Research: Science & Education
Protecting Groups in Carbohydrate Chemistry Sigthór Pétursson University of Akureyri, 600 Akureyri, Iceland The carbohydrates play a fundamental role in biochemistry. In addition, the purely chemical aspects of these compounds have fascinated the most brilliant chemists through the ages. The organic chemistry of the carbohydrates as multifunctional compounds is very demanding and it is only fairly recently, after years of development of suitable chemical methods, that the full potential of these compounds in synthetic chemistry is being realized (1, 2). There are different ways to represent the configurations of carbohydrates, but the best-known methods are the Fischer and the Haworth projections. Fischer projections are more suitable for configurational comparisons of carbohydrates, but the Haworth projection is more commonly used today and shows more clearly the cyclic nature of the molecules, which is the overwhelmingly predominant form even in reducing sugars. A stereochemical representation goes a step further in showing the actual structure of these molecules. The fourth method, common with some synthetic chemists, was initially suggested for carbohydrate chemistry by Mills (3). This represents the ring as a flat hexagon in the plane of the paper and the steric arrangement is given as wedged or dashed bonds. The different ways to represent the D-glucose structure are shown in Figure 1. A recent publication in this Journal presents the isopropylidene group as an introduction to carbohydrate protecting groups (4). This method is one of the earliest methods for protection in carbohydrate chemistry and is still widely used. Because of the multifunctionality of carbohydrates, the development of their use in synthetic chemistry has to a large extent involved protecting group chemistry. The most common protecting methods in carbohydrate chemistry go back to the 19th century (5). The traditional need for protection in carbohydrates was mainly for oligosaccharide synthesis and preparation of
D-Glucose D1 2
O
HO 3 5
OH OH
6
CH2 OH
4
6 CH2 OH 5 O 1
6 CH
2 OH
OH
5
OH OH O HO 3 2 1 OH
4
4
OH
rare monosaccharides and related compounds such as acid (vitamin C). The synthesis of vitamin C by Haworth and Hirst is of historical importance as the first synthesis of a vitamin (6), but Reichstein’s and Grüssner’s synthesis is a dramatic illustration of the industrial potential of a well executed chemical and microbiological synthesis having turned into more than 500 million dollar industry annually (7). Reichstein’s synthesis is a brilliant example of the use of the isopropylidene group for protection in carbohydrate chemistry, as well as an early example of the coupling of microbial and chemical synthesis. A full review of protecting groups in carbohydrate chemistry is beyond the scope of this paper, but a summary of the most common protecting methods will be given. L -ascorbic
Acetals / Ketals Acetals and ketals are formed by the reaction of an alcohol with an aldehyde or ketone in the presence of an acid catalyst.
1
R
R
1
R = H (aldehyde) 1 R = alkyl group (ketone)
O
OH
OH
The H-atoms on C-1 to C-4 are omitted
H
2
R
R C OH OCH3
Hemiacetal
2
R
R C OCH3 + OCH3
H2 O
Acetal
There are two applications of acetal protection in monosaccharide chemistry. The first is where the carbohydrate carbonyl group is protected as an acetal. In this, one of the alcoholic groups normally comes from the monosaccharide itself and the other from an external alcohol. This special type of acetal is called a glycoside. In these cases where an internal alcohol is used (4-OH in furanosides and 5-OH in pyranosides of aldoses), the hydroxyl group involved is also protected by being tied up in the glycosidic bond. The first synthesis of simple glycosides by treating an alcoholic solution of the carbohydrate with hydrogen chloride was introduced by Fischer, one of the pioneers of carbohydrate chemistry (8).
OH
2
HO 3
CH3 OH
1
1
+
C O + 2
HO OH OH OH
HEMIACETAL CH2 OH CH3 OH O OH OH + H H HO OH
(full) ACETAL (α-anomer) CH2 OH O H OH OCH3 HO OH
H-atoms on C-2 to C-5 are omitted
Fischer’s projection (aldehyde form)
Haworth’s projection (hemiacetal form)
Formation of a hemiacetal
6
CH2 OH HO HO
O OH OH
Stereochemical representation
HO HO
O
OH
1
5
2 4
3
OH
OH Mills representation
Figure 1. Representations of carbohydrate structures.
