This journal is c The Royal Society of Chemistry 2013 Chem. Soc. Rev., 2013, 42, 4297--4309 4297 Cite this: Chem. Soc. Rev., 2013, 42, 4297 Design of chemical glycosyl donors: does changing ring conformation influence selectivity/reactivity?† Hiroko Satoh a and Shino Manabe* b This tutorial review focuses on the design of glycosyl donors, especially on attempts to control selectivity/reactivity by employing bulky substituents, cyclic protecting groups, or bridged structures. These structural modifications are performed to change the conformational distributions of pyranoside/ furanoside rings. We also briefly discuss this issue with regard to studies on furanosides and enzymatic glycosylation reactions. Readers will find that some of the designed glycosyl donors have been used to achieve total syntheses of natural products. Key learning points – To learn nomenclatures of ring conformations of pyranoses and furanoses – To understand a basic mechanism of glycosylation reactions – To become familiar with what can be done with cutting-edge computational technologies for conformational search and mechanistic studies – To be able to think about the design of a glycosyl donor according to the strategies which have been taken as intending to change the ring conformations – To learn more about experimental applications of the strategies to control syntheses Introduction Glycosides and glycoconjugates play important roles in biological processes. Ideally, to gain a better understanding of the nature of these biological processes, pure and structurally well-defined mate- rials are desirable. The availability of these sugars, however, is limited; i.e., glycosides are often found in low concentrations, micro-heterogeneous forms, or both. Therefore, synthetic chemistry is a major technique to produce oligosaccharides and glycoconjugates with rigorously defined chemical structures. The most fundamental reaction in carbohydrate chemistry is the glycosylation reaction, which creates a glycosidic linkage that connects sugar units. The chemistry of glycosylation reactions has been developed most intensively in the past few decades. 1–7 Many factors influence the reactivity or selectivity of glycosylation reactions, including the choices of glycosyl donor, leaving group, protecting groups, acceptor, and activation system, as well as the solvent and temperature. Extensive experimental and theoretical efforts have been devoted to revealing the mechanistic details of glycosylation reactions and the relationship between these factors and the resulting reactivity or selectivity. One captivating aspect of these studies is the relationship between the sugar ring conforma- tion and the reactivity/selectivity. Many research groups have synthesized glycosyl donors modified to be atypical sugar structures that show different behavior with regard to reactivity or stereoselectivity in glycosylation reactions. Some glycosyl donors have been used in the total syntheses of natural organic compounds. Although large amounts of experimental and computational data have been accumulated, the details of the relationship between the ring conformation and the reactivity/ selectivity are not yet well known. Therefore, we wish to take this opportunity to survey the computational and experimental studies on this topic. We start with the definition and basic chemistry of sugar ring conformations. We then discuss the basic conceptual framework for designing glycosyl donors with atypical structures, in which the conformations of the pyranoside/furanoside rings are expected to be distorted away from their typical distributions. Subsequently, we describe experimental applications of this framework. We hope that the data presented here will stimulate discussion on or ideas about designing new methodologies of glycosylation reactions. Nomenclature of ring conformations The nomenclature of the pyranose and furanose ring conformations is defined on the basis of the rules for six- and five-membered a National Institute of Informatics (NII), Hitotsubashi 2-1-2, Chiyoda-ku, Tokyo 101-8430, Japan. E-mail: [email protected]; Fax: +81-3-4212-2120; Tel: +81-3-4212-2501 b RIKEN Advanced Science Institute, Hirosawa 2-1, Wako-shi, Saitama 351-0198, Japan. E-mail: [email protected]; Fax: +81-48-462-4680; Tel: +81-48-467-9432 † Part of the carbohydrate chemistry themed issue. Received 8th November 2012 DOI: 10.1039/c3cs35457a www.rsc.org/csr Chem Soc Rev TUTORIAL REVIEW Downloaded by University of Hawaii at Manoa Library on 04/05/2013 23:21:21. Published on 30 January 2013 on http://pubs.rsc.org | doi:10.1039/C3CS35457A View Article Online View Journal | View Issue
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This journal is c The Royal Society of Chemistry 2013 Chem. Soc. Rev., 2013, 42, 4297--4309 4297
Cite this: Chem. Soc. Rev.,2013,42, 4297
Design of chemical glycosyl donors: does changingring conformation influence selectivity/reactivity?†
Hiroko Satoha and Shino Manabe*b
This tutorial review focuses on the design of glycosyl donors, especially on attempts to control
selectivity/reactivity by employing bulky substituents, cyclic protecting groups, or bridged structures.
These structural modifications are performed to change the conformational distributions of pyranoside/
furanoside rings. We also briefly discuss this issue with regard to studies on furanosides and enzymatic
glycosylation reactions. Readers will find that some of the designed glycosyl donors have been used to
achieve total syntheses of natural products.
Key learning points– To learn nomenclatures of ring conformations of pyranoses and furanoses– To understand a basic mechanism of glycosylation reactions– To become familiar with what can be done with cutting-edge computational technologies for conformational search and mechanistic studies– To be able to think about the design of a glycosyl donor according to the strategies which have been taken as intending to change the ring conformations– To learn more about experimental applications of the strategies to control syntheses
Introduction
Glycosides and glycoconjugates play important roles in biologicalprocesses. Ideally, to gain a better understanding of the nature ofthese biological processes, pure and structurally well-defined mate-rials are desirable. The availability of these sugars, however, islimited; i.e., glycosides are often found in low concentrations,micro-heterogeneous forms, or both. Therefore, syntheticchemistry is a major technique to produce oligosaccharides andglycoconjugates with rigorously defined chemical structures.
