Linkers for carboxylic acids

TFA) in DCM (dichloromethane). Linkers for carboxylic acids have also been designed to effect cleavage via photolysis (3-nitro-4-hydroxymethylbenzoic acid, ONb 14) [18] and flouridolysis (N-3 or 4) ((4-hydroxymethyl)-phenoxy-t-butylphenylsilyl)phenyl pentanedioic acid monoamide (PBs) 15 [19] and quinonemethide-based handle 16 [20] (Fig. 

Acid-labile linkers are the oldest and still the most commonly used linkers for carboxylic acids. Most are based on the acidolysis of benzylic C-O bonds. Benzyl esters cleavable under acidic conditions were the first type of linker to be investigated in detail. The reason for this was probably the initial choice of polystyrene as an insoluble support for solid-phase synthesis [13]. Polystyrene-derived benzyl esters were initially prepared by the treatment of partially chloromethylated polystyrene with salts of carboxylic acids (Figure 3.3). 

The trialkoxy benzhydrol linker, developed by Rink in 1987 [46] ( Rink acid resin , Figure 3.4) is a further acid-labile linker for carboxylic acids. Esters of this linker can, like trityl esters, be cleaved with acids as weak as acetic acid or HOBt [47], and care must be taken to avoid loss of the product during synthetic operations. 

Neither the trialkoxybenzhydryl alcohol linker nor other types of benzhydryl alcohols [44,45,48] have found widespread use as linkers for carboxylic acids. These linkers do not seem to offer special advantages compared with benzyl alcohol or trityl linkers. 

Tertiary aliphatic alcohol linkers have only occasionally been used in solid-phase organic synthesis [73], This might be because of the vigorous conditions required for their acylation. Esterification of resin-bound linker 4 with /V-Fmoc-prolinc [72,74] could not be achieved with the symmetric anhydride in the presence of DMAP (20 h), but required the use of /V-Fmoc-prolyl chloride (10-40% pyridine in DCM, 25 °C, 10-20 h [72]). A further problem with these linkers is that they can undergo elimination, a side reaction that cannot occur with benzyl or trityl linkers. Hence, for most applications in which a nucleophile-resistant linker for carboxylic acids is needed, 2-chlorotri-tyl- or 4-acyltrityl esters will probably be a better choice than ferf-alkyl esters. 

Figure 3.7. (4-Acyloxy-2-buten-l-yl)silanes and 2-acyloxyethylsilanes as acid-labile linkers for carboxylic acids.

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... 

Table 3.4. Linkers for carboxylic acids cleavable by base-induced (3-elimination.

Support-bound phenols, oximes, and related compounds yield, upon acylation, esters that are highly susceptible to nucleophilic cleavage. These esters are often used as insoluble acylating agents for the preparation of amides or esters, but only occasionally as linkers for carboxylic acids [113]. These linkers are considered in Sections 3.3.3 and 3.5.1. 

Most photocleavable linkers for carboxylic acids used today are based on the photoisomerization of 2-nitrobenzyl esters and on the light-induced cleavage of phen-acyl esters (Figure 3.10). Several possible mechanisms have been proposed for the photolytic cleavage of benzoin esters. One of the most recent is the dissociation of the excited phenacyl ester into a carboxylate and a phenacyl cation ( photosolvolysis , Figure 3.10 [136]). 

There have been a few reports of enzymatic cleavage of linkers for carboxylic acids from PEG-grafted polystyrene supports, such as Tentagel (Table 3.8). Some of these linkers are also sensitive towards acids or bases, and will, therefore, only remain uncleaved under a narrow range of reaction conditions. 

Thiols bound irreversibly to supports have mainly been used as linkers for carboxylic acids (Sections 3.1.2 and 3.3.3), for pyrimidines and triazines (Section 3.8), or for other thiols (Section 3.12). When working with these resins, special care must be taken to prevent atmospheric oxidation of the thiols to the corresponding disulfides. 

Linkers are usually categorized according to the kind of functional group or substrate class they can selectively immobilize (linkers for carboxylic acids, alcohols, amines, etc.). Because a variety of types of linker is available for solid-phase synthesis, many belong to certain well-established classes of protecting group (Table 6.1.1) and can therefore be grouped into linker families. The members of each family have certain reactivity patterns in common. 

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