[Syntheses and ring-closures of difunctional tetrahydroisoquinolines]

Starting from homoveratrylamine and N-protected amino acids 1,2,3,4-tetrahydroisoquinoline diamines were prepared by a convenient four-step process. This synthetic method was successfully extended to substituted beta-alanine and homoveratrylamine derivatives. In the case of the 1'-methyl-substituted derivatives, the reducing agent applied and the sequence of the reduction and deprotection steps proved to have marked effects on the formation of the possible diamine diastereomers. By N-amination of the corresponding amino alcohols, tetrahydroisoquinoline hydrazino alcohol regioisomers were prepared. Condensation products of the prepared tetrahydroisoquinoline 1,2- and 1,3-diamines containing a primary amino group with aromatic aldehydes proved to participate in three-component ring-chain tautomeric equilibria. The tautomeric equilibrium was sensitive to the electronic effects of the aromatic substituents, the ring size and the methyl substituents of the skeleton. By N-substitution reactions of 1-(Cbz-aminomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline with isocyanates and isothiocyanates, the corresponding urea or thiourea derivatives were obtained some derivatives of which showed a remarkable MDR modulating activity. By ring-closures of tetrahydroisoquinoline diamines and hydrazino alcohols with phosphorus-containing reagents, saturated 1,3,2-diazaphosphino[6,1-a]isoquinolines, and 1,3,4,2-oxadiazaphosphino[5,4-a]- and [4,5-b]isoquinolines as the first representatives of these ring systems were prepared. The conformational behaviour of these compounds was studied by NMR and X-ray diffractional analyses.