Alex Rosenthal

Synthesis of branched-chain nitro and amino sugars by the nitromethane route

Abstract Addition of 5- O -benzyl-1,2- O -isopropylidene-α- d - erythro -pentofuranos-3-ulose ( 1 ) to excess nitromethane and 1 molar equivalent of sodium methoxide in methanol gave 5- O -benzyl-1,2- O -isopropylidene-3- C -nitromethyl-α- d -ribofuranose ( 2 ) in 60% yield. Under essentially the same conditions, 1,2:5,6-di- O -isopropylidene-α- d - ribo -hexofuranos-3-ulose ( 4 ) yielded 1,2:5,6-di- O -isopropylidene-3- C -nitromethyl-α- d -glucofuranose ( 5 ) in 71% yield. Treatment of the ketose 4 with nitromethane and sodium hydride gave 5 and the allo -epimer 5a in a total yield of 91%. The proof of structure of the branched-chain nitro sugars is described. Selective hydrolysis of 5 gave the partially blocked into sugar 6 , which was converted by catalytic hydrogenation into the branched-chain amino sugar 9 (characterized as its N -acetyl derivative). Oxidation of 6 with sodium metaperiodate, followed by reduction of the aldehydo-derivative with sodium borohydride, afforded 1,2- O -isopropylidene-3- C -nitromethyl-α- d -xylofuranose ( 7 ). Reduction of 7 yielded the partially blocked amino sugar 13 . Compounds 7 and 13 were unblocked to afford the unsubstituted, branched-chain, nitro and amino sugars. The 3-acetate of 5 was converted by a Schmidt-Rutz reaction into a nitroolefin (not isolated), which was hydrogenated with sodium borohydride in ethanol to yield mainly 3-deoxy-1,2:5,6-di- O -isopropylidene-3- C -nitromethyl-α- d -glucofuranose ( 17 , assigned on basis of its n.m.r. spectrum).

Branched-chain sugar nucleosides. Synthesis of 3′-C-ethyl (and 3′-C-butyl)uridine

Abstract Syntheses of 3′- C -ethyl(and 3′- C -butyl)uridine ( 13 and 15 ) are described. Addition of ethyl (and butyl)magnesium bromide or the corresponding alkyllithiums to 1,2:5,6-di- O -isopropylidene-α- d - ribo -hexofuranos-3-ulose ( 1 ) gave 3- C -ethyl (and 3- C -butyl)-1,2:5,6-di- O -isopropylidene-α- d -allofuranose ( 2 and 3 ). Selective hydrolysis of 2 and 3 , followed by periodate cleavage of the 5,6-diol and subsequent reduction, yielded the diols 6 and 7 . Selective benzoylation of the latter compounds afforded 5- O -benzoyl-3- C -ethyl(and 3- C -butyl)-1,2- O -isopropylidene-α- d -ribofuranose ( 8 and 9 ). Hydrolysis of the latter compounds, followed by acetylation, yielded anomeric mixtures of branched-chain sugar triacetates 10 and 11 . These were condensed with bis(trimethylsilyl)uracil and the products deacylated with methanolic ammonia to afford in high yield the title nucleosides 13 and 15 .

Branched-chain sugars via the hydroboration—oxidation of unsaturated sugar derivatives

Abstract Hydroboration—oxidation of 5-O-benzyl-1,2-O-isopropylidene-3-deoxy-3-C-methylene-α- D -ribofuranose (2) afforded 5-O-benzyl-1,2-O-isopropylidene-3-C-methyl-α- D -ribofuranose (3), 5-O-benzyl-1,2-O-isopropylidene-3-C-methyl-α- D -xylofuranose (4), and 5-O-benzyl-1,2-O-isopropylidene-3-deoxy-3-C-hydroxymethyl-α- D -ribofuranose (5), in the ratio of 5:7:88. The minor ribo-isomer 3 was also synthesized (in 71% yield) by application of a Grignard synthesis to the ketose 1. The oxymercuration—demercuration reaction of the unsaturated sugar derivative 2 failed. The structures of the isomeric branched-chain sugars 3, 4, and 5 were proved by chemical and physical means.

