CONFORMATIONALLY CONSTRAINED ACPD ANALOGS - SYNTHESIS AND RESOLUTION OF 3-AMINOBICYCLO[3,3,0]OCTANE-1,3-DICARBOXYLIC ACIDS

The synthesis Of racemic 3-aminobicyclo[3.3.0]octane-1,3-dicarboxylic acids (2 and 3) which are conformationally constrained ACPD analogues, has been achieved in seven steps starting from the readily available Weiss diketone (4). Partial reduction of of 4 to 5, followed by phenyl ring oxidation with RuCl3/NaIO4, gave the bicyclic ketoacid 6 which, after Bucherer-Bergs reaction and fractional crystallization, afforded spirohydantoins 7 and 8 in a 2/1 ratio. Both isomers were hydrolyzed to amino acids 2 and 3. Optical resolution of racemic 7 was performed by crystallization of the corresponding (-)-(S)-brucine diasteromeric salts and, after decomposition and hydrolysis, (+)-(1S*, 3R*, 5R*) and (-)-(1R*, 3S*, 5S*)-3-aminobicyclo[3,3,0]octane-1,3-dicarboxylic acids (2a and 2b) were obtained to be biologically compared with (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD). Due to the solubility profile of hydantoins 7 and amino acids 2, the enantiomeric purity was measured in the dimethyl derivative 9, being determined by chiral-HPLC.