlorophenyl)-2,5-anhydro-6-O-(tert-butyldimethylsilyl)-3,4-O-isopropylidene-d-allose (11), which was subjected to the second Wittig reaction with a phosphacumulene to construct 4-[5-O-(tert-butyldimethylsilyl)-2,3-O-isopropylidene-alpha-d-ribofuranosyl]-6,7-dichloroquinolin-2-one (13). Halogenation followed by deprotection of 13 and led to the synthesis of 4-(alpha-d-ribofuranosyl)-2,6,7-trichloroquinoline (17) as the major product. The 2-aminophenone alpha-nucleoside (11) was successfully anomerized to the beta-anomer (19), which led to the synthesis of the targeted 2-chloro- and 2-bromo-6,7-dichloro-4-(beta-d-ribofuranosyl)quinolines (18and 21, respectively).     

The formation of the indolizino[1,2-c]quinolinium system by a novel nucleophilic reaction

2-Methyl-3-(2-pyridyl)quinoline (1) with a bromomethyl ketone or ethyl bromoacetate yields 6-methyl-12-acylindolizino[1,2-c]quinolinium bromides ( 5–9 ). The acyl derivatives can be deacylated in acid yielding 6-methyl indolizino[1,2-c]quinolinium salts ( 4 ). Benzoylation of 4 yields the 12-benzoyl derivative ( 6 ). The deacylation product ( 4 ) has been synthesized from 2-acetamidophenacyl bromide ( 10 ) and 2-pyridylacetone ( 12 ).     

D-Gulonolactone as a synthon for L-noviose: first preparation of 4-O-demethyl-L-noviofuranose and related derivatives

[reaction: see text] A new synthesis of L-noviose (11), a sugar moiety of novobiocin, is presented. D-Gulonolactone was initially converted in a few steps to the key ester derivative 7 [1-O-benzyl methyl 2,3-O-(1-methylethylidene)-alpha-L-lyxofuranosiduronate]. An appropriate selection of protecting groups enabled transformation of 7 under mild reaction conditions to 4-O-demethyl-L-noviofuranose 9a and related 9b-c. Derivatives 9 were further converted either to L-lyxopyranoses (10a and 10b) or to methyl L-lyxofuranoside 12.     

Mass spectrometry of hexuronosyldiglycerides

Conclusions The fragmentation under electron impact of the molecular ions of synthetic methyl esters of 1,2-di-O-acyl-3-O-(2',3',4'-tri-O-acetyl--D-glucopyranuronosyl)-L-glycerides was studied. Mass spectrometry of such compounds gives extensive information on their structure.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 1, pp. 94–102, January, 1975.     

Highly efficient diastereoselective biocatalytic acylation of a diastereotopic furanose diol and synthesis of key intermediates for amino derivatized bicyclonucleosides

The selectivity of Candida antarctica lipase has been demonstrated and employed in the manipulation of a diastereotopic furanose diol as the key step in the synthesis of a novel bicyclo 3-amino-3-deoxy furanose derivative, which is an important intermediate for the synthesis of bicyclic analogs of AZT. The asymmetrization of the diol has been achieved with preferred formation of a monoacylated product with 100% diastereoselectivity. An efficient synthesis of an intermediate in the synthesis of amino derivatized bicyclonucleosides is also described, two such novel compounds containing cycloamino residues have been prepared.     

Easy and stereoselective approach to alpha,beta-unsaturated gamma-lactones fused to pyranoses from furanose scaffolds

The first facile and efficient route to pyranose-fused butenolides from furanose scaffolds, convenient for scaling up production, is described. Wittig olefination of 1,2-O-isopropylidene pentofuranos- or hexofuranos-3-uloses with a resonance-stabilized ylide led to the stereoselective formation of the (Z)-alpha,beta-unsaturated ester. In the presence of acid labile 5-O- or 5,6-di-O-protecting groups, acid hydrolysis of the Wittig product resulted in isomerization to the pyranose form and spontaneous lactonization to give the target molecules in good overall yield.     

