Stereoselective Synthesis of syn-γ-Hydroxynorvaline and Related α-Amino Acids

Abstract

The total syntheses of three enantiomerically pure non-proteinogenic amino acids, l-norvaline, γ-oxonorvaline, and syn-γ-hydroxynorvaline, are reported. The chromatography-free route pivoted on the construction of highly enantiomerically enriched substituted α-amino-γ-oxopentanoic acid, from which all three members were accessed divergently via chemoselective and stereoselective reductions. The rapid synthesis of this key α-amino-γ-oxopentanoic acid was achieved by a highly diastereoselective crystallisation-driven three-component Mannich reaction from the readily available building blocks acetone, glyoxylic acid monohydrate, and (S)-(4-methoxyphenyl)ethylamine. The enantiomeric purity of all target molecules was confirmed by HPLC analysis, either of the amino acids or their derivatives.

Key words

stereoselective synthesis - α-amino acids - Mannich reaction - crystallisation-induced - norvaline - γ-hydroxynorvaline - aza-Michael addition

• References

• 1 Neumann-Staubitz P, Neumann H. Curr. Opin. Struct. Biol. 2016; 38: 119
• 2 Ohfune Y. Acc. Chem. Res. 1992; 25: 360
• 3a Wagner I, Musso H. Angew. Chem. Int. Ed. 1983; 22: 816
• 3b Zarándi M, Szolomájer J. In Amino Acids, Peptides and Proteins, Vol. 42. Ryadnov M, Hudecz F. The Royal Society of Chemistry; Cambridge: 2018: 1
• 4a Chenault HK, Dahmer J, Whitesides GM. J. Am. Chem. Soc. 1989; 111: 6355
• 4b Wang B, Liu Y, Zhang D, Feng Y, Li J. Tetrahedron: Asymmetry 2012; 23: 1338
• 5a Corey EJ. J. Am. Chem. Soc. 1997; 119: 12414
• 5b Kang Q.-K, Selvakumar S, Maruoka K. Org. Lett. 2019; 21: 2294
• 5c Bøgevig A, Juhl K, Kumaragurubaran N, Zhuang W, Jørgensen KA. Angew. Chem. Int. Ed. 2002; 41: 1790
• 5d List B. Synlett 2001; 1675
• 6 Franchino A, Jakubec P, Dixon DJ. Org. Biomol. Chem. 2016; 14: 93
• 7a Fryzuk MD, Bosnich B. J. Am. Chem. Soc. 1977; 99: 6262
• 7b Federsel H.-J. Nat. Rev. Drug Discovery 2005; 4: 685
• 8a Schöllkopf U, Groth U, Deng C. Angew. Chem. Int. Ed. 1981; 20: 798
• 8b Oppolzer W, Moretti R, Thomi S. Tetrahedron Lett. 1989; 30: 6009
• 8c Basso A, Banfi L, Riva R, Guanti G. J. Org. Chem. 2005; 70: 575
• 9a Brands KM. J, Davies AJ. Chem. Rev. 2006; 106: 2711
• 9b Anderson NG. Org. Process Res. Dev. 2005; 9: 800
• 9c Ebbers EJ, Ariaans GJ. A, Houbiers JP. M, Bruggink A, Zwanenburg B. Tetrahedron 1997; 53: 9417
• 9d Yoshioka R. Top. Curr. Chem. 2007; 269: 83
• 10a Kuhn R, Jochims JC. Justus Liebigs Ann. Chem. 1961; 641: 143
• 10b Hassan NA, Bayer E, Jochims JC. J. Chem. Soc., Perkin Trans. 1 1998; 3747
• 11a Belanger F, Chase CE, Endo A, Fang FG, Li J, Mathieu SR, Wilcoxen AZ, Zhang H. Angew. Chem. Int. Ed. 2015; 54: 5108
• 11b Menis J, Twelves C. Breast Cancer 2011; 3: 101
• 11c Brands KM. J, Payack JF, Rosen JD, Nelson TD, Candelario A, Huffman MA, Zhao MM, Li J, Craig B, Song ZJ, Tschaen DM, Hansen K, Devine PN, Pye PJ, Rossen K, Dormer PG, Reamer RA, Welch CJ, Mathre DJ, Tsou NN, McNamara JM, Reider PJ. J. Am. Chem. Soc. 2003; 125: 2129
• 12 Nelson TD. In Strategies and Tactics in Organic Synthesis, Vol. 6. Harmata M. Elsevier; Amsterdam: 2005. Chap. 10, 321
• 13a Ariza J, Font J, Ortuño RM. Tetrahedron 1990; 46: 1931
• 13b Schmeck C, Hegedus LS. J. Am. Chem. Soc. 1994; 116: 9927
• 13c Jacob M, Roumestant ML, Viallefont P, Martinez J. Synlett 1997; 691
• 13d Drummond LJ, Sutherland A. Tetrahedron 2010; 66: 5349
• 13e Simon RC, Busto E, Schrittwieser JH, Sattler JH, Pietruszka J, Faber K, Kroutil W. Chem. Commun. 2014; 50: 15669
• 14 Polis B, Srikanth KD, Gurevich V, Gil-Henn H, Samson AO. Neural Regen. Res. 2019; 14: 1562
• 15 Ming X.-F, Rajapakse AG, Carvas JM, Ruffieux J, Yang Z. BMC Cardiovasc. Disord. 2009; 9: 12
• 16 Fowden L. Nature 1966; 209: 807
• 17 Matzinger P, Catalfomo P, Eugster CH. Helv. Chim. Acta 1972; 55: 1478
• 18a Ribes G, Broca C, Petit P, Jacob M, Baissac Y, Manteghatti M, Roye M, Sauvaire Y. Diabetologia 1996; 39: A234
• 18b Broca C, Manteghetti M, Gross R, Baissac Y, Jacob M, Petit P, Sauvaire Y, Ribes G. Eur. J. Pharmacol. 2000; 390: 339
• 19 Matsunaga S, Fusetani N, Hashimoto K, Wälchli M. Am. Chem. Soc. 1989; 11: 2582
• 20a Schaper W, Beckmann M, Doller U, Krautstrunk G, Jans D, Hempel W, Waibel JM. US2004/6047 A1, 2004
• 20b Nielsen J, Givskov M. WO03106445 (A1), 2003
• 20c Hasegawa H, Shiori N, Narita T, Katori T. US4876359 A1, 1989
• 21a Scheffold R, Dubs P. Helv. Chim. Acta 1967; 50: 798
• 21b Xu C, Bai X, Xu J, Ren J, Xing Y, Li Z, Wang J, Shi J, Yu L, Wang Y. RSC Adv. 2017; 7: 4763
• 22a Yamada M, Nagashima N, Hasegawa J, Takahashi S. Tetrahedron Lett. 1998; 39: 9019
• 22b Kolarovič A, Berkeš D, Baran P, Považanec F. Tetrahedron Lett. 2001; 42: 2579
• 22c Kolarovič A, Berkeš D, Baran P, Považanec F. Tetrahedron Lett. 2005; 46: 975
• 22d Jakubec P, Berkeš D, Šiška R, Gardianová M, Považanec F. Tetrahedron: Asymmetry 2006; 17: 1629
• 22e Berkeš D, Jakubec P, Winklerová D, Považanec F, Daich A. Org. Biomol. Chem. 2007; 5: 121
• 23 Jakubec P, Berkeš D, Kolarovič A, Považanec F. Synthesis 2006; 23: 4032
• 24 Resnick L, Galante RJ. Tetrahedron: Asymmetry 2006; 17: 846
• 25 Sivák I, Toběrný M, Kyselicová A, Caletková O, Berkeš D, Jakubec P, Kolarovič A. J. Org. Chem. 2018; 83: 15541
• 26 Marčeková M, Gerža P, Šoral M, Moncol J, Berkeš D, Kolarovič A, Jakubec P. Org. Lett. 2019; 21: 4580
• 27 For more comprehensive screening results, see the Supporting Information.
• 28a Jakubec P, Petráš P, Duriš A, Berkeš D. Tetrahedron: Asymmetry 2010; 21: 69

