1 / 40

PROTECTING GROUPS

under mild conditions. it is introduced into the molecule to be protected. in a selective manner. in high yield. it does not attack functional groups other than that to be protected. IF.

Download Presentation

PROTECTING GROUPS

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. under mild conditions it is introduced into the molecule to be protected in a selective manner in high yield it does not attack functional groups other than that to be protected IF it is stable under all the conditions used during the synthesis, including those of the purification steps, up to the step in which the protecting group is removed; other protecting groups present in the molecule and unprotected functionalities are not affected by the cleavage conditions; under mild conditions in a selective manner it is cleavable in high yield as far as possible, it has a stabilizing effect on the molecule it suppresses racemization or epimerization; PROTECTING GROUPS A protecting group finds wide application in organic synthesis

  2. be introduced and removed with the help of readily available reagents, such that in both transformations the products can be easily purified should also introduce no additional stereocenters • lend the protected intermediates advantageous physical properties; for example: • the compounds should be • easily crystallized • and/or readily soluble In addition to these minimum requirements, the protecting group

  3. very stable readily liberated • Only a few protecting groups meet all of these demands, and in most cases a compromise must be found, in which the most important criteria are addressed. • In most cases guaranteeing that the protecting group is very stable and, at the same time, readily liberated (an apparent contradiction) is the crucial problem and overshadows the requirements for efficient introduction and the provision of desirable physical and chemical properties.

  4. Acid-Labile Protecting Groups The cleavage of protecting groups by acid-mediated hydrolysis is one of the best established methods in protecting group chemistry. Nevertheless only those protecting groups that can be removed under sufficiently mild (but not too mild) conditions find widespread use. Acetal Protecting Groups Acetals are formed and cleaved under acid catalysis. They are generally stable towards nucleophiles and bases, and are thus suitable for the protection of alcohols, diols, and carbonyl compounds. Furthermore, N,N- and N,O-acetals are utilized for the protection of amino groups.

  5. Carbonyl groups are normally protected as the 1,3-dioxolane or -dioxane by condensation with ethylene glycol or propylene glycol. • Similarly, 1,2- and 1,3-diols are masked by reaction with acetone, (substituted) benzaldehyde, and cyclic ketones (cyclopentanone, cyclohexanone, cycloheptanone) as isopropylidene, (substituted) benzylidene and cycloalkylidene acetals. Cyclic O,O-acetals can be considered as protecting groups for either carbonyl groups or diols, depending on which component is of interest.

  6. Acyclic O,O-acetals are normally used for the protection of alcohols. Most commonly used are the tetrahydropyranyl (THP), the methoxymethyl (MOM), the benzyloxymethyl (BOM), and the methoxyethoxymethyl (MEM) protecting groups. • They can be cleaved readily under mildly acid conditions, and their complexing ability can also be used to control the stereochemical course of a transformation.

  7. condensation with ethylene glycol or propylene glycol as by carbonyl groups 1,3-dioxolane or -dioxane are protect 1,2- and 1,3-diols cyclic are acyclic as protect isopropylidene, (substituted) benzylidene and cycloalkylidene acetals alcohols as by tetrahydropyranyl (THP), methoxymethyl (MOM) benzyloxymethyl (BOM) methoxyethoxymethyl (MEM) • reaction with • acetone, • (substituted) benzaldehyde, • cyclic ketones (cyclopentanone, cyclohexanone, cycloheptanone) O,O-acetals

  8. Formation of Stabilized Cations The second large class of acid-labile protecting groups is characterized by the formation of stabilized cations upon cleavage. The tert-butyl ether along with the corresponding ester and urethane (Boc protecting group) are examples of this class, which find use in the protection of alcohols, thiols, amines, and carboxylic acids. In each case, their cleavage liberates the tert-butyl cation.

  9. By analogy, benzyl cations are generated on the cleavage of benzyl protecting groups, which are also common blocking groups for hydroxyl groups, thiols, esters, and amino groups. By introduction of additional substituents, the stability of the cation can be increased or reduced, and thereby the acid sensitivity of the protecting group can be finetuned. • Thus, the adamantyloxycarbonyl (Adoc) and the paramethoxybenzyloxycarbonyl (MOZ) groups are more acid-labile than the respective parent Boc and Z groups. The 4-NO2-Z group is, however, significantly more stable than the Z-urethane. It should be noted that the silyl ether protecting groups, which are usually removed by treatment with fluoride ion, are also labile under mild acidic conditions.

