1.

06 Protecting Group Manipulations in Carbohydrate Synthesis
´ ´ A. Liptak, A. Borbas, and I. Bajza, Carbohydrate Research Group of the Hungarian Academy of Sciences, Debrecen, Hungary ß 2007 Elsevier Ltd. All rights reserved. 1.06.1 Introduction 1.06.2 General Considerations 1.06.2.1 1.06.3.1 1.06.3.2 1.06.3.3 1.06.3.4 Protecting Group Strategy: Permanent, Temporary, and Unichemo Protection Simultaneous Protection of Three or More Hydroxyl Groups Simultaneous Protection of Two Hydroxyl Groups Internal Protecting Groups Methods for the Regioselective Protection of a Hydroxyl Group
Utilization of the different reactivity of the hydroxyl groups Introduction of the protecting groups by phase-transfer catalysis Regioselective protection with the dibutylstannylene acetal Regioselective protection by using orthoesters

204 204 205 208 208 209 212 213
213 214 214 215

1.06.3 Regioselective Formation of the Protecting Groups

1.06.3.4.1 1.06.3.4.2 1.06.3.4.3 1.06.3.4.4

1.06.3.5 1.06.4.1

Regioselective Cleavage of Protecting Groups Ether Protecting Groups
The benzyl ether The p-methoxybenzyl, (2-naphthyl)methyl, and p-phenylbenzyl ethers The triphenylmethyl ethers The diphenylmethyl (DPM) and 9-fluorenyl ethers The allyl ethers The silyl ethers The acetal protecting groups often discussed as ethers The acetates The benzoates The pivaloates The levulinates The carbonates Formation of acetals Reductive cleavage of dioxane-type benzylidene acetals into benzyl ethers Regioselective hydrogenolysis of dioxane- and dioxolane-type benzylidene acetals Hydrogenolysis of molecules carrying dioxane and dioxolane rings Hydrogenolysis of symmetrical ketals Oxidative cleavage of dioxane- and dioxolane-type benzylidene acetals

216 217 217
217 220 221 222 222 225 227

1.06.4 Protection of Hydroxyl Groups
1.06.4.1.1 1.06.4.1.2 1.06.4.1.3 1.06.4.1.4 1.06.4.1.5 1.06.4.1.6 1.06.4.1.7

1.06.4.2

Esters

228
228 230 231 231 231

1.06.4.2.1 1.06.4.2.2 1.06.4.2.3 1.06.4.2.4 1.06.4.2.5

1.06.4.3

Acetals

232
232 235 235 236 237 241

1.06.4.3.1 1.06.4.3.2 1.06.4.3.3 1.06.4.3.4 1.06.4.3.5 1.06.4.3.6

1.06.5 Protection of Amine 1.06.5.1 1.06.5.2 1.06.5.3 1.06.6.1 1.06.6.2 Amides Imides Carbamates The Effect of the Protecting Group on the Reactivity Protecting Groups Encouraging Structural Elucidations

