Synthesis of (±)-phthalascidin 622

Abstract

A synthesis of functionalized phenolic-amino-alcohols (±)-8 and (±)-16 as synthetic precursors of the catechol tetrahydroisoquinoline structure of phthalascidin 650 was disclosed. (±)-8 was prepared in 5 steps from the commercially available sesamol. Starting from 3-methyl catechol 5, 8 steps gave rise to the synthesis of phenolic-amino-alcohol (±)-16 in 27% overall yield. This synthetic strategy involved the elaboration of fully functionalized aromatic aldehyde 13 and its transformation into a phenolic -amino-alcohol (±)-16, through a Knoevenagel condensation, simultaneous reduction of nitroketene and ester functions, and hydrogenolysis of the benzyl protecting group. The pentacycle (±)-4 was obtained after 4 additional steps. The Pictet-Spengler cyclisation between the phenolic-amino-alcohol (±)-16 and the N-protected -amino-aldehyde 4 allowed to obtain (1,3′)-bis-tetrahydroisoquinoline 17 with N-methylated and N-Fmoc removed. The last step was a Swern oxidation allowing the expected intramolecular condensation. phthalascidin, ecteinascidin, (1,3′)-bis-tetrahydroisoquinoline, Pictet-Spengler, Bishler-Napieralsky