Synthesis of Conformationally Locked Methanocarba-uridine as a Precursor for Nucleotides Agonizing P2Y₆ Receptor

Abstract

Conformationally locked uridine in the ‘southern’ conformation, which could be an important precursor for corresponding nucleotides, was stereoselectively synthesized. Southern uridine nucleotides are expected to be full agonists for the P2Y₆ receptor. Poor diastereoselectivity in the osmium-mediated dihydroxylation on the allyl amine was overcome by introduction of an allyl azide on which osmium medium hydroxylation, and subsequent cyclization yielded 6-oxabicyclo[3.2.0]heptane in a 9:1 ratio. High regio­selectivity between the 2′- and 3′-hydroxyl groups in the intramolecular O-alkylation and construction of uracil moiety from the azido group provided the final target, a southern 2′-benzoylated uridine derivative.

Key words

nucleoside - nucleotide - carbohydrate - carbocycle - stereoselective synthesis

References

• 1 Altona C. Sundaralingam MJ. J. Am. Chem. Soc.  1972,  94:  2182 
• 2a Babu BR. Raunak Poopeiko NE. Juhl M. Bond AD. Parmar VS. Wengel J. Eur. J. Org. Chem.  2005,  2297 
• 2b Petersen M. Bondensgaard K. Wengel J. Jacobsen JP. J. Am. Chem. Soc.  2002,  124:  5974 
• 3a Marquez VE. Siddiqui MA. Ezzitouni A. Russ P. Wang J. Wanger RW. Matteucci MD. J. Med. Chem.  1996,  39:  3739 
• 3b Shin KJ. Moon HR. George C. Marquez VE. J. Org. Chem.  2000,  65:  2172 
• 4 Kim HS. Jacobson KA. Org. Lett.  2003,  5:  1665 
• 5 Ohno M. Costanzi S. Kim HS. Kempeneers V. Vastmans K. Herdewijn P. Maddileti S. Gao A.-G. Harden TK. Jacobson KA. Bioorg. Med. Chem.  2004,  12:  5619 
• 6a Costanzi S. Joshi BV. Maddileti S. Mamedova L. Gonzalez-Moa MJ. Marquez VE. Harden TK. Jacobson KA. J. Med. Chem.  2005,  48:  8108 
• 6b Besada P. Shin DH. Costanzi S. Ko H. Mathe C. Gagneron J. Gosselin G. Maddileti S. Harden TK. Jacobson KA. J. Med. Chem.  2006,  49:  5532 
• 7a Obika S. Morio K.-I. Nanbu D. Hari Y. Itoh H. Imanishi T. Tetrahedron  2002,  58:  3039 
• 7b Obika S. Uneda T. Sugimoto T. Nanbu D. Minami T. Doi T. Imanishi T. Bioorg. Med. Chem.  2001,  9:  1001 
• 8 Hodgson DM. Gibbs AR. Drew MGB. J. Chem. Soc., Perkin Trans. 1.  1999,  3579 
• 9 Ainai T. Wang Y.-G. Tokoro Y. Kobayashi Y. J. Org. Chem.  2004,  69:  655 
• 10 Lee Y.-S. Hyean Kim B. Bioorg. Med. Chem. Lett.  2002,  12:  1395 
• 11 Jeong LS. Beunger G. McCormack JJ. Cooney DA. Hao Z. Marquez VE. J. Med. Chem.  1998,  41:  2572