Chain epimerisation

Many of the older bis-indenyl catalysts are less selective at higher temperatures, which was ascribed initially to a lower selectivity of the insertion reaction itself. More recent work by Busico, based on deuteration studies and again based on very detailed and elegant analysis of 13C NMR spectra of the polymers, has shown that in fact epimerisation of the growing alkyl chain occurs via a series of (3-hydride eliminations and re-insertion reactions [36] involving even tertiary alkyl zirconium species. 

Casey was able to prepare related zirconocene alkenyl complexes according to Scheme 8.18. Alkene coordination was established by a number of NMR techniques. While zwitterionic compounds 38 allowed the determination of the alkene dissociation energy, AG = 10.5 kcal mol , very similar to that of 35. Thermally more stable complexes were obtained by protonation of 37 with [HNMePh2][B(C5F5)4[. Dynamic NMR spectroscopy and line shape analysis allowed the measurement of the barriers of alkene dissociation (AG = 10.7 and 11.1 kcal mol ), as well as for the site epimerisation ( chain skipping ) at the zirconium center (AG = 14.4 kcal mol" ) (Scheme 8.19) [77]. 

F and B NMR spectroscopy. The rate of propene polymerisation with this system was only three times faster than that of 1-hexene. This slow rate contributes to the high regioselectivity of the polymerisation no 2,1-propene misinsertions were detected. H and NMR spectroscopy also provided information about the chain termination mechanism here this occurred by p-H elimination in a first-order process. Polymer chain-end epimerisation, i.e. chirality inversion at the P-carbon of the polymer chain (Scheme 8.31), proceeded via a zirconium tert-alkyl (rather than tt-allyl) intermediate [96c]. 

Primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA), are synthesised via the 5/3-saturation of the cholesterol double bond by enzymes of the hepa-tocyte microsomal fraction, epimerisation of the 3/j-hydroxyl group to the 3a-con-figuration, and further insertion of a 7 -hydroxyl group, with or without a further 12a-hydroxyl group. After shortening of the side chain by three carbons, oxidation of the terminal carbon of the side chain occurs to form the carboxylic group [3]. Alternative metabolic sequences add to the complexity of this metabolic pathway (Fig. 5.4.2). 

Cyorgydeak, Z. Pelyvas, I. F. Monosaccharide sugars - chemical synthesis by chain elongation, degradation and epimerisation. 1998, Academic Press, San Diego, p 450. 

The addition of sulphate occurs very soon after the addition of new residues to growing chains and this determines whether chondroitin 4- or 6-sulphate is produced. Dermatan sulphate is generated at a slightly later point after the addition of new monosaccharides, by epimerisation of blocks of uronic acid residues (in chondroitin-4-sulphate sequences) about C-5. 

The mechanism of chain termination is unknown, but it is possible that it could occur if the A-sulphation/epimerisation sometimes overran polymerisation, to produce a terminal incapable of acting as a further acceptor. 

Penicillins with common amido side chains at C(6) are hydrolysed initially to 3S, SR, 6/ -penicilloic acid without D-incorporation or epimerisation at C(3), C(5) or C(6). However, penicillins without an ionisable NH on the C(6) side chain can undergo epimerisation from 6-P- to 6-a-substituted penicillins faster than ring-opening of the P-lactam (Wolfe and Lee, 1968 Johnson and Mania, 1969). The epimerisation of hetacillins to epihetacillin and that of mecillinam is hydroxide-ion catalysed but shows no general base catalysis (Tsuji et ai, 1977 Baltzer et ai, 1979). 

There have been several reports of the rates and mechanism of epimerisation of asymmetric centres in side chains of P-lactam antibiotics. These have usually involved an asymmetric centre adjacent to the carbonyl carbon of the penicillin C(6) or cephalosporin C(7) amide side chain (Bird et al., 1984 Hashimoto and Tanaka, 1985). 

Present data indicates that chain growth in both gramicidin S and the tyrocidines commences at the D-phenylalanine residue adjacent to proline and that the first step in the synthesis is the conversion of L-phenylalanine to D-phenyldanine. In the case of the tyrocidines, the synthesis then proceeds in order from the amino to the carboxyl terminus to form a linear decapeptide ending with a thiol ester linked leucine. The peptide then cyclises relatively slowly to the final product. Yamada and Kurahashi showed that the epimerisation of L-phenylalanine in the initial step did not require pyridoxal phosphate or FAD and they suggested that the reaction occurs via the thiol ester enzyme bound form (101), Figure 3.18. 

Interestingly, crystal structures of ACPs from type II FAS indicate that the fatty acid acyl chain is sequestered between the helices of the ACP domain (PDB 2FAC and 2FAE), highlighted in Fig. 1.23b [81]. However, this is not believed to be the case for ACPs from type I PKSs, highlighted by the NMR structure of the acyl-ACP from the curacin cluster (PDB 2LIW) [82], Although type I PKS intermediates may not bind in the helical cavity, interactions may indeed occur between the acyl chain and the sides of the heUx bundle. This hypothesis has been somewhat supported by the observation that epimerisation of a-substituted, P-ketothioesters is prevented when tethered to the ACP [83]. 

L-valine to form 5-(L-a-aminoadipyl)-L-cysteinyl-D-valine. This is then cyclised to isopenicillin N. In some microorganisms, such as Cephalo-sporium sp. and Streptomyces clavuligerus, the 8-(L-a-aminoadipyl)-side-chain is epimerised to the D-configuration and the resulting penicillin N is excreted. In Penicillium chrysogenum, and other fungi that produce hydrophobic penicillins, isopenicillin N is converted to one or more penicillins with a monosubstituted acetyl side chain derived from the appropriate monosubstituted acetyl-CoA precursor. Whether this happens by transacylation of isopenicillin N, or deacylation to 6-APA and subsequent reacylation, or by both processes, is not clear. Penicillin biosynthesis is summarised schematically in Fig. 4. 

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