Synthesis of (+/-)-phthalascidin 622

Christian R. Razafindrabe (1, 2) , Sylvain Aubry (1) , Benjamin Bourdon (1) , Marta Andriantsiferana (2) , S Pellet-Rostaing (1, 3) , Marc Lemaire (4)

1 ICBMS - Institut de Chimie et Biochimie Moléculaires et Supramoléculaires
2 Université d'Antananarivo
3 ICSM - UMR 5257 - Institut de Chimie Séparative de Marcoule
4 CASYEN - Catalyse Synthèse et Environnement

A synthesis of functionalized phenolic alpha-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 alpha-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 alpha-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 alpha-amino-alcohol (+/-)-16 and the N-protected alpha-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.

Domaines: Chimie organique

Christian R. Razafindrabe, Sylvain Aubry, Benjamin Bourdon, Marta Andriantsiferana, S Pellet-Rostaing, et al.. Synthesis of (+/-)-phthalascidin 622. Science China Chemistry, 2010, 53 (9), pp.1888-1898. ⟨10.1007/s11426-010-4075-z⟩. ⟨hal-00692051⟩