Novel synthesis of the glycosidase inhibitor deoxymannojirimycin and of a synthetic precursor D-lyxo-hexos-5-ulose

[reaction: see text]. The synthesis of D-lyxo-hexos-5-ulose (5-ketomannose, 1,5-dicarbonyl sugar), a synthetic precursor to the glycoprocessing inhibitor deoxymannojirimycin, was carried out by an in situ epoxidation and hydrolysis of a trimethylsilyl-protected 6-deoxyhex-5-enopyranoside followed by facile removal of the protecting groups. A novel nine-step synthesis of deoxymannojirimycin has also been achieved from methyl alpha-D-mannopyranoside; this involved methanolysis of epoxides derived from an acetylated 1-azido-6-deoxyhex-5-enopyranoside followed by deprotection and catalytic hydrogenation.     

Synthesis of D-hexos-5-uloses by novel in situ hydrolysis of epoxides derived from 6-deoxyhex-5-enopyranosides

[reaction: see text] Epoxides derived from 2,3, 4-tri-O-protected-6-deoxyhex-5-enopyranosides are hydrolyzed in situ to ultimately give novel protected-D-hexos-5-ulose derivatives (sugar 1,5-dicarbonyls, 5-ketohexoses) in moderate to high yields. The products adopt a bicyclic structure (1,6-anhydropyranos-5-ulose) in solution with the pyranose ring in (4)C(1) conformation. The methodology has been used to prepare D-xylo-hexos-5-ulose (5-ketoglucose), a synthetic precursor to 1-deoxynojirimycin and a possible intermediate in the biosynthesis of inositols.     

Preparation of L-Lyxo-Hexos-5-Ulose Through C-3 Epimerization of Bis-Glycopyranosides of L-Arabino-Hexos-5-Ulose1

Abstract

The unreported title compound and its 2,6-di-O-benzyl derivative have been prepared from methyl β-D-galactopyranoside through a sequence involving the bisglycoside methyl 2,6-di-O-benzyl-5-O-methoxv-β-D-galactopyranoside 8, the precursor of L-orabino-hexos-5-ulose, that was converted to the L-lyxo series by inversion at C-3. The inversion was achieved in acceptable yields by selective triflation, followed by displacement with benzoate, and by an oxidation/reduction sequence. Whereas 2,5-di-O-benzyl-L-lyxo-hexos-5-ulose exists entirely as a mixture of the two anomeric 1,4-furanosic forms, the unprotected hexos-5-ulose involves at equilibrium in CD₃CN/D₂O at least eight tautomers, one of which is predominant.     

The Isomeric Composition of D-Xylo-hexos-5-ulose (5-Keto-glucose) in Aqueous Solution

Abstract

1,2-O-Isopropylidene-α-D-xylo-hexofuranos-5-ulose (2) was deprotected in aqueous acid solution to give a mixture of at least six isomeric forms and one anhydro form of the parent ketoaldohexose, D-xylo-hexos-5-ulose (3), commonly referred to as 5-keto-glucose. Structural assignment of each form was made based on high field ¹H and ¹³C NMR studies of the mixture in aqueous (D₂O) solution. The dominant isomeric form of 3 was observed to have the pyranose structure 1R,5R-D-xlyo-hexo-pyranos-5-ulose (3a, 67 %) with the next most abundant form being an anhydro structure, 1S,5S-l,6-anhydro-D-xylo-hexopyranos-5-ulose (3c, 18 %). Included among the other isomers were the a and β-1,4-furanose (3d, 3e) and 1-aldehydrol β-5,2-furanose (3f) structures. The isomer present in least amount (3g, > 1 %) is assigned as the α-anomer of 3f. Experimentally determined J_C-1,H-1 values were useful in support of assigned isomer structures.     

Synthesis of Indole Derivatives from 2-Keto Glycoside

2-Oxo derivatives of glycosides, called 2-keto glycosides or glycoside 2-uloses, are biologically important in carbohydrate metabolism and are very useful in synthesis of branched-chain sugars and amino sugars. Very little is known of their chemistry because of the high susceptibility of these compounds to degradation in solution, and in particular their instability to base. Thus it is important to study the reactivities of 2-keto glycosides. In a previous paper, we reported the transformation of 2-keto glycosides in pyridine solution. During the transformation of 2-and 3-keto glycosides, a demethoxylation reaction of the enol intermediate was shown to take place simultaneously with elimination to give hex-1-enopyran-3-ulose.     

