Chapter 1
Glycals and pseudoglycals of common monosaccharides: useful
intermediates for the synthesis of bioactive carbohydrates
1.1. Chemistry of glycals and pseudoglycals
The synthesis of carbohydrate-based structures is emerging as a major frontier area in organic chemistry. In addition to their well-appreciated roles in supporting structural matrices, in energy storage, and as biosynthetic starting materials, carbohydrates are cast in a variety of interesting settings as glycoconiugate antibiotic, antitumor agents and cardiotonic glycosides.1
The importance of the carbohydrate domains (in the context of glycoproteins and glycolipids) as elements in cell surface recognition is manifested by their role in cellular adhesion and as blood group determinants. Another incentive for focusing on carbohydrates is their usefulness as enantiomerically pure starting materials for the synthesis of various natural products and other types of target molecules.
The major shortcoming encountered in the chemical manipulation of sugars is their overfunctionalization with hydroxyl groups of quite similar reactivity and the lack of versatile functionalities, such as carbon-carbon double bonds.
A prominent place as synthetic intermediates is thus occupied by unsaturated sugars and in particular by two types of compounds derived from the aldopyranose skeleton, the glycals and the
pseudoglycals. In glycals, corresponding to the general structure 1.1, the double bond is situated between C(1) and C(2) carbons, whereas in pseudoglycals, corresponding to the general structure
1.4, the double bond is inserted between C(2) and C(3) carbons. Even if they can apparently appear
as regioisomers (and commonly they are not), glycals and pseudoglycals are basically different as for the functional group present in the molecule and for the reactivity. Glycals, as the tri-O-acetyl- (1.2) or tri-O-benzyl-D-glucal (1.3), are aldopyranoses in which the “anomeric” C(1) is a vinyl carbon: as a consequence, these compounds are practically vinyl ethers and their reactivity is determined by the particular nature of this functional group. On the contrary, pseudoglycals, as the methyl 4,5-di-O-acetyl-α- or -β-D-threo-hex-2-enopyranosides 1.5, are 2,3-unsaturated aldopyranosides and the double bond present is characterized by the reactivity typical of a double bond bearing, commonly, electron-withdrawing substituents on the corresponding allyl carbons.
1.1.2. Glycals
The successful use of glycals for the preparation of biologically important carbohydrates is largely due to the relevant lot of work performed by Danishefsky who has contributed in a preponderant way to the actual popularity of glycals as synthetic intermediates.
The use of glycal substrates is particularly attractive for stereoselective synthesis of carbohydrates and glycoconjugates, provided that, in glycosidic bond formation, contemporary C(2)-functionalization of the carbohydrate donor is achieved in the process.2 The glycal assembly strategy developed by Danishefsky for glycosylation with simultaneous C(2)-hydroxylation involves oxidation of glycal 1.3 with DMDO to give the α-glycal epoxide 1.6 as the intermediate glycosyl donor.3 The subsequent ring opening process with a nucleophilic glycosyl acceptor, carried out in the presence of a Lewis acid such as ZnCl2, occurs with clean inversion of configuration and an excellent yield to give the corresponding β-glycoside. The glycosyl acceptor may be a glycal to give a disaccharide, suitable for a reiterative process for the synthesis of oligosaccharides (Scheme 1.1).4 The power of the reiterative strategy for oligosaccharide construction based on glycal acceptors and glycal-derived donors via epoxidation has found an important application in the synthesis of Lewis and H-type blood group determinants,5 tumor antigens6 and the carbohydrate domains of the enediyne antibiotics calicheamicin and esperamicin.7
O O X RO OR OR RO RO 1.1 1.2, R = Ac 1.3, R = Bn X= CH2OR, CH3, H R= H or protecting group glycals O O X RO BnO BnO 1.4 1.5, ! and " X= CH2OR, CH3, H R = H or protecting group Nu= O-, N-, S-, C-nucleophyles
2,3-unsaturated-O-glycosides (pseudoglycals)
Scheme 1.1. Utilization of glycals and α-glycal epoxides in carbohydrate chemistry.
