Penams, synthesis

Scheme 46 Azomethine ylide strategy for penam synthesis.

This penam synthesis was improved by the use of R = All and R = All or CH2C02Et. In these recent 3-lactam syntheses the Ugi reaction was executed in trifluoroethanol, a magic solvent for such conversions. In a recent carbacephem synthesis ethylene glycol/glycerol gave very good results as the sol-... 

They demonstrated the effectiveness of the alkylation of enolates (160) + (161) - (162) for preparing precursors of penam and cepham derivatives. The penam synthesis by Schutz and Ugi, as well as the cepham synthesis (168) - U73) profited from Just et at. immensely. ... 

In our previous syntheses of penam (ref. 17) and cepham derivatives (ref. 18) one of the less satisfactory features was the use of the methyl group as carboxy protection. In a recent modification of our penam synthesis (ref. 17) (Scheme 7) the allyl group has been shown to be superior to the methyl group, because of its very mild deblocking conditions (ref. 19). 

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),... 

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>. 

Different strategies (I, II, III, and IV) for the synthesis of penams, the backbone of penicillins, are schematically outlined in Scheme 2. 

Penams. The key step in a synthesis of 6-methyl-4-thia-l-azabicyclo-[3.2.0]heptane-7-one (3) is formation of the p-lactam ring by reaction of 2, prepared... 

The copper(I)-catalyzed addition of Grignard reagents to P-(alkylthio)-a,p-unsaturated esters is the preferred protocol for substitution of the alkylthio substituent, e.g. (310 - 311),21 while potassium enolates add to a-ketoketene dithioacetals, e.g. (312 — 313), without dialkylation (Scheme 96).218b,c Further, Hanessian reports an expedient synthesis of penam (315) via intramolecular cyclization of the (3-lactam nitroalkene (314), but loss of the methylthio moiety does not occur spontaneously (Scheme 97).219... 

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...

The possibilities of transformations at the C-2 position are relatively poor. Nonetheless, penicillins can be converted into clavulanic-like derivatives <1983TL2563, 1987TL2283> by changing the hybridization of C-2 from sp3 to sp2. Indeed, 2-carboxylate penam /3-sulfoxides, readily obtained from penicillin V, enable a decarboxylative Pummerer reaction to provide 2-exomethylene penams 13, as well as penems, their endocyclic tautomers (Scheme 9) <1987CC81>. On the other hand, 2-oxo-, 2-thioxo-, and 2-iminopenams <1996CCA1367> could be obtained by total synthesis (see Section 2.03.11.4) and further used for the preparation of 2-heterosubstituted penems (see Section 2.03.6.4). 

In a trend to develop new antibiotics and /3-lactamase inhibitors, comparable to that for the penam, the synthesis of new penem structures and their oxidation reactions on the S-1 atom have been jointly investigated during the last three decades. The first isolated penem sulfoxide was reported in 1979 <1979TL3777>. However, its synthesis was not performed by direct oxidation of a penem but a 2-exomethylene penicillanate 41 (1-thioclavulanic ester), involving a migration of the double bond to afford the penem nucleus (Scheme 23). 

Scheme 43 Synthesis of penams and penems by a ring-contraction approach.

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

The first highly stereocontrolled total synthesis of a natural penicillin was reported 2 years later by Baldwin et al. <1976JA3045>. In this case, the methodology relies on the formation of the fi-lactam ring before the thiazolidine ring closure, via the sulfenic acid intermediate 97 (Rz = OH), which gives electrophilic attack on the double bond to produce a penam sulfoxide 98 (see Section 2.03.5.3) (Scheme 52). A similar route has been developed independently by Kishi for the total synthesis of 6cr-methoxy penicillin derivatives <1975JA5008>. 

---