The step-economical, supply-impacting synthesis of Bryostatin 1 and the development and application of rhodium-catalyzed [5+2] cycloadditions of polyenes and their equivalents [electronic resource]

Some of the most therapeutically relevant enzymes, for which naturally derived molecules have been found to target, are the kinases, a vast family of 500+ proteins that modulate biological pathways by phosphorylating other proteins or small molecule substrates. Dozens of kinase inhibitors, mainly in the oncological space, have been approved by the FDA and other regulatory agencies over the past two decades for the treatment of human diseases. The terrestrial bacterium Streptomyces staurosporeus produces staurosporine, an alkaloid that potently inhibits many human kinases but is too toxic to be used in medicine and is synthetically challenging to access. On the other side of the spectrum, molecules that activate kinases have shown great preclinical promise in a number of indications but have not yet made it to the market. Of these, bryostatin 1, isolated from the marine organism Bugula neritina, shows perhaps the greatest promise and is currently a lead candidate in cancer immunotherapy, the treatment of Alzheimer's disease, and the eradication of HIV/AIDS. Unfortunately, bryostatin 1 is isolable from its natural source in clinically insufficient quantities, and its complex scaffold has (until this year) presented an insurmountable synthetic challenge in terms of scalable access. For these aforementioned reasons, both bryostatin and staurosporine lend themselves to further synthetic refinement so that they can be produced more rapidly, or so that their function can be recapitulated or improved through the design of analogs. This thesis presents a new, step-economical and supply-impacting synthesis of bryostatin 1, which proceeds in 29 total steps (19 longest linear steps), approximately 5% yield overall, and furnished a total of 2g of material. This remarkable achievement will solve the clinical supply problem associated with bryostatin 1, with stocks of previously isolated GMP material now near depletion. More importantly, this synthesis paves the way for the expedited access of new and potentially superior analogs. Highlighted in this chapter are the inspiration for our step-economical route as well as a few of the key reactions needed to access the A- and C-ring fragments. The theme of Function Oriented Synthesis is contextualized by the design of simplified, polycyclic, staurosporine-inspired kinase inhibitors that are produced using a novel rhodium-catalyzed [5+2]/[4+2] cycloaddition cascade. While the general developmental details of this new methodology are not discussed in this thesis, the retrosynthetic strategy is featured alongside computational-guided analog design, synthesis, and accompanying biological assays. Finally, this thesis explores organometallic projects related to new incarnations of the rhodium-catalyzed [5+2] cycloaddition. The first consists of initial results relating to the intermolecular rhodium-catalyzed [5+2] cycloaddition with simple, unactivated allenes, a transformation that has never before been reported. Unfortunately, this process has thus far proceeded in only moderate yields. A second project, re-examining aberrant results from a previously published intermolecular [5+2] cycloaddition of allene-ynes perhaps explains the deficiencies associated with that process: computational work in collaboration with the Houk group at UCLA and accompanying experimental results support the hypothesis that an operative allene-dimerization pathway poisons the desired catalytic process. Finally, in an attempt to address the synthetic challenges of working with allene substrates, a rhodium-catalyzed [5+2] cycloaddition was developed using propargyltrimethylsilanes as stable, easily handled, functional allene equivalents.

Keywords: Chemistry.
Advisor: Wender Paul A. primary advisor. Thesis advisor
Burns Noah
Waymouth Robert M. advisor. Thesis advisor