Synthetic investigations of (1,3′)-bistetrahydroisoquinolines: towards pentacyclic analogues of piperazine core alkaloids

Synthetic investigations of (1,3′)-bistetrahydroisoquinolines are reported as the key intermediates for the synthesis of ecteinascidin and phthalascidin pentacyclic structure analogues through successive Pictet–Spengler cyclization and intramolecular peptide coupling. The direct Pictet–Spengler reaction between a derivative of l-DOPA and N-protected-α-aminoaldehyde was first extended to the synthesis of cis-(1,3′)-bistetrahydroisoquinoline. After introduction of the required amino acid moiety, an efficient six-membered ring intramolecular peptide coupling gave rise to piperazine derivative structures. Complete structural assignments were corroborated by NMR and X-ray spectroscopic methods. Nevertheless, the optical integrity of the N-protected-α-aminoaldehyde seems to be sensitive to the reaction conditions. Pentacylic structures, having an anti C3–C11 backbone stereochemistry, were obtained from cyclization para- and ortho- to the 3-OH group of the l-DOPA derivative.