Kinetic Resolution of α-Hydroxy Carboxylic Acid Derivatives Based on Chiral Recognition of Substrate–Cocatalyst Complex

  • Yinli WangEmail author
Part of the Springer Theses book series (Springer Theses)


In this chapter, the first kinetic resolution of α-hydroxy thioamide using a new aminoindane-based triazolium salt and low acidic carboxylic acid cocatalyst was described.
Chiral recognization of substrate–cocatalyst complex is the crux of this reaction. Further transformation using the resulting enantiopure α-hydroxy thioamide was also investigated.


Kinetic resolution Chiral recognition α-hydroxy thioamide 


  1. 1.
    The first reported observation of kinetic resolution: Pasteur ML (1858) C R Hebd Seances Acad Sci 46:615Google Scholar
  2. 2.
    (1) For a book and a review on α-hydroxy acids, see: (a) Coppola GM, Schuster HF (1997) α-Hydroxy acids in enantioselective syntheses. Wiley-VCH, Weinheim. (b) Gröger H (2001) Enzymatic Routes to Enantiomerically Pure Aromatic α‐Hydroxy Carboxylic Acids: A Further Example for the Diversity of Biocatalysis. Adv Synth Catal 343:547–558. (2) For the compounds described in Figure 2.3 (a) Evans JF, Kargman S (1992) Bestatin inhibits covalent coupling of [3H]LTA4 to human leukocyte LTA4hydrolase. FEBS Lett 297:139–142. (b) Tremblay LV, Xu H, Blanchard JS (2010) Structures of the Michaelis Complex (1.2 Å) and the Covalent Acyl Intermediate (2.0 Å) of Cefamandole Bound in the Active Sites of the Mycobacterium tuberculosis β-Lactamase K73A and E166A Mutants. Biochemistry 49:9685–9687. (c) Ebdrup S, Pettersson I, Rasmussen HB, Deussen HJ, Frost Jensen A, Mortensen SB, Fleckner J, Pridal L, Nygaard L, Sauerberg P (2003) Synthesis and Biological and Structural Characterization of the Dual-Acting Peroxisome Proliferator-Activated Receptor α/γ Agonist Ragaglitazar. J Med Chem 46:1306–1317Google Scholar
  3. 3.
    (a) Gao Y, Hanson RM, Klunder JM, Ko SY, Masamune H, Sharpless KB (1987) Catalytic asymmetric epoxidation and kinetic resolution: modified procedures including in situ derivatization. J Am Chem Soc 109:5765–5780. (b) Bauer T, Tarasiuk J (2002) α-Hydroxy carboxylic acids: new ligands for diethylzinc additions to aldehydes. Tetrahedron Lett 43:687–689. (c) Bauer T, Gajewiak J (2004) α-Hydroxy carboxylic acids as ligands for enantioselective diethylzinc additions to aromatic and aliphatic aldehydes. Tetrahedron 60:9163–9170. (d) Bauer T, Gajewiak J (2005) α-Hydroxy carboxylic acids as ligands for enantioselective addition reactions of organoaluminum reagents to aromatic and aliphatic aldehydes. Tetrahedron Asymmetry 16:851–855Google Scholar
  4. 4.
    (a) Leemhuis M, van Steenis JH, van Uxem MJ, van Nostrum CF, Hennink WE (2003) A Versatile Route to Functionalized Dilactones as Monomers for the Synthesis of Poly(α‐hydroxy) Acids. Eur J Org Chem, 3344–3349. (b) Stuhr-Hansen N, Padrah S, Stromgaard K (2014) Facile synthesis of α-hydroxy carboxylic acids from the corresponding α-amino acids. Tetrahedron Lett 55:4149–4151Google Scholar
  5. 5.