Mass-spectrometric investigations of peracetates of unsaturated carbohydrates, anhydrodeoxyalditols, and a branched-chain sugar

Abstract The mass spectra of a number of peracetates of unsaturated (carbon—carbon double bond) monosaccharides, anhydrodeoxyalditols, and a branched-chain monosaccharide are presented in tabular form. A detailed interpretation of the fragmentation processes undergone by these molecules is presented. The unsaturated carbohydrates are shown to be intermediates in the breakdown of hexose peracetates. The evidence strongly indicates that the stereochemistry of some anhydrodeoxyalditol peracetates can be determined by mass spectrometry. Mass spectrometry is also a useful technique for indicating the position of the branched-chain on a carbohydrate, but not its stereochemistry. The proposed fragmentation processes are supported by the spectra of some isotopically labelled compounds.

Branched-chain glycosyl α-amino acids : Part II. Synthesis of 2-D- and 2-L-(3-deoxy-1,2:5,6-di-O-isopropylidene-α-D-glucofuranos-3-yl)glycine. Analogs of the sugar moiety of the polyoxins

Abstract Stereospecific hydroxylation of 3-deoxy-1,2:5,6-di-O-isopropylidene-3-C-trans-and 3-C-cis-(methoxycarbonylmethylene)-α- D -ribo-hexofuranose (2 and 3, respectively), with potassium permanganate in pyridine afforded 3-C-[S- and R-hydroxy-(methoxycarbonyl)methyl]-1,2:5,6-di-O-isopropylidene-α- D -glucofuranose, (6 and 7, respectively), in a combined yield, after chromatography, of 43%. Selective formation of monomethanesulfonates (9a and 10a) and p-toluenesulfonates (9b and 10b), followed by treatment with sodium azide and reduction of the azide, afforded the methyl 2- D -(and 2- L -)(3-deoxy-1,2:5,6-di-O-isopropylidene-α- D -glucofuranos-3-yl)-glycinates (12a and 13a, respectively). Basic hydrolysis of the latter compounds yielded 2- D - and 2- L -(3-deoxy-1,2:5,6-di-O-isopropylidene-α- D -glucofuranos-3-yl)glycine (12b and 13b, respectively). The structures of the glycosyl amino acids were correlated with that of L -alanine by circular dichroism.

Synthesis of an analog of the nucleoside moiety of the polyoxins

Abstract Addition of methyl nitroacetate to 1,2:5,6-di- O -isopropylidene-α- d - ribo -hexofuranos-3-ulose in the presence of ammonium acetate in anhydrous N , N -dimethylformamide afforded 1,2:5,6-di- O -isopropylidene-3- C -( R,S )nitro(methoxy-carbonyl)methyl-α- d -allofuranose ( 2 ). Reduction of the nitro acetate 3 over palladium-on-charcoal gave the oxime 4 , whereas reduction of 3 over Raney nickel afforded methyl l (and d )-2-(3- O -acetyl-1,2:5,6-di- O -isopropylidene-α- d -allofuranos-3-yl)-glycinates ( 5 and 6 ), in 67 and 8% yields, respectively. Saponification of 5 and 6 afforded the glycos-3-yl-α-amino acids 11 and 12 . Conversion of the allofuranos-3-yl adduct 2 into the glucofuranos-3-yl reduction-products 13 and 14 was achieved by treatment of 2 with methanol and acetic anhydride in the presence of palladium-on-charcoal. The N -trifluoracetyl derivative ( 10 ) of 5 , underwent selective hydrolysis by 66% acetic acid to afford a diol that was acetylated to afford the allo tri-acetate 15 . The 5,6-glycol was selectively degraded by standard reactions to yield methyl N -acetyl- l -2-(5- O -acetyl-1,2- O -isopropylidene-α- d -ribofuranos-3-yl)glycinate ( 19 ). Application of the triflate-alkylation synthesis of nucleosides to the allo trifluoroacetyl amino acid 15 and silylated thymine yielded 1-[2,3,5,6-tetra- O -acetyl-[3- C -(methyl N -trifluoroacetyl- l -2-glycinate)]-β- d -allofuranosyl]thymine ( 23 ) in 93% yield. Deprotection of 23 to yield the nucleoside amino acid 25 was not successful.

