Cepham derivatives synthesis

Just et attempted the synthesis of the oxacepham derivatives (167) as outlined below. This synthesis was planned as a model for analogous syntheses of cepham derivatives. Its design is ingenious, but it was not a complete success, because (164) did not react with NH3 to form (165) it gave (166). The ring closure with NH3 might have worked better with (163). Presumably discouraged by this result of their model study, these authors terminated their efforts in this field. 

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). 

The addition of thiyl radicals to alkenes and alkynes can also occur in an intramolecular fashion to lead to sulfur heterocycles. Surzur and co-workers [33, 34] have shown that the pent-4-enylthiyl radical yields both five- and six-mem-bered rings. The six-membered rings were formed in much higher yield than the five-membered rings (ca. 10 1). Since these cyclizations are reversible, the product distribution reflects a thermodynamic control (Scheme 5). The same type of reactions can be initiated by photolysis of disulfides, as demonstrated by Maki and Sako in the synthesis of cepham and penam derivatives [35]. The photoreaction of (5) is concentration dependent at low concentrations cepham derivatives are formed almost exclusively via 6-endo cyclization, whereas at high concentrations penam derivatives predominate. 

A combination of 1,2- and 1,5-bond cleavage rearrangements has permitted the synthesis of sulphur-free cepham derivatives. Rearrangement of penicillin to anhydropenicillin (133) (SOClj, EtgN) followed by chlorinolysis and esterification gave the sulphur-free azetidinone (134). Monobromination (NBS),... 

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>. 

Hegedus, L.S., Schultze, L.M., Toro, J., and Yijun, C, Photolytic reaction of chromium and molybdenum carbene complexes with imines. Synthesis of cepham, oxapenam, and oxacepham derivatives. Tetrahedron, 41, 5833, 1985. 

Synthesis has enabled, for better or worse, the production of compounds capable of producing powerful biological responses in living organisms. Early on, these were usually natural compounds or derivatives thereof. Notable examples are the myriad of folkloric agents, the P-lactam antibiotics (e.g., cephams and penamsX steroid hormones, and paclitaxel (see below). 

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