Utilisation d'ylides du phosphore en chimie des sucres XXIII Eliminations accompagnant certaines réactions de Wittig

Some reactions of 3-O-alkyl-6-deoxy-1,2-O-isopropylidene-α-D-xylo-hexofuranos-5-uloses (1 and 2) with Wittig reagents are described. These ketosugars react with methylenetriphenylphosphorane and benzylidenetriphenylphosphorane to give the expected unsaturated branched-chain sugars and dienes formed by elimination of H–C(4) and the 3-alkyloxy group. Structural studies on all these compounds have been effected using NMR. spectroscopy and particularly, when necessary, nuclear Overhauser Effect. One important by-product of these reactions is an unsaturated ketone 3,6-dideoxy-1,2-O-isopropylidene-α-D-glycero-hex-3-enofuranos-5-ulose (6). Compounds 1 and 2 do not react with cyanomethylenetriphenylphosphorane.     

Stereoselective synthesis of 2,2-bis(C-branched-chain)glucopyranosid-3-ulose via an autoxidation-Michael addition reaction

2,2-Bis(C-branched-chain)glucopyranosid-3-uloses, designed for the preparation of biologically active natural product iridoid derivatives, are synthesized selectively by the new reaction of butenolide-containing sugar with active methylene compounds, and the new reaction is clarified as autoxidation followed by Michael addition of carbanion.     

Stereoselective synthesis of 2,2-bis(C-branched-chain) glucopyranosid-3-ulose via autoxidation reaction

Many different approaches for synthesis of branched chain sugars have beenestablished,1 because they are very useful intermediates for synthesis of other non-sugar chiralmolecules, and usually occur in nature. Branched chain glycosidulose can be used for construction offive- and six-membered carbocyclic rings to which two chiral carbons of sugar are incorporated byintramolecular aldol condensation and Robinson annulation,2 Therefore they are useful in thesynthesis of natural products which consist of annulated carbohydrates or where a highlyfunctionalised enantiomerically pure cyclopentane or cyclohexane is required. Also, this type ofbranched chain sugar can be considered as the synthons of monoterpenoid natural products of theiridoid class which have the cyclopentan-(c)-pyran structure. In view of the importance of branchedchain glycosiduloses, it is desirable to have a general, convenient methodology to their synthesis.However, none of the literature methods was reported on their synthesis by a nuclephilic addition toa partially protected glycosidulose, due to the fact that these glycosiduloses are very difficult tosynthesize selectively and unstable;3 and what is more, one-step synthesis branched chainglycosidulose using this method is almost impossible.In this paper, we report on a general, convenient method for stereoselective syntheses of2,2-bis(C-branched-chain)glucopyranosid-3-uloses by the new reaction of 1 with various activemethylene compounds. The generality of this method was examined in detail. The optimumtemperature was 18-25℃. The solvent DMF was better than the others. In all cases he yields werehigher than 60%.All the 2,2-bis(C-branched-chain)glucopyranosid-3-uloses were characterized by X-raycrystallographic analyses. In addition, the important iintermediate in this reaction was isolated,which is the product of autoxidation of 1 at C-3 position. Thus the reaction mechanism for thesynthesis of 2,2-bis(C-branched-chain) glucopyranosid-3-uloses can be rationalized by autoxidationof 1 followed by 1,4-Michael addition of various carbanions as the main steps.     

Resolution of 2,3-Dideoxy-DL-2-Enopyranos-4-Uloses Via Chromatographic Separation of their Diastereomeric O-tert-Butyloxycarbonyl-L-Alanyl Esters. A Convenient Synthesis of L- and D-Aculose

ABSTRACT

A simple and effective procedure for the resolution of 2,3-dideoxy-DL-2-enopyranos-4-uloses is presented. This procedure is based on column chromatographic separation of their diastereomeric O-(N-tert-butyloxycarbonyl)-L-alanyl esters, followed by mild acidic cleavage of the ester function. L-Aculose, 2,3,6-trideoxy-L-glycero-hex-2-enopyranos-4-ulose, is also prepared in satisfactory yield.     

