Diterpene scaffold

SCHEME 8.6 Correlation of an array of diterpene scaffolds on common biosynthetic routes. 

Cytochromes P450 that decorate cores with oxygen-based functionality are commonly found in biosynthetic pathways. For example, these enzymes hydroxylate the reduced polycyclic scaffold of the diterpene taxol and install functional groups that are required for target binding and increase its hydrophilic-ity (31). 

Salvinorin A is a tricyclic trans-cis neoclerodane diterpene containing seven chiral centers. Additionally, 1 contains multiple functional groups, which include four carbonyls at C-l, C-17, C-18, and C-21. Two of the carbonyls are esters off of the C-2 and C-4 positions of the decalin core, and the C-17 carbonyl is part of a 5-lactone ring system. Additionally, 1 contains a furan ring off C-12. Along with the functionality present on 1, C-8 has been shown to undergo epimerization readily in acidic or basic conditions. Despite the molecular complexity, total syntheses of 1 have been accomplished and structural modifications have been completed. This chapter will address total synthetic attempts towards the molecule itself and synthetic methodologies developed and applied to modify the salvinorin A scaffold. 

Harding WW, Tidgewell K, Byrd N et al (2005) Neoclerodane diterpenes as a novel scaffold for micro opioid receptor ligands. J Med Chem 48 4765 -771... 

Natural products are generally complex chemical structures, whether they are cyclic peptides like cyclosporin A, or complex diterpenes like paclitaxel. Inspection of the structures that are discussed in Section IV is usually enough to convince any skeptic that few of them would have been discovered without application of natural products chemistry. Recognition of this structural diversity has certainly made an impact on the design of combinatorial strategies, as exemplified by the 2 million plus compound library that was recently assembled by the Schreiber group using natural product-like structures as the initial scaffolds. 

Thus, diterpenes have shown a physiological role in the organisms (gibberelUn, phytol, vitamin A, retinol), a specific taxonomic distribution (jatrophanes, lathyrane), a variety in their scaffold, inspiring chemists for the developing of parallel synthesis, and last but not least a huge array of therapeutic uses. 

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