An indicative example of this original strategy can be found in the synthesis of the saponin
desgalactotigonin (Scheme 1.2).8Scheme 1.2. Danishefsky's synthesis of desgalactotigonin.
Nu glycosyl acceptor !-glycoside "-glycal epoxide (glycosyl donor) !-disaccharide reiteration oligosaccharide Nu Nu !-glycoside 1.3 1.6 O BnO BnO DMDO OBn O BnO BnO OBn O O BnO BnO OR F OBn O BnO BnO OH Nu OBn "-glycoside Nu BnO O BnO BnO OBn Nu O BnO BnO RO OBn Nu !-glycoside, R=Bz, Piv O BnO BnO OH O BnO BnO OH OBn O O BnO BnO O BnO BnO OR2 R 1 OBn 1.9, R1= SEt, R2= Piv 1.10,R1= OPO(OR) 2,R2= H, Piv O BnO BnO RO OBn Nu 1.7, R=Bn 1.8, R=Bz, Piv EtSH or HO(PO)(OR)2 ZnCl2 TBAF PhSeH O BnO BnO HO H OBn SePh 1.11 1.16 1.17 O BnO BnO DMDO O BnO BnO O O HO O O Ph 1.18 O O O O Ph O BnO BnO OBn 1.12 O DMDO OTIPS O O O 1.13 O OTIPS O O O O tigogenin/ZnCl2 O BnO OBn tigogenin OBn 1.20 O O O O Ph O BnO BnO OBn OBn O 1.14 O BnO BnO OBn O O OH O O O Ph HO O BnO OBn tigogenin OBn O HO HO OH OH DMDO 1.15 HO O HO OH O O O O O O HO OH tigogenin OH 1.8/Sn(OTf)2 OH desgalactotigonin 1.19 O BnO OBn tigogenin OBn 1.15 Bu3SnO 1.21 ZnCl2 ZnCl2 (Bu3Sn)2O
D-galactal derivative 1.12 was subjected to epoxidation (DMDO) to give epoxide 1.13 which served to galactosylate tigogenin giving 1.14 (β-anomer), subsequently transformed into the tributyltin derivative 1.15. Glycal 1.16 was oxidized with DMDO to give glycal epoxide 1.17 (a 4:1 mixture of epoxides α and β) which was treated with D-glucal derivative 1.18 to yield, after benzylation, the β-linked disaccharide 1.19. Subsequent epoxidation (DMDO) afforded the corresponding α-epoxide 1.20. β-Glycosylation of 1.15 with 1.20 yielded trisaccharide 1.21. The final β-glycosylation was carried with fluoroglycoside 1.8 (R= Bz) to give, after deprotection, the desired natural compound.8
The glycal epoxide method turned out to be useful for the construction of complex 2-branched β-aryl glycosides, which are salient features of the potent antibiotic vancomycin.9 The use of sodium salts of indoles as the glycosyl acceptors led to an improved total synthesis of the potent antitumor β-N-indolcarbazole glycoside rebeccamycin,10 and to a total synthesis of staurosporine.11
The glycal epoxides can be converted into other glycosylating agents such as β-fluoroglycosides (1.7 and 1.8), which are useful to produce α- or β-glycosides depending on the nature of the vicinal OR group,12 into β-thioethyl glycosyl donors (1.9), which are extremely powerful glycosylating agents able to react also with hindered or unreactive acceptors,13 or into β-glycosyl phosphate (1.10) (Scheme 1.1).14 Only with PhSeH, a corresponding α-glycoside (α-phenylselenoglycoside
1.11) is obtained.15
Evans developed a new method for the synthesis of β-C-allylglycosides based on Bu3 SnOTf-mediated ring opening of glycal epoxides with allylstannanes as nucleophiles.16 This methodology has been efficiently used in the β-stereoselective introduction of the side chain (C44-C51) of spongistatin 2 to give 1.23, the addition product of glycal epoxide derived from glycal 1.22 (Scheme 1.3).17
Scheme 1.3. Evans's protocol for the β-stereoselective introduction of the C44-C51 side chain of spongistatin 2
In a reiterative approach, enol ether epoxidation with DMDO has been coupled with C-C bond formation and ring-closing metathesis to provide trans-fused THP ring systems.18
A conceptually new direct oxidative glycosylation with glycal donors employing a reagent combination of triflic anhydride and diphenyl sulfoxide has recently been reported by Gin.19 This
O O TESO Me HOOMe OTBS Me TES H SnBu3 E 43 1) DMDO 2) O O TESO Me HOOMe OTBS Me TES H E 43 HO 1.22 1.23 spongistatin 2 44 51 Bu3SnOTf F F
new β-glycosylation method works very well with hindered hydroxyl nucleophiles, enclosing sterically shielded carbohydrate hydroxyl, and can be run on a large scale (Scheme 1.4).
