Cepham

3-dithiane behaves like an aldehyde that has undergone umpolung In this case, although aldehydes as electrophiles do not directly react with alkyl halides, the reaction proceeds according to route 1 - 2 — 3 — 4. 

The ketone 4 is formally produced by alkylation of an acyl anion with an alkyl halide. For this reason, 2-lithio-l,3-dithianes are also regarded as synthetic acyl anion equivalents  

Numerous synthetic applications have been described using 1,3-dithianyl anions [133]. For instance, the lithium compounds 2 undergo nucleophilic additions with oxiranes and with carbonyl compounds  

Cepham is a condensed ring system consisting of a 1,3-thiazan and an azetidine ring. The numbering deviates from lUPAC rules, as is the case for penam (see p 159). The molecule is 

Cephalosporins are derived from cepham. Cephalosporin C, a metabolite of Cephalosporium acremonium, was isolated by Newton and Abraham in 1955. Its structure was established in 1961 by chemical methods and X-ray diffraction. It is an acid amide derived from (i )-a-aminoadipic acid and 7-aminocephalosporic acid. The latter is (6i ,7i )-3-acetoxymethyl-7-amino-8-oxoceph-3-em-4-carboxylic acid. 

P-Hydroxyketones and a-hydroxyketones are obtained after dethioacetalization of the addition products 6/7. 

The cephalosporins have a broader spectrum of activity than penicillins, and resistance is less common (see p. 213). The low toxicity of the -lactam antibiotics is due to the fact that the mammalian cell walls lack peptidoglycans and for this reason also lack the 

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Scheme 6 depicts a typical penicillin sulfoxide rearrangement (69JA1401). The mechanism probably involves an initial thermal formation of a sulfenic acid which is trapped by the acetic anhydride as the mixed sulfenic-acetic anhydride. Nucleophilic attack by the double bond on the sulfur leads to an episulfonium ion which, depending on the site of acetate attack, can afford either the penam (19) or the cepham (20). Product ratios are dependent on reaction conditions. For example, in another related study acetic anhydride gave predominantly the penam product, while chloroacetic anhydride gave the cepham product (7lJCS(O3540). The rearrangement can also be effected by acid in this case the principal products are the cepham (21) and the cephem (22 Scheme 7). Since these early studies a wide variety of reagents have been found to catalyze the conversion of a penicillin sulfoxide to the cepham/cephem ring system (e.g. 77JOC2887).

The reaction of a cepham primary amine with 20 eq. of 37% formalin produces the dioxazine in 75% yield. The dioxazine is sufficiently stable to allow the formation of Wittig reagents and to carry out an olefination with formaldehyde. Treatment of the dioxazine with 6 N HCl in CH2CI2 releases the amine in excellent yield. ... 

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. 

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>. 

In general, the inhibitory activity of 7-(2/-pyridylmethylidene) cepham sulfones remains high, but the 7-position carboxylate was low. Similarly, 7-(2/-thiazolidinyl) methylidene cephalosporin 171 lacks significant inhibitory activity. 

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 inline bond of 5,6-dihydro-4//-l,3-oxazines reacts with oxiranes to form bicyclic adducts (Scheme 31) <66AG(E)875) and with ketenes to yield cepham analogues (Scheme 32) (75AP481). 

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 specifically 13C-enriched compounds were useful for the signal identification of the 13C NMR spectrum of this microbial product. Spectral comparison of cephalosporin C with a-aminoadipic acid-N-ethylamide, cephalexin, 3-methyl-7 (2-phenoxyacetamido)-3-cepham and 7-amino cephalosporanic acid led to the total signal identification of this antibiotic. The shifts are listed in Table 5.46. 

Alkoxy-azetidin-2-one has been reported to be transformed into 5-oxa-cepham (VII, Fig. 6) by intramolecular alkylation of the (3-lactam nitrogen atom [255],... 

The mechanism of reaction 285 proposed previously568 has been reinvestigated567 by synthesizing the [4-2H]exomethylene cephalesporin C, 477b, by electrolysis of 476 in a deuteriated buffer. Incubation of 477b with DAOC/DACS provided 475, and also the spiro-epoxide cepham 478. The ratio of 475 to 478 varied with the overall degree of... 

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 accepted conventional nomenclature based on the cepham (the fused /3-lactam-perhydrothiazine system) is used throughout this chapter. Carbon atom bonded to C-3 has been numbered as C-10 (or C-3 ). Stereochemistry at C-7 is specified either as absolute configuration R/S, or as a//3 depending on the orientation of the substituent, below or above the plane, respectively. The above abbreviated common names and numbering for the cephalosporins should not be confused with the IUPAC systematic nomenclature as used by Chemical Abstract, which, for example, designates 7-ACA as (6/3,7/3)-3-(acctoxymcthyl)-7-amino-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. 

The thermochemistry of some cephams and cephems has been investigated by high-level ab initio methods. Particular attention has been paid to estimate the magnitudes of amide resonance and ring strain <2006JPCA10521>. Determination of the kinetic parameters for interactions of three cephalosporins with PBPs has been reported <2006JBC10035>. 

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