Synthetic studies toward pavettamine, the active principle from Pavetta harborii

Abstract

Gousiekte (“quick” disease) is a plant-induced cardiomyopathy of livestock in South Africa, that is characterized by the sudden death of animals within a period of 3-6 weeks after the initial ingestion of toxic plant material. Six species of three genera of the Rubiaceae family viz. Pachystigma pygmaeum, P. thamnus, and P. latifolium; Pavetta harborii and P. schuman-niana, and Fadogia homblei have been identified as the causative agents of the disease. The toxin responsible for the poisoning, named pavettamine, has been isolated and the structure and absolute configuration established as (2S,4R,8R,10S)-1,11-diamino-6-aza-undecane-2,4,8,10-tetraol, or the enantiomer, by mass spectrometry and NMR spectroscopy. Retrosynthetic analysis of the pavettamine molecule as outlined in the dissertation showed that the secondary amine function could be obtained from the amide functional group in an intermediate such as (2R,4S)-N-[(2′R,4′S)-2,4,5-trihydroxypentan-1′-yl]-2,4,5-trihydroxy-pentanamide A. Disconnection of the amide bond then generated two C5 building blocks viz. an amine B and a carboxylic acid C which through a set of functional group transformations led to a common C5 building block, a pentane-1,2,4,5-tetraol D. The terminal primary hydroxy groups required different protecting groups at all times in order to safe-guard the integrity of the two stereogenic centres. In addition identical protecting groups but different to those used for the primary hydroxy groups, were necessary for the secondary hydroxy groups. Further analysis of the C5 building block D showed that it could be obtained from (2S)-malic acid by functional group transformations, chiral sulfoxide methodology and an appropriate protective group strategy. A suitable protective group strategy was developed and an 11 step synthetic route for the C5 building block established. The successful conversion of this moiety through functional group transformations provided the C5 amine B and C5 carboxylic acid C which were linked to give the target compound, the amide D but with the hydroxy groups protected. The synthetic study presented in the dissertation provides an efficient methodology toward the synthesis of any of the 10 possible stereoisomers of pavettamine.