  10. 1,3-dioxolane or –dioxane, isopropylidene, benzylidene and cycloalkylidene acetals CYCLIC ACETAL PROTECTING GROUPS tetrahydropyranyl (THP), methoxymethyl (MOM), benzyloxymethyl (BOM), methoxyethoxymethyl (MEM) ACYCLIC FORMATION OF STABILIZED CATIONS tert-buthyl, benzyl- and adamanthyl carbocations ACID-LABILE PROTECTING GROUPS

  11. Base-Labile Protecting Groups basic hydrolysis base-induced b-elimination The removal of protecting functions under basic conditions is also one of the tried-and-true methods in protecting group chemistry. On the basis of mechanistic considerations, two categories can be distinguished: basic hydrolysis and base-induced b-elimination. base-labile protecting groups

  12. Basic Hydrolysis This method applies to practically all esters, with the exception of the tert-butyl ester. • Carboxylic acids are typically protected as (substituted) alkyl esters. • Alcohols are often esterified with acetic acid, benzoic acid, or pivalic acid. • Basic cleavage of amides to liberate amines is only seldom used on account of the generally harsh conditions required. The phthaloyl group is one exception; it can be cleaved with hydrazine under mildly basic conditions. Again, it should be noted that the silyl ethers can be removed by basic hydrolysis. • The rate of hydrolysis can be modified by adjusting steric and electronic factors. For example, trifluoroacetate can be removed selectively in the presence of acetate, and acetate can be cleaved in the presence of pivalate.

  13. Cleavage by Base-Induced b-Elimination Protecting groups such as the fluorenylmethoxycarbonyl (Fmoc) urethane, which has established itself as one of the standard protecting functions for amino groups in solution-phase and solid-phase peptide synthesis, and the phenylsulfonylethyl group are cleaved by the abstraction of an acidic proton and subsequent b-elimination, with the formation of a vinyl system. Direct attack of the base on a carbonyl function is thus avoided. This type of protecting group has found many applications.

  14. TMS < TES < TBDMS < TIPS~ thexyl Fluoride-Labile Protecting Groups Silyl protecting groups can be cleaved by treatment with fluoride ion under conditions that affect nearly no other functionalities. Variation of the substituents on silicon allows modification of their stability towards acids and bases, as well as the selectivity of the cleavage with fluoride ion. the greater the steric demand the higher the stability Alcohols are typically protected as trialkylsilyl ethers; the order of stability for the ethers is:

  15. For particularly challenging cases, a further level of fine-tuning can be achieved with, for example, isopropyldimethylsilyl, diisopropylmethylsilyl, and diethylisopropylsilyl (DEIPS). • 1,3-Diols can be masked as silanediyl derivatives or by introduction of the tetraisopropyldisiloxane-1,3-diyl (TIPDS) group. • Silyl groups are rarely used for the protection of esters and amines due to the high lability of the resulting derivatives.

  16. For this purpose, trialkylsilylethyl esters and carbamates have been developed, which can be removed by fluoride ion promoted fragmentation analogous to the previously described b-elimination. • The same principle is also behind the trimethylsilylethyl (TMSE) and trimethylsilylethoxymethyl (SEM) protecting groups for alcohols.

  17. function in the pH range 5 - 9 and at room temperature they may display a high specificity for the structures they recognize and the reactions they catalyze may tolerate a wide range of substrates Enzyme-Labile Protecting Groups In many cases the selective removal of different acyl protecting groups from amines and alcohols and the targeted deblocking of carboxylic acids under mild conditions is most readily achieved with biocatalysts. Enzymes Thus enzymes enable the targeted removal of protecting groups (which may in principle also be removed by classical chemical methods) under mild conditions and with a chemo- and regioselectivity that is hardly, if at all, possible by classical chemical techniques.

