Penicillin sulfoxide acid, rearrangement

Utilization of simultaneous silyl protection of the sulfenic acid and of the carboxyl group allowed the development of a process for rearrangement of the penicillin sulfoxide acid (4) into a desacetoxycephem acid (46) in high yield (de Koning et al., 1975). 

In the presence of an acid anhydride, the corresponding thioester (e.g. 226), was formed in good yield (Hatfield et al., 1970). However, use of an acid (e.g., acetic) produced a rra/i -acylate, acetate 227 (Cooper and Jose, 1970 Suarato et al., 1978). Rearrangement of the penicillin sulfoxide acid (228) resulted in involvement of the carboxylic acid in an intramolecular fashion to produce the lactone (229) (R. D. G. Cooper, 1970, unpublished results). 

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).

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). 

Sulfenic acids (45) are generally quite unstable they easily dimerise and eliminate water to form thiol sulfinates (46) (Scheme 28). Several sulfenic acids have, however, been isolated and many of these are stabilised by hydrogen bonding to a carbonyl or amino group. The first sulfenic acid to be isolated was the anthraquinone derivative (47) in 1912. Sulfenic acids have been postulated as transient intermediates in many chemical and biochemical processes, e.g. the oxidation of thiol groups in proteins and the thermolysis of sulfoxides, including the acid-catalysed rearrangement of penicillin sulfoxides (48) to cephalosporins (49) (Scheme 29)... 

They are derivatives of 7-aminocephalosporanic acid (37) in which the RCO group is replaced by hydrogen and R by the acetoxy group. Penicillins and cephalosporins are interconvertible as indicated in Scheme 8, in which the sulfoxide-sulfenic acid rearrangement (see Chapter 4, p. 52) has been applied in the preparation of the pharmaceutically important cephalosporin (39) from the semisynthetic penicillin (32). 

The nature of the products produced in a penicillin sulfoxide rearrangement are determined, in part, by the nature of the 3-substituent. In the normal acid-catalyzed rearrangement of a penicillin sulfoxide ester... 

The rearrangement of a penicillin sulfoxide ester to a A -cephem, originally accomplished using toluenesulfonic acid, has also been achieved with a variety of reagents [e.g., dipyridinium phosphate (Barton et al., 1972 Baldwin et al., 1973), diethyl azodicarboxylate (Tereo et al., 1972), a,a-azobis-N-methylformamide (Tereo et al., 1972), and diethylphos-phorocyanidate (Ninomiya et al., 1976)]. This latter reagent was disclosed as also yielding small amounts of the A - and exomethylenecephem isomers. 

In contrast to several other rearrangements of the penicillin sulfoxide, the reaction with 155 was also successful with the free acid (4) wherein 157 was isolated with no reported decarboxylation. Treatment of the acid (157) with sodium bicarbonate afforded a disproportionation-recombination reaction resulting in the azetidinone disulfide U58) and the benzthiazoyl disulfide (159). 

The normal acidic rearrangement of penicillin sulfoxide derivatives is the well-known one discussed at length previously (Cooper and Spry, 1972). The usage of some alternative acidic reagents has resulted in totally different reaction pathways. The reaction of penicillin sulfoxide (349) with phenylacetyl chloride furnished the thiazinium salt (350)... 

Acid-catalyzed conversion of penicillin sulfoxides to cephalosporins. The rearrangement seems to be general for a variety of other heterocyclic sulfoxides as well. 

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