[Advances in Carbohydrate Chemistry] Volume 22 || D-Fructose and Its Derivatives

D-FRUCTOSE AND ITS DERIVATIVES*

BY L . M . J . VERSTRAETEN~

Department of Experimental Medicine, Reya Institute. Universily of Louvain. Belgium

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 I1 . Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

I11 . Physical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 IV . Estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 V . Isomerization Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

VI . Irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 VII . Acetals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

VIII . Glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 IX . Ortho Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248

. . . . . . . 250

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 2 . Other Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

XI . Ethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 1 . Methyl Ethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 2 . TritylEthers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257 3 . (Trimethylsilyl) Ethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258

XI11 . Halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 XIV . Nitrogen-containing C

1 . General . . . . . . . . . . 2 . Hydrazones and Osazones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 3 . D-Fructosylamines . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 5 . Miscellaneous

XI1 . Anhydrides . . . . . . . . . . . . . . . . 258

XVI . Reduction and Oxidation Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 XVII . Branched-chain Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284

XVIII . Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 XIX . 6-Dicarbonyl Condensation Products . . . . . . . . . . . . . . . . 288 XX . Tables of Properties of Derivatives of D-Fructose . . . . . . . . . . . . . . . . . . . . . . 289

*This Chapter modernizes that by C . P . Barry and J . Honeyman, Advan . Carbo-

t Present address: Laboratory for Nitrogen Research, Department of Soil Science, hydrate Chem., 7 , 53 (1952) .

Institute of Agriculture. Heverlee, Belgium . 229

230 L. M. J. VERSTRAETEN

T. INT~~ODUCTION

During the past decade, D-fructose (especially its p-D-f uranose form) has received increasing recognition of its role in biochemistry, and the use of new chemical and physical methods has permitted the study of certain characteristic properties of the 2-keto grouping. The furanose form is found to occur in most oligo- and poly-saccharides, probably because of the greater stability of this form of the sugar as compared with its pyranoid form. Most of the other sugars having the arabino configuration display the same phenomenon, for this configuration on the furanoid ring results in a more symmetrical distribution of groups than for the pyranoid form, as may be seen from formulas (1) and (2).l

I I c-0

I HO

I I HO

However, the first (and, thus far, the only) exception to this behavior has been found by Stodola and coworkers on treating sucrose solutions with Leuconostoc mesenteroides.2 Leucrose, identified as being a 5- O-~-gluco- pyranosyl-D-fructopyranose, was obtained in 8% yield.3 Isomaltulose, another disaccharide having a ketosyl moiety, was obtained from the mother liquors.4 The action of yeast invertase on sucrose affords several nonreducing trisaccharides, considered to be intermediates in the biochemical formation of the fructans because of their detection in numerous plants and in cane final molasses.6T6 A new tetrasaccharide of the same class, nystose (@-D-fructosyl-l-kestose) , has been identified by Binkley and Altenburg’ after the action of a transfructosylase on sucrose solutions, and the furanose form as well as the p-D configuration for the D-fructose moiety was deduced from ( a ) the results of periodate oxidation and ( b ) calculations made according to Hudson’s isorotation rules. In contrast, honey invertase

(1) D. J. Bell, J . Chem. SOC., 1231 (1953). (2) F. H. Stodola, H. J. Koepsell, and E. S. Sharpe, J. Am. Chem. Soc., 74,3202 (1952). (3) F. H. Stodola, E. S. Sharpe, and H. J. Koepsell, J . Am. Chem. SOC., 78, 2514 (1956). (4) E. S. Sharpe, F. H. Stodola, and H. J. Koepsell, J . Org. Chem., 26, 1052 (1960). (5) R. W. Henderson, R. K. Morton, and W. A. Rawlinson, Riochem. J . , 72,340 (1959).

(6) W. W. Binkley, Intern. Sugar J., 66, 46 (1964). (7) W. W. Binkley and F. W. Altenburg, Intern. Sugar J., 67, 110 (1965).

J. B. Pridham, ibid., 76, 13 (1960).

D-FRUCTOSE AND ITS DERIVATIVES 231

synthesizes a-maltosyl p-D-fructofurarioside in 11 % yield.* The importaim of D-fructose derivatives in biology and chemistry has been discussed by many authorities, and it has been proposed that fructans, including levans, play a prominent part in the chemical changes which occur during the life of plants?JO The presence of these compounds has been correlated with resistance to frost, and effecting this may be their major role.lOJ1

Known originally as fruit sugar (Latin: fructus = fruit) or honey sugar (34.9% by weight, as against 35.4% for D-glucose in honey12), D-fructose has a sweetness eight times that of sucrose.13 More information on its sweetness has been gathered by two different schools. In a first report,14 correlation between sweetness and temperature was attributed to a change in the equilibrium of the isomers, the a-D-pyranose form having only about one-third the sweetness of @-D-fructopyranose. The other report stated that a (?) -D-fructopyranose is 85-90% sweeter than the equilibrium mixture attained three hours after dissolution in water.I5 As p-D-fructopyranose is the only crystalline isomer yet isolated, and the equilibrium mixture contains at least 15% of the furanose these conflicting results may be readily explained. Heating increases the proportion of the furanoses, by the phenomenon known as thermal mutarotation, described by several workers,lJ6 so that /3-D-fructopyranose, erroneously called a - ~ - fructose,lb is in fact the sweetest of the four cyclic isomers of D-fructose.

11. PREPARATION

For a long time, the inulin-containing Dahlia tuber was the most valuable source for the manufacture of D-fructose, but other important materials have become avaiIable through the cultivation of Jerusalem artichoke,'+21

(8) J. W. White, Jr., and J. Mayer, J . Am. Chem. Soc., 76, 1259 (1959). (9) E. L. Hirst, Proc. Chem. Soc., 193 (1957).

(10) J. S. D. Bacon, Bull. SOC. Chim. Biol., 42, 1441 (1960). (11) T. I. Trunova, Fiziol. Rast., 12, 85 (1965). (12) J. Estienne, France Parfums, 7 , 383 (1964). (13) E. E. Percival, "Structural Carbohydrate Chemistry," J. Garnett Miller, Ltd.,

(14) T. Tsuzuki and J. Tamazaki, Biochem. Z., 323, 525 (1953). (15) R. M. Pangborn and S. C. Gee, Nature, 191, 810 (1961). (16) H. S. Isbell and W. W. Pigman, J . Res. Nutl. Bur. Std., 20, 773 (1938). (17) A. Gottschalk, Nature, 166, 540 (1945). (18) R. S. Tipson and H. S. Isbell, J . Res. Natl. Bur. Std., 66A, 31 (1962). (19) J. Yamasaki, Bull. Chem. Soc. Japan, 27, 375 (1954). (20) P. Vergnaud and J. Pigeot, French Pat. 991,635 (1951); Chem. Abstracts, 60, 9772

(21) E. Magyar, Cukoripar, 7, 25 (1962); Chem. Abstracts, 69, 6601 (1963).

London, 2nd Edition 1962, p. 2.

(1956).


Heliandhus tuberosus,21 and Cichorium intybus LSz2 in the Western hemi- sphere, and of Agave Vera Crux in the tr0pics.2~

The main difficulty in the preparation is still that of crystallization, and the addition of absolute ethanol must be carefully controlled, for an excess results in the formation of white, amorphous material.22 Industrial process- ing of inulin by hydrolysis and further purification is only valuable if the content of D-fructose is sufficiently high (20% for chicory), so the use of cheaper materials, such as sucrose or beet molasses, was r e c ~ m m e n d e d . ~ ~ ? ~ ~

A study by Mendicino, in which he obtained 50% yields of D-fructose from D-glucose by the use of borate solutions, was a first step in the right direction, but his very dilute solutions were impractical for use in technical

However, sodium or potassium aluminates give a 70% isomerization, and the isolation of D-fructose is quite easy?' The optimal temperature lies between 25 and 35") and the reaction time was varied from 56 to 14 hours. The use of invert sugar for manufacture decreased this reaction time to 30 and 8 hours, respectively. The use of such ion- exchange resins as Amberlite IR-120 was tried, but the yield was low (12%) and was difficult to increase.28 Another novel method is the manufacture of D-fructose by fermentation of D-glucitol with Bacillus jruct0sus.~9 The re- covery was quite good (73%) , with a purity of 95%, and crystallization was rapid by virtue of the absence of any D - ~ ~ U C O S ~ in this procedure. A similar method involves the fermentation of sucrose by Tricholoma n u d ~ m . ~ ~ About 80-85% of D-fructose remains in the medium when all of the D-glucose has been utilized, and the mycelium may be removed by filtration and used as a f o ~ d s t u f f . ~ ~ The broth is purified by ion exchange, and crystallization of the D-fructose is promoted by addition of ethanol. Dextransucrase, isolated from the culture liquor of Leuconostoc mesenteroides, may be used for the enzymic treatment of sucrose solutions to give an appreciable

(22) M. Genoe, Dissertation, University of Louvain, Belgium (1961). (23) Council of Scientific and Industrial Research (India), Indian Pat. 51,575 (1955);

(24) J. Wade and H. I. Waterman, Chim. Znd. (Paris), 68, 889 (1952). (25) E. Magyar, Cukoripar, 17, 44 (1964); Chem. Abstracts, 61, 15269 (1964). (26) J. F. Mendicino, J . Am. Chem. Soc., 82, 4975 (1960). (27) E. Haack, F. Braun, and K. Kohler, German Pat. 1 , 163,307; Chem. Abstracts, 60,

(28) H. Hisano, K. Miautani, S. Suauki, a.nd T. Kamei, Japanese Pat. 1997 (1964);

(29) K. Ueda and S. Higashi, Kogvo Kugaku Zasshi, 67, 926 (1964). (30) F. Reusser, P. A. J. Gorin, and J. F. T. Spencer, Cun. J . Microbwl., 6, 17 (1960). (31) J. M. Bell, J. D. Erfle, J. F. T. Spencer, and F. Reusser, Can. J . Animal Sci., 38,

Chem. Abstracts, 60, 592 (1956).

14598 (1964).

Chem. Abstracts, 60, 16471 (1964).

122 (1958).


production of D-fructose, so that the method was patented.33 A sweet sirup of high viscosity is obtained with the same enzyme; it is distinguished from other sirups by its greatly increased purity and its enhanced sweetness, due to the high content of ~-fructose.~~

Purely chemical processes, such as the oxidation of D-mannitol by chlorine, normally result in a mixture of D-mannose and D-fructose, but the ratio can be appreciably shifted in favor of either of these produ~ts.3~ Indeed, prolonged treatment (3-5 days) at low temperatures gives D-mannose in good yield, whereas several short periods ( 1 day) afford D-fructose exclusively. After nine chlorinations of 1 day, at 4 to 20”, 53y0 of the hexitol is oxidized and 490/, thereof is converted into D-fructose. A theoretical yield is afforded by the photochemical oxidation of n-mannitol.36 When a small quantity of D-fructose is added to a much greater amount of zinc oxide and exposed to the effects of air and sunlight, D-mannose and D-fructose are formed in amounts almost proportional to the amount of sunlight. It may be concluded that an effort has been made to find a cheap source for preparation of D-fructose and to lower the production costs by use of easier isolation and purification procedures. Of the various methods presented, the isomerization reaction is certainly the most prom- ising.

111. PHYSICAL PROPERTIES Crystallization of n-fructose is usually effected at ice-box temperature

from an ethanol solution, and further purification and recrystallieation is performed at room temperature. The spherulitic aggregates of fine needles obtained by this technique are those of the hemihydrate, as shown by Young and coworker^.^^ This possibility had been put forward by Honig and Jesser, but sufficient proof was lacking a t that time.37 The “ a n ~ m a I o ~ s ~ ’ x-ray diffraction data reported by Wolfrom and Thompson for their preparation of Lfructose, in comparison with those of the normal form of D-fructose, may be explained by hemihydrate format’ion .38 Indeed, purification with ethanol at 25” results in dehydration, with formation of the

(32) H. J. Koepsell, R. W. Jackson, and C. A. Hoffman, U. S. Pat. 2,729,587 (1956);

(33) J. Corman, H. M. Tsuchiya, and C. S. Stringer, U. S. Pat. 2,742,365 (1956); Chem.

(34) R. Bognar and L. Somogyi, Actu Chim. Acad. Sci. Hung., 14, 407 (1958). (35) B. Marinow, Compt. Rend. Acud. Bulgare Sci., 16, 181 (1963). (36) F. E. YoungJ F. T. Jones, and D. R. Black, J . Am. Chem. Soc., 74, 5798 (1952). (37) M. Honig and L. Jesser, Monatsh., 9, 563 (1888). (38) M. L. Wolfrom and A. Thompson, J . Am. Chem. Soc., 68, 791 (1946).

Chem. Abstracts, 60, 6078 (1956).

Abstracts, 60, 15989 (1956).

234 L. M. 3. VERSTRAETEN

normal, anhydrous prisms of P-D-fructopyranose, m.p. 102-104" and [a]D -132 + -92" (in water) ,ag stable above 21.4" as shown by Young and coworkers.40 The phase relationships of this study brought much new information to explain the properties displayed under laboratory conditions. The most important feature is the tendency of anhydrous D-fructose to change into the hemihydrate below 20" (and even into the dihydrate) . The solubility of the hemihydrate decreases much more rapidly with decreasing temperature than that of the anhydrous form, so that purification is possible by simple recrystallization of the hemihydrate. The needles of the hemihydrate are of the hexagonal system, elongated parallel to the c-axis, and the optical properties and x-ray data have been tabulated.4l

Gel formation was observed during the phase-diagram studies of Young and coworkers; this occurred between -20" (62.5% of D-fructose) and +lo" (78% of D-fructose) . Another translucent gel formed during crystallization from a cold solution in absolute methanol containing some calcium

[a]D -132.2 + -92.4" at 20" and -102.6 -+ -89.2" at44 17", an effect known as thermal mutarotation according to Isbe1L38 The specific rotation at higher concentrations has been m e a ~ u r e d ~ ~ ~ ~ ~ from 10 to 90" at concentrations ranging from 50 to 80%; and the following equation was proposed:

In aqueous solution, D-fructose

[a]D = - (103.45 + 0.141~) + (0.584 + 0 . 7 7 ~ - 0.076~') a t

where p = concentration by weight percentage, a = the optical rotation of the sugar solution, and t = temperature. This equation also fits fairly well for concentrations of 10 to 40%) although this range had already been covered by another, more adjusted equation!' Optical rotation and mutarotation are markedly influenced by the addition of different organic solvents.48 In most cases, the velocity of mutarotation is decreased and the values are shifted to higher ranges; this may be explained by change of

(39) H. S. Isbell and W. W. Pigman, J. Res. Nail. Bur. Std., 20, 773 (1938). (40) F. E. Young, F. T. Jones, and H. J. Lewis, J. Phys. Chem., 66, 1093 (1952). (41) F. T. Jones, F. E. Young, and D. R. Black, Anal. Chem., 26,649 (1953). (42) K. Domove and E. H. Freund, J . Dairy Sci., 43, 1216 (1960). (43) F. J. Bates and Associates, National Bureau of Standards Circular C440,

(44) A. de Grandchamp-Chaudun, Compt. Rend., 240, 973 (1955). (45) Y. Tsuzuki and J. Tamasaki, J . Ant. Chem. SOC., 74, 3237 (1952). (46) Y. Tsusuki, Kogyo Shikensho Hokoku, 49, 445 (1954). (47) C. P. Barry and J . Honeyman, Advan. Carbohydrate Chem., 7,57 (1952). (48) A. de Grandchamp-Chaudun, Compt. Bend., 244, 1564 (1957); 247, 1511 (1958);

Washington, D. C., 1942, p. 399.

Bull. Sac. Chim. Biol., 40, 887 (1958).


the relative concentrations of pyranose and furanose forins at equilibrium. An iIlustration is given in Table I. However, acetic acid and formic acid

TABLE I

Changes in Optical Rotation of n-Fructose Caused by Different Solvents

Solution (2.5%) of D-fructose in degrees Time (hours)

Water

Aqueous solution (20%) of

KC1 ethanol methanol 1-propanol 2-propanol pyridine formic acid0

-102.6 + -89.2

-103.4 -+ -96.2 -115.0 -+ -70.2 -118.0 + -71.5 -108.4 -+ -72.1 -108.2 -+ -71.9 -121.2 + -80.0 -105.0 -+ -60.8

2

~~ ~~~~ ~ ~

a Fructose concentration: 10%.

give rise to esters of D-fructose, as shown by chromatography, and this slow esterification could still be observed after 80 days by a change in optical r o t a t i ~ n . ~ t * ~

The observation that mutarotation of monosaccharides is retarded sig- nificantly by such solvents as N , N-dimethylformamide and methy1 sulfoxide induced Kuhn and coworkers to investigate the pyranose-furanose interconversion more closely.60-61 Indeed, the ml mechanism (normal a-@ interconversion) is completely suppressed in these solvents, and the Isbell conversion (the ma mechanism) can be followed according to the equation:

The initial specific rotation in N , N-dimethylformamide was - 129.5", and the final value (at equilibrium) of -22.4' was only attained after 24 hours. According to methylation studies in the same solvent, 80% of this equilibrium mixture is in the furanose form. In methyl sulfoxide, [ a ] ~ changed from -140" to a value of -21.2' after 180 hours. A more fundamental,

(49) A. de Grandcharnp-Chaudun, Compt. Rend., 262, 1397 (1961). (50) R. Kuhn and H. Grassner, Ann., 610, 122 (1957). (51) R. Kuhn and F. Haber, Chem. Ber., 86, 722 (1953).


kinetic approach to the problem was used by Long and Searsls2 after the observation of Iiononenko and I-Ier~tein~~ that methyl sulfoxide is by far the best, nonprotonogenic solvent for sucrose. Working at 25', Long and Searss2 found [ a ] ~ -140.7' after one hour and -43.1' after 192 hours, buk the value was still decreasing after 8 days. However, assuming the applicability of first-order kinetics, the specific rotation at equilibrium (S.R.)eQ was calculated by means of the following equation:

(S.R.) eq was found to lie within the range of - 10 to -9'. Small variations were found to occur with different concentrations, which explains the difference observed between the two studies. For comparison purposes, the rotation values were quite different in methyl sulfoxide and in aqueous solution, in contrast with other sugars. By means of kinetics and the use of a highly active ~-~-fructofuranosidase,~~ the specific rotation of p-D- fructofuranose was determined to be +1.7', and [a]% -4.58'. These values are very close to the eyuilibrium value in methyl sulfoxide, indicating that, in methyl sulfoxide, D-fructose is almost entirely present in the furanose form.