The most fundamental reaction in carbohydrate chemistry isthe glycosylation reaction, which creates a glycosidic linkage thatconnects sugar units. The chemistry of glycosylation reactions hasbeen developed most intensively in the past few decades.1–7 Manyfactors influence the reactivity or selectivity of glycosylationreactions, including the choices of glycosyl donor, leaving group,protecting groups, acceptor, and activation system, as well as thesolvent and temperature. Extensive experimental and theoreticalefforts have been devoted to revealing the mechanistic details ofglycosylation reactions and the relationship between these factors
and the resulting reactivity or selectivity. One captivating aspect ofthese studies is the relationship between the sugar ring conforma-tion and the reactivity/selectivity. Many research groups havesynthesized glycosyl donors modified to be atypical sugarstructures that show different behavior with regard to reactivityor stereoselectivity in glycosylation reactions. Some glycosyldonors have been used in the total syntheses of natural organiccompounds. Although large amounts of experimental andcomputational data have been accumulated, the details of therelationship between the ring conformation and the reactivity/selectivity are not yet well known. Therefore, we wish to take thisopportunity to survey the computational and experimental studieson this topic. We start with the definition and basic chemistry ofsugar ring conformations. We then discuss the basic conceptualframework for designing glycosyl donors with atypical structures,in which the conformations of the pyranoside/furanoside ringsare expected to be distorted away from their typical distributions.Subsequently, we describe experimental applications of thisframework. We hope that the data presented here will stimulatediscussion on or ideas about designing new methodologies ofglycosylation reactions.
Nomenclature of ring conformations
The nomenclature of the pyranose and furanose ring conformationsis defined on the basis of the rules for six- and five-membered
a National Institute of Informatics (NII), Hitotsubashi 2-1-2, Chiyoda-ku,
Tokyo 101-8430, Japan. E-mail: [email protected]; Fax: +81-3-4212-2120;
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rings, respectively. For cyclohexane, a typical six-membered ringstructure with six equivalent carbon atoms, five distinct conformersare defined: chair (C), boat (B), twist/skew-boat (S), half-chair (H), andenvelope (E) conformations (Fig. 1(a)). For pyranoses, the existenceof the ring oxygen and C6 carbon makes all ring carbonsdistinguishable. Because of this asymmetry, 38 types of distinctconformers in total are defined for the pyranose ring: 2C, 6B, 6S,12H, and 12E conformations (Fig. 1(b)).
The nomenclature of five-membered rings, with cyclo-pentane as the typical structure, is applied to the furanose ringin the same way. Two distinct conformers are defined forcyclopentane—the E and twist (T) conformations (Fig. 2(a));for the furanose ring, 20 distinct conformers—10 each of theE and T conformations—are defined (Fig. 2(b)).
These conformers are described numerically by usingCremer–Pople puckering coordinates, which were defined forN-membered rings.8 The coordinate map for a pyranose ring isshown in Fig. 3. If Cartesian (XYZ) coordinates are given to ringatoms, one can calculate the puckering coordinates (y, j, r) byusing simple mathematical equations. This elegant quantitativenotation is useful for automatic assignment of conformation.This notation has also been used for describing coordinates orsetting constraints in conformational analyses by moleculardynamics (MD) simulations. Other sophisticated numericalnomenclature–coordinate systems developed recently areespecially designed for use in MD calculations.9,10
Chemistry of ring conformation: basicconceptual frameworkConformational analyses of pyranose/furanose rings
A typical pyranose ring in the ground state is assumed topreferentially adopt a chair conformation. The staggered natureof chair conformations usually minimizes the steric hindrancearound the C–C/C–O bonds for all pairs of atoms in the ring.
A typical glucopyranose is known to adopt predominantly a 4C1
chair conformation, which allows the substituents at C2, C3,C4, and C5 to occupy an equatorial orientation. Regardingthe substituent at C1 of glucopyranoses, the 1,2-cis (a)
Fig. 1 Nomenclature for conformations of a six-membered ring. The C6 methylgroup is not drawn in the three-dimensional structures. (a) Five types of distinctconformer are defined for a cyclohexane ring. (b) Thirty-eight distinct conformersare defined for a pyranose ring.
Hiroko Satoh
Hiroko Satoh received her PhD inChemistry at OchanomizuUniversity in 1996. In 1996–1998she was a post-doctoral fellow atSynthetic Organic ChemistryLaboratory of RIKEN Institute. In1998–2001 she conducted herresearch project on computationalreaction prediction under aPRESTO program of JSTCorporation. In 2000, she wasappointed assistant professor andin 2002 associate professor atNational Institute of Informatics.
In 2007–2008 she was Guest Professor of Laboratory of PhysicalChemistry of ETH Zurich and in 2010 Guest Professor of PhysicalChemistry Institute of University of Zurich. Her main research interestis finding rules from complex chemical reactions.
Shino Manabe
Shino Manabe received her PhDfrom Tokyo University in 1996under the direction of Prof. KenjiKoga. During this period, shejoined Professor Gilbert Stork’sgroup at Columbia University asa staff-associate. In 1996, shemoved to RIKEN (The Instituteof Physical and ChemicalResearch) as a specialpostdoctoral fellow. Now she isa senior researcher at RIKEN.She also served Japan Scienceand Technology Corporation in
Precursory Research for Embryonic Science and Technology(PRESTO) Program from 2002 to 2006. Her main researchinterests are development of novel methodology for synthesis ofglycoconjugates and synthesis of biologically active compounds.
