Technological products total synthesis

The total synthesis of ( )-estrone [( )-1 ] by Vollhardt et al. is a novel extension of transition metal mediated alkyne cyclotrimeriza-tion technology. This remarkable total synthesis is achieved in only five steps from 2-methylcyclopentenone (19) in an overall yield of 22%. The most striking maneuver in this synthesis is, of course, the construction of tetracycle 13 from the comparatively simple diyne 16 by combining cobalt-mediated and ort/io-quinodimethane cycloaddition reactions. This achievement bodes well for future applications of this chemistry to the total synthesis of other natural products. 

There is a tendency to reserve semisynthetic and totally synthetic methods for the introduction of bonds and residues that cannot be specified by the genetic code. The present chapter will concentrate on these aspects. However, semisynthesis can have a role to play even when building structures that are completely accessible to the genetic code. The first industrial challenge for the emerging technologies of total chemical synthesis, recombinant protein expression, and semisynthesis was the economic production of human insulin in pharmaceutically usable quantity and quality. The semisynthetic human insulin that was made from porcine insulin proved exceptionally convenient to produce, and was the first introduction to human insulin for very many patients. 

Table 15.1. Total synthesis of environmentally, medically, and technologically relevant natural products ( = rarity of the natural product ANR = application of new reactions ANS = application of new strategies ITS = industrial synthesis MRS = most rapid solution S and S/H = molecular and specific molecular complexity, respectively)...

In conclusion, although the large-scale total synthesis of (2 R,4 R,8 R)-a-tocopher-ol (RRR-3) is (so far) not a success story within the area of industrial total syntheses of natural products, the incontestably high potential and usefulness of catalytic methods again became evident. If there ever will be a chemical solution, the key technology contributing decisively to this would very probably have to be labeled as the tide of this book asymmetric catalysis on industrial scale. 

Product yield is very often a factor that limits the development of a natural product as a lead compound. Traditionally, both chemical synthesis and classical strain improvement technologies have been applied to overcome this limitation. As natural products are often molecules of high structural and stereochemical complexity, their total synthesis is usually difficult, and yields are low. Classical strain improvement represents an equally time-consuming and rather undirected process, during which numerous rounds of mutagenesis and subsequent screening are applied to obtain strains with improved production titers. 

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