The other type of application of acetal protection is for the carbohydrate hydroxyl groups. This time an aldehyde or a ketone is usually the external reagent. The net effect of this type of protection is illustrated below. Acetal or ketal protection is very useful for vicinal hydroxyl groups where it gives a 5-membered cyclic ring, but it is also common for a 4,6-protection in a hexapyranose, in which case a stable 6-membered cyclic acetal or ketal is formed. Usually ketones show a preference for 5-membered ketal rings (1,3-dioxolanes),
Vol. 74 No. 11 November 1997 • Journal of Chemical Education
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Research: Science & Education whereas aldehydes prefer 6-membered 1,3-dioxane rings. Formation of 5-membered cyclic acetal/ketal
Formation of 6-membered cyclic acetal/ketal H
H R
O
C
H
O
C
H
+
R
O
C
H
O
C
H
+
C R
H
6
6
O
CH2 O
R
R
H
C O
C
H2 O
O
C
4
H
C
H
5
R
O CH2
R
+
H
C
O
O +
C H
5
R
H
O C
H2 O
H
4
The mechanism for acetal formation is illustrated below. 1. The first two steps (formation of the hemiacetal) can occur in either neutral or acid solution. The first step is protonation of the carbonyl oxygen: 1
R δ+ δ− C O + 2 R
1
1
R
+
R
C
C O
H
2
R
O
2
H
H
R
!
2. The alcohol then reacts with the carbocation: 1
C R
3
+
O
R
2
O
C
R
+
OH +
H
2
H
3
H
OR Hemiacetal
3. In an acid solution, the hydroxyl group is then protonated. This forms an ideal leaving group in the form of water. The net effect of step 3 is dehydration of the hemiacetal: 1
1
2
R
1
R
R C
OH
2
+
+
R
H
3
C
R O
2
H
R
3 OR H
OR
CH2
+
C
@
(CH 3)2C–O–ZnCl2 and the zinc chloride not being a strong enough acid to open the ketal ring once formed. Transacetalations have also been used in kinetically controlled reactions. Thus Evans (11) prepared methyl 4,6-O-isopropylidene-α-Dmannopyranoside in 46% yield. Even better kinetic control was obtained by the use of the acid-catalyzed reaction of methyl isopropenyl ether with the same mannoside, giving 4,6-O-isopropylidene in 65% yield (12).
R
R1
catalyst, conditions under which the isopropylidenes are perfectly stable. Acetals and ketals can also be formed by acid-catalyzed transacetalation/ketalisation using, for example, benzaldehyde dimethyl acetal, Ph-CH(OCH3)2, or 2,2-dimethoxypropane, (CH3)2C(OCH 3)2. These reagents are convenient and toluenesulfonic acid is commonly used as a catalyst. These reactions, as well as the traditional methods for formation of cyclic acetals and ketals using protic acid catalysis, normally give the most thermodynamically stable product. On the other hand, Lewis acid catalysis with zinc chloride has been shown to give products that must be kinetically controlled. An example of this is shown in Figure 3 (10). The formation of the 4,6-ketal is explained by the greater reactivity of the primary 6-OH group with the relatively bulky carbocation
OCH3 C CH3
+
HO HO
H2 O
3
O O HO
DMF
OH
p-CH3-C6H4-SO3H 65 % yield
OCH3 Methyl isopropenyl ether
OR
CH2OH O
O
OH
OCH3
Methyl α-D-mannopyranoside
Methyl 4,6- O -isopropylidene α-D-mannopyranoside
4. Finally, a second alcohol reacts with the carbocation, which results in the full acetal after the loss of a proton: 1
R
CH2 OH O OH OH HO OH
1
R 2
R 3
+ R
C
2
O
3
R
H
OR
3
C OR
+
+
H
3
OR Acetal
D-Glucopyranose
CH2 OH HO O OH OH
CH2 OH O OH HO OHHO
OH
D-Mannopyranose
D-Galactopyranose
O
A very important property of cyclic acetal protection is that it engages two hydroxyl groups, which must therefore be suitably arranged. Figure 2 shows examples of how the hydroxyl groups protected are dependent on the sugar configuration, if the reaction is allowed to come to an equilibrium (thermodynamic control) (9). The ease and selectivity of removal of the protecting group is of crucial importance. The acetals are particularly relevant examples in this connection, because a glycosidic acetal is often present that must not be disturbed. Acetals are acid labile but generally very stable to basic conditions. This, of course, applies also to the glycosidic bond. Nevertheless, it is often possible to remove an acetal protection selectively with acid without disturbing the glycosidic bond. The second most important acetal group for carbohydrate protection, after the isopropylidene group, is the benzylidene group, formed from benzaldehyde and a diol—particularly a 4,6-diol:
+
(acetone) / H
O CH2 O O OH O O 1,2:5,6-Di-O -isopropylideneα-D-glucofuranose
O CH2 O O O O
CH2 OH O O O OO
OH
2,3:5,6-Di-O -isopropylideneD-mannopyranose
1,2:3,4-Di-O -isopropylideneα-D-galactopyranose
Figure 2. Isopropylidene protection of monosaccharides.