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configuration is usually more stable than the 1,2-trans (b)configuration because of a stereoelectronic effect commonlyknown as the anomeric effect.11
The techniques often used for conformational analyses areNMR, X-ray crystallography, and theoretical computations. Thelast of these includes molecular mechanics (MM), quantummechanics (QM), hybrid QM/MM, classical MD based on MMforce fields, and ab initio MD (AIMD). A combination ofNMR and computational techniques is sometimes useful forpredicting conformations, NMR data, or both.12 Only NMR and
ab initio MD yield information about conformations insolution. X-ray crystallography, however, yields importantinsight into the nature of structures, and the computationalcost of static MM or QM simulations is so much lower than thatof MD simulations that one can look into detailed properties(including transition-state information) for several series ofcompounds. Miljkovic well describes the history and basicmethods for conformational analyses of pyranose.13 Furanosesare considered to be more flexible than pyranoses because theirlarger ring strain lowers the barrier between conformers.The extensive investigations of furanoses/furanosides arecomprehensively reviewed in a newly published review by Low-ary and co-workers.14
To present an overview of conformational analysis studiesthat have employed some of the cutting-edge computationaltechnologies, we briefly review some notable studies on theconformational distribution of glucopyranose rings by AIMD orsemiempirical MD simulations. Regarding the notation, anintermediate conformation between canonical ones isdescribed by both conformations separated by a slash. Forexample, 1S5/1,4B denotes the intermediate conformationbetween 1S5 and 1,4B.
Biarnes, Ardevol, and Rovira et al. have carried out remark-able work on conformational analyses for monomers ofb-D-glucopyranose, b-D-mannopyranose, and a-L-fucopyranoseby using the Car–Parrinello MD (CPMD) technology to obtain afree energy landscape of their conformational space undervacuum.15 They implemented the Cremer–Pople puckeringcoordinates in the CPMD code to use the coordinates for settingup the collective variables of metadynamics simulations.
The global minima on the free energy surface (FES) arefound in the 4C1 region for b-D-glucopyranose and b-D-manno-pyranose, and in the 1C4 region for a-L-fucopyranose. Theseinvestigators formulated a model to determine the likelihoodthat a given conformation would be adopted in the Michaeliscomplex by combining the relative free energy with the orienta-tion (axial or equatorial) of the exocyclic C–O bond and withparameters on atomic charge and bond distance for theendocyclic/exocyclic oxygen and the anomeric carbon. A fairlygood relationship is found between the score and theexperimental conformations bound to the enzyme. The mostlikely conformations predicted with the highest scores are 2SO
and 1S3 for glucopyranose, 1S5 for mannopyranose, and 1C4 forfucopyranose. These results are in good agreement with theexperimentally predicted catalytic conformational itinerariesfor retaining glucosidase (1S3 - 4H3 - 4C1 or 2SO - 2,5B -5S1), mannosidase (1S5 - B2,5 - OS2), and fucosidase (1C4 -3H4 -
3S1). Very recently, the same authors, by using conforma-tional analyses based on hybrid QM/MM metadynamicscalculations, demonstrated that in the enzyme–substratecomplex of 1,3-1,4-b-glucanase, b-D-glycopyranose produces adifferent conformational FES view.16
On the other hand, Barnett, Wilkinson, and Naidoo recentlyreported interesting results of semiempirical MD simulations,showing that a pyranose ring located in an oligosaccharidebound to an enzyme is severely distorted away from a 4C1
Fig. 2 Nomenclature for conformations of a five-membered ring. The C5 methylgroup is not drawn in the three-dimensional structures. (a) Three types of distinctconformers are defined for a cyclopentane ring. (b) Eleven distinct conformers aredefined for a pyranose ring.
Fig. 3 Cremer–Pople puckering coordinates. Conformations are described withy, j, and r (radius).
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conformation.17 This is very different from the conformationaldistributions of isolated monomers or oligosaccharides,calculated in the same way either under vacuum or in water.
The results of their investigations show a clear differencebetween the enzyme-bound glucopyranose ring in cellooctaoseand other glucopyranose rings. The enzyme-bound pyranosering is strongly restrained to the 4E, 4H3, and B3,O regions(4E being the most favored), whereas the other pyranose ringsadopt the preferred 4C1 chair conformation, boat and skew-boatconformations, and a 1C4 conformation, all of which areseparated by energy barriers. In the case of pyranose isolatedunder vacuum, these local/global minima are all inter-connected by low energy barriers. This is generally consideredto mean that the pyranose ring changes between the 4C1 and1C4 conformations easily at room temperature. The pyranosering located in cellooctaose is rather restricted to keeping a 4C1
conformation. Apparently, the conformational changes from4C1 to the preferable conformations 4E, 4H3, and BO,3 areassociated with changes in electronic density that make nucleo-philic and acidic attack feasible. These results are also in goodagreement with the suggestion based on X-ray analyses thatenzymes utilize four possible transition-state conformations:4H3, 3H4, 2,5B, and B2,5.
Although these conformational analyses are not simulatedfor glycosylation reactions (which, as will be shown later,include bond breaking and formation via an oxacarbeniumcation), the highly reactive distorted conformations observed inthe enzyme-bound pyranose ring provides important insightinto the reactive conformation during glycosylation reactions.These analyses also show the power of advanced MD technologiesto explore the mechanisms of glycosylation reactions whileconsidering the dynamic changes in pyranose/furanose ringconformations even in condensed matter.
Basic mechanism of glycosylation reactions
The chemical glycosylation reaction, which involves the couplingof a glycosyl donor (electrophile) with a glycosyl acceptor(nucleophile), is promoted by a suitable activator (Fig. 4).
The reaction mechanism of chemical glycosylation remainsan open question, although many experimental and theoreticalefforts have been made thus far. Discussion of the reactionmechanism is best done carefully because the mechanisticdetails can vary according to the structures of the glycosyl
donor/acceptor and the activator, solvent, and temperatureemployed.18 For a typical pyranoside, a glycosyl donor isactivated to give several activated species such as A, separatedion pair B, and contact ion pair C. A, B, and C can beintercepted by a counterion of the activator species X� to giveD, which has a covalent bond at the anomeric center. Thesereactive intermediates are under equilibrium and each speciesprovides a glycoside in the manner of an SN1 or SN2 reaction.When glycosylation reaction proceeds via an oxacarbenium ion,a ratio of products is determined under kinetic control andtransition barriers of the predominantly enthalpic nature. Thereaction mechanism mediated by an oxacarbenium ion isinterpreted to be dissociative (DN + AN) or partially dissociative(DN � AN) with a short-lived intermediate.19
Stubbs and Marx, by using CPMD simulations, suggested aDN � AN mechanism for glycosidic bond formation of a- andb-D-glucopyranosides with methanol in aqueous solution.20 Thesimulation results showed that the reaction is initiated bydeprotonation at the anomeric carbon by a water molecule.