Phase equilibria in water have been described by Kelly, who studied the effect of hexoses, sucrose, and inorganic salts on each other.55 The conclusion was reached that, for sucrose, the solubility of the second solute influences the composition at the invariant point, but for D-fructose, this effect is zero because of the high solubility of this sugar in water. Viscosity and density have also been evaluated at different temperatures in methyl sulfoxide, and were fitted to appropriate equations by use of least-squares methods.56 The apparent molal volume calculated in this way is in perfect agreement with the theoretical data, whereas the differences for D-glucose and sucrose are 8 and 4%, respectively.

Physical methods have been invoked more and more in order to obtain information concerning the keto structure and to determine properties characteristic of this class of sugar. Ultraviolet and infrared spectroscopy have been used for identification of the free carbonyl group,'*JJ and the latter technique also permits the identification of all 2-ketoses by the

(52) G. E. Long and P. G. Sears, Trans. Kentucky Acad. Sci., 24, 85 (1964). (53) 0. K. Kononenko and K. M. Herstein, J . Chem. Eng. Data, 1, 87 (1956). (54) B. Andersen and H. Degn, Acta Chem. Sand., 16, 215 (1962). (55) F. H. C. Kelly, J . Appl . Chem., 4, 401 (1954). (56) P. G. Sears, W. D. Siegfried, and D. E. Sands, J . Chem. Eng. Data, 9, 261 (1964). (57) N. G. Berl and C. E. Feazel, J . Agr. Food Chem., 2, 37 (1954).


assignment of specific absorption bands to the vibration frequency of the C-2 grouping as a whole.68

At the temperatures commonly used in mass spectrosc~py,~~ this method is only valuable for the identification of such derivatives of n-fructose as the methyl ethers and acetates,eo but permits differentiation of ketoses from a l d o ~ e s . ~ ~

The dipole moment of D-fructose was studied by the heterodyne beat method, with pyridine or p-dioxane as the solvent, and a value of 15 Debye units was obtained,B2 whereas other hexoses showed values in the rangeof 11 to 12.

IV. ESTIMATION

Modern methods of estimation of D-fructose IargeIy depend upon the spectrophotometric determination of a color produced by the interaction of amines or phenols with D-fructose in the presence of a mineral acid. Usually, little specificity is shown by these methods, for aldoses also react to give the final 5- (hydroxymethyl) -2-furaldehyde derivative, but always at a lower rate.

One of the chief methods is based on the formation of a blue color with the diphenylamine reagent147 and the limit of estimation has now been extendeda3 to 1 pg. Studies of the reaction product revealed that two molecules of diphenylamine react with one sugar molecule, and 4 molecules of water are split off 5-(Hydroxymethyl)-2-furaldehyde reacts in exactly the same way, and the presence of chloride ions was found in all isolated products. Other amines (such as methyldiphenylamine, triphenylamine, and carbazole) show the same color formation.a6 From these results, formula (3) was proposed, and confirmed, by Japanese workers.E6

Another interesting reagent is resorcinol, which gives a color described

(58) L. M. J. Verstraeten, Anal. Chem., 36, 1040 (1964); Carbohyd. Res., 1, 481

(59) See N. K. Kochetkov and 0. S. Chizhov, Advan. Carbohydrate Chem., 21, 39

(60) D. C. DeJonph and K. Biemann, J . Am. Chem. Soc., 86,2289 (1963); 86,67 (1964). (61) K. Biemann, H. K. Schnoes, and J. A. McCloskey, Chem. Ind. (London), 448 (1963). (62) M. Mizutani, Osaka Daigaku Igaku Zasshi, 8, 1305 (1956); Chem. Abstracts, 61,9762

(63) H. Liesendahl and H. Schreier, Klin. Wochschr., 33, 590 (1955). (64) El. Thies and G. Kallinich, Chem. Ber., 86, 438 (1952). (65) G. Kallinich and H. Thies, Chem. Ber., 87, 759 (1954). (66) T. Momose, Y. Ueda, and M. Nakamura, Chem. Pharm. Bull. (Tokyo), 8, 827

(1966).

(1966).

(1956).

(1960).


by Roe; it has been slightly modified, and gives very satisfactory results?7*6* For work with biochemical material, more concentrated hydrogen chloride was recommended, and acetic acid was used as the solvent instead of ethanol. This permits the estimation of D-fructose phosphates by measuring the optical density at 515 nm (after correction for the heptuloses according to Dische) .6QJO

An extensive study has been devoted to the orcinol-sulfuric acid reagent, resulting in a highly specific reagent for D-fructose: the test solutions are heated at 100" for only 50 seconds, and 31.2 N acid is ~sed .7~

Other characteristic colors are produced by thymol and 3-methylindole (skatole) . The red color formed with thymol, first mentioned by B a l d e ~ n , ~ ~ is at 505 nm, and the purple color given by the skatole reagent is extracted with chloroform and measured74 at 510 nm. This is time-con- suming, but it stops the reaction and permits readings to be made after any desired time-interval.

The Folin-Denis reagent gives a blue color which may be read75 at 682 nm. A sensitive indole reagent, measured at 470 nm, has a limiP of 1 pg. 3-Indoleacetic acid was proposed as a reagent by Heyr~vsky,?~ but the long time required for attainment of maximum color development makes it of little use for routine laboratory work. 3-Methylindole was also proposed,

(67) G. P. Arsenault and W. Yaphe, Nature, 197, 181 (1963). (68) R. G . Kulka, Biochem. J. , 63, 542 (1956). (69) J. H. Roe and N. M. Papadopolos, J . Biol. Chem., 210, 703 (1954). (70) A. Bonsignori, S. Pontremoli, and E. Grazi, Ciorn. Biochim., 7, I 8 5 (1958). (71) J. Briickner, Biochem. J., 60, 200 (1955). (72) E. R. Baldeon, Actas Trabajos Congr. Peruano Quim., 2, 448 (1949). (73) J. Patmalnicks and S. Gardell, Scand. J . Clin. Lab. Invest., 8, 223 (1956). (74) C. A. De Carvalho and B. M. Pogell, Biochim. Biophys. Ada , 26, 206 (1957). (75) F. J. T. Harris, Analyst, 78, 287 (1953). (76) M. J. Karvonen and M. Malm, Scand. J . Clin. Lab. Invest., 7 , 305 (1955). (77) A. Heyrovsky, Chem. Listy, 60, 1593 (1956); Collection Czech. Chem. Commun., 22,

43 (1957).


but merely as a microtest for identificati~n~~; the addition of 3-indoleacetic acid makes it a useful spray for chromat~graphy.~~

Thiobarbituric acid has also been employed as a reagent, and the reaction, measured at 432.5 nm, is at least 100 times faster than with aldoses in the range of 0.2 to 0.02 pmo1e.sa

Another class of reagents is based on the reductive power of D-fructose and, when used in conjunction with chromatography, a variety of problems can be solved?l In this class, a modified anthrone test gives uniform results through better mixing of the reagents and the use of less concentrated acids2 By making readings at 625 nm, ketoses may be estimateda3 in the presence of aldoses in the range of 2 to 3 mM.

Methyl ethers of D-fructose, difficult to estimate by any other means (especially those having the hydroxyl groups at C-1 and C-3 methylated) , have been estimated by the alkaline 3,5-diNtrosalicylic acid reagent proposed by Bell and coworkers,84 and differentiation of the conformation of these methyl ethers was made possibles6 by the addition of borate to the urea-phosphoric acid spray of Dedonder.

An extremely sensitive test, specific for ketoses, has been described, but its colorimetric adaptation has not yet been made, despite the very promis- ing resultss6; D-fructose (0.3 mg.), boiled for 30 seconds with the zinc complex of toluene-3,4-dithiol in dilute hydrochloric acid, forms an orange precipitate almost immediately. Extraction is readily effected with chloroform, and this might possibly be applied to quantitative estimation.

V. ISOMERIZATION REACTIONS

The Lobry de Bruyn-Alberda van Ekenstein transformation is the basic mechanism for a better understanding of the relationship between ketoses, aldoses, and the degradation products thereof [such as the saccharinic acids, 5- (hydroxymethyl) -2-furaldehyde, and the 3-deoxyglycosuloses].87-go

(78) A. Grauer, Anal. Chim. Acta, 8, 436 (1953). (79) A. Heyrovsky, Biochim. Biophys. Beta, 21, 180 (1956). (80) F. Percheron, Bull. SOC. Chim. France, 1684 (1963). (81) J. E. Hodge and B. T. Hofreiter, Methods Carbohydrate Chem., 1,380 (1962). (82) R. Johanson, Anal. Chem., 26, 1331 (1954). (83) M. A. Jerrnyn, Nature, 177, 38 (1955). (84) D. J. Bell, D. J. Manners, and A. Palmer, J . Chem. Soc., 3760 (1952). (85) D. J. Bell and D. H. Northcote, Chem. Ind. (London), 1328 (1954). (86) R. E. D. Clark and R. G. Neville, J . Org. Chem., 24, 110 (1959). (87) J. Kenner and G. N. Richards, J . Chem. Soc., 1784 (1954). (88) F. Petuely, Monatsh., 84, 298 (1953). (89) H. C. Silberman, J . Org. Chem., 28, 1967 (1961). (90) E. F. L. J . Anet, Chem. Znd. (London), 262 (1962).


Reviews devoted to various aspects of the transformation have already been published in this Series, and are very informative to the reader who desires more experimental ev iden~e .~ l -~~ However, explanation of these transformations and rearrangement reactions proved extremely difficult, and, to the 1,2-enediol, long regarded as the only intermediate, had to be added new enediols and dismutation reactions. Ionization of the enediol was proposed for the sake of clarity and to reach more confident con- c l u s i ~ n s . ~ ~ ~ ~ ~ Enediol formation and the benzilic acid type of rearrangement, as well as fragmentation and disproportionation of the molecule, are found to occur, and must be regarded as basic reactions in carbohydrate chemistry. Various combinations of these four mechanisms are responsible for the several reaction products found.

Scheme I illustrates the interesting position of D-fructose in the sugar series, and the widely differing products obtained in the past few years by treatment with acid or alkali. Only intermediates and end products are given; the reaction conditions are described in the text. Emphasis is placed on D-fructose because of its abundant occurrence in Nature and its rapid conversion into other isomers. The 1 ,Zenediol (c) and its ionized form ( f ) have central positions, indispensable to explaining hexose interconversions in alkaline media?Gg9 The enediolate ion was mentioned for the first time during work on the saccharinic acids,100 and, in 1944, Isbell used this same mechanism during development of his electrondisplacement the0ry.9~

Substance (h), arising from this ionized enediol by p-elimination, has never been isolated, but it is known as the enol form of a 3-deoxyglycosulose and is extremely important in the formation of these compounds and in the acid-catalyzed degradation to 5- (hydroxymethyl) -2-furaldehyde.88J01~10z In- deed, in strong acidic media, the chief product is 5-(hydroxymethyl)-2- furaldehyde, formed by steps (h) and (i) , but compound (j) has also been

(91) J. C. Sowden, Advan. Carbohydrate Chem., 12, 35 (1957). (92) J. C. Speck, Jr., Advan. Carbohydrate Chem., 13, 63 (1958). (93) E. F. L. J. Anet, Advan. Carbohydrate Chem., 19, 181 (1964). (94) H. S. Isbell, J . Res. Natl. Bur. Std., 32,45 (1944). (95) C. H. Bamford and J. A. Collins, Proc. Roy. SOC. (London), Ser. A, 228,100 (1955). (96) D. R. Buchler, R. C. Thomas, B. E. Christensen, and C. H. Wang, J . Am. Chem.

(97) S. Matsushita and F. Ibuki, Mem. Res. Inst. Food Sci. Kyoto Univ., 26, 1 (1963). (98) J. K. N. Jones, J . Chem. SOC., 3050 (1955). (99) F. Schneider, Compt. Rend. Assemblee Cornm. Intern. Tech. Sucrerie, 108 (London),

(100) P. A. Shaffer and T. E. Friedmann, J. Biol. Chem., 86, 345 (1930). (101) G . Machell and G. N. Richards, J . Chem. SOC., 1938 (1960). (102) E. F. L. J. Anet, J . Chromutog., 9, 291 (1962).

SOC., 77, 481 (1955).

32 (1957).


HYOH HOCH HOCH

I

R

@')

HC=O HCOH HCOH H,COH H,COH {I

HOCH HOCH H O ~ H

I I I1 I I I I I

HOCH HOCH I I I I

R

HCOH HCOH = COH &= LOH C=O

1: R R R

6 H I I

R R

(f )

\ HC=O

I COH II CH I

R

r/"k HC=O HC=O

L O &OH I

t!H I ?% R SH (i)

COH I

HC=O I t C0,H

I HCOH

I CH,

I R

(0

(k)

I I where R = HCOH and R' = H OH

HCOH H,COH 'i

I &COH

SCHEME I. For clarity, charges have been omitted from charged atoms.


identified, bringing new evidence that enol (h) must be an inter-

In the formation of 5- (hydroxymethyl)-2-furaldehyde, step (g) may be the most convenient, explaining the more rapid conversion of ketoses into this end product. In alkaline media, the other pathway becomes the more important; the amount of 3-deoxyglycosdoses ( j ) formed is greater, and the reaction proceeds further, by the benzilic acid type of rearrangement, to the corresponding metasaccharinic acid (k) ?2J01

Suitable chromatographic techniques were developed, and isolation of products led to the conclusion that enolization is certainly not restricted to C-1 and C-2. The presence of D-ribo-hexulose in the conversion media, for instance, could be explained only if formation of a 2,3-enediol (1) occur~,99J0~~07 Formation of the saccharinic acid (r) proceeds by the same enol, according to the Isbell mechanism, with @-elimination from (p) to the a-diketone (q) .

Another feature common to all hexoses is their fragmentation to trioses and related products (such as lactic acid, l-hydroxy-2-propanone, and pyruvaldehyde) . 1-Hydroxy-2-propanone is formed by heating a solution of D-fructose in potassium acid phosphate buffer solution of pH 6.7; it was proposed that an intermediary 3,4-enediol (s) rearranges to a pdiketone, which yields (t) by fragmentation of the molecule.108 Studies by Wolfrom and S c h u m a ~ h e r ~ ~ ~ and by Blair and Sowdenllo showed that this mechanism, followed by recombination and aldolization, accounts for some of the observed products. The identification of L-xylo-hexulose and DL-xybhexdose was conclusive in this respect, but deuterium studies by Sowden and Thompson'l' proved the minor role of this recombination mechanism in the transformations.

The following conclusion may be formulated: the intermediary 1,2- enediol is a rate-limiting step in the hexose interconversions, so that the characteristic behavior of D-fructose and its analogs must be due to the easier formation of the 2,a-enediol (1) from intermediate (d), and its direct change to the enediolate (g ) by &elimination.

No evidence has yet been found for the presence of 3-ketoses (0) in

mediate.90,102,103

(103) M. Komoto, Nippon Nogeikagaku Kaishi, 36, 546 (1962). (104) G. Malyoth and H. W. Stein, Angew. Chem., 64, 399 (1952). (105) F. Schneider and G . A. Erlemann, Naturwissenschaften, 39, 160 (1952). (106) J. N. Schumacher, Dissertation Abstr., 20, 1057 (1960). (107) W. W. Binkley, Intern. Sugar J. , 66, 105 (1963). (108) J. Hayami, Bull. Chem. SOC. Japan, 34, 927 (1961). (109) M. L. Wolfrom and J. N. Schumacher, J. Am. Chem. Soc., 77, 3318 (1955). (110) M. G. Blair and J. C. Sowden, J. Am. Chem. SOC., 77, 3323 (1955). (111) J. C. Sowden and R. R. Thompson, J . Am. Chem. SOC., 80, 1435 (1958).


these mixtures, as predicted by Nef,l12 although formation would be simple by way of intermediate (h) . Probably, the expected 3-ketoses are unstable under the conditions employed, so that they may quickly re-form the corresponding 2-ketoses. Similar behavior was noted with a chemically synthesized 3-ketopentose (~-threo-3-pentulose) which was reconverted into the isomeric L-threo-pentulose when methylene protecting groups were rem0~ed. l~~

The importance of isomerization is also demonstrated by a German patent for the manufacture of D-fructose by this route (see p. 232).

VI. IRRADIATION

Most of the work reported on irradiation is concerned with changes in physical properties (such as color formation or ultraviolet absorption), and little emphasis has been placed on isolation and identification of products. An earlier review in this Series on this subject mentioned the difficulties encountered, and gave information concerning the technical po~sibilities.1~4

In the solid state, as well as in aqueous solution, D-fructose is destroyed to a greater extent than any other sugar under the same reaction conditions.ll6 Proton magnetic resonance studies showed a characteristic spectrum for the irradiated D-fructose, so that it might be used for identification of the sugar,116 but a nearly identical spectrum displayed by L-sorbose indicates that, through some specific, free-radical formation, the 2-keto grouping may be responsible. Additional evidence was gained by an electron spin resonance study of irradiated, single crystals of different ~ u g a r s . l ~ ~ J ~ *

In solutions under vacuum, absorption maximum at 265 nm is shown after treatment with ionizing but no explanation was apparent until the work of Phillips and coworkers, who proved that 1 ,3dihydroxy- 2-propanone must be responsible for this absorption.120 Indeed, irradiated D-glucose solutions display this same absorption, and the formation of

(112) J. U. Nef, Ann., 376, 1 (1910). (113) A. Sera, Bull. Chem. Soc. Japan, 36, 2033 (1963). (114) G. 0. Phillips, Advan. Carbohydrate Chem., 16, 46 (1961). (115) M. L. Wolfrom, W. W. Binkley, L. J. McCabe, T. M. Shen Han, and A. M.