O H2SO4 HO HO
O O
CH2OH O Thermodynamic product
OH OCH3 Methyl 3,4-O -isopropylidene-α-D- galactopyranoside
CH2OH O OH OCH3
HO CH2
O Ph C
+ H
+
H
HO
O CH2 Ph-CH
Methyl α-D-galactopyranoside
+
H2 O
O ZnCl2
HO
O O
Kinetic product
OH OCH3
O
Methyl 4,6-O -isopropylidene-α-D- galactopyranoside
Protection by the benzylidene group is complementary to the isopropylidene protection, since it can be removed selectively by catalytic hydrogenolysis over a palladium
1298
Figure 3. Thermodynamic and kinetic control in the formation of cyclic ketals.
Journal of Chemical Education • Vol. 74 No. 11 November 1997
Research: Science & Education The initial step in this reaction is the formation of a carbocation, after protonation on the terminal carbon of the double bond as shown below. +
H
+
CH2
OCH3 C CH3
CH3
Table 1. Reductive Opening of Benzylidene Acetal Rings Ether formed by reduction with NaBH3CN/HCl
LiAlH4/AlCl3/THF
Benzylidene
OCH3 C CH3
Ph
O O RO
CH2 OCH2 Ph HO RO
O
CH2 OH O
PhCH2 O HO
O
OR OR OR The carbocation formed must react very seOCH OCH OCH lectively with the primary hydroxyl group. Certain protecting groups are modified once Ether formed by reduction with introduced. This may be done to facilitate reNaBH3CN/CF3COOH/DMF NaBH3CN/(CH3)3SiCl/CH3CN moval or to change and partially remove the p M e t h o x y b e n z y l i d e n e protection. The first example given is the alO CH OCH Ph-OCH -p p-CH O-Ph CH OH O lyl group. Allyl protection has been used exp-CH O-PhCH O HO O O O RO RO RO tensively in oligosaccharide synthesis. Allyl OR OR OR OCH OCH OCH ethers are readily formed by the reaction of allyl bromide with hydroxyl groups and they are fairly stable. They can, however, be isomerized by strong base to vinyl ethers, which are readily removed ters, the acetates and benzoates. These esters are very under mild conditions using a Lewis acid (13). Introducuseful in carbohydrate chemistry, although they must be tion of an allyl protection, isomerization to a vinyl ether, used judiciously because of their propensity to migrate. and removal is shown below. Acetate or benzoate protection of carbohydrate hydroxyl groups can be introduced by reaction of the anhydrides or acid chlorides in pyridine, which both catalyzes these NaH/C6 H6 R O CH2 -CH=CH2 R OH + BrCH2 CH=CH2 - HBr, > 90% reactions and neutralizes the acid liberated. A Lewis acid Allyl ether catalyst such as zinc chloride is also often used for the - + t-BuO K / DMSO R O CH CH-CH acetylation with acetic anhydride. Benzoylation with R O CH2 -CH=CH2 3 100˚C, 15 min. benzoyl chloride in aqueous sodium hydroxide (Schotten– HgCl2 / HgO Baumann) is also possible if the compound is base stable R OH R O CH CH-CH3 acetone/H2 O and sufficiently water soluble. The normal ester-cleaving 5 min, 100% methods can be used for carbohydrate esters if the carDMSO = Dimethyl sulfoxide or methyl sulfoxide bonyl group does not interfere, but because of solubility characteristics, alcoholic rather than aqueous solvents This sequence of reactions avoids strongly acidic condiare commonly used. Thus de-esterification of glycosides tions completely and is therefore compatible with the can be done by treatment with a stoichiometric amount glycosidic bond and acetal protection. of potassium hydroxide in ethanol or by acid-catalyzed Modifications of benzylidene protection, especially hydrolysis, if a glycoside or another acetal protection 4,6-O-benzylidenes, are much more versatile and are does not need to be maintained. Amine-catalyzed hysynthetically very useful. Hanessian introduced a drolysis in aqueous alcohol can also be used. Probably method based on the benzylidene chemistry of carbohythe most useful method for ester removal is a basedrates that has found use in synthesis. It involves the catalyzed transesterification in anhydrous methanol treatment of a 4,6-benzylidene with N-bromosuccinimide with a trace amount of sodium methoxide (the Zemplén (NBS). This results in oxidative opening of the benzylprocedure) (16). This is illustrated below for a carbohyidene by a free-radical mechanism, giving a 6-bromide drate acetate; the principle of the method is that the and a benzoyl group on position 4 (14). strong basic methoxide catalyst sets up an equilibrium between the carbohydrate ester and methyl acetate. O Methanol, being the solvent, is in a large excess and the CH2 Br Ph O Ph C O O equilibrium therefore lies far to the right. NBS O O 3
