The synthesis of biologically relevant natural products and their derivatives & a novel catalytic asymmetric Nazarov cyclization

Abstract

Part I: The Synthesis of Biologically Relevant Natural Products and Their Derivatives Chapter I: The Synthesis of Cannabinergic Ligands The cannabinoid receptors are a promising drug target for the treatment of pain. However, the efficacy remains limited in humans due to dosing restrictions imposed as a result of undesired psychoactive effects. The initial goal of this project was to modulate CB2 agonist activity of the natural product ꞵ-caryophyllene by a variety of structural modifications. For the first round of testing 6 compounds were submitted for biological testing. The most potent of these compounds had a binding affinity of 700 nM, however all compounds, while more active than the natural products, displayed similar activity with no discernable trend. This approach was therefore abandoned as these compounds were substantially less active than known CB2 agonist AM-1241 (2 nM). Rimonabant was a promising antiobesity medication that modulated CB1 receptor activity, however, it was pulled of the market due to negative psychiatric side effects. A series of rimonabant analogs were synthesized and submitted for biological testing. Chapter II: Total Synthesis of Marine Natural Products and Derivatives A large number of pyrroloiminoquones have been isolated primarily from marine sponges of the Latrunculia and Zyzzya genera. In addition to their fascinating and complex structures, a number of these compounds have potent biological activity with the potential to control infectious diseases, cancer, and neurological disorders. Perhaps the most impactful activity for this class is the unusual in vitro selectivity of makaluvamine J (MakJ) and aleutianamine (Aleut) for pancreatic cancer cells vs other forms of cancer and healthy cells. Makaluvamine J was synthesized in 9 in steps in an overall yield of 15.6%. This material was provided to our collaborators and used for further biological studies. Encouraged by the high potency and selectivity against aggressive cancer cell lines a series of analogs were prepared and have been submitted for biological testing. We developed a second-generation route to the tricyclic core of PIQ natural products. This route is currently being used in efforts to synthesize additional PIQ natural products. Part II: Asymmetric Silicon-Directed Nazarov Cyclization Chapter III: A Novel Catalytic Asymmetric Nazarov Cyclization The Nazarov cyclization is a cationic 4π conrotatory cyclization of the pentadienyl cation to produce cyclopentenones. The enantioselective cyclization has been well explored using a variety of chiral catalysts or auxiliaries, however, an enantioselective silicon-directed Nazarov cyclization has not been reported. This work describes our efforts towards that aim. The approach utilized a chiral, non-racemic Brønsted-derived Lewis acid in which the silyl cation was used in place of a proton to initiate cyclization. To make this reaction catalytic, the dienone substrate shown below was designed and synthesized. This work represents foundational efforts towards the development of a novel catalytic asymmetric cyclization, the synthesis of a new class of dienone substrates and an optimized isolation protocol for N,N’-bis(triflyl)phosphoramidimidates.