242 243 244 245 245 245 247

1.06.6 The Protecting Groups Are not Just Passive Bystanders

203

the stereochemical outcome can be highly influenced and regulated by the protecting groups incorporated into the donor and acceptor molecules. Since carbohydrates are polyfunctional compounds. and carbonyl functionalities. in the acceptor molecule.6. and thereby a few synthetic steps may be avoided. namely. or other functional groups in certain chemical transformations. the primary hydroxyl groups are much more reactive than the secondary hydroxyls and.06. and their analogs. which are considered the ‘non plus ultra’ of oligosaccharide syntheses. whose survey. most particularly in biologically .06. due to steric or other factors. The reason for this is quite obvious: the construction of certain complex structures requires the application of a wide variety of protecting group strategies. neoglycoproteins. glycoconjugates (neoglycolipids. and polysaccharides with TEMPO results in the oxidation of the primary hydroxyl groups exclusively. Nevertheless.6. and splitting of the protecting groups in organic syntheses are comprehensively reviewed by excellent monographs. the regioselective glycosidation of unprotected allyl a. The protecting groups inhibit the participation of the substituted hydroxyl.06.06.1 Introduction Carbohydrates play essential roles in a lot of diverse biological processes. We are well aware that the chemistry of sugars is not limited to oligosaccharide syntheses. Related examples from the field of oligosaccharide syntheses are the ‘open glycosylations’3.6. the protecting groups employed in the chemistry of carbohydrates are the same as those generally used in organic chemistry. the presence of a large number of the same functional group – which is mainly the hydroxyl group – at the carbohydrate skeletons. the chemical synthesis – even of the most simple derivatives – requires the application of protecting groups. This chapter is aimed at the discussion of the introduction and removal of the most frequently applied protecting groups in carbohydrate chemistry. At the same time. neoglycopeptides). regioselective processes offering acceptable preparative yields with polyhydroxy derivatives are very necessary.1 1.6. in glycosidation reactions toning the reactivity of the reaction partners.2. but their applicability may be quite limited. carboxyl. 1. In general. Essentially.2 General Considerations During the designing of a synthesis strategy. oligo-.2 the detailed description of these will not be highlighted here.3. which expose and demonstrate the existing rules. including introduction of ester.06. as well as the art of protecting group strategies and manipulations. even two secondary hydroxyl functions may possess different reactivity. There are other. but less frequently emerging groups to be used for the protection of nitrogen.06.3. on a molecular level. it is important to consider the electronic and/or steric influence of these groups on the reactivity of the molecule.1.2 13 C-labelled protecting groups Protecting groups labelled with fluorine 248 248 1. but there is such a great difference between the reactivity of these two groups that for a regioselective transformation no protection of the less-reactive hydroxyl is necessary. Consequently. Application of a protecting group requires at least two synthetic steps: its introduction and removal. At the same time. a great majority of the examples has been taken from this latter particular field.3. application of the possibly least and less variety of protecting groups is desired. consideration of economical factors is very important. the polyfunctionality. Further. ether. and this is more pronounced in the preparation of complex oligosaccharides and glycosaminoglycan fragments.6 Of the similarly regioselective reactions.2 1.4 for example.06. oxidation of mono-. and this is most particularly valid for the generation of the glycosidic linkages. Since many of the aspects of the formation. Utilization of the above observations considerably enhances the efficiency of the syntheses. an emphasis will be made on the application of the protecting groups and manipulation with them in carbohydrate chemistry.06.or b-D-mannopyranosides at the primary hydroxyl group with a glycosyl bromide5 or with glycosyl trichloroacetimidate.204 Protecting Group Manipulations in Carbohydrate Synthesis 1. their removal or occasional migration and various additional transformations. that is.7–9 However. necessitates specific protecting group manipulations. stabilities. However. and acetal groups.2. for example.1 1. In many cases only two hydroxyl groups remain free.6. necessitates the synthesis of various natural mono. as a whole. such selective reactions are not frequent.3 1. nonetheless important.and oligosaccharides.3 Protecting Groups Facilitating the Work-up Procedures Lipophilic protecting groups Fluorinated protecting groups Catch-and-release purification 249 249 250 250 1.6. Therefore.

