A short and efficient synthesis of 5-hydroxymethylcyclopent-2-enol from d-glucose and its elaboration to the carbanucleoside (−)-carbovir

Introduction of an allyl functionality at C-3 of 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose followed by olefination at C-5 and C-6 provided 1,6-diene 5 which, upon ring closing metathesis and subsequent functional group manipulation, furnished the key cyclopentene diacetate 7, which was elaborated to carbanucleoside (−)-carbovir 1.     

A convenient approach to an advanced intermediate for (+)-lactacystin synthesis

A fully stereoselective preparation of the advanced intermediate 24 for the synthesis of (+)-lactacystin from known 1,2:5,6-di-O-isopropylidene-α-d-gulofuranose (2), as the source of chirality, has been achieved. The C-5 methyl group was introduced via a Wittig olefination followed by Pd/C-mediated hydrogenation of the conformationally restricted alkene 11 in a highly stereoselective manner. The stereogenic tetrasubstituted carbon centre at C-3, with an amino group, was installed stereoselectively via an Overman rearrangement, which was efficiently controlled by a saccharide environment.     

Synthesis and characterization of cyclopentadienyl/alkoxo titanium dichlorides: structural analysis of monocyclopentadienyl titanium dichlorides with ligands derived from menthol and borneol

A variety of monocyclopentadienyl alkoxo titanium dichloride and bisalkoxo titanium dichloride complexes have been prepared and characterized by spectroscopic techniques. The titanium derivatives containing both cyclopentadienyl and various alkoxo ligands [Ti(η⁵-C₅H₅)(OR)Cl₂] (1-5) have been synthesized from the reaction of [Ti(η⁵-C₅H₅)Cl₃] with 1 equivalent of the corresponding alcohol in THF in the presence of triethylamine (ROH = Adamantanol, 1R,2S,5R-(−)-menthol, 1S-endo-(−)-borneol, cis-1,3-(−)-benzylideneglycerol, 1,2:3,4-di-O-isopropylidene-α-d-galactopyranose). The bisalkoxo titanium dichloride derivatives [TiCl₂(OR)₂] (6-10) have been prepared by a redistribution reaction between Ti(OR)₄ and TiCl₄ compounds 6-8 (OR = Adamantanoxy, (1R,2S,5R)-(−)menthoxy, (1S-endo)-(−)-borneoxy) and by reaction of [Ti(OR)₂(OPrⁱ)₂]₂ with CH₃COCl compounds 9 and 10 (OR = 1,2:3,4-di-O-isopropylidene-α-d-galactopyranoxy, and 1,2:5,6-di-O-isopropylidene-α-d-glucofuranoxy). The molecular structures of 2 and 3 have been determined by single crystal X-ray diffraction studies.     

One-pot carbanionic access to methylenebis(phosphonate) analogues of natural P,P-glycosyl-disubstituted pyrophosphates

Two novel lithiated carbanions derived from ethyl (1,2:3,4-diisopropylidene-α-d-galactopyranosyl) methyl phosphonate 3a and ethyl (1-O-methyl-2,3-O-isopropylidene-β-d-ribofuranosyl) methylphosphonate 3b were used in the one-pot alkylidene diphosphorylation of 2,3-O-isopropylidene uridine or 2,3:5,6-di-O-isopropylidene-d-mannofuranose to synthesise the methylenebis(phosphonate) analogues of natural P¹,P²-glycosyl-disubstituted pyrophosphates.     

Synthesis and structure of titanium alkoxide complexes with bulky ligands derived from natural products: Asymmetric epoxidation of cinnamyl alcohol

A family of titanium(IV) alkoxide compounds [{Ti(OPrⁱ)₃(OR)}₂], [{Ti(OPrⁱ)₂(OR)₂}₂], and Ti(OR)₄ (1-12) have been prepared using two different routes: by metathesis reaction of TiCl(OPrⁱ)₃ and TiCl₂(OPrⁱ)₂ with ROH in the presence of Et₃N and alternatively by alcohol exchange of Ti(OPrⁱ)₄ and the corresponding higher boiling alcohol (ROH=adamantanol, 1,2:3,4-di-O-isopropylidene-α-d-galactopyranose, 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose, 1R,2S,5R-(−)-menthol). These tetra alkoxide titanium(IV) compounds have been characterized by spectroscopic techniques. In addition, some of these chiral Lewis acid titanium compounds, derived from diacetone galactose and diacetone glucose, have been studied in the asymmetric epoxidation of cinnamyl alcohol in order to evaluate their catalytic activity and stereoselectivity.     