  18. Reduction-Labile Protecting Groups Reductive conditions can be used to cleave a variety of protecting groups that are used more or less frequently in organic synthesis. Cleavage by Hydrogenolysis • Benzyl groups, which can be present as ethers, esters, urethanes, carbonates, or benzylidene acetals, and are used for the protection of alcohols, carboxylic acids, amines, and diols, can be removed under mild conditions by hydrogenolysis. • The rate of hydrogenolysis can be influenced by introducing electrondonating or -accepting substituents in the aromatic ring. Benzyl groups are frequently used.

  19. Cleavage by Reductive Elimination Protecting groups of the 2-haloethyl type can be cleaved by a mechanism involving the donation of electrons into the carbon-halogen bond, leading to a fragmentation corresponding to the b-elimination Zinc is the preferred electron donor, but electrochemical methods are also successfully used.

  20. Cleavage by Hydrogenolysis Cleavage by Reductive Elimination Reduction-Labile Protecting Groups

  21. Oxidation-Labile Protecting Groups The choice of oxidation-labile protecting groups is very limited. • The 4-methoxybenzyl (Mpm) and the more labile 2,4-dimethoxybenzyl (Dmpm) ethers have proved their worth as reagents in the synthesis of complex molecules. • Both of these functions are easily removed under mild conditions with dichlorodicyanoquinone (DDQ) or with cerium(IV) ammonium nitrate (CAN) or under acidic conditions.

  22. It is also worth mentioning that S,S-acetals of carbonyl compounds, such as 1,3-dithianes, can be cleaved after oxidation of the sulfur.

  23. Cleavage of Protecting Groups Assisted by Heavy Metal Salts or Complexes • The activation of protecting groups with noble metals often offers an advantageous alternative to the targeted deblocking of functional groups. Thus carbonyl compounds masked as 1,3-dithianes can be hydrolytically regenerated easily by treatment with stoichiometric amounts of HgII, AgI, CuII, or TiIII salts or alternatively by reaction with other electrophiles or by oxidation of the sulfur.

  24. Catalytic amounts of RhI, IrII and Pd0 complexes and even Pd-C suffice for the removal of protecting groups containing the allyl group. Thus allyl ethers in carbohydrates and peptides can be selectively isomerized to the acid-labile prop-1-enyl system through the action of catalytic quantities of Pd-C or RhI or IrII complexes. Hydrolysis of this group is achieved under mild conditions.

  25. Two further interesting photolabile protecting groups are the 2-oxo-1,2-diphenylethyl (Desyl) and the o-hydroxystyryldimethylsilyl. Photolabile protecting groups can be cleaved under mild conditions with light of a suitable wavelength, and highly selective cleavage in the presence of other functional groups is possible by the choice of an appropriate chromophore. Photolabile Protecting Groups Photolabile protecting groups contain a chromophore of high chemical stability that can be selectively activated by irradiation with light of a suitable wavelength. Of the many known photolabile protecting groups, the o-nitrobenzyl has been used repeatedly in the form of ethers, esters, carbonates, carbamates. and acetals Despite these advantages, photolabile protecting groups are used much less frequently than other types of protecting groups.

  26. Formation of stabilized carbocations Acid-labile Acetals Basic hydrolysis Base-labile Base induced b-elimination Protecting Groups Fluoride-labile Enzyme-labile Hydrogenolysis Oxidation-labile Reduction-labile Reductive elimination Heavy metal salts or complexes Photolabile

  27. STABLE FORM LABILE FORM CLEAVAGE Two-stage Protecting Groups The inherent (and deliberately employed) reactivity of, for example, acid- and base-labile protecting groups is often the source of undesired side reactions. Thus, masking can be (partially) lost at the wrong point in the synthesis. • If several protecting groups of comparable reactivity are present in one molecule, selective removal of a single protecting group can be difficult. protecting functions that initially exist in a chemically stable form and can be converted into a labile group when their cleavage is required “TWO-STAGE” PROTECTING GROUPS.

  28. Examples include the methylthioethyl (Mte) and the 1,3-dithianylmethoxycarbonyl (Dmoc) groups, which are insensitive towards acid and base, but which, after oxidation of the sulfur to sulfone, fragment by base-induced b-elimination. The same principle applies to the 2- and 4-pyridylethyl protecting groups, which, after alkylation of the pyridine nitrogen, can be cleaved even with morpholine.