Scheme 1.4. Gin's direct oxidative glycosylation with glycal donors
This methodology was improved by the same author to effect efficiently the direct installation of the native C(2)-N-acetylamino functionality onto glycal donor and, additionaly, allows glycosidic coupling with various glycosyl acceptor in an overall one-pot acetamidoglycosylation procedure.In this protocol, a new sulfonium reagent derived from thianthrene-5-oxide is employed for glycal activation and the introduction of the acetamido group proceeds upon addition of the acid scavenger N,N-diethylaniline and N-TMS-acetamide (Scheme 1.5).20
Scheme 1.5. Gin’s acetamidoglycosylation of glycals
A very elegant solution to the synthesis of complex oligosaccharides containing several 2-deoxypyranose units is the reiterative procedure proposed by Danishefsky,21 exploiting the concept of “armed” and “disarmed” glycals. The benzyl-protected glucal 1.3 is much more reactive towards the activaction with iodonium dicollidine perchlorate (IDCP) than 2,6-di-O-benzoyl-D-glucal (1.24) which acts as the glycosyl acceptor on the free 4-OH to give the disaccharide 1.25. The substitution of the electron-whithdrawing benzoyl protecting groups with silyl ether ones transforms the “disarmed” glycal 1.25 into the “armed” one 1.26, that would be newly engaged in a
O OBn BnO BnO S S OTf AcNHSiMe3, Et2NPh O OBn BnO BnO O S S Me N SiMe3 TfO thianthrene,
[PhEt2NSiMe3]+ [TfO]
-O OBn BnO BnO O N Me acid, Nu-H O OBn BnO BnO Nu NHAc TfO 1.3 O OBn BnO BnO O BnOBnO O OH Nu OBn Ph2SOTf+ TfO -!-glycoside Nu LA O Ph Ph + O OBn BnO BnO O OBn BnO BnO S Ph PhOTf 1.3 Nu + Ph2S S TfOH
chemoselective iodoalkoxylation with the “disarmed” glycal 1.24. The reductive removal of 2-iodo substituent leads to the desired 2-deoxy-oligosaccharide (Scheme 1.6).
Scheme 1.6. Reiterative Danishefsky’s approach to 2-deoxy-oligosaccharides
1.1.3. Pseudoglycals
2,3-Unsaturated glycosides (pseudoglycals) are valuable synthetic intermediates, since the unsaturation can be further functionalized for the preparation of structural units present in many natural, biologically active compounds.22 As an example, pseudoglycal-related synthetic intermediate are involved in the synthesis of antibiotic-derivative N-acetylactinobolamine,23 of intermediates corresponding to important fragments of the immunosuppressant FK-506,24 of the thiosugar of the antibiotic Esperamicin A1,25 of the pyranoid segment of indanomycin22d and in the preparation of an analogue of orbicuside A, an unusual cardiac glycoside.26
Commonly, pseudoglycals are prepared by the well-known Lewis acid-catalyzed allylic rearrangement of the corresponding glycals, the so-called Ferrier allylic rearrangement of glycals.27 1.2. Transformation of glycals into 2,3-unsaturated glycosyl derivatives (Ferrier Allylic Rearrangement)
General features. Glycals as 1.2 with a leaving groups at the allylic position can be subjected to acid-catalyzed additions or nucleophilic displacements: protonic acids commonly give products
1.31, such as corresponding to the compounds obtained in the previous paragraph, whereas Lewis
acids favour the formation of unsaturated products such as 1.28 and 1.29. Ionic intermediates 1.27 and 1.30 are involved in the respective processes, as indicated in Scheme 1.7. With glycal
O O BnO BnO O I BnO OBn O BzO HO OBz + IDCP DCM 1.3 1.24 "armed" "disarmed" OBn BnO O RO OR 1.25: R= Bz 1.26: R= TBS O BnO O I OBn BnO O TBSO O I OTBS O BzO OBz reiterate IDCP/DCM 1.24
derivatives the great majority of substitution reactions give allylically rearranged products of type
1.28, but in same cases isomers of type 1.29, seemingly formed by direct substitution, are obtained.
