The scalable, step-economical total synthesis of Bryostatin 1 and serialized cycloaddition cascades through reactivity regenerating reagents with applications in the syntheses of novel staurosporine analogs [electronic resource]

Protein kinase modulation is the preeminent mechanism of action for many clinically approved drugs on the market today for treating a broad range of illnesses. Therefore, novel kinase modulators and an efficient means to access those compounds remain top priorities in academia and the pharmaceutical industry. In particular, there is an urgent need for small molecule therapies that target currently unmet medical needs, especially for diseases that have no treatments or cures. In the search for such compounds that satisfy these ambitious goals, scientists can turn to complex natural products, which are diverse and highly evolved functional compounds produced by bacteria, trees, and other bio-diverse organisms. Indeed, over the past several decades, researchers have scoured the land and ocean in search of medicinally relevant natural products in the hopes of discovering new disease treatments directly from nature, or, alternatively, identifying biosynthesized molecules that can serve as inspiration for the development of more effective and human-focused analogs. Two notable examples that have emerged from these isolation efforts are bryostatin 1 and staurosporine. Bryostatin 1 is a marine-derived natural product isolated from the sea bryozoan Bugula neritina, and while in nature its putative role is to serve as a larvae-protecting antifeedant, researchers initially discovered that it had anticancer properties. Since then, its clinical portfolio has significantly expanded to include the eradication of HIV/AIDS, a treatment for Alzheimer's disease and other neurological conditions, and stimulating the immune system to fight cancer via its modulation of PKC. However, isolating bryostatin 1 from the source organism is costly, inefficient, extremely low and variable yielding, and environmentally damaging. Therefore, an alternative means to supply this compound on scale, as well as potentially superior analogs, for sustained preclinical and clinical use is of utmost importance. Additionally, staurosporine is a bacterial natural product that is one of the world's most effective, pan-kinase ATP-competitive inhibitors. Kinase inhibition is one of the leading ways of treating cancer today, and therefore this class of compounds is extremely valuable as novel therapies for this and other indications. However, due to its promiscuity, staurosporine itself is too toxic to be used as a drug, and thus novel and selective analog structures inspired by the key binding elements of this potent compound must be developed to enable safe and practical clinical use. In pursuit of these goals, we have produced a step-economical and scalable total synthesis of bryostatin 1, which proceeded in just 29 total steps (19 longest linear), with ~5% overall yield and over 2g of final product produced, solving the longstanding supply problem of this unrivaled lead and potential analogs for clinical and research needs. This thesis specifically highlights the details of the 13-step southern fragment synthesis and the 6-step endgame sequence. Additionally, a unique and powerful Rh-catalyzed [5+2]/[4+2] cycloaddition cascade methodology utilizing a 1,2,3-butatriene equivalent that enables reactivity regeneration is presented. In addition to demonstrating the substrate scope of this methodology, which produced complex linearly fused polycyclic products in a single step, this work provides a detailed description of the progress towards the utilization of this reaction cascade for the design and synthesis of a first-generation of biologically active 7-6-5 tricyclic kinase inhibitors modeled after the binding pharmacophores of staurosporine. Design strategies, computational tools, analog syntheses, and biological activities are demonstrated.

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