Cepham synthesis

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. ... 

Lactam Antibiotics.—Intramolecular Wittig reactions continue to be used in penam and cepham synthesis, e.g., (121). However, problems can arise. The phosphorane (122) forms the ceph-2-em (123) rather than the expected ceph-3-em and, unlike the corresponding c/j-isomers, the phosphoranes (124) do not give penams (125), but rather thiazoles and oxazolines, presumably due to the instability of the initially formed penams. ... 

Acetal handle 78 synthesized from Merrifield resin and 4-hydroxy-benzaldehyde was applied to the solid-phase synthesis of carbohydrates and 1-oxacephams (Scheme 41) [90]. For the latter, a 1,3-diol was initially anchored to the support to form a cyclic acetal. A ring opening reaction with DIBAL generated a resin-bound alcohol which was converted to the corresponding triflate for A-alkylation with 4-vinyl-oxyazetidin-2-one. A Lewis acid catalyzed ring closure released 1-oxa-cephams from the support. 

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>. 

Ozonolysis has also been demonstrated to play a role in the production of another important intermediate in (3-lactam synthesis, hydroxyl-cepham sulfoxide esters 92.84 Ozonolysis plays a role in the conversion of a methylene group in compound 93 into the required hydroxy group in compound 92 (Scheme 11.25). 

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. 

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. 

Mori et al. have extended their palladium-catalysed ene-halogenocyclization methodology to provide a useful synthesis of the oxa- and carba-homocepham analogues (281) which can be closed readily with base to afford the corresponding cyclopropa-oxa- or -carba-cephams (282). 151... 

Starting from compounds with a cepham structure obtained by a partial synthesis, numerous semisynthetic cephalosporins have been prepared, mainly by... 

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). 

Similar results have been observed with heteroatomic radicals such as aminyl radical (in an example already discussed in Section VIII.3.A, Scheme 44, and more recently as an important step in the total synthesis of the alkaloid dendrobine ) and with the carboxamidyl radical. The intramolecular addition of thiyl radicals to cyclohexenes generally gives a mixture of the (Cy5) and (Cy6) products. In the same way, intramolecular addition to an unsaturated chain of a thiyl radical on a cyclohexane ring also gives a mixture of (Cy5) and (Cy6) products. This lack of selectivity is in accord with the behavior of unsaturated thiyl radicals discussed in Section VIII.4. An interesting exception of possible relevance to the biosynthetic route to cepham has been discussed in Section VIII.4.B (Scheme 58). The behavior of ethylenic aminothiols such as 107 under free radical initiation (Scheme 52, Section VIII.4.A) has been generalized to compounds such as 267, which affords 268 in 87% yield (Scheme 109). 

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 more recent synthesis of 3-methylenecephams from cephalosporins utilizes mercury salts in a metal-assisted reaction with 3-methyl-3-hal-ocepham ester sulfoxides. Although ordinarily dehydrohalogenations of 3-halo-3-methylcephams lead to the thermodynamically more stable 3-methyl-2-cephems and -3-cephems, chemists at Dista Products Limited (England) discovered that electrophilic mercury salts specifically led to 3-methylenecephams (Corfield and Taylor, 1978). When p-nitrobenzyl 7-phenoxyacetamido-3-methyl-3-bromo(or 3-iodo)cepham-4-carboxylate 1-oxide (47) was treated with mercury(I or II) perchlorate in dimethox-yethane for 18 hr at room temperature, p-nitrobenzyl 7-phenoxyacetam-ido-3-methylenecepham-4-carboxylate 1-oxide (48) was obtained in 75% yield. No other metal salt (in a variety of solvents) effected this transformation. Their view of the mechanism of this reaction is detailed later in this chapter. 

The synthesis of a methylene cepham by cyclization of an allylic halide has been described by the Lilly group. Reaction of the chloride (361) with potassium iodide in acetone gave a 50% yield of (362). 

Edwards, J. A., A. Guzman, R. Johnson, P. J. Beeby, and J. H. Fried A New Total Synthesis of ( )-Desacetylcephalothin Lactone. A Synthesis of Novel Furo-[3,4-C]-cephams. Tetrahedron Letters 1974, 2031. 

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). 

Baldwin and Christiehave also used optically active cysteine in a stereo-specific synthesis of penams and cephams. These authors provide an interesting discussion of the lability of certain carbon-sulphur bonds [e.g. bonds (a) and b) in structure (7)], and the application of stereoelectronic control in facilitating the cleavage of such bonds in a desired sense [viz. in Scheme 2, bond b) is broken in preference to bond (a)]. A retrospect and prospect for j8-lactams has been published. 

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 Hoechst group have developed a synthesis of novel cephem systems which also utilizes a monocyclic azetidine as the starting point for the elaboration of the heterocyclic ring. Displacement of acetate from azetidinone (162) by the complex thiol (163) gave the cepham carbinolamide (164) dehydration produced the cephem (165). > Functionalization at C-7, e.g. (166) -> (168), could be achieved by bromination followed by displacement by azide ion. Using this general approach, compounds (169) and (170) were prepared. ... 

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