Carboxylic acid-labile linkers

Two approaches for solid-phase chemical ligation have been described. Canne et al. have developed an elegant system that utilizes an oxime forming ligation to attach the first peptide to the resin, a selectively cleavable ester link to remove the peptide from the resin as a C-terminal carboxylic acid, and the Acm group to protect the N-terminal cysteine residue)311 A complementary approach has been developed by Brik et al. that utilizes native chemical ligation to attach the first peptide to the solid support, a safety-catch acid labile linker to remove the final polypeptide from the support as a C-terminal amide and either Acm or Msc group for N-terminal cysteine protection)32 ... 

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. 

Resin-bound (4-acyloxy-2-buten-l-yl)silanes, which can be prepared from resin-bound allylsilanes and allyl esters by cross-metathesis, react with dilute TFA to yield free carboxylic acids (Figure 3.7 [75]). However, the scope of this strategy remains to be explored. Similarly, esters of polystyrene-bound (2-hydroxyethyl)silanes readily undergo acidolysis and have been used as acid-labile linkers (Figure 3.7 [76]). 

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

The use of the Fmoc-protected 4-nitrophenyl carbamate building blocks and resins with acid-labile linkers allows synthesis of the final products with C-terminal carboxylic acid or amide groups (Fig. 6). Unfortunately, Fmoc solid-phase synthesis of oligourea peptidomimetics with C-terminal carboxylic acid also leads to formation of corresponding hydantoin byproducts (53-56) (Fig. 7). In this case hydantoin formation arises as a result of an acid-catalyzed intramolecular cyclizafion reaction. It has been reported that the ratio of desired oligourea pepfidomimetic acid product and hydantoin byproduct is approximately 2 1 (53). However, these two compounds are in principle separable by preparative HPLC. 

Seven noncommercial acid-labile linkers have been reported recently in the literature and are shown in Figs. 1.8. (1.7-1.10) and 1.9 (1.11-1.13). The THP (tetrahy-dropyran) linker 1.7 (63), which is easily grafted onto Merrifield resin, has been used to support primary alcohols, secondary alcohols, hydroxylamines, and carboxylic acids. It is stable to strong nucleophiles and basic conditions and can be cleaved by... 

Structures 3.3-3.10 possess two potential handles for their support on SP. The obvious choice is the carboxylic function, which could be linked either to a chlo-romethyl or to a hydroxymethyl PS resin through an ester bond. The insertion of a commercially available acid-labile linker, possibly already supported onto the resin, would allow the release of the target into solution under mild conditions. Different functionalities could be released by cleaving the acid-labile linker with, for example, TFA (free acid) and amines (amides). Another possible handle is the secondary amine, which could be anchored to resin-bound carboxylates or halides and finally released as an A-acyl or A-aUcyl moiety. For both handles the protection of the other functional... 

The authors chose, sensibly, to begin by checking the Pauson-Khand outcome on SP using an advanced intermediate, 3.11 (Fig. 3.8), prepared in solution by simple hydrolysis of the methyl ester 3.9. The free carboxylic group was hooked onto the commercially available Wang-PS resin (acid-labile linker) utilizing the mixed anhy-... 

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... 

Most acid-labile benzyl alcohol linkers suitable for the attachment of carboxylic acids to insoluble supports can also be used to attach aliphatic or aromatic alcohols as ethers. The attachment of alcohols as ethers is less easily accomplished than esterification, and might require the use of strong bases (Williamson ether synthesis [395,552,553]) or acids. These harsh reaction conditions limit the range of additional functional groups that may be present in the alcohol. Some suitable etherification strategies are outlined in Figure 3.31. Etherifications are treated in detail in Section 7.2. 

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. 

The cleavage of organic compounds from nucleophile-labile resins usually relies on the addition-elimination chemistry at the carbonyl group of the carboxylic acid derivative (i.e. an ester or thioester) that mediates the linkage between the assembled compound and the linker-resin. The overall reaction is a nucleophilic substitution that involves the release into the solution of the compound of interest with the attacking nucleophile generally incorporated. The linker-resin generally acts... 

Apart from the product classes discussed above, which include the most important types of cleavable surfactants, several more or less exotic examples of surfactants with limited half-life have been reported. For instance, isethi-onate esters with very high degrees of alkali lability have been developed. These products, made by esterification of an alkylpolyoxyethylene carboxylic acid with the sodium salt of isethionic acid, have been claimed to be partially cleaved when applied to the skin [68]. Cleavable quaternary hydrazinium surfactants have been explored as amphiphiles containing a bond which splits very easily. The surfactants are cleaved by nitrous acid under extremely mild conditions [69]. Ozone cleavable surfactants have been developed as examples of environmentally benign amphiphiles. These surfactants, which contain unsaturated bonds, break down easily during ozonization of water, which is a water purification process of growing importance. Both normal surfactants [70] and geminis [71] have been synthesized and tested in ozonolysis. The latter surfactants contained unsaturation either in the hydrophobic tails or in the linker unit. 

---