Branched-chain sugar nucleosides. Synthesis of structural analogues of puromycin
Creators: name: Baker, Donald Arthur
Publisher: name: University of British Columbia
Year: 2011

description: Several new routes to nitrogenous branched-chain sugars have been investigated and the preparation of several novel branched-chain sugar nucleosides having a structural relationship to puromycin has been described. The cyanomethyl branched-chain sugars 3-C-cyanomethyl-3-deoxy-1,2:5,6-di-0-isopropylidene-α-D-allofuranose [LXXXVI], 3-C-cyanomethyl-3-deoxy-l,2:5,6-di-0-isopropylidene-α-D-gulofuranose [LXVII], and 5-0-benzyl-3-C-cyanomethyl-3-deoxy-1,2-0-isopropylidene-α-D-ribofuranose [LXXVIII] were prepared by condensation of diethyl cyanomethylphosphonate with 1,2 :5,6-di-0-isopropylidene-α-D-ribo-hexofuranos-3-ulose [XVIII], 1,2;5,6-di-0-isopropylidene-α-D-xylo-hexofuranos-3-ulose [LXVII], and 5-0-benzyl-1,2-0-isopropylidene-α-D-erythro-pentofuranos-3-ulose [LXVIII], respectively, followed by stereoselective hydrogenation over palladium-on-charcoal of the intermediate unsaturated sugars. Reduction of the nitrile group of LXXXVI and LXXXVIII gave the D-amino sugars, isolated as their acetamido derivatives, 3-C-(2'-acetamidoethyl)-3-deoxy-1,2:5,6-di-0-isopropylidene-α-D-allofuranose [XCII] and 3-C-(2'-acetamidoethyl)-5-0-benzyl-3-deoxy-1,2-0-isopropylidene-α-D-ribofuranose [XCIII]. Selective hydrolysis of the 5,6-0-isopropylidene ketal of LXXXVII followed by sodium periodate degradation and sodium borohydride reduction afforded the L-cyanomethyl branched-chain sugar 3-C-cyanomethyl-3-deoxy-1,2-0-isopropylidene-β-L-lyxofuranose [XCVI]. Reduction of the nitrile group of this compound gave the L-amino sugar characterized as its acetamido derivative 3-C-(2'-acetamidoethyl)-3-deoxy-1,2-0-isopropylidene-β-L-lyxofuranose [XCVI]. The carbamoylmethyl branched-chain sugar 3-C-carbamoylmethyl-3-deoxy-1,2:5,6-di-0-isopropylidene-α-D-allofuranose [C] was prepared via three different routes. Hydrolysis of LXXXVI using alkaline hydrogen peroxide afforded C in 70 % yield. The same compound was also obtained by ammonolysis of 3-C-carbomethoxymethyl-3-deoxy-1,2:5,6-di-0-isopropylidene-α-D-allofuranose [XXXIX] using liquid ammonia and ammonium chloride and by the stereoselective photoaddition of formamide to the methylene branched-chain sugar 1,2:5,6-di-0-isopropylidene-3-C-methylene-α-D-ribo-hexofuranose [XX]. A nitromethyl branched-chain sugar 1,2:5,6-di-0-isopropylidene-3-C-nitromethyl-α-D-glucofuranose [CV] was also prepared by condensing XVIII with nitromethane. The cyanomethyl branched-chain sugar LXXXVI was the key intermediate in the synthesis of the branched-chain sugar nucleosides. Selective hydrolysis of LXXXVI to the 1,2-0-isopropylidene compound followed by benzoylation, hydrolysis of the 1,2-isopropylidene ketal and acetylation yielded 1,2-di-0-acetyl-5,6-di-0-benzoyl-3-C-cyanomethyl-3-deoxy-β-D-allofuranose [CX]. Fusion of CX with 6-chloropurine followed by reaction with methanolic-aqueous dimethyl amine gave the branched-chain sugar nucleoside 6-N,N-dimethylamino-9-(3'-C-N,N-dimethylcarbamoylmethy1-31-deoxy-β-D-allofuranosyl)-purine [CXXI]. Sodium metaperiodate oxidation of CXXI followed by sodium borohydride reduction gave the corresponding ribo nucleoside 6-N,N-dimethylamino-9- (3' -C-N,N-dimethylcarbaraoylmethyl-3'-deoxy-β-D-ribofuranosyl)-purine [CXXII]. In a separate procedure CXXII was obtained by fusion of 6-chloropurine with 1,2-di-0-acetyl-5-0-benzoyl-3-C_-cyanomethyl-3-deoxy-g-D-ribofuranose [CXIII] prepared from LXXXVI by selective hydrolysis of the 5,6-isopropylidene group followed by sodium periodate degradation, sodium borohydride reduction of the aldehydo intermediate, benzoylation, hydrolysis of the 1,2-isopropylidene group and acetylation), followed by reaction with methanolic aqueous dimethylamine. The corresponding unblocked cyanomethyl branched-chain ribo sugar nucleoside 6-N ,N-dimethylamino-9- (3' -C-cyanomethy 1-31 -deoxy-β-D-ribofuranosyl)-purine [CXXXI] was obtained by fusion of CXIII with 6-chloropurine followed by reaction of the blocked nucleoside with anhydrous dimethylamine. Pyrolysis of the N,N-dimethylcarbamoylmethyl ribonucleoside CXXII gave the novel lactone nucleoside 6-N,N-dimethylamino-9-(3'-C-carboxymethyl-2',3'-γ-lactone-3-deoxy-β-D-ribofuranosyl)-purine [CXXVIII]. Condensation of this compound with ammonia afforded 6-N,N-dimethylamino-9-( 3'-C-carbamoylmethyl-3-deoxy-β-D-ribofuranosyl)-purine [CXXIX] and condensation of CVIII with ethyl glycinate gave the peptide nucleoside 6-N,N-dimethylamino-9-(3'-C-carbamoylmethyl-N-glycine ethyl ester-3'-deoxy-β-D-ribofuranosyl)-purine [CXXX]. Reduction of cyanomethyl branched-chain ribo-nucleoside CXXXI afforded an amino branched-chain sugar nucleoside which was characterized as its N-acetyl derivative 6-N,N-dimethylamino-9-(3,-C-(2"-acetamido-ethyl)-3'-deoxy-β-D-ribofuranosyl)-purine [CXXXIV]. Compounds CX and CXIII were also converted into the corresponding blocked adenyl nucleosides 6-benzamido-9-(2'-0-acetyl-5',61-di-0-benzoyl-3'-C-cyanomethyl-3’-deoxy-β-D-allofuranosyl)-purine [CXXXVI] and 6-benzamido-9-(2'-0-acety1-5'-0-benzoyl-3'-C-cyanomethyl-3'-deoxy-β-D-ribofuranosyl)-purine [CXXXXVII] by reaction with hydrogen bromide followed by condensation with chloromercuri-6-benzamido purine.