or when other substituents (e. and Unichemo Protection In order to synthesize a complex oligosaccharide or glycoconjugate. if the target compound is sensitive to basic or alkaline deprotection (i. In general. Temporary. The groups staying in the target molecule until the penultimate step.e.. and which can be selectively split (by distinguishing them from the permanent protecting groups).11 Still another advantage is that monitoring of the compound protected with the given group becomes easier. two types of permanent protecting groups are applied: (1) the benzyl. (2) it should be readily characterized. no problems occur with the separation from a residue due to the cleaved protecting group. for example. T1.06.12 and in certain cases additional practical factors can also be determined. The number and character of the temporary protecting groups are obviously determined by the structure of the target molecule. are the temporary protecting groups (Figure 1)..T2.g. For example. complicated synthetic routes may be disadvantageously influenced or even prevented by the decomposition of the product upon removal of an unfortunately selected protecting group. P¼permanent protecting group.g. in a synthesis of a tetrasaccharide from monosaccharides three hydroxyl groups should be glycosylated and 13 hydroxyls should be protected. and (4) it should be compatible with the work-up conditions. In the case of a branched oligosaccharide.13 1. Obviously. (3) it should be stable in most of the chemical transformations. sulfate. thus making extractive work-ups easier.Protecting Group Manipulations in Carbohydrate Synthesis 205 relevant cases. an unsaturated aglycon15 which changes upon hydrogenolysis of the benzyl groups.T3 ¼temporary protecting groups. acyl) to ensure removal in a single step. are called permanent protecting groups..10 An additional general requirement is that. namely the role of introduction and removal is of primary importance. and carboxyl) must be protected – except the one to be involved in the reaction. its introduction is not accompanied by the formation of a new asymmetric center. and if the product is crystalline. a good manipulation with the protecting groups may significantly shorten the reaction sequence. no heterogeneous catalyst is required upon removal which might be a problem in solid support syntheses. or in a few steps.14 and (2) ester-type permanent protecting groups are used when the product carries. After selection of the permanent protecting groups. the number of the temporary protecting groups is dependent on the structure of the target molecule. but if this cannot be avoided. amino. Monomer 3 PO O PO PO C OP HO O HO HO C O OH HO HO HO HO Figure 1 Protecting group pattern of monomers for the synthesis of a tetrasaccharide. the correct selection of the protecting group strategy/manipulation. so as to offer convenient purification. At the same time. such as the phosphate ester). Monomer 2 PO O X T3O PO HO O B O O HO HO O C OH O A OH B OP X PO T1O T2O Monomer 1 O A OP O Aglycon O Aglycon . only one stereoisomer must be present. A further advantage is that the resulting protected compound is highly hydrophobic. The success of long. involving their removal.2. Other groups that are retained in the molecules only in one step. generally all of the functional groups (hydroxyl. upon removal. Carbohydrate chemists must consider that much more functional groups are to be protected than those required to carry out the desired transformations.1 Protecting Group Strategy: Permanent. Thus. carbonyl. it is quite advantageous to protect all of the 13 groups with the same (or that very similar in character) protecting group (e. or benzyl-equivalent groups. The required properties of an ideal protecting group are as follows: (1) readily available reagents are necessary for its introduction and removal. for example. splits or migrates.

The hydroxyl group which is protected by a monomer is liberated. An interesting alternative of the protecting group manipulations is the so-called unichemo strategy. the repeated degradation cycle furnishes the next free hydroxyl group(s). levulinoyl. or chloroacetyl groups can also be selectively removed in the presence of permanent acetate esters.206 Protecting Group Manipulations in Carbohydrate Synthesis phosphate) are present. A general practice is the application of ester in the presence of ethers or vice versa (Figure 2). 86%. Manipulate OH ii. 99%. 99%. MeOH:DCM (1:10). O O O PO O OR Deprotect O O HO PO O OR i. and then they are cleaved or transformed in a selective manner. not very surprisingly. DCM. HO FmocO OBn O TrocHN SEt 2 OBn O TrocHN SEt i LevO FmocO 1 LevO FmocO OBn O TrocHN SEt ii iii LevO HO 3 OBn O AcHN 4 SEt Figure 2 Conditions: (i) H2NNH2. The pivaloyl. and again. numerous temporary groups are necessary that must be selectively removable in the presence of each other (orthogonal). Following the manipulation of the hydroxyl. then Ac2O.18 which was introduced. which is an oligopeptide. HOAc. In oligosaccharide syntheses. Deprotect O O = Fmoc N O P1O PO Figure 3 The principle of the ‘unichemo’ protection. For cleavage the Edman-degradation is applied. The acetals are usually employed for the simultaneous temporary protection of two hydroxyl groups. and the only difference is in the polymerization degree of the individual protecting group.HOAc.17 In this approach a single type of protecting group is used exclusively. each of the unichemo-protected oligomers is shortened with one monomer unit (Figure 3). by a peptide chemist. (iii) Zn. The permanent and temporary protecting groups are not necessarily the members of another type of compounds. In conclusion. in oligosaccharide syntheses either the representatives of one group of compounds are employed as permanent and temporary protecting groups. and the oligomers protecting the other hydroxyls are degraded with one monomer. or these functions are selected from two or three types of organic substances. Py. (ii) Et3N (20%). OR OH .17.16 benzoate esters are often used as permanent groups together with the selectively removable acetate or chloroacetate esters as temporary protecting groups.