    (a) Hamada Y, Shioiri T (2005) Recent Progress of the Synthetic Studies of Biologically Active Marine Cyclic Peptides and Depsipeptides. Chem Rev 105:4441–4482. (b) Avan I, Tala SR, Steel PJ, Katritzky AR (2011) Benzotriazole-Mediated Syntheses of Depsipeptides and Oligoesters. J Org Chem 76:4884–4893Google Scholar
  6. 6.
    Chen C-T, Bettigeri S, Weng S-S, Pawar VD, Lin Y-H, Liu C-Y, Lee W-Z (2007) Asymmetric Aerobic Oxidation of α-Hydroxy Acid Derivatives by C4-Symmetric, Vanadate-Centered, Tetrakisvanadyl(V) Clusters Derived from N-Salicylidene-α-aminocarboxylates. J Org Chem 72:8175–8185CrossRefGoogle Scholar
  7. 7.
    Onomura O, Mitsuda M, Nguyen MTT, Demizu Y (2007) Asymmetric tosylation of racemic 2-hydroxyalkanamides with chiral copper catalyst. Tetrahedron Lett 48:9080–9084CrossRefGoogle Scholar
  8. 8.
    Clark RW, Deaton TM, Zhang Y, Moore MI, Wiskur SL (2013) Silylation-Based Kinetic Resolution of α-Hydroxy Lactones and Lactams. Org Lett 15:6132–6135CrossRefGoogle Scholar
  9. 9.
    For reviews on additives in organic synthesis, see: (a) Vogl EM, Gröger H, Shibasaki M (1999) Towards Perfect Asymmetric Catalysis: Additives and Cocatalysts. Angew Chem Int Ed 38:1570–1577. (b) Hong L, Sun W, Yang D, Li G, Wang R (2016) Additive Effects on Asymmetric Catalysis. Chem Rev 116:4006–4123Google Scholar
  10. 10.
    (a) Berkessel A, Gröger H (2005) Asymmetric organocatalysis—from biomimetic concepts to applications in asymmetric synthesis. Wiley-VCH, Weinheim, 9. (b) Dalko PI, Moisan L (2001) Enantioselective Organocatalysis. Angew Chem Int Ed 40:3726–3748. (c) Dalko PI, Moisan L (2004) In the golden age of organocatalysis. Angew Chem Int Ed 43:5138–5175Google Scholar
  11. 11.
    For selected example: Dell’Amico L, Albrecht Ł, Naicker T, Poulsen PH, Jørgensen KA (2013) Beyond Classical Reactivity Patterns: Shifting from 1,4- to 1,6-Additions in Regio- and Enantioselective Organocatalyzed Vinylogous Reactions of Olefinic Lactones with Enals and 2,4-Dienals. J Am Chem Soc 135:8063–8070Google Scholar
  12. 12.
    For selected examples (a) Vedejs E, Chen X (1996) Kinetic Resolution of Secondary Alcohols. Enantioselective Acylation Mediated by a Chiral (Dimethylamino)pyridine Derivative. J Am Chem Soc 118:1809–1810. (b) Uraguchi D, Kinoshita N, Ooi T (2010) Catalytic Asymmetric Protonation of α-Amino Acid-Derived Ketene Disilyl Acetals Using P-Spiro Diaminodioxaphosphonium Barfates as Chiral Proton. J Am Chem Soc 132:12240–12242. (c) Cortez GS, Tennyson RL, Romo D (2001) Intramolecular, Nucleophile-Catalyzed Aldol-Lactonization (NCAL) Reactions:  Catalytic, Asymmetric Synthesis of Bicyclic β-Lactones. J Am Chem Soc 123:7945–7946. (d) Frisch K, Landa A, Saaby S, Jørgensen KA (2005) Organocatalytic Diastereo‐ and Enantioselective Annulation Reactions—Construction of Optically Active 1,2‐Dihydroisoquinoline and 1,2‐Dihydrophthalazine Derivatives. Angew Chem Int Ed 44:6058–6063Google Scholar
  13. 13.
    Kuwano S, Harada S, Kang B, Oriez R, Yamaoka Y, Takasu K, Yamada K (2013) Enhanced Rate and Selectivity by Carboxylate Salt as a Basic Cocatalyst in Chiral N-Heterocyclic Carbene-Catalyzed Asymmetric Acylation of Secondary Alcohols. J Am Chem Soc 135:11485–11488CrossRefGoogle Scholar
