Doctor of Philosophy
Department of Chemistry
Stirling, Andrew James, Dihydroxylation of rigid spirocyclic systems as potential corticotropin-releasing hormone antagonists, Doctor of Philosophy thesis, Department of Chemistry, University of Wollongong, 2008. https://ro.uow.edu.au/theses/1138
Preliminary attempts were undertaken to synthesise conformationally restricted bispyrimidine macrocycles as potential CRH antagonists through the incorporation of two different linking tethers between two pyrimidine molecules. One tether incorporates a diamine functionality and the second tether an alkene formed from a metathesis homocoupling reaction. Seven bispyrimidine examples were synthesised containing the diamine tether, with yields ranging from 19-96%. One example of a bispyrimidine with the alkene tether was achieved in a two step process with an overall yield of 19%.
Alkylation and ring-closing metathesis reactions of [3H]indol-2-one were employed to form 5- and 7-membered spirocyclic oxindole scaffolds in overall yields of 57% and 9%, respectively. Subsequent LiAlH4 reduction of the Boc protected spirocyclopentyl [3’H]indol-2’-one carbonyl yielded the 5-membered spirocyclic indol-2’-ol in 69% yield. 5- and 7-Membered spirocyclic indoline scaffolds were synthesised via LiAlH4 or Red-Al reduction of the corresponding deprotected spirocyclic oxindole scaffolds in 70% and 25% yields, respectively. Dihydroxylation of the 5- and 7-membered spirocyclic oxindole scaffolds resulted in the synthesis of the meso cis-diols where the hydroxyl groups were oriented over the oxindole aromatic ring. Dihydroxylation of the 5-membered spirocyclic indol-2’-ol and indoline scaffolds resulted in the synthesis of the meso cis-diols where the hydroxyl groups were oriented away from the oxindole aromatic ring, the opposite diastereomer for the spirocyclic oxindole scaffolds. These results suggest that the orientation of the diol is dependent upon the presence or absence of the carbonyl group of [3’H]indol-2’-one. Epoxidation reactions of the spirocycles followed the same trends as the dihydroxylation reactions except for the case of the 7- membered spirocyclic oxindole scaffold. In this instance both diastereomers of the epoxide were formed, with the epoxide oxygen oriented over the oxindole aromatic ring being the major product in the ratio of 5:3. Esterification of the diols recovered from the dihydroxylation reactions gave derivatives for testing as potential corticotropin-releasing hormone (CRH) antagonists.