Penicillin sulfoxide

The role of IR spectroscopy in the early penicillin structure studies has been described (B-49MI51103) and the results of more recent work have been summarized (B-72MI51101). The most noteworthy aspect of a penicillin IR spectrum is the stretching frequency of the /3-lactam carbonyl, which comes at approximately 1780 cm" This is in contrast to a linear tertiary amide which absorbs at approximately 1650 cm and a /3-lactam which is not fused to another ring (e.g. benzyldethiopenicillin), which absorbs at approximately 1740 cm (the exact absorption frequency will, of course, depend upon the specific compound and technique of spectrum determination). The /3-lactam carbonyl absorptions of penicillin sulfoxides and sulfones occur at approximately 1805 and 1810 cm respectively. The high absorption frequency of the penicillin /3-lactam carbonyl is interpreted in terms of the increased double bond character of that bond as a consequence of decreased amide resonance, as discussed in the X-ray crystallographic section. Other aspects of the penicillin IR spectrum, e.g. the side chain amide absorptions at approximately 1680 and 1510 cm and the carboxylate absorption at approximately 1610 cm are as expected. 

Penicillin sulfoxides can be epimerized by heat to afford thermal equilibrium mixtures of a- and /3-sulfoxides, the position of the equilibrium depending on the C(6) side chain (Scheme 5). Deuterium incorporation studies support a sulfenic acid, e.g. (18), as the intermediate in these transformations. This mechanism is also supported by the finding that when an a-sulfoxide epimerizes to a /3-sulfoxide there is a simultaneous epimerization at C(2) (71JCS(C)3540). With irradiation by UV light it is possible to convert a more thermodynamically stable /3-sulfoxide to the a-sulfoxide (69JA1530). 

Penicillin sulfoxides may be reduced back to the sulfide with P2S5 (76TL971), PCI3 or PBra e.g. 71JCS(C)3540). 

Scheme 6 depicts a typical penicillin sulfoxide rearrangement (69JA1401). The mechanism probably involves an initial thermal formation of a sulfenic acid which is trapped by the acetic anhydride as the mixed sulfenic-acetic anhydride. Nucleophilic attack by the double bond on the sulfur leads to an episulfonium ion which, depending on the site of acetate attack, can afford either the penam (19) or the cepham (20). Product ratios are dependent on reaction conditions. For example, in another related study acetic anhydride gave predominantly the penam product, while chloroacetic anhydride gave the cepham product (7lJCS(O3540). The rearrangement can also be effected by acid in this case the principal products are the cepham (21) and the cephem (22 Scheme 7). Since these early studies a wide variety of reagents have been found to catalyze the conversion of a penicillin sulfoxide to the cepham/cephem ring system (e.g. 77JOC2887).

The intermediate sulfenic acid derived from a penicillin sulfoxide has been trapped by a large assortment of reagents and, in one case, the sulfenic acid itself has been isolated (74JA1609). Only some of these products will be discussed here, and the reader is referred to the cited reviews (especially B-80MI51102) for additional examples. 

Sila-Morin-Rearrangement of Penicillin Sulfoxides to Cephalosporins... 

Rearrangements involving sulfoxides have played an important role in the development of the chemistry of sulfoxides. It is therefore not surprising that all major literature surveys on sulfoxides " , or their sulfenate precursors , also include a discussion of this subject. However, while excellent and detailed coverage exists for certain rearrangements of general mechanistic and synthetic interest, such as, for example, the Pummerer " or the related penicillin sulfoxide-cephalosporin " rearrangement, the treatment of all... 

In this context, it should be pointed out that the correlation between aromatic solvent-induced shifts (ASIS) and the axial or equatorial orientation of protons in cyclic sulfoxides and sulfites is quite distinct (211-213) and may be utilized in the assignment of configurations. For instance, the absolute configuration at sulfur was assigned to the penicillin sulfoxide 202 based on analysis of the effect of aromatic solvents on the chemical shifts of protons of the thiazolidine ring (214,215). 

Phenoxymethyl penicillin sulfoxide methanol solvate S J. Am. Chem. Soc. 1969,97, 1408... 

---