Penam product

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 structure of the penam product denounces migration of a phenylthio group, which requires the involvement of dipolar species 320 in the C2-C3 bond formation. This intermediate would arise from the 3-thiacepham sulfonium ylide 319, which is a reasonable product of intramolecular carbene trapping (318 - 319) by the thioether sulfur atom, in the absence of the thioxo sulfur atom. Thus, three different 3-thiacepham dipolar species (313,314,319) formally participate in as many penem ring formation strategies. This is one of the fascinating aspects of P-lactam chemistry. 

At a later date, these authors reported their observation that this photoreaction was significantly concentration-dependent (Maki and Sako, 1978). The irradiation of benzothiazolyldithioazetidinone (87b), which in an 0.1% solution in acetonitrile gave products 88 and 89 in 45 and 10% yields, respectively, and no detectable amounts of penam products, gave in a 1% solution, benzothiazolylthiomethylpenams 91 and 92 as major products. 

Penam Sulfone B-Lactamase Inhibitors. Natural product discoveries stimulated the rational design of p-lactamase inhibitors based on the readily accessible penicillin nucleus. An early success was penicillanic acid sulfone, (2(5)-cis)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-l-a2abicyclo [3.2.0]heptane-2-carboxylic acid [68373-14-8] (sulbactam) (25, R = = H, R" = R" = CH ), CgH NO S. The synthesis (118), microbiology (119—121),... 

Modification at the C(7) position of the penam ring system (other than ring opening reactions) has not been extensively studied. It was possible, however, to convert the /3-lactam to a /3-thionolactam in 1% yield as shown in Scheme 55 (75JA5628). The deblocking product (73) had greatly reduced antibacterial activity compared to the parent /3-lactam. 

The previously described penem syntheses from 6-APA-derived starting materials have been inefficient in the sense that the C(2) and C(3) atoms of the penam are lost during the sequence. Scheme 71 shows a route in which C(2) and C(3) of the penam become C(2) and C(3) of the penem (79CC665). The major product of this sequence is the (55) enantiomer. A related synthetic approach, starting with the natural product clavulanic acid, has been described (79CC663). 

The reaction was further developed to form a wide range of p-lactam-based products (52). Treatment of the racemic ylide processor 186 with suitable sulfur-based thiocarboxylate or thiocarbonate dipolarophiles gave rise to the expected racemic penams 189 and 190 and penems as single regioisomers (Scheme 3.54). Once again, the use of the chiral dipolarophile 186 furnished the cycloaddition product 191 with complete enantiomeric integrity. Similarly, the use of aldehydes... 

We were surprised to find that despite the general lability of penam derivatives, the products (154) could be purified by sublimation in vacuo. Using a similar scheme, Sjoberg synthesized the amide of a stereoisomer of penicillin G, but in very low overall yield, because formation of the required 3-thiazoline derivative by the Asinger condensation did not proceed satisfactorily. 

Spectra of (3-lactam antibiotics recorded by using direct spectrophotometry do not have desired selectivity due to the paesenoe of related products. A comparison of sharp zero-order spectra and/ or value of absorption maxima for some (3-lactam analogs with ones obtained for CRS chemical reference substance) is recommended by pharmacopeias for an their identification [7]. Lack of desired absorbing species in chemical structure of penam analog often do not allow to apply direct spectrophotometry even for qualitative studies of substance of high purity. 

Fig. 3. The pathways of obtaining of absorbing degradation products of penam analog [9-10].

Similarly, in the case of determination of penam analysis during acidic hydrolysis (1.0 M HCl), formation of non-absorbing degradation products was the intermediate stage of their analysis. Complex which is necessary for achievement of spectrophotometric signals, was formed between penicillamine and palladium(ll) chloride, peak at 334 nm (Fig. 18) [58]. 

Fig. 18. Absorption spectra based on reaction of degradation products of penam analogs and palladium (II) and suggested mechanism of the reaction [58].

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