Carbapenems

The p-lactam ring is formed by an acyl-adenosine monophosphate ester. The 2-oxoglutarate-dependent oxygenase enzyme, carbapenems synthase, dehydrogenates the pyrroHdine ring and also epimerizes the fused ring at position 5. However, the mechanism involved in this conversion is not yet clear [116]. 

In addition to the p-lactam ring, the carbapenem nucleus contains an unsaturated five-membered ring as for penicillins but with the sulfur atom of 

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Fig. 5.5 A, clavulanic acid B, latamoxef C, 1-carbapenems D, olivanic acid (general structure) E, thienamycin F, meropenem G, 1-carbacephems H, loracarbef.

Hammond ML. (2004) Ertapenem A Group 1 carbapenem with distinct antibacterial and pharmacological properties. J Antimicrob. Chemother 53 ii7-9. 

The 1-carbapenems (Fig. 10.5C) comprise a family of fused P-lactam antibiotics. They are analogues of penicillins or clavams, the sulphur (penicillins) or oxygen (clavams) atom being replaced by carbon. Examples are the olivanic acids (section 2.5.1) and thienamycin and imipenem (section 2.5.2). 

Silyl methods of penicillin and cephalosporin modification 82KGS147. Synthesis of 1-carbapenems and 1-carbapenams 83YGK62. 

Prior to the discovery of the naturally occurring 1-carbapenem nucleus (94), a synthesis of the racemic material had been described (J06). The 4-acetoxyethyl substituted p-lactam (124) derived from (113) was converted by standard procedures to the phosphorane (125). Hydrolysis to the alcohol (126) followed by oxidation resulted in cyclisation to the bicyclic ester (127). 

The Beecham group found that thiols add readily to the double bond of C(2)-unsubstituted 1-carbapenems, and this approach has been used to synthesise racemic PS-5 130). The A -silylated 4-allylazetidinone (157) was alkylated with ethyl iodide and the product (158) transformed to the phosphorane (159). Cyclisation to (1 ) was followed by reaction with acetamidoethane thiol to form three isomers of the addition product (161). These could be converted to the carbapenem (162) on reaction with iodobenzene dichloride in the presence of pyridine. Isomerization to (163) and deprotection afforded the racemic natural product. The ester (163) has also been prepared via the diazo-intermediate (164) derived from the 4-acetoxy azetidinone (165) 131). A total synthesis of chiral PS-5 has been achieved using the resolved acid (166) (132). This was converted to (164) and then to optically pure PS-5. It has also been possible to synthesise PS-5 and PS-7 from the olivanic acid derivatives MM 17880 and MM 13902 133). The benzyl ester of ( )-MM 22381 was obtained from the azabicyc-loheptane (167) derived from the addition of acetamidoethane thiol to the appropriate C(2)-unsubstituted nucleus 108). 

Alkynes undergo stoichiometric oxidative reactions with Pd(II). A useful reaction is oxidative carboiiyiation. Two types of the oxidative carbonyla-tion of alkynes are known. The first is a synthesis of the alkynic carbox-ylates 524 by oxidative carbonylation of terminal alkynes using PdCN and CuCh in the presence of a base[469], Dropwise addition of alkynes is recommended as a preparative-scale procedure of this reation in order to minimize the oxidative dimerization of alkynes as a competitive reaction[470]. Also efficient carbonylation of terminal alkynes using PdCU, CuCI and LiCi under CO-O2 (1 I) was reported[471]. The reaction has been applied to the synthesis of the carbapenem intermediate 525[472], The steroidal acetylenic ester 526 formed by this reaction undergoes the hydroarylalion of the triple bond (see Chapter 4, Section 1) with aryl iodide and formic acid to give the lactone 527(473],... 

Depending on the substituents of l,6-enynes, their cyclization leads to 1.2-dialkylidene derivatives (or a 1.3-diene system). For example, cyclization of the 1,6-enyne 50 affords the 1.3-diene system 51[33-35]. Furthermore, the 1.6-enyne 53, which has a terminal alkene, undergoes cyclization with a shift of vinylic hydrogen to generate the 1,3-diene system 54. The carbapenem skeleton 56 has been synthesized based on the cyclization of the functionalized 1,6-enyne 55[36], Similarly, the cyclization of the 1,7-enyne 57 gives a si -mem-bered ring 58 with the 1,3-diene system. 

ANHBIOHCS - BETA-LACTAMS - CARBAPENEMS AND PENEMS] pol 3) 1-Dehydropiperidine [28299-36-7]... 

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