Synthetic studies toward welwistatin, psymberin and a protective pharmaceutical.

摘要

N-Methylwelwitindolinone C isothiocyanate, also known as welwistatin, is a marine natural product isolated from the algae Hapalosiphon welwitschii. Welwistatin has generated significant interest within the synthetic chemistry community due to its demonstrated ability to reverse P-glycoprotein-mediated multidrug resistance (MDR) and additional cytotoxic activity at the nanomolar level against breast carcinoma cells. The challenges involved in the construction of welwistatin's tetracyclic core are highlighted in Chapter 1, which presents a review of recent progress toward the total synthesis of this molecule. The focus of Chapter 2 is the assembly of a key fragment of the molecule in enantiopure fashion, the ultimately unsuccessful attempts to perform a sterically disfavored arylation reaction at C11 with a variety of organometallic arylating reagents.;Psymberin, another potently cytotoxic marine natural product, was isolated separately by two research groups from the marine sponges Psammocinia and Ircinia ramosa. Chapter 3 details efforts toward the total synthesis of psymberin, beginning with a brief review of the first total synthesis and the previous synthetic efforts in this group. Optimized syntheses of three key fragments of the molecule are then presented. A rapid and high-yielding entry to both the 4-epi and natural side chains are described, which possess varying functionality at C7 so as to allow for both flexibility and modularity in attachment to the pyran core. In addition, the development of a second-generation pyran core fragment is described. Highlights include a nearly 10-fold yield increase compared to the first-generation pyran core fragment, and additional functionalization to a variety of substrates suitable for critical studies that would model the envisioned coupling with either of the side chain fragments.;Chapter 4 focuses on process development for the synthesis of 2,2'-anhydro-5-methyluridine, a ribonucleoside-derived drug that has exhibited potent protective effects against mucositis, a side-effect of the drug methotrexate. Following efforts to identify and eliminate unwanted by-products and optimize the isolation and purification steps, the process described herein allowed for kilo-scale synthesis of >99% pure material by a foreign vendor. Data pertaining to the chemical composition, solubility and chiral purity of the compound is also presented.