For selected examples of organocatalysed Mannich reactions, see:
• 28b Pojarliev P, Biller WT, Martin HJ, List B. Synlett 2003; 1903
• 28c Enders D, Grondal C, Vrettou M, Raabe G. Angew. Chem. Int. Ed. 2005; 44: 4079
• 28d De Lamo Marin S, Catala C, Kumar SR, Valleix A, Wagner A, Mioskowski C. Eur. J. Org. Chem. 2010; 3985
• 29 Berkeš D, Kolarovič A, Považanec F. Tetrahedron Lett. 2000; 41: 5257
• 30 Chen C, Genapathy S, Fischer P, Chan W. Org. Biomol. Chem. 2014; 12: 9764
• 31a For further details, see the Supporting Information.
• 31b The observed negligible difference in the dr of adduct 4f (98:2), the er of norvaline (1) (er 97:3), and the er of γ-oxonorvaline (2) (97:3) could be attributed to the precision limits/accuracy of the HPLC measurements. The apparent erosion of the enantiomeric purity of syn-γ-hydroxynorvaline (3) (er 92:8) could be caused by a partial epimerisation of the intermediates during the transformations of 4f to syn-γ-hydroxynorvaline (3).
• 32 Volkov A, Gustafson KP. J, Tai C.-W, Verho O, Bäckvall J.-E, Adolfsson H. Angew. Chem. Int. Ed. 2015; 54: 5122
• 33a Clemmensen E. Chem. Ber. 1913; 46: 1837
• 33b Vedejs E. Org. React. 1975; 22: 401
• 33c Motherwell WB, Nutley CJ. Contemp. Org. Synth. 1994; 1: 219
• 34a Kishner NJ. J. Russ. Phys. Chem. Soc. 1911; 43: 582
• 34b Wolff L. Liebigs Ann. Chem. 1912; 394: 23
• 34c Furrow ME, Myers AG. J. Am. Chem. Soc. 2004; 126: 5436
• 35 Kisumi M, Sugiura M, Kato I, Chibata I. J. Biochem. 1976; 79: 1021
• 36 Osipov SN, Lange T, Tsouker P, Spengler J, Hennig L, Koksch B, Berger S, El-Kousy SM, Burger K. Synthesis 2004; 1821