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Synthesis 2005(10): 1555-1568  
DOI: 10.1055/s-2005-869903
REVIEW
© Georg Thieme Verlag Stuttgart · New York

Resolution of Enantiomers by Non-Conventional Methods

Elemér Fogassy*a, Mihály Nógrádi*b, Emese Pálovicsc, József Schindlerc
a Institute for Organic Chemical Technology, Technical University of Budapest, P.O.Box 91, Budapest, Hungary
b Institute for Organic Chemistry, Technical University of Budapest, P.O.Box 91, Budapest, Hungary
c Research Group for Organic Chemical Technology, Budapest University of Technology and Economics, P.O.Box 91, Budapest, Hungary
Fax: +36(1)2463648; e-Mail: epalo@mail.bme.hu;
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Publication History

Received 12 January 2005
Publication Date:
18 May 2005 (online)

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Abstract

Despite unprecedented advances in enantioselective synthesis and separation techniques, large scale production of enantiopure substances, such as required by the pharmaceutical and pesticide industries, is still heavily dependent upon the separation of diastereomers obtained from the enantiomers and an optically active resolving agent. Economy of the process can be much enhanced when only a half-equivalent of the resolving agent is used. Substitution of the other half-equivalent by some achiral compound, as well as separation of the unreacted portion of the substrate from the diastereomer by various physical methods, is discussed. Methods for selecting optimal conditions of resolution and for the purification of partially resolved mixtures are also discussed.

  • 1 Introduction and Historical Background

  • 2 Resolution Methods Using a Half-Equivalent of Resolving Agent

  • 3 Selection of the Optimal Resolving Agent and Solvent

  • 4 Phase Transformations of Diastereomeric Salts or Complexes (Kinetic and Thermodynamic Control)

  • 5 Resolution by Formation of Covalently Bound Diastereo­mers

  • 6 Racemization of an Unwanted Enantiomer

  • 7 Deracemization

  • 8 Resolution of Conglomerate-Forming Racemates by Induced Crystallization

  • 9 Purification of Partially Resolved Mixtures by Crystallization of Conglomerate-Forming and Racemic-Phase-Forming Compounds

  • 10 Purification of a Partially Resolved Mixture of Racemic-Phase-Forming Enantiomers by Fractional Precipitation

  • 11 Resolution by Supercritical Fluid Extraction or Distillation

  • 12 The Non-Linear Character of the Resolution Processes

Key words

resolution of enantiomers - half-equivalent methods - choice of optimal conditions

