Safety-Catch Linker Units

As outlined above, a drawback of using acid or base labile linker units is that unwanted cleavage can occur when reagents employed in the synthetic sequence resemble the cleavage conditions. One elegant solution to this problem is the safety-catch linker 

Alternatively, alkylation of the sulfur is also a viable safety-catch approach. For example, alkylation of a thioether with triethyloxonium tetrafluoroborate yielded a sulfo-nium ion (Table 1.6, Entry 4) that, in a report by Wagner and coworkers, activated benzyl 

LINKER STRATEGIES IN MODERN SOLID-PHASE ORGANIC SYNTHESIS 

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In such linkers, the latent bond requires activation before cleavage can occur. Many of the linker units discussed elsewhere in this chapter could be considered safety-catch linker units. For example, photolytic activation described in Section 1.2.4 and cyclorelease discussed in Section 1.2.2 are essentially safety-catch strategies. This section, however, will concentrate on synthetic activation. The first example of such an approach was a sulfonamide linker reported by Kenner et al. in 1971. The sulfonamide 7 is stable to both acidic and basic conditions, making it synthetically valuable. However, alkylation of the nitrogen with, for example, diazomethane or iodoacetonitrile, gave 8, from which substrates (e.g., carboxylic acids 9) could be cleaved under nucleophilic conditions (Scheme 1.4). 

Scheme 1.4. Kenner s safety-catch linker unit.

TABLE 1.6. Common Safety-Catch Linker Units... 

Spengler and coworkers [173] have used p-nitromandelic acid (Pnm) as a safety-catch linker for the synthesis of depsipeptides by Boc/Bzl chemistry. The hexafluo-roacetone (HFA)-protected Pnm is loaded on the resin with concomitant deprotection of the hydroxy unit. After the depsipeptide is constructed, reduction of the nitro group with 6M SnCl2/1.6mM HC1 gives the p-aminomandelic (Pam) linker, which can be cleaved in acidic media (5% TFA in dioxane, 50°C, lh), thereby obtaining the target depsipeptides in good yields and purities (Scheme 18.7). 

In 2001, Maclean et al. modified the Kenner safety-catch strategy to obtain secondary sulfonamides 10. Using this reversed Kenner linker, the carboxylic acid remains attached on the solid support while the sulfonamide unit 12 is released into the solution [18] (Scheme 16.3). 

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