An enantio- and diastereoselective approach to indoloquinolizidines in continuous flow

Merging polymer-supported asymmetric organocatalysis with continuous flow in a packed bed reactor has been used as the key, enantiodetermining step in a short synthesis of indoloquinolizidines. Using this approach, a highly enantioselective, solvent-free and rapid conjugate addition of dimethyl malonate to a diverse family of cinnamaldehydes in continuous flow, allowing the preparation of relevant oxodiesters in multigram amounts has been developed. The obtained Michael adducts have been used to complete an expedient diastereoselective synthesis of indoloquinolizidine via cascade Pictet-Splengler cyclisation-lactamisation in continuous flow. The conversion of enantiopure Michael adducts into delta-lactones via telescoped reduction/cyclisation in continuous flow has also been explored.

Automated summary

In this study, the merging of polymer-supported asymmetric organocatalysis with continuous flow in a packed bed reactor was successfully used for the synthesis of indoloquinolizidines. A highly enantioselective, solvent-free and rapid conjugate addition reaction in continuous flow allowed the preparation of multigram amounts of relevant oxodiesters. The obtained Michael adducts were then used for the efficient diastereoselective synthesis of indoloquinolizidines through cascade Pictet-Splengler cyclisation-lactamisation in continuous flow. The conversion of enantiopure Michael adducts into delta-lactones via telescoped reduction/cyclisation in continuous flow was also explored.