The first total synthesis of enisorine D, a natural product isolated from the marine sponge Iotrochota cf. iota, is described in 64% overall yield. The target molecule, which is an inhibitor of T3SS-dependent Yope secretion of Y. pseudotuberculosis, is achieved in seven linear steps from tyramine via simple and effective transformations that include bromination, acylation, alkylation, azidation, reduction and routine acid-amine coupling. A total of sixteen analogues are prepared by coupling with eight different cinnamic acids, two bromopyrrole carboxylic acids, five phenyl carboxylic acids and picolinic acid. © 2019 Georg Thieme Verlag. All rights reserved.