Esters acid-labile linkers

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). 

Chemical ligation methods for peptide synthesis using thioester chemistry in solution have been previously documented (see Vol. E 22a, Section 4.1.5). Generalized procedures for solid-phase ligation have been developed that simplify the overall procedure. One method uses a safety-catch acid labile linker at the C-terminus and was used for the synthesis of a 71-amino acid chemokine, vMIP I (Section 5.3.2.1). Another procedure uses a selectively cleavable glycolate ester linkage (Section 5.3.2.2). 

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]). 

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-... 

Fig. 3 A tumor-targeted polymer-drug conjugate. The major elements include (i) a polymeric drug-carrier that is water-soluble, bicompatible or biodegradable, non-immunogenic (ii) targeting moieties (iii) a linker between a drug and the carrier. The linker can be a) a chemical bond such as ester or amide. An ester bond is more stable at lysosomal pH than at plasma pH (7.4) while an amide bond is stable at both lysosomal and plasma pH b) an oligopeptide linker that is degradable by specific enzymatic hydrolysis and c) an acid labile linker that is degradable at lysosomal pH but stable at plasma pH.

The two main resin linkers developed so far are shown in Scheme 18, i.e. tris(alk-oxy)benzylamide- 412 and 4-alkoxybenzylamide-type linkers)341 the former being TFA labile and thus fully compatible with Fmoc/tBu and the latter strongly acid labile and correspondingly compatible with Boc/Bzl chemistry. As shown in the case of the tris(alk-oxy)benzaldehyde handle such handles may be introduced into the C-terminal amino acid ester by reductive amination, and after suitable N -protection coupled to amino-functionalized resins (see Scheme 18). Alternatively, the tris(alkoxy)benzaldehyde-functionalized resin, BAL resin, (see Scheme 14) is used to link the C-terminal amino acid ester by reductive amination. To overcome the difficult acylation of the V -arylamino acid ester derivative on resin (best results with 10 equivalent symmetrical anhydrides), synthesis in solution of the C-terminal dipeptide building block containing the amide handle followed by its attachment to the resin has been proposed)341 ... 

Dialkoxy- and trialkoxybenzyl esters are even more acid-labile than the Wang linker, and can, for example, be cleaved with dilute TFA, acetic acid, or hexafluoroiso-propanol without simultaneous acidolysis of Boc groups. These linkers thus enable the solid-phase synthesis of protected peptide fragments or other acid-sensitive products [33]. 

The linkage between the oligonucleotide-peptide conjugate and the solid support is usually a base-labile linker inspired by the oligonucleotide synthesis field (Fig. 5). Linkers from the peptide field are acid labile and not compatible with the oligonucleotide moiety. Most the linkers used to anchor the peptide moiety have an ester function that is cleaved with concentrated ammonia [13-17,46], ethylenediamine [34], ethanolamine [26], sodium hydroxide [27], or tetrabutylammonium fluoride (TBAF)... 

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