Robertson, Murray N.
Studies towards a fast and efficient
total synthesis of LL-Z1640-2.
PhD thesis, University of Glasgow.
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LL-Z1640-2 (5Z-7-Oxo-zeaenol) was first isolated in 1978 from a culture broth. Although LL-Z1640-2 was initially classified as an anti-protazoan agent, it was not until 1999 that it’s cytokine release inhibiting activity was discovered. More recently LL-Z1640-2 has been reported to selectively inhibit the kinase activity of TAK1.
TAK1 (transforming growth factor β-activated protein kinase 1) is a major member of the mitogen activated protein kinase kinase kinase (MAPKKK) family. TAK1 is responsible for the activation and control of at least three signalling
pathways that play crucial roles in the inflammatory response. Hence, TAK1 has emerged as a prime target for the treatment and regulation of chronic inflammatory diseases such as rheumatoid arthritis, psoriasis and inflammatory
LL-Z1640-2 is structurally related to other 14 membered resorcylic lactones such as 7-oxo-zeaenol, zeaenol and radicicol. Although there has been a significant amount of work dedicated to the synthesis of radicicol, the efforts towards LLZ1640-2 have been rather limited. At the outset of the research contained within this thesis, only two total syntheses of LL-Z1640-2 had been published. They were both lengthy (>20 steps) making them impractical for lead development.
The work described in this thesis illustrates the attempted flexible and convergent synthesis of LL-Z1640-2 from the simple, commercially available, starting materials 2-deoxy-D-ribose and methyl 2,4,6-trihydroxybenzoate.
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