Amino group is a reactive and easily oxidized group. Compounds with amino groups are sensitive to reactions such as oxidation and substitution. In organic synthesis, in order to keep the amino group unchanged when other functional groups in the molecule react, it is usually necessary to protect the amino group with a group that is easy to remove.
The choice of amino protecting group plays an important role in the success or failure of many synthetic efforts. When choosing an amino protecting group, all reactants, reaction conditions, and all functional groups involved in the reaction process need to be considered. The selected amino protecting group needs to exist stably in the following several steps of reactions, and will not be removed or partially removed in subsequent reactions, post-reaction treatment, separation and purification and other operations.
In synthetic reactions, the amino groups in primary amines, secondary amines, imidazoles, pyrroles, indole and other aromatic nitrogen heterocycles often need to be protected. Commonly used amino protecting groups can be roughly divided into three categories: alkoxycarbonyl, acyl and alkyl. The most commonly used amino protecting groups are Cbz (Z), Fmoc and Boc.
The following are several representative commonly used amino protecting groups:
1. Alkoxy protecting groups
Alkoxy-type protecting groups can be used to protect amino acids and reduce the degree of racemization in peptide synthesis.
Alkoxy amino protecting groups
Benzyloxycarbonyl (Cbz) is an amino protecting group that has been discovered for a long time. The advantages of Cbz are: the preparation of reagents and the introduction of protective groups are relatively easy; its protected amino acids and peptides are easy to crystallize and are relatively stable; its protected amino acids are not easily racemized during activation; it can be selectively desorbed by a variety of mild methods remove.
Tert-butoxycarbonyl (BOC) is a widely used amino protecting group in peptide synthesis. Its advantages are as follows: its protected amino acid is easy to crystallize and easy to be removed by acidolysis, but still has certain stability; generally does not bring side reactions; it is stable to alkali hydrolysis, hydrazinolysis, catalytic hydrogenolysis and many nucleophiles.
9-Fluorenemethoxycarbonyl (FMOC) is frequently used to protect amino groups through carbamate formation, most commonly in peptide solid-phase synthesis methods. The FMOC protecting group is very stable to acidity. In addition, it is also easy to remove under contact reduction conditions. This protecting group has complementary effects with Boc and Cbz protecting groups
Different from Cbz, Boc and Fmoc, allyloxycarbonyl (Alloc) is stable to acids and bases. Its removal is usually carried out in the presence of Pd(0).
Commonly used acyl protecting groups include, for example: Pht, Tos, Tfa, Nbs and SES, etc.
Acyl amino protecting groups
Phthaloyl (Pht) is stable to catalytic hydrogenolysis, HBr/HOAc treatment, and Na/NH3 reduction, but not to bases. Its protected amino acids are not easily racemized during peptide synthesis.
Tosyl (Tos) is one of the most stable amino protecting groups, stable to alkaline hydrolysis and catalytic reduction, and is generally used as the side chain protecting group of basic amino acids.
Trifluoroacetyl (Tfa) was the first group introduced into peptide synthesis. The protected amino acids or peptides are easily vaporized at high temperature, so they can be used in gas chromatography.
Commonly used alkyl protecting groups include such as Trt, DMB, PMB, Bn, Al, SEM and t-Bu.
Alkyl amino protecting group
The trityl group (Trt) with great steric hindrance is used to protect various amino groups, such as amino acids, penicillin, etc.
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2,4-Dimethoxybenzyl (Dmb) is one of the more stable amino protecting groups and is stable to catalytic hydrogenolysis.
p-Methoxybenzyl (PMB) is also one of the most stable amino protecting groups, which is stable to most reactions.
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Benzyl (Bn) is also one of the most stable amino protecting groups. Like PMB, Bn is stable to most reactions. But Bn is more stable than PMB and more difficult to remove.