Side chain precursor

Chemical Modification. The chemistry and synthetic strategies used in the commercial synthesis of cephalosporins have been reviewed (87) and can be broadly divided into ( /) Selection of starting material penicillin precursors must be rearranged to the cephalosporin nucleus (2) cleavage of the acyl side chain of the precursor (2) synthesis of the C-7 and C-3 side-chain precursors (4) acylation of the C-7 amino function to introduce the desked acylamino side chain (5) kitroduction of the C-3 substituent and 6) protection and/or activation of functional groups that may be requked. 

Scheme 7.2 Semi-synthetic Taxol side-chain precursor.

D-p-Hydroxyphenylglycine and its derivatives are important as side-chain precursors for semisynthetic penicillins and cepharosporines. Yamada and coworkers of our laboratory found that these amino acids can be efficiently prepared from the corresponding 5-monosubstituted hydantoins using the microbial enzyme D-hydantoinase [4]. 

An analogous biomimetic route to stizolobinic acid 15, the biosynthetic side chain precursor to acromelic acid A 5, was also carried out.23 Iron(III)-catalyzed peracetic acid cleavage of the catechol portion of 23 gave alanyl muconic acid 24 which was cyclized and concomitantly deprotected to (i)-stizolobinic acid 15 (Scheme 5). Use of Schollkopf bislactim ether methodology26 also allowed the formation of enan-tiomerically pure 15 by an analogous route. 

Semi-Synthetic Antibiotics. In 1959, Batchelor and coworkers in the Beecham Research Laboratories in England discovered that the penicillin nucleus, 6-aminopenicil-lanic acid (6-APA), accumulated during fermentation when side chain precursors were omitted. This 6-APA could be used for the chemical synthesis of entirely new types of penicillin by coupling with new side chains. Shortly thereafter, several sources of penicillin amidase were found that would cleave the phenylacetyl side chain from penicillin G, thus producing a more economical source of 6-APA. A vast number of synthetic penicillins have been generated, and a few have achieved clinical importance. Several objectives were sought ... 

Chlorella ellipsoidea was found to be able to convert tritium-labelled 5a-ergosta-8,14-dien-3/3-ol and 4 -methyl-5a-ergost-8-en-3/3-ol into ergost-5-en-3)8-ol, but brassicasterol (ergosta-5,22-dien-3/3-ol) was not labelled,180 and thus it is probably not derived from a saturated side-chain precursor. 

Figure 2. Comparison of the dynamic mechanical behavior of the long-side-chain and short-side-chain precursors of similar weight percent comonomer content.

Figure 5. Effect of equivalent weight on the wide angle X-ray scattering curves of the short-side-chain precursor.

Figure 7. Variable temperature wide angle X-ray scattering curves for (A) 1200 EW short-side-chain precursor, (B) 1000 EW short-side-chain precursor, and (C) 1140 EW long-side-chain precursor.

Oxazole triflate 79 was treated with alkynamide 80 under the Sonogashira coupling conditions to give the corresponding side chain precursor 81 [6],... 

An efficient and convergent synthesis of the C(l)—C(ll) side chain 83 of leucascandrolide A has been achieved. The key bond connection was made through the use of a Sonogashira cross-coupling [53, 54]. Oxazolyl triflate 82 was treated with alkynamide 80 using the Sonogashira coupling reactions to provide the side chain precursor 83 (part of the synthesis of leucascandrolide A) [53, 54]. 

The diterpene taxol is used as a potent chemotherapeutic agent in cancer treatment. The hmited supply of the drug from the natural source, the bark of the Pacific Yew (Taxus brevifolia), was overcome by a semisynthetic approach. Taxol is presently manufactured by coupling the advanced naturally occurring taxoid 10-deacetylbaccatin 111, isolated from needles of the more abundant Tdxus baccata, to a synthetic side-chain precursor. 

Implicit in the isolation of penicillins with dilferent side-chains is the formation of a common core. Indeed, dilferent penicillins, such as penicillin V could be produced biosynthetically by adding dilferent side-chain precursors, e.g. phenoxyacetic acid, to the fermentation medium. The common core,... 

The discovery that addition of side-chain precursors to the culture medium favoured production of the penicillin that had incorporated this side-chain allowed the production of a whole range of novel penicillins. Although around 100 such structures were prepared, only one had more desirable properties than penicillin G, and this was christened penicillin V or phe-noxymethylpenicillin. Although this compound was not as potent as penicillin G, it was much more stable to acid (in the stomach), and so could be administered by mouth rather than requiring injection like penicillin G. This was a major advantage for patients, and penicillin V rapidly became the antibiotic of choice for GPs. 