  29. 2-Bromoethyl esters can be transformed into salts of the corresponding choline esters by reaction with trimethylamine. The protecting group can then be cleaved either with base or under milder conditions with the enzyme butyrylcholine esterase. Removal of another interesting protecting group, the acetoxypropyl protecting group for amines, requires hydrolysis of the acetate, subsequent oxidation of the liberated hydroxyl group to give the aldehyde, and finally base-induced elimination. This proved to be a useful alternative to classical acyl protecting groups

  30. Other examples of this method of protecting group cleavage are: • the removal of 1,3-dithianes by reaction with electrophiles (or oxidation of sulfur) and subsequent hydrolysis • the removal of allyl groups by isomerization of the allyl system followed by acid hydrolysis or by formation of a p-allylpalladium complex and subsequent reaction with a nucleophile.

  31. Safety-catch Protecting Groups Closely related to the two-stage protecting groups are the “safety-catch” protecting groups. In these systems a chemically stable precursor is introduced, which is converted into an activated intermediate directly before cleavage. In this case no additional reagent, such as a base or a nucleophile, is required in order to remove the protecting groups. • The activated intermediate itself carries a reactive functional group, typically a nucleophile, which intramolecularly attacks the bond to the blocked function and thus causes the cleavage of the protecting group. a chemically stable precursor is introduced, which is converted into an activated intermediate directly before cleavage “SAFETY-CATCH” PROTECTING GROUPS.

  32. Thus, reduction of the nitro-substituted aromaticprecursor generates the aniline derivative, which then cyclizes to give the amide with liberation of the deprotected functional group. The same principle applies for azidobutyrates. Crotyl and 4-oxoacyl protecting groups react with hydrazine by addition to the a,b-unsaturated system and by formation of a hydrazone, respectively, thereby placing the nucleophile in the correct position.

  33. Analogously, chloroacetates are converted to substituted a-thioacetates by reaction with thiourea; subsequent cyclization releases the unprotected functional group.

  34. THE USE OF ORTHOGONALLY STABLE PROTECTING GROUPS THE USE OF PROTECTING GROUPS WITH MODULATED LABILITY STRATEGIES FOR THE CHOICE OF PROTECTING GROUPS DEVELOPMENT OF A PROTECTING GROUP STRATEGY

  35. The principle of orthogonal stability requires that only those protecting functions should be used that can be cleaved under (as a rule totally) different reaction conditions without affecting the other functions present ADVANTAGES: it is possible to deprotect the groups in any order DRAWBACKS: the cleavage of protecting groups requires separate steps

  36. In following the principle of modulated lability, the protecting groups are all sensitive to one set of conditions, but to differing extents. ADVANTAGES: the cleavage of several protecting groups can be done in one step DRAWBACKS: the order of deprotection is fixed

  37. Protecting groups with modulated lability are often utilized in organic synthesis, although they do not provide the same degree of safety offered by orthogonally stable functions. • In particular, this strategy is applied when several of the same type of functional group are present in the molecule to be protected for which an insufficient number of orthogonal groups is available, or when the removal of the most stable protecting group could lead to undesired side reactions.

  38. A strategy based upon the concept of orthogonal stability guarantees a great degree of flexibility in the execution of a synthesis. • However, it is often not possible to find and use the requisite number of orthogonally stable protecting groups, particularly in the case of multifunctional molecules, since cleavage of one protecting group requires not only the stability of all the other protecting groups but also of the masked molecule itself under a wide range of reaction conditions. • Additionally, in the last steps of a synthesis it is often not necessary that all protecting groups have strictly orthogonal stability, since only a few groups must be selectively liberated and a series of selective deblockings extend the synthesis significantly.These disadvantages do not exist if one uses a set of protecting groups of similar but modulated stability. • In practice, a combination of the two strategies is often employed, in which the earlier stages rely more heavily on orthogonal stability and in the latter stages the concept of similar lability is more important.

  39. THE EARLIEST POSSIBLE UNIFICATION OF A PROTECTING GROUP PATTERN THE USE OF PROTECTING GROUPS TO DIRECT REACTIONS THE INTRODUCTION OF "STAND-INS" AUXILIARY STRATEGIES

More Related