Acino International (Germany)

Diastereoselective Hydroxyalkylations in Position 1 of Tetrahydroisoquinolines and Synthesis of Aporphine, Protoberberine, and Pathalide AlkaloidsUnsubstituted and 6,7‐dialkoxy‐N‐pivaloyl‐tetrahydroisoquinolines 1–3 are converted to 1‐bromomagnesium derivatives by sequential treatment with t‐BuLi (−75°/THF) and MBr2.OEt2. Addition of the metalated tetrahydroisoquinolines to aliphatic or aromatic aldehydes occurs with relative topicity ul (Scheme 2). The 1‐hydroxyalkylated 2‐pivaloyl‐tetrahydroisoquinolines a of u‐configuration thus obtained (14 examples) can be converted to free aminoalcohols c of either l‐or u‐configuration (9 examples; Scheme 3). The depivaloylation with retention (→ u‐c) is best achieved by heating in EtOH/KOH, the conversion to 1‐aminoalcohols l‐c by treatment with CF3COOH/(CF3CO)2O (→ l,‐pivalates l‐b), followed by alkaline saponification or by LiAlH4 reduction of the esters. The configuration of the products is assigned by 1H‐NMR spectroscopy, by X‐ray crystal structure analysis, by chemical correlation, and by comparison of the chemical properties of the l‐ and the u‐isomers. The diastereoselective hydroxybenzylation of the tetrahydroisoquinoline is used for short syntheses of ushinsunine/oliveroline (Scheme 4), β‐hydrastine, and ophiocarpine/epiopliocarpine (Scheme 6; aporphine, phthalide, and protoberberine alkaloids, respectively).

Abstract The synthesis of some 5‐alkyl‐ and 5‐alkenyl‐4‐hydroxy (resp. acyloxy‐ resp. alkoxy)‐isophthalic acids and esters is described. Some of the described derivatives exhibit analgetic, antipyretic and antiphlogistic activity.