Penams

Only one successful penem synthesis involving a [nitrogen, C-3] ring closure has been described (119). Cyclization of the ketomalonate (79) usiag hydrofluoric acid-pyridine afforded the penams (80) which were converted to the penem (81). Attempts to adapt the versatile diazoketoester-carbapenem cyclization for penem synthesis failed (120). 

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),... 

Table 5. Activity of Penam Sulfone B-Lactamase Inhibitors ...

Penam P-Lactamase Inhibitors. Penam is the trivial name given derivatives of the penicillin nucleus (31) the chemical name of which is 4-thia-l-a2abicyclo[3.2.0]heptane. Table 6 gives activity data for a diverse group of penams. The report that 6-P-bromopeniciU.anic acid [26631-90-3] [2(3)-(2a,5a,6P)]-6-bromo-3,3-dimethyl-7-oxo-4-thia-l-a2abicyclo[3.2.0]heptane-2-carboxyhc acid, (31, R = Br, R =H, R" = R " = CH3) a potent... 

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).

With certain 6-substituents on the penam nucleus, it has been possible to isolate sulfonium derivatives (Scheme 16) (79JCS(P1)3175). As expected, these are highly reactive compounds. 

Scheme 15 shows an example of the cleavage of a carbon-sulfur bond by chlorinolysis. This reaction can also be carried out on the intact penam ring system as shown in Scheme 17 (71JA6269 and the previous paper). In Scheme 18 this reaction is used to form the epimer of... 

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. 

Scheme 63 illustrates another synthetic route leading to the penam ring system (78JA4597). lis sequence contains some interesting points of synthetic strategy which are discussed in... 

Scheme 64 shows the key steps in two additional routes leading to the penam ring system <79JCR(S)157, 76ACS(B)377). 

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). 

Certain penicillins and penam derivatives have the ability to inhibit the /3-lactamase enzyme, and can provide a variable degree of protection to susceptible /3-lactam antibiotics... 

AICI3, CH3NO2, anisole, 3-6 h, 73-95% yield.These conditions also cleaved the p-MeOC6H4CH2 ester and ether in penam and cephalosporin-type intermediates. 

The clavams differ from penicillins (based on the penam structure) in two respects, namely the replacement of S in the penicillin thiazolidine ring (Fig. 5.1) with oxygen in the clavam oxazolidine ring (Fig. 5.5 A) and the absence of the side-chain at position... 

Acylketenes, derived from Meldrum s acid, add to esters of (R)-4,5-dihydrothiazolin-4-catboxylic acid to give 81 <00OL2065>. A solid-phase synthesis of 2P-methyl substituted penam derivatives utilises a tether through an ester group <99TA3893>. 

The penam nitrile oxide 36 underwent 1,3-DC reactions with various alkenes and alkynes to give cycloadducts of general formula 37. The corresponding acids (37 R=H) exhibited potent P-lactamase inhibitory activity <00OL3087>. 

Buynak et al. [53] synthesized several 6-(mercaptomethyl) penicillanates (9r and 9s, Table 1) that include both C-6 stereoisomers as well as the sulfide and sulfone oxidation states of the penam thiazolidine sulfur. Selected mercaptomethyl penicillanates inactivated both metallo- and serine /5-lactamases, and displayed synergism with piperacillin against various //-lactamase-producing strains, including metallo-/5-lactamase-producing P. aeruginosa strain. Compound 9r would be capable of bidentate chelation of zinc subsequent to enzymatic hydrolysis of the /5-lactam (Scheme 3). 

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