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, specific parts of the molecules cannot survive the required reagents or chemical environments. These parts (functional groups) must be protected. For example, lithium aluminium hydride is a highly reactive reagent that usefully reduces esters to alcohols. It always reacts with carbonyl groups, and cannot be discouraged by any means. When an ester must be reduced in the presence of a carbonyl, hydride attack on the carbonyl must be prevented. One way to do so converts the carbonyl into an acetal, which does not react with hydrides. The acetal is then called a protecting group for the carbonyl. After the hydride step is complete, aqueous acid removes the acetal, restoring the carbonyl. This step is called deprotection.
Protecting groups are more common in small-scale laboratory work and initial development than in industrial production because they add additional steps and material costs. However, compounds with repetitive functional groups – generally, biomolecules like peptides, oligosaccharides or nucleotides – may require protecting groups to order their assembly. Also, cheap chiral protecting groups may often shorten an enantioselective synthesis (e.g. shikimic acid for oseltamivir).
As a rule, the introduction of a protecting group is straightforward. The difficulties rather lie in their stability and selective removal. Apparent problems in synthesis strategies with protecting groups are rarely documented in the academic literature.Michael Schelhaas, Herbert Waldmann: "Schutzgruppenstrategien in der organischen Synthese", in: Angewandte Chemie, 1996, 103, pp. 2194; doi:10.1002/ange.19961081805 (in German).
Orthogonal protection
Orthogonal protection is a strategy allowing the specific deprotection of one protective group in a multiply-protected structure. 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 regarding 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 (see also ).Weng C. Chan, Peter D. White: Fmoc Solid Phase Peptide Synthesis, S. 10–12.
A further important example of orthogonal protecting groups occurs in carbohydrate chemistry. As carbohydrates or hydroxyl groups exhibit very similar reactivities, a transformation that protects or deprotects a single hydroxy group must be possible for a successful synthesis.
Cleavage categorization Many reaction conditions have been established that will cleave protecting groups. One can roughly distinguish between the following environments:Michael Schelhaas, Herbert Waldmann: "Schutzgruppenstrategien in der organischen Synthese", in: Angewandte Chemie, 1996, 103, pp. 2195–2200; doi:10.1002/ange.19961081805 (in German).
Acid-labile protecting groups Base-labile protecting groups Fluoride-labile protecting groups Enzyme-labile protecting groups Reduction-labile protecting groups Oxidation-labile protecting groups Protecting groups cleaved by heavy metal salts or their complexes. Photolabile protecting groups Double-layered protecting groups
Various groups are cleaved in acid or base conditions, but the others are more unusual.
Fluoride ions form very strong bonds to silicon; thus silicon protecting groups are almost invariably removed by fluoride ions. Each type of counterion, i.e. cleavage reagent, can also selectively cleave different silicon protecting groups depending on steric hindrance. The advantage of fluoride-labile protecting groups is that no other protecting group is attacked by the cleavage conditions.
Lipases and other enzymes cleave ethers at biological pH (5-9) and temperatures (30–40 °C). Because enzymes have very high substrate specificity, the method is quite rare, but extremely attractive.
Catalytic hydrogenation removes a wide variety of benzyl groups: ethers, esters, urethanes, carbonates, etc.
Only a few protecting groups can be detached oxidatively: the methoxybenzyl ethers, which oxidize to a quinomethide. They can be removed with ceric ammonium nitrate (CAN) or dichlorodicyanobenzoquinone (DDQ).
Allyl compounds will isomerize to a vinyl group in the presence of noble metals. The residual enol ether (from a protected alcohol) or enamine (resp. amine) hydrolyzes in light acid.
Photolabile protecting groups bear a chromophore, which is activated through radiation with an appropriate wavelength and so can be removed.V.N. Rajasekharan Pillai: "Photoremovable Protecting Groups in Organic Synthesis", in: Synthesis, 1980, pp. 1–26. For examples the o-nitrobenzylgroup ought be listed here.
The rare double-layer protecting group is a protected protecting group, which exemplify high stability.
Common protecting groups
Alcohol protecting groups The classical protecting groups for alcohols are esters, deprotected by nucleophiles; triorganosilyl ethers, deprotected by acids and fluoride ions; and (hemi)acetals, deprotected by weak acids. In rarer cases, a carbon ether might be used.
The most important esters with common protecting-group use are the acetate, benzoate, and pivalate esters, for these exhibit differential removal. Sterically hindered esters are less susceptible to nucleophilic attack:
Chloroacetyl > acetyl > benzoyl > pivaloyl
Triorganosilyl sources have quite variable prices, and the most economical is chlorotrimethylsilane (TMS-Cl), a Direct Process byproduct. The trimethylsilyl ethers are also extremely sensitive to acid hydrolysis (for example silica gel suffices as a proton donator) and are consequently rarely used nowadays as protecting groups.
Aliphatic methyl ethers cleave with difficulty and only under drastic conditions, so that these are in general only used with quinonic phenols. However, hemiacetals and acetals are much easier to cleave.
List Esters: Acetyl (Ac) – Removed by acid or base (see Acetoxy group). Benzoyl (Bz) – Removed by acid or base, more stable than Ac group. Pivaloyl (Piv) – Removed by acid, base or reductant agents. It is substantially more stable than other acyl protecting groups.