Biocatalytic route to well-defined macromers built around a sugar core

By using 4-C-hydroxymethyl-alpha-D-pentofuranose as the sugar core and lipase-catalyzed transformations, a macromer was constructed with exceptional control of substituent placement around the carbohydrate core. The key synthetic transformations performed were as follows: (1) selective lipase-catalyzed acrylation along with prochiral selection of 4-C-hydroxymethyl-1,2-O-isopropylidene-alpha-D-pentofuranose (diastereomeric excess up to 93%); (2) the ring-opening of epsilon-caprolactone, epsilon-CL, from the remaining primary hydroxyl group to give an acryl-sugar capped macromer (M(n) = 11 300, M(w)/M(n) = 1.36, initiator efficiency 50-55%, <5% water initiated PCL chains); (3) selective lipase-catalyzed esterification of the terminal hydroxyl of oligo(epsilon-CL) chains; (4) hydrolysis of the 1,2-O-isopropylidene group at the sugar core without any substantial loss in macromer molecular weight; and (5) homopolymerization of the corresponding macromer. In principle, the method developed is flexible so that it can be used to generate a wide array of unusual macromers and heteroarm stars. In the absence of biocatalytic transformation, such structural control would be extremely difficult or currently impossible to obtain.     

Preparation of Primary and Secondary Azidosugars from Diols using the Dioxaphosphorane Methodology

ABSTRACT

Treatment of methyl 2,3-di-O-benzyl-α-D-glucopyranoside (1), methyl 2,3-di-O-acetyl-α-D-glucopyranoside (4), 3-O-benzyl-1,2-O-(1-methylethylidene)-α-D-glucofuranose (6), 3-O-acetyl-1,2-O-(1-methylethylidene)-α-D-glucofuranose (9), 1,2-O-(1-methylethylidene)-α-D-xylofuranose (11) and methyl 2,3-di-O-acetyl-α-D-galactopyranoside (15) with diisopropylazodicarboxylate-triphenylphosphine in tetrahydrofuran led to the corresponding dioxaphosphoranes, which were opened by trimethylsilyl azide affording the silylated primary azidodeoxysugars. When the same reaction was performed on methyl 2,3-di-O-benzyl-α-D-galactopyranoside (20), an inversion of the regioselectivity of the dioxaphosphorane opening was observed, leading mainly to the 4-azido-4-deoxy-α-D-glucopyranoside derivative 27.     

Novel bicyclic nucleoside analogue (1S,5S,6S)-6- hydroxy-5-hydroxymethyl-1-(uracil-1-yl)-3,8-dioxabicyclo[3.2.1]octane: synthesis and incorporation into oligodeoxynucleotides

The novel bicyclic nucleoside (1S,5S,6S)-6-hydroxy-5-hydroxymethyl-1-(uracil-1-yl)-3,8-dioxabicyclo[3.2.1]octane [2'-deoxy-1'-C,4'-C-(2-oxapropano)uridine] (15), expected to be restricted into an O4'-endo furanose conformation, was synthesized from the known 1-(3'-deoxy-beta-D-psicofuranosyl)uracil 5. The phosphoramidite derivative of 15 was successfully incorporated into oligodeoxynucleotides using standard methods, and thermal denaturation studies showed moderate decreases in duplex stabilities of -2.1 and -1.5 degrees C per modification toward complementary DNA and RNA, respectively.     

The Synthesis of Glycoglycerolipids

A convenient synthetic route was developed for the synthesis of the novel glycolipids: 1,2-di-O-acyl-3-O-(2‘-acylamide-2‘-denxy-ct-D-glucopyranosyl)-sn-glycerols. 10 new compounds of glycolipids with different acyl groups were obtained.     

Synthesis of 4‐alkyl‐1,2‐diphenyl‐3,5‐dioxopyrazolidines possessing aryl methylsulfonyl and sulfonamide pharmacophores for evaluation as selective cyclooxygenase‐2 (COX‐2) inhibitors

