4422 Macromolecules 1994,27, zyxwvu 4422-4428 Synthesis of Cellulose-Type Polyriboses and Their Branched Sulfates with Anti-AIDS Virus Activity by Selective Ring-Opening Copolymerization of 1,4-Anhydro-a-~-ribopyranose Derivatives Takashi Yoshida3 Chengpei Wu, Lixin Song, and Toshiyuki Uryu' Institute zyxwvut of Industrial Science, University zyxwv of Tokyo, 7-22-1 Roppongi, Minuto-Ku, Tokyo 106,Japan Yutaro Kaneko and Toru Mimura Ajinomoto Company, Inc., Chuo-ku, Tokyo 108, Japan Hideki Nakashima and Naoki Yamamoto Tokyo Medical and Dental University School of Medicine, Yushima, Bunkyo-ku, Tokyo 11 3, Japan Received February 28, 1994; Revised Manuscript Received May 6,1994. ABSTRACT Copolymerizations of 1,4-anhydro-2,3-0-benzylidene- and 1,4-anhydro-2,3-bis-O-(tert-b~- tyldimethyleilyl)-cr-D-ribopyranoses in various feeds were carried out with antimonypentachloride as catalyst at 0 "C to give, l,4-&lmked ribopyranan copolymers. Next the copolymers were subjected to a branching reaction by D- and L-glucose ethyl orthoacetates followed by the selective removal of silyl groups to afford branched ribopyranans. These were sulfated with piperidine-N-sulfonic acid to form branched ribopyranan sulfates having potent anti-AIDS virus activities, ECw zyxwvu = 0.3-0.9 IrglmL (a standard curdlan sulfate, ECw = 0.43 pg/mL). Stereoregular ribopyranan sulfates and sulfated poly(ribose)s composed of 1,4B-pyranosidic and 1,S-a-furanoside structures were also synthesized to examinethe relationshipbetween polymer structure and anti-AIDSvirus activity. The structural analysis of the ribopyrananswas performed by high resolution 1% NMR spectroscopy. Introduction Ring-opening polymerization of anhydro sugars has provided various stereoregular polysaccharide derivatives which were deprotected to give biologically active polysac- charides.' Schuerch first synthesized a stereoregular polysaccharide by cationic ring-opening polymerization of l,&anhydro sugars.* Developing Schuerch's method to selective ring-opening polymerization of 1 ,I-anhydrori- boses, we also found a method to prepare cellulose-type (1-4)-@-ribopyranan and furanan-type (1-.5)-a-ribo- f~ranan.~ Previously, (1+5)-a-ribofuranans having branchings, which were obtained by selective ring-opening polymer- ization followed by a branching reaction, were converted into sulfated and branched ribofuranans with high anti- AIDS (acquired immunodeficiencysyndrome) virus activ- ity? However, they also showed high anticoagulant activities6 which are undesirable byproducts with anti- AIDS virus activity. (1-4)-@-Ribopyranans have been obtained from 1,4- anhydro-2,3-0-ba-~~~p~an~ (ABRP) with antimony pentachloride as catalyst. We reported recently that ring-opening copolymerization of ABRP and 1,4- anhydro-2,3-bis-O-(tert-butyldimethylsilyl)-a-~ribopyra- nose (ADSR) in various feeds leads completely to 1,4-8- linked stereoregular copolymers consisting of both benzylidenatad and silylated ribopyranosidic units, even though the ring-opening polymerization of ADSR gave no 1,4-@-linked polymer.6 With use of selective desilylation from the copolymers and a subsequent branching reaction they can be converted into (1+4)-&ribopyranans having branches. t Present address: Division of Biological Sciences, Graduate School e Abstract published in Advance ACS Abstracts, June 15, 1994. of Science, Hokkaido University, Kita-ku, Sapporo zyxwvuts 060, Japan. 0024-9297/94/2227-4422$04.50/0 On the other hand, of pyranose-type polysaccharides, such sulfated polysaccharides as curdlan sulfate,'slentinan sulfate? and mannan sulfatelo exhibited high anti-AIDS virus activities but low anticoagulant activities. These biological activities are assumed to be desirable for an AIDS drug. Accordingly, it is important to synthesize polysaccharides with high anti- AIDS virus activities but with other biological activities being low. In this study, we wish to report the synthesis of branched (1+4)-@-ribopyranans by ring-opening copolymerization followedby a branching reaction. In addition, it is revealed that the sulfated branched (1+4)-@-ribopyranans exhib- ited potent anti-AIDS virus activities. Experimental Section Measurement. The lH (270-MHz) and 1% (67.8MHz) NMR spectrawere recorded on a JEOL GX-270spectrometer. Specific rotation measurements were carried out on polymer solutions in CHCls or HzO at 25 "C with a Perkin-Elmer 241 polarimeter. The molecular weight of polymers was determined by organic phase GPC (column,Toso TSK-gel, G2000H, G3000H,G4000H, G5000H, 7.6 mm X 600 mm X 4 mm; eluent, THF) using polystyrene standards and by aqueous phase GPC (column Toso TSK-gel, G2000SW, G3000SW, G4000SW, 7.6 mm X 600 mm X 3 mm; eluent, 66.7 mmol of phosphate buffer, pH = 6.86) using pullulan standards. Monomers. 1,4-Anhydro-&-D-ribopyranme was obtained by vacuum pyrolysis of Dribose.ll 1,4-Anhydro-2,3-0-benzylidene- a-D-ribopyranose (AELRP) was prepared by protection of 1,4- anhydro-a-D-ribopyrannose zyxw with a benzylidenegroup.1a Toa DMF solution (60 mL) of 1,4-anhydro-cr-~ribopyranose (10 g) was added 18 g of dimethoxytoluene and 30 mg of p-toluenesulfonic acid. The mixture was stirred for 3 h at 60 "C and then poured into 5% sodium bicarbonate solution (300 mL). The organic layer was extracted with dichloromethane, washed with water, dried with anhydrous sodium sulfate, and evaporated to give crude ABRP, which was purified by successive recrystallization from ethanol three times and fiially from n-butyl chloride- petroleum ether. Yield: 12.0 g (71%), as a mixture of syn and 0 1994 American Chemical Society