Synthesis of l-Kynurenine and Homo-l-Kynurenine via an Aza-Fries Rearrangement

Abstract

l-Kynurenine, a non-proteinogenic amino acid, is the primary metabolite of tryptophan via the kynurenine pathway. Kynurenine is involved in a variety of biological processes occurring in the human body, notably in the central nervous system. Thus, the study of this molecule offers multiple opportunities for drug discovery; however, an essential prelude for biological studies is to secure the supply of kynurenine and analogues thereof. A simple synthetic procedure for the efficient preparation of enantiomerically pure l-kynurenine from l-aspartic acid and its implementation to prepare homo-l-kynurenine from l-glutamic acid is presented. The approach relies on a photochemical aza-Fries rearrangement of the corresponding acyl-aniline as the fundamental transformation.

Key words

l-kynurenine - homo-l-kynurenine - non-proteinogenic amino acids - aza-Fries - photochemical rearrangement

• References

• 1a Chen Y, Guillemin G. Int. J. Tryptophan Res. 2009; 2: 19
• 1b Jones SP, Guillemin G, Brew JB. Int. J. Tryptophan Res. 2013; 6: 57
• 1c Stone TW, Darlington LG. Nat. Rev. Drug Discovery 2002; 1: 609
• 2 Guillemin G. FEBS J. 2012; 279: 1356
• 3 Wolf H. Scand. J. Clin. Lab. Invest., Suppl. 1974; 136: 1
• 4 Vecsei L, Szalárdy L, Fülöp F, Toldi J. Nat. Rev. Drug Discovery 2013; 12: 64
• 5 Tan L, Yu JT, Tan L. J. Neurol. Sci. 2012; 323: 1-8
• 6 Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL. Science 1998; 281: 1191
• 7 Castro-Portugueza R, Sutphin GL. Exp. Gerontol. 2020; 132: 110841
• 8 Colpo GD, Venna VR, McCullough LD, Teixeira AL. Front. Neurol. 2019; 10: 778
• 9 Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M. Nature 2011; 478: 197
• 10 Tan VX, Guillemin GJ. Front. Neurosci. 2019; 13: 1013
• 11 Heckathorn RC, Dillon J, Gaillard ER. Anal. Biochem. 2001; 299: 78
• 12 Varasi M, Della Torre A, Heidempergher F, Pevarello P, Speciale C, Guidetti P, Wells DR, Schwarcz R. Eur. J. Med. Chem. 1996; 31: 11
• 13 Phillips RS, Iradukunda EC, Hughes T, Bowen JP. Front. Mol. Biosci. 2019; 6: 3
• 14 Finley JW, Friedman M. J. Agric. Food Chem. 1973; 21: 33
• 15 Ross FC, Botting NP, Leeson PD. Bioorg. Med. Chem. Lett. 1996; 6: 875
• 16 Brown RR, Price JM. J. Am. Chem. Soc. 1955; 77: 4158
• 17 Maitrani C, Heyes DJ. Bioorg. Med. Chem. Lett. 2012; 22: 2734
• 18 Clarence TT, Wong HY, Xuechen L. Org. Biomol. Chem. 2013; 11: 7616
• 19 Moriyama T. J. Biochem. 1957; 44: 289
• 20 Dalgliesh CE. J. Chem. Soc. 1952; 137
• 21 Salituro FG, McDonald IA. J. Org. Chem. 1988; 53: 6138
• 22a Jackson RF. W, Turner D, Block MH. J. Chem. Soc., Chem. Commun. 1995; 2207
• 22b Jackson RF. W, Turner D, Block MH. J. Chem. Soc., Perkin Trans. 1 1997; 865
• 23 Lygo B, Andrews BI. Tetrahedron Lett. 2003; 44: 4499
• 24 Hamdy MS, Scott EL, Carr RH, Sanders JP. Catal. Lett. 2012; 142: 338
• 25 Ferrini FS, Taddei PM. J. Org. Chem. 2006; 71: 9217
• 26 Kleijn LH, Müskens FM, Oppedijk SF, de Bruin G, Martin NI. Tetrahedron Lett. 2012; 53: 6430
• 27 Blatt AH. Org. React. 1942; 1: 342
• 28 Sánchez A, Calderón E, Vazquez A. Synthesis 2013; 45: 1364
• 29 Dunwtz JR, Xiang Y, Baldwin A, Ringling J. Org. Lett. 2011; 13: 5048
• 30 Sheehan JC, Hess GP. J. Am. Chem. Soc. 1955; 77: 1067
• 31 Dent WH. III, Erickson WR. Org. Lett. 2002; 2: 1249
• 32a Chenevert R, Plante R. Can. J. Chem. 1983; 61: 1092
• 32b Iguchi D, Erra-Balsells R, Bonesi SM. Photochem. Photobiol. Sci. 2016; 15: 105
• 33 Greene TW, Wuts PG. M. Protection for the Carbonyl Group . In Protective Groups in Organic Synthesis, 2nd ed. Greene TW. Wiley; Hoboken: 1991