The Synthesis of (2S)-4,4-Difluoroglutamyl γ-Peptides Based on Garner’s Aldehyde­ and Fluoro-Reformatsky Chemistry

Abstract

The development of optically active fluorinated synthetic building blocks of general utility is a current goal of organo­fluorine chemists. The serine-derived Garner aldehyde was converted to a general 4,4-difluoroamino acid building block via fluoro-Reformatsky reaction with ethyl bromodifluoroacetate. The utility of this building block was demonstrated by the synthesis of derivatives of (2S)-4,4-difluoroglutamine, (2S)-4,4-difluoroglutamic acid, and its incorporation into a fluorophore-containing isopeptide 2 designed as a mechanistic probe of γ-glutamyl hydrolase. Compound 2 proved to be a substrate for γ-glutamyl hydrolase and was hydrolyzed at a rate significantly slower than the corresponding non-fluorinated analog.

Key words

fluoroamino acids - fluoropeptides - stereoselective synthesis - γ-glutamyl hydrolase - fluorescence enzyme assay

References

• 2 Welch JT. Eswarakrishnan S. Fluorine in Bioorganic Chemistry   Wiley; New York: 1991. 
• 3 Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications   Filler R. Kobayashi Y. Yagupolskii LM. Elsevier; Amsterdam: 1993. 
• 4 Tsukamoto T. Coward JK. McGuire JJ. In Biomedical Frontiers of Fluorine Chemistry   Ojima I. McCarthy JR. Welch JT. American Chemical Society; Washington D.C.: 1996.  p.118 
• 5 McGuire JJ. Hart BP. Haile WH. Rhee M. Galivan J. Coward JK. Arch. Biochem. Biophys.  1995,  321:  319 
• 6 Hart BP. Haile WH. Licato NJ. Bolanowska WE. McGuire JJ. Coward JK. J. Med. Chem.  1996,  39:  56 
• 7 Tsukamoto T. Kitazume T. McGuire JJ. Coward JK. J. Med. Chem.  1996,  39:  66 
• 8 McGuire JJ. Hart BP. Haile WH. Magee KJ. Rhee M. Bolanowska WE. Russell C. Galivan J. Paul B. Coward JK. Biochem. Pharmacol.  1996,  52:  1295 
• 9 Fluorine-Containing Amino Acids, Synthesis and Properties   Kukhar VP. Soloshonok VA. Wiley; Chichester: 1995. 
• 10 Sutherland A. Willis CL. Nat. Prod. Rep.  2000,  17:  621 
• 11 Asymmetric Fluoroorganic Chemistry: Synthesis, Applications, and Future Directions   Ramachandran PV. American Chemical Society; Washington D.C.: 2000. 
• 12 Enantiocontrolled Synthesis of Fluoroorganic Compounds: Stereochemical Challenges and Biomedical Targets   Soloshonok VA. Wiley; Chichester: 1999. 
• 13 Konas DW. Coward JK. Org. Lett.  1999,  1:  2105 
• 14 Konas DW. Coward JK. J. Org. Chem.  2001,  66:  8831 
• 15 J. J. Pankuch, unpublished results; for a closely related FRET peptide substrate, see: Pankuch JJ. Coward JK. Bioorg. Med. Chem. Lett.  2001,  11:  1561 
• 16 McGuire JJ. Coward JK. In Folates and Pterins   Vol. 1:  Blakley RL. Benkovic SJ. Wiley; New York: 1984.  p.135 
• 17 Liang X. Andersch J. Bols M. J. Chem. Soc., Perkin Trans. 1  2001,  2136 
• 18 Kim KS. Qian L. Tetrahedron Lett.  1993,  34:  7195 