and to avoid undesired side reactions.27. other groups (generally the acetals) have effects on the reactivity and stereoselectivity.28 or on the regioselectivity. Since the generated bond in this case is rather sensitive. following glycosidation the benzyl groups are exchanged to esters (acetyl or benzoyl)15. change of the protecting groups may also emerge. Sometimes it is O HO OBn O OBn OBn O BnO O O OBn NHAc OBn OSE O OBn H3C O OBn BnO OR SPh OBn O O OR O OR O OR OR RO O OSE O OR O NHAc H 3C OR RO O OR R = Bn R = Ac O O OAc O OAc O NHAc OAc O AcO O OAc OAc O O OAc HN OH C13H27 C17H35 O H3C O OAc OAc AcO OH O OH NaOMe.20 and the ester groups diminish.23. 45 C then H2O OH O OH OH HO O O O OH HN O OH C13H27 C17H35 O O O NHAc H3C OH HO O OH Figure 4 Change of the protecting groups during a reaction sequence. where – in order to ensure a-selectivity – application of fucopyranosyl donors carrying the so-called nonparticipating benzyl groups is desired. it must be taken into account that the protecting groups modulate the properties of the whole molecule. A number of protecting groups.31–35 Many examples have been reported on how to tone36 the reactivity of the donor and acceptor molecules by choosing their appropriate protecting groups.37–39 In some longer reaction sequences.21–25 respectively.30 and bulky groups may change the conformation of the sugar skeleton. The alkyl groups generally enhance19 (sometimes even too much).29. so as to reach a good-yielding coupling with high selectivity. first of all the acyl substituents influence the steric outcome of the glycosidation reactions by means of anchimeric assistance. .40.Protecting Group Manipulations in Carbohydrate Synthesis 207 When designing a protecting group strategy.26 Due to steric reasons. MeOH. in an appropriate design of a synthesis strategy practical aspects have also to be considered.41 (Figure 4). the reactivity of the molecules.19. An example for this is the synthesis of the a-L-fucopyranoside-containing oligosaccharides. Apart from the influence on the reactivity and stereoselectivity of the selected number and type of the protecting groups.