3
2
3
2
3
3
2
3
3
HO
2
3
3
HO
OH OCH3 Methyl 4,6-O -benzylideneα-D-glucopyranoside
OH OCH3 Methyl 4- O -benzoyl-6-bromo6-deoxy- α-D-glucopyranoside
Another example of a benzylidene modification is the reduction of 4,6-O-benzylidenes or 4,6-O-p-methoxybenzylidenes by different reducing agents. This releases either the 4- or the 6-hydroxy group, leaving a benzyl protection on the other oxygen, which was part of the acetal (15). This is summarized in Table 1. Esters We have seen, in the acetals, protecting groups that are easily introduced and that can be removed under relatively mild acid conditions or, in the case of the benzylidenes, under neutral conditions by catalytic hydrogenolysis. A protecting group that is base labile, where the acetals are stable, would be a useful addition. Ester protection is the obvious choice. The following discussion is restricted to the most common carboxylic es-
O
O
- +
Carbohydr.O C CH3 + CH3 OH Excess
CH3 O Na
Carbohydr. OH + CH3O C CH3
This takes place by the methoxide ion attacking the ester carbonyl, leaving a carbohydrate alkoxide that accepts a proton from the solvent, regenerating the methoxide catalyst. Not only can an ester protection be removed in the presence of an acetal, but esters are sufficiently acid stable to allow the selective acid removal of an acetal in their presence. Thus 5,6-O-isopropylidene can be removed in the presence of a 3-O-benzoyl group in a glucofuranose in 60% ethanol at pH 2 (17). O O
pH 2
O OBzl
O O
60% C2H5OH
3-O-Benzoyl-1,2:5,6-di- O-isopropylidene-α-D-glucofuranose
HO HO
O OBzl
+
O
O O 3-O-Benzoyl-1,2-O-isopropylidene-α- D-glucofuranose
Acetone
Bzl = O= CPh
Vol. 74 No. 11 November 1997 • Journal of Chemical Education
1299
Research: Science & Education Ethers It is often necessary to use a protection for a carbohydrate hydroxyl group that is stable to both acidic and basic conditions. This brings us to the ethers. The simplest ether is the methyl ether. There are methods available for removing a methyl ether protection, but it is unlikely that methyl ethers will be used as a temporary protection. They have, however, had a fundamental role as permanent protection in structural studies of oligosaccharides and polysaccharides. On the other hand, benzyl ethers (PhCH2–O–R) are very useful protecting groups in synthetic carbohydrate chemistry. They are stable to acid and base, but can be removed readily under neutral conditions by hydrogenolysis over a palladium catalyst. This gives them an important role in carbohydrate chemistry. The following sequence, which forms a part of the synthesis of D-glyceraldehyde-3-phosphate (18), illustrates the use of benzyl ether protection. O H2C HO O O OH CH2 O
O H2C PhCH2O O PhCH2Cl KOH
1,3:4,6-Di- O-methyleneD-mannitol
Regioselectivity for the secondary hydroxyl groups is more demanding and requires special methods. No general rules can be given for the relative reactivities of the secondary hydroxyl groups of monosaccharides, since this is obviously dependent on the configuration and to some extent also on the reaction conditions. Such differences as have been observed are so small that they are not of any synthetic use except where special methods have been developed to enhance these differences (22). Equatorial groups in the pyranose structures are sterically more accessible than axial groups and are therefore often slightly more reactive, except under strongly basic conditions where the acidity of the 2-OH may cause it to be the most nucleophilic site irrespective of equatorial/axial arrangements. HO
O
HO
OH O
OH OR OR
HO +
H + 2 H2O OCH2Ph CH2 O
PhCH2O HO + OH OCH2Ph OH
O
2,5-Di-O-benzyl-1,3:4,6-diO-methylene- D-mannitol
2,5-Di-O-benzylD-mannitol
2 H2CO
Formaldehyde
Both 2- and 3-OH groups are equatorial and relatively accessible in D-glucopyranosides. The 2-OH is marginally more reactive.
3-OH group is equatorial but 2-OH is axial and relatively inaccessible in The 3-OH group is more reactive except under strongly basic conditions.
D -mannopyranosides.
