User:Bernanke's Crossbow/Schutzgruppe



A protecting group is a chemical substituent that, when a complicated multistage chemical synthesis of a molecule is undertaken, temporarily protects an important functional group and so inhibits an undesirable reaction at the group. After execution of the desired reaction at another site in the molecule, the protecting group is detached. For many functional groups, many protecting groups are known, differing in their stability and the environments promoting their cleavage.

In the synthesis of special there are standard choices of protecting groups. Protecting groups have nowadays become a very important tool in the synthesis of complex compounds.

The expectations of a protecting group are quite demanding. They include: that they must attach to a functional group with high yield and specificity and moreover must be cleavable in mild conditions. On both counts, the reaction conditions should be standardized. Moreover, the protecting group must be stable under many possible reaction conditions. Ideally, the constructed product should be easily detachable, and optimally the protecting-group reagent also be cheap. Indeed, the broader the applications of a protecting group, the better the aforementioned reactivities.

History


The history of protecting group theory is inseparably bound up in the desired application of different starting materials to the synthesis of a target molecule. The earliest protecting groups were developed on the principle, that the raw materials were selected to block a reactive functional group with hunk of stuff and make it thereby unreactive. Thus for example anisoles selected over phenols and esters over free hydroxy groups. Beginning at the turn of the 20th century, desirable syntheses started becoming ever-more-complex, and the use of protecting groups became really important. Around 1960, they began to become a subject of chemical investigation in their own right. Around that time, chemists began to synthesize ever-more-complex natural products. In these efforts stand formost the Nobel prize-winners Robert B. Woodward, Elias J. Corey und Albert Eschenmoser, who pioneered the syntheses of complex natural products.

Today, there are many protecting groups, and their properties collected in scientific monographs. Besides the tabulated protecting groups, there are also many exotic protecting groups, developed for a synthesis or unusual area of research.

Requirements on a protecting group
The introduction and removal of protecting groups are not the productive reactions in a sequence of synthetic steps; their products are no closer to the terminal goal of the synthesis. Consequently a protecting group reaction has high standards for price, yield, and skill.

The base requirements for a protecting group have developed to include the following:
 * The reagent must be commercially available and cheaply or easily produced
 * The protecting group must be introducible simply, specifically, and with high yield
 * It must be stable against one or possibly a large number of reaction conditions and workups or separatory techniques
 * It must speicifically, and with high selectivity and yield be cleavable. The conditions thereto should be standard
 * It may not effect a new stereocenter nor a diastereocenter.
 * It should be easily detectible via NMR spectroscopy and possibly not resonate at frequencies that overlap with other parts of the molecule.

A very important aspect is the high selectivity of cleavage, because it must often protect different independent functional groups from each other. In the ideal case, it is just one of many protecting groups involved in a cleavage sequence. In practice, the more different protecting groups modify a molecule, the less the literature accurately describes their behavior. Thus in many cases a great deal of research must be done despite the extensive recorded experience, for both introduction and cleavage.

Orthogonality of protecting groups


Orthogonality of protecting groups means, that if multiple protecting groups of various types are applied, then the corresponding cleaving reagents may be applied in arbitrary order, without attacking the other protecting groups. In the figured example, the protected amino acid tyrosine could hydrogenolyze the benzyl ester, the Fluorenylmethylenoxy group (Fmoc) removed through bases (like i.e. piperidine) and the phenolic tert-butyl ether removed with acids (i.e. with trifluoroacetic acid).

A fully general example of such applications is the Fmoc peptide synthesis, which has great import in solution and in solid state. The protecting groups in the solid-state syntheses must be matched to reaction conditions, like duration, temperature, and reagents, so that they can be automated and thereby yields of over 99% achieved, for otherwise separation of the resulting mixture of reaction products is practically impossible.

