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

Abstract 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 (Tic P ) 2a , a conformationally constrained analogue of phosphophenylalanine Phe P . The procedure is based on the preparation of racemic phosphophenylalanine (Phe P ) diethyl ester followed by chiral chromatographic separation and subsequent Pictet–Spengler chemistry.