Protective group

Protecting group

A protecting group or protective group is introduced into a molecule by chemical modification of a functional group in order 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 (by reacting it with an aqueous acid), 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 (e.g. shikimic acid for oseltamivir). While additional synthetic steps are required for protection and deprotection, reactions are typically much cleaner, proceed in higher yields, and require less optimization with protecting groups than without.

Common protecting groups

Alcohol protecting groups

Protection of alcohols:

Acetyl (Ac) - Removed by acid or base. (see Acetoxy_group)
β-Methoxyethoxymethyl ether (MEM) - Removed by acid.
Methoxymethyl ether (MOM) - Removed by acid.
p-Methoxybenzyl ether (PMB) - Removed by acid, hydrogenolysis, or oxidation.
Methylthiomethyl ether - Removed by acid.
Pivaloyl (Piv) - Removed by acid, base or reductant agents. It is stronger than other acyl protecting groups.
Tetrahydropyran (THP) - Removed by acid.
Silyl ether (most popular ones include trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), and triisopropylsilyl (TIPS) ethers) - Removed by acid or fluoride ion. (such as NaF or TBAF (Tetra-n-butylammonium fluoride))
Methyl Ethers (cleavage is by TMSI in DCM or MeCN or Chloroform the other method to cleave methyl ethers is BBr₃ in DCM)

Amine protecting groups

Protection of amines:

Carbobenzyloxy (Cbz) group - Removed by hydrogenolysis
tert-Butyloxycarbonyl (BOC) group (Common in solid phase peptide synthesis) - Removed by concentrated, strong acid. (such as HCl or CF₃COOH)
9-Fluorenylmethyloxycarbonyl (FMOC) group (Common in solid phase peptide synthesis) - Removed by base, such as piperidine.
Benzyl (Bn) group - Removed by hydrogenolysis
p-methoxyphenyl (PMP) group - Removed by Ammonium cerium(IV) nitrate (CAN)

Carbonyl protecting groups

Protection of carbonyl groups:

Acetals and Ketals - Removed by acid. Normally, the cleavage of acyclic acetals is easier than of cyclic acetals.
Acylals - Removed by Lewis acids.
Dithianes - Removed by metal salts or oxidizing agents.

Carboxylic acid protecting groups

Protection of carboxylic acids:

Methyl esters - Removed by acid or base.
Benzyl esters - Removed by hydrogenolysis.
tert-Butyl esters - Removed by acid, base and some reductants.
Silyl esters - Removed by acid, base and organometallic reagents

Miscellaneous

Terminal alkynes can be protected as propargyl alcohols in the Favorskii reaction.

Orthogonal protection

Orthogonal protection is a strategy allowing the deprotection of multiple protective groups one at the time each with a dedicated set of reaction conditions without affecting the other. It 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

In a 2007 paper Phil Baran notes that even though the textbooks state that the use of protective groups is unavoidable and ideally easily added and removed, in practical terms in organic synthesis their use adds two synthetic steps in a chemical sequence and sometimes dramatically lowers 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 (two confirmed):