Side-chain exchange

While screening for p-lactam antibiotics stable to p-lactamases, a strain of Streptomyces lactamdurans was found to contain several such agents which have a 6-a-methoxy group whose electronic and steric properties protect the antibiotic from enzymatic attack. Cephamycin C (29a), one of these substances, is not of commercial value, but side chain exchange has led to much more potent materials. Of the various ways of effecting this transformation, one of the more direct is to react cephamycin C with nitrous acid so that the aliphatic diazo product (29b) decomposes by secondary amide participation giving cyclic iminoether 30. The imino ether moiety solvolyzes more readily than the p-lactam to produce 7-aminocephamycinic... 

The same reaction was studied by Roush et al. [50]. However, in this case, the cyclization of anti-allylsilane 126 resulted in the production of only cis-2,6-disubstituted dihydropyrans 127. No trans-2,6-disubstituted dihydropyrans 128 were formed. Moreover, significant amounts of adducts 129 and 130 were observed (Scheme 13.45). These products probably originate from a side-chain exchange process (vide infra). 

In the laboratory of R.D. Rychnovsky, the segment-coupling Prins cyciization was utilized for the total synthesis of (-)-centrolobine. This approach avoided the common side reactions, such as side-chain exchange and partial racemization by reversible 2-oxonia Cope rearrangement, associated with other Prins cyciization reactions. The substrate -acetoxy ether was subjected to SnBr4 in DCM, which brought about the formation of the all-equatorial tetrahydropyran in good yield. 

Sulfides can be a-halogenated. 5-Chloro-2-methylthiopyrimidine was monochlorinated in the methyl group (462) using sulfuryl chloride, and the chlorine in the side-chain exchanged with iodine (463) by heating with sodium iodide in acetone <82CSI1>. 

The main feature of the reactivity of alkylpyridines is deprotonation of the alkyl group at the carbon adjacent to the ring. Measurements of side-chain-exchange in methanolic sodium methoxide, 4 2 3, 1800 130 1, and of pK values in tetrahydrofuran each have the 7-isomer more acidic than the a-isomer, both being much more acidic than the / -isomer, though the actual carbanion produced in competitive situations can depend on both the counterion and the solvent. Alkyllithiums selectively deprotonate an a-methyl where amide bases produce the... 

The main feature of the reactivity of alkylpyridines is deprotonation of the alkyl group at the carbon adjacent to the ring. Measurements of side-chain-exchange in methanolic sodium methoxide, 4 2 3, 1800 130 and of pK values... 

The occurrence of deacetoxycephalosporin C (236c) and the 7a-methoxy derivative of cephalosporin C (236f) provide an alternative route to the Morin method [14,74] for the preparation of cephalosporins of clinical usefulness. The side-chain exchange can be solved either using deacylation—reacylation methods [5,193—196] or via a diacyl derivative, successfully introduced for the preparation of cephamycin analogues [1.97]. 

Present knowledge may be summarized as follows. After the appearance of LLL-ACV, the next compound isolated is isopenicillin N. This most probably isomerizes to penicillin N which, after enzymatic hydrolysis, serves as the source of different penicillins and probably 6-APA. In the case of cephalosporins, an isocephalosporin N intermediate appears likely, although its existence has not been verified. Anyway, if Cephalosporium-type synthesis takes place, side-chain exchange does not occur, as the cells probably lack the appropriate enzymes. Recent problems regarding this pathway are that no definite enzymes have been found which are responsible for the isopenicillin N -> penicillin N side-chain... 

The standard synthesis method features side-chain chlorination of a methylpyridine (picoline), followed by exchange-fluoriaation with hydrogen fluoride or antimony fluorides (432,433). The fluoriaation of pyridinecarboxyHc acids by sulfur tetrafluoride (434) or molybdenum hexafluoride (435) is of limited value for high volume production operations due to high cost of fluorinating agent. 

Factor XIII. Factor XIII circulates in the blood as a zymogen composed of two pairs of different polypeptide chains designated A and B. Inert Factor XIII has a molecular weight of 350,000 daltons and is converted to its active transglutaminase form in the presence of thrombin and calcium. Activated Factor XIII, Xllla, induces an irreversible amide exchange reaction between the y-glutamine and S-lysine side chains of adjacent fibrin... 

The side chain in spirostan derivatives (44) can undergo certain exchange reactions which are characteristic for this skeleton. In general, this spiro-ketal moiety is quite stable under alkaline or neutral conditions, but in acidic media it undergoes a reversible opening of ring F (45 and 46). In... 

Side chain fluonnaied aryl isocyanates are an important group of substances used in the manufacture of biologically active compounds The synthetic routes to the meta- and para trifluoromethylphenyl isocyanates permit the chlorine-fluonne exchange with hydrogen fluoride to proceed under moderate conditions and in a virtually quantitative manner (equation 22)... 

The Cornforth rearrangement involves the thermal interconversion of 4-carbonyl substituted oxazoles, with exchange between the C-C-O side-chain and the C-C-O fragment of the oxazole ring. These reactions generally involve compounds where a heteroatom (-OR, -SR, -Cl) is attached to the 5-position (R2) of the starting oxazole. 

Propargylsilanes can also be employed in the Sakurai reaction. For example the enone 6, containing a propargylsilane side chain, undergoes an intramolecular Sakurai reaction, catalyzed by an acidic ion-exchange resin—e.g. Amberlyst-15—to give stereoselectively the bicyclic product 7 in good yield ... 

In general, isotopic exchange is both expensive and difficult. In the case of many room-temperature ionic liquids, however, the manufacture of deuterated ionic liquids is relatively easily achievable. For example, the general synthesis of l-allcyl-3-methylimidazolium salts is shown in Scheme 4.1-1 [2]. This methodology allows maximum flexibility in the deuteration on the imidazolium cation that is, it can be either ring or side chain deuteration or both. 

In Figure 7 the peak at m/e 142, which shifts to m/e 148 in the mass spectrum of 10a and remains at m/e 142 in the spectrum of the D20-exchanged analog, probably arises by the loss of the C-3 and C-4 side chains. This ion could fragment further by eliminating a methyl radical from the ketal to give an ion at m/e 127 which shifts to m/e 130. 

After a strain improvement and development programme similar to, but more complicated than that of penicillin, the D-a-aminoadipyl side chain containing cephalosporin C was obtained by large scale fermentation. However, cephalosporin C could not be isolated as easily as penicillin G or V. Due to its amphoteric nature it is soluble at any pH in the fermentation broth. Several costly isolation procedures involving ion-exchange chromatography have been developed, as a result of which cephalosporin C is much more expensive than penicillin G. 

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