Penam sulfoxide

Oxidation reactions on the sulfur atom of penicillins remain the most important reactivity of S-1 encountered in the literature. Penam sulfoxides and sulfones are indeed important compounds as they confer to the skeleton an ease of thiazolidine ring opening by weakening the C(5)-S(l) and S(l)-C(2) bonds (see Section 2.03.5.9) <2004CHE816>. In particular, the former constitute key intermediates in ring-expansion transformations from penams to cephems (see Section 2.03.5.9), while the latter have a special biological interest as /3-lactamase inhibitors (e.g., sulbactam, tazobactam see Sections 2.03.1, 2.03.5.2, and 2.03.12.4). Since CHEC-II(1996) covers all the aspects of these oxidation reactions on the S-1 atom of penicillins, this section focuses on the most relevant recent papers. As there is no particular change in the subject, only a few articles have been released since 1995. 

The reduction of penam sulfoxides to their corresponding sulfides can be done by treatment with either phosphorus pentasulfide/pyridine in dichloromethane <1993H(36)1529> or trifluoroacetic anhydride/KI in acetone <1998TL8537>. 

Scheme 17 Ring expansion of penam sulfoxides into cephems.

In the penam series, the starting materials for the functionalization of one of the C-2 methyl groups are the chloro-70a, bromo- 70b, or oxycarbonyl 70c derivatives, obtained from the usual penam sulfoxide chemistry (Figure 10)... 

In penams and penems, the ring heteroatoms S-l and N-4 do not bear any exocyclic substituents with the exception, however, of penam sulfoxides, which can rearrange into sulfenic acids (see Sections 2.03.5.3.1, 2.03.5.4, and 2.03.5.9). 

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>. 

In a similar study, 4-penam sulfoxides and sulfones were prepared either by controlled oxidation with hydrogen peroxide in acetic acid over Z days or complete oxidation with KMn04 <2002BML3417>. Selective hydrogen peroxide oxidation of 106 was also used to form sulfoxide 107 in 89% yield (Scheme 37) <2003BML339>. 

The synthesis of (6S)-cephalosporins from 6-aminopenicillanic acid derivatives 90 has been achieved by two routes. The Morin penam sulfoxide-cephem rearrangement was shown to be a practical method for the preparation of cephalosporins 91 with unnatural configurations <00T6053>. 

The thermal equilibration between penam sulfoxides and azetidinone-4-sulfenic acids 109 opens the way to a number of methodologies for obtaining azetidinone 4-thioesters. The oldest one, discovered in 1970 by Hatfield et al. [86], simply involves heating of the penam sulfoxide with a carboxylic anhydride and trimethyl phosphite thioesters 137 are obtained through a mechanism representable by the formation and collapse of penta-coordinate phosphorous intermediate 135. 

Mention has already been made of attempts to obtain 2-hydroxy- and 3-hydroxypenams (compounds 301 and 303), from which penems might have been generated by loss of the elements of water. The reductive elimination performed on the 2,3-diphenylthiopenam 316 by Kametani [182], and the oxidative elimination accomplished by Hanessian on the 2-methylthio compound 298 [29], are successful examples of penem synthesis achieved from isolated penam intermediates. Other examples of this strategy involve Pummerer-type rearrangements. The preparation of penem 306 by treatment of penam sulfoxide... 

Base treatment of the bromomethylpenam also yielded the cephem 172 (Kamiya et al., 1975), together with the novel tricyclic penam 173. Theorizing that inhibition of the episulfonium ion composition would enhance the formation of the cyclopropyl derivative. Kamiya and co-workers reacted the penam sulfoxide (174) with base to give the tricyclic sulfoxide (175) together with the isothiazolone sulfoxide (176). Reduction of 175... 

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