Synthetic studies towards sphingosine-related metabolites

Abstract

Metabolites of the thermophilic fungi Myriococcum albomyces and Mycelia sterilia such as myriocin (thermozymocidin, ISP-1), the mycestericins and the sphingofungins structurally resemble the sphingosines, important components of cell membranes. The close relation of the metabolites to the sphingosines suggests an important role in regulatory processes of eukaryotic cell membranes.

All the compounds revealed in vitro remarkable immunosuppressive activity and their pharmaceutical potential has led to the development of promising novel immunosuppressants. The derivative FTY720 is the first S1P receptor agonist and has a different mode of action than the commonly used calcineurin-inhibitors CsA (Neoral®) and FK506 (Prograf®), or the macrolides RAD (Certican™) and rapamycin. FTY720 is currently in clinical phase III trials for therapeutic use in the areas of transplantation and autoimmunity and was recently found to be effective in kidney transplantation in humans.

Studies on the sphingosines and Garner's aldehyde have prompted us to investigate sphingosine-related metabolites such as myriocin, the mycestericins, or the sphingofungins. Many of these metabolites bear an α-substituted serine moiety as a common feature, and the formation of this quaternary centre represents the main synthetic challenge in total syntheses of these metabolites.

The task of this thesis is to establish a synthetic route for the controlled, stereoselective formation of the quaternary carbon centre of α-substituted serine derivatives, with the option of choice of the absolute configuration. An efficient and stereoselective method for this is based on the principle of self-regeneration of stereocentres (SRS).