Towards the total synthesis of L-783,277

Promoter

Prof. Steve LANNERS, Laboratory of Synthetic Organic Chemistry (COS)

Jury

Steve Lanners (Supervisor), Daniel Vercauteren (President), Stéphane Vincent (Jury), Christoph Tzschucke (Jury) & Gilles Hanquet (Jury)

Summary

Resorcylic Acid Lactones (RALs) are a family of mycotoxins which share the same structural skeleton composed of a β-resorcylic acid core fused with a 12- or 14-membered lactone. Despite their small strutural variations, these macrolides display an astonishingly large spectrum of biological activities, spanning from being Hsp90 inhibitors to antimalarial and antifouling. Three metabolites of the cis-enone containing subfamily have been recently recognised as a structurally unique class of kinase inhibitors. Their inhibition of kinases with a Cys residue properly located in their ATP binding pocket (ca 10% of the kinome), result from the 1,4-adddition of the abovementioned protein thiol to the cis-enone. One of them, L-783,277 has been recently disclosed to owe an anti-angiogenetic potential.
This project aimed for an elegant and modular synthetic pathway towards L-783,277, extracted from the fruitbody of Helvella acetabulum. This thesis outlines the construction of a dialkyne precursor, as the pivotal stage for a ring-closing alkyne metathesis, followed by Lindlar reduction to incorporate the delicate cis-enone.
The first chapter portrays a succinct biological profile of RALs over the period 1968-2014, which have been the target of a myriad of total syntheses. The syntheses of some chosen resorcylides are detailed to illustrate how early studies on structurally simple macrolides built the solid basement for innovative strategies and methodologies. The syntheses targeting cis-enone containing RALs, e.g. L-783,277, elucidate our inspirations and strategies towards the latter.
The second chapter exposed the preparation and tactical assembly of three fragments resulting from the retrosynthetic disconnection of L-783,277: an aromatic core and two straight-chained segments containing both a terminal substituted propyne. The synthesis of one of the latter led to the development of a new method for the one-carbon homologation and opening of lactones via the corresponding phosphine oxide. The key step resides in the direct alkylation at the benzylic position of the aromatic core as the first assembly. Finally, the crucial dialkyne precursor has been obtained on multigram scale, based on robust procedures with simple purification. The first series of assays devoted to RCAM are also discussed at the end of this chapter.
The third chapter depicts the application of our synthetic blueprint to other RALs, namely two natural resorcylides (zeranol and (R)-lasiodiplodin) and two synthetic ones: (S)-lasiodiplodin and Neolasiodiplodin. Their accomplishment illustrates our elegant and concise strategy, promising further synthetic avenues leading to more complex resorcylides, which bear either a 12- or 14-membered ring.