Protecting group

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With the butyloxycarbonyl group (Boc) on the amino group protected α-amino acid glycine . The Boc protecting group is marked in blue .
Typical synthesis using a protecting group ( blue ). The protecting group is not in the starting material (top left) is still in the target molecule B included. It is only needed temporarily to protect another reactive center in the molecule during the reaction with a reagent ( green ). In the absence of the protective group, the starting molecule is attacked at both reactive centers and the undesired product A is obtained.

A protecting group ( English protecting group - therefore often referred to as common abbreviation in formula schemes PG ) is in chemistry a substituent which, during a more complicated, multi-step chemical synthesis in a molecule is introduced to a specific functional group to protect temporarily and so an undesirable reaction to prevent this group. After the desired reaction has been carried out elsewhere on the molecule, the protective group is split off again. For many functional groups several possible protective groups are known which differ in their stability and the conditions for their cleavage.

In the synthesis of special classes of compounds with repeating functional groups - usually biomolecules such as peptides , oligosaccharides or nucleotides - standard sets of protective groups have become established. Protecting groups have become an important tool in the synthesis of complex compounds today.

The requirements for a protection group are quite high. This includes that it can be introduced specifically to a functional group with very good yield and that it must also be able to be split off again under mild conditions. It should be possible to standardize the reaction conditions for both steps. In addition, the protective group must be stable under as many reaction conditions as possible. If possible, the resulting reaction products should be easily separable, and optimally the protective group reagent is also inexpensive. The broader the experience with a protective group, the better the predictability of the reactivity of the protective group.

history

Elias J. Corey
Robert B. Woodward

The history of protective group technology is inextricably linked with the targeted use of different starting compounds for the synthesis of a target molecule. The early protective groups were usually based on the fact that the starting compound was chosen so that a reactive functional group was blocked by a residue and was therefore unreactive. So were z. B. anisoles instead of phenols or esters instead of free alcohol groups . It was only with the targeted synthesis of increasingly complex compounds that emerged from the beginning of the 20th century that protective group technology became really important. From around 1960 onwards, considerable research expenditure began to be invested in the chemistry of the protective groups. During this time chemists began to synthesize increasingly complex natural products . Particularly noteworthy are the previous work of Nobel Prize winners Robert B. Woodward , Elias J. Corey and Albert Eschenmoser , who pioneered the synthesis of complex natural substances.

Today there are a large number of protective groups, which are summarized in monographs with regard to their properties. In addition to established protective groups, there are many exotic protective groups that were only developed for a synthesis or a very special area.

Requirements for a protection group

The introduction and removal of protective groups do not represent productive reactions in a sequence of synthetic steps; their product does not come closer to the desired end product of the synthesis. For this reason, high requirements are often placed on protecting group reactions in terms of price, yield and development effort for the reaction.

The following characteristics have emerged as the basic requirements for a good protection group:

  • The reagent must be commercially available and inexpensive or easy to manufacture
  • The protective group must be simple, specific and capable of being introduced in high yields
  • It must be stable to the greatest possible number of reaction conditions and work-up and purification methods
  • It must be specific, highly selective and capable of being split off in high yields. It should be possible to standardize the conditions.
  • It must not form a new stereocenter or a diastereotopic center
  • It should be easily recognizable in NMR spectra and interfere with as little signal overlap as possible

The high selectivity of the cleavage is a very important aspect, because different functional groups often have to be protected and deprotected independently of one another. Ideally, only one of many protective groups is affected by the cleavage process. The behavior of protective groups in practice cannot always be correctly predicted on the basis of the literature, especially if several different protective groups are used in one molecule. Therefore, in some cases, despite a great deal of experience, considerable development work must still be done during a synthesis for both the introduction and the splitting off.

Orthogonality of protecting groups

Orthogonally protected L- tyrosine (protective groups are marked in blue , the amino acid is drawn in black ). ( 1 ) Fmoc-protected amino group , ( 2 ) carboxy group protected as benzyl ester and ( 3 ) phenolic hydroxyl group of tyrosine protected as tert-butyl ether .

