Penem analogues

Carbanions stabilized by phosphorus and acyl substituents have also been frequently used in sophisticated cyclization reactions under mild reaction conditions. Perhaps the most spectacular case is the formation of an ylide from the >S-lactam given below using polymeric Hflnig base (diisopropylaminomethylated polystyrene) for removal of protons. The phosphorus ylide in hot toluene then underwent an intramolecular Wlttig reaction with an acetyl-thio group to yield the extremely acid-sensitive penicillin analogue (a penem I. Ernest, 1979). 

The reaction has the advantage of utilizing much of the original penem framework from 6-APA, retaining the stereogenic centers of 6-APA and providing a versatile synthetic route to a variety of analogues of penem compounds. 

The search continues for the ideal beta-lactam antibiotic, and numerous esoteric substances have been isolated from natural sources or have been synthesised during the past 15 years. These include the penems, carbapen-ems, cephamycins, monobactams, etc. The penems are wholly synthetic and from a clinical viewpoint have not been successful, while more success has been obtained with the carbapenems, which include the natural product thienamycin (from Streptomyces cattleya) and the analogues imipenem and meropenem. These carbapenems have a remarkable spectrum of antibacterial activity with a very high activity against pseudomonads. Thienamycin is relatively unstable, but the addition of a formamidine group to produce... 

In a similar manner the synthesis of y-lactam analogues of penems (316) from A -benzyloxy-carbonyl-L-aspartic semi-aldehyde benzyl ester (315) has been described (Scheme 57) <86TL346l, 89T4537>. 

New syntheses of ( )-clavulanic acid and its thio-analogue have appeared. The synthesis of the latter compound makes use of yet another internal Wittig reaction (Scheme 136), and it is readily converted into a penem. 

Ekstrom B. Basic design of beta-lactam antibiotics, penems and analogues and monocyclic beta-lactams. Scand J Infect Dis Suppl 1984 42 38-49. 

The influence of the nature of the side-chains on the biological activity of jS-lactam antibiotics remains a puzzle in spite of the numerous analogues that have been prepared and evaluated. The activity intrinsic to the ring system is still under investigation, and to this end various hetero-analogues have been prepared. The penems, a new class of antibiotics, have been announced by the Woodward group. The novel racemic threo-trans-6-a-hydTOxycthylpcnem-3-carboxylic acid (153) and its erythro-trans-isomer have been prepared over 13 steps from the acetoxy-azetidinone (152). The key intermediate (154) was... 

A total synthesis of ( )-l-oxabisnorpenicillin G (40) has been published,and the preparation of a number of l-oxaceph-3-ems, e.g. (41), has been described. Communications have been published on the synthesis of clavulanic acid analogues, e.g. (42), ° and on the transformations of related compounds into oxa-penem systems, e.g. (43) to (44). A total synthesis of a related compound thienamycin (45) has been published/ ... 

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