(116) D. Williams, J. E. Gensic, M. L. Wolfrom, and L. J. McCabe, Proc. Natl. Acad.

(117) H. Ueda, J. Phys. Chem., 67, 966 (1963). (118) H. Ueda, J . Phys. Chem., 67, 2185 (1963). (119) M. A. Khenokh, Dokl. Akad. Nauk SSSR, 104, 746 (1955). (120) G. 0. Phillips, G. J. Moody, and G. L. Mattock, J . Chem. SOC., 3522 (1958).

Michelakis, Radiation Res., 10, 37 (1959).

Sci. U. S. , 44, 1128 (1958).


1,3-dihydroxy-2-propanone was verified. (Oxygenated solutions show a maximum at 287 to 295 nm.)

An extensive study devoted to the effect of 6oCo gamma radiation on aqueous solutions of D-fructose revealed something about the primary and secondary degradation products, the latter being formed by simple transformation of the primary products.121 Differentiation was made possible by following the yield-dose curves for the main products, which were isolated and identified by paper chromatography and radioactive tracer methods. Scheme 11, showing all primary degradation products, explains the relationship between these compounds, and gives their possible mode of formation.

H,COH HCOH I I

c = O COH I I

HC=O HC =O

k) 04 + +

HC=O H,COH I - 1

HCOH --.---. c=o I I

H,COH H&OH

(e ) (f)

t t C0,H HJOH HC=O

I I c=o c=o c=o

I I I

I I I HCOH HCOH HCOH HCOH

I I I I c=o HCOH HCOH HCOH I I I I &COH H&OH H,COH H,COH

HO&H

HOCH - HOYH ~ HOCH HOAH

H,COH HC=O C0,H I I I

HC=O HC=O C0,H

(i) + Z

where Z = four-carbon fragments.

SCHEME 11. For clarity, charges have been omitted from charged atoms.

(121) G. 0. Phillips, J . Chem. SOC., 754 (1960).


The great reactivity of primary hydroxyl groups on oxidation,lzZ not only by chemical reagents but also by the free radicals formed during irradiation, had been mentioned ; the great sensitivity of D-fructose is in striking contrast to the absolute resistance of L-rhamnose, and may be explained by this mechanism.12s Scheme I1 also explains the primary formation of ~-~yxo-5-hexulosonic acid (b) , D-arabino-hexulosonk acid (d) , and D-arabino-hexosulose (D-glucosone) (c) .lZ1 Breakdown of the molecule between C-2 and C-3 is responsible for the appearance of glycolaldehyde (i) and related products, whereas symmetrical splitting gives glycerosdose (9) and 1,3-dihydroxy-2-propanone (f). Lower products, which are mainly formed at higher doses of radiation and by secondary transformation, include formic acid, formaldehyde, and carbon dioxide. Formation of formaldehyde is readily demonstrated.lZ4

Quite similar results have been described for the action of ultrasound on D-fructose solutions. After two hours, an absorption maximum was ob- served126 at 283 nm, probably showing the formation of reductone, as mentioned by Phillips. An effect on the specific rotation was also noted, but this was much less than that observed during some irradiation studies.lZ6 An x-ray investigation proved that at least 15% of the parent sugar is changed to other products, but isolation of the products has not yet been attempted.lZ7

VII. ACETALS

Condensation of D-fructose with dry acetone or benzaldehyde affords cyclic a~etals.~’ The same procedure with cyclopentanone, with concentrated sulfuric acid as the catalyst and stirring at room temperature for some 40 hours, gave a sirupy product which was characterized by its p- tolylsulfonyl derivative.lZ8 Cyclohexanone yielded a crystalline product of m.p. = 142”, readily isolated and purified. For the acetal, structure (4) was proposed from the results of attempted oxidation with potassium permanganate, lack of any reaction indicating that C-1 is involved in an acetal. The same compound was described during the structural investigation of a glucofructan of the Hawaiian “Ti” plant.lZ9 The results, based

(122) G. Binder and A. Vincze, Magy. Tud . Akad. Kozp. Fiz . Kut. Int. Kozlemen., 6,

(123) A. Nishmura and K. Takaoka, Hakko Kogaku Zasshi, 38, 518 (1960). (124) M. A. Khenokh, Dokl. Akad. Nauk SSSR, 128, 1957 (1958); 131, 684 (1960). (125) M. A. Khenokh, Dokl. Akad. Nauk SSSR, 97, 871 (1954). (126) D. Buchner, 2. Zuckerind., 11, 197 (1961). (127) G. Geissler, 2. Lebenm.-Untersuch. EIorsch., 126, 452 (1964). (128) M. M. Micovic and A. Stojiljkovic, Tetrahedron, 4, 186 (1958). (129) L. A. Boggs and F. Smith, J . Am. Chem. Soc., 78, 1880 (1956).

364 (1957).


on methylation studies, gave additional evidence for the proposed structure. 1 , 2-O-Cyclohexylidene-3,4 , 6-tri-O-methyl-~-fructose was also prepared (map. 101’) ; it proved useful in structural analysis, as the corresponding isopropylidene acetal is a sirup.

Catalysis by cation-exchange resins was used for the rapid formation of the 1,2:4 , 5di-0-isopropylidene acetal.130 Working at room temperature and with dry acetone, a 40% yield was obtained in less than 24 hours, and only trace amounts of the mono derivative were observed.

This ease of synthesis of cyclic acetals makes them appropriate for the preparation of certain well-defined, mono-substituted esters of different origin. 2 , 3 : 4 , 5-Di-O-isopropylidene-P-~-fructopyranose has been used for the synthesis of certain phosphoramidate compounds.131 The acetal is dissolved in 20 ml of toluene and refluxed for 6 to 8 hours in the presence of phosphoramidic chloride. The sirupy 1-[N , N-bis- (2-chloroethyl) phosphoramidic chloride] (5) is then used for the preparation of other derivatives, such as the phosphoramidate itself. Hydrolysis with ethanolic hydrogen chloride removes the isopropylidene groups and results in the formation of ethyl 0-D-fructopyranoside 1-[N , N-bis- (2-chloroethyl) phos- p horamidate] .

A Me Me

(130) K. Erne, Acta Chem. Scand., 9, 893 (1955). J. E. Cadotte, F. Smith, and D.

(131) K. M. Vagi, V. W. Adamkievicz, and T. Nogrady, Can. J . Chem., 40,1049 (1962). Spriestersbach, J . Am. Chem. Soc., 74, 1501 (1952).


The acid-catalyzed addition of such olefins as isobutylene to the hydroxyl group at C-1 was also studied.la2 After 24 hours in a bomb at loo", the sirupy 1-0-isobutylene derivative was obtained in 58% yield. A similar product was formed during treatment of the acetal with ethane and nitrogen in a bomb at 150 to 160". The resulting vinyl ether had133 m.p. 4345".

Ester formation of the two di-0-isopropylidene acetals with stearic acid was performed in the molten state (at 180-200") under vacuum. This in- dustria1 process gave two products having almost identical melting p0ints.13~

VIII. GLYCOSIDES

A simple preparation of pure methyl p-D-fructofuranoside has been described135; earlier syntheses had given a l p mixtures of unknown compo- ~ i t i 0 n . l ~ ~ A solution of sucrose (0.2 M ) in anhydrous methanol was refluxed for 1 hour in the presence of dry Dowex-50 (H+), with constant stirring. After evaporation of the solution under vacuum, the resulting sirup was purified on a Dowex-1 (borate) column, and the chromatographically pure methyl D-fructoside showed [ a ] ~ - 60 =t3" (in water); this value agrees with the value of -552" predicted by Purves and Hudson.lS6

For ethyl D-fructofuranoside, both anomers are formed in small proportion during the hydrogenolysis of sucrose in ethan01.l~' When the reaction was performed at 100" in an atmosphere of argon, considerable quantities were obtained. Ethyl p-D-fructofuranoside, [ a ] ~ -36' (in water) , is readily hydrolyzed to D-fructose by invertase (and also by 0.1 N sulfuric acid) at room temperature. The same behavior was observed for a substance isoIated from wheat germ.la* Acetylation yielded a sirupy product, but treatment with trityl chloride gave crystalline methyl 1 , 6-di-O-trityl-~- fructoside (m.p. 180-183'). With p-toluenesulfonyl chloride, a crystalline product is obtained, with m.p. 125-127". Ethyl a-D-fructofuranoside ( [ a ]~ +65", in water) is not attacked by invertase. Tritylation, followed by acetylation, gives ethyl 3 , 4-di-0-acetyl-1 , 6-di- 0-trityl-a-D-fructofuranoside; m.p., 142-144' and [ a ] ~ $44.5' (in chloroform).

Benzyl a-D-fructofuranoside was synthesized, and obtained in pure form, by the addition of zinc bromide (as the catalyst) to a solution of the corre-

(132) V. Prey and F. Grundschober, Chem. Ber., 96, 1845 (1962). (133) W. Reppe, Ann., 601, 81 (1956). (134) K. Knoevenagel and R. Himmelreich, German Pat. 1,183,895; Chem. Abstracts,

(135) A. E. Horvath and R. L. Metzenberg, Biochim. Biophys. Ada, 74, 165 (1963). (136) C. B. Purves and C. S. Hudson, J . Am. Chem. Soc., 66, 702 (1934). (137) H. R. Goldschmid and A. S. Perlin, Can. J . Chem., 38, 2178 (1960). (138) A. Moreno and C. E. Cardini, Arch. Biochem. Biophys., 108, 361 (1964).

62, 9227 (1965).


sponding ortho ester1aB (see p. 249). This synthesis affords a preparative- scale method for a compound hitherto obtained from the corresponding methyl ~-fructoside.l~~ Hydrolysis by invertase was still needed to eliminate the /3-D anomer.

p-Hydroxyphenyl p-D-fructofuranoside has been synthesized by enzymic transglyc~sylation~~~~~~~; it has m.p. 119" and [.ID - 120°, and analysis of its infrared spectrum suggested that it was the furanose form. Further evidence in support of this conclusion has since been gained.60

IX. ORTHO ESTERS

A new series of crystalline orthobenzoates has been synthesized, and the ease of preparation, as well as their crystallinity, makes them very useful for identification rea~tions.l~gJ~~ The corresponding ortho acetates had been prepared by P ~ C S U , ' ~ ~ and their structure was discussed in this Series.145 1 , 3,4 , 6-Tetra-O-benzoyl-/3-~-fructose was converted'43 into the bromide ( 6 ) by passing hydrogen bromide through a solution of the ester in dry benzene. After a time, excess hydrogen bromide was expelled with a stream of warm air, and the resulting derivative ( 6 ) was treated with benzyl alcohol, Drierite, and zinc oxide. Evaporation of the solution under vacuum yielded crystalline 2,3-0-(benzyloxybenzylidene)-tri-0-benzoyl-~-frcto- furanose (7). Saponification with sodium methoxide gave the free ortho ester. Exchange of the benzyl group with another alkyl group is easily effected by dissolving (7) in dry p-dioxane and adding the corresponding alcohol with a trace of acid, to give the new ortho ester after a 20-minute reaction at room temperat~re. '~~J~s Suitable derivatives could be prepared to prove the structure. Thus, the ortho ester linkage at C-2 and C-3 was ascertained by the following reaction sequences. (1) Treatment of the free ortho ester with methanesulfonyl chloride in pyridine yields a tri-O-(methylsulfonyl) derivative which is converted into a 2,3-0- (benzyloxgbenzylidene) -6-deoxy-6-iodo-di-O-( methylsulfonyl) -~-fructofuranose (8) by heating with acetone and sodium iodide at 95-100". This means that the 2,g-diester may be ruled out. (2) The alcohol group is split off by adding calcium chloride, and a new ortho ester (P), linked

(139) B. Helferich and W. Schulte-Hiirmann, Chem. Ber., 87, 977 (1954). (140) C. B. Purves and C. S. Hudson, J . Am. Chem. SOC., 69, 49 (1937). (141) S. Nakamura, T. Miwa, and M. Takeshita, Koso Kagaku Shimpoziumu, 16, 46

(142) S. Nakamura and T. Miwa, Nature, 202, 291 (1964). (143) B. Helferich and L. Bottenbruch, Chem. Ber., 86, 651 (1953). (144) E. Pacsu, J . Am. Chem. SOC., 67, 745 (1935). (145) E. Pacsu, Advan. Carbohydrate Chem., 1, 90 (1945). (146) R. K. Ness and H. G . Fletcher, Jr., J . Am. Chem. SOC., 78, 1001 (1956).

(1962); Chem. Abstracts, 61, 8558 (1965).


to three different hydroxyl groups of the sugar molecule, is formed. The di- 0- (methylsulfonyl) derivative cannot be transformed into a deoxy-iodo- D-fructose, so that the lI2,3-triester is ruled out, and, at the same time, it may be concluded that the original ortho ester was the 2,3-(benzyl orthobenzoate) .

When the ortho ester (7) is treated with benzyl alcohol and fused zinc bromide, benzyl 1,3 ,4 , 6-tetra-O-benzoyl-cr-~-fructofuranoside (10) is formed; this is readily saponified to the free fructoside (11).

I BzO

I BzO

BzOH.$Q H,OBz

OCH,C,H, I

€320 HO

These experimental facts are illustrated in formulas (6) to(l1) and, according to the opposite-face concept of the Walden inversion, discussed by Isbell and Frush, several structural assignments can be made.147,148 The formation of an a-D-fructoside and the 2 , 3 , 6-tri-(ortho ester) corroborates

(147) H. L. Frush and H. S. Isbell, J. Res. Nutl. Bur. Std., 27, 413 (1941). (148) H. S. Isbell and H. L. Frush, J . Res. Nutl. Bur. Std., 43, 161 (1949).


the evidence for a @-D configuration for the intermediate orthobenzoate, which must, in turn, have been formed from an a-D-bromide; this is con- trary to the reported data, but is in agreement with a previous synthesis.149 In addition, although C-1 of the 2-ketoses is free to rotate about the carbon- carbon bond, and the acetoxy or benzoxy groups can be brought into position for the intramolecular reaction, all D-fructose ortho esters so far prepared have this same 2,3 structure. This means that effects of an unknown nature play a part in the mechanism. The interatomic distances may cause this strange behavior, just as the intermolecular forces in solution may have a certain influence on the shape of the molecule, as demonstrated by a comparison of the D-fructofuranosyl moiety in sucrose and in sucrose sodium bromide dihydrate.160J51 More, fundamental work is needed in this field, to permit firmer conclusions to be drawn; crystal- structure analysis of the ortho esters would be especially useful.

X. ESTERS

1. Acetates

A most important theoretical study was presented by H e ~ u i g l ~ ~ on the possible reaction-mechanisms involved in the formation of cyclic and keto derivatives during acetylation (see Scheme 111). When 1 mole of 3,4,5- tri-0-acetyl-1 , 6-di-O-trityl-keto-~-fructose (a) is treated at room temperature with two moles of acetyl bromide in acetic anhydride, 1 ,3 ,4 , 5-tetra- 0-acetyl-/3-D-fructopyranose (e) is obtained in 3040% yield. If the same reaction is performed a t 70°, a fully acetylated product, keto-D-fructose pentaacetate (b) is obtained in 50% yield; it is also obtained by treatment of the cyclic derivative (e) with acetyl bromide. This leads to the conclusion that substance ( e ) is a simple intermediate in the preparation of the keto esters. However, this is not so; and proof was obtained by the use of other reaction-conditions which prevented hydrolysis of the labile acetylated bromide (d) , which might be formed during the reaction. When D-fructopyranose pentaacetate ( g ) is treated with acetyl chloride in acetic anhydride, (d) is again obtained; acetyl chloride in chloroform gives the acetylated chloride (d) , expected by theory. Perchloric acid as the catalyst gives additional proof that substance (e) is not the intermediate, because treatment of substance (e) therewith gives the corresponding pentaacetate (g), whereas (a) gives the keto derivative (b). (149) F. Klages and R. Niemann, Ann., 639, 185 (1937). (150) G . A. Jeffrey and R. D. Rosenstein, Aduan. Carbohydrate Chem., 19, 11 (1964). (151) G . M. Brown and H. A. Levry, Science, 141, 921 (1963). (152) I. Hennig, Chem. Ber., 86, 770 (1953).

D-FRUCTOSE AND ITS DERIVATIVEG 251

CKOTr CH,OAc 1

I I L O c=o

AcOYH Ac,O/AcBr at 70" AcOCH

H OAc

H OAc d HYOAc HClO,/AcBr

HCOAc 7 I CH,OTr CH,OAc

1 A c t F 1 ":"" 1 - HCOAc - HCOAc

HCOAc HCOAc HCOAc

H,CO H,CO H,CO

( 4 (4

AcaO,A\ /(e) Ac,O HCIO,

Ac,O/HC10, ZnC1,

I at 100" HFOH HCOAc

H,CO H,CO

(0 k) where R = Br or C1.

SCHEME III

A new conclusion emerges from these facts: compounds ( g ) and (d) are possible intermediary products. But, substance (g) has never been isolated, and treatment of (a) and ( g ) together results in a greater proportion of (e), but n-fructose pentaacetate can still be identified. The role of the acetylated D-fructosyl bromide could be clearly demonstrated by the addition of three moles of acetyl bromide per mole, giving the theoretical amount of trityl bromide and the corresponding halide. This reaction gave


6&7070 of the tetra-O-acetyl-P-D- fructopyranose derivative. The mode of reaction can be explained by the formation of some sugar anion (c) , which may be stabilized in two different ways: (i) by ring-closure (at room temperature), and (ii) by acetate formation (at 70"). This mechanism was later used by Helferich to obtain cyclic acetates having a free anomeric hydroxyl group by slightly changing the reaction mixture.153 Indeed, acetylation with acetic anhydride and sulfuric acid between 0 and 5", and treatment of the solution with hydrogen bromide and, subsequently, with sodium acetate, resulted in a 55-60% yield of 1,3,4,5-tetra-O-acetyl-fi-~- fructopyranose. The same acetate was also prepared by an ion-exchange methodIU; the yield was not very high, but, at least for preparative work, the technique is useful because of its simplicity.