Silyl ethers: Trimethylsilyl (TMS) — Potassium fluoride, acetic acid or potassium carbonate in methanolP.J. Kocieński: Protecting Groups, p. 29. Triethylsilyl (TES) — 10–100× stabler than a TMS group.P.J. Kocieński: Protecting Groups, p. 31. Cleaved with trifluoroacetic acid in water/tetrahydrofuran,Tod K Jones, Robert A. Reamer, Richard Desmond, Sander G. Mills: "Chemistry of tricarbonyl hemiketals and application of Evans technology to the total synthesis of the immunosuppressant (−)-FK-506", in: J. Am. Chem. Soc., 1990, 112, pp. 2998–3017; doi:10.1021/ja00164a023. acetic acid in water/tetrahydrofuran,Dieter Seebach, Hak-Fun Chow, Richard F.W. Jackson, Marius A. Sutter, Suvit Thaisrivongs, Jürg Zimmermann: "(+)-11,11-Di-O-methylelaiophylidene – preparation from elaiophylin and total synthesis from (R)-3-hydroxybutyrate and (S)-malate", in: Liebigs Ann. Chem., 1986, pp. 1281–1308; doi:10.1002/jlac.198619860714. or hydrogen fluoride in water or pyridineDavid A. Evans, Stephen W. Kaldor, Todd K. Jones, Jon Clardy, Thomas J. Stout: "Total synthesis of the macrolide antibiotic cytovaricin", in: J. Am. Chem. Soc., 1990, 112, pp. 7001–7031; doi:10.1021/ja00175a038. tert-Butyldimethylsilyl (TBDMS or TBS) — Cleaved with acetic acid in tetrahydrofuran/water,James A. Marshall, Richard Sedrani: "A convergent, highly stereoselective synthesis of a C-11-C-21 subunit of the macbecins", in: J. Org. Chem., 1991, 56, pp. 5496–5498; doi:10.1021/jo00019a004. Pyridinium tosylate in methanol,James D. White, Motoji Kawasaki: "Total synthesis of (+)-latrunculin A", in: J. Am. Chem. Soc., 1990, 112, pp. 4991–4993; doi:10.1021/ja00168a071. trifluoroacetic acid in water,Morris J. Robins, Vicente Samano, Mark D. Johnson: "Nucleic acid-related compounds. 58. Periodinane oxidation, selective primary deprotection, and remarkably stereoselective reduction of tert-butyldimethylsilyl-protected ribonucleosides. Synthesis of 9-(β-D-xylofuranosyl)adenine or 3'-deuterioadenosine from adenosine", in: J. Org. Chem., 1990, 55, pp. 410–412; doi:10.1021/jo00289a004. hydrofluoric acid in acetonitrile,R. Roger F. Newton, Derek P. Reynolds, Colin F. Webb, Stanley M. Roberts: "A short and efficient total synthesis of (±) prostaglandin D2 methyl ester involving a new method for the cleavage of a dimethyl-t-butylsilyl ether", in: J. Chem. Soc., Perkin Trans. 1, 1981, pp. 2055–2058; doi:10.1039/P19810002055. pyridinium fluoride in tetrahydrofuran,Kyriacos C. Nicolaou, R. A. Daines, T. K. Chakraborty: "Total synthesis of amphoteronolide B", in: J. Am. Chem. Soc., 1987, 109, pp. 2208–2210; doi:10.1021/ja00241a063. tetrabutylammonium fluoride in THF.Leo A. Paquette, Annette M. Doherty, Christopher M. Rayner: "Total synthesis of furanocembranolides. 1. Stereocontrolled preparation of key heterocyclic building blocks and assembly of a complete seco-pseudopterane framework", in: J. Am. Chem. Soc., 1991, 109, pp. 3910–3926; doi:10.1021/ja00036a045. Commonly protects 2'-hydroxy function in oligonucleotide synthesis. Triisopropylsilyl (TIPS) — Similar conditions to TBS but longer reaction times.P.J. Kocieński: Protecting Groups, p. 40. tertButyldiphenylsilyl (TBDPS) — Similar conditions to TBS but even longer reaction times (100–250× slower than TBS and 5–10× slower than TIPS)
Benzyl ethers:
Benzyl (Bn) — Removed by hydrogenolysis.P.J. Kocieński: Protecting Groups, pp. 46–49. Bn group is widely used in sugar and nucleoside chemistry. Trityl (triphenylmethyl, Tr) — Removed by acidMichel Bessodes, Dimitri Komiotis, Kostas Antonakis: "Rapid and selective detritylation of primary alcohols using formic acid", in: Tetrahedron Lett., 1986, 27, pp. 579–580; doi:10.1016/S0040-4039(00)84045-9.B. Helferich: Carbonhydr. Chem. Biochem., 1948, 3, pp. 79.M.L. García, J. Pascual, L. Borràs, J.A. Andreu, E. Fos, D. Mauleón, G. Carganico, F. Arcamone: "Synthesis of new ether glycerophospholipids structurally related to modulator", in: Tetrahedron, 1991, 47, pp. 10023–10034; doi:10.1016/S0040-4020(01)96051-X. and hydrogenolysis p-Methoxybenzyl (PMB) — Removed by acid, hydrogenolysis, or oxidation – commonly with DDQ.Yuji Oikawa, Tadao Yoshioka, Osamu Yonemitsu: "Specific removal of o-methoxybenzyl protection by DDQ oxidation", in: Tetrahedron Lett., 1982, 23, pp. 885–888; doi:10.1016/S0040-4039(00)86974-9. p,mDimethoxybenzyl — Removed via oxidation with DDQ or ceric ammonium chlorideSee literature for pmethoxybenzyl.
Acetals: 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. Methoxytrityl [(4-methoxyphenyl)diphenylmethyl] (MMT) – Removed by acid and hydrogenolysis.