Synthesis of an octasubstituted galactose zinc(II) phthalocyanine

4,5-Bis(1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl)phthalonitrile (3) was prepared by S_NAr reaction of diacetone galactose 1 and 4,5-difluorophthalonitrile (2) in 96% yield. Cyclotetramerization of 3 was achieved via its isoindoline derivative 4, affording the peripherally octasubstituted galactose zinc(II) phthalocyanine 5 in 29% yield. Deprotection of 5 gave the highly water soluble octasubstituted galactose zinc(II) phthalocyanine 6 in 81% yield which will be applied as a photosensitizer in photodynamic therapy.     

Polyhydroxylated pyrrolidines. Part 4: Synthesis from d-fructose of protected 2,5-dideoxy-2,5-imino-d-galactitol derivatives

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-5-O-methanesulfonyl-β-d-fructopyranose (5) was straightforwardly transformed into its d-psico epimer (8), after O-debenzoylation followed by oxidation and reduction, which caused the inversion of the configuration at C(3). Compound 8 was treated with lithium azide yielding 5-azido-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-α-l-tagatopyranose (9) that was transformed into the related 3,4-di-O-benzyl derivative 10. Cleavage of the acetonide in 10 to give 11, followed by regioselective 1-O-pivaloylation to 12 and subsequent catalytic hydrogenation gave (2R,3S,4R,5S)-3,4-dibenzyloxy-2,5-bis(hydroxymethyl)-2′-O-pivaloylpyrrolidine (13). Stereochemistry of 13 could be determined after O-deacylation to the symmetric pyrrolidine 14. Total deprotection of 14 gave 2,5-imino-2,5-dideoxy-d-galactitol (15, DGADP).     

Polyhydroxylated pyrrolidines, III. Synthesis of new protected 2,5-dideoxy-2,5-iminohexitols from d-fructose

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (6) was straightforwardly transformed into 5-azido-3-O-benzoyl-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (8), after treatment under modified Garegg's conditions followed by reaction of the resulting 3-O-benzoyl-4-O-benzyl-5-deoxy-5-iodo-1,2-O-isopropylidene-α-l-sorbopyranose (7) with lithium azide in DMF. O-debenzoylation at C(3) in 8, followed by oxidation and reduction caused the inversion of the configuration to afford the corresponding β-d-psicopyranose derivative 11 that was transformed into the related 3,4-di-O-benzyl derivative 12. Cleavage of the acetonide of 12 to give 13 followed by O-tert-butyldiphenylsilylation afforded a resolvable mixture of 14 and 15. Compound 14 was transformed into (2R,3R,4S,5R)- (17) and (2R,3R,4S,5S)-3,4-dibenzyloxy-2′,5′-di-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (18) either by a tandem Staudinger/intramolecular aza-Wittig process and reduction of the resulting intermediate Δ²-pyrroline (16), or only into 18 by a high stereoselective catalytic hydrogenation. When 15 was subjected to the same protocol, (2S,3S,4R,5R)- (21) and (2R,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (22) were obtained, respectively.     

Two new examples of the rare C→O migration of ethoxycarbonyl groups

Two new examples of a carbon→oxygen ethoxycarbonyl group shift are described. Treatment of 3-ethoxycarbonylnitromethyl-1,2-O-isopropylidene-6-O-p-toluenesulfonyl-α-d-allofuranose (4) with Bu₄NF leads to a rearrangement to 5-O-ethoxycarbonyl-1,2-O-isopropylidene-3-nitromethyl-6-O-p-toluenesulfonyl-α-d-allofuranose (8). Similar treatment of ethyl-3-O-benzyl-6-deoxy-6-nitro-d,l-glycero-d-glucoheptofuronate (12) gives 3-O-benzyl-4-O-ethoxycarbonyl-6-deoxy-6-nitro-d-glucopyranose (16).     

