Nitriles are valuable key intermediates in organic synthesis: they can easily be converted to various other functional groups and heterocycles. They can also be found from small molecular architectures in pharmaceutical product and fine chemicals. In this thesis the nitriles were found to be key components in the synthesis of the target molecules and so it became important to develop safer and more robust methods for their synthesis. This was achieved by developing and using stable sources of nitrile and controlling its release.
The first part of this thesis focuses on the total synthesis of calyculin C. Particularly studies towards the Z,E,E,E-tetraene fragment. The synthesis was based on controlled formation of E- or Z-alkene from acetylides. However, neither of these fragments was successfully coupled with the model coupling partner.
The second part of the thesis describes the nucleophilic cyanation of terminal alkynes. For this purpose 4-cyanato-1,1'-biphenyl as an electrophilic cynataion reagent was used. The reaction was optimized and the substrate scope was studied to cover propargylic, homo-propargylic, and aliphatic alkynes as well as the tolerance of a variety of alcohol protecting groups giving good to acceptable yields. 4-Cyanato-1,1'-biphenyl simple to prepare, crystalline, and stabile is significantly more convenient electrophilic cyanating method comparing to the generally used.
The third, final part of this thesis describes the resynthesis of first selective GTPase-actvating protein small molecule inhibitor 2,6-Bis(4,5-dihydro-1H-imidazol-2-yl)naphthalene (MINC1) and then eight other analogs. These studies confirmed the dose responsive, selective inhibition of MgcRacGAP. From the synthesized analogues none reached similar inhibition than MINC1. The symmetry of the molecule was also observed to be crucial. Versatile synthesis for disubstituted cyanonaphtalenes, intermediate in the synthesis of analogs, and 2,6-disubstituted heterocyclic naphthalenes was developed.
|Translated title of the contribution||Tutkimukset kalikuliini tetraeenin stereoselektiivisesti muunneltavaan synteesiin ja Rho GTPasi-inhibiittoreiden synteesi- kehittäen vakaampia nitriilisynteesimenetelmiä|
|Publication status||Published - 2016|
|MoE publication type||G4 Doctoral dissertation (monograph)|
- natural product, total synthesis, PP, nitrile, Rho GTPase