By far the simplest and most commonly used way of effecting this conversion involves the removal of the allylic substituent of the glycal and the generation of a highly resonance-stabilized oxocarbenium ion intermediate. This may then react with a nucleophile at the anomeric center to give a reaction product as a mixture of corresponding diastereomers (α- and β-anomers). The transformation is therefore a glycosylation process that allows the bonding of unsaturated sugar moieties through the anomeric C(1) position to a range of O-, S-, N-, and C-linked substituents (Scheme 1.7).27
Scheme 1.7. Competition between 1,2-addition and Ferrier rearrangement
In the presence of Lewis acids cyclic enol ethers having groups at the allylic sites readily undergo nucleophilic displacement reactions with allylic rearrangement (Scheme 1.8). Typically the reactions are conducted with glycal derivatives having acyloxy groups at the allylic positions and with Lewis, and occasionally protonic, acid catalysts to facilitate the departure of these groups with the formation of delocalized oxacarbenium ions. These normally react with O-, S-, N-, and C-nucleophilic species at the anomeric center to give mixtures of diastereomeric products. Commonly, the last step is reversible and very significant regioselectivity and stereoselectivity are observed, but there are exceptions to these generalizations.
Scheme 1.8. Nucleophilic displacement reaction with allylic rearrangement
O AcO AcO OAc 1.2 1 2 3 +H+ (Lewis acid) -AcOH O AcO OAc 1.27 + +Nu --H+ O AcO OAc 1.28 Nu O AcO AcO OAc 1.30 + +Nu --H+ O AcO Nu AcO 1.31 OAc +H+ O Nu AcO OAc 1.29 + O OMe AcO Et3SiH, BF3.Et 2O CH2Cl2, -20°C, 15 min O OMe
There is proof that ionic intermediates are involved in the reaction, at least under some circumstances, since for example, mixtures of different 2,3-unsaturated S-glycosides exchange their aglycons (Nu) under the conditions of their synthesis. Also consistent with occurrence of ionic intermediates in the reaction is the finding that, from tri-O-acetyl-D-glucal, the α- and β-2,3-unsaturated glycosyl products are very commonly formed in the equilibrium ratio of 7:1. In most cases of products formed from this glycal under kinetic control (notably 2,3-unsaturated C-glycosides), the α-anomers are also favored.
