Protection and regeneration of functional groups article. Planning of multistage syntheses. The use of protective groups in the synthesis. Removal of the S-benzhydryl protection

In multistage synthesis, as a rule, one has to deal with polyfunctional compounds. This raises two problems.
1) Not all functional groups are compatible in one molecule. So, for example, an α-amino acid ester is unstable - it easily forms a heterocycle (diketopiperazine) along with a polymer:

It is impossible to obtain a magnesium or organolithium compound containing a carbonyl function in the molecule, etc.

2) The same reagent can interact with different functional groups.

In the situations considered, selective blockade of certain functional groups is used, creating the so-called protective groups that mask this function. For example, the Knoevenagel reaction between vanillin and malonic acid is complicated by other reactions associated with the presence of a phenolic OH group. Therefore, the OH group of vanillin is blocked, "protected".

Thus, the task of using protective groups involves two steps: the creation of a protective group and removal, after making the necessary changes in the molecule.

The same functional group can be protected different ways. For example, here are some ways to create and remove protecting groups for alcohols:

The particular protecting group is chosen taking into account the reactants and reaction conditions so that under these conditions the protecting group is not destroyed.

For example, the THP group is stable under alkaline conditions (pH 6-12), but unstable to aqueous solutions of acids and Lewis acids. The THP group is relatively resistant to the action of nucleophiles and organometallic compounds, to hydrides, hydrogenation and the action of oxidizing agents.

One of the most popular protecting groups for alcohols is the tert-butyldimethylsilyl (TBDMS) group. Esters of alcohols with this group are resistant to the action of many reagents, and the protective group can be easily removed under conditions that do not affect other functional groups. TBDMS protection is approximately 10 4 times more resistant to hydrolysis than trimethylsilyl (TMS) protection.

There is no need to elaborate here on the use of various protecting groups, since comprehensive monographs on this subject are now available. A great advantage of monographs is the presence in them of correlation tables, which make it possible to predict the behavior of a given protective group under certain conditions.

Certain strategies have now been developed to allow the protection of various groups to be used in the process of this synthesis. These approaches are outlined in the review.

Currently, there are two main strategic lines in the use of protecting groups: a) the principle of "orthogonal stability" and b) the principle of "modulated lability". These principles apply when several different protecting groups are used simultaneously during the synthesis.

The principle of orthogonal stability requires that each of the protecting groups used be removed under such conditions that the remaining protecting groups remain unchanged. An example is the combination of tetrahydropyranyl, benzoyl and benzyl groups.

With this approach, this protecting group can be removed at any stage of the synthesis.

The principle of modulated lability implies that all protecting groups used are removed under similar conditions, but with different ease, for example:

At the same time, the least acid-sensitive methoxymethyl protecting group cannot be removed without affecting the remaining protecting groups.

At present, the synthetic chemist has a large number of different protective groups in his arsenal. However, the synthesis should be planned in such a way as to avoid either completely without protective groups, or to reduce their use to a minimum. Here it is appropriate to quote a very important phrase from the review: "The best protecting group is no protecting group".

It should be remembered that the use of protecting groups in the synthesis requires additional operations. This lengthens and increases the cost of synthesis. In addition, the use of protective groups, as a rule, adversely affects the yield of the target product.

Choice of analysis strategy

As already mentioned, the analysis should use as many strategic approaches as possible. However, often one of the strategic lines turns out to be the main one, determining in the analysis (and, accordingly, in the synthesis). Consider, as an example, the analysis of the molecule of lucidulin, an alkaloid contained in some types of club mosses ( Lycopodium).

The presence in the lucidulin molecule of the group

easily created by the Mannich reaction, unequivocally suggests the first division, which gives a significant simplification of the structure:

In essence, the task of synthesizing lucidulin is reduced to the task of synthesizing TM38. In the structure of the molecule of this compound, a certain arrangement of the carbonyl group in ring A with respect to ring B is visible, which prompts the use of the Robinson transform. Then the analysis of TM38 will look like this.

