Protecting group


A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis.
In many preparations of delicate organic compounds, some specific parts of their molecules cannot survive the required reagents or chemical environments. Then, these parts, or groups, must be protected. For example, lithium aluminium hydride is a highly reactive but useful reagent capable of reducing esters to alcohols. It will always react with carbonyl groups, and this cannot be discouraged by any means. When a reduction of an ester is required in the presence of a carbonyl, the attack of the hydride on the carbonyl has to be prevented. For example, the carbonyl is converted into an acetal, which does not react with hydrides. The acetal is then called a protecting group for the carbonyl. After the step involving the hydride is complete, the acetal is removed, giving back the original carbonyl. This step is called deprotection.
Protecting groups are more commonly used in small-scale laboratory work and initial development than in industrial production processes because their use adds additional steps and material costs to the process. However, the availability of a cheap chiral building block can overcome these additional costs.

Common protecting groups

Alcohol protecting groups

Protection of alcohols:
Protection of amines:
Protection of carbonyl groups:
Protection of carboxylic acids:
Orthogonal protection is a strategy allowing the specific deprotection of one protective group in a multiply-protected structure without affecting the others. For example, the amino acid tyrosine could be protected as a benzyl ester on the carboxyl group, a fluorenylmethylenoxy carbamate on the amine group, and a tert-butyl ether on the phenol group. The benzyl ester can be removed by hydrogenolysis, the fluorenylmethylenoxy group by bases, and the phenolic tert-butyl ether cleaved with acids.
A common example for this application, the Fmoc-peptide synthesis, in which peptides are grown in solution and on solid phase is very important. The protecting groups in solid-phase synthesis with regard to the reaction conditions such as reaction time, temperature and reagents can be standardized so that they are carried out by a machine, while yields of well over 99% can be achieved. Otherwise, the separation of the resulting mixture of reaction products is virtually impossible.
The technique was introduced in the field of peptide synthesis by Robert Bruce Merrifield in 1977. As a proof of concept orthogonal deprotection is demonstrated in a photochemical transesterification by trimethylsilyldiazomethane utilizing the kinetic isotope effect:
Due to this effect the quantum yield for deprotection of the right-side ester group is reduced and it stays intact. Significantly by placing the deuterium atoms next to the left-side ester group or by changing the wavelength to 254 nm the other monoarene is obtained.

Criticism

The use of protective groups is pervasive but not without criticism. In practical terms their use adds two steps to a synthesis, either or both of which can dramatically lower chemical yield. Crucially, added complexity impedes the use of synthetic total synthesis in drug discovery. In contrast biomimetic synthesis does not employ protective groups. As an alternative, Baran presented a novel protective-group free synthesis of the compound hapalindole U. The previously published synthesis according to Baran, contained 20 steps with multiple protective group manipulations :

Industrial applications

Although the use of protecting groups is not preferred in industrial syntheses, they are still used in industrial contexts, e.g.: