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Eclipsing of exocyclic carbon–oxygen bonds in methyl ether derivatives of inositols and carbohydrates is reported and discussed. Structural fragments stereotypical for eclipsing are recognised, namely an axial or equatorial alkoxy group on a six-membered ring with equatorial substituents on either side. The X-ray crystal structure of hexa-O-methyl-epi-inositol is reported. Some analogous compounds which also have eclipsed bonds are reported.

Hexa- O -methyl- scyllo -inositol was synthesized and its crystal structure was determined by X-ray diffraction. As predicted by calculations, each oxygen-methyl bond eclipses the adjacent carbon-hydrogen bond. NMR studies show that the same conformation predominates in solution.

The composition of aldohexoses, aldopentoses, and hexuloses has been determined by 13C NMR spectroscopy in dimethyl sulfoxide (Me2SO) solution.

Alditols form stronger complexes with Nd3+, Sm3+, and Eu3+ than with La3+ cations, but weaker ones with the higher lanthanides. There is a clear relationship between ionic radii and stability constants. Chromatographic ion-exchange columns can be smaller when prepared with Nd3+ rather than the usual Ca2+ columns. Galactitol, alone amongst the hexitols, can form 1:2 complexes with lanthanide ions. The crystal structure of galactitol·2PrCl3·14H2O has been determined.

Publisher Summary This chapter analyzes the composition of reducing sugars in solution. It elaborates the concepts of relative stabilities of various forms of sugars and elaborates the composition of aldoses, ketoses, and substituted and derived sugars in aqueous solution. Neuclear Magnetic Resonance (NMR) spectrometers have considerably improved over the past few years, and important advances now allow the detection and measurement of components that occur in the range of 0.01 -0.1%. Gas-liquid chromatography (GLC) of trimethylsilyl derivatives has been used to determine the composition of some dozen sugars in water and in pyridine. In the latter solvent, the results agree well with previous determinations; in aqueous solution, however, some of the values for furanoses prove to be too high and the values for idose (presumably mutarotating) rapidly differ considerably from those obtained by NMR spectroscopy. GLC of the trimethylsilyl derivatives is also used for studying the mutarotation of D-fructose. The composition data obtained for the major components agree well with those given by NMR spectroscopy.

3- C -Hydroxymethyl- d -glucose, when heated with dilute acids, rapidly forms 96% of the 1,3 1 -anhydride. 3- C -Hydroxymethyl- d -xylose, - l -lyxose, and - d -ribose each form an equilibrium that contains similar anhydrides to a progressively lesser extent. Each of these branched-chain sugars has six cyclic forms in aqueous solution and their proportions have been determined.

The molecular structures of the title heptitols were determined by X-ray crystallography, using direct methods, and refined to final residual parameters of R = 0.037 and 0.039, respectively. Each compound adopts a bent conformation. For α-sedoheptitol ( 1 ), this is not the expected conformation (with O-6 in the extended planar position). Instead, 1 adopts a conformation with a 1,3- parallel interaction between O-4 and C-7.

Di-D-fructose 2′, 1:2,1′-dianhydrides form complexes with metal cations if the two anomeric carbon atoms have the same configuration. Such anomers have the central 1,4-dioxane ring in a flexible form; complex formation involves O-1, O-1′, O-3, and O-3′, as confirmed by the X-ray crystal structure of the strontium complex of the β,β-dipyranose anomer. The α,β-anomers, and dianhydrides containing only furanose rings, do not form such complexes. Keywords: difructose dianhydrides, complex formation with cations, crystal structure of complex, chromatographic separation on ion-exchange resins.

Contrary to statements in the literature, Cu2+ ions form only weak complexes with polyols. At pH > 5, however, strong complex formation is observed which is attributed to [Cu2(OH)2]2+ or similar binuclear ions. The formation of tetradentate complexes is postulated with compounds having four hydroxyl groups in suitable steric relationship, especially alditols.

Publisher Summary This chapter presents the various aspects of the history of International Carbohydrate Symposia. The first meeting calling itself the “International Symposium on Carbohydrate Chemistry” was held in Birmingham, England, in 1962. At the first two symposia where plenary lectures were held, R. U. Lemieux gave talks on Nuclear Magnetic Resonance (NMR) in carbohydrate chemistry and conformational analysis. Lemieux was the outstanding carbohydrate chemist of the second half of the century and these were the subjects where he made his most important contributions. Apart from attending lectures, the principal aim of the symposia is to provide an opportunity for the exchanges of views and discussion of problems among participants. This is only practical if adequate seating space is provided close to the lecture theaters. The best provisions for that were at San Diego with plenty of seats, indoors, and outdoors, where refreshments was also available. The Award is presented at the beginning of each Symposium after the opening ceremony. The awardee then delivers a lecture on his work, scheduled as the first lecture of each symposium. Most of the logos of the symposia are a combination of carbohydrate symbols with some local features.

It is postulated that, in the epimerization of glucose in alkaline solution catalyzed by Ca 2+ ions (and other cations of similar size), the intermediate is a complex of the cation with O-1, O-2, O-3 and O-4 of the sugar and that the reaction proceeds, like the Bilik reaction, with rearrangement of the carbon chain.

Recent examples of the use of a very old synthetic method are discussed. Discovery of the cation-catalyzed epimerization explains some of the previously controversial results. The mechanism of the reaction is discussed. Suggestions are made for improvements in yield and in the method of work-up.

myo-Inositol 4,6-carbonate, a compound having three syn-axial hydroxyl groups, was synthesized in four steps suitable for gram-scale preparation. It readily forms complexes with cations.

Robert V. Stick is a carbohydrate chemist; and so am I. Carbohydrate chemistry is a special branch of organic chemistry. The carbohydrates differ from the common organic chemicals in many ways: they do not dissolve in organic solvents, they cannot be distilled; and when a pure sugar is dissolved in water, a solution results that contains six different compounds. Carbohydrate chemists have their own journals and textbooks. Carbohydrate chemistry did not develop until the end of the 19th century; then Emil Fischer[1] determined the structures and configuration of all the simple sugars, established conversions, and studied their reactions. I worked for my Ph.D. degree in sugar chemistry with Zemplen, a former student of Fischer; he was not a brilliant chemist, and was a poor supervisor. When I completed my degree, I decided not to work on sugars any more: I thought that the problems there had already been solved by Fischer himself and his team. I went into the pharmaceutical industry. But soon I realised that my judgment was not right: there was plenty to learn still about the properties of sugars. Thus, we did not know why d-glucose is mainly in the β-pyranose form but d-mannose mainly the α-pyranose. Why does the equilibrium of d-glucose contains very little furanose but that of d-idose quite a lot? Why do some sugars readily form a 1,6-anhydride but others do not? When I obtained a university position in 1946, I returned to carbohydrate chemistry. In the middle of the century, three new methods revolutionized carbohydrate chemistry: NMR spectroscopy,[2] X-ray crystallography,[3] and conformational analysis.[4] NMR spectroscopy allowed the determination of the exact proportions of isomers in equilibrium; the X-ray method indicated the exact shapes of the molecules; and conformational analysis supplied the explanations and allowed predictions of behaviour. It became now much easier to deal with the structures and synthesis of complex carbohydrates, such as oligosaccharides and glycosides. And synthesis has been improved by new methods and new reagents, and by better control of conditions. Separation methods were also improved, for example chromatography – originally an analytical technique – was turned into an efficient method of preparative separation. When Stick established his group in the Department of Chemistry at the University of Western Australia his collaborators and Ph.D. students carried out a range of reactions with a variety of sugars. Many of the compounds thus obtained were natural products, but others were artefacts. These, of course, were compounds of interest to biochemists because they could be tested for potential biological activity. Soon many papers appeared on the biochemical behaviour of sugar derivatives. By now, there were biochemists in some chemistry departments and chemists in some biochemistry departments. Ideally, close cooperation was desired between them but, in fact, was seldom achieved. In most universities, the chemistry and the biochemistry departments are in different faculties and not even close to each other. [In my case, the two schools do not even inform each other of their seminars.] By contrast, by the time of the retirement of Robert Stick in 2008, his department had been renamed the School of Biomedical, Biomolecular and Chemical Sciences. The changes in carbohydrate chemistry are easily surveyed by looking at two sources of information: the series Advances in Carbohydrate Chemistry, published annually since 1945, and the programs of the International Symposia on Carbohydrate Chemistry, held biennially since 1960. The Advances contain chapters of current interest on carbohydrates; the symposia consist of talks on subjects in which work was currently carried out. Both indicate which way carbohydrate research is moving. Both organizations realised how much it was tending towards biochemistry. In 1989 Advances in Carbohydrate Chemistry added the words ‘and Biochemistry’ to its title; in 1980, the Symposia made room for biochemistry in the opposite way by omitting in Vancouver the word ‘Chemistry’ and becoming International Carbohydrate Symposia. Neither of these bodies used the term ‘Glycoscience’, much liked by some of the biochemists. [However, a recent book on carbohydrate chemistry and biochemistry is entitled Glycoscience; Chemistry and Chemical Biology. It contains more than 9000 references!] At the Symposium in Hamburg (in 2000), about one-third of the presented papers and the posters were on biochemistry and biotechnology. By then, interest in carbohydrates had grown very much: there were almost 1000 talks and posters presented. At the latest Symposium, in 2007 in Oslo, again about onethird of the papers and posters were on biochemical subjects. Curiously, the proportion was smaller for the plenary and invited lectures; apparently there were few biochemists on the organizing committee. Unfortunately, Robert Stick missed this meeting, his first absence in over 20 years. All this development affected Robert Stick’s interest and research too. Most of his work was published in the Australian Journal of Chemistry but gradually shifted to journals of