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. Nucleotide synthesis presents a similar case. Here one has the problem (much like peptide synthesis) of working with a sequence-controlled polymers ("vectorial molecule"). Among other things one has here also the problems of carbohydrate chemistry with the sugar residue ribose in the synthesis of RNA molecules.

Of course also the synthesis of complex natural products or pharmaceuticals with many functional groups directs one towards orthogonality of protecting groups.

Lability, i.e. cleavage of protecting groups


Acid-labile protecting groups release through the application of acids. The driving force here is often the formation of a relatively stable carbocation or an acid-catalyzed equilibrium that stabilizes on the side of the free functional group. Examples of acid-labile protecting groups include tert-butyl esters, ethers, and carbamates, which form stable cations and acetals, which in the presence of water have a n acid-catalyzed equilibrium on the side of the corresponding aldehyde or ketone. With the base-labile protecting groups, one can distinguish mechanistically between basic hydrolysis and base-induced β-elimination. Esters (with the exception of tert-butyl esters) are nucleophilically attacked by hydroxide ions and thereby hydrolyzed. Amides are contrariwise seldom cleaved that way, for they require truly harsh conditions. An exception lies in the phathoyl group, for this is released under quite mild conditions with hydrazine. The βelimination goes by a domino reaction: first a proton is abstracted by the base, and then a carbanion forms. With a suitable leaving group, now the protecting group cleaves to form an olefin. The latter case includes first and foremost the Fmoc group.



Flouride ions for very strong bonds to silicon. Thus silicon protecting groups are almost invariably removed by fluoride ions. Each type of counterions i.e. cleavage reagents 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.

Esters can often be removed with enzymes like lipases. As enzymes work at a pH value between 5 and 9 and at moderate temperatures around 30–40 °C, and can be very selective on what the carboxylic acid connects to, this method is quite rarely used, but a very attractive method for protecting-group removal.

Benzyl groups can be removed reductively through catalytic hydrogenation. For instance, benzyl groups in ethers, esters, urethanes, carbonates, or acetals can protect alcohols, carboxylic acids, amines, or diols.

Only a few protecting groups can be detached oxidatively are practicable. In general, they are as a rule methoxybenzyl ethers. They can be removed with ceric ammonium nitrate (CAN) or dichlorodicyanobenzoquinone (DDQ) to a quinomethide.

The double bond of an allyl group can be isomerized to a vinyl group with platinum group elements (like palladium, iridium, or platinum). The residual enol ether from a protected alcohol or enamine of a protected amine can be hydrolyzed in light acid.

Photolabile protecting groups bear a chromophore, which is activated through radiation with an appropriate wavelength and so can be removed. For examples the o-nitrobenzylgroup ought be listed here.



The double-layer protecting group presents an special kind of protecting group. These exemplify a high stability, for the protecting group must first be transformed to a removable one through a chemical transformation. This kind of protecting group finds application rarely, for here an additional activating step is important, which lengthens the synthesis by another reaction.

Amines
For the amine groups, a great wide range of protecting groups are available. This connects with the fact that amines have a special importance in peptide synthesis, but also to their characteristics: they are a quite potent nucleophile and also relatively strong bases. These characteristics imply that new protecting groups for amines are always under development.

Many protecting groups for amines are based on carbamates. These take the form of carbonic chloride esters. Their driving force during cleavage obtains from the formation of the very stable carbon dioxide molecule. Based on different side-chains, the carbamates develop different resistances to cleavage. The commonest-used carbamtes are the tert-butoxycarbonyl, benzoxycarbonyl, fluorenylmethylenoxycarbonyl, and allyloxycarbonyl compounds.

Besides the carbamates, there is another family of N-acyl–derived protecting groups of importance, but in general not so well-known. To these belong for example the phthalimides, which are accessible either through the reaction of primary amines with phthalic anhydride or through the construction of an amine group in the Gabriel synthesis. The cleavage of a phthalimide then normally follows with hydrazine hydrate or sodium borohydride. Trifluoracetamide is generally simple to saponify in base; thus the acetamides generated by treatment with trifluoroacetic anhydride serve occasionally as protecting groups for amines.

For indoles, pyrroles und imidazoles &mdash; verily any heterocyclic compound &mdash; the Nsulfonyl derivates find application as protecting groups. With normal amines these protecting groups are generally too stable. The outline here specifies sulfonation with phenylsulfonyl chloride and the deprotonated heterocycle. Cleavage proceeds from base hydrolysis. Nacyl derivatives of primary and secondary amines are relatively simple to access through treatment of the amine with an arylsulfonylchloride, but can be rather hard to remove, e.g. under Birch reduction conditions (sodium in liquid ammonia) or through treatment with sodium naphthalide.

Amongst the Nalkyl derivatives, the Nbenzyl derivatives producible through alkylation or reductive alkylation have a certain importance. The cleavage proceeds like the Cbz-group: reductively and normally through catalytic hydrogenation or Birch reduction. Nalkyl amines here have a decided drawback relative to the carbamates or amides, in that they retain a basic nitrogen.

Alcohols
The classical protecting groups for alcohols are esters. Typically the ester is contained in a commerical precursor or can be easily synthesized from the alcohol with the acyl chloride or anhydride in a Schotten-Baumann reaction or simply produced through transesterification. Ester cleavage proceeds as a rule through reaction with nucleophiles like alkali hydroxides, alkali alkoxides, or organolithium or Grignard reagents; alternatively also reduction via reaction with complex hydrides like lithium aluminum hydride. The reactivity of esters against nucleophilic attack sinks with increased steric hindrance of the carboxylic acid in the following way:
 * Chloroacetyl > acetyl > benzoyl > pivaloyl

The reactivity of alcohols sinks also with the increased steric hindrance of the alcohol:
 * Phenols > primary alkohols > secondary alkohols > tertiary alkohols



The most important esters, which see common use as a protecting group, are the acetate esters, the benzoate esters, and the pivalate esters, for these exhibit differential cleavage reactivities relative to each other.

Counted among the most important protecting groups for alcohols and also phenols are the well-researched and documented trisubstituted silyl ethers. Therein silicon carries organic groups, typically alkyl but also aryl groups. This kind of protecting group has the advantage, that with regard to introduction and especially cleavage it requires extremely moderate conditions. They are formed either in a Williamson ether synthesis from chlorosilane and an alkoxide ion or perhaps through the effects of an activating reagent like imidazole.

For the purpose of analytical pyrity, i.e. to liquify a carbohydrate and be able to detect it with the help of GC-MS, there exist commercially available reaction kits. Silyl ethers are fundamentally sensitive to acids and fluoride ions. The latter are typically used for their cleavage. The market price of chlorosilanes is however quite variable upon substitution. The most economical chlorosilane here is chlorotrimethylsilane (TMS-Cl), itself a byproduct of Rochow und Müller's silicon refinement process. Another typical source of the trimethylsilyl group is hexamethyldisilazane (HMDS). Although the trimethylsilyl ethers are extremely sensitive to acid hydrolysis (for example silica gel suffices as a proton donator) and are consequently rarely used nowadays as protecting groups.

Another class of protecting groups for alcohols are the alkyl ethers. Here too there are numberous orthogonal possibilities to cleave the ether. Aliphatic methyl ethers cleave with difficulty and only under drastic conditions, so that these are in general only used with phenols.

1,2-Diols
The 1,2diols (glycols) present for protecting-group chemistry a special class of alcohols. One can exploit the adjacency of two hydroxy groups, e.g. in sugars, in that one protects both hydroxy groups codependently as an acetal. Common in this situation are the benzylidene, isopropylidene and cyclohexylidene or cyclopentylidene acetals.