Orthogonality of protective groups means that when several protective groups of different types are used, each protective group can be split off individually and in any order on the basis of the various splitting off reagents without any of the other protective groups being attacked. In the example of the protected amino acid tyrosine shown , the benzyl ester can be split hydrogenolytically , the fluorenylmethyleneoxy group (Fmoc) by bases (e.g. piperidine ) and the phenolic tert-butyl ether with acids (e.g. trifluoroacetic acid ).

A widespread example of this application is Fmoc peptide synthesis, which has gained great importance both in solution and on the solid phase. The protective groups in the solid phase synthesis must be standardized with regard to the reaction conditions such as reaction time, temperature and reagents so that they can be carried out by an automatic device and yields of well over 99% can be achieved, since otherwise the separation of the resulting mixture of reaction products is practically impossible .

  • Schematic representation of a solid phase peptide synthesis with orthogonal protecting groups X and Y

  • Fmoc solid phase peptide synthesis with orthogonal protecting groups

Principle of vector molecules

Another important application of orthogonal protecting groups is in carbohydrate chemistry. Since carbohydrates have hydroxyl groups with very similar reactivity, the protection or deprotection of individual hydroxyl groups must be possible for a targeted synthetic conversion. The synthesis of nucleotides represents a similar case . On the one hand, there is the problem (as with peptide synthesis) that the molecules are vectorial. On the other hand, there is also the problem of carbohydrate chemistry with the sugar residue of the ribose in the synthesis of RNA molecules.

But also in the synthesis of complex natural substances or active ingredients with many functional groups one is dependent on the orthogonality of the protective groups.

Lability or splitting off of protective groups

In the case of protective groups, various reaction conditions have been established which correspond to the principle of orthogonality, under which protective groups are split off. One can roughly differentiate between the following cleavage conditions:

Acid-labile protective groups can be split off through the action of acids. The driving force here is often the formation of a relatively stable carbocation or an acid-catalyzed equilibrium that is on the side of the free functional group. Examples of acid-labile protective groups are the tert-butyl esters, ethers and carbamates, which form stable cations, and the acetals , in which the acid-catalyzed equilibrium is on the side of the corresponding aldehydes or ketones in the presence of water.

Elimination of tert- butyl groups
Cleavage of the protecting group: mechanism of β-elimination

In the case of the base-labile protective groups, a mechanistical distinction can be made between basic hydrolysis and base-induced β-elimination . Carboxylic acid esters (with the exception of the tert-butyl esters) are attacked nucleophilically by hydroxide ions and thus split hydrolytically. Amides, on the other hand, are seldom split in this way because they require very harsh conditions. The phthaloyl group is an exception here , as it is cleaved with hydrazine under very mild conditions. A cascade of reactions occurs during β-elimination: First, a proton is split off by the base and a carbanion is formed. The protective group is then cleaved by a suitable leaving group to form a vinyl compound . In the latter case, the Fmoc group is particularly important.

Cleavage by nucleophilic attack, a carboxylic acid ester, a phthalimide and an Fmoc group by β-elimination

Fluoride ions form a very stable bond with silicon . Therefore, the silicon protective groups are almost without exception cleaved by fluoride ions. Depending on the type of counterion or the cleavage reagent, however, different silicon protective groups can also be selectively cleaved depending on the steric hindrance of the silicon atom. The advantage of fluoride-labile protective groups is that no other protective group is attacked under the cleavage conditions.

Esters can often be cleaved by enzymes such as lipases . Since enzymes work at a pH value between 5 and 9 and at moderate temperatures of around 30–40 ° C and are also very selective with regard to the carboxylic acid, this method is a rarely used but very attractive method for splitting protecting groups .

Structure of dichlorodicyanobenzoquinone

Benzyl groups can be cleaved reductively by catalytic hydrogenation . Benzyl groups are used as ethers, esters, urethanes, carbonates or acetals and are used to protect alcohols, carboxylic acids, amines and diols.