    References

  • 2a Stereoselective Synthesis, In Houben-Weyl Methods of Organic Synthesis   Vol. E21a-E21f:  Helmchen G. Hoffmann RW. Mulzer J. Schaumann EG. Georg Thieme Verlag; Stuttgart, New York: 1996. 
    Google Scholar
  • 2b Stereoselective Synthesis, A Practical Approach   Nógrádi M. VCH; Weinheim: 1995. 
    Google Scholar
  • 4 Pasteur L. C. R. Hebd. Seances Acad. Sci.  1853,  37:  162 
    Google Scholar
  • 5 Pope WJ. Peachey SJ. J. Chem. Soc.  1899,  75:  1066 
    CrossrefGoogle Scholar
  • 6a inventors; Hung. Patent  146896.  , Chem. Abstr. 1958, 54, 11287
  • 6b inventors; Hung. Patent  163526.  , Chem. Abstr. 1984, 79, 104924
  • 7 inventors; Hung. Patent  177583.  , Chem. Abstr. 1978, 96, 6258
  • 8 inventors; Ger. Patent  1274586.  , Chem. Abstr. 1968, 71, 50521
  • 9 Cai D. Hughes DL. Verhoeven TR. Reider PJ. In Organic Syntheses, Vol. 76   Martin SF. John Wiley & Sons; New York: 1998.  p.1 
    Google Scholar
  • 10 Brandt J. Gais H.-J. Tetrahedron: Asymmetry  1997,  8:  909 
    CrossrefGoogle Scholar
  • 11a inventors; Hung. Patent  178516.  , Chem. Abstr. 1978, 97, 38959
  • 11b Fogassy E. Ács M. Tóth G. Simon K. Láng T. Ladányi L. Párkányi L. J. Mol. Struct.  147,  143 
    Google Scholar
  • 12a inventors; Hung. Patent  169845.  , Chem. Abstr. 1974, 85, 192335
  • 12b Ács M. Kozma D. Fogassy E. Ach. Mod. Chem.  1995,  132:  475 
    Google Scholar
  • 13 Rábay J. Angew. Chem., Int. Ed. Engl.  1992,  31:  1631 
    CrossrefGoogle Scholar
  • 14 Fogassy E. Ács M. Szili T. Simándi B. Sawinsky J. Tetrahedron Lett.  1994,  35:  257 
    CrossrefGoogle Scholar
  • 15 Simon H. Ph.D. Dissertation   Technical University, Budapest; Hungary: 2003. 
    Google Scholar
  • 16 Tanaka K. Kato M. Toda F. Heterocycles  2001,  54:  405 
    CrossrefGoogle Scholar
  • 17 Kobayashi Y. Kodama K. Saigo K. Org. Lett.  2004,  6:  2941 
    CrossrefGoogle Scholar
  • 18 Kassai Cs. Ph.D. Dissertation   Technical University, Budapest; Hungary: 2000. 
    Google Scholar
  • 19 Ács M. Mravik A. Fogassy E. Böcskei Zs. Chirality  1994,  6:  314 
    CrossrefGoogle Scholar
  • 20a Optical Resolutions via Diastereomeric Salt Formation   Kozma D. CRC Press; London: 2002. 
    Google Scholar
  • 20b Faigl F. Kozma D. In Enantiomer Separation: Fundamentals and Practical Methods   Toda F. Kluwer Academic Press; Dordrecht: 2004. 
    Google Scholar
  • 21 Kozsda KE. Keserž Gy. Böcskei Zs. Szilágyi J. Simon K. Bertók B. Fogassy E. J. Chem. Soc., Perkin Trans. 2  2000,  149 
    CrossrefGoogle Scholar
  • 22a inventors; Hung. Patent  214720.  , Chem. Abstr. 1995, 124, 117097
  • 22b inventors; US Patent  02133894.  , Chem. Abstr. 2001, 139, 90595
  • 23 Bálint J. Egri G. Kiss V. Gajáry A. Juvancz Z. Fogassy E. Tetrahedron: Asymmetry  2001,  12:  3435 
    Google Scholar
  • 24 Sakai K. Sakurai R. Hirayama N. Tetrahedron: Asymmetry  2004,  15:  1073 
    CrossrefGoogle Scholar
  • 25 Sakai K. Sakurai R. Yuzawa A. Hirayama N. Tetrahedron: Asymmetry  2003,  14:  3713 
    CrossrefGoogle Scholar
  • 26 Sakai K. Sakurai R. Nohira H. Tanaka R. Hirayama N. Tetrahedron: Asymmetry  2004,  15:  3495 
    CrossrefGoogle Scholar
  • 27 Schanz HJ. Linseis MA. Gilheany DG. Tetrahedron: Asymmetry  2003,  14:  2767 
    Google Scholar
  • 28 Sakai K. Sakurai R. Yuzawa A. Kobayashi Y. Saigo K. Tetrahedron: Asymmetry  2003,  14:  1631 
    CrossrefGoogle Scholar
  • 29a Fogassy E. Lopata A. Faigl F. Ács M. Darvas F. Tőke L. Tetrahedron Lett.  1980,  21:  647 
    CrossrefGoogle Scholar
  • 29b Fogassy E. Faigl F. Ács M. Grofcsik A. J. Chem. Res., Synop.  1981,  11:  346 ; J. Chem. Res., Miniprint 1981, 11, 3981
    CrossrefGoogle Scholar
  • 29c Fogassy E. Faigl F. Ács M. Tetrahedron  1985,  41:  2837 
    CrossrefGoogle Scholar
  • 30 Kozma D. Pokol G. Ács M. J. Chem. Soc., Perkin Trans. 2  1992,  435 
    CrossrefGoogle Scholar
  • 31 Fogassy E. Kozma D. Tetrahedron Lett.  1995,  36:  5069 
    CrossrefGoogle Scholar
  • 32 Bálint J. Egri G. Vass G. Schindler J. Gajáry A. Friesz A. Fogassy E. Tetrahedron: Asymmetry  2000,  11:  809 
    CrossrefGoogle Scholar