The use of zinc chloride in acetylating mixtures was studied by Hudson and B r a u n ~ ' ~ ~ in trying to obtain both anomers; instead, keto-D-fructose pentaacetate was formed. The same derivative was obtained on using a fused melt of several cyclic acetates of D-fructose and zinc chloride.156 Yields as high as 20-25% resulted from D-fructose tetra- and penta-acetates, even after reaction for only 40 seconds. Fully acetylated products are obtained in high yield (75%) with perchloric acid as the catalyst.157 By the same method, D-fructofuranose pentaacetate (a liquid having [ a ] ~ +38.3" in chloroform) was synthesized for the first time in a yield of 62y0. Proof of its structure was obtained by acetylation of 2 ,3 ,4-tri-O-acetyl-1 , 6-di-0- trityl-D-fruc tof uranose and by ultraviolet spec t r o s ~ o p y . ~ ~ ~ J ~ * Indeed, the absorption in the ultraviolet reveals not only the carbonyl group, but also a characteristic absorption for the furanoid in contrast with the pyranoid structure. Now that even anomers of the tetraacetates can be separated by high-vacuum distillation, this technique, as well as infrared spectroscopy, is a valuable tool in the assignment of structure and composition.159 By acetylation of D-fructose oxime, two isomeric hexaacetates are obtained having the following constants (A) m.p. 101" and [ a ] ~ +78.6"; and (B) m.p. 157" and [ a ] ~ +4.0" (in chloroform). Derivative A has the keto structure as found experimentally : (1) keto-D-fructose pentaacetate, treated with hydroxylamine and the product subsequently acetylated, gives substance A; (2) 3,4,5-tri-O-acetyl-l , 6-di-0-trityl-keto-D-fructose oxime (see p. 257) also gives substance A on acetylation. However, compound B has,

(153) B. Helferich, Chem. Ber., 91, 1794 (1958). (154) G. M. Christensen, 6. Org. Chem., 27, 1442 (1962). (155) C. S. Hudson and D. H. Brauns, J . Am. Chem. Soc., 37, 2736 (1915). (156) H. Bredereck and G. Hoschele, Chem. Ber., 86, 1286 (1953). (157) H. Bredereck, Chem. Ber., 91, 515 (1958). (158) H. Bredereck, G. Hoschele, and W. Huber, Chem. Ber., 86, 1271 (1953). (159) H. Bredereck and G. Hoschele, Chem. Bey., 86, 47 (1953).


instead, a cyclic form, for it was obtained from the furanose pentaacetate described on p. 252) , and confirmation was afforded by an infrared study.lBO

Synthesis of 1-0-acetyl-D-fructose was first achieved by Kuhn and coworkers.lB1 l-Amino-ldeoxy-D-fructose was treated with nitric acid, and the product was dissolved in glacial acetic acid at -15' and treated with isoamyl nitrite. The resulting 1-0-acetyl derivative (m.p. 123-133') was obtained in 25% yield. Definite proof of its structure was not given, but the optical rotation of -67.7' (in water) and the mutarotation, - 82 + - 11 ' (in N ) Ndimethylformamide) , suggests that the product is probably the p-D-pyranose form. Esterification of the primary alcoholic group has also been achieved by the use of 50% acetic acid at lOO", and, since C-6 takes part in ring formation, the reaction is restricted to C-1 of the ketoses. However, no physical constants were reported . IG2

2. Other Esters

Four different mono-esters are formed on heating D-fructose with malic acid, according to which carboxyl group reacts with either of the primary hydroxyl groups. It is known that primary hydroxyl groups are more reactive than secondary hydroxyI groups toward acylation and alkylation, and, if the reaction time is short, the primary derivatives may be isolated.163 The four products have been identified, but only D-fructose 6- (a-hydrogen malate) has been obtained in crystalline form (m.p. 118') .lB4 Interaction between D-fructose and malic acid had been studied earlier, to find if there was any effect on nonenzymic browning, but this ester formation was pre- sumably overlooked.166

An entirely different ester is D-fructosyl phosphate, both ring forms of which, (14) and (15), were synthesized, isolated, and identified.'68 Im- portant as a possible intermediate in the biochemical synthesis and breakdown of the fructans, the pyridine saIt of the l-phosphate (12) was treated with dicyclohexylcarbodiimide, to form the cyclic 1 ,&ester (13) , which is very labile and is hydrolyzed to a mixture of both forms, (14) and (15), of the 2-phosphoric ester.IB7 This cyclization mechanism was first mentioned by Khorana and coworkers,la8 and later confirmed.'"JB7 Separation was effected (160) H. Bredereck, Chem. Ber., 89, 1532 (1956). (161) R. Kuhn, G. Kriiger, and A. Seelinger, Chem. Ber., 93, 1447 (1960). (162) R. B. Duff, J. Chem. Soc., 4730 (1957). (163) F. D. Cramer, Methods Carbohydrate Chem., 2 , 244 (1963). (164) D. L. Ingles and T. M. Reynolds, Australian J . Chem., 12, 483 (1959). (165) G. E. Livingston, J. Am. Chem. Soc., 76, 1342 (1953). (166) H. G. Pontis and C. L. Fischer, Biochem. J . , 89, 452 (1963). (167) R. Piras and E. Cabib, Anal. Chem., 36, 755 (1963). (168) H. G. Khorana, G. M. Tener, R. S. Wright, and J. G. Moffatt, J. Am. Chem. Soc.,

79,430 (1957).


by chromatography, and the pyranose form was isolated as the barium salt, whereas the furanose form was obtained as the sodium salt. According to their molecular rotation, both isomers have the /3-D configuration. The results show that, after cyclization and subsequent hydrolysis, the D-fructosyl phosphate is highly favored by the reaction conditions.

XI. ETHERS

1. Methyl Ethers

Methylation is still conducted in much the same manner as previously, except that the use of such solvents as N ,N-dimethylformamide and methyl sulfoxide is widely accepted; it results in higher yields and in conformational c h a n g e ~ . l ~ ~ J ~ ~ For example, the furanose ethers are formed when N , Ndimethylformamide is used as the solvent during the methylation of D-fructose, and most of the reducing monosaccharides are now methylated at room temperature in one step."' Many of these ethers have already been described in this Series,47 fundamental structure-analysis being based on the identification of the different methyl derivatives, but the ones that were then missing and which have since been synthesized are discussed below.

a. 1,3,4,6-Tetra-O-methyl-~-fructose.-This ether was first synthe-

(169) R. Kuhn, H. Trischmann, and I. Low, Angew. Chem., 67, 32 (1955). (170) H. C. Srivastava, S. N. Harshe, and P. P. Singh, Indian J . Chem., 1, 304 (1963). (171) H. G. Walker, Jr., M. Gee, and R. M. McCready, J . Org. Chem., 27, 2100 (1962).


sized by permethylat i~n.~~~ The 3 , 4 , 6-tri-0-methyl derivative was dissolved in absolute ether, and sodium metal and dimethyl sulfate were added. Methyl 1 ,3 ,4 ,&tetra-O-methyl-~-fructoside was formed in 78% yield as a sirup having [.ID +39.7" (in chloroform); hydrolysis gave the title compound, of [ a ] ~ +30' (in chloroform), in perfect agreement with the literature. Use of other alkali metals (potassium and cesium) gave the same

b. 1,3,4-Tri-O-methyl-~-fructose.-This sugar was isolated174 in 1931, and definite proof of its structure was given; but it was not synthesized from D-fructose. In the following reaction sequence, Hirst and coworkers176 synthesized the sugar. Methyl l-O-p-tolylsulfonyl-D-fructofuranoside + methyl l-O-p-tolylsulfonyl-6O-trityl-D-fructofuranoside + methyl 1 , 3,4- tri-0-methyl-6-O-trityl-D-fructofuranoside -+ 1 , 3 , 4-tri-O-methyl-~-fructofuranose [m.p. 75"; [a]. -56.2' (in chloroform)].

c. 1,4,5-Tri-O-methyI-~-fructose.-This ether was aIso prepared and described by Hirst and c0workers.l7~ Preferential hydrolysis of the known 2 , 3 :4 , 5di-O-isopropylidene-~-fructose gave the 2 , 3-O-isopropylidene acetal. Acetylation, foIlowed by methylation and hydrolysis, yielded a sirup having [ a ] ~ -143" (in chloroform) and TAD 1.4772. The specific rotation clearly indicates that it is most probably the p-D anomer. A crystalline phenylosazone (m.p. 66-67") was prepared; it proved to be identical with the osazone of the 4 , 5dimethyl ether.

d. 1,4,6-Tri-O-rnethyl-~-fructose.-l, 2:4,5-Di-O-isopropylidene-~- fructose was used by T. N. Montgomery in preparing a trimethyl ether assigned this ~onstitution,'~6 although only an optical rotation was recorded, and this was different from the ones described by other workers. Hirst and coworkers176 used the same derivative, but protected the hydroxyl group at C-3 with a p-tolylsulfonyl group. Hydrolysis was followed by glycoside formation and methylation. Removal of the p-tolylsulfonyl group gave the trimethyl ether. Its structure was mainly proved by oxidation with nitric acid to 4 , 6-di-O-methyl-~-arabino-hexulos-l-onic acid [m.p. 107-108", and [ a ] ~ +18.4" (in water)].

e. 3,4,6-Tri-O-methyl-~-fructose.-synthesis~~~ of this sugar started from 2 , 3 :4 , 5-di- 0-isopropyfidene-D-fructose, which was converted into the

(172) H. Bredereck and 0. Muller, Chem. Ber., 93, 1246 (1960). (173) H. Bredereck and E. Hamlsch, Chem. Ber., 87, 38 (1954). (174) H. Hibbert, R. S. Tipson, and F. Brauns, Can. J . Res., 4, 221 (1931). (175) E. L. Hirst, W. E. A. Mitchell, E. E. Percival, and E. G. V. Percival, J . Chem.

(176) T. N. Montgomery, J . Am. Chem. SOC., 66, 419 (1934). SOC., 3170 (1953).


1- O-p-tolylsulfonyl derivative. Hydrolysis and subsequent methylation gave the desired product. Characterization was achieved by oxidation to 3 ,4 , 6-tri-O-methyl-~-arabino-hexulos-l-onic acid, and by further treatment with barium permanganate, to give 2 , 3 , 5- tri-0-methyl-~-arabinono-l,4- lactone.

f. 3,4-Di-O-methyl-~-fructose.-The physical constants recorded by McDonald and Jackson177 were confirmed. Synthesis was perf0rmedl7~ by two different reaction routes, but only the more interesting will be described. 2 , 3-O-Isopropylidene-1 , 6-di-O-ptoly~s~fonyl-~-fructose was hydrolyzed and, after glycoside formation, the resulting methyl 1 , 6-di-O-p-tolyl- su~fony~-~-fructoside was methylated and then saponified, to give methyl 3,4-di-O-methyl-~-fructoside; this gave the desired ether on hydrolysis. Characterization was effected by oxidation with sodium periodate and bromine water, followed by amide formation to give (-)-dimethoxy- succinamide [m.p. 275-276"; [.ID - 132" (in water)].

g. 4,5-Di-O-methyl-~-fructose.-This crystalline ether [m.p. 104- 105"; [ a ] ~ -167" (in water)] was prepared from 1 ,2:4,5-di-O-isopropylidene-3-O-p-toly~sulfony~-~-fructose, the 4 , 5-acetal group being split off by preferential hydrolysis. Methylation of the product, followed by reduction and subsequent hydrolysis, gave the desired ether. A crystalline phenylosazone (m.p. 67-68"> and a (2,5-dichlorophenyI) hydrazone (m.p. 102O) thereof were also prepared.

h. l-O-methyl-D-fructose.-Ohle prepared this ether as a sirup,178 and it was always obtained in this form until, in 1954, Bayne and WildylTg obtained it as crystals; the constitution was confirmed by preparation of the di-0-isopropylidene acetal. Reduction yielded the corresponding 1-0- methyl-D-mannitol; and the crystalline phenylhydrazone melted at 133".

i. 4-O-Methyl-~-fructose.-McDonald and Jackson'77 described this sirupy ether, and identified it by its crystalline phenylosazone. Hirst and cow0rkersl7~ methylated 2 , 3-O-isopropylidene-1 , 6-di-O-ptolylsdfonyl-~- fructose, and reduction and hydrolysis of the product yielded the same sirupy sugar (16). Characterization was achieved by oxidation with sodium periodate and bromine water. Conversion into the methyl ester gave a sirup ( 17) which, after treatment with methanolic ammonia, yielded crystalline D-threo-2-hydroxy-3-methoxysuccinamide ( 18), m.p. 198-200".

(177) E. J. McDonald and R. F. Jackson, J . Res. Natl. Bur. Std., 24, 181 (1940). (178) H. Ohle, Ber., 68, 2577 (1925). (179) S. Bayne and J. Wildy, J . Chem. Soc., 1147 (1954).


HC=O CO COOMe c o w I

HOYH I I I

HTH __c HOYH I HOYH -

HCOMe I

HCOMe HCOMe HCOMe

HC=O CO,H COOMe I 1

HCOMe I

(16) (17) (18)

2. Trityl Ethers

1- 0-Trityl-D-fructose, previously prepared by Helferich and Bredereck,l80 and already described:' has been re-investigatedlS1; its tetraacetate was also studied. The identity of the ether was confirmed by treatment of l-0-trityl-keto-D-fructose tetraacetate with phosphorus pentachloride, resulting in formation of l-chloro-l-deoxy-keto-D-fructose t e t r a a ~ e t a t e . ~ ~ ~ . ~ ~ ~ A second proof was furnished by the following reaction sequence: 1-0- benzoyl-2 , 3 : 4,5-di-O-isopropylidene-~-~-fructopyranose + 1-0-benzoyl-p- D-fructopyranose + 1-0-benzoyl-keto-D-fructose tetraacetate. Benzoylation of keto-D-fructose tetraacetate gave the same reaction product.

Bredereck and coworkers184 also studied the 1,Mitrityl ether, and definite proof of its structure was afforded by an outstanding series of experi- ments. The amorphous material (m.p. 94-96') was treated with the ordi- nary acetylation mixture, and yielded 3 , 4,5-tri-O-acetyl-l, 6-di-O-trityl- keto-D-fructose. Preparation of the oxime followed by further acetylation gave the crystalline acetate of the oxime [m.p. 207-208'; [ a ] ~ +118' (in chloroform) ].l84 The oxime of l,&di-o-trityh-fructose affords the same product on acetylation. The keto form was proved by formation of the crystalline diethyl dithioacetal from the acetyl derivative.

Another crystalline material (m.p. 165'), probably the furanoid form, was obtained when sodium acetate and acetic anhydride were used for acetylation of 1,6-di-O-trityl-D-fructOse, and treatment of the product with hydroxylamine resulted in splitting of one acetyl group. A monotrityl (m.p. 150-153") and a ditrityl ether (m.p. 221-226") were prepared from 2 , 6-anhydro-p-D-fructofuranose during the work of Goldschmid and

(180) B. Helferich and H. Bredereck, Ann., 466, 166 (1928). (181) H. Bredereck and W. Protser, Chem. Ber., 87, 1873 (1954). (182) M. L. Wolfrom, S. W. Waisbrot,, and R. L. Brown, J . Am. Chem. Soc., 64, 1701

(183) M. L. Wolfrom, S. W. Waisbrot, and R. L. Brown, J . Am. Chem. Soc., 66, I516

(184) H. Bredereck, I. Hennig, and H. Zinner, Chem. Ber., 86, 476 (1953).

(1942).

(1943).


Perlin,137 but a definite structure was not given. During the same work, both anomers of ethyl D-fruchfuranoside were treated with chlorotriphenyl- methane. Only the P-D anomer gave a crystalline 1, Bdi- O-trityl derivative. The positions of the ether groups were determined by periodic acid oxidation, and, in both cases, one mole was consumed per mole.

3. (Trimethylsilyl) Ethers

The increasing use of mass spectroscopy and gas-liquid chromatography in the identification of organic molecules has stimulated the synthesis of new, highly volatile derivatives. Their use permits lower operational temperatures, and results in decreased breakdown of the substituted molecules. An almost quantitative yield (80%) of the (trimethylsilyl) ether was obtained by the dropwise addition of chlorotrimethylsilane to a pyridine solution of D-fructose.'S

Hydrolysis was readiiy effected by dilute mineral acid, even in the cold, and refluxing of the product for 2 hours in 50% aqueous methanol re- generated the parent sugar.ls6 Pent% 0- (trimethylsilyl) -D-fructose, having [ a ] ~ 3-3.85" (in benzene) and nD 1.4328, was formed, but the ring form has not yet been ascertained. The method has been adapted to gas-liquid chromatography, and has some advantages over those using older reagents.'"

Prey and Gump187* have, for the first time, studied the formation and structure of mono-0- (trimethylsilyl) derivatives obtained by treatment of di-0-isopropylidene acetals of D-fructose. The use of chlorodimethylsilanes and related substances yielded organosilanes having two, three, and even four sugar components as in (Ma). Tris(2,3:4,5-di-O-isopropylidene-~-

(RO),--Si-(CH&. . ." (184

fructopyranose)-l-oxymethylsilane, m.p. 189-194" and [.ID -5.6" (in CHCls) was synthesized, as well as other derivatives.

where R = a sugar acetal residue.

XII. ANHYDRIDES

Until 1959, the anhydrides known for D-fructose were restricted to the dimeric compounds known as the dianhydrides and the diheterolevulosans.

(185) F. A. Henglein, G. Abelsnes, H. Heneka, K. Lienhard, P. Nakhre, and K.

(186) E. J. Hedgley and W. G. Overend, Chem. Ind. (London), 378 (1960). (187) R. Bentley, C. C. Sweeley, M. Makita, and W. W. Wells, J . Am. Chem. Soc., 86,

Scheinost, Makromol. Chem., 24, 1 (1957).

2497 (1963).


Some monomeric anhydro-D-fructoses have now been prepared, and their structure has been established in a more or less definite manner, depending on the difficulties encountered. In view of their original character, these substances will be discussed first, and a general mode of preparation will be described.