Concise synthesis of 3-deoxy-d-manno-oct-2-ulosonic acid (KDO) as a protected form based on a new transformation of α,β-unsaturated ester to α-oxocarboxylic acid ester via diol cyclic sulfite

A concise synthesis of KDO (1) as the suitably protected form (2) from 2,3:5,6-di-O-isopropylidene-α-d-mannofuranose (3) was achieved in five steps (overall 65% yield). The key step is the efficient transformation of readily available α,β-unsaturated ester to α-oxocarboxylic acid ester. The newly β-elimination of the corresponding diol cyclic sulfite and the in situ trap (DBU/TMSCl) into enol silyl ether was developed to give the tautomeric equivalent of α-oxocarboxylic acid ester. The deprotection of acid labile TMS ether provided the desired product.     

Direct vinylation of glucose derivatives with acetylene

Vinyl ethers, promising chiral carbohydrate synthons, have been synthesized by the addition of glucose acetals (1,2:5,6-di-O-isopropylidene-α-d-glucofuranose, methyl 4,6-O-benzylidene-α-d-glucopyranoside, 1,2-O-cyclohexylidene-α-d-glucofuranose, methyl α-d-glucopyranoside) to acetylene under atmospheric and elevated pressures in an autoclave in the presence of superbase catalytic systems (KOH-DMSO, t-BuOK-DMSO). The complete vinylation of 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose and methyl α-d-glucopyranoside has been realized under elevated pressure of acetylene in the system KOH-THF as well.     

Polyhydroxylated pyrrolidines: synthesis from d-fructose of new tri-orthogonally protected 2,5-dideoxy-2,5-iminohexitols

The readily available 3-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (2) was transformed into its 5-O- (3) and 4-O-benzoyl (4) derivative. Compound 4 was straightforwardly transformed into 5-azido-4-O-benzoyl-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (7) via the corresponding 5-deoxy-5-iodo-α-l-sorbopyranose derivative 6. Cleavage of the acetonide in 7 to give 8, followed by regioselective 1-O-silylation to 9 and subsequent catalytic hydrogenation gave a mixture of (2S,3R,4R,5R)- (10) and (2R,3R,4R,5R)-4-benzoyloxy-3-benzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (12) that was resolved after chemoselective N-protection as their Cbz derivatives 11 and 1a, respectively. Stereochemistry of 11 and 1a could be determined after total deprotection of 11 to the well known DGDP (13). Compound 2 was similarly transformed into the tri-orthogonally protected DGDP derivative 18.     

Synthesis of (+)-1-epi-castanospermine from l-sorbose

Diastereoselective synthesis of 1-epi-castanospermine (2) from l-sorbose is described. The successful approach involved the use of 8-azido-2,8-dideoxy-α-l-gulo-oct-4-ulo-4,7-furanosononitrile intermediate (17). This compound was easily made in five steps from 3-O-benzoyl-2-deoxy-4,5:6,8-di-O-isopropylidene-α-l-gulo-oct-4-ulo-4,7-furanosononitrile (7) previously synthesized from l-sorbose. Catalytic hydrogenation of the azido intermediate 17 with Pd-C afforded with total stereocontrol one of the two possible piperidine diastereomers. Acid-catalyzed internal reductive deamination of the nitrile derivative completed the total synthesis of (1R,6S,7R,8R,8aR)-1,6,7,8-tetrahydroxyindolizidine [(+)-1-epi-castanospermine, 2].     

Concise and practical route to tri- and tetra-hydroxy seven-membered iminocyclitols as glycosidase inhibitors from d-(+)-glucurono-γ-lactone

An efficient and short total synthesis of tetrahydroxy-1c and trihydroxy-azepane 1d is reported in 72% and 57% overall yields, respectively, from d-(+)-glucurono-γ-lactone. Thus, d-glucuronolactone 2 on acetonide protection, DIBAL-H reduction and one-pot intermolecular reductive amination followed by -NCbz protection afforded 6-(N-benzyl-N-benzyloxycarbonyl) amino-6-deoxy-1,2-O-isopropylidene-α-d-gluco-1,4-furanose 5a. 1,2-Acetonide hydrolysis in 5a and Pd-mediated intramolecular reductive aminocyclization afforded tetrahydroxyazepane 1c. An analogous pathway with 5-deoxy-1,2-O-isopropylidene-α-d-glucurono-6,3-lactone 3b gave trihydroxy-azepane 1d. Glycosidase inhibitory activity of 1c/1d was studied and 1d was found to be potent inhibitor of α-mannosidase and β-galactosidase.     

