Total synthesis of the analogues of pavettamine

Abstract

Pavettamine, a plant toxin isolated from Pavetta harborii, was previously identified as a polyamine with C-2 symmetry and a 1,3-syn-diol moiety on a C-10 carbon backbone (one of very few to be isolated from nature). Biological studies have shown that this toxin is responsible for “quick disease” (gousiekte) in ruminant animals which causes inhibition of protein synthesis in the cardiovascular organs. The uniqueness of pavettamine coupled with its toxicological effects prompted this study, which aims to contribute towards the complete study of the structure activity relationships associated with its toxicity. To this end, the first total synthesis of the enantiomer of pavettamine was achieved together with the development of a suitable method for the synthesis of reduced functionality analogues. The symmetrical structure of the molecule allows for the synthesis of two individual C5 fragments to be coupled at a later stage. Retrosynthetic analysis identified commercially available S-malic acid as a suitable starting material for synthesis of the two individual C5 fragments. This chiral hydroxyl acid from nature’s pool constitutes a β-hydroxy ketone group. Several transformations of S-malic acid allowed for the addition of the R-methyl p-tolyl sulfoxide chiral auxiliary, facilitating stereoselective reduction of the ketone, and affording the desired 1,3-syn-diol functionality. A protecting group strategy was also developed for the orthogonal protection of the alcohol and amine functional groups as they were unveiled. From this point onwards the terminal carbon atoms of the separate C5 fragments were functionalised, followed by coupling of the fragments via reductive amination revealing the C-10 carbon backbone. Deprotection of the alcohols and amines successfully provided the enantiomer of pavettamine as a TFA salt. Application of a similar synthetic protocol afforded acetonide protected pavettamine. A method was also developed for the synthesis of the reduced functionality analogues lacking certain hydroxyl groups.