In 1958, the nitration of D-fructose by means of nitrogen pentaoxide and sodium fluoride was described.'@ These reagents were used in order to eliminate, or at least to lessen, the dimerization reactions, which proceed quite readily under the normal, acidic c o n d i t i o n ~ . ' ~ ~ J ~ ~ This nitrating agent afforded a nonreducing trinitrate ( 19) by the following procedure. Nitrogen pentaoxide (73 g.) is added to chloroform; after being mixed with 12 g. of sodium fluoride, the solution is cooled to -5O. Finely powdered, dry n-fructose (9 g.) is added portionwise, with stirring, and the temperature is allowed to rise, over a long period of time, to just above 14". Catalytic hydrogenation of ( 19) yields the free (but amorphous) anhydro-D-fructose (20) [ a ] ~ +79", which can be hydrolyzed to the parent sugar. The furanose

080

(19)

form of compound (20) was proved by ultraviolet spectroscopy, and the possibility of a 1 , 3-ring was ruled out by the ease of hydrolysis. Further- more, the formation of a ditrityl ether and a di-0-p-tolylsulfonyl derivative provided additional proof for the furanose ring and evidence that neither of the primary hydroxyl groups was involved in the snhydro ring. Therefore, compound (20) was regarded as being 2,3- anhydro-D-fructofuranose.

Another monomeric compound was described by Goldschmid and Perlin and proved to be 2 , 6-anhydro-P-~-fructofuranose (22) .I3' This anhydro- ketose was obtained in 10% yield during the hydrogenolysis of sucrose in ethanol at 180". Tritylation and p-toluenesulfonation proceeded very slowly, supporting the view that the reactive hydroxyl group at C-6 is involved in the anhydro ring. The occurrence of the anomeric ethyl D-fructo- furanosides (23) , together with the anhydride, in the reaction products suggests that the same carbonium ion (21) is possibly an intermediate.

Starting from 2-deoxy-Zfluoro- l-O-methyl-P-D-fructopyranose, the same (187a) V. Prey and K.-H. Gump, Ann., 682, 228 (1965). (188) M. Sarel-Imber and J. Leibowitz, J. OTg. Chem., 24, 1897 (1959). (189) A. Schwager and J. Leibowitz, Bult. Res. Council Israel, Sect. A , 6 , 266 (1956). (190) G. V. Caesar and M. Goldfrank, J. Am. Chem. SOC., 68, 372 (1946).


Hb HO

(23) (21) (22)

anhydride was 0btained.'9~~ A 7% yield resulted after treatment with 50% alkali for 15 hours at room temperature. The structure could be assigned by the usual methylation techniques. When methanol was added to the mixture, the anomeric methyl wfructosides resulted, as might be expected if the same carbonium ion was involved.

The dimeric, cyclic anhydrides reviewed by McDonald,191 and formed during the acetolysis and subsequent hydrolysis of fructans, have now been obtained in much higher yields by the use of fuming nitric However, during these reactions, the fructofuranose form was already present, before ring-closure between adjacent molecules occurred to form the stable ring (24). Competing reactions to neutralize the positive charge of the carbonium ion by a negative nitrate ion or hydroxyl ion were confi~-med.'~~J~~

HO

f24)

The mechanism of formation is evidently the same when D-fructose is taken as the starting material, but, in most of these cases, the pyranose form is adopted, and this gives rise to the so-called diheter~levulosans,~S~ in addition to the di-D-fructose dianhydrides.

The products formed by the action of heat or concentrated hydrochloric acid at 0" on D-fructose were almost identical, and were identified by Wolfrom and coworkers,19s and confirmed by Wickberg.lB7 Separation and (19Oa) F. Micheel and E.-A. Kleinheidt, Chem. Ber., 98, 1668 (1965). (191) E. J. McDonald, Aduan. Carbohydrate Chem., 2, 253 (1946). (192) L. A. Boggs and F. Smith, J. Am. Chem. Soc., 78, 1878 (1956). (193) A. H. Shamgar and J. Leibowita, J . Org. Chem., 26, 430 (1960). (194) A. H. Shamgar and J. Leibowitz, J. Org. Chem., 26, 1596 (1961). (195) A. Pictet and J. Chavan, Helv. Chim. Acta, 9, 809 (1926). (196) M. L. Wolfrom and M. G. Blair, J. Am. Chem. Soc., 70, 2406 (1948); M. L.

(197) B. Wickberg, Acta Chem. Scund., 8, 436 (1964). Wolfrom, H. W. Hilton, and W. W. Binkley, ibid., 74, 2867 (1952).


identification were made possible by new chromatographic techniques developed during these studies.198 The configuration and conformation of the dianhydride I have been definitely proved by a study of its proton magnetic resonance spectrum, and the high resistance of this compound to periodate oxidation has been correlated with the quasi-axial positions of the hydroxyl groups at C-3' and C-4' in this 1',2-anhydro-l-O- (a-D-fructofuranosy1)- p-~-fructofuranose.~~~ Nitration by means of nitronium sulfate yielded a mixture of two crystalline, dimeric hexani tra tes . ,lg3 Catalytic reduction of each gave the same di-D-fructose dianhydride I. Renitration formed only one substance, so that a dimorphous material had been isolated, a phenomenon frequently encountered in this field. Synthesis and acetylation of the common dimeric anhydrides have been reviewed by HiItonlZoo and most of their physical constants were listed.2OO 1,4:3,6-Dianhydro-~-fructose (26), a viscous sirup, was obtained during

the catalytic oxidation of 1,4: 3,6-dianhydro-~-mannitol (25) to the corresponding diketone (27) .201,202 A reaction time of 20 hours at room temper-

ature is sufficient to provide these diketones, and the endo-hydroxyl groups of bicyclic systems are in this way selectively oxidized by oxygen and platinum oxide. Conformational studies by this technique are made possible by the selectivity of the reaction, as in the formation of benzyl 0-D-threo- pentopyranosid-4-ulose from benzyl ,&~-arabinopyranoside.~~~

XIII. HALIDES

Most of the 0-acetylfructosyl halides have been prepared by Brauns,204 but some of these crystalline derivatives are difficult to store. An interesting solution to this problem was given by the high-vacuum distillation described by Bredereck and HO~chele,'~~ because, after such treatment, no deterior-

(198) M. L. Wolfrom, W. W. Binkley, W. L. Schilling, and H. W. Hilton, J . Am, Chem.

(199) R. U. Lemieux and R. Nagarayan, Can. J . Chem., 42, 1270 (1964). (200) H. W. Hilton, Methods Carbohydrate Chem., 2, 199 (1963). (201) K. Heyns, W. Trautwein, and H. Paulsen, Chem. Ber., 96, 3195 (1963). (202) K. Heyns and H. Paulsen, Advum. Carbohydrate Chem., 17, 169 (1962). (203) K. Heyns, J. Lenz, and H. Paulsen, Chem. Ber., 96, 2964 (1962). (204) D. H. Brauns, J . Am. Chem. Soc., 46, 2381 (1923).

SOC., 73, 3553 (1951).


ation was shown, even after several months of storage, probably because every trace of acid had been removed. Ness and Fletcherzo5 first synthesized crystalline 1 , 3 , 4 , 5-tetra-0-benzoyl- P-~-fructopyranosyl bromide by dissolving the pentabenzoate in glacial acetic acid and adding hydrogen bromidelZo5 but solvent of recrystallization was always retained. However, the most important contribution was made by Micheel and Klemer,206 who investigated the glycosyl fluorides, and, especially, the interaction of D-fructose with hydrogen fl~oride.~~7**0* The following general procedure was adopted. D-Fructopyranose pentaacetate is added portionwise to the hydrogen fluoride, precooled to -60". After 40 minutes, the O-acetylfructosyl fluoride is obtained in a 65% yield. Treatment with methanolic ammonia at 0" during 6 hours results in pure P-D-fructopyranosyl fluoride. To prepare the a-D anomer, 0-acetyl-0-D-fructosyl chloride is treated with silver fluoride in acetonitrile at 0". (The chloride had been prepared by addition of aluminum chloride and phosphorus pentachloride to a chloroform solution of the t e t r a a ~ e t a t e . ~ ~ ) Characteristic reactions of these glycosyl fluorides with aqueous or methanolic alkali were attributed to the cis or trans position of the hydroxyl or amino group adjacent to the fluorine- bearing carbon atom, and the intramolecular ethylene oxide or ethylenimine formation is dependent on this stereospecific position.

XIV. NITROGEN-CONTAINING COMPOUNDS

1. General

This Section is not only the most voluminous, but is also important because of the mechanisms of formation involved and the biochemical role of the compounds in numerous biological processes. This Section describes at least four different kinds of nitrogen-containing derivatives of D-fructose.

First of all, new (substituted) hydrazones and osazones will be described; these have been characteristic derivatives in sugar chemistry for a long time, but are now, to a certain degree, replaced by the osotriazoles. The common substituted hydrazones have been reviewed,210 but during the past decade a great deal of work has been done in this field, not only to resolve the last remaining doubts about osazone formation, but especially in a study of the

(205) R. K. Ness and H. G. Fletcher, Jr., J . Am. Chem. SOC., 76, 2619 (1953). (206) F. Micheel and A. Klemer, Advan. Curbohydrale Chem., 16, 85 (1961). (207) F. Micheel, Chem. Ber., 90, 1612 (1957). (208) F. Micheel and L. Tork, Chem. Ber., 93, 1013 (1960). (209) D. H. Brauns, J . Am. Chem. SOC., 42, 1850 (1920). (210) E. G. V. Percival, Advun. Curbohydrute Chem., 3, 23 (1948).


influence, on the reaction, of certain substituents (on the phenyl group) and in checking the specificity of these substituted phenylhydrazines in respect to certain monosaccharide configurations.

The next part is devoted to the D-fructosylamines; the substituted amino function includes acyl- as well as aryl-amines, and even amino acids. At the time of the previous review:' principally acylamines had been synthesized, but the mechanism of formation has since been elucidated, and it thus became possible, by adjusting the reaction medium, to obtain higher yields and crystalline derivatives.

The most extensive part of this Section collects the Amadori compounds of D-fructose, that is, the l-amino-1-deoxy-D-fructoses. These substances, derivatives of the amino sugar ('isoglucosaminel1' are known to be rearrangement products of D-glucosylamines. Many problems, reviewed by Hodge (see Ref. 251), regarding their structure and possible mode of formation have been solved during the past few years.

Finally, those nitrogen-containing compounds that are difficult to include in the other subsections are mentioned in the last subsection. Of these, the most interesting are surely the pyrazines and azines.

2. Hydrazones and Osazones

The methods routinely used for preparing hydrazones of aldoses yield only a gel-like, orange mass from D-fructose and (2,4-dinitrophenyl)- hydrazine.21l However, by use of p-dioxane containing catalytic proportions of water (3%) and hydrogen chloride (0.3%), small needles of the p-dioxane solvate are obtained after 5 minutes. Dissolution of these crystals in 1 : 1 pyridine-96yo ethanol gives the pyridine solvate. These crystals (m.p. 173-175") were found to belong to the monoclinic system, elongated parallel to the b-axis.212

The influence, on the reaction, of different substituents in the phenylhydrazine molecule and the specificity due to these molecular changes have been s t ~ d i e d . 2 ' ~ ~ ~ ~ ~ The specificity in respect to certain aldose configurations was proved, and it was also shown that D-fructose and other 2-ketoses react with such weakly basic hydrazines as (p-bromo-, (p-carboxy-, (p-carbethoxy- and (p-nitro-pheny1)hydrazine. Correlations between the reaction rate and ease of interconversion between cyclic and acyclic forms were also determined.215 Studies with tritium-labeled D-fructose showed that the

(211) L. M. White and G. E. Secor, J. Am. Chem. Soc., 76, 6343 (1953). (212) F. T. Jones, D. R. Black, and L. M. White, A n d Chem., 27, 1203 (1955). (213) H. H. Stroh, Chem. Ber., 90, 352 (1957). (214) H. H. Stroh and E. Ropte, Chem. Ber., 93, 1148 (1960). (216) H. H. Stroh, Chem. Ber., 91, 2645 (1958).


velocity of reaction is influenced by the splitting of the G H bond and by the stereospecificity between both hydrogen atoms, but the reacting form in the formation of osazones is almost certainly the cyclic hemiacetal.216 However, nuclear magnetic resonance spectroscopy has shown that these results must be interpreted very cautiously, for this new technique demonstrated that the acyclic form (27a), which has two imino protons, is almost

NHPh NHPh I

H C ~ ~ N H I I

F"

I

HC/N-. I ;7H

C<-',NPh I N

certainly the major constituent of osazone miXtures.2168 This formulation is in complete agreement with Mester's observation that the C-1 hydrazone is more reactive than the (3-2 hydrazone.116b The chelate structure of the acyclic form was, therefore, changed216a in a minor way to the quasi- aromatic, chelate structure (27b).

The rather peculiar, catalytic role of acetic acid was also mentioned; it favors formation of the osazone without the necessity for any excess of the substituted hydrazine, in contrast with the formation of hydrazones when alcohol is the ~olvent.~~7,2~* These results agree with a mechanism proposed by Butler and CretcherI2lg and were confirmed by analysis of the reaction products. D-Glucose (2 , 3-dichlorophenyl) hydrazone (28) yielded the osa-

HC=N-NHR' HC=O HsOo I I

HC=N-NHR' I

I 3 HCOH

I I R R R

A C=N--NHR' + 2 HCOH -b R'-NH, i- NH,

(28) (29) (30)

zone (29) in 50% yield after heating in 30% acetic acid for 45 minutes, and the filtrate contained free g glucose (30 ) , 2,3-dichloroaniline, and ammonia. Studies on the possible condensation with several 1-alkyl-, 1 , ldiaryl-, and heterocyclic-substituted hydrazines showed that only the heterocyclic, 1-pyridyl derivatives of hydrazines react.=O

(216) H. Simon, H. D. Dorrer, and A. Trebst, Chem. Ber., 96, 1285 (1963). (216a) H. El Khadem, M. L. Wolfrom, and D. Horton, J . Org. Chem., 30, 838 (1965). (216b) L. Mester, Angew. Chem., 77, 580 (1965). (217) H. H. Stroh and H. Lamprecht, Chem. Ber., 96, 651 (1963). (218) H. H. Stroh and B. Ihlo, Chem. Ber., 96, 658 (1963). (219) C. L. Butler and L. H. Cretcher, J . Am. Chem. Soe., 61, 3161 (1929). (220) H. H. Stroh, personal communication (to be published later)


The mixed osazones prepared by Henseke and BinteZz1 during studies on the osones and related compounds brought forth new facts regarding the mechanism of formation. They postulated a linkage of glycosyl to nitrogen, whereas the bond between a disubstituted hydrazine residue and C-2 is very labile and is subject to hydrazone wandering.

Michee1222 postulated a mechanism, based on Weygand’s Scheme B,

HC=O HC=N-”H-Ph HC-NH- NH-F‘h

HYOH - HCOH I I I1

COH I

R R R I

I HC-NH-NH-Ph H,C-NH-NH -Ph H,C-NH-NH- Ph

II I I C-NH-NH-Ph - C=N-NH-Ph - C=O I I I

R R R

(35) (34)

HC= NH HC=N- NH-Ph I I

C=N-NH-Ph C=N-NH-Ph I I

R R

(37) (38)

(37a)

I

HCOH I

HCOH I

H&OH

where R = HO H ’i

SCHEME IV

(221) G. Henseke and H. J. Binte, Chena. Ber., 88, 1167 (1955). (222) F. Weygand, Ber., 73, 1284 (1940).


which explains most of the experimental facts observed and, especially, the fast and ready formation of osazones starting from Amadori p r o d u ~ t s . ~ ~ ~ ~ ~ ~ The first step is disproportionation of the phenylhydrazine molecule to aniline and ammonia (with subsequent formation of benzene and nitrogen). The formation of aniline in excessive proportions had been mentioned by other w0rkers,2~~,*4 and was confirmed by Stroh.220 The next step yields the intermediate 1-anzno-1-deoxy-D-glucose, in addition to the normal phenylhydrazone; both may react to give the 1 , 1-dianilino derivative or else 1-anilino- 1-phenylhydrazino-D-glucose. An Amadori rearrangement now gives 1-anilino- 1-deoxy-D-fructose, as expected by theory.

To eliminate the possibility that the free carbonyl group of the Amadori product (34) is responsible for the ease of the reaction, the same reaction was performed with 1-deoxy-1-p-toluidino-D-fructopyranose, which gives the hydrazone in high yield and with the same The de- hydrogenation which takes place during osazone formation is not a simple oxidoreduction, as shown by the use of phenyl-W-hydrazine. A most probable intermediate is structure (40a) :

A most interestin contribution by Haas and SeeligerZz5 co cerned isolation (after isolation of the main reaction products) of a compound which also proved the validity of Weygand’s mechanism B for aldoses. Indeed, by an outstanding reaction sequence, the formation of 3- (D-arabino-tetra- hydroxybutyl) cinoline by this pathway was established. Although slightly modified, formulas (31) to (37) of Scheme IV are still correct in Micheel’s mechanism and the imine of D-arabino-hexosdose 2-phenylhydrazone or the corresponding phenyl derivative of Micheel (37a) may form the cinoline derivative by intramolecular reaction to give (39) and then (40). However, no reaction of this kind occurred with D-fructose, D - “ ~ S O ~ ~ U C O S - amine,” or 1-deoxy-1-p-toluidino-D-fructose, or with the isomeric 2-amino- 2-deoxy-~-glucose; this suggests an entirely different reaction route for the ketoses.

(223) F. Micheel and I. Dijong, Ann., 669, 136 (1963). (224) G. Henseke and H. Dalibor, Chem. Ber., 88, 521 (1955). (224a) I. Dijong and F. Micheel, Ann., 684, 216 (1965). (225) H. J. Haas and A. Seeliger, Chem. Ber., 96, 2427 (1963).


According to Micheel, osazone formation starts from an aldose and requires an Amadori rearrangement, so that his scheme may not account for the reaction in the ketose series. It may be concluded that the Fischer mechanism is not valid, and that further studies are needed in order to solve the problem of interaction between ketoses and substituted phenylhydrazines.