Diastereoselective syntheses of 1-deoxyhomonojirimycin and two new 1,5,6-trideoxy-1,5-iminoheptitols with d-allo- and l-talo-configuration

The synthesis of 1-deoxyhomonojirimycin 2, as well as two new diastereomers, namely 1,5,6-trideoxy-1,5-imino-d-allo-heptitol 3 and 1,5,6-trideoxy-1,5-imino-l-talo-heptitol 4, is described. Compound 2 was obtained from 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose—while 3 and 4 were obtained from 1,2:5,6-di-O-isopropylidene-α-d-allofuranose. These compounds were transformed in a few steps to the corresponding β-ketoesters 12 and 18, respectively, which were hydrogenated diastereoselectively in the presence of chiral ruthenium complexes with total control of the C-5 stereogenic centre. The resulting β-hydroxyesters 13, 19a and 19b are key intermediates for the syntheses of the 1,5,6-trideoxy-1,5-iminoheptitols 2, 3 and 4, respectively.     

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.     

Selective iodination of vicinal cis-diols on ketopyranose templates

A regio- and stereoselective iodination has been performed on vicinal diols located on ketopyranose templates using the controlled- Garegg conditions. 3-O-Benzyl-1,2-O-isopropylidene-β-d-fructo- or psicopyranoses (1 or 4) were selectively iodinated, respectively, at C-5 or C-4 of the ketoses to afford the l-sorbo or d-sorbo iodohydrins.     

The microbiological transformation of steroidal saponins by Curvularia lunata

The microbiological transformation of polyphyllin I (compound I), polyphyllin III (compound II), polyphyllin V (compound III) and polyphyllin VI (compound IV) by Curvularia lunata into their corresponding subsaponins, for example, diosgenin-3-O-α-l-arabinofuranosyl (1→4)-β-d-glucopyranoside (compound V), diosgenin-3-O-α-l-rhamnopyranosyl (1→4)-β-d-glucopyranoside (compound VI), diosgenin-3-O-β-d-glucopyranoside (compound VII) and pennogenin-3-O-β-d-glucopyranoside (compound VIII), were studied in this paper. Curvularia lunata is able to hydrolyze terminal rhamnosyls that are linked by 1→2 C- bond to sugar residues of steroidal saponins at C-3 position with high activity and regioselectivity.     

Enantioselective synthesis of (1S,2S)-1,2-di-tert-butyl and (1R,2R)-1,2-di-(1-adamantyl)ethylenediamines

An enantioselective synthesis of sterically congested 1,2-di-tert-butyl and 1,2-di-(1-adamantyl)ethylenediamines has been developed. Thus, diastereomerically pure trans-1-apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinones 6 and 7 were successfully prepared by optical resolution of (±)-trans-4,5-dimethoxy-2-imidazolidinone using apocamphanecarbonyl chloride (MAC-Cl) followed by stereospecific and stepwise substitution of the dimethoxyl groups using tert-butyl or 1-adamantyl cuprates to provide (4S,5S)-4,5-di-tert-butyl and (4R,5R)-4,5-di-(1-adamantyl)-2-imidazolidinones 12 and 15, respectively. Furthermore, N-acetyl 4,5-di-tert-butyl and 4,5-di-(1-adamantyl)-2-imidazolidinones 16a,b were enantioselectively deacetylated using a catalytic oxazaborolidine system to provide enantiopure 1-p-tolylsulfonyl-4,5-di-tert-butyl-2-imidazolidinones 12 and 19 and 1-p-tolylsulfonyl-4,5-di-(1-adamantyl)-2-imidazolidinones 18 and 20, respectively. Finally, N-p-tolylsulfonyl-2-imidazolidinones 12 and 15 were treated with 30 equiv of Ba(OH)₂·8H₂O to achieve ring cleavage and to provide (1S,2S)-1,2-di-tert-butylethylenediamine 3 and (1R,2R)-1,2-di-(1-adamantyl)ethylenediamine 4.     

Strukturelle Abwandlungen an Kohlenhydraten, 7. Mitt.

The synthesis of the title compound from 1,2:5,6-Di-O-isopropyliden-α-D-glucofuranose (1) via 1,2:5,6-Di-O-isopropyliden-α-D-gulofuranose (4) is reported. The key-step is the introduction of the azido function into4 which is achieved by using Triphenylphosphane/Diethylazodicarboxylate/HN₃.