Aminal type-linkers

In a recent study, this so-called SPOT synthesis was applied for the preparation of pyrimidines [45]. The group of Blackwell described primarily the appropriate support modification of commercially available cellulose sheets (Scheme 7.28). The initial introduction of the amine spacer was achieved within 15 min utilizing micro-wave irradiation, as compared to 6 h by conventional heating. The acid-cleavable Wang-type linker was attached by classical methods at ambient temperature. 

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-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. 

Amines derived from p-alkoxybenzyl-type linkers, despite not being acid cleav-able, still have synthetic utility. Anilines anchored to Wang resin, once converted into carboxamides or sulfonamides by reaction with the appropriate electrophile, can be cleaved with TFA (Figure 14.6) [34]. Sulfonamides of aliphatic amines may also be cleaved with TFA [36]. Stronger acids are generally required for acyl derivatives of amines but this can cause cleavage of the linker benzylic ether bond, leading to formation of p-hydroxybenzylated by-products. 

One interesting variation of this kind of linker is the formylindole linker of Estep (20) [61]. It is used in exactly the same manner as other formylalkoxybenzyl-type linkers and has properties similar to the BAL linker. The low steric hindrance of the indole group compared to the o-alkoxybenzyl moiety means acylation of secondary amines prepared on the former linker is easier. 

Lamaty et al. further presented the first examples of the A-supported aza-MBH reaction between PEG-SES amine 220, prepared from a novel SES-type linker attached to an appropriate PEG polymer, acrylate and aldehydes... 

A main feature for all BAL-type linkers is the anchoring of the first residue by reductive amination through a resin-bound aldehyde functionality, which acts as the electrophile. The first building block, which has a primary amine, acts as the nucleophile. This is normally achieved by anchoring the first residue by RA to the resin-bound linker precursor (i.e., BAL handle). 

The diisopropoxy-bis-(triethanolamine)-titanate, TYZORTE [36673-16-2] is an excellent cross-linker for aqueous solutions of hydroxyl-containing polymers. The reaction product of TYZORTPT with a mixture of trialkano1 amines and dialkanolarnines or monoalkano1 amines can be used to cure polyester-based powder coatings (109). Other ligands of this type iaclude triisopropano1 amine [122-20-3] ... 

Traceless linker 60 based on a benzotriazole scaffold was reacted with amines and aldehydes to produce Mannich-type amine products [69]. Final product release was achieved by treatment with Grignard reagents (Scheme 29). 

Several different types of linker have been developed that yield amides upon cleavage. These linkers can often also be used to prepare sulfonamides, carbamates, or ureas. There are essentially three different strategies for the release of amides from insoluble supports (a) cleavage of the benzylic C-N bond of resin-bound N-alkyl-N-benzylamides (backbone amide linkers, BAL linkers), (b) nucleophilic cleavage of resin-bound acylating agents with amines, and (c) acylation/debenzylation of resin-bound /V-benzyl-/V,A -dialkylamines. 

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. 

The most common preparations of amines on insoluble supports include nucleophilic aliphatic and aromatic substitutions, Michael-type additions, and the reduction of imines, amides, nitro groups, and azides (Figure 10.1). Further methods include the addition of carbon nucleophiles to imines (e.g. the Mannich reaction) and oxidative degradation of carboxylic acids or amides. Linkers for primary, secondary, and tertiary amines are discussed in Sections 3.6, 3.7, and 3.8. 

Isothioureas can be prepared on insoluble supports by S-alkylation or S-arylation of thioureas (Entry 7, Table 14.6). Further methods for the preparation of isothioureas on insoluble supports include the N-alkylation of polystyrene-bound, A/,/V -di(alkoxy-carbonyl)isothioureas with aliphatic alcohols by Mitsunobu reaction (Entry 7, Table 14.6) and the addition of thiols to resin-bound carbodiimides [7]. Resin-bound dithio-carbamates, which can easily be prepared from Merrifield resin, carbon disulfide, and amines [76], react with phosgene to yield chlorothioformamidines, which can be converted into isothioureas by treatment with amines (Entry 8, Table 14.6). The conversion of support-bound a-amino acids into thioureas can be accompanied by the release of thiohydantoins into solution (see Section 15.9). The rate of this cyclization depends, however, on the type of linker used and on the nucleophilicity of the intermediate thiourea. 

---