Penicillin sulfoxide synthesis

Mata et al. also described a new and robust protocol for the solid-phase synthesis of 2(3-methyl substituted penam derivatives using Merrifield resin as support [210]. The work begins with immobilization of 6,6-dibromopenicillanic acid (171) onto Merrifield resin followed by oxidation with m-chloroperbenzoic acid (MCPBA) to obtain the resin-bound sulfoxide (173). The key-step involves the thermal rearrangement of the corresponding penicillin sulfoxide (Scheme 49). 

A new and efficient method for the preparation of penicillin sulfoxide esters has been developed (Bywood et al., 1975). This procedure involved treatment of the penicillin sulfoxide with a hydrazone in the presence of an oxidizing agent (e.g., iodine) (Barton et al., 1974). This method appeared to be especially useful for the synthesis of benzhydryl esters (Scheme 2). The hydrazide (1) was reported to be a useful alternative... 

Other azetidinone derivatives useful for the synthesis of new p-lactam structures have been prepared by variations in the reaction of a trialkyl-phosphite with the sulfenic acid derived from a penicillin sulfoxide. 

As previously described, one of the major advances in penicillin sulfoxide chemistry in the last few years has been the rearrangement of the sulfoxide to the exomethylenecephem. The importance of this reaction resides in its utility in the successful synthesis of the clinically important oral antibiotic, cefaclor (388) (Volume 1, Chapter 2). The exomethylene isomer has also been utilized as an intermediate for the synthesis of the naturally occurring acetoxymethyl-substituted cephems. 

The synthesis takes advantage of the well-documented sulfoxide - sulfenate rearrangement , as well as of its retro-process, leading to cyclization and formation of the desired four-membered ring sulfoxide system (i.e. 211, 212). A closely related ring enlargement is based on the reversibility of this rearrangement and has found wide use in penicillin chemistry . 

The possibilities of transformations at the C-2 position are relatively poor. Nonetheless, penicillins can be converted into clavulanic-like derivatives <1983TL2563, 1987TL2283> by changing the hybridization of C-2 from sp3 to sp2. Indeed, 2-carboxylate penam /3-sulfoxides, readily obtained from penicillin V, enable a decarboxylative Pummerer reaction to provide 2-exomethylene penams 13, as well as penems, their endocyclic tautomers (Scheme 9) <1987CC81>. On the other hand, 2-oxo-, 2-thioxo-, and 2-iminopenams <1996CCA1367> could be obtained by total synthesis (see Section 2.03.11.4) and further used for the preparation of 2-heterosubstituted penems (see Section 2.03.6.4). 

The first highly stereocontrolled total synthesis of a natural penicillin was reported 2 years later by Baldwin et al. <1976JA3045>. In this case, the methodology relies on the formation of the fi-lactam ring before the thiazolidine ring closure, via the sulfenic acid intermediate 97 (Rz = OH), which gives electrophilic attack on the double bond to produce a penam sulfoxide 98 (see Section 2.03.5.3) (Scheme 52). A similar route has been developed independently by Kishi for the total synthesis of 6cr-methoxy penicillin derivatives <1975JA5008>. 

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