Deprotection Using Zinc Metal
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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 Lithium aluminium hydride, commonly abbreviated to LAH, is an inorganic compound with the chemical formula Li Al H4. It is a white solid, discovered by Finholt, Bond and Schlesinger in 1947. This compound is used as a reducing agent in organic ...
is a highly reactive but useful reagent capable of reducing esters to
alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...
s. 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).


Common protecting groups


Alcohol protecting groups

Protection of
alcohols In chemistry, an alcohol is a type of organic compound that carries at least one hydroxyl () functional group bound to a saturated carbon atom. The term ''alcohol'' originally referred to the primary alcohol ethanol (ethyl alcohol), which is ...
: : *
Acetyl In organic chemistry, acetyl is a functional group with the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, acetyl is called ethanoyl, ...
(Ac) – Removed by acid or base (see Acetoxy group). * Benzoyl (Bz) – Removed by acid or base, more stable than Ac group. * Benzyl (Bn) – Removed by hydrogenolysis. Bn group is widely used in sugar and nucleoside chemistry. * Methoxyethoxymethyl ether (MEM) – Removed by acid. *
Dimethoxytrityl Dimethoxytrityl, often abbreviated DMT, is a protecting group widely used for protection of the 5'-hydroxy group in nucleosides, particularly in oligonucleotide synthesis Oligonucleotide synthesis is the chemical synthesis of relatively short f ...
, is-(4-methoxyphenyl)phenylmethyl(DMT) – Removed by weak acid. DMT group is widely used for protection of 5'-hydroxy group in nucleosides, particularly in oligonucleotide synthesis. * Methoxymethyl ether (MOM) – Removed by acid. * Methoxytrityl 4-methoxyphenyl)diphenylmethyl(MMT) – Removed by acid and hydrogenolysis. * ''p''-Methoxybenzyl ether (PMB) – Removed by acid, hydrogenolysis, or oxidation - commonly with
DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (or DDQ) is the chemical reagent with formula C6Cl2(CN)2O2. This oxidant is useful for the dehydrogenation of alcohols, phenols, and steroid ketones. DDQ decomposes in water, but is stable in aqueous mi ...
. * ''p''-Methoxyphenyl ether (PMP) – Removed by oxidation. * Methylthiomethyl ether – Removed by acid. * Pivaloyl (Piv) – Removed by acid, base or reductant agents. It is substantially more stable than other acyl protecting groups. * Tert-butyl ethers (tBu) - Removed by acid. * Tetrahydropyranyl (THP) – Removed by acid. * Tetrahydrofuran (THF) – Removed by acid. * Trityl (triphenylmethyl, Tr) – Removed by acid and hydrogenolysis. *
Silyl ether Silyl ethers are a group of chemical compounds which contain a silicon atom covalently bonded to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl group. Silyl ethers are usually used as protecting g ...
(most popular ones include trimethylsilyl (TMS), ''tert''-butyldimethylsilyl (TBDMS or TBS), tri-''iso''-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers) – Removed by acid or
fluoride Fluoride (). According to this source, is a possible pronunciation in British English. is an inorganic, monatomic anion of fluorine, with the chemical formula (also written ), whose salts are typically white or colorless. Fluoride salts typ ...
ion. (such as NaF, TBAF ( tetra-''n''-butylammonium fluoride, HF-Py, or HF-NEt3)). TBDMS and TOM groups are used for protection of 2'-hydroxy function in nucleosides, particularly in oligonucleotide synthesis. * Methyl ethers – Cleavage is by TMSI in dichloromethane or acetonitrile or chloroform. An alternative method to cleave methyl ethers is BBr3 in DCM * Ethoxyethyl ethers (EE) – Cleavage more trivial than simple ethers e.g. 1N hydrochloric acid


