Benzhydrylamine linker

Table 3.25. Benzylamine and benzhydrylamine linkers for aromatic amines.

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). 

Tritylamines can serve as both linkers and protective groups for aliphatic amines because, unlike benzhydrylamines, they do not usually undergo acylation when treated with activated acid derivatives. Tritylation of aliphatic amines is readily accomplished by adding excess amine to a support-bound trityl chloride. Illustrative cleavage reactions are listed in Table 3.21. 

Table 3.21. Benzhydrylamine and tritylamine linkers for aliphatic amines.

Related resins 8e [349] and 8f [350] have been used in Suzuki coupling reactions cleavage was possible under conditions of lower acid concentration for 8f, attributable to anchimerically assisted ipso protonation by the amide carbonyl. Similar observations have been made concerning the conditions required to cleave this silane anchoring group from a linker that had been attached to benzhydrylamine resin [351]. 

The same method can be used for the construction of Asn- or Gin-containing head-to-tail cyclic peptides, using a benzhydrylamine instead of a benzyl alcohol linker, as shown by Tromelin et al. [19]. The synthesis of an 18-mer head-to-tail cyclic peptide designed to mimic a loop involved in the curaremimetic action of a snake toxin protein, cycto(Asn-Tyr-Lys-Lys-Val-Trp-Arg-Asp-His-Arg-Gly-Thr-Ile-Ile-Glu-Arg-Gly-Pro), was prepared. 

Early examples of the use of resin-bound amines for the solid synthesis of peptidyl amides involve the use of linkers such as benzhydrylamine or benzyl-amine. Following peptide assembly, these linkers require highly acidic (e.g. 

Note that many of the hnker units described above are available in multiple forms, aUowing a range of substrates to be attached and cleaved. A discussion of all these related linker units is outside the scope of this chapter, but Kurosu has written a comprehensive review. By way of example, multiple versions of the Rink (Table 1.1, Entries 2 and 3) and trityl hnker units (Table 1.1, Entries 5 and 6) are commercially available and can be selected according to the desired substrate. However, beyond these general hnker units, there are also examples of substrate-specific hnker units. Eor example, the benzhydrylamine (BHA, Table 1.1, Entry 8) and Sieber (Table 1.1, Entry 9)" linkers find widespread use as acid labile carboxamide linker units, while the DHP (Table 1.1, Entry 10)" and sUyl linker units (e.g.. Table 1.1, Entry 11) can be used to attach alcohols to polymer supports. ... 

The use of acidic gaseous reagents, HCl and TFA, for cleavage of acids, alcohols, and amines attached to trityl linker functionalized supports has been reported (15). Jayawickreme et al. (16) used TFA for gradual cleavage of compounds from a solid support. The use of gaseous hydrogen fluoride (HF) has also been described for the release of compounds from the / -methyl-benzhydrylamine (MBHA) (17-20) and dialkoxybenzylamine (21-23) linkers. 

Carbamate linker systems (Fig. 9, [19,182-191]) are often produced by the transformation of an alcohol to a carbonate functionality. Afterwards, the carbonate can be reacted with amines and amide coupUng reagents to give carbamates. This strategy is for example used by Und n et al. [192] by the addition of 4-nitrophenylchloroformate (4-NPCF) to a 4-methyl-benzhydrylamine polystyrene (MBHA-PS)-based resin and further addition of an alkylamine. A similar sequence is conducted with a solid-supported hydroxy-functionality that is converted via phosgene addition into the chlo-roformate. Addition of amines then gives resin-bound carbamates [193]. 

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