Synthesis (19): 3327-3331  
DOI: 10.1055/s-0029-1216963
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of a Conformationally Rigid Analogue of 2-Aminoadipic Acid ­Containing an 8-Azabicyclo[3.2.1]octane Skeleton

Vladimir S. Kubyshkina,c, Pavel K. Mykhailiuk*a,c, Anne S. Ulrichb,c, Igor Komarova
a Department of Chemistry, Kyiv National Taras Shevchenko University, Vul. Volodymyrska 64, 01033 Kyiv, Ukraine
b Institut für Biologische Grenzflächen, Karlsruhe Institute of Technology, Forschungszentrum Karlsruhe, POB 3640, 76021 Karlsruhe, Germany
c Institut für Organische Chemie, Karlsruhe Institute of Technology, Universität Karlsruhe, Fritz-Haber-Weg 6, 76133 Karlsruhe, Germany
Fax: +380(44)2251273; e-Mail:;
Further Information

Publication History

Received 11 May 2009
Publication Date:
21 August 2009 (online)


A new, conformationally rigid analogue of 2-amino­adipic acid, 8-[(benzyloxy)carbonyl]-3-methylene-8-azabicyclo[3.2.1]octane-1,5-dicarboxylic acid, is synthesized from dimethyl rac-2,5-dibromohexanedioate. The key steps involve alkylation-cyclization of 1-benzyl 2,5-dimethyl pyrrolidine-1,2,5-tricarboxylate with 3-chloro-2-(chloromethyl)prop-1-ene to yield the 8-azabicyclo[3.2.1]octane skeleton.


  • 1 Hassian S. Auzzas L. Acc. Chem. Res.  2008,  41:  1241 
  • 2a Hanessian S. McNaughton-Smith G. Lombart H.-G. Lubell WD. Tetrahedron  1997,  53:  12789 
  • 2b Cativiela C. Díaz-de-Villegas MD. Tetrahedron: Asymmetry  2000,  11:  645 
  • 2c Cativiela C. Díaz-de-Villegas MD. Tetrahedron: Asymmetry  1998,  9:  3517 
  • 2d Park K.-H. Kurth MJ. Tetrahedron  2002,  58:  8629 
  • 2e Cativiela C. Díaz-de-Villegas MD. Tetrahedron: Asymmetry  2007,  18:  569 
  • 3a Biscoe TJ. Evans RH. Francis AA. Martin MR. Watkins JC. Davies J. Dray A. Nature  1977,  270:  743 
  • 3b McLennan H. Hall JG. Brain Res.  1978,  149:  541 
  • 3c Lodge D. Headley PM. Curtis DR. Brain Res.  1978,  152:  603 
  • 4 Kubyshkin VS. Mykhailiuk PK. Komarov IV. Tetrahedron Lett.  2007,  48:  4061 
  • 5 Dimethyl meso-2,5-dibromohexanedioate 5a was obtained using an identical procedure to that described for diethyl meso-2,5-dibromohexanedioate, see: Guha PC. Sankaran DK. Org. Synth.  1955,  3:  623 
  • 6 Three diastereomers of 4: meso-, (2R,5R)- and (2S,5S)- are formed during the synthesis, each being suitable for alkylation. We chose the crystalline (2R,5R)-isomer 4, which was easily separated from the reaction mixture as it crystallizes upon standing in a fridge; the product was filtered off and was washed with hexane. For the original procedure, see: Yamamoto Y. Hoshino J. Fujimoto Y. Ohmoto J. Sawada S. Synthesis  1993,  298 
  • 8a Romesberg FE. Collum DB. J. Am. Chem. Soc.  1994,  116:  9198 
  • 8b Ferey V. Vedrenne P. Toupet L. Le Gall T. Mioskowski C. J. Org. Chem.  1996,  61:  7244 
  • 10 Xu Y.-z. Choi J. Calaza MI. Turner S. Rapoport H. J. Org. Chem.  1999,  64:  4069 
  • 11 Einhorn J. Einhorn C. Ratajczak F. Pierre J.-L. Synth. Commun.  2000,  30:  1837 
  • 12 Masschelein KGR. Stevens CV. Dieltiens N. Claeys DD. Tetrahedron  2007,  63:  4712 

The configurations at C-2 and C-5 in compounds 6, 9, 12a,b, 14 and 15a,b were not determined since they are lost upon subsequent transformation into the non-chiral 8-azabicy-clo[3.2.1]octane skeleton.


The conversion without addition of HMPA was only 15% after 12 h at 20 ˚C. After 160 h, the transformation was complete; however, in the ¹H NMR spectrum of the crude mixture, together with 6, a number of unidentified side products were detected. All subsequent alkylations were performed in the presence of HMPA.