and needed to be free in the target molecule. the 2. compilation of a successful protecting group strategy necessitates an excellent knowledge of the literature procedures. for the removal of an acyl group. Such functionalizations of disaccharides that are dependent on the configuration are often applied. since the regioselective introduction. as well as allows the economical preparation of the oligosaccharide fragments of arabinogalactans.208 Protecting Group Manipulations in Carbohydrate Synthesis most advantageous if the protected saccharide is well-detectable and characterizable. three secondary and one primary hydroxyl groups have to be protected – except the anomeric center.6. proved to be suitable.1 Simultaneous Protection of Three or More Hydroxyl Groups In a few cases there is a possibility for the protection of more hydroxyl groups in a single step so that one of the hydroxyls remains free. removal.49. This strategy permits a significant reduction of the steps required. the isopropylidene48 and the benzylidene acetal.6-tri-O-acetyl derivative can be mentioned.3 Regioselective Formation of the Protecting Groups The synthesis of a synthon carrying free hydroxyl group(s) in the given position(s) can be accomplished by (1) protection of the hydroxyls of the polyol. and to realize the plan good practice is needed besides a bit of luck pulling the strings from time to time.40 -O-isopropylidene lactosides in detail. Moreover. OR O OBn OR O O O O OBn O Ph O O CH(OMe)2 O . In theory. as well as highly lipophilic that makes the work-up procedure more convenient. even in the most simple case.42 In conclusion.43. For lactose and laminaribiose.06. for example. acetylation of benzyl b45 D-glucopyranoside with NaOAc/Ac2O to result in the 2.47 An acetal represents a most particularly useful protecting group to simultaneously substitute more hydroxyl groups of a saccharide derivative.20 . for the preparation of 3-O-methyl-lactose.3. O O OR O O OR HO 5 R = Bz 6 R = Bn Ph O O HO Ph O O 7 OMe O O OH O O O O 8 Figure 5 Simultaneous protection of hydroxyls.46 The lactosides can also be alkylated (6) at the same positions. However. or (2) the regioselective cleavage of the protecting groups of a fully protected derivative. for example. 8 and 7 were synthesized (Figure 5).60 -tetrabenzoate 5 could be isolated with a good yield.50 thus. respectively.44 Such a substitution reaction in the monosaccharide field is quite rare. and transformation of a given group is also dependent on the configurational properties of the individual sugar. Tsukida et al. 1. studied the conditions of the benzoylation of b-alkyl 30 . which are not involved in the transformations. it does not mean that an analogous protection scheme can be applied for all of the sugars. a successful manipulation with a monosaccharide cannot necessarily be transferred to a higher-membered oligomer. in the case of all of the aldohexoses.06.4. 1. As an example. and following optimization.

15.3-diols is very often accomplished with acetal (e. The susceptibility of the hydroxyl groups to be included in an internal orthoester is dependent on the configuration. Apart from incorporating three hydroxyl groups. Various reasons contributed to the success of acetal protecting groups in carbohydrate chemistry. Of the silylene acetals.and 1. O O O 12 Ph Ph O HO MeO2C 13 O O OH Figure 7 Simultaneous protection of three hydroxyls by the 6-benzoyl-3. and cyclohexylidene77 acetals are less often employed. simple.g. the application of the isopropylidene acetal (acetonide) is shown on a sugar with D-gluco-configuration (Figure 9).and trans-diols can be effected.3 diols can be distinguished. 1.76 diphenylmethylene.2. respectively.2.60 orthoester (26).4. selective protection of the cis. in the inositol field the orthoformate (11. a further advantage of such orthoesters is that they fix the ring-conformation.3-positions.59 by introducing the 6-benzoyl3. Methoxybenzylidene.81 whereas with 2-methoxypropene the product is the 4.82 Acetalation of saccharides of D-manno-83 and D-galacto84 configurations with 2-methoxypropene also results in good .and 1.Protecting Group Manipulations in Carbohydrate Synthesis 209 OH O O O O R TrO O O OH 9 10 O R1O O O O O R3O OR2 11 Figure 6 Simultaneous protection of three hydroxyls by internal orthoester group. readily available. Several review materials and book chapters deal with the preparation. In the case of vicinal diols.2-orthoesters. the ring-size of the sugar can be influenced.2:5.06.52 A novel method for the protection of triols was worked out by Rawlings et al. and 1.2. In addition. In the case of monosaccharides51 and inositols. D-xylo. They combined the protecting capability of dihydropyran and a carbonyl group in a single molecule. Thus.58 Internal orthoesters are not very often used as protecting groups.2-diacetals of carbohydrates. 16).61–63 cyclic carbonate (17). transformation. and the acetalation reactions are convenient to carry out with high yields. the di-t-butylsilylene acetal78 and the TIPDS group34.57 and prepared from sugars with D-arabino.3.69–74 Of such acetals. 1. and cleavage of carbohydrate acetals.6-di-O-isopropylidene-D-glucofuranose 19 can be obtained. R¼Me) protecting groups are routinely applied. L-rhamno. A new and well-utilizable group of acetals is the 1.4-dihydro-(2H)pyran reagent 12.75. cheap. R¼H) or orthoacetate (11.51 At the same time.2. Such tricyclic or internal orthoesters of carbohydrates are long known. the isopropylidene and benzylidene derivatives are by far the most frequently applied.6-O-isopropylidene glucopyranose derivative 20. can be simultaneously protected this way. Treatment with acetone.2 Simultaneous Protection of Two Hydroxyl Groups Joint protection of the hydroxyls of carbohydrate 1.80 For demonstration.. 14.52–55 an orthoester function offers the joint protection of three hydroxyl groups.79 are to be mentioned. In D-xylo (9) or D-gluco sugars and D-manno derivatives (10)..56.and 1. thus permitting further regioselective substitutions. and nontoxic reagents are used for their preparation.4-dihydro-(2H) pyran reagent. it is very important that by an adequate selection of the type of the acetal and of the reagents and conditions.64–67 or boronate (18)68 functions (Figure 8). migration. The susceptibility of the procedure was demonstrated with sugar alcohols and d-gluconolactone 13 (Figure 7). rather their capability for polymerization is utilized in syntheses of certain types of oligosaccharides (Figure 6). the 1. D-gluco and D-manno configurations from 1.

