Of cepham derivatives

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. 

Morin et al. showed that the reaction of penicillin sulfoxides (162) with refluxing acetic anhydride leads to formation of the ring-expanded cepham derivatives (165) and compound (166 Scheme 41). Although this transformation was effected under Pummerer conditions, it occurs by a different mechanism, hence the term Abnormal Pummerer reaction . 

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. 

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. 

The reaction of the thiazoline sulfur with iodine depended upon the side chain and reaction conditions (Micetich and Morin, 1976). The thiazoline (162) reacted to give complex A or B depending upon the stoichiometry. Addition of water to complex A gave the symmetrical disulfide (246) which on further iodination yielded the 3-iodocepham (247). Complex B with water gave 247 directly. Other workers have reported catalytic effects of free radical initiators or heavy metal oxides in this transformation (W. Germ. Patent 2,534,811 Micetich and Morin, 1977). It was postulated that the sulfenyl iodide intermediate (248) was obtained on aqueous treatment of the original complexes which then spontaneously cyclized to the cepham derivative. 

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),... 

The CJS insertion reaction was suppressed completely upon catalytic decomposition of diazoketones 361, where the sulfur substituent was alkyl, acyl or thioacyl. It is presumed that sulfonium ylides occur as intermediates which give cepham (or cephem) derivatives in all cases270,343) rather than products of a Stevens rearrangement. 

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>. 

The cephalosporins, discovered in the 1950s, are produced by various species of the mold Cephalosporium. Cephalosporin C (9.46) is the prototype of these antibiotics, and its structure shows a close similarity to the penam stmcture. The 5-thia-l-azabicyclo[4.2.0] octane ring system is therefore called the cepham ring. The parent compound carries the aminoadipate side chain, which can be cleaved to supply the 7-amino-cephalosporanic acid. This amine can easily be acylated and thus forms the basis of many useful derivatives. The 3-acetoxymethyl substiment is also amenable to modifications. 

The tetrahydro compounds are strongly basic and may be jV-alkylated directly with alkyl halides (64T1173). A number of N-nitroso derivatives have been made by the oxidation of tetrahydro- 1,3-oxazines with peracids (74T3315). Sequential treatment of the oxazine (77) firstly with diketene and then with 4-methyIbenzenesulphonyl azide and triethylamine gives the diazoketone (78), which on irradiation with UV light yields the cepham (79) exclusively (79CC846). 

The 2 + 2-cycloaddition of chlorosulfonyl isocyanate with chiral alkoxyallenes, derived from ethylidene and benzylidene L-erythritol and D-threitol, produces azetidi-nones that are readily converted into the corresponding tricyclic cephams. NMR and CD spectroscopy were used to assign the absolute configurations of the azetidinones... 

The ADEPT approach has been recently investigated as a means of overcoming the side-effects of using taxol to treat breast cancer by utilizing a /Mactamasc enzyme antitumor antibody conjugate and a cepham sulfoxide derivative of taxol (PROTAX). The localized /Mactamase enzyme, which is not normally found in any other tissues, ensures selective release of taxol at the tumor site. The prodrag is almost as effective as... 

The naturally-occurring penicillins and cephalosporins, and thousands of their semisynthetic derivatives, are based on two fundamental structural units, the penam (1) [2] and cepham (2) [3] systems. The numbering of these bicyclic systems is different from that usual for heterocycles [4], The numbering system for penicillin is also used in the case of cephalosporins and other derivatives, including new members of the group of jS-lactam antibiotics [3]. 

In spite of the fact that these compounds are not so widely known as the classical semisynthetic derivatives, a large number of 5-substituted penams and 6-substituted cephems and cephams have already been produced. These compounds are usually inactive, due to the lack of peptide character and other essential substituents (e.g. the 3(4)-carboxyl... 

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