There are further complicating factors. Some kinetic products (primary reaction products) can rearrange to equilibrated mixtures that include high proportions of isomers which are glycals having the nucleophile substituent at C(3) (secondary reaction products). This is especially, but not exclusively, the case when ambident nucleophiles such as azide or thiocyanate are used (Scheme 1.9).27
Scheme 1.9. Products rearrangement with ambident nucleophiles
Incoming nucleophiles. Alcohols and phenols are most commonly used as sources of O-nucleophilic species, but may be replaced by orthoesters or acetals in which instances hydroxyl-containing by-products of reaction, which are competitive nucleophiles, are not formed concurrently with the 2,3-unsaturated glycosides. Thiols can react similarly, but their trimethylsilyl derivatives may be used with advantage to enhance the regioselectivity of the reaction. Likewise,
N-bases are commonly trimethylsilylated, but need not be. Among C-nucleophiles used are
organometallic compounds, various alkenes, vinyl ethers, vinyl esters, allyl ethers and esters, organosilanes, silyl ketene acetals, and β-dicarbonyl compounds. C-Aryl glycosides are obtained by use of activated phenols or bromomagnesium phenates. Hydrogenfluoride, dialkyl phosphates, and triethylsilane are, respectively, used in the preparation of 2,3-unsaturated glycosyl fluorides, phosphonates, and hydrides. The last group of products are 1,5-anhydroalditol derivatives.27
Leaving groups and activators. The most common allylic leaving groups used are the carboxylates present in O-acetylated and O-benzoylated glycals, several of which are commercially available and which, provided sufficiently high temperatures are used, can take part in the rearrangement
O AcO AcO OAc 1.2 1 2 3 O AcO OAc O AcO OAc X Z Y Z Y X O AcO OAc X Y Z O AcO OAc Z Y X
process with simple alcohols and with phenols to give alkyl or aryl 2,3-unsaturated O-glycosides without the need for added catalyst. To describe these reactions as “uncatalyzed”, however, may well be inappropriate since carboxylic acids are usually generated as by-products, which may facilitate the removal of the allylic groups, particularly in later stages of the reactions. When glycals with better allylic leaving groups are involved the reactions can proceed without added catalyst and by the SN2’ mechanism. The leaving potential of allylic ester groups can be increased by the introduction of electron-withdrawing substituent; the trichloroacetimidate has been employed for the preparation of 2,3.unsaturated O- and C-glycosides, and the uses of trifluoroacetyl and p-nitrobenzoyl esters for making C- and N-linked analogs. The more general and simpler method involves the use of acid catalysts. Frequently, however, it is inappropriate to use protonic acids because they preferentially catalyze additions to the vinyl ether groups of the glycals and lead to saturated-2-deoxyglycosyl derivatives. With heterocyclic bases as nucleophiles, protonic acids can promote the allylic rearrangement, and instances have been reported of the production of 2,3-unsaturated pyranosylpurines under the influence of p-toluensulfonic acid, trichloroacetic acid, and trifluoroacetic acid. The first of these acids has also been used to effect the allylic rearrangement of a compound akin to a 3-hydroxyglycal.
Much more useful are Lewis acids, boron trifluoride etherate being most commonly with many glycals. However, yields of products are modest when this catalyst is used with tri-O-acetyl-D-galactal and di-O-acetyl-L-rhamnal, and with these compounds tin(IV) chloride gives higher yields of 2,3-unsaturated-O-glycosides. Other Lewis acids have been employed as follows: FeCl3 (O, C), SbCl5 (O, N), TiCl4 (C), (i-PrO)2TiCl2 (C), InCl3 (O, C), SnBr4 (O, C), ZnBr2 (C), LiBF4 (O, C, S), LiClO4 (C), LiClO4/TrClO4 (N), TMSOTf (O, C), Sc(OTf)3 (O, C), Yb(OTf)3 (O, N, C), Montmorillonite (O, C), DDQ (2,3.dichloro-5,6-dicyanobenzoquinone) (O, C), and iodide (O, C,
N). In addition, organoaluminium compounds such as EtAlCl2, Et2AlCN, and Me3Al, which are Lewis acids that also provide nucleophiles, can be employed in the synthesis of 2,3-unsaturated C-glycosides, and EtAlCl2 has been used to catalyze a related displacement of a methanesulfonyloxy group from the homoallylic C-4 position of a 3-deoxyglycal to give 2,3-cyclopropanucleosides. Very few comparative studies of these catalysts have been conducted, but “more readily controlled reactions” have been claimed with ZnCl2, and there are examples in which it is extremely effective while BF3.Et2O is not. Likewise FeCl3 has been described as a “particularly attractive catalyst”, SnBr4 can lead to satisfactory reaction when the more commonly used catalysts are ineffective, and InCl3 and Montmorrilonite K-10 have been identified as being more effective than some others. Relatively poor leaving groups at the allylic centers of glycals may also permit allylic displacement reactions to occur. Thus, 4,6-di-O-benzoyl-3-O-methyl-D-glucal (1.32) affords the 2,3-unsaturated glycosyl fluorides 1.33 on treatment with hydrogen fluoride at –70°C (Scheme 1.10). In general, however, reactions proceed more effectively when glycals with good leaving groups at C(3) are used; those with 3-O-methyl ethers can give low yields of 2,3-unsaturated glycosides.