Synthesis of various derivatives of amino-3-didesoxy-3,5-D-lyxose

LAH reduction of 3, 5-dideoxy-1, 2-O-isopropylidene-β-D -threo-pentofuranose-3-ulose oxime leads with a high stereoselectivity to 3-amino-3, 5-dideoxy-1, 2-O-isopropylidene-β-D -lyxofuranose. Some derivatives of the latter compound are described.     

Optimized thiol derivatizing reagent for the mass spectral analysis of disubstituted epoxy fatty acids

A novel procedure is described for the derivatization of fatty acid epoxides in the presence of their corresponding diols. The acidic character of 2,3,5,6-tetrafluorobenzenethiol promotes favorable mass fragmentation of linoleate and arachidonate derived epoxide derivatives and reduces alkene isomerization to a manageable side reaction, eliminated through the addition of a thiol scavenger. After silylation, regioisomeric mixtures of epoxy- and dihydroxylipids are simultaneously detected and discriminated using gas chromatography with electron impact mass spectral detection. Silylated hydroxysulfanyloctadecanoids yielded instrumental detection limits of 5 pg/microl, sufficient sensitivity for the quantification of endogenous epoxylipids.     

Isomérisations en chimie des sucres. II Fermetures de cycles par attaque nucléophile intramoléculaire sur des carbones sp2 à caractère électrophile: Furannoses hybridés sp2 en C3

When heated with one equivalent of H₂O, the 1,2: 5,6-di-O-isopropylidene-α-D-ribo- and -xylo-hexofuranos-3-uloses loose one molecule of acetone and yield the 3, 6-anhydro-1, 2-O-isopropylidene-α-D-ribo- and -xylo-hexofuranos-3-ulose ketohydrols. The carbonyl group of the starting material seems to provide some kind of intramolecular electrophilic assistance to the hydrolysis of the 5, 6-O-isopropylidene group. When the oxygen of the carbonyl group is replaced by cyanomethylene, an analogous cyclisation takes place under base catalysis, provided that C6 bears a free hydroxyl group.     

5-Keto-Mannose (D-Lyxo-Hexos-5-Ulose) in Aqueous Solution-Isomeric Composition Dominated by α/β D-Fructofuranose Related Structures

Abstract

Selective C-6 hydroxyl triphenylmethylation of methyl 2,3-O-isopropylidene-α-D-mannofuranose (1), followed by C-5 hydroxyl oxidation and sequential removal of protecting groups in aqueous acid, yielded D-lyxo-hexos-5-ulose (5-keto-mannose, 5) as a mixture of isomeric forms. The isomeric mixture of 5 in D₂O solution was carefully examined using ¹H and ¹³C NMR techniques and structural assignments were made for seven isomers. The most prevalent form of 5 observed was the ketofuranose isomer 2S, 5R-D-lyxo-hexo-5,2-furanos-5-ulose 1-hydrate (5a, 52%), with its 2S, 5S-ketofuranose anomer (5b) being the next most abundant (14%). Also identified in the mixture were the α and β-hexofuranos-5-uloses 5c (6%) and 5d (< 2%), the pyranose structure 1R,5R-lyxo-hexopyranos-5-ulose 5e (10%), and the anhydro isomer 1R,5R-1,6-anhydro-D-lyxo-hexopyranos-5-ulose (5f, 5%), present in ¹ C ₄ conformation. Limited spectral information suggests that the remaining isomer 5g (8%) is a hydrated acyclic aldehyde form of 5.     

A facile solid-phase synthesis of substituted 2(5H)-furanones from polymer-supported alpha-selenocarboxylic acids

The synthesis of polystyrene-supported alpha-selenoacetic acid, alpha-selenopropionic acid, and alpha-selenophenylacetic acid is described. The reaction of the dilithio derivatives of polymer-supported alpha-selenocarboxylic acids with racemic epoxides or optically active styrene oxide afforded polystyrene-supported gamma-substituted alpha-selenobutyrolactones. The alpha-alkylation reaction of gamma-substituted polystyrene-supported alpha-selenobutyrolactones provided another route for the synthesis of polystyrene-supported alpha,gamma-disubstituted alpha-selenobutyrolactones. Subsequent oxidation-elimination with an excess of 30% hydrogen peroxide at room temperature afforded substituted (3- and 5-mono-; 3,4- and 3,5-di) 2(5H)-furanones in high yields and good purities.     

