Linkers ester-type

These authors developed the use of a 4-alkyloxybenzyl ether-type linker attached to the Merrifield resin via an ester function that allowed the cleavage of the oligosaccharides under two different conditions. Using the reactivity of the activated... 

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 ... 

Benzyl Alcohols, Esters Benzyl-type linkers... 

Benzyl-type linkers are the most common anchoring groups for various kinds of functionality. Esters, amides, amines, alcohols, and thiols, in particular, can be immobilized by this linker family. This was demonstrated by Merrifield [2] and Wang [19] and is the starting point of modern linker development. Benzylic linkers are typically cleaved by strong acids (for example trifluoroacetic acid, TFA), which cause protonation and subsequent elimination. A nucleophilic scavenger usually quenches the resonance-stabilized cation thus formed. 

As discussed above, each linker family is sensitive toward a certain spectrum of cleavage conditions and is therefore stable to dissimilar conditions. Since most of the linkers are based on well-established protecting groups, table 6.1.2 can be used for the determination of orthogonality. For example, benzyl-type linkers, most of which are cleaved by electrophiles, and are stable towards nucleophiles, can be combined with ester-based protective groups. 

Cleavage reagents Benzyl- type linkers Ketal/ acetal linkers Esters/ amide linkers Silyl linkers Triazene linkers Selenium/ sulfur/ stannane linkers... 

Hydroxy linkers bearing an electron-withdrawing group such as an a-carbonyl (oxyacyl resins, phenacyl type-linkers or glycolic acid derivatives) are also suitable for the nucleophilic release of ester bound compounds. The glycolamidic ester linker 10 has been successfully used to synthesize peptides by the Fmoc/tBu strategy. It is compatible with the repetitive piperidine treatment but peptides can be cleaved with dilute NaOH solutions, ammonia or alkoxides [9], Esters bound to oxyacyl resins 8 have been reported to be cleavable by thiolysis, saponification, ammonia, hydrazine and potassium cyanide (complexed with dicyclohexyl-18-crown-6) [10, 11],... 

Apart from the common heteroatom-derived nucleophiles described, cleavage with other nucleophiles is also possible. For example, reductive cleavage with hydride sources is possible. For ester-linked substrates, Kurth et al. reported an example in which substituted propane-1,3-diols were prepared (Table 1.2, Entry 11). In related work, Chandrasekhar et al. prepared tertiary alcohols by treating an ester-linked substrate with excess Grignard reagent (Table 1.2, Entry 12). If, however, it is desirable to prepare the carbonyl derivative (and not reduce all the way to the corresponding alcohol), then Weinreb-type linker units can be used (Table 1.2, Entries 13 and 14). Treatment of substrates attached via such linkers... 

One of the oldest and up to now most important multifimctional linker classes is the ester-type Hnker. Ester linkers are of the general structure A or B (Fig. 1). Cleavage methods are similar for both types of Unkage but the resulting molecules end up with different functional groups. 

The importance of sulfonyloxy—or sulfonate ester—linkers results from their stability under several conditions including compatibihty with Grignard additions, Wittig reactions, NaBH4-reduction, reductive aminations, acylations, Suzuki couplings and treatment with various other electrophiles. Some linkers of the sulfonate ester type are shown in Fig. 15. 

Suitably protected amino acids (112) (cysteine, serine, and lysine) have been added via the side-chain heteroatom (S, O, and N, respectively) to conjugated alkynones, alkynoic ester and alkynoic amide (113). The expected heterosubstituted vinyl product (114) was formed in each case, mainly as the ii-isomer. In an accompanying paper, this type of addition was applied to the derivatives of fluorescein, 7-hydroxycoumarin, Sudan 1, and dansyl chloride with linker arms containing a conjugated terminal alkyne. 

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