Protecting group

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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.

Acetal protection of a ketone during reduction of an ester, vs. reduction to a diol when unprotected.

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).

Common protecting groups[edit]

Alcohol protecting groups[edit]

Protection of alcohols:

  • Acetyl (Ac) – Removed by acid or base (see Acetoxy group).
  • Benzoyl (Bz) – Removed by acid or base, more stable than Ac group.
  • Benzyl (Bn, Bnl) – Removed by hydrogenolysis. Bn group is widely used in sugar and nucleoside chemistry.
  • β-Methoxyethoxymethyl ether (MEM) – Removed by acid.
  • Dimethoxytrityl, [bis-(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.
  • Methylthiomethyl ether – Removed by acid.
  • Pivaloyl (Piv) – Removed by acid, base or reductant agents. It is substantially more stable than other acyl protecting groups.
  • Tetrahydropyranyl (THP) – Removed by acid.
  • Tetrahydrofuran (THF) - Removed by acid.
  • Trityl (triphenylmethyl, Tr) – Removed by acid and hydrogenolysis.
  • Silyl ether (most popular ones include trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers) – Removed by acid or fluoride 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 DCM or MeCN 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[1]

Amine protecting groups[edit]

BOC glycine. The tert-Butyloxycarbonyl group is marked blue.

Protection of amines:

Carbonyl protecting groups[edit]

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[edit]

Protection of carboxylic acids:

Phosphate protecting groups[edit]

  • 2-cyanoethyl – removed by mild base. The group is widely used in oligonucleotide synthesis.
  • Methyl (Me) – removed by strong nucleophiles e.c. thiophenole/TEA.

Terminal alkyne protecting groups[edit]

Orthogonal protection[edit]

Orthogonal protection of L-Tyrosin (Protecting groups are marked in blue, the amino acid is shown in black). (1) Fmoc-protected amino group, (2) benzyl ester protected carboxyl group and (3) tert-butyl ether protected phenolic hydroxyl group of Tyrosine.

Orthogonal protection is a strategy allowing the deprotection of multiple protective groups one at a time each with a dedicated set of reaction conditions without affecting the other. In the example shown, the protected amino acid tyrosine, 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.[5] 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.[6]

The technique was introduced in the field of peptide synthesis by Robert Bruce Merrifield in 1977.[7] As a proof of concept orthogonal deprotection is demonstrated in a photochemical transesterification by trimethylsilyldiazomethane utilizing the kinetic isotope effect:[8]

Orthogonal protection Application in Photochemistry

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[edit]

In a 2007 paper[9] Phil Baran notes that even though the textbooks state that the use of protective groups is unavoidable and that they are ideally easily added and removed, in practical terms in organic synthesis their use adds two synthetic steps (protection-deprotection sequence) to 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[10][11][12] according to Baran, contained 20 steps with multiple protective group manipulations (two confirmed):

Protected and unprotected syntheses of the marine alkaloid, hapalindole U.
Hideaki Muratake's 1990 synthesis using Tosyl protecting groups (shown in blue).
Phil Baran's protecting-group free synthesis, reported in 2007.

Industrial applications[edit]

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

External links[edit]

For introduction of protecting group and mechanism of deprotection See : http://www.biocis.u-psud.fr/spip.php?article332

References[edit]

  1. ^ Kamaya, Yasushi; T Higuchi (2006). "Metabolism of 3,4-dimethoxycinnamyl alcohol and derivatives by Coriolus versicolor". FEMS Microbiology Letters 24 (2–3): 225–229. doi:10.1111/j.1574-6968.1984.tb01309.x. 
  2. ^ Moussa, Ziad; D. Romo (2006). "Mild deprotection of primary N-(p-toluenesufonyl) amides with SmI2 following trifluoroacetylation". Synlett 2006 (19): 3294–3298. doi:10.1055/s-2006-951530. 
  3. ^ Romanski, J.; Nowak, P.; Kosinski, K.; Jurczak, J. (Sep 2012). "High-pressure transesterification of sterically hindered esters". Tetrahedron Lett. 53 (39): 5287–5289. doi:10.1016/j.tetlet.2012.07.094. 
  4. ^ Clayden, Jonathan; Greeves, Nick; Warren, Stuart; Wothers, Peter (2000). Organic Chemistry. Oxford University Press. p. 1291. ISBN 978-0198503460. 
  5. ^ Chan, Weng C.; White, Peter D. (2004). Fmoc Solid Phase Peptide Synthesis. Oxford University Press. ISBN 0-19-963724-5. 
  6. ^ Weng C. Chan, Peter D. White: Fmoc Solid Phase Peptide Synthesis, S. 10–12.
  7. ^ Merrifield, R. B.; Barany, G.; Cosand, W. L.; Engelhard, M.; Mojsov, S. (1977). "Proceedings of the 5th American Peptide Symposium". Biochemical Education 7 (4): 93–94. doi:10.1016/0307-4412(79)90078-5. 
  8. ^ Blanc, Aurélien; Bochet, Christian G. (2007). "Isotope Effects in Photochemistry: Application to Chromatic Orthogonality". Org. Lett. 9 (14): 2649–2651. doi:10.1021/ol070820h. 
  9. ^ Baran, Phil S.; Maimone, Thomas J.; Richter, Jeremy M. (22 March 2007). "Total synthesis of marine natural products without using protecting groups". [[Nature (journal)|]] (446): 404–408. doi:10.1038/nature05569. 
  10. ^ Synthetic studies of marine alkaloids hapalindoles. Part I Total synthesis of (±)-hapalindoles J and M Tetrahedron, Volume 46, Issue 18, 1990, Pages 6331–6342 Hideaki Muratake and Mitsutaka Natsume doi:10.1016/S0040-4020(01)96005-3
  11. ^ Synthetic studies of marine alkaloids hapalindoles. Part 2. Lithium aluminum hydride reduction of the electron-rich carbon-carbon double bond conjugated with the indole nucleus Tetrahedron, Volume 46, Issue 18, 1990, Pages 6343–6350 Hideaki Muratake and Mitsutaka Natsume doi:10.1016/S0040-4020(01)96006-5
  12. ^ 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 doi:10.1016/S0040-4020(01)96007-7