Abstract:We report here a practical and efficient synthesis of α-aminophosphonic acid incorporated into 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline heterocycles, which could be considered to be conformationally constrained analogues of pipecolic acid. The principal contribution of this synthesis is the introduction of the phosphonate group in the N-acyliminium ion intermediates, obtained from activation of the quinoline and isoquinoline heterocycles or from the appropriate δ-lactam with benzyl chloroformate. Finally, the hydrolysis of phosphonate moiety with simultaneous cleavage of the carbamate afforded the target compounds.

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The synthesis of two new α‐aminophosphonic acids, namely (2S*,3aS*,7aS*)‐ and (2R*,3aS*,7aS*)‐octahydroindole‐2‐phosphonic acids, is described. They are analogues of phosphoproline with a cyclohexane ring fused to the pyrrolidine moiety. The ring junction has cis stereochemistry in both cases, but the two compounds differ in the relative orientation of the cyclohexane and phosphonate moieties. The two amino acids were prepared from a common starting material following stereodivergent routes that provide the desired stereoisomer with complete stereocontrol. The relative configurations of the compounds synthesised were confirmed by X‐ray diffraction analysis.

The synthesis of two phosphoproline analogues possessing an octahydroisoindole structure is described for the first time. The new α‐aminophosphonic acids can be viewed as the result of fusing a cyclohexane ring to the [c] face of the five‐membered pyrrolidine unit. The junction of the bicyclic system is cis in both compounds, but they differ in the relative stereochemistry of the cyclohexane and phosphonate moieties. Using phthalimide as a common precursor and following stereodivergent routes, the target α‐aminophosphonic acids, (1R*,3aR*,7aS*)‐ and (1S*,3aR*,7aS*)‐octahydroisoindole‐1‐phosphonic acids, have been prepared with completestereocontrol and in high overall yields. The structurally related isoindoline‐1‐phosphonic acid, containing a benzene ring [c]‐fused to pyrrolidine, has also been obtained.