Stereoselective synthesis of functionalized 1,2,3,4-tetrahydroisoquinolines (THIQs) via highly diastereoselective Ugi three-component reactions (U3CRs) with chiral 3,4-dihydroisoquinolines (DHIQs)

Abstract

A highly diastereoselective Ugi three-component reaction (U3CR) involving chiral 3,4-dihydroisoquinolines (DHIQs), isocyanides and carboxylic acids has been developed to synthesize enantiopure 1,2,3,4-tetrahydroisoquinolines (THIQs). The inherent chirality of DHIQ at C-3 and C-4 controls the addition of isocyanide at C-1 to induce excellent diastereoselectivity. The method was applied to a variety of aromatic and aliphatic acids, and in most cases the reaction proceeded smoothly without formation of any side products. The experimental and computational studies demonstrated the role of internal chirality in the conformational stability of the intermediate in order to control the facial selectivity and strong solvent effect on the reaction. Cytotoxicity of selected compounds was also evaluated against four types of human cancer cell lines, MCF-7 (breast cancer), MDA MB-231 (breast cancer), DU-145 (prostate cancer), A549 (lung cancer) and HepG2 (liver cancer), where few compounds exhibited GI₅₀ values in the submicromolar range.