Stereoselective Synthesis of rac-4′-Ethynyl-2′-deoxy- and 4′-Ethynyl-2′,3′-dideoxy-2′,3′-didehydronucleoside Analogues

Abstract

Synthesis of a racemic 4′-ethynyl-2′-deoxyribose intermediate using stereoselective chelation control is presented. This intermediate is further transformed to 4′-ethynyl-2′-deoxy- and 4′-ethynyl-2′,3′-dideoxy-2′,3′-didehydronucleoside analogues.

Key words

HIV - nucleosides - stereoselective synthesis - carbohydrates - chelation control

References

• 1a Fisch MA. AIDS  1999,  13 (Suppl.1):  S49 
• 1b Mitsuya H. Erickson J. In Textbook of AIDS Medicine   Merigan TC. Bartlet JG. Bolognesi D. Lippincott Williams & Wilkins; Baltimore: 1999.  p.751 
• 3 Agarwal RPA. Olivero O. Mutat. Res.  1997,  390:  223 
• 4a Summerer D. Marx A. Bioorg. Med. Chem. Lett.  2005,  15:  869 
• 4b Dutchman GE. Grill SP. Gullen EA. Haraguchi K. Takeda S. Tanaka H. Baba M. Cheng Y.-C. Antimicrob. Agents Chemother.  2004,  48:  1640 
• 4c Kodama E.-I. Kohgo S. Kitano K. Machida H. Gatanaga H. Shigeta S. Matsuoka M. Ohrui H. Mitsuya H. Antimicrob. Agents Chemother.  2001,  45:  1539 
• 5a Secrist JA. Winter WJA. J. Am. Chem. Soc.  1978,  100:  2554 
• 5b Youssefyeh RD. Verheyden PH. Moffat JG. J. Org. Chem.  1979,  44:  1301 
• 5c Haraguchi K. Tanaka H. Miyasaka T. Tetrahedron Lett.  1990,  31:  227 
• 5d Haraguchi K. Tanaka H. Itoh Y. Saito S. Miyasaka T. J. Org. Chem.  1992,  33:  2841 
• 5e Johnson CR. Esker JL. Van Zandt MC. J. Org. Chem  1994,  59:  5854 
• 5f Haraguchi K. Tanaka H. Itoh Y. Yamaguchi K. Miyasaka T. J. Org. Chem.  1996,  61:  851 
• 5g Marx A. Erdmann P. Senn M. Korner S. Jungo T. Petretta M. Imwinkelried P. Dussy A. Kulicke KJ. Macko L. Zehnder M. Tiese B. Helv. Chim. Acta  1996,  79:  1980 
• 5h Shuto S. Knanzaki M. Ichikawa S. Matsuda A. J. Org. Chem.  1997,  62:  5676 
• 5i Shuto S. Knanzaki M. Ichikawa S. Minakawa N. Matsuda A. J. Org. Chem.  1998,  63:  746 
• Compound 1:
• 5j Sugimoto I. Shuto S. Mori S. Shigeta S. Matsuda A. Bioorg. Med. Chem. Lett.  1999,  9:  385 
• Compound 2:
• 5k Haraguchi K. Takeda S. Tanaka H. Nitanda T. Baba M. Dutschman GE. Cheng Y.-C. Bioorg. Med. Chem. Lett.  2003,  13:  3775 
• 5l Haraguchi K. Takada S. Tanaka H. Org. Lett.  2003,  5:  1399 
• 5m Haraguchi K. Itoh Y. Takeda S. Honma Y. Tanaka H. Nitanda T. Baba MD. Dutschman GE. Cheng Y.-C. Nucleosides, Nucleotides Nucleic Acids  2004,  23:  647 
• Compound 3:
• 5n Ohrui H. Kohgo S. Kitano K. Sakata S. Kodama E. Yoshimura K. Matsuoka M. Shigeta S. Mitsuya H. J. Med. Chem.  2000,  43:  4516 
• 6a Marco JA. Carda M. Gonzalez F. Rodriguez S. Castillo E. Murga J. J. Org. Chem.  1998,  63:  698 
• 6b

  This reference explains the observed syn addition of ethynylmagnesium bromide by an α-chelate where the oxygen atom alpha to the ketone forms a 5-ring chelate as shown in Figure [2] . Ether protecting groups other than MOM are expected to afford good chelation control since the authors in reference 6 report 91:9 syn-selectivity using ethynylmagnesium chloride and a ketone substrate having α-OBn in place of MOM and TBDPS in place of TBDMS.

• 7 For another nucleoside example of building functionality into an acyclic intermediate followed by ring-closure, see: Zhu W. Chong Y. Choo H. Mathews J. Schinazi R. Chu CK. J. Med. Chem.  2004,  47:  1631 
• 8 Vorbruggen H. Ruh-Pohlenz C. In Handbook of Nucleoside Synthesis   Wiley; New York: 2001.  p.15 
• 9 Duschinsky R. Gabriel T. Hoffer M. Berger J. Titsworth E. Grunberg E. Burchenal JH. Fox JJ. J. Med. Chem.  1966,  9:  566 
• 10a Tan C.-H. Stork T. Feeder N. Holmes AB. Tetrahedron Lett.  1999,  40:  1397 
• 10b Song J. Hollingsworth RI. Tetrahedron: Asymmetry  2001,  12:  387 

2

Parikh, U.; Koontz, D.; Sluis-Cremer, N.; Hammond, J.; Bacheler, L.; Schinazi, R.; Mellors, J. 11 ^th Annual Conference on Retroviruses and Opportunistic Infections; San Francisco, CA, February 8-11, 2004; Paper #54.