Doctor of Philosophy
School of Chemistry and Molecular Bioscience
The hyacinthacine C-type alkaloids are polyhydroxylated pyrrolizidine alkaloids that were first isolated in 1999 from the fruits and stalks of Hyacinthoides non-scripta and later in 2007 from the bulbs of Scilla socialis. Today they comprise hyacinthacines C1, C2, C3, C4 and C5 and have attracted considerable attention within the large community of those interested in iminosugars, since they exhibit inherent glycosidase inhibitory activities. Their low to moderate IC50 values (13 – 100 μM) against various α-glucosidases makes the hyacinthacine C-type alkaloids important scaffolds towards finding medicines that help treat type-2 diabetes as well as the increasing obesity epidemic.
The hyacinthacine C-type alkaloids can contain up to seven possible stereogenic centres. This means that there are 128 unique stereoisomers (64 diastereomers and their enantiomers) containing a 3-hydroxymethyl-5-methylpyrrolizidine-1,2,6,7-tetraol core that have potentially different glycosidase inhibitory activities. Their constitutional complexity has resulted in structural insecurities in four of the five naturally occurring hyacinthacines, namely hyacinthacines C1, C3, C4 and C5. Their configurational ambiguity coupled with their relatively low glycosidase inhibitory activity presents an enticing challenge for many chemists and so has led to an increasing number of publications that detail synthetic work towards this class of compounds.
To shed light on the current inconsistencies in the literature, the work presented in this Ph.D. describes the successful total synthesis and consequent correction of the structures for hyacinthacines C1 (Chapter 5), and C5 (Chapter 4B). More specifically, it was found that the true structure for hyacinthacine C1 is the C8 epimer of the purported structure. Moreover, the true structure for hyacinthacine C5 has the opposite configuration at the three contiguous stereogenic centres, C5, C6, and C7, to that of the originally proposed structure.
Carroll, Anthony Walter, Total synthesis of eleven hyacinthacine C-type analogues and the correction of the structures of natural hyacinthacine C1 and C5, Doctor of Philosophy thesis, School of Chemistry and Molecular Bioscience, University of Wollongong, 2019. https://ro.uow.edu.au/theses1/545