Of penems

Historically, the development of penems is contemporary with that of the naturally occurring carbapenems and the direction of penem research has clearly been influenced by the stmctures of the closely related natural products. The origins of the two groups of compounds is, however, quite different. Unlike carbapenems, no penems have been found in nature. When first described (84,85) they were viewed as hybrid molecules combining stmctural features of penicillins and cephalosporins. 

Extension of the Phosphorane Route. Ample evidence of the versatihty of the phosphorane synthesis strategy is provided by the proliferation of penems that followed. Nucleophilic displacement of the acetate function of the acetoxy-azetidinone (51, R = OCOCH ) [28562-53-0] (86) provided azetidinones where R = SCOCH, SCSSC2H, and SCSOC2H, which on elaboration gave the penems (52, R = CH ) (87), (52, R = SC2H ) (88), (52, R = 0C2H ) (89). Similar treatment of 3-substituted (or disubstituted) acetoxyazetidinones allowed the synthesis of a number of 2-substituted- 6-alkyl-and 6,6-dialkylpenems (90). 

Displacement of the sulfinyl group of penems (85), obtained by regio selective oxidation of (74, R = R" = CH2CHCH2) (Fig. 5)... 

Penem B-Lactamase Inhibitors. The synthesis and antibacterial properties of penems, the trivial name for the 4-thia-l-azabicyclo[3.2.0]hept-2-ene ring system (24), have been reviewed (107,108). Like the closely related carbapenems, many of the penems are potent antibacterials. Additionally, penems are also susceptible to degradation by renal dipeptidase, but to a lesser extent. The limited -lactamase inhibitory data available for penems are presented in Table 4. SCH-29,482 [77646-83-4] (24, R = H, R = CH(OH)CH2, R = SCH2H ), C2qH23NO S2, is reported to be an inhibitor of type I Cephases and the OXA-2 enzyme (109). Compounds [101803-54-7] and [101914-68-5] (24, R = H, R = CH2CH(OH),... 

Modifications at this position are described in various other sections. See, for example, the preparation of 2-substituted methylpenams in Section 5.11.3.3.1, the total synthesis of 2-spirocycloalkylpenams in Section 5.11.4.4, and the synthesis of penems in Section 5.11.4.6. 

Scheme 6.218 Synthesis of penem derivatives by azomethine ylide—thione cycloadditions.

JPR269>. 1,3,5-TriaIIyl-hexahydro-l,3,5-triazine has been used in the preparation of a C-4 unsubstituted azetidinone which is the starting material for the synthesis of penems and cephams <00S289>. A novel method for the preparation of AfW-disubstituted-Af"-nitroguanidines via 2-nitroimino-hexahydro-1,3,5-triazine derivatives has been studied <00TL7187>. 

This process in the synthesis of penem azetidin-2-one-intermediates is performed effectively with Ce(NH4)2(N03)6(CAN) [46,126,136,137],... 

The continued importance of 3-lactam ring systems in medicine has encouraged a number of research groups to investigate their synthesis via a nitrone cycloaddition protocol. Kametani et al. (60-62) reported the preparation of advanced intermediates of penems and carbapenems including (+)-thienamycin (29) and its enantiomer (Scheme 1.7). They prepared the chiral nitrone 30 from (—)-menthyl... 

Penem ff-Lactamase Inhibitors. The synthesis and antibacterial properties of penems have been reviewed. Like die closely related carbapenems, many of the penems are potent antibacterials Additionally, penems are also susceptible to degradation by renal dipeptidase, but to a lesser extent. 

Reactivity Associated with the Biological Activity of Penems 199... 

As the penem nucleus was not described in both CHEC-II(1996) and CHEC(1984), the following sections go through aspects of the systematic reactivity of penems in a qualitative way since their first synthesis, considering each atom of the skeleton. 

Scheme 21 Chemical patterns of penems under nucleophilic conditions.

Scheme 24 Side-chain effects on the selectivity of the mono-S-oxidation of penems.

Since the 2-ethylthiopenem 53 could readily be synthesized from the commercially available acetoxyazetidinone <1982JA6138>, it has become a starting material of choice for further modification at the C-2 position of penems. In the following example (Scheme 29), it allows the access to 2-unsubstituted penems 54 via an oxidation/reduction sequence, and to 2-oxo- 55 and 2,2-dichloropenams 56 <1987CC691>. 

Scheme 40 Two chirons for the synthesis of penems related to penicillins and thienamycin, respectively.

Scheme 44 Synthesis of penems by S or S02 extrusion from 2-thiacephem precursors.

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