Another hydrazine reagent, described by Hu11,226 is (thiomethoxythio- carbonyl) hydrazine; this gives abnormal products with D-fructose and with 2-amino-2-deoxy-~-g~ucose, affording a possible tool for investigating the ketose series more closely during osazone formation. A solution of the sugar and two molecular proportions of the substituted hydrazine in aqueous methanol, on refluxing for 20 minutes, yields a product, so that an osazone was postulated, but D-glucose gave a different product (41). On the other hand, 2-amino-2-deoxy-~-glucose afforded an identical one, so structure (42) was proposed.

I&F-NH-NH-CS&e

C=N-NIi- C S N e I

R’

I where R‘ = HOCH

I

H ~ O H I

HCOH I

H&OH

3. D-Fructosylamines

From the results of early studies by SorokiP and Irvine and McNico11,228 it was long believed that only aldoses react readily with arylamines; research on these derivatives was revived by Barry and Honeyman in 1950.229 As a result of careful experimentation, the reaction conditions were so changed that the product was obtained crystalline, and even derivatives could be prepared.230~2~~ At first, a mixture of D-fructose and the amine hydrochloride in anhydrous ethanol was boiled, but this method was criticized in

(226) R. Hull, J . Chem. SOC., 2959 (1952). (227) B. Sorokin, J . Prakt. Chem., 37, 292 (1888). (228) J. C. Irvine and D. McNicoll, J . Chem. SOC., 97, 1450 (1910). (229) C. P. Barry and J. Honeyman, J . Chem. SOC., 4147 (1952). (230) B. Helferich and W. Portz, Chem. Ber., 86, 604 (1953). (231) J. G. Douglas and J. Honeyman, J . Chem. Soc., 3674 (1955).


?I HC- HNC-CH,OH

I

' I HozC HOCH

H OH

HCOH 7

HCOH __L_

HCOH

&A0 - (4 (b)

HCNH-CH I

HOCH

I

H0,C I I HC -HNC%-COH

I I HC-HNCH R H T H

I HCOH

HCOH HOCH I

HCOH

HCO

&.&OH

%A0 -

(d) (4 SCHEME V.

1957 when yields much lower than predicted were obtained.233 Addition of catalytic amounts of such reagents as phosphoryl chloride, boric acid, and even benzoic acid, resulted in high yields, and crystallization resulted at room temperature simply by dilution of the solution. However, when the amine hydrochloride was added, the Schiff base of 5- (hydroxymethyl) -2- furaldehyde was formed. The yield has been increased by adding activated silica gel, to preserve anhydrous conditions throughout the reaction, and by keeping the temperature at 0" for 48 Important work by Heyns and coworkers,234--2a~ regarding the effect of different amines, resulted mostly in formation of the corresponding 2-amino-2-deoxy-~-glucose derivatives by the Heyns rearrangement. The existence of the intermediate D-fructosylamines could be proved by chromatography, but crystalline products have seldom been obtained. A comparative study on L-sorbose clearly indicated that the stability of the pyranose ring is extremely im-

(232) F. Knotz, Monatsh., 88, 703 (1957). (233) W. Kahl and W. Setark, Dissertuiiones Pharm., 16, 407 (1963). (234) K. Heyns, H. Paulsen, and H. Breuer, Angew. Chem., 68, 334 (1956). (235) K. Heyns, H. Breuer, and H. Paulsen, Chem. Ber., 90, 1379 (1957). (236) K. Heyns, H. Paulsen, R. Eichstedt, and M. Rolle, Chem. Ber., 90, 2039 (1957).


portant to the formation of these products, for all of the Gsorbosylamines expected by theory were ~ b t a i n e d . ~ ~ ~ , ~ ~ ~ Proof of the equilibrium between D-fructosylamines and the rearranged products was given by condensation studies with amino acids , when Amadori compounds were f0rrned.23~~2~~ Scheme V may illustrate such an equilibrium mixture, and can be explained on the basis of Isbell and Frush‘s theory of the conversion of glycosylamines, which predicted such a mixture (without any experimental evidence) .239 The very mild, anhydrous conditions needed for these reactions have been emphasized by Carson.240f241 Rearrangement of D-fructosylamines takes place even in methanolic solution, so that alteration on storage may also be encountered ; this possibility conflicts with earlier reports.230~231

According to Erickson, D-fructose condenses more readily than aldoses with acylamines, so that diamino derivatives were obtained.242~2~3 This report on a ketose is of interest regarding the recent findings of Micheel and Dij0ng,2~~ who stated that a diamino derivative is the necessary intermediate in the Amadori rearrangement. A t present, it is not known if this di-D-fructosylamine really is the counterpart of the Micheel derivative. Further proof is needed in order to confirm this statement, but the present author considers that this conclusion is correct, in view of the similarity between the two mechanisms. However, Erickson’s products, according to their elementary analysis, do not agree very well with the theoretical intermediate, so that future studies must bring the answer.

Mapping of all of the reactions displayed by the D-fructosylamines in- dudes the mechanism of formation and hydrolysis, mutarotation, and rearrangement, with the immonium ion postulated by I ~ b e 1 1 ~ ~ ~ (“enolimine”) a t the center of the entire plan.246 Scheme VI shows the reversibility of almost every stage of the mechanism proved238 and deduced from the effect of added acid and an excess of amino compound.

a. Formation and hydrolysis of the D-fructosylamine is schematized in the formula sequence (a) through ( f ) , according to Isbell. Acid catalysis was used in all studies. Formulas (f) and (f’) are of anomers, one of which is usually favored.

(237) K. Heyns, R. Eichstedt, and K. Meinecke, Chem. Ber., 88, 1551 (1955). (238) K. Heyns and H. Breuer, Chem. Ber., 91, 2750 (1958). (239) H. S. Isbell and H. L. Frush, J . Org. Chem., 23, 1309 (1958). (240) J. F. Carson, f. Am. Chern. Soc., 77, 5957 (1955). (241) J. F. Carson, J. Am. Chem. SOC., 78, 3728 (1956). (242) J. G . Erickson, J. Am. Chem. Soc., 76, 2784 (1953). (243) J. G. Erickson, J. Am. Chem. Soc., 77, 2839 (1955). (244) F. Mioheel and I. Dijong, Ann., 668, 120 (1962). (245) H. S. Isbell, Ann. Rev. Biochem., 12, 205 (1943). (246) H. S. Isbell and H. L. Frush, J . Res. Natl. Bur. Std., 46, 132 (1951).

270 L. M

. J.

VE

RS

TR

AE

TE

N

-0-

11


b. Mutarotation, a property common to all glycosylamines, is rather large in this case, but may be explained by the conformational instability of n-fructose; similar observations have been reported by Isbell and Pigman.I6 Occurrence of conformational changes means that the intermediate kelo form is also formed, and there is the possibility of enol formation (leading to further rearrangement). Indeed, rearrangement is easier than with aldosylamines, and sometimes occurs spontaneously. Usually, there is establishment of an equilibrium between the anomers ( f ) and (f’), and this also involves the forms (g), (e), and (h). Although acid-catalyzed, a strongly acid medium blocks the mechanism by formation of the ammonium ion (h’) , which changes into (i) . This form may be reconverted into (h) by simple dilution, and mutarotation may start again.23e

c. Immonium ion (e) is also an intermediate in the Carson-Eeyns rearrangement and in the formation of the enol (el) needed for further reaction. However, enol-forming conditions are very delicate to achieve; removal of the hydrogen ion may be promoted by the positive nitrogen atom of the amine, but this is dictated by substituents on the nitrogen atom.238J39 Despite this influence, carboxylic a ~ i d , ~ ~ ~ , ~ ~ ~ and methylenic compounds can also effect this tran~ition.~37,~~* These catalytic effects will be discussed in the Section on Amadori compounds (see p. 272).

Another mechanism of formation starts from the bisamino derivative (q) to the tautomeric aldoses (k) and (m) by way of (p) and carbonium ion (0) .244 The diamino compound may be formed from the D-fructosylamine by opening of the ring and addition of a second amine molecule. Compound (s) , a possible Erickson product, may be formed by this same route. Whether the factor responsible is a proton shift or a proton exchange is still unknown, so that differentiation between sequence (f-e-e’-k and m) or (q-p-m-e’) has not yet been made.

Secondary amines and amino acids react in an entirely different way.249 Indeed, L-proline forms a mixture of the four possible tautomers, but, after a time, ninhydrin-positive substances may be formed by breakdown of the proline molecule. (Other ketoses do not give this reaction.) Secondary amines, such as piperidine, will not react at O”, but, at higher temperatures (40-60°), some D-fructosylamine is formed, together with a higher proportion of D-glucose by isomerization. Morpholine or dicyclohexylamine give a 20 to 25% yield of D-ribo-hexdose, and may be used on a preparative

(247) L. Rosen, J. W. Woods, and (W.) W. Pigman, J . Am. Chem. SOC., 80,4697 (1958). (248) J. E. Hodge and C. E. nit, J . Am. Chem. SOC., 76, 316 (1953). (249) K. Heyns, H. Paulsen, and H. Schroeder, Tetrahedron, 13, 247 (1961).


scale. Tertiary amines, such as triethylamine, also yield D-ribo-hexulose by isomerization, but pyridine gives no reaction.

The reaction mechanism is known in its essential features, but the final details of some aspects are not yet fully understood; however, future work along these lines will certainly succeed in providing the needed information.

4. Amadori Compounds

Hodge stimulated research on these 1-amino-1-deoxy-D-fructoses, not only by his fundamental contrib~tions,~~~~2~0 but even more by his reviewlZ6* which mentioned the problems encountered during crystallization, and formulated questions about possible intermediates. Their basic role in the nonenzymic browning of foods (Maillard reaction) is another aspect of the biochemical importance of these products in Nature, which has been proved by later work on the stimulation of protein synthesis and the analysis of liver t i s s ~ e s . ~ ~ ~ - ~ "

The catalytic role of methylenic compounds, discussed by H ~ d g e , ~ ~ ~ proved to be a first step in the solution of the mechanism of formation, for this resulted in higher yields and in crystalline material. Acid catalysis had been mentioned by Weygand, and has been confirmed by M i ~ h e e 1 , ~ ~ ~ Akijal2= and and their coworkers. In all these studies, carboxylic acids were used, and, as most of the media were strongly basic owing to the presence of an excess of the amine compounds, a kind of catalysis differing from the usual acid catalysis was proposed by Isbell and F r ~ s h ~ ~ ~ (see Scheme VII) . This mechanism was identical to the one proposed for the methylenic compounds, which permitted the supposition that some trans-enolization occurs. In contrast with the D-fructosylamines, acylamino derivatives are difficult to prepare, and several modes of preparation were independently tried. Micheel chose the 4,6-0-benzylidene acetals (to eliminate ring-formation, a possible reason for a difficult rearrangement), and he was the first to obtain crystalline products from acylamines, arylamines, and amino a~ids.2~7 The negative effect produced by some substituents on the aromatic ring was diminished in this way. Rearrangement

(250) J. E. Hodge and C. E. Rist, J . Am. Chem. SOC., 74, 1494 (1952). (251) J. E. Hodge, Aduan. Carbohydraze Chem., 10, 169 (1955). (252) A. Abrams, P. H. Lowry, and H. Borsook, J . Am. Chem. SOC., 77, 4794 (1955). (253) H. Borsook, A. Abrams, and P. H. Lowry, J . Biol. Chem., 216, 111 (1955). (254) K. Heyns and H. Paulsen, Ann., 622, 160 (1959). (255) F. Micheel and A. Frowein, Angew. Chem., 69, 562 (1957). (256) S. Akiya and S. Tejima, Yakugaku Zasshi, 77, 214 (1957); Chem. Abstracts, 61,

(257) F. Micheel and A. Frowein, Chem. Ber., 90, 1599 (1957). 10382 (1957).


H I

H I

RC* + I __+c RC< [ 0-C-NRR' ,O C-NRR'

B

A R R

,O C=NRR' -RC'

'OH + !OH 0 HCOH \o--H(~oH

I

I HYOH

HYOH

where R = HOCH

C€&OH.

SCHEME V I I

was catalyzed by oxalic acid, and the oxalates obtained were treated with sodium hydroxide to set free the Amadori bases. On changing to the 4,6- dimethyl ether, the oxalate salts were formed by working in 2-propanol.268 However, the free bases were only obtained after treatment with sodium methoxide in absolute methanol, as in the case of nonsubstituted aldoses.269 By experiment, it became clear that only under anhydrous conditions may Amadori products be obtained quickly and in high yield. The suggestion was made that, under moist conditions, the intermediate D-glucosyl- nitrogen bond is hydrolyzed and that this hydrolysis is even more likely to occur in the presence of acids. As a matter of fact, Micheel prepared the 4 , 6-0-benzylidene-D-ghcosyl compounds by shaking a methanolic solution of the substance with the amine until crystallization Treatment with oxalic acid gave the same products as are obtained from a normal reaction mixture, and the yield was always between 80 and 100~o. This constitutes additional proof that no isomerization had taken place prior to the amino condensation, as suggested before.261 Starting from the same 4 , 6- 0-benzylidene derivatives, Weygand attempted the synthesis of methyl-arylamino compounds.2so Difficulties encountered with the acylamines are diminished in this way, and a quantitative yield was obtained. Huber and coworkers261 synthesized the same products without employing

(258) F. Micheel and A. Frowein, Chem. Ber., 92, 304 (1959). (259) F. Micheel and G . Hagemann, Chem. Ber., 92, 2836 (1959); 93, 2381 (1960). (260) F. Weygand, H. Simon, and R. van Ardenne, Chem. Ber., 92, 3117 (1959).


the acetals. Cyclic forms were obtained, for the carbonyl absorption band was absent from their infrared spectra.

Reaction of free D-glucose with certain polypeptides, mostly of the glycine class, also resulted in the expected Amadori products, and purification was readily effected by chromatography.262 ~-G1ucuronic acid or its 6,3-1actone were readily rearranged, and the intermediate D-glucosyluronic derivative could be separated and identified. After the formation of the normal arylamino derivatives1263 other amines were also p r e p a ~ - e d . ~ ~ ~ - * ~ ~

Most of these compounds are furanoid; this was readily proved by infrared spectroscopy and by lack of any reaction with benzaldehyde to give the characteristic oxazolidine derivative. Micheel prepared this acetal product for the first time, but he could only prove that C-2 is involved in the reaction. Definite proof of structure was given by Kuhn and during the first assignment of structure to an Amadori compound by methylation. I-Deoxy-l-p-toluidino-D-fructose (43) was treated with zinc

CHs-C,€&-HNHsCCOH CHs- C,&-N€&CCO

ROCH

HCOH HCOR I

HYOR

I

(a) C,H,CHO I h

CH,I/A~,O

&CO -

(43) (44) R = H (45) R = Me

HOCCGOH

MeOCH

HCOMe

HCOMe I

(46)

(261) G. Huber, 0. Schier, and J. Druey, Helu. Chim. Ada, 43, 713 (1960). (262) J. Enselme and A. Chapat, BulE. SOC. Chim. Biol., 42, 279 (1960). (263) K. Heyns and W. Baltes, Chem. Ber., 91, 622 (1958). (264) K. Heyns and W. Schuh, Chem. Be?., 93, 128 (1960). (265) K. Heyns and W. Baltes, Chem. Ber., 93, 1616 (1960). (266) K. Heyns and W. Schulz, Chem. Ber., 96, 709 (1962). (267) R. Kuhn, G. Krtiger, and A. Seeliger, Ann., 018, 82 (1958).


chloride and benzaldehyde, and the benzylidene derivative (44) yielded a trimethyl ether (45) which, after dearylation and treatment with sodium nitrite, gave 3 ,4 ,5-tri-O-methy~-&~-fructose (46). Permethylation followed by hydrolysis with methanolic hydrogen chloride gave the pure 1 , 3 , 4 , 5- tetra-O-methyl-~-D-fructopyranose, m.p. 98-99" and [CY]D - 121.5 + - 118" (in water). This study provided two novelties in the chemistry of the Amadori compounds, for it demonstrated for the first time, by chemical means, the cyclic form of the product, and the parent sugar D-fructose was prepared by starting from the amino compound. Another contribution to this last reaction was the synthesis of 1-0-acetyl-D-fructose, described on p. 253.

The nonreducing oxazolidine derivative is stable in solution, in contrast with Amadori products. Simple refluxing of the Amadori compound with benzaldehyde in absolute ethanol gives the desired Starting from D-fructose, Heyns and were able to prepare the amino- deoxy-D-fructoses from a number of amino acids, confirming in a direct way the absence of any enolization reaction. Another proof was obtained by treatment of the known di-0-isopropylidene-1-0-p-tolylsulfonyl-D- fructose with 2 , 2'-iminodiethanol at 160-170" for 7 h o ~ r s . ~ ~ ~ Related products were formed by adjusting the reaction medium, so merely a substitution mechanism (rather than a rearrangement process) is operative. Here again, the structure of the parent sugar is known and proved, and as a matter of fact the configuration of the resulting derivative was established.

An Amadori product was prepared from D-glucose 4, &(hydrogen phosphate) and cycl~hexylamine.~~~ The keto structure was assumed (for conformational reasons) , and was confirmed by ultraviolet spectroscopy. Information as to the conformation of these amino-deoxy-ketoses was gained by infrared absorption s p e c t r o s ~ o p y . ~ ~ ' ~ ~ ~ ~ Indeed, not only was the carbonyl absorption used for assignment of the keto structure, but a characteristic absorption band, found at 3570 cm.-' was attributed to the special grouping at C-1. The structure assigned was later changed to the folIowing extent: the nitrogen atom must bear a free hydrogen atom and an unsubstituted glycosyl group. The ring form was readily determined by this technique, without further proof.272 The use of such enediol reagents as 2 , 6-dichlorophenolindophenol was made possible by their remarkable reducing power, and so use of polarography gave the opportunity to study this reductive a c t i ~ n . ~ ' ~ Only the acylamines were polarographicalIy active,

(268) A. Wickstrom and J. K. Wold, Acta Chem. Scand., 16, 686 (1961). (269) L. Vargha, 0. Fehr. and S. Lendvai, Ada Chim. Acad. Sci. Hung., 19, 307 (1959). (270) J. Baddiley, J. G. Buchanan, and L. Szabo, J . Chem. Soc., 3826 (1954). (271) H. Micheel and V. Huhne, Chem. Ber., 93, 2383 (1960). (272) F. Lingens and H. Hellmann, Ann., 630, 84 (1960). (273) F. Micheel and E. Heiskel, Chem. Ber., 94, 143 (1961).


and the addition of acid completely suppressed the wave of the cyclic forms. This phenomenon was explained on the basis of complex-formation between the glycosyl group and the boric acid used, as in (47) -+ (48) ---f

(49). In contrast, the isomeric D-glucosyl-nitrogen compounds were in- active.

