Penams synthetic approaches

The previously described penem syntheses from 6-APA-derived starting materials have been inefficient in the sense that the C(2) and C(3) atoms of the penam are lost during the sequence. Scheme 71 shows a route in which C(2) and C(3) of the penam become C(2) and C(3) of the penem (79CC665). The major product of this sequence is the (55) enantiomer. A related synthetic approach, starting with the natural product clavulanic acid, has been described (79CC663). 

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. 

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