Short stereocontrolled synthesis of trans and cis-tetrahydro-pyrazinoisoquinolinediones

Abstract

Addition of aldehyde dimethyl acetals (here acetaldehyde) to unisolated O-trimethylsilyl derivatives of 1-acetyl-3-arylmethylpiperazine-2,5-diones (here 2,5-dimethoxyphenyl), in the presence of TMSOTf as the catalyst, gave nearly quantitatively the corresponding N-methoxyalkyl derivatives which, under acidic treatment, gave in very good yield through a Pictet–Spengler-type reaction involving N-acyliminium cations (6 S*,11a R*)-2-acetyl-6-alkyl-3,6,11,11a-tetrahydro-2 H-pyrazino[1,2- b]isoquinoline-1,4-diones. Epimerization of the 11a-stereocentre was accomplished by radical bromination, spontaneous hydrobromide elimination and catalytic hydrogenation, to give the (6 S*,11a S*)-isomers. We propose these compounds as precursors of tetrahydroisoquinoline antitumour antibiotics.