A Novel Octahydropyridobenzothiazepine Metabolite in Human Urine: Biomimetic Formation from the Melanogen 5-S-Cysteinyldopa and Formaldehyde via a Peculiar Sulfur-Controlled Double Pictet-Spengler Condensation.

HPLC evidence is reported demonstrating the occurrence in some human urine samples of a novel catecholic metabolite, (3R,7S)-3,7-dicarboxy-10,11-dihydroxy-2,3,4,5,6,7,8,9-octahydropyrido[4,3-g][1,4]benzothiazepine (I). The compd. was shown to arise by a double Pictet-Spengler condensation of the urinary melanogen 5-S-cysteinyldopa with formaldehyde, in which regioselective formation of the six-membered ring ortho to the activating hydroxyl group lends assistance to the subsequent closure of the seven-membered 1,4-thiazepine moiety. Under physiol. relevant conditions, i.e., in 0.1 M phosphate buffer pH 7.4 and at 37°, the 7,8-dihydroxytetrahydroisoquinoline II (R = H) was the sole detectable intermediate in the formation of I. N-Acetylcysteinyldopa reacted likewise with formaldehyde to give the 7,8-dihydroxytetrahydroisoquinoline II (R = Ac). The anomalous regiochem. underlying formation of II (R = H, Ac) was rationalized with the aid of AM1/PM3 calcns. on a model alkylthiocatechol, predicting a higher HOMO-controlled reactivity on the position ortho rather than para to the activating hydroxyl group. The potential of the reported chem. as a convenient synthetic access to the 2,3,4,5-tetrahydro[1,4]benzothiazepine ring system is suggested by the efficient conversion of a cysteinylcatechol to III in the presence of formaldehyde.