Base protecting group

Fig. 23. Representative protecting groups for phenolic and carboxylic acid-based systems, (a) The polymer-based protecting groups are fisted in order of increasing activation energy for acid-catalyzed deprotection, (b) Acid-labile monomeric dissolution inhibitors, a bifunctional system based on protected bisphenol A. (c) Another system that combines the function of dissolution inhibitor and PAG in a single unit.

Trityl resins are particularly suitable for immobilization of nucleophilic substrates such as acids, alcohols, thiols, and amines. They are quite acid-sensitive and are cleavable even with acetic acid this is useful when acid-labile protecting groups are used. The stability of trityl resin can be tailored by use of substituted arene rings, as shown by chlorotrityl resin, which furnishes a more stable linker than the trityl resin itself. Steric hindrance also prohibits formation of diketopiperazines during the synthesis of peptides. Orthogonality toward allyl-based protective groups was demonstrated in the reverse solid-phase peptide synthesis of oligopeptides [30] (Scheme 6.1.4). 

As discussed above, each linker family is sensitive toward a certain spectrum of cleavage conditions and is therefore stable to dissimilar conditions. Since most of the linkers are based on well-established protecting groups, table 6.1.2 can be used for the determination of orthogonality. For example, benzyl-type linkers, most of which are cleaved by electrophiles, and are stable towards nucleophiles, can be combined with ester-based protective groups. 

The synthetic potential of silyl ethers as protecting groups for hydroxyls is based on the fact that they can be easily introduced and cleaved under mild conditions and their relative stability can be tuned by varying the substituents on silicon. In carbohydrate chemistry, the tert-butyl-dimethylsilyl (TBDMS), terl-butyldiphenylsilyl (TBDPS) and triethyl-silyl (TES) ethers are the most often applied silicon-based protecting groups (Scheme 2.9).23... 

Silicon-based protecting groups for alcohols are the best because they are the most versatile. They are removed by nucleophilic displacement with fluoride or oxygen nucleophiles and the rate of removal depends mostly on the steric bulk of the silyl group. The simplest is trimethylsilyl (Mt Si or often just TMS) which is also the most easily removed as it is the least hindered. Tn fact, it is removed so easily by water with a trace of base or acid that special handling is required to keep this labile group in place. 

The 4-methyltrityl group (Mtt, 115) has been used mainly for co-protection of lysine, ornithine, or histidine residues.It is cleaved under very noild acidic conditions (Table 12) where the terf-butyl alcohol-based protecting groups are unaffected.f Similarly, the... 

It must be remembered that hydrazine treatment of peptides containing allyl-based protecting groups also results in reduction of the aUyl moiety 0 4 this is successfully prevented by adding a 200-fold excess of allyl alcohol as a scavenger.O Moreover, hydrazine treatment of peptides may lead to aspartimide formation in the case of cyclization-prone Asn-Xaa and Asp-Xaa sequences (see Section 2.2.2). 

Scheme 8 The Structures of Benzyl-Based Protecting Groups Containing a Dimethylcarbamoyl Moiety ...

With a similar intention, 1-adamantyl and 2-adamantyl residue-based protecting groups were developed. (3-1- and (3-2-Adamantylaspartates,P Y-(2-adamantyl)glutamate,P A -(2-ada-mantyloxycarbonyl)lysine,P l A -(2-adamantyloxycarbonyl)histidine,P Af -(l-adamantyl-... 

Human parathyroid hormone, hPTH (1-84) was synthesized by the maximum protection method using Bzl-based protecting groups. The synthetic route is shown in Scheme 29. 

Protected peptides were also quantitatively detached from Trt(2-Cl)-Cl resin using HFIP/CH2CI2 (1 4) (5mL g of resin, 3 min). Neutralization of the effluents with MeOH/pyridine (9 1) was carried out because several tBu-based protecting groups were not completely stable to the cleavage conditions. 

Protection of the Trp side chain in Fmoc synthesis is not always essential. However, if it is in close proximity to an Arg in the sequence where sulfonyl-based protection is employed then protection of the indole nitrogen with Boc is often recommended. This eliminates the back addition of the sulfonyl-based protecting group since the indole is protected as a carbamic acid during the TFA treatment. Exposure to mildly acidic aqueous conditions releases the free indole nucleus. 

---