Only a few protective groups that can be removed by oxidation are used. This is usually methoxybenzyl ether. They can be cleaved with cerium (IV) ammonium nitrate (CAN) or dichlorodicyanobenzoquinone (DDQ) via a quinomethine .

PMB deprotection.svg
PMB deprotection mechanismn.svg

The double bond of an allyl radical can be isomerized to the vinyl compound by platinum group elements (such as palladium , iridium or platinum ) . The enol ethers thus obtained in the case of protected alcohols or enamines in the case of protected amines can easily be hydrolyzed under acidic conditions.

Photolabile protective groups contain a chromophore that can be activated by irradiation with a suitable wavelength and thus split off. The o -nitrobenzyl group (ONB) is listed here as an example .

Mechanism of the photodeprotection of an o -nitrobenzyl ether and formation of the alcohol

The two-stage protective groups are a special form of protective groups . These are characterized by high stability, since the protective group must first be converted into a cleavable group by chemical transformation. However, this type of protective group is rarely used, since an additional activation step is necessary here, which extends the synthesis by a further stage.

Functional groups

Amines

By far the greatest variety of protecting groups is available for the amino function . This is due on the one hand to the fact that amines are of particular importance in peptide synthesis , but also to their properties: On the one hand, they are quite potent nucleophiles , but also relatively strong bases . These properties have led to the development of new protective groups for amines.

Many protecting groups for amines are based on carbamates . These can easily be introduced in the form of carboxylic acid chlorides. They get their driving force in the split from the formation of the very stable carbon dioxide molecule. Various cleavage options have been developed based on different residues on the carbamate. The most commonly used carbamates are the tert -butyloxycarbonyl, benzyloxycarbonyl, fluorenylmethyleneoxycarbonyl and allyloxycarbonyl compounds.

rest formula Surname abbreviation cleavage
tert -butyl Structural formula of the Boc protecting group tert -Butyloxycarbonyl Boc angry; Trifluoroacetic acid (TFA) pure or as a solution in dichloromethane , 3 M hydrochloric acid in ethyl acetate or 10% sulfuric acid in dioxane
Benzyl Structural formula of the Cbz protecting group Benzyloxycarbonyl Cbz or Z hydrogenolytic; Hydrogen and palladium on activated carbon , lithium or sodium in liquid ammonia
Fluorenylmethylene Structural formula of the Fmoc protecting group Fluorenylmethylene oxycarbonyl Fmoc basic; 20–50% piperidine in dimethylformamide (DMF) or N-methyl-2-pyrrolidone , 50% morpholine in DMF for sensitive glycopeptides
Allyl Structural formula of the Alloc protecting group Allyloxycarbonyl Alloc transition metal catalyzed cleavage; Metals such as palladium (0) or nickel (0) complexes

In addition to the carbamates, a number of other N- acyl derivatives are important as protective groups, but are nowhere near as widespread. These include, for example, the phthalimides , which are accessible either by reacting the primary amines with phthalic anhydride or by building up the amino group via a Gabriel synthesis . The phthalimides are normally split by hydrazine hydrate or sodium boronate . Trifluoroacetamides are extremely easy to saponify in the base , which is why the acetamides obtained by the reaction with trifluoroacetic anhydride are occasionally used as a protective group for amines.

In the case of indoles , pyrrole and imidazoles , i.e. heterocyclic compounds, the N- sulfonyl derivatives are used as protective groups. In the case of normal amines, this protective group is often too stable. They are represented here by sulfonation with phenylsulfonyl chloride and the deprotonated heterocycle. The cleavage takes place by basic hydrolysis. N- acyl derivatives of primary and secondary amines are relatively easily accessible by reacting the amines with an aryl sulfonic acid chloride, but they can only be obtained with difficulty, e.g. B. under the conditions of a Birch reduction ( sodium in liquid ammonia ) or by reaction with sodium naphthalide .

Among the N -alkyl derivatives, the representable by alkylation or reductive alkylation have N -benzyl derivatives of some importance. As with the Cbz group, the cleavage takes place reductively and normally by catalytic hydrogenation or by Birch reduction. Here, N- alkylamines have the decisive disadvantage compared to carbamates or amides that the basic nitrogen is retained.