Analysis 1

Compound (35) contains a Robinson annulation retron, according to which we carry out further subdivisions:

Thus, the considered analysis of TM38 led to the available compounds: crotonic acid ester, acetone, and methyl vinyl ketone. This analysis makes it possible to plan the construction of the skeleton of the TM38 molecule, but does not make it possible to create the necessary stereo ratios in the molecule. To solve this problem, one should be guided by another strategy, namely, based on stereochemistry.

The TM38 structure is based on the cis-decalin system, which can be created based on such powerful reactions (see Table 1) as the Diels-Alder reaction and sigmatropic rearrangements, which proceed stereoselectively.

Let us consider the core of the TM(38) molecule (36). The addition of two multiple bonds to the structure (36) forms the Cope rearrangement retron in (37), and the corresponding transform leads to the Diels-Alder retron in the molecule (38).

Analysis 2.

The resulting compound (39) is of little use as a dienophile in the Diels-Alder reaction (there is no electron-withdrawing group). Taking this into account, as well as the fact that the core (36) does not contain the necessary functional groups, we modify the molecule (37) by introducing into it groups that are easily converted into carbonyl:

In this case, the backbone (36) turns into an intermediate (in the synthesis of TM38) compound (40), the analysis of which is now obvious.

Analysis 3

Of course, in the process of synthesis, instead of ketene in the Diels-Alder reaction, it is better to use its synthetic equivalent - a-chloroacrylonitrile. Diene (42) can be obtained by isomerization of a non-conjugated diene, a product of Birch reduction of anisole:

At this stage of synthesis, the nature of the problem changes. Now we need to plan the synthesis of TM38 from the given compound (40), the approach to which is dictated by the previous stereochemical strategy. Essentially, it is necessary to modify and move to a neighboring position the functional group in TM38. The most rational way to implement such an approach is to create a multiple C=C bond between adjacent positions of the molecule. This practice, in addition, will make it possible to control the stereochemistry of reactions due to the peculiarities of the cis-decalin system.

In the molecule (43), the raised six-membered ring (A) creates steric obstacles for the approach of the reagent to the C=C bond from above (this is clearly seen in the model).

PROTECTION GROUPS, are temporarily introduced into the org. conn. for preservation in chem. reactions of certain reactions. centers. 3. g. must answer the following. requirements: a) selectively protect (block) certain functions. groups; b) be resistant to the intended transformations. molecules; c) selectively removed, regenerating the original group under conditions where the remaining parts do not change. 3. g. is introduced using substitution reactions, addition, etc. For the main. funkt. groups (OH, CO, COOH, NH 2 , NHR, SH) more than 1200 are known protecting groups Often protecting groups used in peptide synthesis; thanks to their use, a complete synthesis of many others was carried out. complex org. molecules, for example. bullish. Below are the naib. common protecting groups Alkyl and structurally similar groups protect OH, COOH, SH with the formation of resp. . and sulfides. Methods for removing such 3. g.: methyl - by the action of ВВr 3, Me 3 SiI with a hydroxyl or alkaline carboxyl group; allyl - in with last. hydrolysis; b-methoxyethoxymethyl CH 3 OCH 2 CH 2 OCH, -treatment with Lewis acids such as ZnBr 2 , TiCl 4 ; methylthiomethyl CH 3 SCH 2 - by the action of Hg, Ag, Cu. Arylalkyl groups protect NH 2 (NHR), OH, COOH, SH to form resp. substituted . ethers and esters, sulfides. Examples of such 3. g.: benzyl - easily removed under conditions. P-methoxybenzyl is selectively removed at 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, triphenylmethyl - along with hydrogenolysis is removed in an acidic medium. Heterocyclic groups are used to protect OH and SH to form mixed acetals and thioacetals. Tetrahydropyranyl and tetrahydrofuryl 3. are resistant to the action of metallorg. reagents and are easily removed by the action of acids; tetrahydrothiopyranyl and tetrahydrothienyl are more resistant to acids, but are easily hydrolyzed in the presence of Hg and Ag. Alkylidene and arylalkylidene groups protect primary amines, 1,2- and 1,3-diols to form resp. azomethines, cyclic acetals and ketals. Such protecting groups, for example, methylene, ethylidene, isopropylidene, benzylidene and its analogues are easily removed by acid hydrolysis. Acyl groups protect OH, NH 2 (NHR), SH with the formation of esters, carbonates, carbamates, thioethers, ureides. These groups, for example, formyl, acetyl, benzoyl, pivaloyl, 1-adamantoyl, are sufficiently stable in an acidic environment and are easily removed by the action of bases or LiAlH 4 . The adamantoyl group, unlike the other acyl groups, is resistant to the action of magnesium and lithium org. connections. Alkoxycarbonyl groups are similar in properties to acyl groups. The N-Phenylcarbamoyl group is more resistant to alkaline hydrolysis. Silyl groups protect OH, SH, NH 2 (NHR), COOH, forming silyl ethers and silyl-substituted amines. Trimethyl-, triethyl-, triisopropyl-, tert-butylmethyl-, tert-butyldiphenylsilyl groups (resistance under acid hydrolysis conditions increases in this series) are easily removed by the action of fluoride anion; the last two of the enumerated silyl groups are one of the largest. universal and naib. commonly used OH defenses. Alkoxy and structurally similar groups protect the carbonyl function, forming acetals and dithioacetals, including cyclic ones. Such protecting groups, for example, dimethoxy, diethoxy, ethylenedioxy and propylenedioxy groups are removed by acid hydrolysis, and cyclic. protecting groups are more stable, and the rate of hydrolysis of the propylenedioxy group is higher than that of the ethylenedioxy group. Di(methylthio)-, di(benzylthio)-, ethylenedithio and propyleneditio groups are hydrolyzed under neutral conditions in the presence of Hg, Ag, Cu. Nitrogen-containing groups protect the carbonyl function with the formation of oximes, hydrazones, azomethines, carboxyl - with the formation of hydrazides; these derivatives are removed by the action of acids. Lit.: Protective groups in organic chemistry, trans. from English, M., 1976; Greene T.W., Protective groups in organic synthesis, N.Y., 1981, AT. G. Yashunsky.

