Traceless methods

Decarboxylation of appropriately substituted alkanes [130-134] and arenes [135] is also a traceless method that has been used to generate hydrocarbons. Since the... 

Dipolar cycloadditions on solid supports have been widely studied. A diverse amount of nitrogen-containing five-membered heterocycles has been obtained, and various linkers and cleavage strategies have been exploited. Esters and ethers have been the most common linkers. In addition, much effort has been put into the development of traceless methods, and various linker strategies have been studied. To obtain products in high yields and purities from solid supports, efficient synthetic methods are necessary. 

Nowadays, solid-phase synthesis has been used as a powerful tool in organic chemistry, especially to prepare small molecule libraries. New linkers to obtain different functionalities after cleavage have been developed. There are different linkers strategies (Fig. 3.2), for example traceless linkers, multifunctional linkers, safety catch linkers, fragmentation/ cycloreversion cleavage linkers, cyclization cleavage linkers, which are useful methods for combinatorial solid-phase chemistry. 

Therefore it has to be distinguished from traceless-cleavage. As the intramolecular step is in general faster than any intermolecular step, this strategy provides an additional purification step, because only cychzed structures are detached from the resin. The method of cyclative cleavage by nucleophihc displacement has been... 

The isorniinchnone cyclization/isocyanate cycloreversion process for substituted furan synthesis has been well studied, as exemplified by the conversion of 104 to 106 (Scheme 19.19). In a solid-phase adaptation of this transformation, two groups independently utilized this reaction to estabhsh a traceless self-cleaving method for the synthesis of substituted furans [176, 177]. Further investigation of the thermal requirements of this cycloreversion led to its application in the split-pool synthesis of a small library of amides [178]. 

May P, Bradley M, Harrowven D, Pallin D, A new method of forming resin bound thioesters and their use as traceless linkers in solid phase synthesis, Tetrahedron Lett., 41 1627-1630, 2000. 

A second approach relies on the traceless Staudinger ligation between an appropriately functionalized phosphine and an azide to produce a new amide bond [54]. This method has found extensive utility in the labeling of peptides and proteins [215]. Importantly, this method has also been used for the construction of native iV-linked glycans through the reaction between a glycosyl azide and a phosphine containing amino acid [216,217]. 

Equation 12.97 illustrates use of catalyst 104 in the synthesis of a bicyclic ring system.207 Note that the presence of a catalyst also allows the transformation to occur under a CO pressure of 1 bar. Equation 12.98 demonstrates a clever application of the so-called traceless tether method for running a Ru-catalyzed P-K reaction.208 Although this is an intermolecular P-K reaction, the alkene is tethered to a pyridylsilyl group (compound 105), which directs regioselective reaction of the alkene fragment with the alkyne. The presence of residual H20 in the reaction mixture removes the silyl group, which can be recycled. 

In the traceless system outlined in Scheme 35, an electrophilic cleavage, either iododesilylation (IClin CH2CI2) or bromodesilylation (Br2/pyridine in CH2CI2), is required after the Suzuki coupling. These methods of electrophilic cleavage have been found to be superior to protodesilylation. 

Other possibility for a traceless release of combinatorial compounds from solid supports. As only the desired products are cleaved during fhe reaction, these are obtained in high purity. The method is compatible wifh a whole variety of different functionalities, such as carboxylic acids, carboxylic acid anhydrides, amides, aldehydes, ketones, alcohols, and sulfonamides. 

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