Triterpenoids

 

Oleanane as an example of a natural triterpenoid.

 

Triterpenes, such as oleanane, figure 1, are a class of chemical compounds with a carbon skeleton based on six isoprene units which are derived biosynthetically from the acyclic C30 hydrocarbon, squalene; they may also be thought of as consisting of three terpene units. Triterpenoids are functionalized triterpenes and are widely distributed in nature, they can be found in animals, plants and fungi and all produce triterpenes, including squalene, the precursor to all steroids.

 

Triterpenoids are very interesting from a chemical point of view since they have a variety of functional groups as well as from a pharmaceutical point of view since they possess a rich pharmacology (e.g. oleanolic acid, figure 1) with several pentacyclic motifs.

 

 

Oleanolic acid. It exhibits antitumor and antiviral properties.

 

Synthesis of Triterpenoids

 

Biosynthesis of triterpenoids in cells involves a handful of enzymes and can be divided into four stages. The formation of geranyl diphosphate from isopentenyl diphosphate units, formation of farnesyl diphosphate which is then converted to squalene and epoxysqualene. In the last stage, epoxysqualene is cyclized to the triterpenoid. This complicated pathway shows that it’s a challenging task for a synthetic chemist to synthesize triterpenoids in a laboratory setting.

 

The main synthetic strategies described in literature for pentacyclic triterpenes are:

 

 

 

AAPharmaSyn has a lot of experience in using approach (b) in which a BC-ring system is first converted into an ABC system. Subsequent attachment of ring E and a consecutive cyclization finally affords the ABCDE ring system.

 

 

Scheme 1. Synthesis of a Triterpenoid 9.

 

An example of such a synthesis is shown in scheme 1 and starts with a Wieland Miescher ketone derivative 1. Using commercially available or literature known building blocks can be very time saving and is a strategy that’s applied at AAPharmaSyn whenever possible. Functional group protection / interconversion / deprotection, techniques that are applied frequently at AAPharmaSyn, and in which we have ample experience, leads to intermediate 4. Oxidation of 4 with elemental oxygen followed by a selective 1,4-addition reaction of the Grignard-reagent 6, yields 7, the ABC(E)-system. Conversion of compound 5 to 7 is an example for a thoughtful and deliberately executed synthetic step, a strategy used at AAPharmaSyn in order to limit the amount of total steps needed and/or to improve yields. Cyclization of 7, followed by a Birch reduction finally affords compound 9, an ABCDE triterpenoid. Reactions such as the Birch reduction, the Benkeser reaction or the Bouveault-Blanc reduction are just a few examples of reactions performed at AAPharmaSyn.