Alcohols

The classic protective group for alcohols are carboxylic acid esters . The esters of precursors are often commercially available or can easily be obtained by reacting the alcohols with the acid chlorides or anhydrides by a Schotten-Baumann reaction or by transesterification . The esters are usually cleaved by reacting them with nucleophiles such as alkali hydroxides, alkali alcoholates or lithium or magnesium organic compounds ; alternatively also reductive by reaction with complex hydrides such as lithium aluminum hydride . The reactivity of the esters towards nucleophilic attack decreases with the steric hindrance of the carboxylic acid in the following order:

Chloroacetyl> acetyl> benzoyl> pivaloyl

The reactivity of the alcohols also decreases with the increasing steric hindrance of the alcohols:

Phenols> primary alcohols> secondary alcohols> tertiary alcohols
Protection of a secondary alcohol with a trimethylsilyl protecting group with imidazole as an activating agent
Hexamethyldisilazane

The most important esters that are commonly used as protective groups are the acetic acid esters , the benzoic acid esters and the pivalic acid esters , since these can be split off from one another in a differentiated manner according to the stated reactivities.

The most important protective groups of alcohols and phenols include the very well investigated and documented trisubstituted silyl ethers . The silicon carries both alkyl and aryl groups as organic radicals. This type of protective group has the advantage that it can be moderated very easily with regard to the introduction and especially with regard to the cleavage. These ethers are produced either in a Williamson ether synthesis from the chlorosilane and an alcoholate ion or through the use of activating reagents such as imidazole .

For purely analytical purposes, e.g. B. to make a carbohydrate volatile and to be able to detect it with the help of GC-MS , there are commercially available reaction kits. Silyl ethers are generally sensitive to acids and fluoride ions. The latter is mostly used to split them. However, the commercial prices of the chlorosilanes vary greatly depending on the substitution. The cheapest chlorosilane is the chlorotrimethylsilane (TMS-Cl), which is a by-product of the silicone production according to Rochow and Müller . Another common source of the trimethylsilyl group is hexamethyldisilazane (HMDS). However, the trimethylsilyl ethers are also extremely sensitive to acidic hydrolysis (for example silica gel is sufficient as a proton donor) and are therefore rarely used as a protective group today.

Surname formula abbreviation cleavage
Trimethylsilyl TMS is.svg TMS Potassium fluoride , acetic acid or potassium carbonate in methanol
Triethylsilyl Tes is.svg TES 10-100 times more stable than a TMS group; Trifluoroacetic acid in water / tetrahydrofuran , acetic acid in water / tetrahydrofuran, hydrofluoric acid , pyridinium hydrofluoride in pyridine
tert -butyldimethylsilyl Tbs is.svg TBS, TBDMS Acetic acid in tetrahydrofuran / water, pyridinium tosylate in methanol, trifluoroacetic acid in water, hydrofluoric acid in acetonitrile , pyridinium hydrofluoride in tetrahydrofuran, tetrabutylammonium fluoride in THF
Triisopropylsilyl Tips is.svg TIPS Under the same conditions as TBS but longer reaction times; Tetrabutylammonium fluoride in tetrahydrofuran, hydrofluoric acid in acetonitrile, pyridinium hydrofluoride in tetrahydrofuran.
tert -Butyldiphenylsilyl Tbdbs is.svg TBDPS Under the same conditions as TBS but longer reaction times (100–250 times slower than TBS and 5–10 times slower than TIPS); Tetrabutylammonium fluoride in tetrahydrofuran, hydrofluoric acid in acetonitrile, pyridinium hydrofluoride in tetrahydrofuran

Another class of protecting groups for alcohols are the alkyl ethers. Here, too, there are various and orthogonal possibilities to split the ethers. Aliphatic methoxy ethers are difficult to cleave and under drastic conditions, so that they are generally only used with phenols.