Choose the first letter in the title of the article.

The very idea of ​​using protective groups is well known in general organic chemistry. Here is a classic example. It is necessary to nitrate aniline and get n-nitroaniline. Nitric acid is a strong oxidizing agent, while aniline is easily oxidized. Therefore, it cannot be nitrated directly. Therefore, the amino group of aniline is preliminarily protected: it is converted into acetate, which is much more resistant to oxidizing agents, then it is nitrated and, finally, the protection from the amino group is removed by alkaline hydrolysis:

Everything is simple here. Aniline contains two very different reaction centers - an amino group and an aromatic nucleus. Therefore, it is not a problem to selectively protect one of them. The reaction product, p-nitroaniline, is a very stable compound and easily survives the conditions of rather severe alkaline hydrolysis. Therefore, the removal of the protection is also straightforward. In the chemistry of carbohydrates, the situation is incomparably more complicated. First of all, here the functional groups are very similar, so it is very difficult to introduce protection selectively - and this is the whole point of such an operation. There are several such groups in the molecule (to say the least), and all but one or two must be protected. It is clear that this circumstance, generally speaking, does not simplify the problem. Finally, carbohydrates themselves and almost all of their derivatives are highly reactive compounds. Because of this, the possibilities of actions suitable for the removal of protections in the final stages, and therefore, the types of protective groups used, are severely limited.

The basic requirements for protecting groups are fairly obvious. First, they must allow selective administration. Secondly, the defenses themselves must be quite stable under the conditions of the main reaction. Thirdly, the protections must allow removal under conditions that ensure the safety of both the carbohydrate structure itself and, of course, the results of the main reaction, for the sake of which the protective structures were erected. Finally, it is not so important, but very important, that the reactions of introduction and removal of protective groups take place with high yields: otherwise, the entire multistage synthesis will be associated with too significant losses.

Of all the above, the most difficult is selective administration. Here there are no developed rules, following which one can mechanically select the necessary sequence of transformations and types of protective groups. Nevertheless, there are a number of well-developed reactions leading to the formation of protections, and a number of principles for ensuring their regiospecificity. So now a competent synthesist can draw up a realistic synthesis plan leading to the selective release of any functional group in any monosaccharide. But, we emphasize once again, this is not a mechanical application of ready-made rules, but a creative process that requires careful consideration of the tasks of a particular synthesis and the choice of the optimal scheme from a number of possible ones. Therefore, we will not try to give, so to speak, an algorithm for the selective protection of functions, but we will describe only some elementary methods used in carbohydrate chemistry for this purpose.

