First Synthesis of (R)- and (S)-1,2,3,4-Tetrahydroisoquinoline-3-phosphonic Acid (TicP) Using a Pictet-Spengler Reaction

We report here a practical and efficient synthesis of diethyl 1,2,3,4‐tetrahydroisoquinoline‐3‐phosphonate derivatives. The target compounds were prepared in good yield using a Pictet–Spengler reaction involving α‐amino phosphonates that were easily obtained. We have paid special attention to the synthesis of (R)‐ and (S)‐1,2,3,4‐tetrahydroisoquinoline‐3‐phosphonic acid (TicP) 2a, a conformationally constrained analogue of phosphophenylalanine PheP. The procedure is based on the preparation of racemic phosphophenylalanine (PheP) diethyl ester followed by chiral chromatographic separation and subsequent Pictet–Spengler chemistry. We report here the first practical and efficient synthesis of (R)‐ and (S)‐1,2,3,4‐tetrahydroisoquinoline‐3‐phosphonic acids (TicP), by application of a Pictet–Spengler reaction using enantiomerically pure α‐amino phosphonates easily obtained by chiral HPLC resolution.