Synthesis of 6-substituted uridines. synthesis of (R or S)-6-(3-amino-2-carboxypropyl)uridine

Abstract Addition of 5-bromo-2′,3′-O-isopropylidene-5′-O-trityluridine (2) in pyridine to an excess of 2-lithio-1,3-dithiane (3) in oxolane at 78° gave (6R)-5,6-dihydro-(1,3-dithian-2-yl)-2′,3′-O-isopropylidene -5′-O-trityluridine (4), (5S,6S)-5-bromo-5,6-dihydro-(1,3-dithian-2-yl)-2′,3′-O-isopropylidene-5′-O-trityluridine (5), and its (5R) isomer 6 in yields of 37, 35, and 10%, respectively. The structure of 4 was proved by Raney nickel desulphurization to (6S)-5,6-dihydro-2′,3′-O-isopropylidene-6-methyl-5′-O-trityluridine (7) and by acid hydrolysis to give D -ribose and (6R)-5,6-dihydro-6-(1,3-dithian-2-yl)uracil (9). Treatment of 4 with methyl iodide in aqueous acetone gave a 30&%; yield of (R,S)-5,6-dihydro-6-formyl-2′,3′-O-isopropylidene-5′-O-trityl-uridine (10), characterized as its semicarbazone 11. Both 5 and 6 gave 4 upon brief treatment with Raney nickel. Both 5 and 6 also gave 6-formyl-2′,3′-O-isopropylidene-5′- O-trityluridine (12) in ∼41%; yield when treated with methyl iodide in aqueous acetone containin- 10%; dimethyl sulfoxide. A by-product, identified as the N-methyl derivative (13) of 12 was also formed in yields which varied with the amount of dimethyl sulfoxide used. Reduction of 12 with sodium borohydride, followed by deprotection, afforded 6-(hydroxymethyl)uridine (17), characterized by hydrolysis to the known 6-(hydroxymethyl)uracil (18). Knoevenagel condensation of a mixture of the aldehydes 12 and 13 with ethyl cyanoacetate yielded 38%; of E- (or Z-)6-[(2-cyano-2-ethoxycarbonyl)ethylidene]-2′,3′-O-isopropylidene-5′-O-trityluridine (19) and 10%; of its N-methyl derivative 20. Hydrogenation of 19 over platinum oxide in acetic anhydride followed by deprotection gave R (or S)-6-(3-amino-2-carboxypropyl)uridine (23).

Branched-chain N-sugar nucleosides : Part IV. Nucleosides of 3-C-branched-chain, 3-C-(cyanomethyl)- and 3-C-(2-aminoethyl)-2,3-dideoxy-D-threo-pentose

Abstract 2-Deoxy- D - erythro -pentose ( 1 ) was treated with 0.05% methanolic hydrogen chloride, followed by chlorotriphenylmethane in pyridine, to afford methyl 2-deoxy-5- O -trityl-α(and β)- D - erythro -pentofuranoside ( 3 and 4 ). Oxidation with ruthenium tetraoxide and reaction of the product with diethylphosphonate cyanomethylid, followed by hydrogenation, afforded methyl 3- C -(cyanomethyl)-2,3-dideoxy-5- O -trityl-α- D - erythro (and threo )-pentofuranoside ( 9 and 10 ) and methyl 3- C -(cyanomethyl) 2,3-dideoxy-5- O -trityl-β- D - threo -pentofuranoside ( 11 ). Compounds 10 and 11 were converted into the same p -bromobenzoyl derivative, which was directly fused with 2,6-dichloropurine to yield 9-[4- O -( p -bromobenzoyl)-3- C -(cyanomethyl)-2,3-dideoxy-β (and α)- D - threo -pentopyranosyl]-2,6-dichloropurine ( 14 and 15 ) and 1,5-anhydro-4- O -( p -bromobenzoyl)-3- C -(cyanomethyl)-2,3-dideoxy- D - threo -pent-1-enitol ( 16 ). Both 14 and 15 were treated with 25% aqueous dimethylamine solution, to give 2-chloro-9-[3- C -(cyanomethyl)-2,3-dideoxy-β(and α)- D - threo -pentopyranosyl]-6-( N,N -dimethylamino)purine. Compound 14 was reduced over platinum oxide in acetic anhydride and ethanol to give 9-[3-(2-acetamidoethyl)-2,3-dideoxy-β- D - threo -pentopyranosyl]-2-chloro-6-( N,N -dimethylamino)purine ( 19 ).