As regards the precise mechanism of formation, Micheel demonstrated the intermediate position of the diamino derivative in the following reaction sequencezM: 3,4,5,6-tetra-O-benzoyl-aldehydo-D-glucose (SO), treated with an excess of p-toluidine, forms 1-deoxy-1 , 1-bis-p- toluidino- aldehyde-D-glucose tetrabenzoate (52) , which rearranges to the Amadori compound (53) on treatment with oxalic acid for two minutes. The reverse mechanism, described on p. 268, is almost identical, except for the still- unidentified bis--D-fructosylamino product, whereas compound (52) had been mentionedn4 in 1944 (but without knowledge of its specific role in this rearrangement).

However, by using tracer techniques, it was shown that Micheel's mechanism is not valid for N-glycosyl derivatives having free hydroxyl

(274) E. Mitts and R. M. Hixon, J . Am. Chem. Soc., 66, 483 (1944).


Indeed, treatment of N-p-tolyl-P-~-glucosylamine in water-free p-dioxane with acetic acid gives the Amadori product in high yield.

Once the preparative method was sufficiently controlled, new ways were sought for making use of the products obtained. An interesting and valuable technique was found by Kuhn and H a a ~ , 2 ~ ~ who synthesized ('iso-D-glucosamine" by catalytic hydrogenation of Amadori comp0unds.~~8 According to HodgejZS1 hydrogenation usually results in dihydro compounds, as described in the previous review.251 The mixture of palladium oxide hydrate and barium sulfate, used in the presence of hydrogen chloride, removes the aryl group, and the free amino sugar is formed. Palladium oxide alone is also effective, but in a minor way.263 Druey and Huber277 obtained the same results on using ammonium chloride at 95-100" (in a bomb).

Regarding the importance of these compounds in various fields of biochemistry, many remarkable reactions have been outlined for the formation of other valuable derivatives. The synthesis of imidazolines begins with the addition of isocyanic acid or thiocyanic acid, as described by Huber and coworkers2n and Garcia Gonz61ez and co~orkers.~7~ Thiocyanic acid is especially well suited for a direct and easy characterization of the Amadori compounds. ,4 reaction time of 2-3 hours results in a 6@-70y0 yield.

Treatment with diazonium salts proceeds between 0 and -5" in pyridine- methanol solution,280 and this affords an outstanding reagent for distin- guishing between N-glycosyl derivatives and aminodeoxyketoses. When the reaction is performed in aqueous solution, two isomeric compounds are formed.281 Depending on the acidity of the medium, the triazine (54) or the azo form (55) preponderates.

qc+ N=N d1 - ?$ $ H,CN H,CN-N=N

+=0 c=o c1

R c1 B (54) (551

(274a) D. Palm and H. Simon, 2. Naturforsclt., 20, 32 (1965). (275) R. Kuhn and H. J. Haas, Ann., 600, 148 (1956). (276) H. J. Haas, Chem. Ber., 94, 2442 (1961). (277) J. Druey and G. Huber, Helv. Chim. Acfa, 40, 342 (1957). (278) G. Huber, 0. Schier, and J. Druey, Helv. Chim. Acta, 43, 1787 (1960). (279) J. Fernandez-Bolanos, F. Garcia Gonzitlez, J. Gasch Gomez, and M. Menendez

Gallego, Tetrahedron, 19, 1883 (1963). (280) R. Kuhn, G. Kruger, and A. Seeliger, Ann., 628, 240 (1959). (281) H. E. Zaugg, J. Org. Chem., 26, 2718 (1962).


Nitrosation of an ice-cold solution of the Amadori compound yields a characteristic derivative (56) , with substitution at the nitrogen atom.

H,CN-NO I c=o I

R

(56)

A pyrimidinylamino derivative, prepared by Nelson and Wood,282 is a possible intermediate for the preparation of flavines and other pteridine derivatives.

Amadori products of primary amines may react with a second molecule of aldose, and the product rearranges to form a di-D-fructose amine (see Scheme VIII) , as found experimentally by Anet.283 Similar compounds of

HO~CH,NHCH,CO,H I I 0

I R H C V

’ HCOH 7 R HCOH I R I 10 R

CH,- C Q H

0 7 HOCCH2-N-HZCCOH ‘I I r : R I I

I where R = HOCH

I HCOH

I HCOH

%dOH

SCHEME Vm

(282) T. Neilson and H. C. S. Wood, J . Chem. Soc., 44 (1962). (283) E. F. L. J. Anet, Chem. Ind. (London), 1438 (1958); E. F. L. J. Anet and T. M.

Reynolds, Australian J . Chem., 10, 182 (1957); E. F. L. J. Anet, ibid., 12, 491 (1959).


the aldoses had been previously identified, and a possible mechanism of formation was postulated by Isbell and F r ~ ~ h . ~ ~ ~ v ~ ~ ~

In aqueous solution, decomposition is very fast, and the resulting Amadori compound is not accompanied by the free sugar; but carbonyl compounds of an unsaturated nature are found, and these may be responsible for the nonenzymic browning of these substances. Two isomeric 3-deoxyglycosuloses were prepared in high yield by treatment286 of an aqueous solution of “di-D-fructose-plycine” a t pH 5 and 100”. The glycino derivatives were obtained in crystalline form; many others were isolated from chemical media or from browned, freeze-dried apricots, but were not

The yield was increased by addition of bisulfite, dihydrogen phosphate, or hydrogen m a l a t ~ . ~ ~ 7 Structure analysis by infrared spectroscopy suggested that the D-fructose moiety is most probably present in its /3-D-pyranose form.

The same reaction was found to occur with piperazine, an aromatic secondary amine.2aa In this case, the di-~-glucosylamine was prepared by condensation in 95% ethanol, with ammonium chloride as the catalyst. If the reaction was performed at 80-100”, an 80% yield resulted within 30 minutes. Refluxing with diethyl malonate gave the corresponding Amadori product in 35% yield.

A most interesting application having commercial value is the formation of surface-active derivatives by the condensation of hydrophilic sugars with fatty Only Amadori rearrangement gave hydrolysis-resist- ant compounds, displaying a considerable decrease in the surface tension of water, in contrast to the glucosylamine derivatives.

5. Miscellaneous

Reaction of D-fructose with potassium thiocyanate in the presence of hydrogen chloride affords a thiooxazoline derivative of unknown structure. From indirect evidence, formula (59) was suggested, as all attempts to isolate the amino sugar expected from structure (58) have been fruitless. In contrast, the D-glucosylamine and even the di-D-ghcosylamine compound were found, by chromatography, as products from the corresponding

(284) See also, K. Heyns and H. Paulsen, “Veranderungen der Nahrung durch in- dustrielle und haushaltsmasige Verarbeitung,” Steinkopff Verlag, Darmstadt, Germany, 1960, Vol. 5, p. 15.

(285) E. F. L. J. Anet, Aust~alian J . Chem., 13, 396 (1960). (286) D. L. Ingles and T. M. Reynolds, Australian J . Chenz., 11, 575 (1958). (287) T. M. Reynolds, AustTalian J . Chem., 12, 265 (1959); E. F. L. J. Anet, ibid., 12,

(288) C. Panagopoulos, A. Kovatsis, and C. Sekeris, Arzneimittel-Forsch., 11, 629 (1961). (28%) F. Schnieder and H. U. Geyer, Staerke, 16, 309 (1964).

281 (1959).


D-glucose derivative (57).289~290 Their structure has been re-examined by periodate oxidation and by ultraviolet and infrared spectroscopy.%’ Using “~-gZuco-oxazolidine-2-thione” as a reference compound, formula (58) was adopted in the case of the n-fructose compound, namely, “2 , 3-oxazolidine- 2-thione-D-fructopyranose.” Despite isolation of this derivative, there was evidence for the existence of an open-chain form, difficult to remove from the other product.

HNCCH,OH

I HOCH 1

I R R R

(57) (58) (59)

Another class is represented by &acetamido-&deoxy-D-fructose, formed by the oxidation of 1-acetamido-1-deoxy-D-mannitol by Acetobacter sub- 0xydans.2~~ This sirupy compound, of [.ID -8.0” (in water) , was obtained in high yield (84%). At least 5% of this substance was in the keto form, as indicated by the slight oxidation of Fehling solution at room temperature.

Pyrazine formation is also shown by the amino sugars, and so fructosazine (60) is formed when D-“isoglucosamine” tetraacetate is boiled with di- ethylamine in methanolic s0lution.29~ The compound was described2g4 in 1899, but the yield has now been increased to 26% of the theoretical. The

corresponding n-glucosamine tetraacetate yields a deoxyfructosazine (61) in 49% yield. Proof of structure was obtained by hydrogenation and subsequent hydrolysis, yielding a mixture of D-“isoglucosamine” and 3-deoxy-n-L‘isoglucosamine.”

Azines, obtained from interaction of D-fructose with 0.5 M hydrazine in

(289) G. ZemplEn, A. Gerecs, and E. Ill&, Ber., 71, 590 (1938). (290) J. J. Edwards and E. F. Martlew, Chem. Znd. (London), 1034 (1952). (291) A. Wickstrom, Actu Chem. Scund., 13, 1129 (1959). (292) J. C. Turner, Can. J . Chem., 40, 826 (1962). (293) R. Kuhn, G. Kruger, H. J. Haas, and A. Seeliger, Ann., 644, 122 (1961). (294) C. A. Lobry de Bruyn, Rec. Trau. Chim., 18, 72 (1899).


methanol,2gK may be mentioned in this Section. Structure (62) was proposed as a result of analysis of suitable derivatives. However, addition of an excess of hydrazine results in normal hydrazones, as indicated by T i p ~ o n . ~ ~ ~

I I HOHC CHOH

R

XV. SULFUR-CONTAINING COMPOUNDS

The first representative of this class was prepared by S. B. Baker,Zg7 who used 2 , 3 : 4 , 5-d~-O-~sopropylidene-l-O-p-toly~su~fony~-~-fructose as the starting material. The usual hindrance of the p-tolylsulfonyloxy group at C-1 was less in the presence of sodium ethanethiolate. The resulting thio derivative was hydrolyzed to remove the isopropylidene groups, and crystalline 1- f&ethyl-l-thio-D-fructopyranose, m.p. 87-88", was obtained. When the dianhydrides are treated with sodium ethanethioxide, only a small proportion of the compound is formed. A similar method was used for the formation of Bthio-D-fructose.288 Sodium a-toluenethioxide reacts with 2,3- 0-isopropylidene- 1 ,6-di- 0-p-tolylsulfonyl-D-fructofuranose (63) to give the 6benzylthio derivative (64) , as the nucleophilic displacement is restricted to C-6. Several crystalline derivatives were obtained, so that definite proof of structure was readily established. Dissolution of (64) in tetrahydrofuran cooled to 0" and addition of lithium aluminum hydride gave 6-S-benzyl-l-deoxy-2 , 3-O-isopropylidene-6-thio-~-fructose (65), which was desulfurized to the 1, Mideoxy derivative (66), having properties in agreement with those of the product of a former synthesis.299 The benzyl group was removed by addition of liquid ammonia and sodium, resulting in 1-deoxy-2 , 3-0-isopropylidene-6-thio-~-fructose (68). When compound (64) is desulfonylated by sodium amalgam, 6-8-benzyl-2 , 3-0- isopropylidene-6thio-D-fructose (67) is formed; this may, in turn, be desulfurized by Raney nickel, to the corresponding derivative (70), and removal of the benzyl group by liquid ammonia gives 2 , 3-0-isopropylidene- 6thio-D-fructose (69).

(295) H. H. Stroh, A. Arnold, and H. G. Scharnow, Chem. Ber., in press (personal

(296) R. S. Tipson, J . Org. Chem., 27, 2272 (1962). (297) S. B. Baker, Can. J . Chem., 33, 1459 (1955). (298) M. S. Feather and R. L. Whistler, J . Org. Chem., 28, 1567 (1963). (299) W. T. J. Morgan and T. Reichstein, Helu. Chhim. Ada, 21, 1023 (1938).

communication).

282 L. M . J. VERSTRAETEN


XVI. REDUCTION AND OXIDATION PRODUCTS Reduction of D-fructose generally results in a mixture of variable pro-

portions of D-mannitol and D-glucitol, the proportions of the products being dependent on the procedure. An interesting method for reduction of ketoses, using hydrogen and Raney nickel catalyst, was described by Karabinos and Ballun.300 Refluxing of a 70% ethanolic solution of the sugar and the catalyst for 1.5 hours gives both hexitols, but one may be isolated prefer- entially. This method, adapted to a preparative scale by activation of the catalyst with platinum chloride and by using an autoclave, provides a 90% yield of D-glucitol.Sol In contrast, use of a zinc-nickel complex gives D-mannitol as the sole product, and the same result is given by pure nickel catalyst, with a lower alcohol (aqueous) as the sol~ent .~~2J~3

Later, the metallo borohydrides became available, and their mode of action was carefully studied. Whereas sodium borohydride reacts quite well with D-fructose in pure borate buffer disturbs the action; this led to the conclusion that ketoses are reduced more slowly than aldoses, the intermediary formation of the zig-zag conformation being responsible.305 Indeed, it was suggested that the carbonyl group is sterically hindered by the neighboring substituents, and additional evidence was found in the resistance of maltulose to this reagent.306 However, the explanation may simply be the greater complex-forming capability of D-fructose, followed by a more difficult interaction with the reducing agent.307 This would explain why lithium borohydride in p-dioxane or other organic solvents reduces D-fructose faster than it does any other sugar; D-fructose has a greater percentage of the keto form in solution.30s Indeed, the cyclic hemiacetals react very slowly, in contrast to aldehydo forms (such as aldehyde-D-glucose pentaacetate) and the ease of reaction correlates well with the mutarotation.3os Decreasing the concentration of water in organic solvents results in a marked lowering of the rate of reaction (except for the aldehydo forms) ; this is again in complete agreement with the former statement regarding

(300) J. V. Karabinos and J. T. Ballun, J . Am. Chem. SOC., 76, 4501 (1953). (301) M. Damodaran and S. S. Subramanian, J . Sci. Znd. Res. (India), 10B, 279 (1951). (302) Fabriques de produits de chimie organique de Loire, French Pat. 971 , 429; Chem.

(303) Usines de Melle, British Pat. 801,732; Chem. Abstracts, 63, 8673 (1959) (304) M. Abdel-Akher, J. K. Hamilton, and F. Smith, J . Am. Chem. Soc 73 , 4691

(305) P. D. Bragg and L. Hough, J . Chem. SOC., 4347 (1957). (306) S. Peat, W. J. Whclan, and J. G. Roberts, J . Chem. Sac., 2258 (1956) (307) B. A. Lewis, F. Smith, and A. M. Stephen, Methods Carbohydrate Chem., 2, 71

(308) H. Endrcs and M. Oppelt, Chem. Zler., 91, 478 (1958). (309) J. B. Lee, Chem. Znd. (London), 1455 (1959).

Abstracts, 47, 2193 (1953).

(1951).

(1963).


the importance of the acyclic form as an intermediate. The overall order of reaction rate, as found experimentally, is: deoxy sugars > D-fructose > aldoses.

Oxidation by means of alkaline solutions of bivalent copper, in the presence of such chelating agents as tartrate or citrate, was studied ki- netically, and the velocity of reaction was found to be higher for D-fructose than for aldoses, showing that less energy is needed for the intramolecular rearrangement and that reactivity is intimately related with configuration and conf~rmation.~'~

On studying the mechanism of oxidation by hexacyanoferrate, it was found that the first step in the reaction is the formation of the 1 ,2-enediol, so that the rates of oxidation of aldoses and ketoses are their corresponding rates of enolizationj'o" (see p. 242).

Oxidation by Acetobacter results in a mixture of the normal isomers of D-arabino-hexulosonic acid and ~-lyxo-5-hexulosonic acidlall but, in addition, D- threo-2 , 5-hexodiulose and 3 , 5-dihydroxy-2-methyl-y-pyrone (5-hydroxy- maltol) are On the other hand, Gluconobmter cerinus var. ammoniacus Asai also forms ~-threo-:!, 5-hexodiulose having the following constants: m.p. 157-159" and [ a ] ~ -85" (in water) ?lZa

Addition of an excess of manganese dioxide to an aqueous solution of D-fructose, followed by shaking for 15 hours, changes the optical rotation from -92.5 to - 16.9" through the formation of ~-arabino-hexosu~ose.~~~ This was proved by the formation of a quinoxaline derivative on reaction with o-phenylenediamine. A comprehensive study on this subject has been published in this Series.316

XVII. BRANCHED-CHAIN DERIVATIVES

The cyanohydrin (71) of D-fructose is formed by treatment of a solution of the sugar in N , N-dimethylformamide with anhydrous hydrogen cyanide; and this product may be converted into an aldimine (72) by the new

(310) M. P. Singh and S. Ghosh, 2. Physik. Chem., 207, 187, 198 (1957). (310a) N. Nath and M. P. Singh, J . Phys. Chem., 69, 2038 (1965). (311) 0. Terada, S. Suzuki, and S. Kinoshita, Nippon Nogeikagaku Kaishi, 36, 212

(312) 0. Terada, S. Suzuki, and S. Kinoshita, Nippon Nogeikagaku Kaishi, 36, 178

(312a) G. Avigad and S. Englard, J . Biol. Chem., 240, 2290 (1965). (313) 0. Terada, S. Suzuki, and S. Kinoshita, Nippon Nogeikagaku Kaishi, 36, 623

(314) G. J. Moody, Nature, 196, 71 (1962). (315) G. J. Moody, Advan. Carbohydrate Chem., 19, 149 (1964).