Phase-Transfer Reactions Regioselective Reactions of Carbohydrate Hydroxyl Groups Certain reagents allow regioselective protection of carbohydrates, especially the primary hydroxyl group. The triphenylmethyl or trityl ether has had a special role in this connection. Because of the bulky phenyl groups, trityl chloride reacts selectively with the primary hydroxyl group on carbohydrates. Trityl ethers are also relatively acid labile, and their p-methoxy derivatives were developed by Khorana as special reagents for the 5-O protection of ribose and deoxyribose in oligonucleotide synthesis (19). Apart from the cyclic acetals, the trityl group is probably the oldest example of the use of regioselectivity in synthetic carbohydrate chemistry (20). This method for the protection of the primary hydroxyl group has to a large extent been taken over by the bulky t-butyldiphenylsilyl and t-butyldimethylsilyl reagents, which are more efficient and easier to use (21). Numerous examples of the uses of silyl protection in synthetic carbohydrate chemistry can be found in the literature (see for example ref 2, pp 371 and 395). Methods for introducing and removing these groups are illustrated in Table 2. Yields are usually close to quantitative, and selectivity for the primary hydroxyl group is excellent.
Phase-transfer methods have been applied successfully to carbohydrates in effecting mono- alkyl- or esterifications of compounds containing more than one hydroxyl group. In these reactions the reagent, typically benzyl or tosyl chloride, and the phase transfer catalyst, for example tetrabutylammonium bromide, are in an organic phase in contact with excess base in an aqueous phase. Phase transfer–catalyzed tosylations of methyl 4,6-O-benzylidene-α-D-glucopyranoside gave 78% yield of the 2-tosylate and 95% yield of the 2-tosylate of methyl 4,6-O-benzylidene-α- D -mannopyranoside. Similar benzylation of α- and β-D-glucopyranosides also resulted in selectivity for the 2-OH, although not to the same extent as in the case of the tosylations (23). This selectivity is explained by the relatively high acidity of the 2-hydroxyl group, which consequently forms the nucleophilic anion more readily than the 3-hydroxyl group. Cyclic Stannylene Derivatives A method for the selective acylation and alkylation of carbohydrates with axial/equatorial 2,3-diols of carbohydrates was reported by Anderson and Nashed and has since been widely used for other vicinal and 4,6-diols
Table 2. Use of Silyl Protection for Hydroxyl Groups Protection
Deprotection t-Butyldimethylsilyl ethers
R’ OH + Cl-Si(R,R)CMe3
Imidazole DMF, > 90%
R’ O Si(R,R)CMe3
+ Im•HCl
R’ = carbohydrate moiety; R = Me; Im = imidazole; DMF = N,N-Dimetylformamide R′ = carbohydrate moiety; R = Me; Im = imidazole; DMF = N,N -dimethylformamide
1. Bu4 NF / THF R’ OH + F Si(R,R)CMe3 2. H2 O, > 90% R’ = carbohydrate moiety; R = Me; THF = Tetrahydrofuran R’ O Si(R,R)CMe3
R′ = carbohydrate moiety; R = Me; THF = tetrahydrofuran
t-Butyldiphenylsilyl ethers R’ OH + Cl-Si(R,R)CMe3
Imidazole DMF, > 90%
R’ O
Si(R,R)CMe3
+ Im•HCl
R’ == carbohydrate carbohydrate moiety; Ph;Im Im = imidazole;DMF DMF = N,N-Dimetylformamide R′ moiety; RR==Ph; = imidazole; = N,N -dimethylformamide
1300
1. Bu4 NF / THF R’ OH + F Si(R,R)CMe3 2. H2 O, > 90% R’R′ = carbohydrate moiety; R = Ph; Bu = normal Butyl; THF = Tetrahydrofuran = carbohydrate moiety; R = Ph; Bu = n -butyl; THF = tetrahydrofuran R’ O Si(R,R)CMe3
Journal of Chemical Education • Vol. 74 No. 11 November 1997
Research: Science & Education Table 3. Stannous Chloride–Catalyzed Reactions of Diaryldiazomethanes with Methyl 4,6-O -Isopropylidene-α-Dmannopyranoside 2-O -Ether % isolated yield
Reagents O O HO
OH O
CH3 O +
OCH3
SnCl2 CH3 OCH2 CH2 OCH3
CN2 CH3 O
3-O -Ether % isolated yield
0
61
(24). This method uses dibutyltin oxide to form a cyclic 2,3-O-dibutylstannylene intermediate. Both benzylation and benzoylation of the cyclic dibutylstannylene derivative give an overwhelming reaction on the equatorial 3-OH group of mannosides. The benzylation of methyl 4,6-O-benzylidene-α-D -mannopyranoside to give the 3-ether is shown below. Ph
O O HO
OH O
CH3
CN2
+
8
SnCl 2 CH3OCH2CH2OCH3
CH3
60
O O HO
OH O OCH3
OCH3
O O HO
OH O
OH O
+
38
SnCl 2 CH3OCH2CH2OCH3
CN2
O O HO
OH O
Methyl 4,6- O-benzylideneα-D -mannopyranoside
