Synthetic Studies of Bio-active Molecules

Plant extracts have been used for treating ailments for several thousand years. It is known today that the effect of many historical plantbased remedies can be ascribed to certain biologically active compounds. For instance, salicylic acid is the active component of willow bark, which has been used by Native Americans to lover fever, while quinine from bark of the quina tree counteracts malaria. The thesis describes several findings related to drug discovery inspired by such naturally occurring bio-active molecules.

Most approved drugs have simple and easy-to-synthesize structures. However, with the constant evolution of existing diseases and the emergence of new ones, more complicated three-dimensional structures are in demand. For industry to embark on this path, academia has a responsibility to develop new tools and methodologies and to set an example by carrying out synthesis of complicated bio-active compounds.

Firstly, a photo-labile protecting group for hydroxylamines was developed. This is a tool which allows chemists to carry out more types of transformations. The optimized synthesis of this photo-protected hydroxylamine proceeds in 50 % overall yield over four steps, and is ideal for multi-gram scale synthesis.

Secondly, an asymmetric variant of a newly developed method for synthesizing 1,2,3,4-tetrahydrocarbazoles was developed. In this variant of the reaction chiral phosphoric acids are used to induce chirality. It was found that indoles carrying large substituents in the 2-position gave excellent enantiomeric access when employed as the external nucleophile, but at the cost of lower yield due to a decline in reactivity. The final products were obtained in yields ranging from 12 % to 72 % over three steps, with antiomeric excess in the range of 18-98 %.

Thirdly, a number of different routes for synthesis of the bioactive natural product (+)-Sieboldine A were explored with the purpose of testing the practical usefulness of existing methodology known in literature and developed in-house at DTU. An effective way of carrying out the key 1,4-addition using a Hosomi- Sakurai type reaction was identified.

Finally, so-called stapled peptides were explored. The thesis describes the development of stapling linkers designed to increase cell permeability, and the development of a photo-crosslinking moiety, which is applicable in photo-affinity labeling. It is demonstrated that a fragment from a larger protein can be used to selectively label other proteins, even in complicated mixtures. The technique ca easily be employed in assays to determine overexpression of certain genes.