and galacto-configurations. manno-. 2. for the synthesis of the 4.2-dimethoxypropane was the best reagent for choice.86 Di-t-butylsilylene acetal is useful for the protection of 1.6-O-isopropylidene acetals.6-O-isopropylidene acetal of 2-deoxy-2-acetamido-D-glucopyranose. selectivity to furnish the 4. in a great majority of cases. This is a general way to protect the 4.3-diols is the conversion into arylmethylene acetals. O OH O Si O Bu O O 16 O OMe O 15 OH O O O HO Ph B 18 O Glucose OMe Acetone O O O OH O 19 Figure 9 Formation of different acetonides from glucose.4-hydroxyl groups in ido-compound 21 (Figure 10).210 Protecting Group Manipulations in Carbohydrate Synthesis Bu O O O 14 O O 17 Figure 8 Possible protection of diols. and less trivial. by introducing.3-diols. but clever selective substitution of the 2. benzylidene and methoxybenzylidene functions.À78  C. At the same time. Et2O. which – apart from the selective protection – has a general role29 in influencing the stereoselectivity of glycosidation reactions. Et3SiH. O O O HO O OH OH 20 MeOOC O O OBn BnO O O 21 i OBn O N3 OAll pMeOPh MeOOC PMBnO O OBn BnO O OH 22 OBn O N3 OAll Figure 10 Conditions: (i) PhBCl2. .6-positions in the case of gluco-.85 A general way for the protection of 1. 90%.

