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-alpha-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-alpha-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. (c) 2005 Elsevier Ltd. All rights reserved.