Consider D-glucose. Suppose we need to protect all hydroxyl groups, except for the hydroxyl at C-6. Such a task is relatively simple, since the hydroxyl of interest to us is primary and differs markedly in reactivity from the other hydroxyls in the molecule - secondary alcohol and hemiacetal. This increased reactivity is used at the key stage of the synthesis. Glucose is treated with triphenylmethyl chloride (trityl chloride as it is often abbreviated) in pyridine. When trityl chloride reacts with alcohols, trityl ethers are formed. The trityl group is very bulky; therefore, tritylation of spatially more hampered secondary alcohols proceeds slowly, while primary tritylation is easy. Due to this, tritylation of glucose proceeds with high selectivity and leads to the formation of trityl ester 12. All other hydroxyls can be further protected by acetylation with acetic anhydride in pyridine. In the resulting derivative 13, all functional groups are protected, but protected differently. The trityl ester can be destroyed by acid hydrolysis under conditions that do not affect acetate esters. The product of such hydrolysis is tetraacetate 14, in which the only hydroxyl is free - at C-6.

Notice how paradoxical this synthesis goes: in order to selectively release the hydroxyl at C-6, we start by protecting it. Nevertheless, the ultimate goal is achieved very successfully. The example is characteristic in two respects: firstly, the chemistry of carbohydrates in terms of the logic of introducing selective protections is full of such paradoxes, and secondly, the use of selective tritylation is a common (which is rare in this field) method of freeing the primary hydroxyl in sugars.

Another site in the monosaccharide molecule, which also has specific properties, is the glycosidic center. For its selective protection, the synthesis of lower glycosides is most often used, in the simplest case, by acid-catalyzed condensation of monosaccharides with alcohols (Fischer glycoside synthesis). The most common derivatives for this purpose are methyl glycosides, such as α-methyl-D-glucopyranoside (15), α-methyl-D-rhamnopyranoside (16) or β-methyl-L-arabinopyranoside (17). For the cleavage of methyl glycosides, it is necessary to perform a sufficiently severe acid hydrolysis or acetolysis, which is not always acceptable in terms of the stability of the main product. To avoid this complication, benzyl glycosides are used (eg (β-benzyl-D-galactopyranoside (18)), in which the protection can be removed under specific conditions by hydrogenolysis over a palladium catalyst (see scheme).

The greatest difficulties arise when it is necessary to selectively protect some of the secondary hydroxyls of monosaccharides, since these groups have the closest chemical properties. Most often, the key step in such syntheses is the formation of various acetals or ketals. As is known, aldehydes and ketones can easily condense with alcohols in the presence of acid catalysts to form acetals or ketals 19. If a dihydric alcohol with a suitable arrangement of hydroxyl groups is introduced into the reaction, then such a reaction leads to similarly constructed cyclic derivatives of type 20. Acetals and ke- Thalis are cleaved by acid hydrolysis under relatively mild conditions and are highly resistant to alkalis, making them useful as protecting groups in numerous types of syntheses.

In order for cyclic derivatives of type 20 to be formed quite easily, certain requirements on the structure of the starting dihydric alcohol must be met. Its two hydroxyl groups should not be located too far from one another, since otherwise the probability of ring closure drops sharply and the reaction proceeds preferably intermolecularly with the formation of linear oligomers. In addition, the appearance of a cyclic system should not cause significant additional stresses in the rest of the molecule.

For these reasons, the possibility of forming cyclic acetals or ketals is subject to tight control of the entire structure, stereochemistry, and conformation of the substrate. As a result, the reactions leading to such alkylidene derivatives proceed very selectively and affect not all, but only well-defined hydroxyl groups of the monosaccharide or its partially protected derivative. Thus, the introduction of alkylidene groups makes it possible to sharply break the monotonicity of the functional groups of the initial compounds and creates the basis for various methods of selective protection of alcohol hydroxyls.

