Total synthesis of discorhabdins - a generalized approach

This postdoctoral research proposal consists of two objectives. The first is the generalized approach to the discorhabdin family, of which the total synthesis of discorhabdin A, B, C, Q and T are worked out in detail. The second part will cover the undecided question of sulfur introduction in the course of the biosynthesis of these natural products. The choice of discorhabdins was made along several requirements: - The target has to be of biological interest. - The structure targeted has to be unique, challenging and contain unsolved synthetic problems. - The opportunity to develop new methodology. Discorhabdins belong to the pyrroloiminoquinone alkaloids. Their family consists of more than 15 members. They have been isolated from sponges of very diverse marine habitats all over the oceans. They show promising antitumor activity as they are powerful topoisomerase II inhibitors. Many synthetic approaches, especially to the pyrroloiminoquinone system of these molecules have been done, but so far only a single total synthesis of a sulfur containing member, discorhabdin A, exists. This suffers from the disadvantages of long reaction sequences and low yields that makes accessing gram quantities for further biological testings impractical. In this proposal we present a catalytic enantioselective total synthesis for discorhabdins. The number of steps is shortened by a halve and should give access to large quantities of these natural products. Additionally we devised a new methodology for the pyrroloiminoquinone synthesis. The key transformations in our synthetic plan for the formation of the pyrroloiminoquinone system are the Hauser Kraus annulation, or the Dötz reaction with its chromium free variants. The installation of the quarternary carbon center is performed via a catalytic enantioselective dearomatization using a rhodium carbenoid, or alternatively with the chiral lewis acid catalyzed opening of an aziridine. A very challenging task will be the formation of the sulfur bridge. Here we want to use unprecedented methodology and complete the total synthesis. The second main objective of this proposal constitutes the elucidation of the biosynthesis, especially of the sulfur incorporation into the target structures. For this purpose a biomimetic total synthesis was developed that should bring to light how this event could take place in nature.