Abstract

This research examines the synthesis of γ-lactam analogues of combretastatin A4 (CA4). Many anticancer drugs including CA4 lacking great specificity pose a major drawback; equal risk to non-malignant cells as cancerous cells. β-Lactam moieties have been explored by other research groups, as appropriate substitutes for the ethylene bridge in CA4 to compromise cytotoxicity to normal cells. Despite their likeness, no groups have reported successful syntheses for compounds that utilize γ-lactams in the way β-lactams have been used in this research. The integrity of the ring system in γ-lactams may prove to give more stable, less synthetically vulnerable compounds that maintain proper tubulin binding features of CA4.The synthetic route explored to access CA4 derivatives of this variety utilizes β-lactams as precursors. The N1-C4 bond in a β-lactam may be cleaved with lithium diisopropylamide (LDA) to allow a ring expansion process affording γ-lactams. To prepare the necessary β-lactam precursors, specific ketenes, generated from their respective acid chlorides, and imines were used in a Staudinger [2+2] cycloaddition. The synthesis of imines that can generate these γ-lactam derivatives via passage through the β-lactam intermediates has received much attention. To date, success has been found in preparing these imines, while attention has recently shifted towards the process of preparing the β-lactams. β-Lactam forming reactions have proven to give complex mixtures that cannot be easily identified prior to isolation. Despite this fact, the Staudinger [2+2] cycloaddition followed by the ring expansion still appears to be a viable approach to access the γ-lactam analogues of CA4, especially as encouraging results regarding the potential transformation of a doubly trimethoxy substituted imine into a β-lactam have been found.

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