THE REACTION OF UNSATURATED CARBOHYDRATES WITH CARBON MONOXIDE AND HYDROGEN

Di-O-acetyl-~-xylal reacted with carbon n~onoxide and hydrogen in the presence of clicobalt octacarbonyl to yield 1,5-anhydro-4-deoxy-~-arab~)zo-hexitol (I) ancl 1,s-anhydro-4- deoxy-L-sylo-hexitol (11). The stereochemistry at C-5 of the hesitols was elucidatecl by correlation with the triol ether (VI) obtained by sodi~~iil borohydride reduction of the perioclate oxidation product of 1,4~anhytlro-5-cleosy-~-arabi?~o-hexitol (VII). Reaction of 3,4-di-0- acet~l-D-xylal with carbon monoside and deuteri~~rll afforded 1,5-anhydro-4-cleosy-~-n1~1bit1o- hc~itol-4,6,6-H3~ (VIII) and 1,5-anhydr0-4-deoxy-~-.vylo-hexitol-4,,6-H (IS). Examination of the nuclear magnetic resonance (n.m.r.) spectra of the nor~ual and cleuterated anhydro- deosyhexitols confirmed the structural assignments and shorvcd that cis-addition to the double bond takes place to give (IX).

9-[3-acetamido-3-C-(carboxymethyl)-3-deoxy-32,2-lactone-α (andβ)-D-xylofuranosyl]adenine-analogs of the nucleoside moiety of the polyoxins

Abstract Treatment of (Z)-3-deoxy-1,2:5,6-di-O isopropylidene-3-C-(methoxycarbonyl) methylene-α- D -ribo-hexofuranose (1) with a mixture of sodium azide, hydrazoic acid. and N,N-dimethylformamide afforded 3-azido-3-deoxy-1,2:5,6-di-O-isopropylidene 3-C-(methoxycarbonyl)methyl-α-D-glucofuranose (3) and 3-amino-3-deoxy-1,2:5,6- di-O-isopropylidene-3-C-[2-diazo(methoxycarbonyl)methyl]-α- D -glucofuranose (4) in 80 and 7% yields, respectively. Treatment of 1 with sodium azide in N,N-dimenthyl-formamide gave 4 in 45% yield. Reduction of 3 or 4 with hydrogen over palladium afforded 3-amino-3-deoxy-1,2:5,6-di-O-isopropylidene-3-C-(methoxycarbonyl)menthyl-α- D -glucofuranose (5) in quantitative yield. Oxidation of the N-acetyl diol 8, derived from 7, with sodium metaperiodate yielded a dialdose that was reduced with sodium borohydride to give 9 in 90% yield. Benzoylation of 9 afforded 3-acetamido 5-O-benzoyl-3-deoxy-1,2-O-isopropylidene-3-C-(methoxycarbonyl)methyl-α- D -xylofuranose (10). Treatment of 10 with trifluoroacetic acid, followed by acetylation, yielded 3-acetamido-1-O-acetyl-5-O-benzoyl-3-C-carboxymethyl-3-deoxy-β-(and α)- D -Xylofuranose-32,2-lactones (12 and 13) in 75 and 25% yields, respectively. Condensation of the glycosyl bromide, derived from 12, with 6-N-benzoyl-6-N,9-bis(trimethylsilyl)adenine afforded an anomeric mixture of protected nucleosides 14 and 15 in 50% yield. Treatment ofthe latter compounds with sodium methoxide in methanol yielded 9-[3-acetamido-3-C-(carboxymethyl)-3-deoxy-32,2-lactone-β- D -xylofuranosyl]adenine (16) and the α- D anomer 17 in 79 and 65% yields, respectively.