Amines acid-labile linkers

The successful assembly of organic compounds on a solid support represents only part of the challenge in SPOS. After completion of synthetic sequence, the compounds must be cleaved from linkers attached to polymer by a chemical or photochemical reaction, for example, treatment of a polymer-bound compound with acids, bases, nucleophiles, redox reagents, and even photons. Acid-labile linker and amine-cleavable Marshall linker are two major classes of hnkers used in combinatorial synthesis. 

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). 

Primary and secondary aliphatic amines can be linked to polymeric supports by acid-labile linkers or by linkers sensitive to nucleophiles. Linkers cleavable by light or by transition metal catalysis have also been described. The main types of linker for amines are sketched in Figure 3.24. 

Benzhydrylamines are better suited than benzylamines as acid-labile linkers for amines. The MBHA linker ( methylbenzhydrylamine ), which is usually used to prepare peptide amides (see Section 3.3), can also be used as a linker for amines (Entry 1, Table 3.21). Hydrogen fluoride is, however, required as the cleavage reagent. Easier to cleave are alkoxy-substituted benzhydrylamines (Entries 2-5, Table 3.21), which can be prepared from the corresponding benzhydryl chlorides [263] or by reductive alkylation [410] or solvolysis [411] of the Rink amide linker. In the case of benzhydrylamines linked to polystyrene as benzyl ethers, treatment with TFA can lead to the release of the linker into solution (acidolysis of the benzylic C-O bond, see Figure 3.18). 

This brief, incomplete survey should have provided a flavor of the many functional groups that can be hooked onto and released from a solid support using acid-labile linkers. Acids, alcohols, phenols, amines, hydroxylamines, and halides have been successfully attached to a variety of resins through the judicious choice of the linker... 

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... 

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

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 ... 

One of the oldest linkers for amides is the (4-methylbenzhydryl)amine linker (MBHA Entry 1, Table 3.11). In contrast to the corresponding benzhydrol linker (which is cleavable by 5% TFA in DCM, 5 min [45]), acidolysis of the benzylic C-N bond of the MBHA linker requires treatment with hydrogen fluoride or a similar acid. As for A-benzylamides, the acid-lability of Al-(diarylmethyl)amides increases with the number of electron-donating substituents on the aryl groups. 

One type of synthesis was described by Ding et al.15 (Fig. 1). A drawback to this approach is the low reactivity of a polymer-bound amine. This problem may be alleviated to some extent by activating the heterocycle with ammonium salts16 and by the choice of linker. Mainly acid-labile indole24 (28) and PAL linkers25 (26) have been employed. The possibility of activating C2 by acylation of N626 of the purine scaffold was not... 

Trityl resins are particularly suitable for immobilization of nucleophilic substrates such as acids, alcohols, thiols, and amines. They are quite acid-sensitive and are cleavable even with acetic acid this is useful when acid-labile protecting groups are used. The stability of trityl resin can be tailored by use of substituted arene rings, as shown by chlorotrityl resin, which furnishes a more stable linker than the trityl resin itself. Steric hindrance also prohibits formation of diketopiperazines during the synthesis of peptides. Orthogonality toward allyl-based protective groups was demonstrated in the reverse solid-phase peptide synthesis of oligopeptides [30] (Scheme 6.1.4). 

The reactors selected were 432 aminomethylated MicroTubes 7.63, which are polystyrene-grafted polypropylene tubes with a 50 xM loading capacity per reactor, that encapsulate a preencoded radiofrequency tag (Fig. 7.38). The tubes were reacted with the Fmoc-protected, acid-labile Knorr linker (step a), the residual amine functions... 

In order to obtain alkyl-, aryl- and acyl- guanidines Wang linker is treated with carbonylimida-zole and thiourea consecutively. The displacement of sulfur by primary or secondary amines leads to acid-labile carbamate linkage [119]. 

A benzyl halide solid support If (Table 1) has been reported [77] that affords anchoring groups which are less labile than trityl anchors Ib-le but more labile than anchors to chloromethyl-PS (la). Resin If has been used to prepare amides and sulfonamides by reaction with an amine followed by acylation or sulfonylation, respectively, and cleavage using 95% TFA. When the same reaction sequence was conducted on an analogous resin Ig prepared from Tentagel AC (acid-cleavable linker), the products could be cleaved under milder conditions (5% TFA) because of the greater stability... 

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