Protecting group
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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).
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[edit] Common protecting groups
[edit] 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)
[edit] 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)
[edit] 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.
[edit] 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
[edit] Miscellaneous
- Terminal alkynes can be protected as propargyl alcohols in the Favorskii reaction.
[edit] 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 [1]. As a proof of concept orthogonal deprotection is demonstrated in a photochemical transesterification by trimethylsilyldiazomethane utilizing the kinetic isotope effect [2]:
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.
[edit] Criticism
In a 2007 paper [3] Phil Baran notes that even though the textbooks state that the use of protective groups is unavoidable and ideally easy added and removed, in practical terms in organic synthesis their use adds two synthetic steps in a chemical sequence and sometimes 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 [4] [5] [6] according to Baran, contained 20 steps with multiple protective group manipulations (two confirmed):
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| Hapalindole U Baran 2007 protective-group free | Hapalindole U Muratake 1990 Ts protective groups in blue |
[edit] External links
- A good first set of senior undergraduate study notes on this subject, opening with important citations, from Prof. Rizzo.
- A further set of study notes in tutorial form, with insightful guidance and comments, from Profs. Grossman and Cammers.
- A review by Prof. Kocienski (et al.), masters in this field.
- A user site excerpting the classic Greene and Wuts text regarding stability of a few key groups, from this reference's extensive tables.
[edit] References
- ^ Merrifield, R. B.; Barany, G.; Cosand, W. L.; Engelhard, M.; Mojsov, S. Pept.: Proc. Am. Pept. Symp. 5th 1977
- ^ Isotope Effects in Photochemistry: Application to Chromatic Orthogonality Aurélien Blanc and Christian G. Bochet Org. Lett.; 2007; 9(14) pp 2649 - 2651; (Letter) doi:10.1021/ol070820h 10.1021/ol070820h
- ^ Total synthesis of marine natural products without using protecting groups Phil S. Baran, Thomas J. Maimone1 & Jeremy M. Richter Nature 446, 404-408 (22 March 2007) doi:10.1038/nature05569
- ^ 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
- ^ 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
- ^ 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
