Solid-phase synthesis selection, reaction conditions

For the development of new reaction sequences for solid-phase synthesis, the optimum conditions for each step must be identified. This includes determination of the minimum reaction time and temperature, and the minimum amounts of reagents required to obtain sufficiently pure products with a representative selection of different reagents. If reaction times or amounts of reagents are excessive, library production will be costly and inefficient. 

Linkers are molecules which keep the intermediates in solid-phase synthesis bound to the support. Linkers should enable the easy attachment of the starting material to the support, be stable under a broad variety of reaction conditions, and yet enable selective cleavage at the end of a synthesis without damage to the product. Several types of linker have been developed, which meet these conflicting requirements to different extents [1]. Newer developments include linkers containing fluorine to facilitate the monitoring of solid-phase chemistry by NMR (see Section 1.3.5), and enantio-merically pure linkers that enable the synthesis on solid phase of enantiomerically enriched products [2],... 

Silyl ethers of aliphatic alcohols are inert towards strong bases, oxidants (ozone [81], Dess-Martin periodinane [605], iodonium salts [610,611], sulfur trioxide-pyridine complex [398]), and weak acids (e.g., 1 mol/L HC02H in DCM [605]), but can be selectively cleaved by treatment with HF in pyridine or with TBAF (Table 3.32). Phenols can also be linked to insoluble supports as silyl ethers, but these are less stable than alkyl silyl ethers and can even be cleaved by treatment with acyl halides under basic reaction conditions [595], Silyl ether attachment has been successfully used for the solid-phase synthesis of oligosaccharides [600,601,612,613] and peptides [614]. 

Support-bound organoselenium compounds have mainly been used as synthetic intermediates and linkers. The use of organoselenium compounds as linkers for solid-phase synthesis has been investigated by several groups [1-4]. The selenium-carbon bond is stable under a broad variety of reaction conditions, but can be selectively cleaved by tin radicals or by oxidants (see Sections 3.15.1 and 3.16.4). 

Carbamates are by far the most common type of amine protection used in solid-phase synthesis. Various types of carbamate have been developed that can be cleaved under mild reaction conditions on solid phase. Less well developed, however, are techniques that enable the protection of support-bound amines as carbamates. Protection of amino acids as carbamates (Boc or Fmoc) is usually performed in solution using aqueous base (Schotten-Baumann conditions). These conditions enable the selective protection of amines without simultaneous formation of imides or acylation of hydroxyl groups. Unfortunately, however, Schotten-Baumann conditions are not compatible with insoluble, hydrophobic supports. Other bases and solvents have to be used in order to prepare carbamates on, for example, cross-linked polystyrene, and more side reactions are generally observed than in aqueous solution. 

In solid-phase synthesis intermediates and products are bound to a solid support via a covalent linker. The linker must allow selective removal of the final product from the support, but must be stable under the reaction conditions throughout the synthesis. The advantage of a solid-phase approach is that reagents can be used in large excess to drive reactions to completion and most side products are just washed off from the solid support. However, the solid-phase implies steric constraints onto the reactions performed. The choice of method depends on the synthetic problem it is often not obvious and usually results from a reaction optimization study. 

Cesium salts of iV-protected amino acids were introduced by Gisin [15] for the synthesis of ester bonds under mild reaction conditions in the solid phase synthesis according to Merrifield [48]. Cesium salts of short chained carboxylic acids like cesium propionate found broad application for the selective inversion of the stereochemistry of secondary alcohols which could be performed with cesium salts under careful reaction conditions [49, 50]. 

In gas phase synthesis under plasma conditions the use of catalysts is probably the only way to improve the selectivity and reaction yields. Very little has been done so far on the application of low pressure plasmas for treatment of solid catalysts. The authors hope that both of these problems will be solved on the basis of research of a very fundamental nature. 

In another paper, a development of the microwave-assisted parallel solid-phase synthesis of a collection of 21 polymer-bound enones was described. The two-step protocol involves initial high-speed acetoacetylation of polystyrene resins with a selection of seven common P-ketoesters. When microwave irradiation at 170 °C was employed, complete conversions were achieved within 1-10 min, a significant improvement over the conventional thermal method, which takes several hours for completion. Significant rate enhancements were also observed for the subsequent microwave-heated Knoevenagel condensations. Reaction times were reduced to 30-60 min at 125 °C in the microwave protocol compared to 1-2 days using conventional thermal conditions. Kinetic comparative studies indicate that the observed rate enhancements can be attributed to the rapid direct heating of the... 

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