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Manipulations of compound 77 facilitated incorporation of three additional points of diversity (to 78 and 79). These were (i) Sonogashira coupling of terminal alkynes to the aryl iodide functionality; (ii) addition of primary amines to selectively open the lactone; and (iii) use of carboxylic acids to esterify the resulting alcohol. The chemistry was cleverly designed to avoid protecting-group manipulations. Photochemical cleavage of the products from the solid support gave the primary amides 79. This reaction sequence was adapted to split-pool methods giving a 2.18-million-member library. Analysis of this library via nanodroplet assay techniques gave compounds showing selectivity toward TNF activation.
The solid-phase syntheses of natural products and natural product derivatives that have been reported to date illustrate several different approaches to the challenge of preparing libraries of bioactive products. Total syntheses
264 RECENT ADVANCES IN SOLID-PHASE SYNTHESIS OF NATURAL PRODUCTS
of complex materials are possible. Derivatization of highly functionalized intermediates is another approach. It is even possible to derivatize a natural product, giving a supported scaffold that can be used to prepare totally different materials that look as if they are natural products that have not yet been discovered.
Arguments that are frequently made to justify natural product synthesis (e.g., leads to methodological developments) can certainly be made in this field. Several interesting methods, some of which feature the resin as an integral part, have been developed in the course of these syntheses.* Moreover, and perhaps unlike some solution-phase syntheses, these works have well-defined practical applications. Products of significant numbers of compounds having likely looking structures tend to lead to biological hits. This field will undoubtedly undergo significant expansion in the next decade.
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