Some experimental investigations21,22 and calculationsfor 2,3,4,6-tetra-O-methyl-D-glucopyranosyl-triflate23,24 haveindicated that glycosylations via triflate intermediates proceedby a DN � AN or DNAN mechanism. Satoh and Hunenbergerperformed QM calculations with continuum solvation methodsstarting with comprehensive sampling of dominant conforma-tions by using classical MD simulations in an explicit solventfor an oxacarbenium cation–counter anion (OTf�) complex toinvestigate the nature of solvent effects in glycosylationreactions.23 This study suggests an alternative hypothesis—the so-called conformer and counterion distribution hypothesis—concerning solvent effects in glycosylation reactions. According tothis new hypothesis, the stereoselectivity is explained by solvent-induced variations in the ring conformational preferences of theoxacarbenium cation and in the preferential location of thecounterion relative to this cation. Taken together, these effectscontrol the side of the anomeric carbon that can be attacked by thenucleophile. In acetonitrile, the oxacarbenium ion preferentiallyadopts a B2,5 boat conformation and the counterion ispredominantly located moderately close (on average) to the cationand on the a side. Both effects prevent the acceptor from attackingthe a face and enhance the formation of the b-linked product. Incontrast, in ether, toluene, or dioxane, the oxacarbeniumion preferentially adopts a 4H3 half-chair conformation, and thecounterion is preferentially located very close to the cation and onthe b side. Both effects prevent the acceptor from attacking theb face and enhance the formation of the a-linked product.
Whitfield used QM calculations with continuum solvationmethods to find the transition state (TS) of glycosylationreactions by plotting energy profiles associated with the elongationof the C1–OOTf bond length for 2,3,4,6-tetra-O-methyl-D-gluco-pyranosyl-triflate (and for 3,4,5-tri-O-acetyl-2-O-methyl-a-gluco-pyranosyl-triflate) as a contact ion pair (CIP) model, with Li+ asthe counterion.24 The energy profile analyses were performedfor several combinations of the ion pair for the a or b triflatewith a few explicit solvent molecules (CH2Cl2) and onemethanol molecule as an acceptor. He found plausible TSs
Fig. 4 Generic mechanism of a glycosylation reaction, in a solution containingan anion. Glycosylation involving a protected pyranoside donor, an alcoholacceptor, and counter anions in solution. LG = leaving group.
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for the a-triflate ion pair complex with b-MeOH attack (model I)and a theoretically certain TS for the b-triflate ion pair complexwith a-MeOH attack (model II). Although both models considerthat a glycosidic linkage is formed with MeOH, they showdifferent conformational trajectories in the course of ioniza-tion. In model I, the ring conformation changes from 4C1
toward a 4H3-like conformation followed by a jump at theapparent TS to a 2SO-like species. In model II, the conforma-tional change is a discontinuity that includes OH5, E3, and B3,O
extensions, and the subsequent nucleophilic attack leads to a4C1-like conformer.
In the case of an enzymatic system, Ardevol and Rovira,using QM/MM metadynamics simulations of the glycosylationreaction with the CPMD technique, obtained evidence for ashort-lived oxacarbenium-like species in enzymatic glycosyltransfer with trehalose-6-phosphate synthase, suggesting aDN � AN mechanism.25 By using the same technique, Biarnesand co-workers obtained evidence for another short-livedoxacarbenium-like species in the biochemical glycosylationreaction catalyzed by the enzymatic glycoside hydrolase, 1,3-1,4-b-glucanase, suggesting a DN � AN mechanism, but with amore SN2-like character in terms of the charge distribution inthe reaction center.16 This study clearly shows the conforma-tional transition in the reaction pathway—1,4B/1S3 (reactant) -4E/4H3 (TS) - 4C1 (product)—not proceeding straightforwardlybut tottering along the reaction pathway. These computedconformational changes are similar to the ideal changespredicted from the available Michaelis complex structuresand glycosyl–enzyme intermediates of glucosidases (1S3 -4H3 -
4C1). Interestingly, this itinerary obtained by the reactionsimulation lies in the same region where the itinerary obtainedby conformational analyses for the Michaelis complex expands(1,4B/1S3 - E5/4H5 - 4C1). These results indicate that theconformational changes obtained by conformational analysescan be a good approximation for the conformational changesalong the reaction pathway.
Some notable experimental studies on the reaction mecha-nism were reported. Tan performed mechanistic investigationsof a MeOH-induced kinetic epoxide-opening spirocyclization ofglycal epoxides, suggesting an SN2 or SN2-like mechanismbased on Hammett analysis.26 Taylor suggested an SN2-typemechanism for the borinic acid-mediated glycosylation withsubstrates that disfavor oxacarbenium ion formation.27 Crichand co-workers investigated the glycosylation reaction mechanismfor the 4,6-O-benzylidene-protected mannopyranoside system.They suggested an associative SN2-like mechanism for b-O-manno-sylation, but a dissociative and an SN1-like mechanism fora-O-mannosylation and b-C-mannosylation.21,28
Strategies for designing glycosyl donors
A glycosylation reaction creates a glycosidic linkage andinduces a new chirality at the anomeric carbon. The productsusually consist of a mixture of the two possible stereoisomers.Although efforts to develop stereoselective synthetic technologiesfor oligosaccharides and glycoconjugates have made considerable
progress in recent years, a high stereoselectivity is still oftendifficult to achieve.
