Multistep Use of Supported Reagents in Natural Product Synthesis

3 MULTISTEP USE OF SUPPORTED REAGENTS IN NATURAL PRODUCT SYNTHESIS 

Although these examples illustrate opportunities for using a variety of immobilized reagents for individual transformations, a more imaginative use of these methods is in multistep syntheses. In this respect our group s approach has been to minimize the use of conventional workup procedures, yet be able to prepare complex natural products and related compounds simply and efficiently. In this chapter we refrain from commenting on the use of on-bead synthesis of natural compounds or on the diversity-oriented procedures. 

Other analogs were also prepared from oxomaritidine by hydrogenation to give 24, which on reductive amination with polymer-supported cyanoborohydride afforded a small library of unnatural analogs based on the structure of 25. Obviously, many other derivatives would be possible given the efficiency of this route to the natural products, and clearly many of the intermediates, such as the spirodienone 23, could usefully be diverted to other combinatorial chemistry programs for further elaboration and decoration. 

Finally, compound 38 had to be epimerized to epibatidine, and this was best done using microwave heating in the presence of potassium f-butoxide in f-butanol. This was one of the early examples of focused microwave heating. The natural product was then isolated by catch-and-release caught with a polymer-supported sulfonic acid followed by release using methanolic ammonia. 

Many of the steps employed eoncepts that we established earlier during the synthesis of simpler alkaloids therefore, they are not discussed in detail. However, some steps are noteworthy. First, it should be noted that the use of immobilized hypervalent iodine once again served us well in the oxidative formation of the spirodienone (54). The conjugate addition of the amidic nitrogen atom to complete the tricyclic scaffold (55) proceeded nicely when a Naflon-H fluorosulfonic acid resin was used as a source 

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Supported reagents have been used in synthesis since 1946, but their application in natural product synthesis has been very limited. Indeed, where they had been used, it was only to effect a spedlic transformation where conventional systems had previously failed. Our group, however, has sought to develop the application of immobilized systems to complex synthetic challenges in a multistep mode. The first serious application of supported reagents for natural product synthesis was published in 1999. ° Here, concise routes to two amarylUdaceae alkaloids, oxomaritidine (1) and epimaritidine (2), in just five and six steps, respectively, were reported (Scheme 6.1). 

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