Wang linkers

For the solid-phase experiments [115], the commercially available Wang and HMPB-AM resins were chosen due their stability under the applied reaction conditions and an easy cleavage with TFA/DCM mixtures. Moreover, a novel, tailor-made and readily available linker, derived from inexpensive syringaldehyde was designed and proven to be superior to both standard Wang and HMPB-AM resins. For an initial study, as a proof of concept , the Wang linker was mimicked with a 4-methoxybenzyl group at N-1 position of a pyrazinone, and the sequence was evaluated in solution (Scheme 41). 

Wang linker, mimic 297 Wang resin, phthalimide library synthesis 103... 

G3] At7l ether dendronized support with Wang-linkers... 

Derivatization of functional groups in a natural-product scaffold can also be effectively performed on the solid-phase. An example of this is the synthesis of a small compound collection (27-compounds) based on the tetrahydroquinoline scaffold. A chiral tetrahydroquinoline scaffold was synthesized in solution from 5-hydroxy-2-nitrobenzaldehyde (Scheme 4). The synthesis involved a key asymmetric aminohydroxylation step. This building block was anchored to the solid support with a Wang linker and diversity was introduced by selective deprotection and derivatization of the protected hydroxyl and amino substituents. 

In a parallel study, Wipf and Fritch11041 have shown that also urethane-protected (Boc), and even amino acid segments, are tolerated as acyl compounds on the aziridine nitrogen. The best results were obtained with alkylcopper reagents derived from CuCN and an alkyl-lithium in the presence of boron trifluoride-diethyl ether complex. Some 6-alkylated compounds (11-15%) were isolated as well. This work was extended to a solid-phase procedure that resulted in resin-bound alkene isosteres that could immediately be used in further peptide synthesis.11051 For this purpose, the 2-nitrophenylsulfonyl (oNbs) group was used for nitrogen protection and aziridine activation. It could be readily cleaved with benzenethio-late, which was compatible with the acid-sensitive Wang linker used. 

Dialkoxy- and trialkoxybenzyl esters are even more acid-labile than the Wang linker, and can, for example, be cleaved with dilute TFA, acetic acid, or hexafluoroiso-propanol without simultaneous acidolysis of Boc groups. These linkers thus enable the solid-phase synthesis of protected peptide fragments or other acid-sensitive products [33]. 

Illustrative examples of the cleavage of support-bound ethers are listed in Tables 3.30 and 3.31. Acidolytic cleavage is the most commonly used strategy, but base-mediated, photolytic, and oxidative cleavage have also been reported. Wang linker... 

Nitro- or 2,4-dinitrobenzenesulfonamides of primary or secondary amines can be hydrolyzed under mildly basic conditions, and are increasingly being used for amine protection (see Section 10.1.10.7 [123,139,140]). /V-(2-Nitrobenzenesulfonyl)amino acids can be used as an alternative to TV-Fmoc amino acids for the solid-phase synthesis of peptides [141]. Deprotection is achieved by treatment of the polystyrene-bound sulfonamide with a solution of PhSH (0.5 mol/L) and K2C03 (2 mol/L) in DMF for 10 min at room temperature [141], conditions that do not lead to cleavage of esters (e.g. of the Wang linker) or to racemization. The condensation of polystyrene-bound sulfinamides H2N-SO-Pol with aldehydes yields /V-sulfinylimines, which add... 

Examples of the preparation of oxazines and thiazines on insoluble supports are listed in Table 15.34. 3,l-Benzoxazin-4-ones can be prepared by intramolecular O-acy-lation of /V-aminocarbonyl anthranilic acids (Entry 1, Table 15.34). The resulting ben-zoxazinones are sufficiently stable towards acids to enable TFA-mediated cleavage from a Wang linker [410]. 1,3-Oxazines have also been obtained by acidolytic cleavage of functionalized 3-amino-l-propanols from Wang resin (Entry 4, Table 3.30). 

The Wang linker 1.1 (57) is a very popular choice that is based on ap-alkoxybenzyl alcohol moiety. It is typically cleaved by trifluoroacetic acid (TFA)-DCM 1/1 in 30 min at room temperature (rt) to produce carboxylic acids or alcohols. Two slight modifications to this linker have produced the super-acid-sensitive resin (SASRIN)... 

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