In discussions of the structures (geometries) and reactivityof carbohydrates, the theory of stereoelectronic effects t is oftenused. The stereoelectronic effect can influence geometries,reactivity, or stereoselectivity. This means that if the geometriesof the pyranose ring can be changed, the reactivity or stereo-selectivity can be controlled. The conformational change caninduce changes not only of stereoelectronic features but also ofother electronic properties that influence reactivity. For example,one might mimic the puckering ring in an enzymatic glyco-sylation to enhance the reactivity, stereoselectivity, or both.According to the theory of stereoelectronic effects, an exocyclicanomeric C–O bond (or a C–S bond for thioglycosides) in a(pseudo)axial orientation enhances exocyclic cleavage, whereasa C–O bond in a (pseudo)equatorial orientation makes exocycliccleavage energetically unfavorable. Experimental studies byBols and co-workers suggest that polar substituents (OH, OR,and F) in a (pseudo)axial orientation at C3, C4, or both enhancethe basicity at an anomeric site.29 This means that an oxacarbeniumintermediate with such axial substituents can be stabilized and thatthe glycosylation reaction can be enhanced. On the basis of theseexperimental data, they formulated the so-called superarmed concept,which will be discussed later.
As described above, typical pyranose and pyranosides areknown to predominantly adopt chair conformations, whichachieve the least hindered staggered structures aroundthe cyclic bonds. However, interchange between the chairconformations and the skew-boat, boat, half-chair, or envelopeconformations remains energetically possible15–17,25 dependingon the temperature, the type of solvent, whether the pyranose isa monomer or a part of an oligosaccharide, whether it is anenzyme-bound or isolated form, the type and size of sub-stituents, and the existence of cyclic protecting groups. In somecases, however, one chair conformation can flip to the otherchair conformation (at the opposite pole of the Cremer–Poplepuckering coordinates in Fig. 3). Typical glucopyranoses/glucopyranosides are assumed to adopt predominantly a 4C1
conformation. Some reports suggest that the pyranosideconformation can flip away from a 4C1 conformation (Fig. 5).C- and O-Glycosides with bulky substituents such as TBDPS(tert-butyldiphenylsilyl) group 1 have a conformation distortedfrom or inverted to 1C4.30–32 These structures presumably adoptthe inverted conformation because they avoid the steric repul-sion between the bulky substituents that occupy the equatorialorientations in a 4C1 conformation. Jackson reported X-raycrystallography data of tri-(tert-butyldimethyl)silyl-protectedthioglycoside, demonstrating that this structure adopts a 1C4
conformation.33 O-glycosides are also influenced by cyclicprotecting groups or bulky substituents. For example, con-formations of a glycoside with a cyclic 2,3- or a 3,4-acetal(dispoke)-protecting group 2 are assumed to be more restrictedto a 4C1 region. The bicyclic trans-decaline-type structure isassumed to lock the conformation with the help of the methoxygroups in the acetal moiety, which are expected to be the sourceof the anomeric effects. Another study reported that the
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2,5-cyclic-borate-protected pyranoside 3 adopts a 1C4 conforma-tion. A series of glycosides with 2,3-trans cyclic protectinggroups 4 was developed for glycosyl donors, leading the glycosyllinkage to exhibit higher 1,2-cis (a) selectivity. Another interest-ing spinoff reaction was found for this class of compounds:these glycosides easily undergo anomerization reactions from the1,2-trans (b) anomer to the 1,2-cis (a) anomer.34 Computationalstudies based on density functional theory (DFT) calculations foundthat strong inner strain caused by the cyclic protecting group,which forces itself to be flatter, activates endocyclic cleavage.35 Incontrast, the calculations suggest that the presence of the cyclicprotecting group decelerates exocyclic cleavage reactions.Mechanistic details leading to this interesting stereoselectivityand reactivity have not yet been revealed. One possibility may bethat the force from the cyclic protecting groups controls theconformational transition along the reaction pathway in a mannerdifferent from the transition of a typical glycoside.
Learning from these theoretical and experimental studies, anumber of investigators have attempted to design new glycosyldonor structures with high reactivity or selectivity. They havechanged substituents or protecting groups, introduced cyclicprotecting groups, or constructed bridged structures expecting thatsuch structural modifications would change the conformationaldistributions that influence the reactivity/stereoselectivity. Thestrategies are categorized into two classes: those using donors withcyclic protecting groups/bridged structures (Strategy I), and thoseusing donors with bulky substituents (Strategy II, the superarmedconcept) (Fig. 6). Experimental studies on the design and synthesisof glycosyl donors according to these strategies will be reviewed indetail in the following sections.
Strategy I: stereoselective glycosylationreactions by using donors with cyclicprotecting groups, bulky protecting groups,and bridged structures
In this section, we present glycosylation reaction via stereo-selective chemical glycosylation reactions using donorsdesigned mainly according to Strategy I (Fig. 6).
Shuto prepared pyranosides restricted to the 4C1 form byusing a 3,4-cyclic diketal protecting group (due to its trans-decaline structure and methoxy anomeric effect) and preparedpyranosides restricted to the 1C4 form by using a bulky silylgroup.36,37 The conformational changes in the pyranosideswere confirmed by 1H-NMR coupling constants. The conforma-tionally unrestricted pyranoside 5 gave C-glycoside 6 in moderatea-selectivity (a : b 2.2 : 1) under Lewis acidic conditions(Scheme 1(i)). The same reaction conditions with pyranosidesin the 4C1 conformation 7 resulted in high a-selectivity (a : b >50 : 1; Scheme 1(ii)). The vicinal bulky siloxy groups in donor 9cause ring flipping when they become antiperiplanar to eachother to avoid the severe gauche interaction. When starting withdonor 9, which has the 1C4 conformation, the stereochemistrywas inverted and only the b-C-glycoside was obtained(Scheme 1(iii)).36 The radical C-glycosylation reaction shows asimilar tendency, namely, the donor with 4C1 conformation 11gave an a-glycoside as a major product (Scheme 2(i)). The donor
Fig. 5 Examples of bulky substituents or cyclic protecting groups that influencepyranoside ring conformations. R, R0 = substituent, P = protecting group, Ph =phenyl, TBDPS = tert-butyldiphenylsilyl. Fig. 6 Strategies for the design of glycosyl donors with high reactivity/
stereoselectivity.
