Conformationally constrained ACPD analogues. Synthesis and resolution of 3-aminobicyclo[3,3,0]octane-1,3-dicarboxylic acids

Add time:09/02/2019    Source:sciencedirect.com

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.

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