A group of 1,2‐diphenyl‐3,5‐dioxopyrazolidines possessing a methylsulfonyl ( 11 ) or sulfonamide ( 15 ) substituent at the para position of the N¹‐phenyl ring, in conjunction with a hydrogen, methyl or fluoro sub‐stituent at the para position of the N²‐phenyl ring, and a C‐4 n‐butyl, methyl or spiro‐cyclopropyl substituent were synthesized for evaluation as potential cyclooxygenase‐2 (COX‐2) selective inhibitor antiinflammatory agents. The title compounds 11 and 15 were synthesized using a four‐step and a three‐step reaction sequence, respectively. Thus, the acetic acid promoted condensation of a nitrosobenzene 5 with an aniline derivative ( 6, 12 ) gave the corresponding azobenzene product ( 8, 13 ) which was reduced with zinc dust in the presence of ammonium chloride to yield the corresponding hydrazobenzene ( 9, 14 ). Base‐catalyzed condensation of 9 and 14 with a malonyl dichloride ( 10 ) afforded the target 3,5‐dioxopyrazolidine product ( 11,15 ). 4‐n‐Butyl‐1‐(4‐methylsulfonylphenyl)‐2‐phenyl‐3,5‐dioxopyrazolidine ( 11a ) was a selective COX‐1 inhibitor (COX‐1 IC₅₀ = 8.48 μM). In contrast, 4‐n‐butyl‐1‐(4‐methylsulfonylphenyl)‐2‐(4‐tolyl)‐3,5‐dioxopyrazolidine ( 11b , COX‐2 IC₅₀ = 11.45 μM) and 4‐n‐butyl‐1‐(4‐methylsulfonylphenyl)‐2‐(4‐fluorophenyl)‐3,5‐dioxopyrazoli‐dine ( 11c , COX‐2 IC₅₀ = 9.86 μM) were about 46‐fold and 20‐fold less selective COX‐2 inhibitors respectively, relative to the reference drug celecoxib.     

Bicyclic nucleosides; stereoselective dihydroxylation and 2'-deoxygenation

A series of polyhydroxylated bicyclic nucleoside derivatives is approached applying stereoselective dihydroxylation reactions. Three out of four isomeric and protected products were obtained after the stereoselectivity of dihydroxylation has been completely inverted comparing a bicyclic nucleoside with a tricyclic furanose substrate. A corresponding 2'-deoxynucleoside derivative has been obtained after an optimized deoxygenation procedure.     

Transannular O-heterocyclization of twelve and thirteen membered trienes by methoxybromination procedure

The reaction of (E,E,Z)-cyclododeca-1.5,9-triene (1) with NBS and methanol gives bicyclic tetrahydrofuran derivatives (3) and (4) as well as usual 1,2-addition products while the related reaction with (Z,E,Z)-cyclotrideca-1,5,9-triene (7) leads to the bicyclic tetrahydropyran derivative (6), in both cases like O-heterocyclization products as the result of transannular participation of a methoxy group.     

Reaction of adenine with an α-chlorooxetane: An approach to the synthesis of oxetane nucleosides

The reaction of adenine with 3,5-anhydro-5R-chloro-1,2-O- isopropylidenexylofuranose, a stable α-chlorooxetane, gives a mixture of the two epimers of 5-[9-adenyl]-3,5-anhydro- 1,2-O-isopropylidenexylofuranose; the structure of 5R-[9- adenyl)-3,5-anhydro-1,2-O-isopropylidenexylofuranose was established by X-ray crystallography.     

Domino reactions of 4,5-dicyanopyridazine with dihydroheterocycles: synthetic and mechanistic features

The title pyridazine 1 was found to react with both 2,3-dihydrofuran (2) and 3,4-dihydro-2H-pyran (9) to give the tetracyclic skeletons 5-8 and the phthalonitrile 12 through the intermediates 4 and 10, respectively. A more complex mechanism was ascertained for the reaction of 1 with the pyrroline 14 which, under suitable conditions, afforded the bicyclic derivative 19 as the predominant product; selective elaborations of this species into the 5,6-dicyanoindoles 22 and 23 are reported.     

Synthesis of 1-(2′-O-methyl-β-d-ribofuranosyl)-uracil (2′-O-methyluridine) and 3-(2′-O-methyl-β-d-ribofuranosyl)uracil

1-O-Acetyl-3,5-di-O-benzoyl-2-O-methyl-β-d-ribofuranose has been prepared in five steps from benzyl 2-O-methyl-β-d-ribopyranoside. Reaction of the furanose derivative with 2,4-bis-(trimethylsilyl)uracil in the presence of stannic chloride provides a new synthesis of 2′-O-methyl uridine and also yields the hitherto unknown 3-(2′-O-methyl-β-d-ribofuranosyl)uracil.     