Scheme 1 C-Glycosylation under Lewis acidic conditions with various confor-mations of xylosides. Bn = benzyl, TIPS = triisopropylsilyl.
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conformationally flipped by bulky silyl groups 13 gave theb-glycoside in high selectivity albeit low yield (Scheme 2(ii)).37
The donor conformationally flipped by borate clipping tactics15 gave high b-selectivity and better yield (Scheme 2(iii)). Theb-glycoside 16 was obtained not only with Bu3SnCH2CHQCH2
but also when using acrylonitrile with a xyloside having bulky silylgroups 13 (Scheme 2(iv)). C-Glycosylation typically gave a-productsunder both Lewis acidic and radical conditions, and Shuto showedthat both a- and b-glycosides can be prepared with high stereo-selectivity by changing the pyranoside conformation.
Matsuda used the ring-flip strategy in the first total synthesis ofthe nucleoside antibiotic herbicidin B 21 (Scheme 3).38 In thissynthesis, the reduction of the 3,4-O-(1,1,3,3-tetra-iso-propyl-1,3-disiloxanylidene)-protected compound with normal pyranoside
conformation 17 by Pd/C catalysis gave the wrong stereoisomer18 at the anomeric position, but the reduction of the flippedpyranosides with bulky silyl groups 19 gave the intermediate,yielding the correct isomer 20.
Aryl C-glycosides are frequently found in antibiotics.Because of steric hindrance and the absence of anomericeffects, b-glycosides with phenolic substituents 22 are dominantlyproduced from a-glycosides 24 via quinone methide species 23, asshown in Scheme 4.31 The ring-flipped donor 26 featuring the bulkyTBDPS group selectively produced the a-glycoside in high yield(Scheme 5), and this glycoside did not undergo anomerization. Incontrast, the less hindered silyl group TBS-protected donor 27exhibited b-selectivity. From a synthetic point of view, this strategyis a powerful tool for preparing a-aryl C-olivoside antibiotics.
The b-rhamnosylation reaction is rather difficult because ofthe steric hindrance of the axial 2-O-substituent and thethermodynamic anomeric effect, which strongly assists in theformation of a-anomers. Yamada used TBS and TBDPS ashydroxyl protecting groups to flip the conformation of rhamno-side, which improved b-selectivity significantly but not satis-factorily.32 They therefore systematically investigated suitableprotecting groups for ring conformation conversion of glucoseand found that the bulkiness of TBDPS ether was necessary toconvert the glucoside conformation. When using a TBDPSether-protected glucosyl donor with the 3S1 conformation 30,high b-selectivity was observed (Scheme 6).
Yamada and co-workers recently reported a completelyb-selective glycosylation reaction with conformationally distortedpyranoside fluoride 33 by using a 3,6-O-(o-xylene) bridge(Scheme 7).39 3,6-O-(o-xylene) Group that can be removed under
Scheme 2 C-Glycosylation under radical conditions with various conformationsof xylosides. AIBN = 2,20-azobisisobutyronitorile, Bz = benzoyl, DMAP =4-(dimethylamino)pyridine, TIPS = triisopropylsilyl, Ph = phenyl.
Scheme 3 Synthesis of Herbicidin B with conformational change strategy.Bz = benzoyl, TBS = tert-butyldimethylsilyl.
Scheme 4 Anomerization of C-phenolic glycoside. M = metal, L = ligand,P = protecting group.
Scheme 5 Selectivity difference of aryl C-olivosides by changing protectinggroup. Ac = acetyl, TBDPS = tert-butyldiphenylsilyl.
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hydrogenolytic reaction conditions. Interestingly, the glycosylationreaction gave both a- and b-glycosides 35 at the initial stage of thereaction, but subsequent anomerization to the b-form via exocycliccleavage was observed under strong Lewis acidic conditions.DFT calculations indicated that the energy of the b-glycoside was21.0 kJ mol�1 higher than that of the a-glycoside when the OBngroup occupied the anomeric position.
As shown in Scheme 8, Kaneko reported the synthesis of apotent selective inhibitor of fungal elongation factor 2,GM-237354, by using a conformationally flipped donor.40 Tominimize the gauche interaction between the bulky C3- andC4-OTBDPS protecting groups, the donor 38 assumed a twist-boat
conformation. The silyl-protected glycosyl donor 38 exhibitedcomplete b-selectivity with the aglycon of GM-237354, whereasselectivity was low when the normal-conformation pyranoside41 was used as a donor under a variety of Lewis acidicconditions.41
As early as the 1990s, Toshima and Tatsuta et al. reportedthe use of the conformationally flipped bicyclic thioether donor4242 to overcome the difficulty of the stereoselective prepara-tion of 2,6-dideoxyglycoside (Scheme 9). Although 2,6-dideoxy-glycosides are found in antitumor antibiotics such asesperamicin and calicheamicin, the stereoselective O-glyco-sylation is rather difficult. The deoxy positions 2 and 6 arebridged by sulfide bonds to give the conformationally changeddonor 42. The donor 42 was easily activated at �40 1C andreacted with various alcohols to give b-glycoside 44. In contrast,the thioglycoside with normal conformation 46 required highertemperatures for activation, and stereoselectivity was notobserved regardless of the used solvent, including Et2O andCH3CN. Hydrogenolysis of the glycosides in the presence ofRANEYsNi gave 2,6-dideoxy a-glycoside 45. These 2,6-anhydro-2-thio compounds were effective donors for the glycosylation ofthe antibiotic erythromycin, a complex natural product.43
Multiple hydroxyl groups in 9-dihydroerythronolide A 48 wereproperly protected and a desosamine moiety was introduced togive 49. With acceptor 49, donors with the typical 4C1 confor-mation did not yield glycosides because of steric hindrance andthe lower reactivity of the hydroxy group near the carbonylgroup in the aglycon moiety. Fortunately, the bridged donor50 gave glycoside 51 in 90% yield, and the synthesis oferythromycin A was successful (Scheme 10).