Surname formula abbreviation cleavage
methyl Me is.svg Me Usually only used for phenols; Iodotrimethylsilane in chloroform , dichloromethane or acetonitrile, boron tribromide or boron trichloride in dichloromethane, Lewis acids (aluminum chloride, boron trifluoride in the presence of thiols)
Benzyl Bn is.svg Bn reductive; Catalytic hydrogenation (palladium on activated carbon, Raney nickel or rhodium on aluminum oxide as a catalyst)
p -methoxybenzyl PMB is.svg PMB, MPM oxidative; DDQ (dichlorodicyanoquinone) in dichloromethane, ceric ammonium chloride in water
3,4-dimethoxbenzyl DMB is.svg DMB, DMPM like PMB oxidative; DDQ (dichlorodicyanoquinone) in dichloromethane, ceric ammonium chloride in water
Triphenylmethyl (trityl) Tr is.svg Tr angry; Formic acid in ether or water, 80% acetic acid, 1 M hydrochloric acid
tert -butyl TBu is.svg angry; anhydrous trifluoroacetic acid, hydrobromic acid / acetic acid, 4N hydrochloric acid
Allyl Allyl is.svg Potassium tert -butanolate, palladium on activated carbon, DABCO in methanol, various platinum element complexes - then acidic processing.
Allyloxycarbonyl Alloc is.svg Alloc Like allyl; Potassium tert -butanolate, palladium on activated carbon, DABCO in methanol, various platinum element complexes - then acidic processing
Methoxymethyl Mom is.svg MOM Angry; 6 M hydrochloric acid in tetrahydrofuran / water
Methylthiomethyl MTM is.svg MTM Mercury (II) chloride / calcium carbonate in acetonitrile / water, silver nitrate in tetrahydrofuran / water
(2-methoxyethoxy) methyl Mem is.svg MEM Aqueous hydrobromic acid in tetrahydrofuran, zinc bromide in dichloromethane
Benzyloxymethyl Bom is.svg BOM Comparable to the stability of MOM, MEM and SEM; Reductive; Sodium in liquid ammonia, catalytic hydrogenation (palladium hydroxide on activated carbon), Raney nickel in ethanol
β- (trimethylsilyl) ethoxymethyl SEM is.svg SEM More unstable than MEM and MOM towards acid hydrolysis; 0.1 M hydrochloric acid in methanol, concentrated hydrofluoric acid in acetonitrile, boron trifluoride etherate in dichloromethane, tetrabutylammonium fluoride in HMPT ( hexamethylphosphoric acid triamide ) or in tetrahydrofuran
Tetrahydropyranyl THP is.svg THP Acetic acid in tetrahydrofuran / water, p -toluenesulfonic acid in methanol

1,2-diols

A special class of alcohols in protecting group chemistry are the 1,2-diols ( glycols ). The neighboring position of two hydroxyl groups can e.g. B. in the case of sugars , take advantage of the fact that both hydroxyl groups are protected as acetals depending on one another . The benzylidene , isopropylidene and cyclohexylidene or cyclopentylidene acetals are common here .

Common acetals

The acetals are generally produced by shifting the equilibrium of a mixture of the glycol with the carbonyl component by removing the water of reaction or by transacetalization with a simple acetal and removing the alcohol formed from the reaction mixture.

Manufacture of acetals

In sugar chemistry in particular, the different positions of the hydroxyl groups with respect to one another are used to protect them selectively in a certain stereochemical dependency. In addition to the other possible combinations, the two adjacent hydroxyl groups which form the most stable conformation react preferentially with one another.

Preparation of glyceraldehyde acetonide

Acetals can in principle be split again in aqueous acidic solvents. The benzylidene protective group, which can also be split reductively, is a special case here. This is done either by catalytic hydrogenation or by the hydride donor diisobutylaluminum hydride (DIBAL). However, the cleavage by DIBAL only deprotects one alcohol group, since the benzyl residue remains on the second and more sterically hindered hydroxy group than benzyl ether.

