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Synthesis 2009(19): 3327-3331  
DOI: 10.1055/s-0029-1216963
PAPER
© 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: pashamk@gmx.de;
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Publication History

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

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Abstract

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.

Key words

conformational restriction - bicyclic compounds - pyrrolidines - alkylations - cyclization

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7

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.

9

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.