Protecting groups basic-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. 

Enamines derived from simple ketones and aliphatic amines are too acid-labile and nucleophilic to be useful as protective group for amines. Triacylmethanes, however, form less basic enamines, which are sufficiently stable to be of use as amine protection. 

In the final product there is scrambling of label between the 17 and 15 positions. The strongly basic conditions required in the Wittig reaction necessitate the protection of base-labile groups. Thus the 3- and 13-hydroxy groups can be converted to trimethylsilyl ethers (38) or tetrahydropyranyl ethers which are then easily removed by mild acid treatment. 

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. 

Alternatively, acid fluorides are used to activate the acid. Acyl fluorides are less sensitive to moisture and are more reactive toward primary and secondary amines than the corresponding acyl chloride. Furthermore, they are compatible with basic- (Fmoc and Cbz) or even acid- (Boc) labile amine protecting groups and less prone to promote racemization than their chlorinated homologs (26). Thus, the acid fluoride method is often used in peptide synthesis (27). Cyanuric fluoride 9 (28), TFFH (29), DAST (30), and deoxofluor (31) are used commonly as fluori-nating reagents (see Fig. 4). 

The Af -acyl groups used in these protection schemes are the formyl and trifluoroacetyl groups. With the advent of alternative alkali-labile amine protecting groups that are cleaved via (3-elimination under milder basic conditions, e.g. 9-fluorenylmethoxycarbonyl (see Section 2.1.1.1.1.3) and substituted sulfonylethyloxycarbonyl groups (see Section 2.1.1.1.1.4), the... 

The stability of ethers and mixed acetals as protecting groups for alcohols varies from the very stable methyl ether to the highly acid-labile trityl ether. However, all ethers are stable to basic reaction conditions. Hence, ether or mixed acetal protecting groups specifically tolerate... 

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