Solid-support chemistry

The book also outlines recent developments in synthe (e.g., combinatorial chemishy, solid support chemistry, fluorous chemistry) and the corresponding purification procedures that will provide maiiy of the commercially supplied chrnnical substances in years to come. Additionally, interesting perspective out the future of purification Is jHovided by the autiuxrs, based on their years of experience. 

Under certain condition, however, reactions are still preferably conducted in solution. This is the case e.g., for heterogeneous reactions and for conversions, which deliver complex product mixtures. In the latter case, further conversion of this mixture on the solid support is not desirable. In these instances, the combination of solution chemistry with polymer-assisted conversions can be an advantageous solution. Polymer-assisted synthesis in solution employs the polymer matrix either as a scavenger or for polymeric reagents. In both cases the virtues of solution phase and solid supported chemistry are ideally combined allowing for the preparation of pure products by filtration of the reactive resin. If several reactive polymers are used sequentially, multi-step syntheses can be conducted in a polymer-supported manner in solution as well. As a further advantage, many reactive polymers can be recycled for multiple use. 

However, oxidation processes like epoxidation or dihydroxylation reactions are important transformations in solid support chemistry, because they allow the synthesis of ketones [226], aldehydes [227, 228] and even sulfoxides and sulfones [229]. 

The formation of C-C bonds is of great importance for the synthesis of nonpepti-dic small molecules. For this, there is an increasing interest in the development of solid-phase methodology for this kind of transformation. Well-known liquid-phase reactions have been successfully transferred to solid-supported chemistry. 

Additionally, for comparison purposes, all steps in the solid-phase protocol (linking, cycloaddition, cleavage) were carried out both under thermal and controlled microwave heating conditions. In general, significant rate enhancements were found for each step and it has been demonstrated that microwave mediation could be combined with the efforts of solid-supported chemistry to enable the development of novel pathways in organic synthesis. 

One major drawback of the current methods is the low atom economy45 of solid-supported chemistry with conventional resins in comparison to solution-phase synthesis. The low loadings are one important reason for excluding solid-supported methods from many resource-and cost-sensitive applications such as scale-up projects. Furthermore, polystyrene-based resins are restricted by solvent compatibility, thermal and chemical stability, and extensive adsorption of reagents. 

In summary, ULTRA resins can be prepared with extremely high loading compared to standard resins in use today. Secondary amine groups of the resin were very accessible to various derivatizations and even larger product molecules could be assembled successfully in the resin interior. Thus, these resins allowed solid-supported chemistry that was greatly improved in atom economy and provide a significant contribution to the efficient scale-up of polymer-supported syntheses. 

The number of solid-supported reagents has grown with the growth of solid-supported chemistry. Many reagents have been developed to ease the work-up and isolation by selectively fishing out products and impurities [28—30]. 

A new approach to obtain increased diversity in the search for new lead compounds called kombiNATURik has been co-developed by the German companies AnalytiCon and Jerini Bio Tools. The kombiNATURik program starts from natural compounds which are further diversified by solid-support chemistry introducing e.g. peptide or carbohydrate moieties. KombiNATURik libraries generally comprise several hundreds to thousands of single molecules derived from multi-parallel synthesis. 

Simultaneously, numerous academic groups started and even reoriented their activities towards the implantation of solid-phase strategies in their laboratories. Although progress towards fulfillment of the initial great expectations has slowed in recent years, solid-supported chemistry is now a very useful tool in all modern organic chemistry laboratories [11] and, of course, is the method of choice for both research and industrial synthesis of peptides [12] and oligonucleotides [13]. 

In conclusion, the concept of solid-supported chemistry has been extended from the preparation of peptides and other biomolecules to any organic molecule. PS-and PEG-based resins are the most widely used however, syntheses can be carried out in any solid support. The development of new solid supports and linkers/ handles is crucial to fulfill the new requirements of modem drag discovery programs. 

The particular advantage of solid-supported chemistry is in purification sequential reactions can be carried out and by-products washed away without the need for extractions, chromatography, or isolation of intermediates. The product is finally cleaved from the support with minimal impurities. Although some individual reactions may be slower on solid phase, overall processes are generally faster because only one isolation step is needed. These features also make reactions suitable for automation. 

The role of solid-supported chemistry in modern drug discovery... 

Solid-supported chemistry is very useful for the synthesis of larger series of compounds investments in the development of methods will be paid off by faster production through simple robotic methods. 

An N-methylimidazolium chloride-based ionic support bearing an aldehyde, analogous to the known AMEBA [52] solid support [53] readily dissolves in an ionic liquid solvent such as n-butylimidazolium herafluorophosphate ([BMIM][PF6]). It has been used to prepare a set of diverse sulfonamides and amides according to (Scheme 5.5-34) [39] with isolated yields ranging from 26 to 54% and purities from 55 to 95%, as determined by NMR spectroscopy, comparable to those obtained from solid support chemistry [53]. Reactions were monitored by H PLC. No leakage of the ionically supported substrate into the aqueous or organic phase occurred. 

This approach suffers from problems related to the influence of the support on reaction chemistries and the optimization of solid-supported chemistries, which may have completely different kinetics from their solution-phase analogues. Difficulties exist in assessing product purity or structure of compounds in the solid phase, often leading to expensive spectroscopic solutions. Working in the solid phase also limits the range of chemistry, which can be applied to a synthetic problem, not least because many solid phase approaches are so dependent upon amide bond formation. A further issue arises from the need for the perfect linker uncleaved in normal reaction conditions but perfectly cleaved when desired, preferably without a footprint in the target molecule. 

Umarye, J. D., Lessmarm, T., Garcia, A. B., Mamane, V., Sommer, S., and Waldmarm, H. 2007. Biology-oriented synthesis of stereochemically diverse natural-product-derived compound collections by iterative allylations on a solid support. Chemistry 13(12) 3305-19. 

Solid-supported chemistry, yields 55-64%, imidazole, benzimidazole, pyrazole, benzotriazole... 

Solid-supported chemistry, primary or secondary amine immobilized, yields 21-75%... 

Ring-Opening Metathesis. The ring-opening metathesis (ROM) reaction has also been employed in solid-supported chemistry, but to a lesser extent. However, a sohd-supported ROM reaction has been used in the selective formation of bicyclic lactams. Since the bicyclic alkene 53 is immobilized on the resin, any potential side products formed from the solution-phase metathesis homodimerization of the styrene 54 are simply removed in the filtration and washing of the resin (Scheme 6.14). In addition. 

The Naito laboratory has investigated the applicability of radical reactions in solid-supported chemistry. A pronounced effect of the solid support on the stereochemical outcome of a radical reaction was reported for the addition of an alkyl radical onto the chiral oxime 139, delivering a-amino acid derivatives 140 in good yield and with high stereoselectivity (Scheme 6.32). Higher diastereoselectivities were observed with the substrate 139 immobilized on the solid support (>90% de), compared to comparable solution-phase reactions of 139 (72-85% de). This effect was rationalized based on the lower reactivity and reduced reaction rate of the immobilized oxime, inducing an enhanced selectivity. ... 

It can be concluded that solid supports have been successfully employed in order to enhance the selectivity or organic transformations and to facilitate the isolation of desired products from multistep reaction sequences. Several different approaches to take advantage of these opportunities have been discussed in this chapter, without comprehensively reviewing every reaction that displays an enhanced selectivity when conducted on a solid support. The presented examples should allow researchers to gauge if solid-supported chemistry has the potential to solve selectivity issues encountered in their research. 

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