  14. 14.
    Bordwell FG (1988) Equilibrium acidities in dimethyl sulfoxide solution. Acc Chem Res 21:456–463CrossRefGoogle Scholar
  15. 15.
    (a) Olah GA, White AM, O’Brien DH (1970) Protonated heteroaliphatic compounds. Chem Rev 70:561–591. (b) Lee HJ, Choi YS, Lee KB, Park J, Yoon CJ (2002) Hydrogen Bonding Abilities of Thioamide J Phys Chem A 106:7010–7017Google Scholar
  16. 16.
    (a) Bertlett PA, Spear KL, Jacobsen NE (1982) A thioamide substrate of carboxypeptidase A. Biochemistry 21:1608–1611. (b) Yu K-L, Torri AF, Luo G, Cianci C, Grant-Young K, Danetz S, Tiley L, Krystal M, Meanwell NA (2002) Structure–activity relationships for a series of thiobenzamide influenza fusion inhibitors derived from 1,3,3-Trimethyl-5-hydroxy-cyclohexylmethylamine. Bioorg Med Chem Lett 12:3379–3382. (c) Wei Q-L, Zhang S-S, Gao J, Li W-H, Xu L-Z, Yu Z-G (2006) Synthesis and QSAR studies of novel triazole compounds containing thioamide as potential antifungal agents. Bioorg Med Chem 14:7146–7153. (d) Gannon MK II, Holt J, Bennett SM, Wetzel BR, Loo TW, Bartlett MC, Clarke DM, Sawada GA, Higgins JW, Tombline G, Raub TJ, Detty MR (2009) Rhodamine Inhibitors of P-Glycoprotein: An Amide/Thioamide “Switch” for ATPase Activity. J Med Chem 52:3328–3341. (e) Petersson EJ, Goldberg JM, Wissner RF (2014) On the use of thioamides as fluorescence quenching probes for tracking protein folding and stability. Phys Chem Chem Phys 16:6827–6837Google Scholar
  17. 17.
    Jagodziński TS (2003) Thioamides as Useful Synthons in the Synthesis of Heterocycles. Chem Rev 103:197–228CrossRefGoogle Scholar
  18. 18.
    Hudkins RL, DeHaven-Hudkins DL, Stubbins JF (1991) Muscarinic receptor binding profile of para-substituted caramiphen analogs. J Med Chem 34:2984–2989.CrossRefGoogle Scholar
  19. 19.
    De Rycke N, Couty F, David ORP (2011) Increasing the Reactivity of Nitrogen Catalysts. Chem Eur J 17:12852–12871Google Scholar
  20. 20.
    (a) Kagan HB, Fiaud JC (1988) Kinetic resolution. Top Stereochem 18:249–330. (b) Babine RE, Bender SL (1997) Molecular Recognition of Protein−Ligand Complexes:  Applications to Drug Design. Chem Rev 97:1359–1472. (c) Moloney MG (1999) Excitatory amino acids. Nat Prod Rep 16:485–498Google Scholar
  21. 21.
    (a) Noyori R (1994) Asymmetric catalysis in organic synthesis. Wiley-Interscience, New York. (b) Seyden-Penne J (1995) Chiral auxiliaries and ligands in asymmetric catalysis. Wiley, New York. (c) Soai K, Niwa S (1992) Enantioselective addition of organozinc reagents to aldehydes. Chem Rev 92:833–856. (d) Gómez M, Muller G, Rocamora M (1999) Coordination chemistry of oxazoline ligands. Coord Chem Rev 193–195:769–835Google Scholar
  22. 22.
    Tokuyama H, Yokoshima S, Lin S-C, Li L, Fukuyama T (2002) Reduction of Ethanethiol Esters to Aldehydes. Synthesis 1121–1123CrossRefGoogle Scholar
  23. 23.
    Dawson PE, Muir TW, Clark-Lewis I, Kent SB (1994) Synthesis of proteins by native chemical ligation. Science 266:776–779CrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan

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