Introduction and removal of alkyl protecting groups of several common amino groups

Introduction and removal of alkyl-protecting groups of several common amino groups

In the previous article, we reviewed the common alkoxy carbonyl amino-protecting groups. In this article, we will review another common amino-protecting group—the alkyl-protecting group. These common protecting groups mainly include trityl (Trt), benzyl (Bn), p-methoxybenzyl (PMB), and 2,4-dimethoxybenzyl(DMB). The main features of this type of protecting group are: that they are stable under alkaline conditions, and usually the protected amino group does not easily continue the alkylation reaction. In contrast, the amino group protected by the alkoxycarbonyl group is prone to further alkylation reaction under alkaline conditions due to the enhanced hydrogen acidity on the nitrogen.

(1) Trityl (Trt)

Trityl (Trt) was first used in the synthesis of polypeptides in the 1950s and was also used to protect various amino groups, such as amino acids, penicillins, and cephalosporins. The esters of N-Trt-α-amino acids cannot be hydrolyzed and require strong deprotection conditions. The α-protons are also not easy to remove, which means that esters elsewhere in the molecule can be selectively hydrolyzed.

In the peptide-grafting reaction, Trt-amino acids (except Trt-Gly and Trt-Ala) generally cannot be grafted to peptides by the mixed anhydride method, and the esters of Trt-amino acids cannot be hydrolyzed, so the azide method cannot be used to graft peptides, but only A method such as DCC is used to pick up the peptide. However, the steric hindrance of Trt is only reflected in the reaction to Trt-amino acids, so Trt is still available for the protection of the terminal amino groups of long-chain peptides, especially for peptides with sulfur-containing amino acids, because it cannot be used Catalytic hydrogenolysis is used to achieve selective removal between Cbz and Boc, and Trt will be a better choice.

1.1 Introduction of Trityl (Trt)

Amino groups and triphenylchloromethane can react easily under alkaline conditions. It should be noted that due to the large steric hindrance of Trt, generally Trt-amino acid esters are difficult to saponify (except glycine esters), and strong conditions (such as high temperature) are likely to cause racemization. In addition, if the nitrogen atom on the amino acid needs to introduce trityl (Trt), the following methods can be used: (1) First prepare Trt-amino acid benzyl ester, and then control the amount of hydrogen absorbed for selective hydrogenolysis, but part of Trt is hydrogenated, it is necessary to remove the associated free amino acid; (2) use excess Trt-Cl to generate Trt-amino acid trityl ester, and then use HCl/HOAc to remove the trityl ester to obtain Trt-amino acid; (3) use Trt-Cl /Me3SiCl/Et3N and Trt-Cl/TMSCl/Et3N are also easy to get Trt-amino acid

Introducing a protected base instance:

1.2 Removal of Trityl (Trt)

Trt is easily removed by acid, such as HOAc or 50% (or 75%) HOAc aqueous solution at 30 ° C or reflux for several minutes to remove smoothly. At this time, N-Boc and O-But can be stable. Others such as HCl/MeOH, HCl/CHCl3, HBr/HOAc, and TFA can easily remove Trt.

The sensitivity of Trt to acid also varies with the acid used. For example, Trt is more sensitive to acetic acid. In 80% acetic acid, the removal rate of Trt is about 21,000 times faster than that of Boc, so it can be selectively removed in the presence of Boc. If 0.1M HBr/HOAc is used as the reagent, the removal rate of Trt is slower than that of Boc.

Trt can also be removed by catalytic hydrogenolysis, but at a much slower rate than O-benzyl and N-Cbz. Depending on the reagents used and the removal method, the products formed by the decomposition of Trt are also different (see the formula below).

Example of deprotection:

(2) Benzyl (Bn)

Benzyl (Bn) is also one of the most stable amino-protecting groups and is stable in most reactions. The benzyl group of the amide is not easily removed by conventional hydrogenation methods but can be removed by Na/NH3.

