The University of British Columbia
The Total Synthesis of Amanitin and Natural Product Inspired Peptides
Alpha-amanitin is a classic natural product that was isolated 80 years ago from the notorious death-cap mushroom, A. phalloides, which, since Roman times, has been an agent of murder and suicide.
Alpha-amanitin, a potent, orally available, highly selective allosteric inhibitor of RNA polymerase II, Pol II, has been featured in thousands of publications, most notably: x-ray and NMR total structure elucidation, affinity chromatography for the purification of RNA Pol II7, co-crystallization with RNA Pol II, recent cryo-EM studies, and as a toxic payload for antibody-drug conjugates. Its bicyclic octapeptide structure contains two key oxidized amino acids: trans-4-hydroxy-proline, Hyp, and notably (2S,3R,4R)-4,5-dihydroxy-isoleucine, DHIle. In addition, a crosslink comprising 6-hydroxy- tryptathionine-(R)-sulfoxide is unique among natural products.
These key structural motifs have represented a long-standing synthetic challenge in total synthesis. By addressing a delicate three-fold oxidation of tryptophan to deliver the key 6-hydroxy-tryptathionine- (R)-sulfoxide along with the first enantioselective DHIle, we sealed the first total synthesis of amanitin in the synthetic record. This work now provides access to derivatives to probe critical structure-activity relationships as well as a means of accessing scalable quantities of the toxin.
Hence, we have applied aspects of this methodology to the synthesis of a prototypical phalloidin library as well as other monocyclic peptides of clinical interest12. The underlying methods that provided the synthesis of this venerated toxin along with other medicinally important peptides will be discussed.