Cleavage of a benzylidene acetal with DIBAL

Carbonyl groups

Carbonyl groups are primarily at risk from nucleophilic attacks such as Grignard reagents or from hydride ions. Aldehydes can also be oxidized to carboxylic acids. But also unwanted reactions caused by acid- and base-catalyzed reactions of the carbonyl group such. B. Aldol reactions can be prevented by a suitable protective group.

The most common protective groups for carbonyl groups are acetals and especially cyclic acetals with diols. In addition, cyclic acetals with 1,2-hydroxythiols or dithioglycols are also used - the so-called O , S or S , S acetals.

Ethylene glycol
1,3-propanediol

In principle, the same applies to acetals as a protective group for carbonyl compounds as to acetals as a protective group for 1,2-diols. Both the production and the cleavage are naturally identical. However, with acetals as a protective group, the process of transacetalization plays a subordinate role, and they are usually produced from the glycols by splitting off water. More modern variants also use glycols, in which the hydroxy hydrogen atoms have been replaced by a trimethylsilyl group. Normally, simple glycols such as ethylene glycol or 1,3-propanediol are used as diols for the acetals.

Acetals can be cleaved under acidic aqueous conditions. The mineral acids are used as acids. The cosolvent is often acetone , which is used as a solubilizer. As a non-acidic elimination method, a palladium (II) chloride- acetonitrile complex in acetone or iron (III) chloride on silica gel absorbed in chloroform can be used.

Cyclic acetals are much more stable to acid hydrolysis than acyclic acetals. Therefore, acyclic acetals are used almost exclusively if a very mild cleavage is necessary or if two different protected carbonyl groups have to be differentiated with regard to their release.

However, in addition to their sole function as a protective group, acetals are also used as a chiral auxiliary reagent. So acetals of chiral glycols such as. B. derivatives of tartaric acid can be opened asymmetrically with high selectivity. This enables the creation of new centers of chirality.

Lardolure is.svg

In addition to the O , O -acetals, the S , O- and S , S -acetals also have an, albeit lesser, importance as a carbonyl protective group. Thiols , which have to be used to produce these acetals, have a very unpleasant odor and are poisonous, which limits their use very much. Thioacetals and the mixed S , O -acetals are, compared to the pure O , O -acetals, much more stable towards acid hydrolysis. This enables the selective cleavage of these carbonyl groups protected by sulfur in the presence .

The S , S acetals are normally produced analogously to the O , O acetals by acid catalysis from the dithiols and the carbonyl component. Due to the great stability of the thioacetals, the equilibrium is on the side of the acetals. In contrast to the O , O acetals, no water of reaction has to be removed in order to shift the equilibrium.

S , O acetals are hydrolysed 10,000 times faster than the corresponding S , S acetals. They are produced in analogy to these from the thioalcohols. Their cleavage also takes place under comparable conditions and primarily through mercury (II) compounds in aqueous acetonitrile.

Temporary protection of the carbonyl group in the presence of ketones as hemiaminal anions has been described for aldehydes . This exploits the fact that aldehydes have a much higher carbonyl activity than ketones and that many addition reactions are reversible.

Temporary protection of an aldehyde

Carboxy groups

The most important protecting groups for carboxy groups are the esters of various alcohols. Ortho-esters and oxazolines are also used, but of minor importance. There are basically different methods for the production of carboxylic acid esters:

  • Direct esterification of carboxylic acids and alcohol components. Because of the unfavorable equilibrium in the reaction between alcohols and carboxylic acids, equilibrium must either be achieved by removing the water of reaction or by working with large excesses of alcohol. To do this, however, the alcohol has to be very cheap. This reaction is acid-catalyzed (sulfuric acid, p -toluenesulfonic acid or acidic ion exchangers are the most common esterification catalysts).
  • The reaction of acid anhydrides or acid chlorides with alcohols in the presence of auxiliary bases. Pyridine , diisopropylethylamine or triethylamine are often used here as auxiliary bases . This reaction can be catalyzed with 4- N , N- dimethylaminopyridine , which increases the reaction rate by a factor of 10 4 compared to pure pyridine . Compared to direct esterification, these methods are carried out under very mild conditions.
  • The reaction of carboxylic acid salts with alkyl halides is another method for the preparation of carboxylic acid esters.
  • The reaction of carboxylic acids with isobutene is a gentle method for making tert-butyl esters. Here isobutene is reacted with the carboxylic acid in the presence of a strong acid such as sulfuric acid.
  • The reaction of carboxylic acids with diazoalkanes is a very gentle and quantitative method to make esters. Due to the poor accessibility of complex diazoalkanes, however, it is mostly only used for the production of methyl and benzhydril esters.