2.1 Introduction of benzyl (Bn)

Generally, it is introduced by reacting C6H4CH2Br or C6H4CH2Cl with K2CO3, DIPEA, NaH, Et3N in an organic solvent (such as DMF, dichloromethane, acetonitrile, etc.), or using a reducing agent such as NaBH4, NaBH3CN or NaBH(OAc)3 with benzaldehyde Under the condition of, it is prepared by reductive amination.

Introducing a protected base instance:

2.2 Removal of benzyl group (Bn)

Bn is often removed by catalytic hydrogenolysis, such as H2, 20%Pd(OH)2/C, H2/Pd-C, H2/PdCl2, Pd/HCOOH or Pd-C/HCOOH, Pd-C/HCOONH4, Pd-C/ NH2NH2 or Pd-C/cyclohexene as hydrogen source transfer hydrogenation. When using catalytic hydrogenation (H2, Pd/C) to debenzyme, the reaction is usually slow due to the chronic poisoning of the palladium catalyst by the amine, and the reaction is not complete. Generally, add acid or Boc2O to promote the departure of Bn. Catalytic hydrogenolysis selectivity: Cbz, -OBn>R2NBn

When there are hydrogenation-sensitive functional groups in the molecule, the commonly used methods are CH3CHClOCOCl, bromonitrile, and CCl3CH2COCl/CH3CN. Li/MH3, Na/NH3, and CAN are also available. The benzyl group on the amide is generally difficult to remove by hydrogenolysis, and AlCl3 can be used to remove it at this time.

Example of deprotection:

(3) p-methoxybenzyl (PMB)

p-Methoxybenzyl (PMB) is also one of the most stable amino-protecting groups. It is stable to most reactions and can be used for selective removal of PMB by CAN or DDQ oxidation in the presence of Bn; similarly, selective removal of PMB by CAN oxidation can be used in the presence of Boc and tert-butyl ester; H2/Pd(OH) can also be used 2 Remove Bn while retaining PMB.

3.1 Introduction of p-methoxybenzyl (PMB)

PMB is generally introduced by reacting amino groups with MeOC6H4CH2Cl under alkaline conditions (K2CO3, i-Pr2NEt, etc.) in organic solvents (such as DMF, dichloromethane, and acetonitrile, etc.), and can also be prepared by reductive amination.

Introducing a protected base instance:

3.2 Removal of p-methoxybenzyl (PMB)

The removal of p-methoxybenzyl (PMB) is more, generally using CAN, DDQ, or SmI2 oxidation deprotection, and heating in TFA is also often used.

Example of deprotection:

(4) 2,4-Dimethoxybenzyl (DMB)

2,4-Dimethoxybenzyl (DMB) is one of the more stable amino protecting groups, and it is more stable than Cbz, PMB, and Bn for catalytic hydrogenolysis, so it can be treated with H2/8%Pd-C/EtOH Bn is removed while N-DMB remains. Be careful not to replace 2,4-dimethoxy benzyl with 3,4 - 3,4-dimethoxy benzyl, 3,5 -3,5-dimethoxy benzyl

Similarly, by treating with Pd(PPh3)4/HOAc/THF, N-DMB can be retained and Alloc can be removed. The benzyl group of amides is not easily removed by conventional hydrogenation methods, but DMB and PMB are easily removed. In addition, 2,4-dimethoxybenzylamine can be used as an equivalent of ammonia when designing a synthetic route.

4.1Introduction of 2,4-dimethoxy benzyl (DMB)

2,4-dimethoxybenzyl (DMB) is generally introduced by reductive amination, or 2,4-dimethoxybenzylamine is introduced as an amino equivalent.

Introducing a protected base instance:

4.2 Removal of 2,4-dimethoxy benzyl (DMB)

DMB is easy to remove with acid, such as an organic solution of TFA, TsOH or HCl can be removed smoothly at 0°C or room temperature. Others such as DDQ/CH2Cl2 can also remove DMB very conveniently, while tert-butyl ester and N-Boc can be unaffected.

Example of deprotection:

Although the alkyl-protecting group of the amino group is not as commonly used as the alkoxycarbonyl-protecting group, it shows its unique value and function in some specific syntheses. Therefore, we need to comprehensively consider the advantages and characteristics of various protecting groups in the synthesis to give full play to their value.

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