Protecting group

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Acetal protection of a ketone with ethylene glycol during reduction of an ester, vs. reduction to a diol when unprotected. Acetal-protection-example.png
Acetal protection of a ketone with ethylene glycol during reduction of an ester, vs. reduction to a diol when unprotected.

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. [1]

Contents

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

Alcohol protecting groups

Protection of alcohols:

Protection of alcohol as tetrahydropyranyl ether followed by deprotection. Both steps require acid catalysts. THPmeth.png
Protection of alcohol as tetrahydropyranyl ether followed by deprotection. Both steps require acid catalysts.

Amine protecting groups

BOC glycine. The tert-butyloxycarbonyl group is marked blue. Tert-Butoxycarbonyl protected Glycine Structural Formulae V.1.png
BOC glycine. The tert-butyloxycarbonyl group is marked blue.

Protection of amines:

Carbonyl protecting groups

Protection of carbonyl groups:

Carboxylic acid protecting groups

Protection of carboxylic acids:

Phosphate protecting groups

Terminal alkyne protecting groups

Other

Orthogonal protection

Orthogonal protection of L-Tyrosine (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. Tyrosine Protected V.4.png
Orthogonal protection of L-Tyrosine (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 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. [6] 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. [7]

The technique was introduced in the field of peptide synthesis by Robert Bruce Merrifield in 1977. [8] As a proof of concept orthogonal deprotection is demonstrated in a photochemical transesterification by trimethylsilyldiazomethane utilizing the kinetic isotope effect: [9]

OrthogonalprotectionApplicationInPhotochemistry.png

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. [10] 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 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 [11] [12] [13] 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). HapalindoleUsynthesisMuratake1990.svg
Hideaki Muratake's 1990 synthesis using Tosyl protecting groups (shown in blue).
Phil Baran's protecting-group free synthesis, reported in 2007. AmbiguineSynthesisBagan2007.svg
Phil Baran's protecting-group free synthesis, reported in 2007.

Industrial applications

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

Related Research Articles

Ester Chemical compounds consisting of a carbonyl adjacent to an ether linkage

An ester is a chemical compound derived from an acid in which at least one –OH hydroxyl group is replaced by an –O– alkyl (alkoxy) group, as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides are fatty acid esters of glycerol; they are important in biology, being one of the main classes of lipids and comprising the bulk of animal fats and vegetable oils.

Benzyl group

In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure C6H5CH2–. Benzyl features a benzene ring attached to a CH2 group.

Peptide synthesis Production of peptides

In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. Peptides are chemically synthesized by the condensation reaction of the carboxyl group of one amino acid to the amino group of another. Protecting group strategies are usually necessary to prevent undesirable side reactions with the various amino acid side chains. Chemical peptide synthesis most commonly starts at the carboxyl end of the peptide (C-terminus), and proceeds toward the amino-terminus (N-terminus). Protein biosynthesis in living organisms occurs in the opposite direction.

In chemistry, solid-phase synthesis is a method in which molecules are covalently bound on a solid support material and synthesised step-by-step in a single reaction vessel utilising selective protecting group chemistry. Benefits compared with normal synthesis in a liquid state include:

Benzyl chloroformate Chemical compound

Benzyl chloroformate, also known as benzyl chlorocarbonate or Z-chloride, is the benzyl ester of chloroformic acid. It can be also described as the chloride of the benzyloxycarbonyl group. In its pure form it is a water-sensitive oily colorless liquid, although impure samples usually appear yellow. It possesses a characteristic pungent odor and degrades in contact with water.

Nicolaou Taxol total synthesis

The Nicolaou Taxol total synthesis, published by K. C. Nicolaou and his group in 1994 concerns the total synthesis of taxol. Taxol is an important drug in the treatment of cancer but also expensive because the compound is harvested from a scarce resource, namely the pacific yew.

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 groups for alcohols in organic synthesis. Since R1R2R3 can be combinations of differing groups which can be varied in order to provide a number of silyl ethers, this group of chemical compounds provides a wide spectrum of selectivity for protecting group chemistry. Common silyl ethers are: trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS) and triisopropylsilyl (TIPS). They are particularly useful because they can be installed and removed very selectively under mild conditions.

Dioxolane is a heterocyclic acetal with the chemical formula (CH2)2O2CH2. It is related to tetrahydrofuran by interchange of one oxygen for a CH2 group. The corresponding saturated 6-membered C4O2 rings are called dioxanes. The isomeric 1,2-dioxolane (wherein the two oxygen centers are adjacent) is a peroxide. 1,3-dioxolane is used as a solvent and as a comonomer in polyacetals.

Danishefsky Taxol total synthesis

The Danishefsky Taxol total synthesis in organic chemistry is an important third Taxol synthesis published by the group of Samuel Danishefsky in 1996 two years after the first two efforts described in the Holton Taxol total synthesis and the Nicolaou Taxol total synthesis. Combined they provide a good insight in the application of organic chemistry in total synthesis.