Publisher Summary This chapter analyzes the composition of reducing sugars in solution. It elaborates the concepts of relative stabilities of various forms of sugars and elaborates the composition of aldoses, ketoses, and substituted and derived sugars in aqueous solution. Neuclear Magnetic Resonance (NMR) spectrometers have considerably improved over the past few years, and important advances now allow the detection and measurement of components that occur in the range of 0.01 -0.1%. Gas-liquid chromatography (GLC) of trimethylsilyl derivatives has been used to determine the composition of some dozen sugars in water and in pyridine. In the latter solvent, the results agree well with previous determinations; in aqueous solution, however, some of the values for furanoses prove to be too high and the values for idose (presumably mutarotating) rapidly differ considerably from those obtained by NMR spectroscopy. GLC of the trimethylsilyl derivatives is also used for studying the mutarotation of D-fructose. The composition data obtained for the major components agree well with those given by NMR spectroscopy.

Inositols have been converted into their triphenylsilyl derivatives. In all cases only five substituents could be introduced, the remaining free hydroxy group being hindered. The derivative of myo-inositol and one of two of neo-inositol were found to be in the inverted chair conformation, but those of other inositols are in the normal chair form. The structures of two penta-substituted derivatives have been determined by X-ray crystallography.

An old method has been updated to provide an easy one-step process for the synthesis of l-ribose.

Chromatography on a column of cations immobilized on a cation-exchange resin is particularly suitable for the separation of polyhydroxy compounds, particularly carbohydrates. Neodymium is recommended as the cation of choice.

The variation of the strength of complex formation of small polyols with cations has been examined along the series of lanthanides. The strength depends on the ionic size of the cation and on the shape and flexibility of the complexing molecule. In many cases a maximum is found around the middle of the lanthanide series. Some compounds which do not form complexes with cations separate satisfactorily on cation-exchange resin columns. More frequent use of such columns is advocated.

