Aspects of Beta-Lactam Syntheses

Abstract

A brief review of the methods available for the synthesis of β-lactams is presented together with a discussion of the physical, chemical and biological properties of these compounds. The main work described in this thesis concerns the stereo specific synthesis of cis-β-lactams from copper acetylides and nitrones, This reaction is found very useful in introducing a large range of substituents, such as alkyl, aryl, aminoalkyl and ester functions into the 3-position of the azetidin-2-one. Thus, various β-lactam derivatives of active drug molecules could also be obtained from the appropriately substituted copper acetylides. The copper acetylide reactions have also been shown to be applicable to cyclic nitrones to produce both five- and six membered rings fused to β-lactams. An investigation into the mechanism has shown that the 1-, 3-and 4-substituents of the azetidin-2-one are derived directly from that of the starting materials; the proton gained by the β-lactam is from the solvent and the g-lactam carbonyl oxygen atom is derived from the nitrone. The mechanism of the reaction of the copper acetylides with nitrones is discussed in the light of these experimental results. In an attempt to achieve a better understanding of the mode of epimerisation of cis-β-lactams, a reaction found to decrease the yield of cis-β-lactams, epimerisation of various 3-substituted β-lactams was performed. The results clearly indicated that the prime factor governing the rate of epimerisation is the electronegativity of the C-3 substituent. A study into the stability of cis- and trans-β-~lactams revealed that the cis-3-aryl-substituted β-lactams are more stable then the trans-isomers., However, the reverse is true for the3-alkyl-compounds. Cis- and trans-triphenylazetidin-2-ones are also obtained from photocyclisation of acrylamides. The preparation of 3,3-diphenyl-substituted azetidin-2-oneswas achieved from diphenyl ketene and imines. Except for spiroazetidin-2-ones, these azetidin-2-ones were found to undergo rearrangement in the presence of concentrated sulphuric to 3,4-dihydroquinolin-2-ones. In addition to this product, diphenylacetanilide was also isolated. The mass spectra of many of the compounds prepared in this work are recorded and possible fragmentation pathways are suggested for these compounds.