Studies towards stereoselectively versatile calyculin tetraene and Rho GTPase inhibitor synthesis - development of robust nitrile synthesizing methods

Annika Fagerholm

Research output: ThesisDoctoral ThesisMonograph


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 contributionTutkimukset kalikuliini tetraeenin stereoselektiivisesti muunneltavaan synteesiin ja Rho GTPasi-inhibiittoreiden synteesi- kehittäen vakaampia nitriilisynteesimenetelmiä
Original languageEnglish
QualificationDoctor's degree
Awarding Institution
  • Aalto University
  • Koskinen, Ari, Supervising Professor
Print ISBNs978-952-60-6857-2
Electronic ISBNs978-952-60-6858-9
Publication statusPublished - 2016
MoE publication typeG4 Doctoral dissertation (monograph)


  • natural product
  • total synthesis
  • PP
  • nitrile
  • Rho GTPase

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