A novel approach to #beta#-lactam and quinolone antibacterial agents.
The f)-lactam or azetidinone 4-membered heterocyclic nng system has been
synthesised by many different synthetic strategies and these are well documented in the
literature. Many of these strategies give substituted azetidinone rings displaying
defined stereochemistry which are used as the building block for many modern day
antibiotics. It was therefore intended to pursue a method of azetidinone ring formation
using cheap and readily available starting materials employing a [2+2] cycloaddition
reaction which, according to the literature, had only a few examples and was seen to
be an area ripe for research.
Taking urethane in anhydrous THF and metalating with n-butyl lithium, followed by
the subsequent addition of phenyl vinyl sulfone, it was envisaged that the two would
react in such a way to give the -l-membered azetidinone ring. It was found however
that the carbon-nitrogen bond was formed but subsequent cyclisation did not follow
and therefore no azetidinone was formed. Although azetidinone ring was not detected
the novel compound N,N-bis-(phenylsulfonylethyl) urethane was isolated. This
compound was of interest since it was hoped that it could provide a new route to
substituted pyridines. Various methods were undertaken in an attempt to cyclise this
molecule via the generation of a-sulfonyl carbanions and reactions with a variety of
electrophiles. During our experiments no cyclised products were detected.
TIle replacement of phenyl sulfonyl group with triphenylphosphonium bromide
provided a new hope for azetidinone synthesis since its ability to stabilise a-sulfonyl
carbanions and promote reaction with electrophiles was well established. Experiments
of this nature failed to produce an azetidinone.
TIle next stage of research was to investigate a new route to the production of
quinolone antibiotics. Quinolones, particularly those which are furnished with a fluorine at C-6 position, are the new generation of antibiotics which exhibit a high
activity and selectivity towards pathogens which have become resistant to older
antibiotics such as penicillin. Needless to say their importance in the pharmaceutical
industry has increased dramatically over recent years and research into the
improvement of synthetic strategies towards the total synthesis of these molecules has
attracted much commercial interest. Meth-Cohn showed that quinolones can be
formed in excellent yield by the reaction of N-alkylformanilides in phosphorus
oxychloride and activated acid chlorides e.g. methyl malonyl chloride. This approach
is examined regarding the synthesis of both novel and known quinolone antibiotics
(norfloxacin and ciprofloxacin). Work on this topic has produced encouraging results
with the synthesis of important antibacterial intermediates.