Synthesis of a Dihydropyranonucleoside Using an Oxidative Glycosylation Reaction­ Mediated by Hypervalent Iodine

Abstract

As a part of our ongoing studies of structure–activity relationships regarding cyclohexenyl nucleosides, we were prompted to synthesize a dihydropyranonucleoside as a potential anti-HIV agent. The synthesis of a glycal moiety started from but-2-enediol, which was converted into a di-PMB derivative in several steps. The introduction of an allyl group followed by ring-closing metathesis gave a dihydropyran derivative. After isomerization of the double bond catalyzed by Wilkinson’s catalyst, the resulting glycal, 2,3-bis[(4-methoxybenzyloxy)methyl]-3,4-dihydro-2H-pyran, was subjected to an oxidative glycosylation reaction mediated by hypervalent iodine. Treatment of 2,3-bis[(4-methoxybenzyloxy)methyl]-3,4-dihydro-2H-pyran with (PhSe)₂/PhI(OAc)₂/TMSOTf (cat.) gave the desired pyranyluracils as a mixture of anomers that were converted into the final target, dihydropyranocytidine, after several manipulations and separation of the anomers.

Key words

glycosylation - nucleoside - oxidation - iodine - antiviral

• References

• 1 Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, Bolognesi D, Barry DW, Broder S. Proc. Natl. Acad. Sci. U.S.A. 1985; 82: 7096
• 2a De Clercq E. Curr. Opin. Pharmacol. 2010; 10: 507
• 2b Broder S. Antiviral Res. 2010; 85: 1
• 2c Cihlar T, Ray AS. Antiviral Res. 2010; 85: 39
• 3 Ichikawa E, Kato K. Curr. Med. Chem. 2001; 8: 385
• 4a Baba M, Pauwels R, Herdewijn P, De Clercq E, Desmyter J, Vandeputte M. Biochem. Biophys. Res. Commun. 1987; 142: 128
• 4b Hamamoto Y, Nakashima H, Matsui T, Matsuda A, Ueda T, Yamamoto N. Antimicrob. Agents Chemother. 1987; 31: 907
• 5a Gumina G, Chong Y, Choo H, Song GY, Chu CK. Curr. Top. Med. Chem. 2002; 2: 1065
• 5b Sabini E, Hazra S, Konrad M, Lavie A. J. Med. Chem. 2007; 50: 3004
• 6a Coates JA, Cammack N, Jenkinson HJ, Mutton IM, Pearson BA, Storer R, Cameron JM, Penn CR. Antimicrob. Agents Chemother. 1992; 36: 202
• 6b Schinazi RF, Chu CK, Peck A, McMillan A, Mathis R, Cannon D, Jeong LS, Beach JW, Choi WB, Yeola S. Antimicrob. Agents Chemother. 1992; 36: 672
• 7a Yoshimura Y, Asami K, Matsui H, Tanaka H, Takahata H. Org. Lett. 2006; 8: 6015
• 7b Yoshimura Y, Yamazaki Y, Kawahata M, Yamaguchi K, Takahata H. Tetrahedron Lett. 2007; 48: 4519
• 7c Yoshimura Y, Ohta M, Imahori T, Imamichi T, Takahata H. Org. Lett. 2008; 10: 3449
• 7d Yoshimura Y, Yamazaki Y, Saito Y, Takahata H. Tetrahedron 2009; 65: 9091
• 7e Yoshimura Y, Asami K, Imamichi T, Okuda T, Shiraki K, Takahata H. J. Org. Chem. 2010; 75: 4161
• 7f Yoshimura Y, Yamazaki Y, Saito Y, Natori Y, Imamichi T, Takahata H. Bioorg. Med. Chem. Lett. 2011; 21: 3313
• 8 Daluge SM, Good SS, Faletto MB, Miller WH, St Clair MH, Boone LR, Tisdale M, Parry NR, Reardon JE, Dornsife RE, Averett DR, Krenitsky TA. Antimicrob. Agents Chemother. 1997; 41: 1082
• 9 Katagiri N, Shiraishi T, Sato H, Toyota A, Kaneko C, Yusa K, Oh-hara T, Tsuruno T. Biochem. Biophys. Res. Commun. 1992; 184: 154
• 10 Hayashi S, Norbeck DW, Rosenbrook W, Fine RL, Matsukura M, Plattner JJ, Broder S, Mitsuya H. Antimicrob. Agents Chemother. 1990; 34: 287
• 11 Gollner A, Altmann K.-H, Gertsch J, Mulzer J. Chem. Eur. J. 2009; 15: 5979
• 12a Vorbrüggen H, Krolikiewicz K, Bennua B. Chem. Ber. 1981; 114: 1234
• 12b Ueda T, Watanabe S.-I. Chem. Pharm. Bull. 1985; 33: 3689
• 13 Yoshimura Y, Kan-no H, Kiran YB, Natori Y, Saito Y, Takahata H. Synthesis 2012; 44: 1163
• 14 Schmidt B. J. Org. Chem. 2004; 69: 7672
• 15 Díaz Y, El-Laghdach A, Matheu MI, Castillón S. J. Org. Chem. 1997; 62: 1501
• 16a Pedersen CM, Nordstrøm LU, Bols M. J. Am. Chem. Soc. 2007; 129: 9222
• 16b Mydock LK, Demchenko AV. Org. Lett. 2008; 10: 2103
• 17 Compound 25α showed 8.8% of NOE at H6 of uracil when irradiated at H5′ and 25β revealed 6.9% of NOE at H1′ when irradiated at H5′.
• 18 Sekine M, Matsuzaki J, Satoh M, Hata T. J. Org. Chem. 1982; 47: 571
• 19 Anti-HIV-1 activities of the compounds were evaluated by suppression of HIV replication in PBMCs by p24 antigen capture assay. At any concentrations less than 100 μM, neither 6α nor 6β showed anti-HIV activity.