UC Riverside

The aim of this dissertation is the discovery of novel small molecule insulin mimics. Natural product demethylasterriquinone B1 (DAQ B1) is an orally active insulin mimic, but this small molecule contains a quinone moiety that hindered further development of this drug class. The Pirrung lab has successfully replaced the offensive quinone with a pyrone ring derived from the natural product kojic acid, while maintaining the promising biological activity of DAQ B1.

The first part of the dissertation describes work toward the synthesis of a diverse library of potential activators of the insulin receptor, indolylkojates. Past work in the Pirrung lab developed a synthetic route to candidate kojate-based insulin mimics that relies on the Claisen rearrangement as a key step. This route employs iodoanilines as a starting point in a Sonogashira reaction with an O-propargylated kojate to make the target indolylkojates, but the use of iodoanilines is limited by the low commercial availability of iodoarenes. In the present study, various functionalized arenes were examined as replacements for iodoaniline, but all failed to be productive coupling partners with our functionalized kojate. Finally, success was achieved through the use of a benzyloxy-substituted iodoaniline.

The second part discloses results from the examination of our indolylkojate target compounds for signs of axial chirality. We hypothesized that a large group in the 4-position of the indole would provide sufficient steric bulk that rotation about the indole-kojate bond would be restricted. The synthesis of a (4-bromo)indolylkojate disproved this theory, as chiral chromatography failed to indicate the presence of discreet atropisomers.

The third part details work done to develop a catalyst that would allow the Claisen rearrangement step to be conducted at lower temperatures than those typically required under thermal conditions (160-190 °C). Literature surrounding the catalyzed Claisen rearrangement of O-allyl kojates is scarce, but, using catalysts known to efficiently mediate the rearrangement of (allyloxy)acrylates and allyl aryl ethers, a catalyst screen was developed. Lewis acid Zn(OTf)2 was determined to be the best catalyst for the rearrangement of O-allyl kojates at low temperatures, with the best yield arising from the use of trans-cinnamyl kojate as the substrate.