Acetal formation occurs in general through shifting the equilibrium of a mixture of glycols and the carbonyl compound via removal of water from the solvent or through transacetalation with a simple acetal and removal of the resulting alcohols from the reaction mixture.

This is used directly in sugar chemistry to differentiate the locations of hydroxy groups from one another, to selective protect them dependent on stereochemistry. Thus two neighboring hydroxy groups react (besides the other possible combinations), such that the most stable conformation formed is with each other.

Acetals can absolutely be cloven in aqueous acid solutions. An exceptional case appears with the benzylideneprotecting group,which also admits reductive cleavage. This proceeds either through catalytic hydrogenation or with the hydride donor diisobutyl aluminum hydride (DIBAL). The cleavage with DIBAL deprotects one alcohol group, for the benzyl moiety stays as a benzyl ether on the second, sterically hindered hydroxy group.

Carbonyl groups
Carbonyl groups are above all threatened with attack by nucleophiles like Grignard reagents or hydride ions. Aldehydes can relevantly be further oxidized to carboxylic acids. But also undesirable reactions, like the acid- and base-catalyzed reactions of carbonyl groups, i.e. aldol reactions can be inhibited through an appropriate protecting group.

The most common protecting groups for carbonyls are acetals and typically cyclic acetals with diols. The runners-up used are also cyclic acetals with 1,2hydroxythiols or dithioglycols – the so-called O,S– or S,S-acetals.

The same applies to acetals protecting carbonyl compounds as applies to acetals protecting 1,2diols. So too the formation and removal of these moeities are naturally identical. Overall, the process of trans-acetalation plays a lesser roll in acetals as protecting groups, and they are formed as a rule from glycols through dehydration. Modern variants also use glycols, but with the hydroxyl hydrogens replaced with a trimethylsilyl group. Normally a simple glycol like ethylene glycol or 1,3-propadiol is used for acetalation.

Acetals can be removed in acidic aqueous conditions. For those ends, the mineral acids are appropriate acids. Acetone is a common cosolvent, used to promote dissolution. For a non-acidic cleavage technique, a palladium(II) chloride acetonitrile complex in acetone or iron(III) chloride on silica gel can be performed with workup in chloroform.

Cyclic acetals are very much more stable against acid hydrolysis than acyclic acetals. Consequently acyclic acetals are used practically only when a very mild cleavage is required or when two different protected carbonyl groups must be differentiated in their liberation.

Acetals find nevertheless an application besides their unique function as protecting groups as chiral auxiliaries. Indeed acetals of chiral glycols like, e.g. derivatives of tartaric acid can be asymmetrically opened with high selectivity. This enables the construction of new chiral centers.

Besides the O,O-acetals, the S,O- and S,S-acetals also have an application, albeit scant, as carbonyl protecting groups too. Thiols, which one begins with to form these acetals, have a very unpleasant stench and are poisonous, which severely limit their applications. Thioacetals and the mixed S,O-acetals are, unlike the pure O,O-acetals, very much stabler against acid hydrolysis. This enables the selective cleavage of the latter in the presence of sulfur-protected carbonyl groups.

The formation of S,S-acetals normally follows analogously to the O,O-acetals with acid catalysis from a dithiol and the carbonyl compound. Because of the greater stability of thioacetals, the equilibirum lies on the side of the acetal. In contradistinction to the O,Oacetal case, it is not needed to remove water from the reaction mixture in order to shift the equilibrium.

S,O-Acetals are hydrolyzed a factor of 10,000 times faster than the corresponding S,S-acetals. Their formation follows analogously from the thioalcohol. Also their cleavage proceeds under similar conditions and predominantly through mercury(II) compounds in wet acetonitrile.

For aldehydes, a temporary protection of the carbonyl group the presence of ketones as hemiaminal ions is detailed. Here it is applied, that aldehydes are very much more activated carbonyls than ketones and that many addition reactions are reversible.