Structure and orientation of puroindolines into wheat galactolipid monolayers

Puroindolines (PINs), basic and cysteine-rich proteins of wheat endosperm, are composed of two proteins, puroindoline-a (PIN-a) and puroindoline-b (PIN-b). Using a monolayer assay at the air/liquid interface, both PIN-a and PIN-b were studied in pure components and mixed with wheat galactolipids, 1,2-di-O-acyl-3-O-(beta-d-galactopyranosyl)- sn-glycerol (MGDG) and 2-di-O-acyl-3-O-(beta-d-galactopyranosyl-1,6-beta-d-galactopyranosyl)-sn-glycerol (DGDG). Following the adsorption of PINs at the air/liquid interface thanks to surface pressure increases, we concluded that PIN-a displays a more amphipathic character than PIN-b. Compression isotherms combined with ellipsometric measurements showed that the area per molecule is smaller and the protein film is more condensed for PIN-a than for PIN-b. According to the polarization modulation-infrared reflection-absorption spectroscopy data, both proteins display a highly alpha-helical structure and the alpha-helices are oriented rather parallel to the interface. By measuring the overpressure due to PIN adsorption into MGDG and DGDG monolayers, we observed that PIN-a interacts more strongly into lipid films than PIN-b. The observation by atomic force microscopy of mixed protein/lipid films showed that the nature of the lipid plays a significant role in the organization of PINs, particularly for PIN-a. The presence of galactolipids at the interface stabilizes the alpha-helical structure of PINs, but significant changes were observed concerning the orientation of the alpha-helices. They adopt a perfect parallel orientation to the interface in the MGDG monolayer, whereas the bundle of alpha-helices orients normal to the interface in the DGDG film.     

Cyclisation of 4-[2-Cyclofentenyl]-3-Hydroxy [1] Benzopypan-2-One

4-[2-cyclopentenyl]-3-hydroxy [1] bonzopyran-2-one(3) was cyclised to the bicyclie coumar in-1,3-ethano-2-bromo-1,2-dihydro-3H-pyrano [2,3-c] [1] benzopyran-5-one (6) by a sequence of reactions viz. acetylation of 3, addition of bromine to cyclopenteny double bond and treating the resulting acetyldibromo compound (5) with 4% alcoholic KOH, Cyclisation of compound (3) with mercuric acetate in methanol gave condensed furan derivative 7 which on reductive demercuration with zinc borohydride in dimethoxyethane gave the 1,3-propano-1,2-dihydrofuro [2,3-c] [1] benzopyran-4-one, 8. Cyclisation of compound 2 with come. H₂SO₄ furnished a mixture of bicyclic derivative 9 ad furo coumarin derivative 8.     

Total Synthesis of Cyclothialidine

A total synthesis of cyclothialidine ( 1 ), a new DNA gyrase inhibitor isolated from Streptomyces filipinensis, is described. The synthetic concept was tested by preparing the lactone 13 (Scheme 2) which contains the characteristic bicyclic core entity of 1 . Key features of the synthesis of 1 are: preparation of 3,5-dihydroxy-2,6-dimethylbenzoic acid ( 23 ) from 3,5-dihydroxybenzoic acid ( 19 ) by two consecutive Mannich aminomethylation/hydrogenation sequences; benzylic N-bromosuccinimide bromination of an ester derivative 25 thereof and its subsequent coupling with Boc-Ser-Cys-OMe ( 11 ); cyclization of the ω-hydroxy acid 29 29 to the 12-membered lactone 30 using preferably Mitsunobu conditions; completion of the peptidic side chains of 1 using Boc strategy (Scheme 4). Optically pure cis-N-(tert-butoxycarbonyl)-3-hydroxy-L -proline ((–)- 14 ) was obtained by resolution of the racemate via an efficient reaction sequence containing a lipase-catalyzed enantiospecific acetate hydrolysis (Scheme 3). The structure of natural 1 was confirmed by comparison with the synthetic material. The synthetic route described provides also easy access to analogues of 1 , e.g., via the intermediate 30 .