MBHA linker

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. 

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). 

In order to facilitate the generation of peptide thioesters, several groupst have developed generalized versions of the thioester linker pioneered by Hojo and Aimoto.f A 3-sulfanylpropanoic acid residue is generated on an acid-labile linker such as Boc-Leu-PAM-resin or Boc-Leu-MBHA-resin. It is important to have a one-residue spacer between the MBHA linker and the thiol for optimal acid stability of the amide bond.f All twenty Boc-protected amino acids can be coupled to this thiol on the solid support to generate the thioester.Despite the potential reactivity of the thioester to the amino terminus, the formation of a dioxopiperazine is not generally observed when using in situ neutralization protocols. However, when the sequence was Leu-Tyr-Arg-Ala-Pro, 20% of a dipeptide deletion product, Leu-Tyr-Arg, was observed. It is likely that sequences such as C-terminal Pro-Gly would also be subject to this side reaction.t ... 

The recommended linker for synthesizing C-terminal amides compatible with Boc chemistries is the MBHA linker (Table 5). For Fmoc chemistries either the PAL (Fig. 4) or the Rink handles are recommended (Table 5). 

The MBHA resin (substitution 0.63 mmol-g 1) was acylated in CH2C12 with the Boc N-protected linker 15 (2 equiv) in the presence of BOP as coupling agent and DIPEA as base. After 4 h and classical washings, the coupling was controlled by Kaiser s test. The protected resin 16 was ready for classical solid-phase synthesis. 

Coupling of 4-(4-hydroxymethyl-3-methoxyphenoxy)-butyric acid (HMPB, for synthesis of peptide acids) or p-[(R S)-a-[l- (9H- fluorenyl- methoxyform-amido]- 2,4- dimethoxybenzyl] - phenoxyacetic acid (modified Rink linker, for synthesis of carboxamide peptides) linkers to MBHA resin For Fmoc chemistry several types of solid supports are available, which include hydroxymethyl-based, aminomethyl-based, and trityl chloride resins. We describe the use of the MBHA resin. In this case the respective linker (to achieve peptide acid or amide) is coupled to the resin and first amino acid is then coupled to the linker. Attachment of the linker to the resin is a reaction between the carboxyl-group of the linker and amino-group of the MBHA resin. Commercially available resins with linkers already attached could also be used. 

CO-NH-MBHA X = Fmoc, Boc Y = Boc, Ac.. Figure 11. Synthesis of peptide aldehydes via the phenyl ester linker. 

Merrifleid resin, MBHA, or (Met)Expansion, X = Fmoc, Boc Figure 12. Synthesis of peptide aldehydes by ozonolysis of the linker. 

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. 

The acid lability of both the Merrifield esters 8 and MBHA amides 10 was increased by introducing electron-donating groups on the aromatic ring of the linker. Thus the Wang resin 11 (36) and derivatized BHA linkers 12 (17) and... 

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]. 

---