Azetidinone penem from

The products arising from cleavage of the azetidinone ring of bioactive penems are of particular interest in the comprehension of an acyl-enzyme complex formation with the target enzymes (see Section 2.03.6.2). 

Mori used the anodic decarboxylative acetoxylation for the synthesis of the valuable penem precursors 4-acetoxy-2-azetidinones. Thus, 4-carboxy-2-azetidinone was electrolyzed in acetonitrile/AcOH (3 1) in the presence of NaOAc (4.5 equivalents) to give the desired product in 76% yield. Starting from the enantiopure 4-carboxy-3-[l-(t-butyldi-methylsilyloxy)ethyl]-2-azetidinone, the enantiopure 4-acetoxy compound was obtained in 85% yield [Eq. (48)] [244]. 

The enthusiasm for the pharmaceutical potential of the monocyclic P-lactams was matched by renewed interest in the chemistry of these compounds both in industry and academe. This review will focus on recent developments in the chemistry of monocyclic P-lactam antibiotics, emphasizing new or improved methods for construction of the azetidinone ring as opposed to a discussion of the functional group manipulation of preformed P-lactams and the structure-activity relationships of the ultimate products. Emphasis will be placed on key advances in the preparation of true monocyclic antibiotics and intermediates for their synthesis and not on the voluminous chemistry dealing with the preparation of azetidinone intermediates for the synthesis of bicyclic compounds such as penems. The latter topic is covered elsewhere in this volume. The review is intended to cover the period from 1983 through early 1989 with an emphasis on more recent developments. Attention is drawn to previous reviews [4-14] which deal with the early phases of development of the monocyclic p-lactam antibiotics as well as those aspects of their chemistry not discussed in this work. 

Intramolecular nucleophilic substitution by an active methylene linked to the nitrogen atom of a-substituted carboxamides was first utilized in azetidinone synthesis by Sheehan and Bose in 1950 [27]. When 3-hydroxyethylazetidinones became an important research target, it was realized that L-threonine or D-allo-treonine, easily converted to bromohydrins 57,61 or to epoxyacid 64, are by this method one of the most convenient natural chiral source for penem and carbapenem synthesis. Shiozaki et al. [28] at Sankyo s laid down the fundaments of the threonine route . Early works from D-a//o-threonine-derived 2R-bromo-3R-hydroxybutyric acid 57 were run using malonate anions as the nucleophilic moiety, as shown in amide 58, which in presence of DBN cyclized to azetidinone 59a with complete inversion of configuration [28a, c]. 

In the early years of penem and carbapenem research, the easy preparation and commercial availability of azetidinone 10 prompted the devisal of several protocols for its conversion into an optically active equivalent (Scheme 1, F). Thus, acetate displacement with thioglycolic acid and resolution with d-( +)-ephedrine gave the 4/ -carboxymethylthio derivative 94, in turn elaborated to 95a [44], the 4R-enantiomer of the key intermediate of Woodward s first synthesis of racemic 6a-hydroxyethylpenems [45]. In another approach, analog 95b was obtained by diastereomer separation after displacement of 4-acetoxy-azetidinone with a chiral mercapto-alcohol [46]. Along a still different approach [43], optically active 93b was obtained from racemic 10 and thiophenol via asymmetric induction from the reaction medium (cinchonidine-containing benzene). 

The high degree of antibacterial activity associated with 2-alkylthiopenems and the ease by which these compounds could be obtained from a common 2-thioxopenam precursor made the 6-hydroxyethyl-2-thioxopenam 290b a major target of penem synthesis. To prepare this intermediate, the tritylthio-azetidinone 102c was selected as starting material at Schering s [174]. 

Although cyclization of 330 is spontaneous at room temperature, which allows high-yield generation of sensitive penem products to be achieved, two major problems are apparent. The first one relates to the stereoselective preparation of 4S-chloroazetidinones, which is required in order to obtain the biologically active 5R-configured penems. The second problem is the limited choice of usable R groups. Both problems boil down to the most appropriate preparation of chloro-mesylates 331, which can be achieved from penams, clavams, or total synthetic azetidinones. These approaches were all pioneered by Glaxo chemists. 

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... 

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