Considerable work went into modification of the strain (through the use of X-rays or UV light to induce mutations) and improvements were made in the technology of isolation and purification. However, the mould was much more difficult to handle and would not accept alternative side-chain precursors as did Penicillium chrysogenum hence, it was impossible to prepare semi-synthetic cephalosporins by this route. In addition, the discovery of methicillin with its resistance to penicillinases negated the advantages of cephalosporin C, and for a while it appeared that this new class of antibiotics was doomed. 

There was a general lack of interest in the penicillins in the 1950s after the exciting progress made during World War II. By that time, it was realized that P. chrysogenum could use additional acyl compounds as side-chain precursors (other than phenylacetic acid for penicillin G) and produce new penicillins, but only one of these, penicillin V (phenoxymethylpenicillin), achieved any... 

During the same period, Sheehan was working toward a total synthesis of penicillins. In 1958, he announced the synthesis of 6-amino-penicillanic acid (6-APA) and its utility for the preparation of new penicillins by acylation (67, 68). (Almost 10 years earlier, this substance had been postulated to be an intermediate in the biosynthesis of penicillins (69, 70). Prior Japanese literature also contained clear suggestions that it had been formed by enzymatic hydrolysis of benzylpenicillin (71) and in fermentations carried out in the absence of side chain precursors... 

Of the nine complementation groups, coq2—coq8 are involved in the synthesis of the benzoquinone, while coql participates in the synthesis of the prenyl side chain. The isopentenyl diphosphate (IPP), required for the biosynthesis of the side chain precursor, hexaprenyl diphosphate (HexPP), for the yeast Q 6 unlike that of E. coli, is derived from the mevalonate pathway. " ... 

E. coli and other Gram-negative bacteria synthesize the IPP and dimethylallyl diphosphate (DMAPP) by the mevalonate-independent pathway, also known as the nonmevalonate pathway (other names are deoxyxylulose phosphate or methylerythritol phosphate pathway). In contrast. Gram-positive bacteria and eukaryotes, including yeast, synthesize the side chain precursors by the mevalonate pathway. Interestingly, Streptomycetes possess both the mevalonate and nonmevalonate pathways. These pathways are the subject of Chapters 1.12, 1.13, 1.14, 1.22. 

To date there is no report about the biosynthesis of aromatic cytokinins. In view of the dissimilarity between the aromatic and the isoprenoid(-derived) A side chains it is likely that their biosynthetic pathways are quite different. Phenylalanine may be considered as a starting compound and benzaldehyde and/or hydroxylated benzaldehydes as immediate side chain precursors. However, the existence of some crossing-points between aromatic and isoprenoid side chain formation cannot be completely excluded. There is also the possibility that the enzymes of adenine and/or purine metabolism, which are not strictly specific, may catalyse some mutual conversions among BA-bases, nucleosides and nucleotides [81]. 

Penicillium chrysogenum on complex solid media, with the result that they were mixtures differing from one another in the identity of the side-chain moiety. When a sufficient supply of phenylacetic acid is present in liquid media, this is preferentially incorporated into the molecule to produce mainly benzylpenicillin (penicillin G in the old nomenclature). Use of phenoxyacetic acid instead leads to phenoxymethyl penicillin (penicillin V). More than two dozen different penicillins have been made in this way, but these two are the only ones that remain in clinical use. The bicyclic penicillin nucleus itself is prepared biosynthetically via a complex process from an acylated cysteinyl valyl peptide. The complete exclusion of side chain precursor acids from the medium produces the fundamental penicillin nucleus, 6-APA, but in poor yield. By itself, 6-APA has only very weak antibiotic activity, but when substituted on its primary amino group with a suitable... 

Another Bristol-Meyers Squibb process represents an enzymatic route for the production of side-chain precursors of Paclitaxel (33, Scheme 10) [69]. Racemic czs-azetidinone acetate (rac-31) is subjected to the hydrolytic treatment of Pseudomonas cepacia lipase (PCL), which is used in its immobilized form on polypropylene beads. Thus, (3R,4S)-acetate 31 can be obtained in high ee as well as the remaining alcohol 32. The process takes place in 150 1 reactors where 1.2 kg mc-31/batch can be resolved with a hydrolysis rate of 0.12 g/lh. Lowering the reaction temperature to 5 °C after full conversion causes (3R,4S)-31 subsequently to crystallize. Due to the immobilization, the enzyme can be reused for at least ten cycles without any loss of activity, productivity, or optical purity of the product. Paclitaxel is finally accessible by further chemical steps. 

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