Carboxylic acids
The most important protecting groups for carboxylic acids are the esters of various alcohols. There next-most-used are the ortho-esters and oxazoline, but of much lesser importance. For the formation of carboxy-esters there are a wide variety of methods:
 * Direct esterification of a carboxylic acids and an alcoholic compound. Because of the adverse reaction-equilibrium balance between alcohols and carboxylic acids, the equlibrium must be transformed via either removal of water or a workup with a great excess of alcohol. Therefore the alcohol must be absolutely quite cheap. This reaction is acid-catalyzed (sulfuric acid, p-toluenesulfonic acid or acid ion-exchange media are the typical trans-esterifiaction catalysts).
 * The reaction of acid anhydrides or chlorides with alcohols in the presence of an auxiliary base. For the base co-reactant one finds commonly pyridine, diisopropylethylamine or triethylamine applied. These reactions can be catalyzed with 4N,Ndimethylamino&shy;pyridine, which raises the reaction rate relative to pure pyridine by a factor of 104. Compared to the direct esterification procedure these methods are under quite mild conditions.
 * The reaction of carboxylic acid salts with alkyl halides is another method to form carboxylic acid esters.
 * The reaction of carboxylic acids with isobutene is a gentle method to form tertbutyl esters. Here isobutene and the carboxylic acid react in the presence of a strong acid like sulfuric acid.
 * The reaction of carboxylic acids with diazoalkanes is a very gentle and quantitative method to form esters. It is used primarily for the formation of methyl and benzyl esters on account of the inaccesibility of compex diazoalkanes.

Besides these classical methods for esterification, other modern techniques have been developed for special reactions.


 * The activation of carboxylic acids with dicyclohexylcarbodiimide and reaction of the so-formed Oacyl&shy;isoureas with the alcoholic compound in the presence of 4N,Ndimethylamino&shy;pyridine (the Steglich esterification).
 * Activation of a carboxylic acid with formation of a mixed anhydride with 2,4,6-trichlorobenzoic acid via reaction of the carboxylic acid with benzoyl chloride in the presence of 4N,Ndimethylamino&shy;pyridine and triethylamine. The mixed anhydride is formed in situ and immediately reacted with the alcoholic compound (Yamaguchi esterification).
 * Activation of the alcoholic compound via reaction under Mitsunobu conditions with diethylazodicarboxylate and triphenylphosphine and associated reaction in situ with the carboxylic acid (Mitsunobu esterification).

Many groups can suffice for the alcoholic component. Here the methyl, tert-butyl, benzyl, and allyl esters are very commonly used. Moreover, a whole family of protecting groups are formed therefrom, which derive from the ester protection of the hydroxy group. The specific cleaving conditions are contrariwise generally quite similar. Basically, each ester can be hydrolyzed in the presence of hydroxide ions in a mixed water-alcohol solution. For sensitive substrates, it is typically appropriate to apply lithium hydroxide in tetrahydrofuran and methanol. From the hydrolytic tendencies the same rules naturally apply to esters as a protecting group for alcohols.

Alkene
Alkenes rarely need protection or are protected. They are as a rule only involved in undesired side reactions with electrophilic attack, isomerization or catalytic hydration. For alkenes two protecting groups are basically known:
 * Temporary halogenation with bromine to a trans1,2dibromo&shy;alkane: the regeneration of the alkene then follows with preservation of conformation via elemntal zinc    or with titanocene dichloride.
 * Protection through a Diels-Alder reaction: the transformation of an alkene with a diene leads to a cyclic alkene, which is nevertheless similarly endangered by electrophilic attack as the original alkene. The cleavage of a protecting diene proceeds thermically, for the Diels-Alder reaction is a reversible (equilibrium) reaction.