Synthesis and reactions of some chloro-2,2-dimethylchromens

5-, 6-, 7-, and 8-Chloro-2,2-dimethylchromins have been prepared from the corresponding chloro-coumarin and their conversion into the 3,4-dihalogenochroman derivatives is described. The 4-halogen atom is shown to be the more susceptible to hydrolysis by conversion of the resulting halohydrins into chromanones and epoxides. The formation of bis-chromens during the dehalogenation of 3-halogenochromanones is reported.     

Regioselective synthesis of N-substituted-4-substituted isothiazolidine-1,1-dioxides

A novel and efficient synthesis of a range of racemic and enantioenriched N-substituted-4-substituted isothiazolidine-1,1-dioxides from epoxides and sulfonamides is described. The critical choice of the activating group for the cyclization event is discussed. The application of this methodology to the synthesis of N-substituted-4,5-disubstituted derivatives is also described.     

Stereospecific Synthesis of D-Glycero-D-ido-oct-2-ulose

Summary.  D-Glycero-D-gulo-heptose reacted with 2,2-dimethoxypropane to give its 2,3:6,7-di-O-isopropylidene derivative. Its base-catalyzed addition to formaldehyde resulted in the formation of 2,3:6,7-di-O-isopropylidene-2-C-(hydroxymethyl)-D-glycero-D-gulo-heptofuranose. After acid hydrolysis of this aldolization product, a new branched-chain aldose, 2-C-(hydroxymethyl)-D-glycero-D-gulo-heptose, was obtained, which was stereospecifically rearranged under the catalytic action of molybdic acid to D-glycero-D-ido-oct-2-ulose. Received October 17, 2000. Accepted December 4, 2000     

The Isomeric Composition of 6-Deoxy-D-XYLO-Hexos-5-Ulose in Aqueous Solution as Determined by 1H and 13C NMR

Abstract

Acid hydrolysis of 6-deoxy-1,2-O-isop ropylidene-α-d-xylo-hexo-furanos-5-ulose (4) yielded gummy 6-deoxy-d-xylo-hexos-5-ulose (1) as an isomeric mixture of two furanose forms, 6-deoxy-α-d-xylo-hexo-furanos-5-ulose and 6-deoxy-β-d-xylo-hexofuranos-5-ulose, and a pyranose structure 1R, 5R-6-deoxy-d-xylo-hexopyranos-5-ulose. The combined percentage (64%) of the furanoses represents an unusually large amount of free carbonyl form for a sugar when compared to simple hexoses and 2-hexuloses. Isomeric structures were determined in deuterium oxide solution by ¹H and ¹³C NMR.     

Synthesis of Protein Conjugates of 2-Carboxy-L-Arabinitol 5-Phosphate and 2-Carboxy-L-Ribitol 5-Phosphate

Abstract

The synthesis of 5-O-[5-(pentanoic acid)]-phosphono-L-erythro-pent-2-ulose 2 was successfully achieved by coupling benzyl 5-hydroxypentanoate 9b and 1-O-benzyl-L-erythro-pent-2-ulose ethane- 1,2-diyl dithioacetal 13 with the enediol pyrophosphate 18. Compound 2 was coupled to carrier proteins, porcine thyroglobuline and bovine serum albumin and the conjugates were treated with KCN to give conjugates of the hapten 1, designed to raise catalytic antibodies.     

Base-promoted reaction of methyl 4,6-O-benzylidene-3-deoxy-hexopyranosid-2-ulose and various arylamines

Reaction of methyl 4,6-O-benzylidene-3(2)-deoxy-hexopyranosid-2(3)-ulose (1) with various arylamines under Bargellini reaction conditions was investigated. A series of unique enaminoketones 3-12 was obtained unexpectedly under basic conditions in 52-72% yield.