When the axial 3,4-diol was protected by using an acetonidegroup, 1H-NMR coupling constant analyses revealed that thepyranoside conformation was changed to a boat-like conforma-tion.44 The fuco-thioglycoside with acetonide group 53 producedglycoside 54 in an a-selective manner, but the diacetate-protected donor 54 showed less selectivity (Scheme 11). Interestingsolvent effects on these two donors were observed. Althougha-selectivity is generally known to increase in Et2O and dioxane–toluene, in this case it increased greatly in CH2Cl2 and decreased inEt2O. Conversely, the donor with the diacetate group showed higha-selectivity in Et2O.
Glucuronic acid is a component of glycosaminoglycans, andglucuronidation is an important pathway in drug metabolism.
Scheme 6 b-Glucosylation reaction with a conformationally distorted donor.Et = ethyl, MeOTf = methyl trifluoromethanesulfonate, Piv = pivaloyl, TIPS =triisopropylsilyl.
Scheme 7 Glycosylation reaction and anomerization by using a distorted con-formation donor with 3,6-O-(o-xylene)bridge. Bn = benzyl, BTF = benzotrifluoride.
Scheme 8 Synthesis of potential antifungal agent GM-237354. Ac = acetyl,MS = molecular sieves, TMSOTf = trimethylsilyl trifluoromethanesulfonate,TBDPS = tert-butyldiphenylsilyl.
Scheme 9 a-2,6-Deoxy sugar synthesis with a bridged donor. Ac = acetyl, NBS =N-bromosuccimide, MS = molecular sieves, Ph = phenyl.
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In investigating drug metabolism, the synthesis and evaluationof drug-glucuronic acid conjugates are important. A facileaccess to 2,6- and 3,6-lactones by TEMPO-BAIB oxidation of6-hydroxy diol and lactonization in one pot was reported by vander Marel.45 The conformation of pyranosides was flipped to1C4, and the thioglycoside 57 smoothly gave a-glycoside 59when the Ph2SO–Tf2O activation protocol was used at �60 1C,a temperature lower than that used with pyranosides in thenormal conformation (�40 1C; Scheme 12). Nishimura andHinou et al. converted glucuronic acid to the 1C4 conformationby introducing bulky 2,4-O-di-tert-butylsilylene groups (Scheme 13).46
Complete b-selectivity was observed when using variousglycosyl acceptors. Molecular mechanics (MM) calculationsand NOESY (Nuclear Overhauser Effect correlated Spectro-scopY) NMR spectra showed that the tert-butyl group blockedthe a-face of the pyranoside to prevent the approach of glycosylacceptors. These results show that the intrinsic low reactivityof 1-thio urinates was overcome by a change in the 1C4
conformation with several axial hydroxyl groups (discussed ingreater detail below).
Strategy II: superarmed concept—changingconformations with bulky substituents
Bols et al. focused on the difference in the reactivity of glycosyldonors with different conformations and reported that positivecharge was stabilized by axial rather than equatorial hydroxylgroups.5,29 When investigating glycosidase inhibitors, theyfound that the substituents on piperidines influenced thebuild-up of positive charge in the ring system (Fig. 7). pKa
measurements of piperidonium ions revealed that an axialsubstituent was significantly less electron-withdrawing thanits equatorial counterpart. This behavior can be explainedthrough the differences in the charge–dipole interactionsbetween positive charges in the ring and axial or equatorialC–O dipoles.29 Further study on this effect in carbohydrates bymeasuring the hydrolysis of methyl glycosides yielded the sameconclusion: positively charged glycosylation intermediatesadopted a conformation with the maximal number of axialsubstituents to improve stabilization.47 On this basis,
Scheme 10 Synthesis of erythromycin A. Bn = benzyl, Mc = methoxycarbonyl,NIS = N-iodosuccimide, Me = methyl, TfOH = trifluoromethanesulfonic acid.
Scheme 11 Stereoselectivity and solvent effect of glycosylation reaction byusing a pyranoside donor with the 3,4-acetonide group and the 3,4-diacetategroup. Ac = acetyl, NBS = N-bromosuccimide, MS = molecular sieves, Ph = phenyl.
Scheme 12 Glycosylation reaction with the 3,5-lactone featuring donor. Ac =acetyl, Bn = benzyl, Tf2O = trifluoromethanesulfonic anhydride, TTBP = tri-tert-butylpyrimidine.
Scheme 13 Stereoselective glycosylation reaction with a cyclic silyl groupdonor. Bn = benzyl, Bu = butyl, MP = p-methoxylphenyl, TTBP =tri-tert-butylpyrimidine.
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the ‘‘superarmed’’ glycosyl donor 68 in the twist-boatconformation and with bulky silyl moieties to protect thehydroxy group was prepared.48 As shown in Scheme 14, thehighly reactive ‘‘superarmed’’ thioglycoside 68 was selectivelyactivated in the presence of the benzyl-group-protected armedthioglycoside 69 at �78 1C to afford disaccharide 70 in 85%yield with b-selectivity; the homocoupling product was notobserved.
The enzyme lysozyme induces conformational changes in4H5 at the cleavage site in the sugar unit, which is very similar tothe oxacarbenium ion intermediate during hydrolysis of anoligosaccharide (Scheme 15). The cation is stabilized by Asp51in the lysozyme, and subsequent hydrolysis gives the product.49
Inspired by the mechanism of lysozyme hydrolysis, Toshimaet al. designed conformationally distorted glycosyl donors with2,3-double bonds into a half-chair conformation to enhance thereactivity of pyranoside donors (Scheme 16).50 Consistent withthe expectation that the double bonds effectively stabilize thecation generated at the anomeric center, the competitivereaction between 77 and 78 in the presence of acceptor 79 gaveglycoside 80 as a major product.