Amine protecting groups

Protection of amines: * Carbobenzyloxy (Cbz) group – Removed by hydrogenolysis * ''p''-Methoxybenzyl carbonyl (Moz or MeOZ) group – Removed by hydrogenolysis, more labile than Cbz * ''tert''-Butyloxycarbonyl (BOC) group (common in solid phase peptide synthesis) – Removed by concentrated strong acid (such as HCl or CF3COOH), or by heating to >80 °C. * 9-Fluorenylmethyloxycarbonyl (
Fmoc The fluorenylmethoxycarbonyl protecting group (Fmoc) is a base-labile protecting group used in organic synthesis. Protection & Formation Fmoc carbamate is frequently used as a protecting group for amines, where the Fmoc group can be introduce ...
) group (Common in solid phase peptide synthesis) – Removed by base, such as piperidine *
Acetyl In organic chemistry, acetyl is a functional group with the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, acetyl is called ethanoyl, ...
(Ac) group is common in oligonucleotide synthesis for protection of N4 in cytosine and N6 in adenine nucleic bases and is removed by treatment with a base, most often, with aqueous or gaseous ammonia or
methylamine Methylamine is an organic compound with a formula of . This colorless gas is a derivative of ammonia, but with one hydrogen atom being replaced by a methyl group. It is the simplest primary amine. Methylamine is sold as a solution in methanol, ...
. Ac is too stable to be readily removed from aliphatic amides. * Benzoyl (Bz) group is common in oligonucleotide synthesis for protection of N4 in cytosine and N6 in adenine nucleic bases and is removed by treatment with a base, most often with aqueous or gaseous ammonia or methylamine. Bz is too stable to be readily removed from aliphatic amides. * Benzyl (Bn) group – Removed by hydrogenolysis *
Carbamate In organic chemistry, a carbamate is a category of organic compounds with the general formula and structure , which are formally derived from carbamic acid (). The term includes organic compounds (e.g., the ester ethyl carbamate), formally o ...
group – Removed by acid and mild heating. * ''p''-Methoxybenzyl (PMB) – Removed by hydrogenolysis, more labile than benzyl * 3,4-Dimethoxybenzyl (DMPM) – Removed by hydrogenolysis, more labile than ''p''-methoxybenzyl * ''p''-Methoxyphenyl (PMP) group – Removed by ammonium cerium(IV) nitrate (CAN) * Tosyl (Ts) group – Removed by concentrated acid (HBr, H2SO4) & strong reducing agents ( sodium in liquid ammonia or sodium naphthalenide) * Troc (trichloroethyl chloroformate ) group – Removed by Zn insertion in the presence of acetic acid * Other Sulfonamides (Nosyl & Nps) groups – Removed by samarium iodide, thiophenol or other soft thiol nucleophiles, or tributyltin hydride


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 acid A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any sp ...
s. * Dithianes – Removed by metal salts or oxidizing agents.


Carboxylic acid protecting groups

Protection of
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...
s: *
Methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...
esters – Removed by acid or base. * Benzyl esters – Removed by hydrogenolysis. * ''tert''-Butyl esters – Removed by acid, base and some reductants. * Esters of 2,6-disubstituted phenols (e.g. 2,6-dimethylphenol, 2,6-diisopropylphenol, 2,6-di-''tert''-butylphenol) – Removed at room temperature by DBU-catalyzed methanolysis under high-pressure conditions. * Silyl esters – Removed by acid, base and
organometallic Organometallic chemistry is the study of organometallic compounds, chemical compounds containing at least one chemical bond between a carbon atom of an organic molecule and a metal, including alkali, alkaline earth, and transition metals, and so ...
reagents. * Orthoesters – Removed by mild aqueous acid to form ester, which is removed according to ester properties. * Oxazoline – Removed by strong hot acid (pH < 1, T > 100 °C) or alkali (pH > 12, T > 100 °C), but not e.g. LiAlH4, organolithium reagents or Grignard (organomagnesium) reagents


Phosphate protecting groups

* 2-cyanoethyl – removed by mild base. The group is widely used in oligonucleotide synthesis. *
Methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...
(Me) – removed by strong nucleophiles ''e.c''. thiophenole/TEA.


Terminal alkyne protecting groups

*
Propargyl In organic chemistry, the propargyl group is a functional group of 2-propynyl with the structure . It is an alkyl group derived from propyne (). The term propargylic refers to a saturated position ( ''sp''3-hybridized) on a molecular framework n ...
alcohols in the Favorskii reaction, * Silyl groups, especially in protection of the
acetylene Acetylene (systematic name: ethyne) is the chemical compound with the formula and structure . It is a hydrocarbon and the simplest alkyne. This colorless gas is widely used as a fuel and a chemical building block. It is unstable in its pure ...
itself.


Other

*
Photolabile protecting groups A photolabile protecting group (PPG; also known as: photoremovable, photosensitive, or photocleavable protecting group) is a chemical modification to a molecule that can be removed with light. PPGs enable high degrees of chemoselectivity as they all ...


Orthogonal protection

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 (Fmoc) by bases (such as piperidine), and the phenolic ''tert''-butyl ether cleaved with acids (e.g. with trifluoroacetic acid). 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 (protection-deprotection sequence) 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 the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by ...
. 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''Synthetic studies of marine alkaloids hapalindoles. Part 3 Total synthesis of (±)-hapalindoles H and U'' Tetrahedron, Volume 46, Issue 18, 1990, Pages 6351–6360 Hideaki Muratake, Harumi Kumagami and Mitsutaka Natsume according to Baran, contained 20 steps with multiple protective group manipulations (two confirmed):


Industrial applications

Although the use of protecting groups is not preferred in industrial syntheses, they are still used in industrial contexts, e.g.: * Oseltamivir (Tamiflu, an antiviral drug) synthesis by Roche *
Sucralose Sucralose is an artificial sweetener and sugar substitute. The majority of ingested sucralose is not broken down by the body, so it is noncaloric. In the European Union, it is also known under the E number E955. It is produced by chlorination of ...
(sweetener)


References


External links


Introduction of protecting group and mechanism of deprotection

Senior undergraduate study notes on this subject, from Prof. Rizzo.

A further set of study notes in tutorial form, with guidance and comments, from Profs. Grossman and Cammers.

A review by Prof. Kocienski.

A user site excerpting the classic Greene and Wuts text regarding stability of a few key groups, from this reference's extensive tables.
{{DEFAULTSORT:Protecting Group Chemical synthesis