Penam derivatives

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... 

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>. 

Other potential elastase inhibitors based on the /3-lactam nucleus include cephem derivatives [64], penam derivatives [65], as well as novel bicyclic /3-lactams [66]. Monocyclic y-lactams (5.21) with appropriated substitution might also yield useful inhibitors [67]. 

The synthesis of penams has been reported to be conveniently prepared from Meldrum s acid [55] and thiazoline [56]. The substrates were reacted in dry benzene containing dry HC1 (gas) at reflux to afford a series of penam derivatives with aryl, n-hexyl. and cyclohexyl substituents (Scheme 9), [57]. 

Mata et al. also described a new and robust protocol for the solid-phase synthesis of 2(3-methyl substituted penam derivatives using Merrifield resin as support [210]. The work begins with immobilization of 6,6-dibromopenicillanic acid (171) onto Merrifield resin followed by oxidation with m-chloroperbenzoic acid (MCPBA) to obtain the resin-bound sulfoxide (173). The key-step involves the thermal rearrangement of the corresponding penicillin sulfoxide (Scheme 49). 

Scheme 49 Solid-phase synthesis of 2-P-methyl substituted penam derivatives...

Scheme 50 Last step of Sheehan s total synthesis of penam derivatives.

Penam derivatives with different C-2 and C-3 substituents were synthesized by the group at Astra Lakemedel Co. [19,20] (14) using a new /3-lactam ring-closure, but they do not report any activity data either. 

A number of differently-substituted penam derivatives (79f,g) have been obtained as intermediates in the total syntheses developed mainly by the Woodward-Heusler and Sheehan groups, but no exact biological data are known. For the corresponding hydroxy penams and cephems, see [55] and [142]. The 3-hydroxypenam is in equilibrium with the open form ((81) (82)), but its methyl ether (83) and acetyl derivative (84) can be prepared pure. It is most surprising that the derivative (85) possesses an appreciable biological effect MIC values, S. aureus 6.3 jug/ml, Strept. 

The first preliminary studies towards the synthesis of penam derivatives by the Ugi reaction were carried out roughly 30 years ago. 3-Thiazoline derivatives (153) were allowed to react with isocyanides in the two-phase system water/petroleum ether to yield up to 95% of the penam derivatives (154). 

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. 

Schutz and Ugi129 developed the synthesis of penam derivatives (155 R = Me) - (159 R4 = Bu ). This penam synthesis was improved by the use of R = All and R4 = All or CHzCChEt.122 In these recent 3-lactam syntheses the Ugi reaction was executed in trifluoroethanol, a magic solvent for such conversions.73125 In a recent carbacephem synthesis ethylene glycol/glycerol gave very good results as the solvent."811... 

The fact that 43 is readily available the through the photolysis of 44 (ref. 28) suggests the idea to synthesize carba-penam derivatives 41 by 4CC of 42. 

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