Date of Award
Doctor of Philosophy (PhD)
Part 1: Having developed a reaction to synthesize the protein-sugar crosslink glucosepane, we sought to apply our lessons to the synthesis of structurally similar molecules. Marine alkaloids containing a diaminoimidazole-derived core possess intriguing chemical structures and have displayed promising antimicrobial activity in preliminary screens. However, these compounds generally contain densely functionalized multicyclic cores and relatively large numbers of nitrogen atoms. For these reasons, they have proven difficult to synthesize. In this work, we report a novel total synthesis of the marine alkaloid (±)-dibromoagelaspongin. Our key intermediate is a 2,5-diaminoisoimidazole accessed in one step from a suitably protected guanylhydrazine and an amidoketone through a [3,3]-sigmatropic rearrangement-elimination. The incorporation of the densely functionalized core in a single step enabled a dramatically simplified synthetic route, and the natural product was obtained in fewer than half the number of steps of the sole prior published route in excellent overall yield.Part 2: It is well known that glucosepane, which is associated with many diseases and aging, forms on opposing strands of collagen subunits that are comprised of three intertwined polypeptides. Because glucosepane is a post-translational modification that forms very slowly in vivo, no method to express glucosepane-crosslinked collagen exists, and isolation of the crosslink through tissue digestion has yielded few fruits. Accordingly, a need for model systems exists. Since optical tweezers often find application in characterizing large molecules—including expressed tropocollagen molecules—and chemical changes to them that are too fast or too slow for an ensemble average to be effective, they stand to play a major role in the characterization of synthetic collagen-mimicking peptides bearing an artificially installed crosslink. We believe the data presented herein constitute a significant advance toward what to the best of our knowledge would be the first force-extension data generated on an optical tweezer from a synthetic collagen-mimicking peptide.
Hale, Robert Donald, "Two Projects Informed by Work on Glucosepane" (2022). Yale Graduate School of Arts and Sciences Dissertations. 600.