  • 33 inventors; Hung. Patent  193199.  , Chem. Abstr. 1984, 104, 168835
  • 34 Gizur T. Péter I. Harsányi K. Fogassy E. Tetrahedron: Asymmetry  1996,  7:  1589 
    CrossrefGoogle Scholar
  • 35 Kaptein B. Elsenberg H. Grimbergen RFP. Broxterman QB. Hulshof LA. Vries T. Tetrahedron: Asymmetry  2000,  11:  1343 
    CrossrefGoogle Scholar
  • 36 Vries T. Wynberg H. van Echten E. Kock J. ten Hoeve W. Kellogg RM. Broxterman QB. Minnard A. Kaptein B. van der Sluis S. Hulshof LA. Angew. Chem. Int. Ed.  1998,  37:  2349 
    CrossrefPubMedGoogle Scholar
  • 37 Kellogg RM. Nieuwenhuijzen WJ. Pouwer K. Vries T. Broxterman QB. Grimbergen RFP. Kaptein B. La Crois RM. de Wever E. Zwaagstra K. van der Laan A. Synthesis  2003,  1626 
    Article in Thieme ConnectGoogle Scholar
  • 38 Liu A. Mok KF. Leung PH. Chem. Commun.  1997,  2397 
    CrossrefGoogle Scholar
  • 39 Mravik A. Chem. Eur. J.  1998,  4:  1621 
    CrossrefGoogle Scholar
  • 40 Várkonyi SE. Takács K. Hermecz I. J. Heterocycl. Chem.  1997,  34:  1064 
    Google Scholar
  • 41 Robinson DEJE. Bull SD. Tetrahedron: Asymmetry  2003,  14:  1407 
    CrossrefGoogle Scholar
  • 42 Eames I. Angew. Chem. Int. Ed.  2000,  39:  885 
    CrossrefGoogle Scholar
  • 43 inventors; Hung. Patent  195174.  , Chem. Abstr. 1984, 102, 61849
  • 44 Tsunoda T. Kaku H. Nagaku M. Okuyama E. Tetrahedron Lett.  1997,  38:  7759 
    CrossrefGoogle Scholar
  • 45 Enantiomers, Racemates and Resolutions   Jacques J. Collet A. Wilen SH. Wiley; New York: 1981. 
    Google Scholar
  • 46 Stereochemistry of Organic Compounds   Eliel EL. Wilen SH. Wiley; New York: 1994. 
    Google Scholar
  • 47 Pasteur L. Ann. Chim. Phys.  1848,  24:  442 
    Google Scholar
  • 48 Mravik A. Lepp Zs. Fogassy E. Tetrahedron: Asymmetry  1996,  718:  2387 
    Google Scholar
  • 49a Pincock RE. Wilson KR. J. Am. Chem. Soc.  1971,  93:  1291 
    CrossrefGoogle Scholar
  • 49b Kondepudi DK. Laudadio J. Asakura K. J. Am. Chem. Soc.  1999,  121:  1448 
    CrossrefGoogle Scholar
  • 50a inventors; Hung. Patent  179452.  , Chem. Abstr. 1978, 97, 6331
    Crossref
  • 50b Fogassy E. Ács M. Tóth G. Simon K. Láng T. Ladányi L. Párkányi L. J. Mol. Struct.  1986,  147:  143 
    CrossrefGoogle Scholar
  • 51 Dolchi C. Fumagalli L. Moroni B. Pallavicini M. Valoti E. Tetrahedron: Asymmetry  2003,  14:  3779 
    CrossrefGoogle Scholar
  • 52 Tamura R. Fujimoto D. Lepp Z. Misaki K. Miura H. Takahasi H. Ushio T. Nakai T. Hirotsu K. J. Am. Chem. Soc.  2002,  124:  13139 
    CrossrefGoogle Scholar
  • 53a inventors; Hung. Patent  181416.  , Chem. Abstr. 1979, 99, 22300
    Crossref
  • 53b Ács M. Pokol Gy. Faigl F. Fogassy E. J. Therm. Anal.  1988,  33:  1241 
    CrossrefGoogle Scholar
  • 54 Ács M. Fogassy E. Faigl F. Tomor K. Simon K. Marsó K. Mol. Cryst. Liq. Cryst.  1988,  156:  193 
    CrossrefGoogle Scholar
  • 55 Simon H. Kassai Cs. Madarász Z. Fogassy E. Kozma D. Chirality  2001,  13:  29 
    CrossrefGoogle Scholar
  • 56 Noyori R. J. Am. Chem. Soc.  1995,  117:  2675 
    CrossrefGoogle Scholar
  • 57 Girard C. Kagan HB. Angew. Chem. Int. Ed.  1998,  37:  2922 ; Angew. Chem. 1998, 110, 3088
    CrossrefPubMedGoogle Scholar
  • 58 Kozma D. Fogassy E. Mol. Cryst. Liq. Cryst.  1996,  276:  25 
    CrossrefGoogle Scholar
  • 59 Markovits I. Egri G. Fogassy E. Chirality  2002,  14:  674 
    CrossrefGoogle Scholar
  • 60a Kozma D. Madarász Z. Ács M. Fogassy E. Chirality  1995,  7:  381 
    CrossrefGoogle Scholar
  • 60b Kozma D. Simon H. Kassai Cs. Madarász Z. Fogassy E. Chirality  2001,  13:  29 
    CrossrefGoogle Scholar
1

Present-day nomenclature will be used throughout this review.

3

Catalog prices, 2004: (R)-1,1′-binaphthol: ı 44/g; (R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP): ı 335/g; (-)-α-pinene: ı 12/g; (+)-α-pinene: ı 13/g; (+)-1,4-bis(diphenylphospino)-1,4-dideoxy-2,3-O-isopropylidene-d-threitol [(+)-DIOP]: ı 118/g; (R,R)-tartaric acid: ı 46/100 g; (S,S)-tartaric acid: ı 70/100 g; dibenzoyl-(R,R)-tartaric acid: ı 81/100 g; (S)-lactic acid: ı 33/kg; (R)-1-phenylethylamine: ı 82/100 mL; (R)-1-phenylethylamine: ı 84/100 g; brucine hydrate: ı 83/100 g; quinine: ı112/100 g.