Chemical syntheses, source

The molecules comprising small-molecule screening collections maybe obtained from natural (natural products) or nonnatural (chemical synthesis) sources [4]. 

An in vitro ensymatic synthesis of sucrose was carried out ia 1944 (5). A successful chemical synthesis was performed by Lemieux and Huber (6) ia 1953 from acetylated sugar precursors. However, the economics and chemical complexities of both processes make them unlikely sources of supply. 

Cocoa butter substitutes and equivalents differ greatly with respect to their method of manufacture, source of fats, and functionaHty they are produced by several physical and chemical processes (17,18). Cocoa butter substitutes are produced from lauric acid fats such as coconut, palm, and palm kernel oils by fractionation and hydrogenation from domestic fats such as soy, com, and cotton seed oils by selective hydrogenation or from palm kernel stearines by fractionation. Cocoa butter equivalents can be produced from palm kernel oil and other specialty fats such as shea and ilHpe by fractional crystallization from glycerol and selected fatty acids by direct chemical synthesis or from edible beef tallow by acetone crystallization. 

Fig ure 6-12. Profiles of equilibrium conversion Xg versus temperature T for ammonia synthesis. (Source Schmidt, L. D., The Engineering of Chemical Reactions, Oxford University Press, New York, 1998.)... 

There are a large number of naturally occurring molecules which have not yet been obtained by chemical synthesis. A convenient source of information on such compounds is The Dictionary of Organic Compounds, Fifth Addition (1982) and Supplements 1-5, published as a multivolume series by Chapman and Hall, New York and London J. Buckingham, Executive Editor. This compendium contains references to syntheses which are not included in this collection, especially those involving simpler target structures. 

A number of examples of the use of molten pyridinium chloride (mp 144 °C) in chemical synthesis are known, dating back to the 1940 s. Pyridinium chloride can act both as an acid and as a nucleophilic source of chloride. These properties are exploited in the deallcylation reactions of aromatic ethers [4]. An example involving the reaction of 2-methoxynaphthalene is given in Scheme 5.1-2 [16, 18], and a mechanistic explanation in Scheme 5.1-3 [18]. 

When compared to traditional chemical synthesis, processes based on biocatalysts are generally less reliable. This is due, in part, to the fact that biological systems are inherently complex. In bioprocesses involving whole cells, it is essential to use the same strain from the same culture collection to minimise problems of reproducibility. If cell free enzymes are used the reliability can depend on the purity of the enzyme preparation, for example iso-enzyme composition or the presence of other proteins. It is, therefore, important to consider the commercial source of the enzyme and the precise specifications of the biocatalyst employed. 

Figure 2 Comparison of cloning and expression methods. In the conventional strategy (left), dehydrogenase genes obtained by PCR amplification of the original source DNAs are cloned into overexpression plasmids and verified by sequencing. Those with the desired structure are individually transformed into suitable host strains and the proteins are obtained, either as crude extracts or as purified samples. In the proposed streamlined approach (right), full-length dehydrogenase genes obtained by chemical synthesis are used directly in coupled transcription/translation reactions to obtain the proteins of interest.

As the first isolable intermediate in the bioconversion of arachidonic acid into prostaglandins and thromboxanes (Eq. 3), PGG2 is a bicyclic peroxide of immense biological importance. It is difficult to obtain pure from natural sources and the presence of the 15-hydroperoxide group adds a further dimension of chemical lability to that associated with the 9,11-peroxide bridge. The chemical synthesis of PGG2 is thus a landmark in prostaglandin chemistry. It also represents a pinnacle of success for the silver-salt route to bicyclic peroxides. 

An alternative to chemical synthesis is to use human CYP enzymes to generate the desired human drug metabolites. Various means of making human P450s have been used, all with certain drawbacks [81]. The most common source is pooled HLMs, which has been described in detail previously, but these microsomal preparations contain a mixture of many different enzymes, and their cost, batch-to-batch variability in activity and restrictions on availability can limit the usefulness of HLMs for preparative synthetic work. These limitations can become particularly acute when the required amount of a pure metabolite exceeds 5-10 mg. 

Kojic acid, 5-hydroxy-2-(hydroxymethyl)-4//-pyran-4-one1 (II), is produced from carbohydrate sources in an aerobic process by a variety of microorganisms. The acid was discovered in 1907, its structure was established in 1924, and its chemical synthesis from D-glucose was achieved in 1930. Since then, a considerable amount of study has been devoted to the biosynthesis of kojic acid, and numerous publications have dealt with its chemical and biological properties. After nearly half a century, kojic acid remains a scientists curiosity, without industrial importance. It con-... 

In addition to chemical-based drugs, a range of pharmaceutical substances (e.g. hormones and blood products) are produced by/extracted from biological sources. Such products, some major examples of which are listed in Table 1.2, may thus be described as products of biotechnology. In some instances, categorizing pharmaceuticals as products of biotechnology or chemical synthesis becomes somewhat artificial. For example, certain semi-synthetic antibiotics are produced by chemical modification of natural antibiotics produced by fermentation technology. 

Trace amounts of bromine in sodium diclofenac, sodium (2-[(2, 6-dichlorophenyl)amino] phenyl acetate, have been determined using XRF [82], since the drug substance should not contain more than 100 ppm of organic bromine remaining after the completion of the chemical synthesis. Pellets containing the analyte were compressed over a boric acid support, which yielded stable samples for analysis, and selected XRF spectra obtained in this study are shown in Fig. 7.19. It was found that samples from the Far East contained over 4000 ppm of organic bromine, various samples from Europe contained about 500 ppm, while samples from an Italian source contained less than 10 ppm of organic bromine. 

Oligosaccharides and glycoconjugates in living cells often exist as closely related mixtures. Their isolation from natural sources in homogeneous form is therefore very difficult, involving tedious purification and difficult characterization. This sequence of steps tends to result in low yields. This difficult situation presents chemical synthesis with a major opportunity to positively affect progress in the biochemical understanding of the processes described above.4... 

Source Cabri W, Di Fabio R. From Bench to Market The Evolution of Chemical Synthesis, Oxford University Press, Oxford, 2000. 

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