Cleavage acid labile linkers

For these reasons, an alternative route and more acid labile linkers compared to p-carboxy trityl linker 24a initially used were sought, to avoid high concentrations of TFA for the final cleavage. The synthesis of the alkoxysubstitued linkers 24b (Meisenbach and Voelter 1997) and 24c, which can be synthesised directly on the solid support in five steps, offer the possibility of linkers with tailor-made stability. 

Many acid-labile linkers are used to assemble combinatorial libraries. Compounds are cleaved in the final step by TFA/DCM solution with various concentrations for a certain period of time. Mild cleavage conditions may lead to incomplete cleavage of the desired compound from a solid support. On the other hand harsh conditions may cause compound degradation and side reactions. Harsh conditions will also cause the partial breakdown of resin and the leaching of unidentified impurities into the final products. Harsh cleavage conditions demand the stabihty of all compounds under such conditions. This may limit the scope of combinatorial synthesis... 

For resin-bound ureas (22-25), Indole and Rink linkers, generally ranked 1 and 2 in cleavage kinetics, were still the most acid-labile linker for this class of compounds. Resins (24) and (25) were cleaved with 0.5% TFA in 2 and 23 min, respectively. Resins (22) and (23) were cleaved with 1% TFA in more than 10 h. The order of cleavage rates is similar to carbamate compounds. 

The Marshall Unker [23] has been widely used to synthesize compounds that can be cleaved by primary and secondary amines to afford the corresponding amides. Marshall linker was used in the synthesis of three or more diversity-site hbraries because it allowed the addition of one more diversity element at the cleavage step. While the original reported linker [23] involved the oxidation of the Unker before cleavage, the efficient release of the resin-bound compounds using nucleophiles from the unoxidized linker has been reported [16, 24]. Similarly to the acid-labile linkers, the kinetics of the cleavage reaction and time required for this reaction directly affect the synthesis efficiency, purity and yield of the final products. A cleavage study was carried out on seven resin-bound thiophenol esters (34—40) on Marshall Unker with 3 amines (41-43) (Scheme 12.11 and Tab. 12.4). 

Benzhydrylamines are better suited than benzylamines as acid-labile linkers for amines. The MBHA linker ( methylbenzhydrylamine ), which is usually used to prepare peptide amides (see Section 3.3), can also be used as a linker for amines (Entry 1, Table 3.21). Hydrogen fluoride is, however, required as the cleavage reagent. Easier to cleave are alkoxy-substituted benzhydrylamines (Entries 2-5, Table 3.21), which can be prepared from the corresponding benzhydryl chlorides [263] or by reductive alkylation [410] or solvolysis [411] of the Rink amide linker. In the case of benzhydrylamines linked to polystyrene as benzyl ethers, treatment with TFA can lead to the release of the linker into solution (acidolysis of the benzylic C-O bond, see Figure 3.18). 

This is the most widely used class of SP linkers. Historically, the SPS of peptides (see Section 2.1) was developed using building blocks protected with acid-labile groups, thus allowing a convenient simultaneous cleavage and deprotection in the final step of the synthesis. Four commercially available acid-labile linkers are depicted in Fig. 1.7 in resin- and compound-bound forms. The preferred cleavage conditions for each linker are also provided. 

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

Table 3.1. Acid-labile benzyl alcohol linkers. See text for additional cleavage reagents.

A special group of base-labile linkers for carboxylic acids rely on cleavage by 3-elimination. Here, the resin-bound alcohol must bear an electron-withdrawing group in the [3 position (Figure 3.8), which facilitates elimination by acidifying this position. Mechanistically, these linkers are closely related to the Fmoc protective group, and... 

Polystyrene-derived phenylboronic acids have been used for the attachment of diols (carbohydrates) as boronic esters [667]. Cleavage was effected by treatment with acetone/water or THF/water. This high lability towards water and alcohols severely limits the range of reactions that can be performed without premature cleavage of this linker. Arylboronic acids esterified with resin-bound diols can be oxidatively cleaved to yield phenols (Entry 8, Table 3.36). Alcohols have also been prepared by nucleophilic allylation of aldehydes with polystyrene-bound, enantiomerically enriched allyl-silanes [668], as well as by Pummerer reaction followed by reduction of resin-bound sulfoxides [669]. 

So far undisclosed in the peer-reviewed literature are contributions by the company Graffinty (www.graffmity.de.) [31]. It has built up a technology platform in which combinatorial libraries are generated by solid-phase methodology using an acid-labile S-trityl linker. After cleavage the free thiols of the small molecules react... 

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