Development of a modular, enzyme -assisted approach to etoposide

Podophyllotoxin is a lignan natural product that has long been known to possess medicinal properties. Although podophyllotoxin was found to function as an antimitotic, it showed prohibitive toxicity in Phase I cancer trials. Etoposide, a semisynthetic derivative of podophyllotoxin, is currently in clinical use in the treatment of many cancers. Etoposide apparently acts by an entirely different mechanism compared with podophyllotoxin, but the mechanism of action of this drug is incompletely understood. This dissertation describes a modular synthetic approach to (−)-podophyllotoxin and etoposide designed to permit a systematic variation of ring E, and a new glycosylation method that efficiently interfaces with our ring E modular synthetic route. The ability to easily obtain analogs with varied structures in both ring E and the “northern” (carbohydrate) sector provides a new tool for studying the roles of these substructural units of the clinically valuable chemotherapeutic drug. The first catalytic, asymmetric synthesis of (−)-podophyllotoxin has been achieved in 19 steps from piperonal in 7.9% overall yield. The introduction of 16 E rings (including the natural one) has been achieved via Cu I-mediated aryl-Grignard addition to an α,β-unsaturated N-acyloxazolidinone. The conjugate addition of ArMgBr occurs exclusively from the desired re face. Only three steps separate the conjugate addition product from the (−)-podophyllotoxin (or congeners) itself. A new method for the generation of epipodophyllotoxin conjugates, namely “reverse Kahne-type” glycosylation with an activating sulfoxide, has been developed. To our knowledge, this is the first example of reversed polarity version of the Kahne activation method. The activating sulfoxide functionality is positioned on the aglycon, rather than on the sugar. Exposure of epipodophyllotoxin C4-sulfoxide to triflic anhydride, followed by addition of nucleophiles such as silyl glycosides, alcohols, phenols, p-fluoroaniline, or allyl silane, provides the corresponding O-, N-, and C-linked epipodophyllotoxin conjugates