By the use of the SIMPLE NMR method, strong intramolecular hydrogen bonds were found in the Me2SO solutions of sugars having two syn-axial hydroxy groups, like the talopyranoses. Weaker hydrogen bonds were detected between hydroxy groups in a 1,3-arrangement when one was outside the ring but only weak, although numerous, hydrogen bonds were detected in solutions of other sugars and inositols.

Several cyclohexanepentols have been synthesized from inositols by blocking all but one hydroxyl group, converting the free hydroxyl group into its S -methyl dithiocarbonate, and treating it with tributylstannane. Suitable blocking-groups are methyl, benzyl, and methylthiomethyl ethers, and acetals. One cyclohexanepentol was prepared by the reductive deamination of an aminodeoxyinositol.

On acid-catalyzed equilibration in aqueous solution, three aldoheptoses, d -glycero- l -manno-, d -glycero- l -allo-, and d -glycero- l -altro-heptose, give 15, 54, and 98%, respectively, of the 1,6-anhydropyranose, a much higher proportion than is formed from the homomorphous aldohexoses. This is another example of the greater tendency of secondary, compared to primary, hydroxyl groups to participate in the formation of cyclic acetals.

The relative rates of protium-deuterium exchange, catalysed by deuterated Raney nickel in deuterium oxide, in various positions of 1,6-anhydrohexopyranoses and -furanoses have been studied. Conditions have been found under which 1,6-anhydro-β- D -galactopyranose may be labelled on C-3 and 1,6-anhydro-α- D -galactofuranose on C-2.

Three-dimensional, single-crystal, X-ray diffraction methods were used to determine the structure of the calcium chloride complex of α - d -allopyranosyl α - d -allopyranoside. The crystal is monoclinic with cell dimensions: a = 16.262(5), b = 8.345(5), c = 8.298(5)A, β = 98.428(5)A, and z = 2. The space group is P2 1 . The structure was solved by three-dimensional Patterson and Fourier methods, and was refined by least-squares techniques to give a conventional discrepancy factor of R = 0.026; 2435 diffractometer-read reflections were used. The cation was found to be in 9-fold co-ordination to O-1, O-2, O-3, O-2′, O-3′, and four water molecules.

The rate of protium-deuterium exchange, catalyzed by deuterated Raney nickel, on all carbon atoms of four inositols, was measured. The rate of exchange is lowered by methylation of an adjacent hydroxyl group; this effect was studied on seven isomeric, inositol methyl ethers. Correlations between the rate of exchange and the configuration, the conformation, and the site of O -methylation of the inositols have been established.

The 1H- and 13C-n.m.r. spectra of seven inositol methyl ethers were recorded and assigned. They were classified into five types, and the effect of O-methylation on the chemical shifts of each type is discussed.

The 13 C-n.m.r. spectra of the eight diastereomeric inositols and the ten diastereomeric cyclohexanepentols have been recorded and all of the signals have been assigned by a variety of methods. The additive empirical constants used to correlate the configuration of hydroxyl groups with the 13 C-chemical shifts differ, in the latter group, from those derived for the inositols; the removal of one hydroxyl group had altered the “rules” considerably. A better correlation was found between the spectra of the cyclohexanepentols and those of the inositols derived therefrom, in each case, by the addition of an equatorial hydroxyl group.

The 1 H-n.m.r. spectra of all eight diastereomeric 1,6-anhydrohexofuranoses were recorded for solutions in D 2 O at 270 or 300 MHz, and were interpreted first order. For the same solutions, the broad-band decoupled 13 C-n.m.r. spectra of these compounds were recorded at 67.9 or 75.5 MHz, and the 13 C-n.m.r. spectra of the triacetates in ( 2 H)chloroform were tentatively interpreted.