In addition to these classic methods of esterification, other and more modern methods have been developed for special reactions.

Various groups can serve as the alcohol component. However, the methyl, tert- butyl, benzyl and allyl esters are very common here . In addition, there are a number of protective groups, which are derived from the ether protective groups of the hydroxyl groups. However, the specific cleavage conditions are often very similar. In principle, any ester can be hydrolyzed in the presence of hydroxide ions in an aqueous-alcoholic solution. With more sensitive substrates, however, lithium hydroxide in tetrahydrofuran and in the presence of methanol is often used . The same rules naturally apply to the tendency towards hydrolysis as to esters as alcohol protecting groups.

Surname formula abbreviation cleavage Special manufacture
methyl Me is.svg Me nucleophilic-alkaline by metal hydroxides or carbonates in aqueous methanol or tetrahydrofuran, alkali metal halides in moist aprotic solvents such as dimethyl sulfoxide, N , N -dimethylformamide in the heat, enzymatically z. B. by pig liver esterase Diazomethane in diethyl ether, cesium carbonate and methyl iodide in N , N -dimethylformamide, methanol and catalytic trimethylsilyl chloride
tert -butyl TBu is.svg tert -Bu angry; Trifluoroacetic acid (pure or in dichloromethane), formic acid, p -toluenesulfonic acid Isobutene in dioxane and catalytic sulfuric acid
Benzyl Bn is.svg Bn hydrogenolytic; Hydrogen / palladium on activated carbon
Benzhydryl Benzhydrol is.svg hydrogenolytic; Hydrogen / palladium on activated carbon (very easy to split)
Allyl Allyl is.svg Allyl analogous to ethers; Potassium tert- butanolate, palladium on activated carbon, DABCO (1,4-diazabicyclo [2.2.2] octane) in methanol, various platinum element complexes - then acidic processing

Alkenes

Alkenes are and rarely need to be protected by a protective group. As a rule, they are only affected by electrophilic attacks, isomerization and, during catalytic hydrogenation, of undesired side reactions. Basically, two protective groups are known for alkenes:

  • Temporary halogenation with bromine to form the trans -1,2-dibromoalkyl compound: The alkene is regenerated by restoring the conformation with elemental zinc or with titanocene dichloride .
  • Protection through a Diels-Alder reaction : the reaction of an alkene with a diene leads to a cyclic alkene, which is at risk from electrophilic attack in a similar way to the original alkene. The diene serving as a protective group is split off thermally, since a Diels-Alder reaction is a reversible or equilibrium reaction.
Scheme of alkene protecting groups

Alkynes

Two types of protective groups are also known for alkynes. With terminal alkynes it is sometimes necessary to mask the acidic hydrogen atom. This is usually done by deprotonation (using strong bases such as methylmagnesium bromide or butyllithium in tetrahydrofuran / dimethylsulfoxide ) and subsequent reaction with chlorotrimethylsilane to form the terminally TMS-protected alkyne. The cleavage takes place hydrolytically - with potassium carbonate in methanol - or by fluoride ions such as, for example, by means of tetrabutylammonium fluoride .

TMS alkyne protection

To protect the triple bond itself, a complex of the alkyne compound with dicobalt octacarbonyl is sometimes used. The cobalt is split off by oxidation.

