Ecteinascidin

Overview
Ecteinascidin 743 is a potent anti-tumor drug. First isolated from aqueous ethanol extract of tunicates in 1969, the complex molecule was found to have impressive cytocytic activities in the pico- to nanomolar range. It is composed of 3 tetrahydroquinoline moieties, 8 rings including one 10-membered heteocyclic ring containing a cystine residue, and 7 chiral centers. This structure was not determined until 1984, and was first totally synthesized by Elias James Corey in 1996.

The biological mechanism of action is believed to involve the production of superoxide near the DNA strand, resulting in DNA backbone cleavage and cell apoptosis. The actual mechanism is not yet known, but is believed to proceed from reduction of molecular oxygen into superoxide via an unusual auto-redox reaction on a hydroxyquinone moiety of the compound following. There is also some speculation the compound becomes 'activated' into its reactive oxazolidine form.

Biosynthesis is also beleieved to involve the dimerization of two tyrosine residues to form the pentacyclic core of the molecule. The total synthesis by E.J. Corey used this proposed biosynthesis in their attempt at the compounds synthetic creation. Their synthesis utilized such reactions as the Mannich reaction, Pictet-Spengler reaction, the Curtius rearrangement, and the use of chiral Rhodium-based diphosphine complex, in order to conver Z isomers into "S" enantiomers with ~100% yield. A separate synthetic process also involved the Ugi reaction to assist in the formation of the pentacyclic core. This reaction was unprecidented for using such a one pot multi-component reaction in the synthesis of such a complex molecule.