Scheme 1.10. Allylic displacement reaction with poor leaving group at the allylic position
Glycals with unprotected hydroxyl groups at the allylic centers can also take part in the allylic rearrangement process even in the presence of protonic acids. Clearly, when they do, the intermolecular substitution with rearrangement process is favored relative to proton-catalyzed addition. An example is the reaction of D-glucal with benzaldehyde dimethyl acetal in the presence of TsOH which gives the compound 1.34 in high yield offering a convenient one-step route to the compound (Scheme 1.11).27
Scheme 1.11. Glycals with unprotected hydroxyl groups in the allylic rearrangement
Configuration at the allylic center of the glycals. Because of the relatively high natural abundance of D-hexoses with the R(“β”)-configuration at C(3), and the consequent ready availability of the corresponding glycals (notably D-glucal and D-galactal) and their derivatives, the allylic rearrangement reaction has been carried out predominantly with these epimers.
In examples of reactions occurring under neutral conditions, epimeric pairs of 3-pentenoyl glycal derivatives, such as D-allal/D-glucal and D-gulal/D-galactal esters, appear to react in “orthodox” manner to give D-erythro- and D-threo-2,3-unsaturated disaccharide compounds, respectively, when coupled with other sugar derivatives following activation with IDCP. Indications are that compounds with pseudo-axial leaving groups undergo substitution/rearrangement more readily than the 3-epimers as expected on the basis of the “vinylogous anomeric effect”,28 which favors the departure of allylic leaving groups of glycal derivatives when they are pseudo-axial and anti-periplanar to an unshared electron pair on the ring oxygen atom.27
Configuration at the homoallylic center of the glycals. The relative orientation of the groups at the homoallylic C(4) position of pyranoid glycals, which may provide anchimeric assistance to the departure of the allylic leaving groups, can affect the substitution reactions appreciably. Thus, under conditions in which the normal BF3-catalyzed reaction gives high yields of
erythro-O MeO BzO OBz 1.32 HF -70°C, 0.2h O BzO OBz 1.33 F O HO HO OH O 1.34 (90%) !:"= 99:1 D-glucal + PhCH(OMe)2 TsOH rt O O Ph OMe
glycosides 1.35 from tri-O-acetyl-D-glucal (1.2), the threo-analogs 1.37 are not obtained satisfactorily from tri-O-acetyl-D-galactal (1.36) which has cis-related C(3), C(4) ester groups (Scheme 1.12), the difference being so significant that the ethyl α-threo-glycoside has been prepared for synthetic work from the readily available erythro-analog by carrying out a Mitsunobu inversion at C(4) rather than directly from tri-O-acetyl-D-galactal as starting material.
Scheme 1.12. Anchimeric assistance of homoallylic groups
The hypothesis that neighbouring group participation is involved in the ejection of the allylic group and establishment of a dioxocarbenium ion from tri-O-acetyl-D-glucal seems sound, this being the more probable since the latter is deemed to react in the conformation 1.38 to lead to the delocalized cyclic reaction intermediate 1.39/1.40. It is clear, however, that all D-glucal derivatives do not require such neighbouring group participation to take part in the substitution/rearrangement reaction since derivatives with groups at C(4) that cannot participate can be active. Problems with the conversion of tri-O-acetyl-D-galactal into 2,3-unsaturated-O-glycosides can be solved simply by change of the Lewis acid catalyst to SnCl4 or to LiBF4 in MeCN, but in the latter case the yields are only moderate. With SnCl4 the allylic rearrangement process is specifically promoted, and simple primary alcohols are converted into the α-unsaturated glycosides in high yield. With secondary alcohols and phenols yields are in the 60% region. SnCl4 can also be a superior catalyst with glycals that have trans-related groups at C(3), C(4).27
