Synthesis 2006(8): 1386-1389  
DOI: 10.1055/s-2006-926419
© Georg Thieme Verlag Stuttgart · New York

Convenient Multigram Synthesis of (R)-Homopipecolic Acid Methyl Ester

Matthias Breuning*, Melanie Steiner
Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
Fax: +49(931)8884755; e-Mail: [email protected];
Further Information

Publication History

Received 10 January 2006
Publication Date:
10 April 2006 (online)


(R)-Homopipecolic acid methyl ester has been prepared on a multigram scale from 3,4-dihydro-2H-pyran in five steps and 36% overall yield. The stereochemistry was introduced via an asymmetric Michael addition and a fractional crystallization.


  • 2 Hermet J.-PR. McGrath MJ. O’Brien P. Porter DW. Gilday J. Chem. Commun.  2004,  1830 
  • 3a Morley C. Knight DW. Share AC. Tetrahedron: Asymmetry  1990,  1:  147 
  • 3b Ledoux S. Marchalant E. Célérier J.-P. Lhommet G. Tetrahedron Lett.  2001,  42:  5397 
  • 4 Back TG. Hamilton MD. Lim VJJ. Parvez M. J. Org. Chem.  2005,  70:  967 
  • 5 Barilli A. Belinghieri F. Passarella D. Lesma G. Riva S. Silvani A. Danieli B. Tetrahedron: Asymmetry  2004,  15:  2921 
  • 6 Angoli M. Barilli A. Lesma G. Passarella D. Riva S. Silvani A. Danieli B. J. Org. Chem.  2003,  68:  9525 
  • 7a Danilewicz JC. Abel SM. Brown AD. Fish PV. Hawkeswood E. Holland SJ. James K. McElroy AB. Overington J. Powling MJ. Rance DJ. J. Med. Chem.  2002,  45:  2432 
  • 7b Katori M. Tamaki T. Tanaka M. Konoeda Y. Yokota N. Hayashi T. Uchida Y. Hui Y. Takahashi Y. Kakita A. Kawamura A. Transplant. Proc.  1999,  31:  1016 
  • 7c Groneberg RD, Zhan J, Askew B, D’Amico D, Han N, Fotsch CH, Liu Q, Riahi B, Zhu J, Yang K, Chen JJ, and Nomak R. inventors; PCT Int. Appl. WO  2004092164.  2004
  • 8 Ledoux S. Célérier J.-P. Lhommet G. Tetrahedron Lett.  1999,  40:  9019 
  • 9a Chippindale AM. Davies SG. Iwamoto K. Parkin RM. Smethurst CAP. Smith AD. Rodriguez-Solla H. Tetrahedron  2003,  59:  3253 
  • 9b Davies SG. Iwamoto K. Smethurst CAP. Smith AD. Rodriguez-Solla H. Synlett  2002,  1146 
  • 9c Enders D. Wiedemann J. Justus Liebigs Ann. Chem.  1977,  699 
  • 10a Wanner KT. Kärtner A. Arch. Pharm. (Weinheim, Ger.)  1987,  320:  1253 
  • 10b Wanner KT. Kärtner A. Heterocycles  1987,  26:  921 
  • 10c Matsumura Y. Kanda Y. Shirai K. Onomura O. Maki T. Tetrahedron  2000,  56:  7411 
  • 11a Calvet S. David O. Vanucci-Bacqué C. Fargeau-Bellassoued M.-C. Lhommet G. Tetrahedron  2003,  59:  6333 
  • 11b David O. Calvet S. Chau F. Vanucci-Bacqué C. Fargeau-Bellassoued M.-C. Lhommet G. J. Org. Chem.  2004,  69:  2888 
  • 11c Pousset C. Callens R. Marinetti A. Larchevêque M. Synlett  2004,  2766 
  • 12a Gray D. Concellón C. Gallagher T. J. Org. Chem.  2004,  69:  4849 
  • 12b DeVita RJ. Goulet MT. Wyvratt MJ. Fisher MH. Lo J.-L. Yang YT. Cheng K. Smith RG. Bioorg. Med. Chem. Lett.  1999,  9:  2621 
  • 13a Pousset C. Callens R. Haddad M. Larchevêque M. Tetrahedron: Asymmetry  2004,  15:  3407 
  • 13b Chung H.-k. Kim H.-w. Chung K.-H. Heterocycles  1999,  51:  2983 
  • For some examples of enantioselective Michael additions of lithiated derivatives of 4 to α,β-unsaturated esters, see:
  • 14a Davies SG. Fenwick DR. J. Chem. Soc., Chem. Commun.  1995,  1109 
  • 14b Davies SG. Dixon DJ. J. Chem. Soc., Perkin Trans. 1  1998,  2635 
  • 14c Bull SD. Davies SG. Roberts PM. Savory ED. Smith AD. Tetrahedron  2002,  58:  4629 
  • 14d

    Ref. 9a.

  • 15 For related approaches to the corresponding ethyl and tert-butyl esters, see ref. 2 and the following: Baenziger M. Gobbi L. Riss BP. Schaefer F. Vaupel A. Tetrahedron: Asymmetry  2000,  11:  2231 
  • 19 Tsukada N. Shimada T. Gyoung YS. Asao N. Yamamoto Y. J. Org. Chem.  1995,  60:  143 
  • 24 Craig D. Geach NJ. Pearson CJ. Slawin AMZ. White AJP. Williams DJ. Tetrahedron  1995,  51:  6071 

According to a Beilstein search; for some examples see references 2-7.


In the presence of two equivalents of (S)-4 and no additional base, compound 5 was obtained in a slightly improved yield (86%), but with a decreased diastereomeric ratio (67:33).


The analogous cyclization of the tosyloxy derivative of 3 gave comparable results; nevertheless this route was less efficient - the tosyl derivative was prepared in a lower yield (73% from 2).


For a related cyclization of an ω-iodo enoate, see ref. 2.


Mesylate (E)-3 was synthesized from (E)-2, which was accessible by distillation of (E/Z)-2, see ref. 23.


The crude product can also be purified by distillation (bp 75-85 °C, 0.02 mbar) through a Vigreux column (10 cm). Even though the lower boiling fractions were enriched with the minor diastereomer (S,S)-5, satisfactory separation of the two diastereomers was not achieved.


There is just a short filtration through a pad of silica gel prior to the fractional crystallization.


All fractions boiling below 70 °C/0.1 mbar were discarded; fractions boiling at 71-75 °C/0.1 mbar contained mainly (Z)-2, fractions boiling at 92-96 °C/0.1 mbar provided pure (E)-2.