38
SnCl 2 CH3OCH2CH2OCH3
CN2 Cl
42
40
70
5
N2 C SnCl 2 CH3 OCH2 CH2 OCH3
+
OCH3
Table 4. Stannous Chloride–Catalyzed Reactions of Diaryldiazomethanes with Methyl 4,6-O -Benzylidene-α-Dmannopyranoside 2-O -Ether % isolated yield
Reagents Ph O HO
O
OH O
+
SnCl 2 CH3OCH2CH2OCH3
CN2
3-O -Ether % isolated yield
6
70
0
81
0
65
OCH3
Ph O HO
O
OH O
Cl CN2
+ Cl
SnCl 2 CH3OCH2CH2OCH3
OCH3
Ph O HO
O
OH O
N2 C
SnCl2 CH3OCH2CH2OCH3
+
Table 5. Structural Relationship of Three Polyhydroxylated Cyclic Amines with Common Monosaccharides Amine
Monosaccharide y
Structurally related to
HO OH Deoxynojirimycin D (1,5-Dideoxy-1,5-imino-D-glucitol)
OH OH H
HO
HO H
N
HO
N OH
y
HO OH Castanospermine ((1S,6S,7R,8R,8aR)-1,6,7,8tetrahydroxyoctahydroindolizine)
OH OH H N
O
O
O Bu
Sn
BnBr DMF
Ph
O O BnO
OH O
OCH3
OCH3 Methyl 3- O-benzyl-4,6-Obenzylidene-α- D-mannopyranoside, 85% yield
CH2OH O OH OH HO OH D D-Glucopyranose
CH2 OH O OH OH HO OH D D-Glucopyranose
CH2 OH
HO H
OH
N
HO
HO OH Swainsonine ((1S,2R,8R,8aR)-1,2,8trihydroxyoctahydroindolizine)
N OH HO
HO
O
OHHO
When an equatorial/equatorial pair is involved, the selectivity depends on the adjacent oxygens, substitution occurring next to an axial oxygen in preference to the –OH adjacent to an equatorial oxygen. Unexpected selectivities have also been reported for stannous chloride-catalyzed reactions of diazo compounds with 2,3-diols of 4,6-O-protected mannopyranoside derivatives. The results obtained for reactions of some 4-substituted diphenyldiazomethanes with methyl 4,6-O-isopropylidene-α-D-mannopyranoside are summarized in Tables 3 and 4 (12). These reactions show a trend from 3-OH selectivity for the more reactive diazo compounds to a more even or a preferential selectivity for the 2-OH in reactions of the more stable ones. This is particularly interesting when compared to reactions of the same compounds with the related methyl 4,6-O-benzylidene-α-D-mannopyranoside as shown in Table 4, where a preferential reaction with the equatorial 3-OH is always observed. These methods have not been developed for synthetic purposes but they are included here because the results raise interesting theoretical questions. Examples of Application of Protecting Groups in Synthesis
OCH3
CH2 OH N OH
O
Bu = n-butyl; Bn = PhCH2; DMF = N ,N,-dimethylformamide
Cl
+
OCH3
O
Bu
OCH3
O O HO
Ph Bu2 SnO CH3 OH
OH
D D-Mannofuranose
Polyhydroxylated cyclic amines with indolizine, piperidine, and pyrrolidine skeletons extracted from plants and microorganisms have biological activities that in most cases are probably due to their glycosidaseinhibiting properties. Recent developments in the investigation of oligosaccharide processing, which is of great importance in immunological studies (25), and affinity chromatography for the isolation of glycosidase enzymes (26) have resulted in increased interest in synthetic methods for these compounds. Inspection of the structures of these compounds reveals a close relationship with common carbohydrate structures (see Table 5). Figures 4 and 5 show a synthetic sequence that illustrates a typical use of protecting groups to make the 4-OH of a hexose available for transformation into a good leaving group, trifluoromethanesulfonyl ester, for SN2 displacement with azide (27). The easily accessible methyl 2,3-O-benzyl-α-D-glucopyranoside is then used in the sequence shown in Figure 5. The azide of the end product of the above sequence can be selectively hydrogenated over palladium to methyl 4-amino-2,3-di-O-benzyl-4-deoxy-α-D-galactopyranoside, which is easily deprotected by catalytic hydrogenolysis to give the methyl glycoside of D -galactosamine (chondrosamine), a major constituent of chondroitin sul-
Vol. 74 No. 11 November 1997 • Journal of Chemical Education
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Research: Science & Education
HO HO
Ph
CH2 OH O HO
PhCHO/ZnCl2 RT, 4 h
Ph NaH/BnBr DMF, 85%
O HO
OCH3
Methyl α−D-glucopyranoside
I
O O HO
fate of connective tissues. If, however, the glycosidic bond is hydrolysed first followed by hydrogenation of the azide, an intramolecular cyclic imine results, which upon more vigorous hydrogenation/hydrogenolyses results in the fully deprotected polyhydroxylated cyclic amine 1,4dideoxy-1,4-imino- D-galactitol, as shown in Figure 6.
