Substrate-supported synthesis

It is important to note that although several of the intervening steps in Scheme 1 involve substrate-supported synthesis, had the resin simply been loaded and cleaved in the same pot (which works well in practice), then this approach is readily placed under the heading of reagent-supported synthesis. As shown, 4 reflects the virtues of both a safety-catch linker (see Chapter 7 for a discussion of this concept) and an immobilized reagent. 

High selectivity and substrate specificity of glycosyl transferases make them valuable catalysts for special linkages in polymer-supported synthesis. There is, however, still a rather limited set of enzymes available to date, and the need to synthesize a variety of natural and non-natural oligosaccharides prevails. Particularly with regard to combinatorial approaches, chemical solid-phase oligosaccharide synthesis promises to meet the demands most effectively. 

Chiral benzamides I and the pyrrolobenzodiazepine-5,11-dio-nes n have proven to be effective substrates for asymmetric organic synthesis. Although the scale of reaction in our studies has rarely exceeded the 50 to 60 g range, there is no reason to believe that considerably larger-scale synthesis will be impractical. Applications of the method to more complex aromatic substrates and to the potentially important domain of polymer supported synthesis are currently under study. We also are developing complementary processes that do not depend on a removable chiral auxiliary but rather utilize stereogenic centers from the chiral pool as integral stereodirectors within the substrate for Birch reduction-alkylation. 

Carboxylation of Oiganic Substrates. Selective Synthesis of 4-OH-Benzoate from Phenol and Carbon Dioxide Catalyzed by a "Supported Enzyme. ... 

Solid-supported synthesis offers a number of practical advantages over solution-phase approaches. For example, it is possible to use excess reagent to drive reactions to completion, and then, at the end, it is possible to isolate the supported product easily by filtration. In addition, library synthesis can be facilitated using solid-supported approaches. One disadvantage, however, is that the rate of reactions can be significantly slower when substrates are confined to a solid support. This has been overcome in many cases by using microwave heating. ... 

Guthrie and co-workers (1971, 1973) have described the use of a copolymer containing preformed monosaccharide units as esters of vinyl benzoate or vinylbenzene sulphonate and styrene. This is the only example of a polymer-supported synthesis wherein the substrate is first linked to the monomer and then polymerized to give the polymer-bound substrate. High and uniform loading of the polymer has been possible in this way, leaving no unreacted sites on the polymer. These noncross-linked polymers are soluble in solvents such as benzene, toluene, acetone. 

In order to demonstrate the advantages of IL-supported synthesis over the conventional solution-phase synthesis, Sun and coworkers examined reactions between various IL-grafted diamines and different substrates... 

Recently, the Bartoli indole synthesis was extended to solid supports. In contrast to the earlier reports in the liquid phase, o,o-unsubstituted nitro analogs (see 25) prove to be useful substrates. In addition, fluoro/chloro substituted nitro derivatives are well tolerated, which typically undergo nucleophilic substitution under Bartoli conditions in the liquid phase. 

The adaptation of the Bischler-Napieralski reaction to solid-phase synthesis has been described independently by two different groups. Meutermans reported the transformation of Merrifield resin-bound phenylalanine derivatives 32 to dihydroisoquinolines 33 in the presence of POCI3. The products 34 were liberated from the support using mixtures of HF/p-cresol. In contrast, Kunzer conducted solid-phase Bischler-Napieralski reactions on a 2-hydroxyethyl polystyrene support using the aromatic ring of the substrate 35 as a point of attachment to the resin. The cyclized products 36 were cleaved from the support by reaction with i-butylamine or n-pentylamine to afford 37. 

The Pictet-Spengler reaction has been carried out on various solid support materials " and with microwave irradiation activation.Diverse structural analogues of (-)-Saframycin A have been prepared by carrying out the Pictet-Spengler isoquinoline synthesis on substrates attached to a polystyrene support. Amine 20 was condensed with aldehyde 21 followed by cyclization to give predominantly the cis isomer tetrahydroisoquinoline 22 which was further elaborated to (-)-Saframycin A analogues. 

Yields much lower than the upper bound value indicate that there is significant substrate utilisation to support growth, maintenance or synthesis of other products. 

Since 1986, when the very first reports on the use of microwave heating to chemical transformations appeared [147,148], microwave-assisted synthesis has been shown to accelerate most solution-phase chemical reactions [24-27,32,35]. The first application of microwave irradiation for the acceleration of reaction rate of a substrate attached to a solid support (SPPS) was performed in 1992 [36]. Despite the promising results, microwave-assisted soHd-phase synthesis was not pursued following its initial appearance, most probably as a result of the lack of suitable instriunentation. Reproducing reaction conditions was nearly impossible because of the differences between domestic microwave ovens and the difficulties associated with temperature measurement. The technique became a Sleeping Beauty interest awoke almost a decade later with the publication of several microwave-assisted SPOS protocols [37,38,73,139,144]. There has been an extensive... 

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