Wang-type linker

In a recent study, this so-called SPOT synthesis was applied for the preparation of pyrimidines [45]. The group of Blackwell described primarily the appropriate support modification of commercially available cellulose sheets (Scheme 7.28). The initial introduction of the amine spacer was achieved within 15 min utilizing micro-wave irradiation, as compared to 6 h by conventional heating. The acid-cleavable Wang-type linker was attached by classical methods at ambient temperature. 

Electrophilic alkenes have been appended to imidazolium-type ILs for use in the Diels-Alder cycloaddition, 1,4-addition, Heck and Stetter reactions.Electrophilic alkenes containing Wang-type linkers were alkylated to imidazole followed by ion exchange and esterification giving the desired TSIL. Diels-Alder cycloaddition was carried out with 2,3-dimethylbutadiene and cyclopentadiene to give corresponding adducts. After washing with ether, transesterification resulted in cyclohexene derivatives. Scheme 29. 

The o-fluoro-nitroarene was attached to TentaGel resin as a phenolic ether 73 via a modified Wang-type linker. Following aminolysis of 73, reduction of the intermediate nitroaniline to di-aniline 74 proceeded poorly... 

Several methods have been reported to monitor solid-phase reactions using F NMR without a Fluoro-Wang type linker. For example, the monitoring of solid-phase nucleophilic aromatic substitution reactions via F NMR through the loss of the aromatic fluorine atom has been reported. F NMR monitors the progress of the reaction, hence monitoring the reaction kinetics of product formation (Scheme 2.8). 

For anchoring of the first amino acid onto hydroxymethyl-based resin, which upon cleavage provides a C-terminal carboxylic acids, it is recommended to use a protocol without the use of tertiary bases, such as DIEA. This type of protocol is designed to minimize the degree of self-acylation, hence, donble incorporation, and racemiza-tion of the first residne. The most common hydroxymethyl-based resins are Wang-type linkers (fcc Table 2). Two different protocols are described below for loading of hydroxymethyl-based resins (1) the symmetrical anhydride method and (2) the MSNT/Melm method. The MSNT/Melm method is recommended for difficnlt sitnations, which inclndes the attachment of amino adds that are prone to epimerization. For the synthesis of C-terminal adds where the first residue is either Cys or Pro, it is recommended to use the trityl-based resins. Many ofthe resins with a hydroxymethyl linker can be obtained with the first amino acid already preloaded. 

On the other hand, if the phosphopeptides are intended to be used in solution-phase assays, the synthesis can be carried out on a standard resin with common linkers. This includes the Rink amide or Wang-type linkers on polystyrene, TentaGel, or ChemMatrix supports. Upon completion of the peptide chain assembly, the peptides are released from the solid support by treatment with TFA-containing cocktails with concomitant removal of acid-labile side-chain protecting groups. Using these conditions robust protocols for rapid and efficient synthesis of phosphopeptides have been established. 

Benzyl-type linkers are the most common anchoring groups for various kinds of functionality. Esters, amides, amines, alcohols, and thiols, in particular, can be immobilized by this linker family. This was demonstrated by Merrifield [2] and Wang [19] and is the starting point of modern linker development. Benzylic linkers are typically cleaved by strong acids (for example trifluoroacetic acid, TFA), which cause protonation and subsequent elimination. A nucleophilic scavenger usually quenches the resonance-stabilized cation thus formed. 

TW HNYAr V 0 H2N nh2 [178] One example using a carbamate linker has been decribed. The amidoxime formation is much slower on resin than in solution. The acid-labile linkers (Wang-type) gave higher yields than the photolabile linker. [178]... 

Amines derived from p-alkoxybenzyl-type linkers, despite not being acid cleav-able, still have synthetic utility. Anilines anchored to Wang resin, once converted into carboxamides or sulfonamides by reaction with the appropriate electrophile, can be cleaved with TFA (Figure 14.6) [34]. Sulfonamides of aliphatic amines may also be cleaved with TFA [36]. Stronger acids are generally required for acyl derivatives of amines but this can cause cleavage of the linker benzylic ether bond, leading to formation of p-hydroxybenzylated by-products. 

Another Fluoro-Wang type resin that was reported is devoid of an amide bond in the attachment of the linker to the polymer support. This resin is readily available from 2-fluoro-4-hydroxy-acetophenone, and offers the advantage of being more chemically robust than the resins previously discussed. For example, the resin hnkage is stable to hthium aluminum hydride (LAH) and inert to strongly basic conditions, such as treatment... 

The strategy of releasing amides (Scheme 43) can be applied to the synthesis of lactams by immobilization of acids containing a /3-hydroxy functionality 284. Ring closure can be carried out under Mitsunobu conditions as shown in a publication of Taddei et al. in 2001 [219]. The authors chose an 0-trityl-hydroxylamine resin for the reaction sequence because other linker types as for example a Wang-type resin carrying a hydroxylamine functionality failed. 

Wang-type resins Wang/PHB linker Peptide acids Chapter 2... 

The following procedure is described for 4-formylphenoxy acetic acid, which is the precursor for the monoBAL handle, but it can equally be used for the o-BAL handle, see Chapter 9. However, treatment with cone. TFA will release the peptide from the support, thus providing the phosphopeptide directly in solution. Other linkers, such as Rink amide or Wang-type handles, can also be used for the Fmoc-SPPS of peptides in solution however, the first amino acid is then anchored by conventional N-acylation. 

As the pioneering development of Merrifield [21] and Wang [22] are based on the benzyl linker type, this type represents the starting point of modern linker development. 

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