Co alkyne protection

Applications

Protecting groups are used in a wide range of synthetic organic chemistry. This applies to both laboratory syntheses and large-scale syntheses of complex active ingredients. As soon as a functional group proves to be disruptive or can be attacked undesirably, the protective group technique is used. Protecting groups are used in almost every synthesis of a complex target molecule. Since both the introduction and the cleavage of the protective groups result in both the effort and a loss of yield, it is desirable to manage without protective groups, which, however, is often difficult to achieve.

In the automated synthesis of peptides and nucleotides, protecting group chemistry is an integral part of the synthesis concept. Protecting groups are also indispensable in sugar chemistry due to the very similar hydroxyl groups in the sugar molecules.

An important example of the industrial application of protective group technology is the synthesis of ascorbic acid (vitamin C) according to Reichstein .

Reichstein synthesis

In order to prevent the secondary alcohols from being oxidized by potassium permanganate , they are protected by acetalization with acetone and then deprotected again after the primary hydroxyl group has been oxidized to the carboxylic acid.

A very spectacular example from the synthesis of natural products for the application of protective groups is the total synthesis of palytoxin carboxylic acid by the working group of Yoshito Kishi from 1994. Here 42 functional groups (39 hydroxyl groups, one diol, one amino group and one carboxylic acid group) had to be protected. This was done using eight different protective groups (one methyl ester, five acetate groups, 20 TBDMS ethers, nine p- methoxybenzyl ethers, four benzoates, one methyl hemiacetal, one acetal with acetone and one SEM ester).

Palytoxin

The introduction or modification of a protective group sometimes also influences the reactivity of the entire molecule. As an example, an excerpt from the synthesis of an analogue of Mitomycin C by Danishefsky is shown here.

Part of the synthesis of an analogue of mitomycin C with altered reactivity due to a change in protecting group

Switching the protective group from a methyl ether to a MOM ether prevents the epoxide from opening to form the aldehyde .

An important application of protecting group chemistry can be found in the automated synthesis of peptides and nucleosides. In the peptide synthesis by automatic synthesizers, the orthogonality of the Fmoc group (basic cleavage), the tert- butyl group (acidic cleavage) and various protective groups for functional groups in the side chain of the amino acids are used. In the automated nucleotide synthesis of DNA and RNA sequences, protective groups are used on the one hand to block functional groups, but redox chemistry also takes place on the protected atoms. The phosphorus is protected and oxidized to phosphate during the coupling cycle.

Automated oligonucleotide synthesis

As a rule, introducing a protective group is not a problem. The difficulties lie more in their stability and selective splitting. Problems that arise in synthesis strategies with protective groups are only rarely documented in the specialist literature.

Atomic economy

Syntheses using protective groups generally have a low atom economy . Sometimes the detour of using protective groups has to be taken in order to eliminate undesired competing reactions and to achieve the desired selectivity of a synthesis. Protecting group strategies are often indispensable in the synthesis of complex structures.

The syntheses of Hapalindol U are compared as an example of a protecting group strategy compared to a synthesis free of protecting groups . While the synthesis by Hideaki Muratake from 1990 used tosyl as a protecting group, in the synthesis by Phil S. Baran from 2007 no protecting group was used. The number of synthesis steps was significantly reduced.

  • Hapalindol U Muratake 1990 Ts protective group synthesis (protective groups in blue .)

  • Hapalindol U Baran 2007 Protection group-free synthesis

literature

Web links

Commons : Protecting groups  - collection of pictures, videos and audio files
Wiktionary: Schutzgruppe  - explanations of meanings, word origins, synonyms, translations

Individual evidence

  1. ↑ a b Kyriacos C. Nicolaou, Erik J. Sorensen: Classics in Total Synthesis: Targets, Strategies, Methods , 1996, ISBN 3-527-29284-5 .
  2. ↑ a b c Kyriacos C. Nicolaou, Scott A. Snyder: Classics in Total Synthesis II , Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2003, ISBN 3-527-30684-6 .
  3. ↑ Philip J. Kocienski: Protecting Groups , 1st edition, Georg Thieme Verlag, Stuttgart 1994, ISBN 3-13-135601-4 .
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This article was added to the list of excellent articles on January 19, 2011 in this version .