Linkers, base-labile

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. 

It has long been recognized that polymeric supports for oligosaccharide synthesis do not need to be insoluble.33 Wang et al. applied the sulfoxide glycosylation method to the synthesis of disaccharide 79 (Scheme 3.14). The key feature of this work was the base-labile linker. Sulfoxide 74 was used to glycosylate polyethylene glycol... 

A special group of base-labile linkers for carboxylic acids rely on cleavage by 3-elimination. Here, the resin-bound alcohol must bear an electron-withdrawing group in the [3 position (Figure 3.8), which facilitates elimination by acidifying this position. Mechanistically, these linkers are closely related to the Fmoc protective group, and... 

Imidazo[2- ]pyridines bound to solid supports via acid or base labile linkers can be prepared by reaction of resin-bound a-bromoketones with 2-aminopyridines <2003TL6265>. 5-Azaindoles may be prepared by cyclization of ortho-alkynyl aminopyridines in moderate to high yield in the presence of catalytic amounts of Cul <1998TL5159> (Equation 58). 

The wide use of acid-labile linkers and protecting groups in peptide SPS has reduced efforts toward the development of base-labile linkers. The commonly used SP Fmoc peptide coupling protocols require Fmoc deprotection under basic conditions during the synthesis, thus ruling out base-labile linkers. However, base-labile linkers are popular in oligonucleotide SPS and will be described in Section 2.2. Other examples of base- or nucleophile-labile linkers are shown in Fig. 1.10. 

The solid-phase synthesis of DNA oligomers has reached a high level of maturity and is extensively used for the synthesis of primers for polymerase chain reaction or the design of new genes (13). In contrast to the cellular process, the synthetic route forms the polymer in 3 -to-5 direction. The oligomerization is carried out on CPG using a base labile linker. Typically, the nucleobases are introduced as acyl-protected phosphoramidites,... 

Below, the usefulness of nucleophile- and base-labile linkers and resins is reviewed in the preparation of various organic compounds. First, intermolecular nucleophilic displacement (saponification, transesterification and amminolysis and related reactions) are analyzed. Finally, the obtention of cyclic products by intramolecular nucleophilic reactions is reviewed. 

Figure 19.10 Base-labile linkers for the synthesis of oligonucleotide 3 - or 5 -phosphates or phosphorothioates.

The linkage between the oligonucleotide-peptide conjugate and the solid support is usually a base-labile linker inspired by the oligonucleotide synthesis field (Fig. 5). Linkers from the peptide field are acid labile and not compatible with the oligonucleotide moiety. Most the linkers used to anchor the peptide moiety have an ester function that is cleaved with concentrated ammonia [13-17,46], ethylenediamine [34], ethanolamine [26], sodium hydroxide [27], or tetrabutylammonium fluoride (TBAF)... 

Our group has initiated a project to search for milder methods for the preparation of organometallic peptide conjugates by SPPS. By using a base-labile linker to the resin and suitable side-chain protecting groups, we were able to prepare acid-sensitive organometallics amendable to SPPS techniques. As an example, enkephalin derivatives with the covalently bound Mo(allyl)(GO)2 moiety such as 17 were successfully prepared (Scheme 19). An attractive... 

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