I
OCH3
Methyl 4,6-O -benzylideneα−D-glucopyranoside
O O BnO
HO BnO
80% AcOH 80˚C, 1 h, 95%
O
Conclusion
CH2 OH O BnO OCH
BnO OCH3
3
Methyl 2,3-O-benzyl-4,6-O benzylidene−α−D-glucopyranoside
Methyl 2,3-O -benzylα−D-glucopyranoside
Bn = PhCH2 ; DMF = N,N-Dimethylformamide; AcOH = acetic acid
Figure 4. 2,3-O -Benzyl protection of methyl α- D-glucopyranoside.
CH2 OH O OBn
Ph +
DMF imidazole
t-Bu Si Cl
OCH3 OBn
HO
Ph t-Bu Si O CH2 O Ph OBn HO
Ph
imidazole•HCl
+
OCH3 OBn
Methyl 2,3-O -benzylα-D- glucopyranoside
Ph t-Bu Si O CH2 Ph O OBn HO
(CF3 SO2 )2 O
pyridine CH2 Cl2
OCH3 OBn
Ph t-Bu Si O CH2 Ph O OBn CF3 -SO2 -O
+
Ph t-Bu Si O CH2 Ph O OBn
+
DMF
NaN3
Ph t-Bu Si O CH2 Ph N3 O OBn
OCH3 OBn
+
-
+
CF3 -SO2 -O Na
OCH3 OBn
OCH3 OBn
Ph t-Bu Si O CH2 Ph N3 O OBn
Literature Cited pyridine•HCl
+
OCH3 OBn
CF3 -SO2 -O
+
-
1. (n-Bu)4 N F / THF 2. H2 O
CH2 OH N3 O 50% yield overall OBn OCH3 OBn Methyl 4-azido-2,3-di-O -benzyl4-deoxy-α-D-galactopyranoside
Bn = CH2Ph; DMF = N,N -Dimethylformamide; t-Bu = Tertiary butyl
Figure 5. Use of silyl protection in synthesis and the introduction of a nitrogen.
H2 /Pd Ethanol (selective) CH2 OH N3 O OBn OCH3 OBn +
1. H 2. H2 /Pd, 90% AcOH (exhaustive)
H2 N
CH2 OH O OBn
OCH3 OBn 4-amino-2,3-di-O-benzyl-4deoxy−α−D-galactopyranoside
H N OH OH OH CH2 OH 1,4-Dideoxy-1,4-iminoD-galactitol
Figure 6. Two transformations of the D-galacto 4-azide.
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The literature on protecting methods for carbohydrates is extensive and I have made no attempt to cover these methods exhaustively. The aim was to highlight some of the most important protecting methods, both traditional and modern, and to provide some important examples of the application of these methods. It is hoped that this will be a useful introduction to the field. The excellent monographs, reviews, and original papers given in the references will prove an ample source of further examples. In an industrial environment that places everincreasing demands on stereochemical purity of commercial products, there is no doubt that synthetic carbohydrate chemistry is gaining increasing importance, and there is still scope for theoretical work in this field as well as for development of new methods and further refinement of known ones.
