Synthesis and biological evaluations of macrolactam natural products

Nature and its biosphere through evolution constitute an important source of therapeutics or what may be seen as prototypical leads. Indeed, approximately one half of the drugs which are currently on the market are either natural products themselves or analogues which have been inspired by molecules made by Nature. Hence, this process of learning and cooperating with Nature, has led to immense benefits for mankind, allowing an array of diseases and ailments to be treated. The natural product heronamide C, also known as ML-449, which has been the focus of this project, was first obtained from seabed material 449 meters deep in the Trondheim fjord as part of a marine bioprospecting programme. Synthetic studies towards said natural product has been undertaken, and even though a complete total synthesis was not reached during the project period, important knowledge and experience concerning the synthetic preparation of key fragments have been acquired. Additionally, studies related to effecting the union of said key fragments, have been performed. In the methodology part of the project, an important elaboration of the Zincke chemistry has been achieved. This is a reaction which transforms activated pyridinium salts into substituted diene compounds. Given the versatility of these highly functionalised synthons with regard to pertinent unsaturated molecular architecture, this has become an active field of research. Indeed, many natural products, drugs, pesticides and other important organic compounds contain domains of unsaturated architecture, and new and more effective protocols for their preparation, is of great importance.

Syntetiske studier mot naturproduktet heronamid C, også kalt ML-449, som ble isolert uavhengig av hverandre både i Trondheimsfjorden og Heronøyen i Australia, har blitt utført. Til tross for at en fullstendig fremstilling av nevnte naturprodukt ikke ble oppnådd i prosjektperioden, har viktig kunnskap og erfaring for syntese av ulike nøkkelfragmenter blitt erhvervet, og studier for å sette disse sammen er gjort. I metodeutviklingsdelen av prosjektet har en videreutvikling av Zincke-kjemien blitt gjennomført. Dette er en reaksjon som går på å transformere aktiverte pyridinforbindelser til substituerte diene-forbindelser. Grunnet nyttigheten av disse byggeklossene innenfor feltet syntetisk organisk kjemi, er dette i nyere tid blitt et aktivt forskningsfelt. Mange naturprodukter, medisiner, plantevernmidler og andre viktige organiske forbindelser innehar domener av umettet arkitektur, og nye, mer effektive og presise måter å kunne fremstille disse på, er svært nyttig.

The proposed project details the development of a synthetic route to the natural product known as heronamide C, a polyketide macrolactam of marine origin, found in water sediment samples at two different locations, namely the Trondheim fjord in Norway and the Heron Island in Australia. On the successful preparation of this compound, efforts will be made to identify the appropriate conditions for its pericyclic transformation into heronamide B. All compounds produced will undergo thorough biological testing - especially with regards to antibacterial and anticancer activity. Furthermore, in the methodology part of the project we would like to effect the synergistic union of the chemistry pertaining to dienals derived from activated pyridinium salts with the Takai olefination using 1,1-dihalo substrates. The latter chromium-promoted condensation is commonly employed to make vinyl halides, however, its application to the construction of internal olefins is rarely seen. In the last decade, progress has been made towards the general preparation of 1,1-dihalo compounds from aldehydes, and it is anticipated that this will facilitate the above-mentioned objective.