Five Step Total Synthesis of Lythranidine.

A concise synthesis of the alkaloid lythranidine is reported. The strategy exploits the target's local C2 symmetry by adopting a two directional synthetic approach, first in an acyclic environment, then in a cyclic system and finally in a bridged macrocyclic domain. The latter phase of the synthesis, which installs all four stereocenters, involves a thermodynamically controlled, twofold intermolecular/transannular aza-Michael addition and a twofold hydride reduction. The synthesis is one third of the length of the most step-economic previous approach, providing access to gram quantities of the natural product. The broad-spectrum nature of the synthesis is demonstrated through the preparation of three diastereomeric analogues of the natural product.