On the synthesis of nitrogen-containing medium rings from simple carbohydrate and amino acid building blocks using the Grubbs’ catalysed ring-closing metathesis reaction

Submission note: A thesis submitted in total fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Molecular Sciences, Faculty of Science, Technology and Engineering, La Trobe University, Bundoora.

Nitrogen-containing medium rings have huge potential in modern science as medicinal therapeutics and tools for structure elucidation in studies of complex biological systems. Of the medium ring family, 8-, 9- and 10-membered rings have traditionally been the most difficult to synthesise, and their full potential in science has not yet been realised. The advent of the Grubbs’ catalysed ring-closing metathesis (RCM) reaction has in recent times provided a more effective means of synthesising these compounds, and the window of opportunity for full and effective use of these molecules has been opened. This thesis will provide an insight into the efficacy of the Grubbs’ reaction in the synthesis of nitrogen-containing 8-, 9- and 10-membered medium rings. Both aza-cycle and lactam RCM precursor molecules were synthesised from 5-membered sugar starting materials. Synthetic schemes were developed that were applicable to all members of this sugar family. Following hydroxyl protection of the starting materials, synthetic sequences for the most part proceeded through alkenylation and N-alkylation reactions to install terminal olefin tethers, followed by subjection to Grubbs’ RCM reaction conditions. Lactam RCM precursor molecules were also synthesised from α-amino acid starting materials. The synthetic scheme devised was applicable to the majority of the common amino acids found in nature. The synthetic sequence proceeded by synthesising the orthogonally protected free amino and free carboxyl forms of N-butenyl amino acids, followed by homo- or hetero-dimerisation of the monomers and subjection of di-Nbutenyl peptides to Grubbs’ reaction conditions. The Grubbs’ RCM reaction was performed on the full suite of RCM precursors, including an investigation of the optimal conditions, whereby alternative catalysts, loadings and reaction conditions were investigated. Despite extensive experimentation, the Grubbs’ reaction remained unsuccessful for reasons believed to be associated with unfavourable cyclisation energetics and/or non-productive catalyst chelation.