• 19 Otaka A. Miyoshi K. Burke TR. Roller PP. Kubota H. Tamamura H. Fujii N. Tetrahedron Lett.  1995,  36:  927 
• 20 Delle Monache G. Di Giovanni MC. Maggio F. Misiti D. Zappia G. Synthesis  1995,  1155 
• 21 Leanna MR. Sowin TJ. Morton HE. Tetrahedron Lett.  1992,  33:  5029 
• 22 Jurczak J. Gryko D. Kobrzycka E. Gruza H. Prokopowicz P. Tetrahedron  1998,  54:  6051 
• 23 Hallinan EA. Fried J. Tetrahedron Lett.  1984,  25:  2301 
• 24 Barton DHR. McCombie SW. J. Chem. Soc., Perk. Trans. 1  1975,  1574 
• 25 Chatgilialoglu C. Ferreri C. Res. Chem. Intermed.  1993,  19:  755 
• 26 Studer A. Amrein S. Synthesis  2002,  835 
• 27 Barton DHR. Jaszberenyi JC. Tetrahedron Lett.  1989,  30:  2619 
• 28 Barton DHR. Jang DO. Jaszberenyi JC. Tetrahedron Lett.  1990,  31:  4681 
• 29 Barton DHR. Jang DO. Jaszberenyi JC. Tetrahedron Lett.  1991,  32:  7187 
• 30 Barton DHR. Jang DO. Jaszberenyi JC. Tetrahedron Lett.  1992,  33:  2311 
• 31 Barton DHR. Jang DO. Jaszberenyi JC. Tetrahedron  1993,  49:  7193 
• 32 Barton DHR. Jang DO. Jaszberenyi JC. J. Org. Chem.  1993,  58:  6838 
• 33 Barton DHR. Jacob M. Tetrahedron Lett.  1998,  39:  1331 
• 34 Jang DO. Cho DH. Barton DHR. Synlett  1998,  39 
• 35 Zalkin H. Adv. Enzymol. Relat. Areas Mol. Biol.  1993,  66:  203 
• 36 Zalkin H. Smith JL. Adv. Enzymol. Relat. Areas Mol. Biol.  1998,  72:  87 
• 37 Huang XY. Holden HM. Raushel FM. Ann. Rev. Biochem.  2001,  70:  149 
• 38 Tsukamoto T. Coward JK. J. Org. Chem.  1996,  61:  2497 
• 39a Meffre P. Dave RH. Leroy J. Badet B. Tetrahedron Lett.  2001,  42:  8625 
• 39b Note added in proof: A recently published correction to Ref. 39a indicates that the reported synthesis of l-4,4-difluoroglutamine is in error; the product isolated was l-4,4-difluoroglutamic acid, see: Meffre P. Dave RH. Leroy J. Badet B. Tetrahedron Lett.  2002,  43:  6279 . Thus, removal of the Cbz group in 15 (Scheme 3) by catalytic hydrogenolysis in modest yield (ca 50%) as reported for the racemic material in Ref. 38 represents the only tenable route to the synthesis of L-4,4-difluoroglutamine reported to date
• 40 Ding Y. Wang JQ. Abboud KA. Xu YL. Dolbier WR. Richards NGJ. J. Org. Chem.  2001,  66:  6381 
• 41 Zhao M. Li J. Song Z. Desmond R. Tschaen DM. Grabowski EJJ. Reider PJ. Tetrahedron Lett.  1998,  39:  5323 
• 42 Kitagawa O. Hashimoto A. Kobayashi Y. Taguchi T. Chem. Lett.  1990,  1307 
• 43 Mathias LJ. Synthesis  1979,  561 
• 44 Yao R. Schneider E. Ryan TJ. Galivan J. Proc. Natl. Acad. Sci. USA  1996,  93:  10134 
• 45 Licato NJ. Coward JK. Nimec Z. Galivan J. Bolanowska WE. McGuire JJ. J. Med. Chem.  1990,  33:  1022 
• 47 Chave KJ. Auger IE. Galivan J. Ryan TJ. J. Biol. Chem.  2000,  275:  40365 

1

Current Address: Department of Immunology NB-30, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195.

46

Pankuch, J.; Hui, M. (University of Michigan, Ann Arbor), unpublished results.