this method also involves two steps.94. Py. but the application of ethylene carbonate has opened a convenient route for the selective substitution of the cis-diol function of inositols (33. r.38. 2.102 carrying a free C2 hydroxyl group 30.. The reaction of the 1-OH derivatives of carbohydrates 27 with 1-chloro-2. these are rather unstable.79.75.66 Recently.2-orthoesters (Figure 12). cyclic carbonates ensure to fix the conformation of the substrate.2-orthoesters. orthoesters are resistant to bases and to alkaline conditions.96 No matter whatever they are called. Although not directly from the polyol. thus greatly contributing to the success of structural investigations.92 which are important for the substitution of diol-systems.88 One of the procedures to achieve protection of trans-diols was elaborated by van Boeckel by applying the TIPDS acetal. also affords 1.and cis-vicinal diols.Protecting Group Manipulations in Carbohydrate Synthesis 211 Protection of cis-vicinal diols is not a problem: most of the acetalation reagents are suitable for this purpose. 80%.6-O-acetal the 3.4-protected derivative can be prepared (24. Orthoesters can be hydrolyzed with dilute trifluoroacetic acid to yield the free reducing sugars 27. or the glycosyl acetates38.62.t. therefore.N.t. (ii) TsOH.91 The benefit of acetals for protection of diols is not just in that two hydroxyl groups can be simultaneously substituted and liberated in single step. Protection of trans-vicinal diols was worked out by Ley by introducing dispiroketals and butane-1.and O2 hydroxyl group is the incorporation in orthoesters. The orthoesters 26 are easy to prepare (however. a 1. The arylmethylene acetals can be selectively cleaved into the respective substances carrying one of the previously protected hydroxyl groups free. Orthoesters are ready to transform into glycosyl chlorides 28 directly by treatment with chlorotrimethylsilane.62.97–100 The outstanding utility of protection in the form of orthoesters is manifested in their manifold chemical transformations as shown in Figure 13.23.107 Also. EtOH. and leaving the other substituted with an alkyl (or acyl) function.103–105 into 1. Figure 11). r. can be rearranged67.06. By means of isomerization of this latter function. such compounds are shown to enhance the reactivity of ethylthio glycosyl donors.3-O-isopropylidene derivatives from gluco-compounds can be prepared.87 However. A practical methodology of simultaneous protection of the anomeric.2-trans glycosides 29 with protic or Lewis acids.67 HO HO OH O HO OMe 23 i-Pr i. ii i-Pr Si O O O Si i-Pr i-Pr 24 OH O HO OMe Figure 11 Conditions: (i) TIPDSCl.90 Simultaneous protection of the anomeric and O2 hydroxyl groups can be achieved by utilizing an allyl aglycon. Figure 14).106 Cyclic carbonates have long been known for the protection of vicinal diols. many carbohydrate chemists are not really happy with them when appearing as the byproducts of glycosidations in some cases6.3.63 and can be reduced into 1. PentOH) in the presence of an N-base. O AcO Br 25 Figure 12 Formation of 1. O O H3C 26 O OR 27 O AcO OH . by acid-catalyzed migration of the initially formed 4.86.2-diacetals.101.2-ethylidene acetal can be constructed that can be cleaved with acid hydrolysis following the required transformations at other positions of the molecule. In general. The regularity and conditions of such kinds of ring cleavages are discussed in detail in Section 1.4. this is not the case with the trans-vicinal diols.2-ethylidene acetals 31.62. cyclic carbonates can be produced from trans. DMF.89 Actually.. removal of ester groups and regioselective or exhaustive alkylations can be readily accomplished with carbohydrates protected with orthoesters. followed by treatment with an alcohol and triethylamine.63.N-trimethylpropenylamine.64 and used in certain solid support oligosaccharide syntheses.93–95) from glycosyl halides 25 and simple alcohols (MeOH.80.