Stereoselective O-furanoside formation bycyclic protecting groups
Furanosides are important components of the microbacterialcell wall and plant polysaccharides. The b-glycosylation of
arabinofuranosides, like 1,2-cis linkage formation, is ratherdifficult because of the weak anomeric effect and a structuremore flexible than that of pyranosides.51 The development ofconformationally restricted donors would be a rationalapproach for stereoselective furanoside synthesis. The firstexample of a conformationally restricted furanosyl donor wasbased on the 2,3-anhydro donor 82 (Scheme 17).52 This donorgave various furanosides in a b-selective manner, and theepoxide was opened by lithium alkoxides in the presence of(�)-sparteine.53
Boons et al. designed the cyclic 3,5-O-di-tert-butylsilane-protected arabinofuranoside donor 85 to achieve b-glyco-sylation (Scheme 18).54,55 The more flexible five-memberedfuranoside conformation is restricted by a cyclic silylene group,indicating that attack from the b-face is favored in the presenceof a bulky silylene group. DFT calculations support the use ofthe E3 conformer to give the b-glycoside because it encountersonly staggered constituents. 3,5-O-di-tert-Butylsilane favors theE3 conformation, resulting in a perfect chair conformation ofthe cyclic protecting group. The donor 85 gave only b-arabino-furanoside with the trisaccharide acceptor 86. Double glyco-sylation by using donor 85 gave the arabinogalactan fragmentpentasaccharide 89. Ito developed a cyclic 3,5-tetra-iso-propyl-1,3-disiloxanediyl-protected arabinofuranoside donor 90, reasoningthat the b-selectivity was due to the minimization of torsional strainduring the attack on the furanosyl oxacarbenium ion (Scheme 19).
Fig. 7 Substituent influence on pKa of piperidonium ions.
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These selectivities are also explained by Woerpel’s ‘‘inside attack’’model.56,57 The 22-mer containing the arabinan motif of theMycobacterium tuberculosis cell wall arabinofuranoside was synthe-sized by Lowary and Ito using 85 as the glycosyl donor and by Itousing 90 as the glycosyl donor.58,59
Although these furanoside donors with a 3,5-cyclic protect-ing group 85 and 90 showed high b-selectivity, several steps areneeded to manipulate the protecting group after glycosylationwhen O-3, O-5, or both are modified. Lowary developed a 2,3-O-xylylene-protected furanoside donor to achieve efficient
synthesis of mannose-capped lipoarabinomannan becausemodification at O-5 of arabinofuranoside is often found inlipoarabinomannan structures (Scheme 20).60 The 5-PMB-protected donor 93 gave high b-selectivity compared with the5-Bn and Bz donors. The electron-donating group at O-5 isknown to enhance b-selectivity in furanoside donors, althoughthe reason is still unclear.
Conclusions
In this tutorial review, we discussed the designing of glycosyldonors by attaching to them bulky substituents, cyclic protect-ing groups, and bridged structures assumed to drive the typicalpyranosides that adopt chair conformations to adopt distortedring structures (e.g., boat, skew-boat, or half-chair conforma-tion). The chair can even flip to other types of chair conforma-tion at the opposite pole of the Cremer–Pople puckeringcoordinates. The ring distortion can switch the orientationof the substituents from (pseudo)axial positions to (pseudo)-equatorial positions and vice versa. These conformationalchanges will be associated with changes in electronic density,which in turn will stabilize/destabilize the oxacarbenium cationassumed to be an intermediate of glycosylation reactions. Thepositioning of substituents and the conformational transitionin the glycosylation reaction pathways can influence thepreferential coordination of the nucleophilic (glycosyl acceptor)attack of the oxacarbenium cation to one side of the anomericcarbon, leading to stereoselective formation of a glycosyllinkage.
We reviewed several attempts to synthesize new glycosyldonors based on this concept. The conformations of thesecompounds were elucidated by NMR spectroscopy or X-raycrystallography, in some cases combined with calculations.However, in cases where the local minima of conformers areseparated by low energy barriers, the actual preferential con-formations in solution are difficult to determine experimen-tally. Identifying the conformational changes from the reactantto the product via an intermediate (an oxacarbenium cation) inthe glycosylation reaction pathway remains a major challengeworth tackling. On the other hand, as demonstrated in thisreview, alternative computational technologies can providedirect views of the conformational transitions, even withdynamics in condensed matter, on the basis of quantummechanical theory. These cutting-edge technologies as well asconventional approaches to conformational analyses will be
Scheme 19 b-Arabinofuranoside synthesis by using a donor with a cyclicsilylene group. AgOTf = silver trifluoromethanesulfonate, Bn = benzyl, NIS =N-iodosuccimide, TIPS = triisopropylsilyl, Tol = tolyl.
Scheme 18 Pentasaccharide synthesis by using a donor with a cyclic silylenegroup. Ac = acetyl, AgOTf = silver trifluoromethanesulfonate, Bu = butyl,Bn = benzyl, Bz = benzoyl, NIS = N-iodosuccimide, MS = molecular sieves.
Scheme 20 b-Arabinofuranoside synthesis by using a donor with a 2,3-o-xyleneprotecting group. AgOTf = silver trifluoromethanesulfonate, Bn = benzyl, NIS =N-iodosuccimide, PMB = 4-methoxybenzyl.
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powerful tools that help experimental studies provide ideas fordeveloping new methodologies for glycosylation reactions.
Acknowledgements
The authors would like to thank Professor Yukishige Ito at theRIKEN Advanced Science Institute and Professors Kwan SooKim and Injae Shin at Yonsei University for inviting us tocontribute to this themed issue on carbohydrate chemistry.
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