Studies towards the total synthesis of the fumonisin B natural products

Abstract

Fumonisins B1 6 and B3 8 are toxic secondary metabolites of the fungus Fusarium moniliforme that inhibit enzymes of sphingolipid biosynthesis. This dissertation describes work towards the stereocontrolled total synthesis of the fumonisin natural products. The proposed highly convergent strategy allows for the late stage stereocontrolled coupling of the two fragments C1-C10 58 and C11-C20 57 with concomitant installation of the C10 hydroxyl using key boron aldol methodology. A directed hydrogenation installs the final methyl-bearing stereocentre at C12. Syntheses of the left- and right-hand fragments 57 and 58 by means of substrate-based stereocontrol and asymmetric catalytic methods is reported. A completed synthesis of the protected FB3 carbon backbone 59 is achieved in a linear reaction sequence of 14 steps. Tentative assignment of stereogenic centres within 59 was made by analogy to the C4-C20 fragment 190 of fumonisin B3. Synthesis of C4-C20 190 by the coupling of C11-C20 57 with heptaldehyde is also described.