Penicillin Rearrangement

In spite of the considerable progress in developing methods for total synthesis, this route to cephalosporins cannot compete with fermentation or penicillin rearrangement (see Sections 5.10.4.1 and 2) for the industrial production of cephalosporin antibiotics. While total synthesis does provide access to nuclear analogs not readily obtainable from fermentation products, none of the totally synthetic materials have displayed sufficient advantages to Warrant their development as new drug products (b-81MI51000). 

MORIN Penicillin Rearrangement Ring expansion of penams to cephems under acidic catalysis. 

Sometimes, reactive intermediates are formed that are known or suspected to be toxic. For example, penicillins rearrange under acidic pH conditions to penicillenic acids, which are suspected to contribute to the allergenicity of penicillins (Scheme 3).4 Gosselin et al. 

Conversion of semisynthetic penicillins, e.g. 9, into 7-acylamino-3-methyl-8 oxoceph-3-em-4-carboxylic ester 12 (penicillin rearrangement, Morin reaction 1969) [135]. 

At this juncture, however, it was not quite possible to decide between the two structures (III) and (IV) on the ground of chemical evidence alone, since penicillin is prone to undergo abrupt molecular rearrangement, e.g., on treatment with dilute acid, penicillin rearranges to penillic acid. 

Another interesting penicillin rearrangement which involves j8-elimination and a thiol intermediate is that of methyl 6a-chloropenicillate (176) to the 1,4-thiazine 177, through the pathway shown . Ring opening... 

Another type of penicillin rearrangement is that which starts with proton elimination from C-6. Such mechanism explains the epimerization at C-6 on treating phthaloylpenicillin methyl ester (173) with sodium hydride . The first step is the opening of the thiazole ring to the thiol salt 174 which recyclizes to 173 with epimerization. Support for this mechanism was provided by the isolation of the thiazepine 175 as a by-producti. ... 

Bond Cleavage.—The second major type of penicillin rearrangement is... 

Chemical Modification. The chemistry and synthetic strategies used in the commercial synthesis of cephalosporins have been reviewed (87) and can be broadly divided into ( /) Selection of starting material penicillin precursors must be rearranged to the cephalosporin nucleus (2) cleavage of the acyl side chain of the precursor (2) synthesis of the C-7 and C-3 side-chain precursors (4) acylation of the C-7 amino function to introduce the desked acylamino side chain (5) kitroduction of the C-3 substituent and 6) protection and/or activation of functional groups that may be requked. 

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).

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

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 . 

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... 

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