Total synthesis of casbane diterpenoids

1 Terpenes and terpenoids belong to a class of natural products containing more than 30000 substances, all deriving from isoprene. They are characterized by a wide variety of different structures which can be differently functionalized. Terpenes and terpenoids are often interesting from a biologically or pharmacologically point of view, but their exact manner of functioning is often not or only partially known. Monoterpenes and terpenoids, consisting of two isoprene units, are for example known as essential oils such as citronellol or menthol. Diterpenes and diterpenoids consist of four isoprene units, known representatives of this group are for example retinal and other derivatives of vitamin A. Casbane diterpenoids occur only rarely and in small amounts in Nature, mainly in plants of the Euphorbiaceae (spurge) family, but also in Sinularia corals in the Indo-Pacific Region. Until now more than 40 derivatives has been isolated, some of them possess interesting biological properties (e.g. cytotoxic or antimicrobial activity). Although a handful of synthesis for the unfunctionalized casbene- skeleton exists, no total synthesis for functionalized casbane diterpenoids has been performed so far. The development of a easily modifiable synthesis route to casbane diterpenoids does not only allow the first preparation of a series of these substances in the laboratory, but also provides the opportunity to transfer and refine approved and newly developed methods onto complex target molecules and thus significantly broaden their application scope. Special attention will be focused on the role of propargylic alcohols possessing two different functional groups in direct proximity which can be further converted by various fashions. One of the key steps of the targeted synthesis is the development of a macrocylization by asymmetric addition of silylalkynes to an aldehyde to give propargylic alcohols. Another important aspect is the synthesis of differently trisubstituted allylic double bonds, a common structural motif in natural products, from propargylic alcohols. Therefore it is planned to use the trans-hydrostannation recently introduced by Fürstner to demonstrate the versatility of this method for complex systems. The first total synthesis of selected biologically active casbane diterpernoids will be used to develop methods for the preparation of complex asymmetric propargylic alcohols and to show their utility for the conversion to trisubstituted double bonds which are commonly occurring in natural products.

Casbane diterpenoids are a family of natural products, that means they are chemical compounds with a similar structure that are found in some natural sources such as in plants or marine sponges for example. Some of these compounds possess antimicrobial activity or a cytotoxic to cells, which makes some natural targets interesting for e.g. drug research. In this project, it was aimed to produce some of these casbane diterpenoids in the laboratory via a total synthesis. This means that only readily available chemicals are used as starting materials and via different more or less challenging reactions the actual target is produced. Total syntheses have two main purposes: one is to synthesize the target which often is found only in very, very small amounts in Nature, in order to perform some e.g. biological tests. And the other is to push chemical synthesis forward and test the potential of a newly developed or well-established methods on a more complex chemical compound. During this project several difficulties have been observed as e.g. some promising methods didn't work as expected. One of the biggest (and still unsolved) challenges remained the construction of a specific unit of the molecule, in which the atoms form a triangle and this triangle has four different carbon atom chains at the three atoms on its edges. The challenge is that these four carbon chains has to be arranged in a certain way, as for example switching one chain from one side to another will make another molecule which might have completely different properties. These properties might be more or less desired, but the important and difficult thing is, to get only one of the different molecules alone, so that one can unequivocally assign the observed properties to a specific molecule.