1. Ferrier, R. J.; Collins, P. M. Monosaccharides, their Chemistry and their Roles in Natural Products; Wiley: New York, 1994; Hanessian, S. Total Synthesis of Natural Products, the Chiron Approach; Pergamon: Oxford, 1983; Inch, T. D. Tetrahedron 1984, 40, 3161; Kochetkov, N. K.; Suiridov, A. F.; Ermolenko, M. S. Carbohydrates in the Synthesis of Natural Compounds; Nauka: Moscow, 1984. 2. Hale, K. J. In Rodd’s Chemistry of Carbon Compounds; M. Sainsbury, Ed.; Elsevier: Amsterdam, 1993; Vol 1E, F, G, 2nd Supplement, pp 315–436. 3. Mills, J. A. Adv. Carbohydr. Chem. 1955, 10, 1. 4. Darcy, R. J. Chem. Educ. 1994, 71, 1090–1091. 5. Hough, L.; Richardson, A. C. In Rodd’s Chemistry of Carbon Compounds, 2nd ed. I F; Carbohydrate Chemistry; Coffey, S., Ed.; Elsevier: Amsterdam, 1967; pp 320–432. 6. Haworth, W. N.; Hirst, E. L. Chem. Ind. 1933, 52, 645; Ault, R. G.; Baird, D. K.; Carrington, H. C.; Haworth W. N.; Herbert, R.; Hirst, E. L.; Percival, E. G. V.; Smith, F.; Stacey, M. J. Chem. Soc. 1933, 1419–1423. 7. Reichstein, T.; Grüssner, A. Helv. Chim. Acta 1934, 17, 311– 328. 8. Fischer, E. Ber. Dtsch. Chem. Gesell. 1893, 26, 2400–2412. 9. Percival, E. G. V. Structural Carbohydrate Chemistry; J. Garnet Miller: London, 1953, p 55. 10. Hough, L.; Richardson, A. C. In Rodd’s Chemistry of Carbon Compounds, 2nd ed. I F; Carbohydrate Chemistry; Coffey, S., Ed.; Elsevier: Amsterdam, 1967; p 356. 11. Evans, M. E. Carbohydr. Res. 1977, 54, 105–114. 12. Pétursson, S.; Webber, J. M. Carbohydr. Res. 1982, 103, 41– 52. 13. Corey, E. J.; Suggs, W. J., J. Org. Chem., 1973, 38, 3224; Gigg, R.; Warren, C. D. J. Chem. Soc. C 1968, 1903–1911. 14. Hanessian, S. Carbohydr. Res. 1966, 2, 86–88. 15. Garegg, P. J.; Lindberg, A. A. In Carbohydrate Chemistry; Kennedy, J. F., Ed.; Oxford University: New York, 1988; p 523. 16. Hough, L.; Richardson, A. C. In Rodd’s Chemistry of Carbon Compounds, 2nd ed. I F; Carbohydrate Chemistry; Coffey, S., Ed.; Elsevier: Amsterdam, 1967; pp 379–390. 17. Reist, E. J.; Spencer, R. R.; Baker, B. R. J. Org. Chem. 1958, 23, 1757; also, Pétursson, S., unpublished results.
Journal of Chemical Education • Vol. 74 No. 11 November 1997
Research: Science & Education 18. Ballou, C. E.; Fischer, H. O. L. J. Am. Chem. Soc. 1955, 77, 3329. 19. Khorana, H. G. J. Am. Chem. Soc. 1963, 85, 3821. 20. Helferich, B.; Moog, A.; Jünger, A. Ber. Dtsch. Chem. Gesell. 1925, 58, 872. 21. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6191; Clark, J. H. Chem. Rev. 1980, 80, 429–452. 22. Haines, A. H. Adv. Carbohydr. Chem. Biochem. 1976, 33, 11–109. 23. Garegg, P. J.; Iversen, F.; Oscarson, S. Carbohydr. Res. 1976, 50, C12–C14; Garegg, P. J.; Iversen, F.; Oscarson, S. Carbohydr. Res. 1977, 53, C5–C7; Garegg, P. J. Pure Appl. Chem. 1984, 56, 845–858. 24. Nashed, M. A.; Anderson, L. Tetrahedron Lett. 1976, 39, 3503; Nashed, M. A. Carbohydr. Res. 1978, 60, 200;
Grindley, T. B. In Synthetic Oligosaccharides: Indispensable Probes for the Life Sciences; Kovác, P., Ed.; ACS Symposium Series 560; American Chemical Society: Washington, DC, 1994; pp 61–76. 25. Fellows, L. E. Pesticide Sci. 1986, 17, 602–606; Fulmann, U.; Bause, E.; Plough, H. Biochem. Biophys. Acta 1985, 825, 95–150; Scofield, A. M.; Fellows, L.; Wash, E. R. J.; Fleet, G. W. J. Life Sci. 1986, 39, 645–650; Bernachi, R. J.; Niedbala, M. J.; Korztuzk, W. Cancer Metas. Rev. 1985, 4, 81–102. 26. Butters, T. D.; Scudder, P.; Rotsaert, J.; Pétursson, S.; Fleet, G. W. J.; Willenbrock, F. W.; Jacob, G. J. Biochem. J. 1991, 279, 189–195. 27. Fletcher., H. G., Jr. Methods Carbohydr. Chem. 1963, II, 307; also, Pétursson, S.; Fleet, G. W. J., unpublished results.
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