Date of Award
Doctor of Philosophy (PhD)
In the first chapter, I describe the development of a synthetic strategy towards (–)-myrocin G (8), the putative active form of the antiproliferative fungal metabolite (+)-myrocin C (4). Myrocin C (4) has been proposed to cross-link DNA by two-fold nucleotide addition; however, this proposed bioalkylation hypothesis has not been tested with native DNA. Our synthetic efforts provided a highly convergent total synthesis of myrocin G (8) in 15 steps from simple starting materials. A key steps in the sequence involved a carefully designed fragment coupling–cyclization cascade (see 85 + 89 → 90). This transformation effectively unites the iodocyclopropane 85 with the enoxysilane 89 to provide in a single step and in 38% yield the protected form of the target. Next, I present our preliminary biological activity studies of the diosphenol (–)-myrocin G (8) including DNA cleavage and DNA cross-linking studies. The data collected from these studies indicates that myrocins do not cross-link or cleave DNA and rather suggests an alternative mode of action potentially involving a protein target. In the second chapter, I present the development of an enantioselective synthesis of the heavily oxidized sesquiterpenoid (–)-euonyminol (99). Euonyminol (99) is the dihydro-β-agarofuran nucleus of the macrocyclic terpenoid alkaloids known as the cathedulins. This natural product is characterized by a tricyclic framework comprising of a trans-decalin fused to a tetrahydrofuran ring and by possessing nine free hydroxyl groups. Our synthetic route to access euonyminol features several highly diastereoselective transformations that were specifically designed to overcome problems encountered. For example, we developed a metal catalyzed [3+2] dipolar cycloaddition reaction provided the vinylogous carbonate 147 and simultaneously established the C9 oxidation and the C10 quaternary stereocenter, a tandem lactonization–epoxide opening to form the trans-C2–C3 vicinal diol residue, and a late-stage diastereoselective α-ketol rearrangement necessary for the syn-C8–C9 oxidation pattern. The body of work presented in this chapter may set the stage for synthesizing the macrocyclic cathedulin alkaloids, such as cathedulin E-4 (104).
Tomanik, Martin, "Development of Enantioselective Synthetic Routes to (–)-Myrocin G and (–)-Euonyminol." (2021). Yale Graduate School of Arts and Sciences Dissertations. 430.