Synthesis of Enantiopure cis- and trans-Fused Octahydroisoindole-1-Phosphonic Acids from Octahydroisoindolones

Phosphonic analogs of octahydroisoindole-1-carboxylic acids are bicyclic proline derivatives of interest in drug design and enzymatic mechanism studies. Here we report the stereoselective synthesis of the cis- and trans-fused octahydroisoindole system using oxazoloisoindolone lactam and 1,2-cyclohexanedicarboxylic anhydride as advanced chiral precursors, respectively, yielding enantiopure octahydroisoindolone intermediates with the desired stereochemistry at the ring junction. Finally, using these intermediates, the target (1R,3aR,7aS)- and (1R,3aR,7aR)-octahydroisoindole-1-phosphonic acids and their enantiomers were obtained with complete stereocontrol via highly diastereoselective addition of trimethyl phosphite to chiral N-acyliminium ions as the key step.