Methyl α- d -idopyranoside and its 2,3-dimethyl ether give only the known 4,6- O -( S )-benzylidene acetals on benzylidenation. Methyl α- d -idopyranoside 2,3-carbonate was prepared, and it gave a small proportion of the ( R )-benzylidene acetal, but, again, the ( S )-isomer was the main product. Surprisingly, in chloroform solution, methyl 4,6- O -( R )-benzylidene-α- d -idopyranoside assumes the 4 C 1 ( d ) conformation, having an axial phenyl group, rather than the 1 C 4 ( d ) form (which would have an equatorial phenyl group). The 4 C 1 forms of the ( R ) and the ( S ) derivatives are stabilized by two hydrogen bonds that can be observed in their n.m.r. spectra. In the presence of water, methyl 4,6- O -( S )-benzylidene-α- d -idopyranoside is mainly in a skew form, but methyl α- d -idopyranoside exists as a mixture of the two chair forms. Several other compounds that have three or more axially attached oxygen atoms have been studied, but none were found to be in a skew form.

The rate of protium-deuterium exchange, catalyzed by deuterated Raney nickel in deuterium oxide, in various positions in methyl glycopyranosides and furanosides has been studied. In general, the exchange process is not highly regio-selective in these compounds. However, conditions were found under which methyl β- d -fructopyranoside can be selectively labelled on C-5, methyl β- d -fructofuranoside on C-3, and methyl β- d -galactopyranoside on C-3 and C-4.

Molecular rotations and molecular-rotation differences are tabulated for the methyl furanosides of all of the aldopentoses, aldohexoses, and hexuloses. The n.m.r. spectra of most of the methyl aldofuranosides have been determined and analyzed, and from the data, the conformations of the glycosides have been deduced. In the d series, the β-pentofuranosides are found to be in the 3 T 2 form, with the methoxyl group quasi -axial and the side-chain quasi -equatorial. The α- d -pentofuranosides are mixtures of two twist forms, or assume an envelope conformation. The correlation between conformation and optical rotation of the methyl furanosides is discussed.

The crystal structure of d -threo-3,4-hexodiulose was determined, and it showed that the crystalline form is the ββ anomer. In solution, the αα anomer is preponderant, although all of its hydroxyl groups are cis to each other. In the crystal, the diulose assumes the endo,exo conformation; in the aqueous solutions of both anomers, the endo,endo form preponderates, whereas the acetates in chloroform are mainly in the exo,exo conformation.

In alkaline solution, periodate ions form complexes with three consecutive hydroxyl groups in an axial-equatorial-axial arrangement but not with three syn -axial hydroxyl groups. Borate ions form complexes with three syn -axial hydroxyl groups but not with the ax  eq  ax sequence. Accordingly, cis -inositol gives a 1,2,3-periodate and a 1,3,5-borate complex. Cations form complexes with either type of conformation, but complex formation provides little energy towards achieving it by ring inversion. Lanthanide ions have been used to establish the sites of complex formation.

The 13 C-n.m.r. signals of the pentitols and hexitols in aqueous solution, and of their acetates in chloroform solution, have been assigned by the use of specifically deuterium-substituted compounds. Qualitative correlations have been established between the chemical shifts and the configuration and preponderant conformation of each of the alditols.

The 13 C-n.m.r. signals of the heptitols in aqueous solution, and of their acetates in chloroform solution, have been assigned by the use of specifically deuterium-substituted compounds. From these spectra, the preponderant conformation of each heptitol has been determined, particularly by comparisons with the spectra of the homomorphous hexitols. The results are in good agreement with the predictions made, on the basis of theoretical considerations, by J.A. Mills ten years ago.

The molecular and crystal structure of d - glycero - l - allo -heptitol has been determined. It crystallises in the orthorhombic space-group P 2 1 2 1 2 with a = 8.399(2), b = 23.484(8), c = 4.664(2) A, α = β = γ = 90°, and Z = 4. The heptitol was found to be in the 3 G − form, which has a 1,3-parallel interaction between C-2 and O-5. In solution, as determined by 1 H-n.m.r. spectroscopy, the heptitol and its hepta-acetate also assume conformations which have a C,O parallel interaction. Such an interaction has also been found to occur in several other heptitols and in hexose dialkyl acetals. Because conformers with such an interaction had been disregarded in the past, the conformations of several heptitols had been wrongly assigned.