Di-<i>tert</i>-butyl dicarbonate Chemical compound

Di-tert-butyl dicarbonate is a reagent widely used in organic synthesis. Since this compound can be regarded formally as the acid anhydride derived from a tert-butoxycarbonyl (Boc) group, it is commonly referred to as Boc anhydride. This pyrocarbonate reacts with amines to give N-tert-butoxycarbonyl or so-called Boc derivatives. These carbamate derivatives do not behave as amines, which allows certain subsequent transformations to occur that would be incompatible with the amine functional group. The Boc group can later be removed from the amine using moderately strong acids. Thus, Boc serves as a protective group, for instance in solid phase peptide synthesis. Boc-protected amines are unreactive to most bases and nucleophiles, allowing for the use of the fluorenylmethyloxycarbonyl group (Fmoc) as an orthogonal protecting group.

Holton Taxol total synthesis

The Holton Taxol total synthesis, published by Robert A. Holton and his group at Florida State University in 1994, was the first total synthesis of Taxol.

<i>tert</i>-Butyloxycarbonyl protecting group

The tert-butyloxycarbonyl protecting group or tert-butoxycarbonyl protecting group is a protecting group used in organic synthesis.

The Rubottom oxidation is a useful, high-yielding chemical reaction between silyl enol ethers and peroxyacids to give the corresponding α-hydroxy carbonyl product. The mechanism of the reaction was proposed in its original disclosure by A.G. Brook with further evidence later supplied by George M. Rubottom. After a Prilezhaev-type oxidation of the silyl enol ether with the peroxyacid to form the siloxy oxirane intermediate, acid-catalyzed ring-opening yields an oxocarbenium ion. This intermediate then participates in a 1,4-silyl migration to give an α-siloxy carbonyl derivative that can be readily converted to the α-hydroxy carbonyl compound in the presence of acid, base, or a fluoride source.

Wender Taxol total synthesis

Wender Taxol total synthesis in organic chemistry describes a Taxol total synthesis by the group of Paul Wender at Stanford University published in 1997. This synthesis has much in common with the Holton Taxol total synthesis in that it is a linear synthesis starting from a naturally occurring compound with ring construction in the order A,B,C,D. The Wender effort is shorter by approximately 10 steps.

Oseltamivir total synthesis

Oseltamivir total synthesis concerns the total synthesis of the antiinfluenza drug oseltamivir marketed by Hoffmann-La Roche under the trade name Tamiflu. Its commercial production starts from the biomolecule shikimic acid harvested from Chinese star anise and from recombinant E. coli. Control of stereochemistry is important: the molecule has three stereocenters and the sought-after isomer is only 1 of 8 stereoisomers.

Kuwajima Taxol total synthesis

The Kuwajima Taxol total synthesis by the group of Isao Kuwajima of the Tokyo Institute of Technology is one of several efforts in taxol total synthesis published in the 1990s. The total synthesis of Taxol is considered a landmark in organic synthesis.

Mukaiyama Taxol total synthesis

The Mukaiyama taxol total synthesis published by the group of Teruaki Mukaiyama of the Tokyo University of Science between 1997 and 1999 was the 6th successful taxol total synthesis. The total synthesis of Taxol is considered a hallmark in organic synthesis.

<i>tert</i>-Butyldiphenylsilyl

tert-Butyldiphenylsilyl, also known as TBDPS, is a protecting group for alcohols. Its formula is C16H19Si-.

Carbonyl reduction

In organic chemistry, carbonyl reduction is the organic reduction of any carbonyl group by a reducing agent.

Reductions with hydrosilanes are methods used for hydrogenations and hydrogenolysis of organic compounds. The approach is a subset of Ionic hydrogenations. In this particular method, the substrate is treated with a hydrosilane and auxiliary reagent, often a strong acid, resulting in formal transfer of hydride from silicon to carbon. This style of reduction with hydrosilanes enjoys diverse if specialized applications.

References

  1. ↑ Theodora W. Greene, Peter G. M. Wuts (1999). Protecting Groups in Organic Synthesis (3 ed.). J. Wiley. ISBN   978-0-471-16019-9.{{cite book}}: CS1 maint: uses authors parameter (link)
  2. ↑ 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 .
  3. ↑ 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.
  4. ↑ Romanski, J.; Nowak, P.; Kosinski, K.; Jurczak, J. (September 2012). "High-pressure transesterification of sterically hindered esters". Tetrahedron Lett. 53 (39): 5287–5289. doi:10.1016/j.tetlet.2012.07.094.
  5. ↑ Clayden, Jonathan; Greeves, Nick; Warren, Stuart; Wothers, Peter (2000). Organic Chemistry . Oxford University Press. pp.  1291. ISBN   978-0198503460.
  6. ↑ Chan, Weng C.; White, Peter D. (2004). Fmoc Solid Phase Peptide Synthesis. Oxford University Press. ISBN   978-0-19-963724-9.
  7. ↑ Weng C. Chan, Peter D. White: Fmoc Solid Phase Peptide Synthesis, S. 10–12.
  8. ↑ 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.
  9. ↑ Blanc, Aurélien; Bochet, Christian G. (2007). "Isotope Effects in Photochemistry: Application to Chromatic Orthogonality" (PDF). Org. Lett. 9 (14): 2649–2651. doi:10.1021/ol070820h. PMID   17555322.
  10. ↑ Baran, Phil S.; Maimone, Thomas J.; Richter, Jeremy M. (22 March 2007). "Total synthesis of marine natural products without using protecting groups". Nature . 446 (7134): 404–408. Bibcode:2007Natur.446..404B. doi:10.1038/nature05569. PMID   17377577.
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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
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