Natural products direct synthetic methods

Since its recognition and systematic exploration by Otto Diels and Kurt Alder in the 1920s, the Diels-Alder reaction motif (5.84b) has provided one of the most powerful tools of organic synthesis. The Diels-Alder reaction led directly to the dramatic pre-World War II development of the chemical industry for production of synthetic rubber and other polymeric materials. Today, the commercial impact of Diels-Alder methods extends to virtually all areas of agricultural, pharmaceutical, and natural-products chemistry. 

Of the various synthetic processes that are available, two are of most relevance in the present context - precipitation from aqueous solution and melt forming. These methods are used where it is not possible to produce adequate products directly from natural sources. This will be because there is no suitable mineral, due to the chemical nature of the product, of particle size and shape requirements, or to purity considerations. The other principal synthetic method in use for filler production is pyrolysis/combustion. This type of process in which the particles are formed in the gas phase is used where very small particles are required, such as with carbon blacks and some silicas. This type of filler is not widely used in thermoplastics and so these processes are not discussed in any detail here, although some information specific to the production of antimony oxide will be found later. 

An unusual feature of dactomelyns is the presence of two halogen-substituted chiral centers. Since few methods are so far known for selective introduction of halogen atoms ai sp -hvbridi/ed carbon, the dactomelyns pose an extraordinary synthetic challenge. Another interesting feature of these natural products is the appearance of both chlorine and bromine atoms in the same molecule. One is struck, upon closer examination of the bicyclic pyran skeleton 1. by the fact that the chlorine atom is oriented toward the steri-cally less lavorable side of the molecule (the concave side), whereas the bromine atom is directed toward the convex side. 

P-Hydroxy sulfoximines are thermally labile and revert to their starting carbonyl compound and sulfoximine on mild thermolysis. This property has been exploited effectively as a method for the resolution of racemic chiral cyclic ketones.65 For example, the addition of the lithium salt of (+)-(S)-2b (99% ee) under kinetically controlled conditions (-78 °C) to racemic menthone gave three of the four possible diastereomeric adducts. The major two adducts resulted from attack on the menthone from the equatorial direction. These diastereomeric adducts could be readily separated by column chromatography. Thermolysis of the individual two major diastereomeric carbinols at 140 °C gave d- and /-menthone, respectively, in high enantiomeric purities (90-93% ee). This methodology has been successfully applied to the resolution of other 2-substituted cyclohexanones as well as other chiral ketones that have served as advanced synthetic intermediates for the synthesis of natural products.66-69... 

The reasons why natural products have not been an area of focus for pesticide company discovery efforts are several. They include the relatively high cost of bioassay-directed isolation, the probability of rediscovery, and the often prohibitively complex structure of the active molecule. Furthermore, the strategies for discovery of natural product-based pesticide discovery are different from those for synthetic compounds, requiring a somewhat different laboratory infrastructure. New methods, including semi-automated bioassays, automated chemical extraction and analysis, and molecular biology methods to... 

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