PROTECTION GROUPS, are temporarily introduced into molecules org. conn. for preservation in chem. p-tions of certain reactions. centers. Protective groups must meet the following. requirements: a) selectively protect (block) certain functions. groups; b) be resistant to the intended transformations. molecules; c) selectively removed, regenerating the original group under conditions where the remaining parts of the molecule do not change. Protective groups are introduced using p-tions of substitution, addition, cyclization, etc. For the main. funkt. groups (OH, CO, COOH, NH 2 , NHR, SH) more than 1200 protective groups are known. Very often protecting groups are used in peptide syntheses; thanks to their use, a complete synthesis of many others was carried out. complex org. molecules, e.g., insulin, bovine ribonuclease. Below are the naib. common protecting groups. Alkyl and structurally similar groups protect OH, COOH, SH with the formation of resp. ethers, esters and sulfides. Methods for removing such protective groups: methyl - by the action of ВВr 3, Me 3 SiI with hydroxyl or alkaline hydrolysis from the carboxyl group; allyl - isomerization to vinyl ether with last. hydrolysis; b -methoxyethoxymethyl CH 3 OCH 2 CH 2 OCH, -treatment with Lewis, such as ZnBr 2 , TiCl 4 ; methylthiomethyl CH 3 SCH 2 - by the action of salts of Hg, Ag, Cu. Arylalkyl groups protect NH 2 (NHR), OH, COOH, SH to form resp. substituted amines, ethers and esters, sulfides. Examples of such protective groups: benzyl - is easily removed under hydrogenolysis conditions, p-methoxybenzyl is selectively removed by oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, triphenylmethyl - along with hydrogenolysis is removed in an acidic environment. Heterocyclic groups are used to protect OH and SH to form mixed acetals and thioacetals. Tetrahydropyranyl and tetrahydrofuryl protective groups are resistant to the action of metallurgical. reagents and are easily removed when action set; tetrahydrothiopyranyl and tetrahydrothienyl are more resistant to to-there, however, they are easily hydrolyzed in the presence. salts of Hg and Ag. Alkylidene and arylalkylidene groups protect primary amines, 1,2- and 1,3-diols to form resp. azomethines, cyclic acetals and ketals. Such protecting groups, eg methylene, ethylidene, isopropylidene, benzylidene and its analogs, are readily removed by acid hydrolysis. Acyl groups protect OH, NH 2 (NHR), SH with the formation of esters, carbonates, carbamates, thioethers, ureides. These groups, for example, formyl, acetyl, benzoyl, pivaloyl, 1-adamantoyl, quite stable in an acidic environment and easily removed by the action of bases or LiAlH 4 . The adamantoyl group, unlike the other acyl groups, is resistant to the action of magnesium and lithium org. connections. Alkoxycarbonyl groups are close in St-you to acyl. The N-Phenylcarbamoyl group is more resistant to alkaline hydrolysis. Silyl groups protect OH, SH, NH 2 (NHR), COOH, forming silyl ethers and silyl-substituted amines. Trimethyl-, triethyl-, triisopropyl-, tert-butylmethyl-, tert-butyldiphenylsilyl groups (in this series stability increases under acid hydrolysis conditions) are easily removed by the action of fluoride anion; the last two of the enumerated silyl groups are one of the largest. universal and naib. commonly used OH defenses. Alkoxy and structurally similar groups protect the carbonyl function, forming acetals and dithioacetals, including cyclic ones. Such protective groups, for example, dimethoxy, diethoxy, ethylenedioxy and propylenedioxy groups, are removed by acid hydrolysis, and cyclically. the protecting groups are more stable, and the rate of hydrolysis of the propylenedioxy group is higher than that of the ethylenedioxy group. Di(methylthio)-, di(benzylthio)-, ethylenedithio- and propyleneditio groups are hydrolyzed under neutral conditions in the presence. salts Hg, Ag, Cu. Nitrogen-containing groups protect the carbonyl function with the formation of oximes, hydrazones, azomethines, carboxyl - with the formation of hydrazides; these derivatives are removed by the action of to-t.
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Use literature for the article "PROTECTIVE GROUPS" In: Protecting groups in organic chemistry, trans. from English, M., 1976; Greene T.W., Protective groups in organic synthesis, N.Y., 1981, V. G. Yashunsky.

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