Regioselectivity. To this point this survey has not dealt with the possibility that the oxocarbenium intermediates in the acid-catalyzed rearrangements of glycals can bond to nucleophiles not just at C(1) but, alternatively, via C(3) (Scheme 1.13). To a major extent this neglect is because the
O AcO AcO OAc 1.2 O AcO OAc 1.35 (80-90%) ROH, inert solvent
BF3.Et 2O OR O AcO OAc 1.36 O OAc 1.37 ROH, inert solvent
BF3.Et 2O OR AcO AcO O O OAc O O O O OAc O O + O OAc O O + 1.38 1.39 1.40
general features discussed so far have related to cases with alcohols or phenols as nucleophiles which attack virtually only at the anomeric center to give O-glycosides. The very occasional reference to glycal derivatives affording saturated alkyl 3-O-alkyl-2-deoxyglycosides cannot be taken as evidence of initial formation of 3-O-alkylglycals, and more likely suggests the intermediacy of 2,3-unsaturated aldehydes. On the other hands, S- and N-nucleophiles can give products derived by attack at C(3) in major proportions, and there has been the occasional report of the generation of C(3) branched-chain glycal derivatives having been produced by the use of C-nucleophiles.27
Scheme 1.13. Nucleophilic attack at C(1) or C(3) of glycals
It has been pointed out that the above-mentioned regioselectivities correlate with the hard nature of
O-nucleophiles and the softer character of N- and S-, and to a lesser extent, C-nucleophiles
according to the Pearson classification.27,29 The latter groups (N- and S-compounds in particular) therefore tend to lead to 3-substituted glycals under equilibrium conditions. For example, the reaction of tri-O-acetyl-D-galactal (1.36) with MeSH in the presence of SnCl4 finally gives the gulal derivative 1.43 almost exclusively, but significant proportions of the kinetic product 1.41 are formed during the early stages of the reaction. This may suggest the ion 1.42 is an intermediate in the isomerization process (Scheme 1.14).
Scheme 1.14. Conversion of 2,3-unsaturated glycosyl product into 3-substituted glycal isomer
Various N-nucleophiles also initially attack the cyclic oxocarbenium ions derived from glycals at C(1), and rearrangement of the first products then occur to afford the C(3) N-bonded glycal isomers. Given the relatively soft nature of C-nucleophiles it is unexpected that the most common products derived by their use result from attack on the oxocarbenium ions at the relatively hard
O AcO OAc 1.27 + O AcO OAc Nu O AcO OAc Nu NuH or Nu- 1.28 1.29 O AcO OAc 1.36 AcO MeSH, ClCH2CH2Cl SnCl4 O OAc 1.41 AcO SMe O O OAc 1.42 O + O OAc 1.43 AcO SMe
anomeric center. This apparent anomaly has been explained by invoking kinetic factors and the greater chemical stability of the first-formed C-glycosides. Products derived by bonding of the nucleophiles to C(3) can, however, be encountered under normal circumstances involving acid catalysts, but it is not known whether they are formed by isomerization of C-glycosidic precursors as could happen in specific instances.
In summary, under acidic conditions, reactions of glycal derivatives with nucleophiles which lead to C-O bonding give 2,3-unsaturated glycosyl derivatives, and the same applies in the few cases recorded of reactions leading to C-F and C-P bond formation. In contrast, nucleophiles leading to new C-N and C-S bonds give mixtures of 2,3-unsaturated glycosyl products and 3-substituted glycals with the latter predominating at equilibrium. Most reactions involving C-nucleophiles give 2,3-unsaturated C-glycosides, but there are several reports of the formation of glycal products having branched chains at C(3).
