Organic synthesis is an important part of organic chemistry. Through organic synthesis, people have synthesized many products with excellent properties that exist or do not exist in nature. However, in organic synthesis, it is often encountered that several sites or functional groups in a molecule may react with the reactants, and only specific sites are needed for the reaction process, but no reaction conditions or reagents with selectivity can be found. In this case, the corresponding functional groups can be selectively protected and then reduced after the end of the reaction. Thus, the target product can be synthesized in the targeted manner. These groups that can temporarily introduce some functional groups from the reaction are called protecting groups, and the reagents that can provide the protecting groups are called protection reagents.
Characteristics of the ideal protection reagents
For a protection reagent to find wide application in organic synthesis, it must fulfill several criteria.
- Selectively and easily reacts with protected groups to achieve high conversion rates.
- Be stable under all the conditions used during the synthesis, including those of the purification steps, up to the step in which the protecting group is removed, it should, as far as possible, have a stabilizing effect on the molecule and should suppress racemization or epimerization.
- The protecting group in the protection reagents can be safely removed at the end of the synthetic process or when the functional group requires manipulation.
- The protection reagents used are readily available, and the reaction is easy to handle and less contaminated.
The main applications of protection reagents in organic synthesis are as follows.
- In carbohydrate chemistry
Protection reagents play a key role in the synthesis of complex natural products. This holds especially true for the synthesis of oligosaccharides, of which the monomeric carbohydrate building blocks usually contain up to five different hydroxyl functions and can also bear amino and carboxylate groups. Discrimination of these functionalities requires a careful protecting group strategy and typically involves multistep protocols. Protecting groups in carbohydrates not only differentiate the same sort of functional groups to expose the one needed to be reacted, but also confer other effects to the molecules in glycosylation reactions. For example, Yang and Yu introduced the N-dimethylphosphoryl (DMP) group for the protection of the glucosamine nitrogen. The DMP-group was used in the synthesis of several β-glucosamines, and shown to be stable to certain basic and acidic reaction conditions and could be readily removed using NaOH or hydrazine. Alternatively, the N-DMP could be transformed into N-acyl derivatives using an acyl chloride in refluxing pyridine.
Figure 1. Novel glucosamine N-protection reagents
- In peptide chemistry
There are many methods for peptide synthesis, among which the more common method is to apply N, N'-Dicyclohexylcarbodiimide as condensation agent. Several polypeptides can be synthesized with long peptide chains by linking them together in the same way. The key of peptide synthesis is the protection of amino group. Some amino acids contain other functional groups in addition to amino and carboxyl groups. In the synthesis of peptides, they are also protected by appropriate protection reagents. Proper protection reagents manipulation strategies can maximize the yield of the desired product or allow the construction of complex peptide-based structures. A simple protocol for the protection of amines was realized through a base-catalyzed one-pot reaction of dimedone, β-nitroalkene, and amine. Employing this strategy, a variety of amines/amino acids were protected in excellent yields. These acid/ base stable protected amines can be deprotected by either ethylene diamine or hydrazine hydrate under mild conditions.
Figure 2. Protection and deprotection of amines and amino acids
- In oligonucleotide synthesis
Nucleotides are composed of pentose (ribose, deoxyribose), substituted purine or pyrimidine bases and phosphoric acid. In the chemical synthesis of natural products having phosphoric acid esters, the selection of the phosphate protection reagents is of great importance. Up to date, a few silicon-based phosphate protection reagents have been proposed. For instance, 2-(trimethylsilyl) propen-2-yl, 2-(triphenyl silyl) ethyl, and 2-(trimethylsilyl)ethyl groups were explored for the phosphomonoester protection. These groups involve "trialkylsilylethyl" backbone structures, which can be deprotected by fluoride ion via p-elimination mechanism.
Figure 3. phosphate protection reagents and deprotection mechanisms
At present, Alfa Chemistry mainly provides various protective reagents, such as silylation reagents, acylation reagents, thioacetalization reagents, etc. If you do not find what you need, please contact us. We also offer product customization according to customer's detailed requirements.
- Yang, Y.; et al. N-Dimethylphosphoryl-protected glucosamine trichloroacetimidate as an effective glycosylation donor. Tetrahedron Lett. 2007, 48: 4557-4560.
- Sivanna, C.; et al. Application of dimedone enamines as protecting groups for amines and peptides. Organic Letters. 2020, 22: 2391-2395.