Amines base-labile linkers

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. 

The successful assembly of organic compounds on a solid support represents only part of the challenge in SPOS. After completion of synthetic sequence, the compounds must be cleaved from linkers attached to polymer by a chemical or photochemical reaction, for example, treatment of a polymer-bound compound with acids, bases, nucleophiles, redox reagents, and even photons. Acid-labile linker and amine-cleavable Marshall linker are two major classes of hnkers used in combinatorial synthesis. 

The Kenner sulfonamide-based SC linker 1.27 was supported on PS resin (84) allowing the attachment of carboxylic acids or amino acids to the sulfonamide function. After synthetic elaboration, treatment with diazomethane produces the A-methylacylsulfonamide, which can be cleaved with nucleophiles such as 0.5 N NHs-dioxane or hydrazine-MeOH, 0.5 N NaOH, releasing amides, hydrazides, or carboxylic acids, respectively. A modification using iodoacetonitrile produces the more labile A-cyanomethyl derivative, which can be cleaved completely with stoichiometric amounts of amines to release the corresponding amides into solution. 

Treatment of the linker with diazomethane or bromoacetonitrile gives base-labile N-alkylsul-fone amide. The N-cyanomethyl-sulfone amide linker is also cleaved by sterically hindered amines. 

Trityl resins are particularly suitable for immobilization of nucleophilic substrates such as acids, alcohols, thiols, and amines. They are quite acid-sensitive and are cleavable even with acetic acid this is useful when acid-labile protecting groups are used. The stability of trityl resin can be tailored by use of substituted arene rings, as shown by chlorotrityl resin, which furnishes a more stable linker than the trityl resin itself. Steric hindrance also prohibits formation of diketopiperazines during the synthesis of peptides. Orthogonality toward allyl-based protective groups was demonstrated in the reverse solid-phase peptide synthesis of oligopeptides [30] (Scheme 6.1.4). 

The hydroxyl version of the Rink amide linker, known as the Rink acid resin (25), was developed as a tool for the preparation of protected peptide fragments [13]. The peptide-linker ester bond is labile to extremely weak acids, such as HOBt or acetic acid, allowing peptides bearing t-butyl-based side-chain protection to be cleaved intact. Conversion of the hydroxyl group into chloride [66] or trifluoroacetyl [67] provides linkers that have been used for immobilization of various nucleophiles, including alcohols, N-protected hydroxylamines, phenols, purines, amines, anilines and thiols [66-68], The stability of the cation derived from this tinker is such that even thiols and amines can be cleaved from this tinker with TFA (Figure 14.12). 

An oxalyl linkage has also been used to attach nucleosides to LC AA-CPG (41). In this method, oxalyl chloride replaces succinic anhydride as the linker that joins the nucleoside to the support (Fig, 8), This oxalyl linkage is quite labile and is cleaved in <5 min by 5% ammonium hydroxide in methanol. Other mildly basic reagents, such as wet triethylamine or 40% trimethylamine/methanol, also rapidly cleave the oxalyl linkage. However, it was quite resistant to normal conditions employed in either phosphoramidite or H-phosphonate synthesis and to anhydrous amines, such as pyridine, triethylamine, and diisopropylamine. This support is particularly well suited for use when synthesis is performed without base-protecting groups (38). 

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