It should be noted that several 2,3-unsaturated glycosyl derivatives and their 3-substituted glycal isomers could interconvert by [3.3]-sigmatropic processes to facilitate the production of thermodynamic products from precursors formed under kinetic control (Scheme 1.9). This can account, for example, for the production of tri-O-acetyl-D-gulal (1.46) from its C(3) epimer, tri-O-acetyl-D-galactal (1.36), on heating in acetic acid, since these isomers can equilibrate thermally with the 2,3-unsaturated α- and β-glycosyl acetates 1.44 and 1.45, which, in turn, can anomerize under acidic conditions (Scheme 1.15). The possibility of sigmatropic isomerization makes it difficult to define specific mechanisms for the reaction of glycal esters with, for instance, azide ions or purines and pyrimidines. Not only the initial products subject to thermal rearrangement, but so are the carbohydrate starting materials.27
Scheme 1.15. [3.3]-Sigmatropic process
Diastereoselectivity at the anomeric center. Although the question of the configurations at the anomeric centers of 2,3-unsaturated glycosyl products formed by the reaction under consideration is complex, and may depend upon many variables such as the substrate, the leaving groups, the nucleophiles, the catalysts, the reaction conditions, the mechanism of the reactions, and whether the products are formed under kinetic or thermodynamic control, some generalizations can be made. In its reaction with alcohols and phenols in the presence of Lewis acids tri-O-acetyl-D-glucal gives predominantly 2,3-unsaturated α-glycosides with the anomeric α,β ratios usually being in the range (7±2):1. Because of the reversibility of the reactions under most conditions used, these represent
O AcO OAc 1.36 AcO O OAc 1.44 AcO O OAc 1.45 AcO OAc O OAc 1.46 AcO OAc OAc heat H+ heat
equilibrium figures. At low temperatures, however, highly stereoselective formation of α products has been observed in the synthesis of both O- and C-glycosides. On the other hand, the α,β ratio can be reduced to about 2:1 for reactions involving secondary carbohydrate alcohols as acceptors.27 An interesting stereochemical point emerges from the analogous acid-catalyzed reaction of alcohols with tri-O-acetyl-D-galactal for which the corresponding equilibrium ratios of products are significantly larger than 7:1. In an extreme case this glycal gives 2,3-unsaturated α-glycosides “almost totally” on treatment with simple alcohols in the presence of SnCl4. This is somewhat surprising since inversion at C(4) of the main products 1.47 derived from tri-O-acetyl-D-glucal might not be expected to affect the energies of the C(4) epimers 1.47 and 1.48 relative to their respective β-anomers to any appreciable extent. It is therefore suggested that the anti-arrangement of the allylic substituents in the α-D-threo-glycosides 1.48 may be particularly stable, because both are pseudo-axial and therefore favored by the allylic30 and the vinylogous anomeric effects.28 That is, configuration 1.48 may be stabilized by a “double allylic effect”. This conclusion is consistent with the finding, from energetics calculations, that, for acyclic allylic alcohols and ethers, the lowest energy rotamers have the oxygen-bonded substituents over the double bonds.31 It is noteworthy also that axial O-bonded substituents at C(4) on pyranoid rings stabilize oxocarbenium ions at C(1) by through-space effects, which suggests that this observed factor could also result to some extent from a transannular anomeric effect. The observation that α-selectivity seems also to be greater in the formation of 2,3-unsaturated C-glycosides from tri-O-acetyl-D-galactal, which is unlikely to be reversible, suggest that the formation of the C-glycosidic analogs of 1.48 is also relatively favored kinetically.
As with O-nucleophiles high diastereoselectivity in favor of α products is also commonly observed in the rearrangement reaction of glucal derivatives with carbon nucleophiles under the influence of Lewis acids. For example, the allyl C-glycosides are obtained in 85% yield with an α,β ratio of 16:1 from tri-O-acetyl-D-glucal with allyltrimethylsilane and TiCl4 as catalyst (Scheme 1.16).
Scheme 1.16. Allylic rearrangement reaction with C-nucleophiles
O O 1.47 1.48 OR AcO AcO OAc AcO OR O AcO AcO OAc 1.2 O AcO OAc (85%) !:" = 16:1 AllylSiMe3, TiCl4 -78°C, 20 min
When tri-O-acetyl-D-allal, epimeric at C(3) with the glucal isomer, is employed, the same products are obtained in 95% yield, but the anomeric ratio is now 6:1 which indicates that, to some degree, the nucleophile takes part in bond forming at C(1) before a free oxocarbenium ion has been generated, i.e. there is an element of the anti-SN2’ to the reaction mechanism. Tri-O-acetyl-D -galactal also undergoes very efficient reaction with allyltrimethylsilane and, as with O-nucleophiles, gives a higher α,β ratio (30:1) than is obtained with tri-O-acetyl-D-glucal.27
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