3 Internal Protecting Groups A clever.6-lactone can be acylated in a regioselective manner at the C4 hydroxyl group (40).109 whose anomeric acetyl group is further transformed into. 42). 80%. and under more vigorous conditions the product is the 2. but their utility as the recognizing elements of various sensors is rather important. lactones (in the case of uronic acids).2.124 Apart from selective protection. the readily available glucono-3.6-di-O-acetyl derivatives 36. In synthetic works they are not applied very often.119 By an appropriate selection of the reaction conditions. cleavage of the [3.6-anhydro derivatives).112 6-O-benzylated glycosyl halides.and thioglycosides. Ando et al. In the case of uronic acids.68 Such derivatives are also useful for the protection of vicinal diols.109–111 Such compounds are readily available from aryl-O.113 or from other 6-O-benzyl (or p-methoxybenzyl) derivatives.68 1. namely a thioglycoside 34.6-anhydro sugars 35 are successfully applied as synthons for the preparation of oligosaccharides and glycoconjugates (Figure 15). For this. a glycosyl bromide 38.114–117 Following manipulations at the other hydroxyl groups of the molecule.118 The examples shown above demonstrate that the 1. 30min.121 The 1.5-lactam (44. acetolysis is rather useful to furnish 1.6-anhydro derivatives can be most successfully utilized in the syntheses of oligosaccharides linked with a 1-6 bond.212 Protecting Group Manipulations in Carbohydrate Synthesis O AcO OH 27 O AcO 29 O H3C 31 Figure 13 Possible transformations of 1.42. The 1. or lactams (in the syntheses of NeuAc derivatives). Splitting of the ring can also be performed to provide a glycosyl donor. Opening of the lactone ring then provides either the 2.06.3-di-OH (41.1] bicyclic skeleton can be accomplished.123. NaHCO3.7-lactones of sialic acids were used by Schmidt et al.4-di-O-acyl derivative.122 Recently.2-orthoesters.16. or 3-OH derivative with a good yield (Figure 16)120 and this strategy can also be transferred to the oligosaccharide syntheses. O O O O AcO Cl 28 O HO OAc 30 O OR H 3C OR 26 O HO OBn HO 32 OH OH OBn i O O OBn O 33 OH OH OBn Figure 14 Conditions: (i) ethylene carbonate. or glycosyl trichloroacetamidate (by means of the selective cleavage of the anomeric acetyl group 37). for example. . a lactone ring incorporating the carboxyl group and one of the hydroxyl groups may temporarily protect these two functions. as acceptors in glycosidations. Figure 17). such a substitution was found to be advantageous with regard to the reactivity of the C4 and C8 hydroxyl groups in glycosidation reactions. The chemistry of cyclic boronates has been reviewed by Ferrier108 and Duggan.3. protected the carboxyl and amino functions at the sialyl acceptor in form of a 1. 120  C. economical way for the protection of carbohydrates is to appropriately manage the substituents of the molecule: internal acetals (1.

HOAc. DMAP.127. Tr) group.1. HOAc. and this is followed by the equatorial and the axial hydroxyls. 3h. 5d.128 the 9-phenyl-xanthen-9-yl (Px) and 9-tolyl-xanthen-9-yl (Tx) . DMF. AcOH. DMF. drierite. ZnI2. 89%. (iii) HBr. therefore. (iv) H2NNH2. MeOH. (ii) MeOH. anhydrous AcONa. O HOOC HO HO 39 ii MeOOC RO HO O OAll OH 41 R = Bz 42 R = Piv Figure 16 Conditions: (i) Bz2O (6 equiv. the relative reactivity of the hydroxyl groups of sugars is dependent on their configuration.125 For temporary protection of the primary hydroxyl groups the bulky triphenylmethyl (trityl. DMF.t.). (ii) Ac2O.Protecting Group Manipulations in Carbohydrate Synthesis 213 OH O OR1 34 SPh O i O OR1 35 ii OAc O OR1 R iii 36 R = OAc 37 R = OH 38 R = Br iv Figure 15 Conditions: (i) TMSSPh. OAll O OAll OH OR 40 OH i O Ph O O TFAHN AcO AcO 43 i. H2O. H2SO4. ii Ph O O AcO AcO 44 Figure 17 Conditions: (i) NaOMe.126 its variants the more acid-sensitive dimethoxytrityl (DMT).4 Methods for the Regioselective Protection of a Hydroxyl Group 1.06. then TFA. it still can be stated that the primary hydroxyl group is the most reactive.3. no general order for the reactivity that is unequivocally valid in each case can be given.06.) or Piv2O (38 equiv. As a first approximation. 80  C. Py. DCM. reflux.1 Utilization of the different reactivity of the hydroxyl groups As mentioned in Section 1.3. COOMe O SPh O HN O SPh 1.4. DCE.06. r. (ii) Ac2O.

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