This research examines the synthesis of gamma-lactam analogues of combretastatin A4 (CA4). Many anticancer drugs such as CA4 pose equal risk to normal and cancerous cells. In the case of CA4, enhancement of pharmacokinetic features such as specificity and energetic stability are desirable whilst maintaining tubulin binding activity. This warrants the search for synthetic routes to gamma-lactam analogues of CA4. In CA4, tubulin binding activity has been attributed to the cis arrangement of two specific rings around an ethylene bridge, and molecules that contain the beta-lactam functionality (beta-lactams are the functional portion in penicillins) have been explored as appropriate substitutes for this bridge to compromise cytotoxicity to normal cells. Gamma-Lactams are an appealing replacement for the alkene bridge seen in CA4, and have the potential of maintaining appropriate activity for tubulin binding. To date, no groups have aimed to expand territory towards gamma-lactams as medicinally significant moieties which may facilitate similar spatial arrangements of the rings in a more stable fashion than their beta-lactam counterparts. The synthetic route explored to access these CA4 derivatives utilizes lithium diisopropylamide to cleave beta-lactams, permitting expansion to the desired gamma-lactams. To prepare the necessary beta-lactam precursors, specific ketenes generated from their respective acid chlorides, and imines were used in a Staudinger [2+2] cycloaddition. Generation of CA4 beta-lactam derivatives via imines has recently been the focus of this study as success has been found in preparing various imines that can undergo the beta-lactam transformation. The specific strategies surrounding the synthesis of beta and gamma-lactams will be discussed in detail.