Alkynes
For alkynes there are in any case two types of protecting groups. For terminal alkynes it is sometimes important to mask the acidic hydrogen atom. This normally proceeds from deprotonation (via a strong base like methylmagnesium bromide or butyllithium in tetrahydrofuran/dimethylsulfoxide) and subsequently reaction with chlorotrimethylsilane to a terminally TMS-protected alkyne. Cleavage follows hydrolytically – with potassium carbonate in methanol – or with fluoride ions like for example with tetrabutylammonium fluoride.

In order to protect the triple bond itself, sometimes a transition metal-alkyne complex with dicobalt octacarbonyl is used. The release of the cobalt then follows from oxidation.

Applications
Protecting groups have applications through organic synthesis writ large. This includes both laboratory syntheses and also large-scale syntheses of fine chemicals. As soon as a functional group has proven itself disturbable or capable of undesired attack, does the theory of protecting groups find an application. Near to any synthesis of a complex target molecule do protecting groups find application. For although the introduction and also removal of protecting groups takes effort and reduces yield, so that one aspires to eschew protecting groups, that is nevertheless hard to realize.

In the automated syntheses of peptides and nucleotides, protecting group chemistry is an integral part of any synthetic scheme. In sugar chemistry, omitting protecting groups is inconceivable, on account of the very similar hydroxy groups in the sugar molecule.

An important example of industrial applications of protecting group theory is the synthesis of ascorbic acid (Vitamin C) à la Reichstein. In order to prevent oxidation of the secondary alcohols with potassium permanganate, they are protected via acetalation with acetone and then deprotected after the oxidation of the primary alcohols to carboxylic acids.

A very spectacular example application of protecting groups from natural product synthesis is the 1994 total synthesis of palytoxin acid by Yoshito Kishi's research group. Here 42 functional groups (39 hydroxyls, one diol, an amine group, and a carboxylic acid) required protection. These proceeded through 8 different protecting groups (a methyl ester, five acetals, 20 TBDMS esters, nine pmethoxy&shy;benzyl ethers, four benzoates, a methyl hemiacetal, an acetone acetal and an SEM ester).

The introduction or modification of a protecting group occasionally influences the reactivity of the whole molecule. For example, diagrammed below is an excerpt of the synthesis of an analogue of Mitomycin C by Danishefsky. The exchange of a protecting group from a methyl ether to a MOM-ether inhibits here the opening of an epoxide to an aldehyde.

Protecting group chemistry finds itself an important application in the automated synthesis of peptides and nucleosides. For peptide synthesis via automated machine, the orthogonality of the Fmoc group (basic cleavage), the tertbutyl group (acidic cleavage) and diverse protecting groups for functional groups on the amino acid side-chains are used. Up to four different protecting groups per nucleobase are used for the automated synthesis of DNA and RNA sequences in the oligonucleotide synthesis. The procedure begins actually with redox chemistry at the protected phosphorus atom. A tricoordinate phosphorus, used on account of the high reactivity, is tagged with a cyanoethyl protecting group on a free oxygen. After the coupling step follows an oxidation to phosphate, whereby the protecting group stays attached. Free OH-groups, which did not react in the coupling step, are acetylated in an intermediate step. These additionally-introduced protecting groups then inhibit, that these OH-groups might couple in the next cycle.

As a rule, the introduction of a protecting groups is straightforward. The difficulties honestly lie in their stability and in selective removal. Apparent problems in synthesis strategies with protecting groups are rarely documented in the academic literature.

Atom economy
Syntheses using protecting groups show, as a rule, poor atom economy. Sometimes an indirect route using protecting groups is necessary, in order to eliminate an undesirable side reaction and achievee desired selectivity in a synthesis. In the syntheses of complex structures, protecting group strategies are oft unavoidable.

For an example of a protecting-group strategy, compared to a protecting-group-free synthesis, compare the syntheses of Hapalindol U. In Hideaki Muratake's 1990 synthesis, tosyl is applied as a protecting group,  but all protecting groups are eschewed in Phil S. Baran's 2007 synthesis. In that way, the number of synthetic steps is massively reduced.