Synthesis of Enantiopure - and -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 - and -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 (1,3a,7a)- and (1,3a,7a)-octahydroisoindole-1-phosphonic acids and their enantiomers were obtained with complete stereocontrol via highly diastereoselective addition of trimethyl phosphite to chiral -acyliminium ions as the key step.