Anchoring acid labile

Albericio F, Barany G. Hypersensitive acid-labile (HAL) tris(alkoxy)benzyl ester anchoring for solid-phase synthesis of protected peptide segments. Tetrahedron Lett 1991 32 1015-1018. 

Breipohl G, Knolle J, Stuber W. Synthesis and application of acid labile anchor groups for the synthesis of peptide amides by Fmoc-solid-phase peptide synthesis. Int J Peptide Protein Res 1989 34 262-267. 

Seiber P. A new acid-labile anchor groups for the solid phase synthesis of C-terminal peptide amides by the Fmoc method. Tetrahedron Lett 1987 28 2107-2110. 

M. Megler, R Tanner, J Gosteli, P Grogg. Peptide synthesis by a combination of solid phase and solution methods. 1. A new very acid-labile anchor group for the solid phase synthesis of protected fragments on 2-methoxy-4-alkoxy-benzyl resins. Tetrahedron Lett 29, 4005, 1988. 

Because O-glycosylation can also be accomplished with active esters (e.g., penta-fluorophenyl esters) [11] of Fmoc serine and threonine, the Fmoc technique provides a general method for the synthesis of glycopeptides. Thomsen-Friedenreich antigen glycopeptides and neoglycoproteins have been obtained by this method in preparative amounts [12], In combination with acid-labile polymeric benzyl ester anchors, this Fmoc technique was applied to solid-phase syntheses of glycopeptides [11,13,14]. 

Recently, CD52 glycopeptide 17 with an acid-labile fucosidic linkage was also prepared by this new method (Scheme 4). CD52 is a glycosylphosphatidyl-inositol (GPI)-anchored glycopeptide that plays an important role in the human immune system (29,30) and human reproduction process (31-33). 

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... 

The efficiency of the fluoride method was further confirmed by the synthesis of pep-taibols. These peptides are characterized by a high content of the C -dialkylamino acids Aib or isovaline and an amino alcohol at the C-terminus such as phenylalaninol (Pheol) or valinol (Valol). Degradation of the peptides in the final cleavage step due to the acid-labile Aib-Pro linkages,can be prevented by the use of the 2-chlorotrityl-resin.P l This achieves direct anchoring of Fmoc-protected amino alcohols which allows the final cleavage to occur under very mild conditions.P l... 

The second subgroup, which contains the largest number of acid-labile anchors, can be characterized by their ability to form stable cations. Typical members of this group include functional groups linked with benzyl-, benzhydryl- and trityl-anchor (Fig. 5.4). 

Very acid-labile anchor, even HOBt can partially cleave the product from the solid support (this problem is circumvented by adding DIEA). 

An interesting acid-labile linker has been designed for a non-standard RNA synthesis with 5 -Fmoc protection [303] and methyl phosphoramidite chemistry by Palom et al. [304], The authors prepared an acetal anchor for the ribonucleoside 2, 3 -diol group (Figure 19.15) by the reaction of 5 -Fmoc-uridine with 4-formyl-phenoxyacetic acid, and attached it to LCAA-CPG (30-40 gmolg"1). The nucleoside can be detached from this support in ca. 70% yield by overnight treatment with dilute aqueous HC1, pH 2, conditions now believed to be too drastic for RNA. 

---