(1962); Chem. Abstracts, 62, 3090 (1965).

(1961); Chem. Abstracts, 62,9279 (1965).

(1962); Chem. Abstracts, 62, 3090 (1965).

D-FRUCTOGE A

ND

IT

S

DE

RIV

AT

IVE

S

285

X Bf


hydrogenation method of Kuhn, followed by cyclization with a y- or 6-hydroxyl group316,317 to give (73). By acid catalysis, the ammonium group is split off, and the corresponding branched-chain sugar (74) is obtained (m.p. 174-175"). This is the first synthesis which makes no use of the lactone (77) of the acid form (76), as in the normal Kiliani method. However, studies by Woods and Neish318 demonstrate the possible utility of sodium amalgam for reduction, on the preparative scale, of this lactone, in view of the high yield (65%) of the new Definite proof of structure was obtained319 by reduction with phosphorus-hydrogen iodide to give the hexanoic acids (78).

During the synthesis of D-apiose, 3-O-benzyl-~-fructose was treated in the same way (Kiliani method) , and a crystalline 3-O-benzyl lactone was formed (m.p. 150-152"). Reduction by means of sodium borohydride gave the branched-chain heptitol (75), showing that this method provides an interesting tool for the synthesis of branched-chain s ~ g a r s . ~ * ~ * ~ ~ ~

XVIII. COMPLEXES

Much work has been done during the past few years on the chelate- forming capability of the sugars with ( a ) polyvalent metallic ions in alkaline media, and ( b ) such polyhydroxy acids as germanic acid, telluric acid, and boric acid. All of these studies reveal the exceptional chelating ability of D-fructose; which is attributed to the greater proportion of the open-chain form in aqueous (see also, p. 283). The formation of complexes with cobalt, nickel, copper, and iron atoms clearly indicates that two hydroxyl groups are usually involved, as was to be Applications in the fields of plant and animal nutrition have been mentioned, especially where a deficiency of metals occurs. The iron-D-fructose interaction was thoroughly investigated, and several physical properties were listed.324 The red-brown ferric-D-fructose complex formed at pH 9 was isolated by pre- cipitation with ethanol, and an estimation of the molecular weight gave

(316) R. Kuhn and H. Grassner, Ann., 612, 55 (1957). (317) R. Kuhn and H. J. Haas, Angew. Chem., 67, 785 (1955). (318) R. J. Woods and A. C. Neish, Can. J . Chem., 31, 471 (1953). (319) A. S. Perlin and C. B. Purves, Can. J . Chem., 31, 227 (1953). (320) R. J. Woods and A. C. Neish, Can. J. Chem., 32, 404 (1954). (321) P. A. J. Gorin and A. S. Perlin, Can. J . Chem., 36, 480 (1958). (322) P. J. Antikainen, Acta Chenz. Scand., 13, 313 (1959). (323) E. J. Bourne, R. Nery, and H. Weigel, Chem. Ind. (London), 998 (1959). (324) P. J. Charley, B. Sarkar, C. F. Stitt, and P. Saltman, Biochim. Biophys. Ada, 69,

313 (1963).


594, in agreement with a 2 Fe:2 D-fructose: 1 Na complex, so structure (79)

was proposed. The association constant of the ferric complex was found to be approximately 1 e 2 . With ferrous ions, the carbohydrateliron ratio must be doubled, and a blue-green complex is obtained. In the case of boric acid, the work of BoesekenaZ6 was very informative as regards the need for vicinal hydroxyl groups for complexation, and application has been made in conformational studies. The work of Antikair~en~~* on the same subject showed that acid/hexose complexes in the ratios of 1 : 1 and 1 : 2 are formed.

The acid strength of benzeneboronic acid is also considerably increased by the addition of D-fructose, and, as Raman spectroscopy and x-ray analysis showed that addition of water is most probably a first step in the dissociation of boric acid, the former conclusion was also applied to benzeneboronic a~id.3~7 However, the presence of the phenyl group inhibits di-sugar complex-formation, giving rise to a compound having the following structure:

To illustrate the specific position of D-fructose in these metal-sugar interactions, the instability constants of several sugars are listed in Table 11, and the difference is at least 100 times in favor of the D-fructose com-

(325) J. Boeseken, Advan. Carbohydrate Chem., 4, 189 (1948). (326) P. J. Antikainen, Suomen Kemislilehti, 31B, 255 (1958). (327) K. Torssell, Arkiv Kemi, 10, 541 (1957).


TABLE I1

Complexes of Sugars with Germanic AcidS8Jm

Instability Ionization Sugar constant constant

D-Fructose 4.24 X lo-' 1.04 x 10-4 D-Galactose 7.64 x 10-8 2.39 x D-GIUCOS~ 3.54 x 10-a 8.35 x lo-&

p l e ~ e s . ~ ~ ~ , ~ ~ ~ However, when the proportion of D-fructose is far in excess (in relation to germanic acid), the specific rotation of the sugar is quite normal, so that only part of the mixture is c o m p l e ~ e d . ~ ~ ~ With telluric acid, the only complex formed in significant concentration has a ratio of 1 : 1. The free energy of the system (calculated) did not correlate very well with that of the other complexes, and this may be due to the fact that one hydroxyl group of the octahedral tellurate ion pushes against the sugar ring?31

XIX. @-DICARBONYL CONDENSATION PRODUCTS

Reaction of such compounds as ethyl acetoacetate or 2,4pentanedione with n-fructose gives @-substituted furan derivatives; this is in contrast with the ru-substituted compounds obtained from ald0ses.33~ The mechanism of reaction is identical in both cases, and the structure has been proved by degradation methods and by infrared and ultraviolet spectroscopy. With sucrose as the starting material, a mixture of a- and @-substituted compounds was obtained333 in the ratio of 65:35.

When added to Amadori products, the @-substituted pyrrole derivatives are formed, as expected by theory.334 The l-arylamino-l-deoxy-D-fructoses behave in the same manner, but the yield is decreased to 20-30%, whereas the simple Amadori compounds were 0btained3~~ in yields of SO-SO%. On the other hand, D-fructosylamines give a-substituted pyrrole derivatives,

(328) V. A. Naearenko and G. V. Flyantikova, Zh. Neorgan. Khim., 8, 2271 (1963). (329) V. A. Naearenko and G. V. Flyantikova, Zh. Neorgan. Khim., 8, 1370 (1963). (330) T. Otsu, Tanken, 16,89 (1960); Chem. Abstracts, 66, 13155 (1960). (331) H. R. Ellison, J. 0. Edwards, and E. A. Healy, J . Am. Chem. Soc., 84, 1820 (1962). (332) F. Garcfa GonzAlez, Advan. Carbohydrate Chem., 11, 97 (1956). (333) H. H. Samant and M. L. Estevez, Mem. Conf. Anual Asoc. Tec. Azucar. Cuba, 33,

(334) F. Garcfa GonzAlez, A. G6mee Shchee, and J. G. Gomez, Anales Real SOC. Espan.

(335) F. Garcfa GonaAlea, A. Gdmez Shchee, and J. G. Gomea, Anales Real SOC.

155 (1959).

Fis. Quim. (Madrid), Ser. R, 64, 513 (1958).

Espan. Fis. Quim. (Madrid), Ser. B, 64, 519 (1958).


just as for the 2-amino-2-deoxy-~-glucoses.~~~ These products may be extremely important in biochemistry, for the existence of an intermediate

R "COCH, I

H CC=O R "CO-CH-CHOH s I HOCH I H,C-c=O )H--R'

A t Ha (80)

(81)

such as (80) might explain the ready conversion of sialic acid into 2-pyrrole- carboxylic acids (al) , as we11 as the formation of the sialic acid (by an aldol reaction) from oxaloacetate and 2-amino-2-deoxy-~-glucose (or D-fructosylamine) , and subsequent decarboxylation, as proposed by Gott- s~ha lk .~~7 Various products have been obtained, and are listed at the end of this Chapter.

XX. TABLES OF PROPERTIES OF DERIVATIVES OF D-FRUCTOSE

TABLE I11

Acetals of D-Fructose and Their Esters and Ethers ~ ~ ~

m.p., [ a ] D , Rotation Refer- Derivative of D-Fructose "C. degrees solvent ences

1,2 : 4,5-Di-O-cyclohexylidene- 145 - 123 Me&O 130 129 129 129

1,2 : 4,5-Di-O-isopropylidene- 118-119 -147 CHC4 176 120 -139.5 CHCls 130

3-O-benzy l- sirup - 95 EtOH 321 3-0-ptolylsulfonyl- 97-98 - 161 MeOH 176 3-O-(trimethylsilyl)- 65-66 - 123 CHCla 187a

2 ,3 : 4, SDi-O-isopropylidene- 96-97 -34.1 CHCls 176 95.5 -37.6 pet. ether 130

- - 142

3-O-p-tol ylsulfonyl- 116 1,2 : 4,5-Di-O-cyclopentylidene- sirup - -

- -

(336) F. Garcia GonzBlez, J. G. Gomez, J. B. Gutierrez, and A. Gbmez SBnchez, Anales

(337) A. Gottschalk, Nature, 176, 881 (1955); Yale J. Biol. Med., 28, 525 (1956). Real Sac. Espan. Pis. Quim. (Madrid), Ser. B, 67, 383 (1961).


TABLE I11 (Continued)

Acetals of D-Fructose and Their Esters and Ethers

m.p., [a]D, Rotation Refer- Derivative of D-Fructose "C. degrees solvent ences

1-0-butylene- 1-N-(bis-2-chloroethy1)-

phosphoramidate benz ylphosphoramidate phosphoramidic chloride

l-deoxy-l-hydraeino-bis- (phenylcarbamate)

l-deoxy-l-(3-methyl-Soxo- pyrasolidine-1-y1)-

1-0-p-toly lsulfony l- I-0-(trimethylsily1)-

1 ,2-o-Isopropylidene-p-D- fructopyranose

3-0-acetyl- 3,4,5-tri-O-(trimethylsilyl)- 3,4-di-O-acetyl- 4, 5-di-0-methyl- 3,4,5-tri-O-methyl- 3-0-pt olylsulfony 1-

4, Sdi-O-methyl- 3-O-(methylsulfonyl)-

2,3-O-Isopropyfidene-~- fructopyranose

1,4, Stri-O-methyl- 1,4,5-tri-O-acetyl-

2,3-O-Isopropylidene-D- fructofuranose

40-me thyl- 1 ,6-di-O-p-tolylsulfonyl-

40-methyl-

sirup

sirup

sirup sirup

195-197

201-203 82

sirup

149 sirup

81 64-65 sirup

124-125 84-85

142

sirup sirup 55-56

sirup

129-130 132-133

112-113

-23.7

- 18 -16.2 - 18

-

- - 26 - 25

- 153 -26.2 -

- 169 -156.6 -112 - 121 -

+29 +35 +I8

$6.5 +15 +I8 + 23

pet. ether 133

MeOH 132 MeOH 312 MeOH 132

338 -

338 MeOH 176 cyclohexane 187a

-

HzO 339 CHCls 187a

340 MeOH 176 HzO 267 CHC1, 176 MeOH 176

340

-

-

EtOH 176 EtOH 176 EtOH 176

EtOH 176 EtOH 176 EtOH 144 EtOH 176

(338) W. M. Corbett and D. Winters, J . Chem. Soc., 4823 (1961). (339) P. A. J. Gorin, L. Hough, and J. K. N. Jones, J . Chem. SOC., 2699 (1955). (340) J. K. N. Jones and W. A. Nicholson, J . Chem. SOC., 3050 (1955).


TABLE I V

n-Fructosides, and Their Esters arid Ethers

m.p.9 [ o l ] ~ , Rotation Refer- Glycoside “C. degrees solvent ences

Benzyl u-D-fructofuranoside 1,3,4,6-tetra-O-benzoyl- 1,3,4tri-0-bcnroyl-6-0-p-

1,3,4,6-tetra-O-(methylsulfonyl)- 1,6-di-O-p-toly]sulfonyl-

Ethyl 6-D-fructofuranoside 1 ,3,4,6-tetra-O-acetyl- I, 6-di-0-trityl-

3,4di-O-acetyl- 1 ,6-di-O-p-tolylsulfonyl-

Ethyl a-D-fructofuranoside 1 ,3,4,6-tetra-O-acetyl- 1 ,6-di-0-trityl-

tolylsulfonyl-

3, 4di-0-acetyl-

Ethyl a-D-fructopyranoside 1-N- (bis-2-chloroethy1)-

phosphoramidate

Methyl a(?)-n-fructofuranoside 1,4,6-tri-O-methyl- 3,4,6-tri-O-methyI- 1 -0-p-tolylsul fonyl-

3,4,6-tri-O-methyl-

3,4di-O-methyl- 3-O-p-toly lsulf ony l-

1,4,6-tri-O-methyl- 1 ,6-di-O-p-toIylsulfonyl-

3,4di-O-mcthyl- 6-0-trityl-

1,3, 4tri-0-methyl- 3,4di-O-methyl-

Methyl 6-D-fructopyranosidc I , 3,4,5-tetra-O-benaoyl-

6-O-trityl-

0.25 CHaOH 0.25 CzHaOH

Methyl a-D-fructopyranoside 3,4,5-tri-O-acetyl-l-O-methyl- 1-0-methyl-

108-109

168-169 102-104 155-158

sirup sirup

180-183 207-208 125-127

sirup sirup

140-150 142-144

sirup

sirup sirup

sirup nmorph. sirup sirup sirup glass sirup

amorph. sirup

amorph.

109-112 77-79 67-69

79-81

109 113

$33.7

+47.8 +47.1 $23.7

- 36 - 25 -2.3

$35.8

+65 +76

$44.7

-12.8

-

-8.3

+44 +67.6 +15.2 +32 +7.5

+14 $14 +28 +14.7 + 20 $12 +9.2

+24

-171 - -

+14.7 +34.1

CHCla

CHCls CHCla CHCls

H20 CHCls CHCls

CHCla

H20 CHCIs

CHCls

CHCI,

-

MeOH

MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH

CHCla - -

CHCla Ha0

140

140 140 140

138 138 138 138 138

138 138 138 138

132

176 176 176 176 176 176 176 176 176 176 176 176 176

206 206 206

209 209


TABLE V

Ortho Esters of D-Fructofuranose

m.p., [a]D, Rotation Refer- Ortho ester "C. degrees solvent ences

2,3-(Benzyl orthobenzoate) 1 , 4,6triacetate 1,4,6-tribenzoate 6-deoxy-6iodo-1 , 4-di-O-

(methylsulfony1)- 1 , 4,6trimethanesulfonate 1 , 4,6-tri-p-toluenesulfonate

2 , 3-(Cyclohexyl orthobenzoate) 1 ,4 , 6-tribenzoate

2,3-(Ethyl orthobenzoate) 1,4 , 6-tribenzoate

2,3-(Methyl orthobenzoate)

2,3-(Propyl orthobenzoate)

2,3,6-Orthobenzoate. CaClz

1 , 4,6tribenzoate

1,4,6-tribenzoate

1, Pdiacetate 1 , 4dibenzoate l14-dimethanesulfonate 1,4-di-p-toluenesulfonate

amorph.

145-147 67-68

100-102 96-97 95-96

11 1-112

113-1 14 126-127

91-92

140-141 amorph.

84 136-137 96-97

101-103

+17.3 +7.3 +5.8

-7.4 +17.4 +21

-9.4

-1.5 -2.3

-0.99

-4.2 -23.4 -38.2 -52.6 -12.9 -43.9

CHCla CHCl3 CHCl3

CHCls

CHCl3 CHCh

CHCli

CHCL CHCL

CHCls

CHCla MeOH CHCls CHCla CHCl, CHCla

144 144 144

140 144 144

144

147 147

144

144 140 140 140 140 140

TABLE VI

Esters of Cyclic D-Fructoses

Ester m.p., [a]D, Rotation Refer-

"C. degrees solvent ences

a-D-Fructopyranose 2,3,4,5-tetra-O-acetyl-l-O-

methyl- 99 - 120 CHC1, 209 3,4,5-tri-O-acetyl-l-O-methyl- 113 -115 CHCla 209 3-O-benzy l- amorph. -24.9 HzO 321

321 - - phenylosazone 151-152 8-D-Fructofuranose

1-0-p-tolylsulfonyl- sirup - 23 MeOH 176 3-0-pt olylsulfonyl- amorph. -36.5 MeOH 176

or-D-Fructofuranose 1 ,6-di-O-p-tolylsulfonyl- amorph. +17.1 CHCb 140


TABLE VII

1-c Derivatives of D-Fructopyranosea4*

map., Rotation Derivative "C. degrees solvent

1-C-Phenyl-&n-fructop yranose 163 -58.1 HzO -93.6 ---t -34.2 CsHaN

2 ,3 : 4,5-di-O-isopropylidene- 95-95.5 -15.4 CHC4 1-0-methyl- 151 -50.3 CHCla

1-0-methyl- 158.5 -94.5 HsO -127.22 --t -66.8 CsHsN

(341) F. Weygand and H. Golz, Chem. Ber., 87, 707 (1954).

TABLE VIII

keto-D-Fructose Derivatives

Derivative of m.p.7 [cu]D, Rotation Refer- keto-D-fructose "C. degrees solvent ences

3,4 , 5,6-Tetra-O-acetyl-l-deoxy- oxime

1,3,4,5,6-Penta-O-acetyl- dibenzyl dithioacetal diethyl dithioacetal 2,2-diethylsulfonate

1,S-Di-O-trityl-

oxime

diethyl dithioacetal

3,4,5,6-tetra-O-acetyl-

1-0-benzoyl-

3,4,5-tri-O-acetyI-

acetate

1-0-Trityl-

3,4,5,6-Tetra-O-acetyl-

80-80.5 112-113 68-69

110-111 80-81

144-145 140-141 94-96 159 225

13.2-135 170

148-149 112

112-113

207-208

+55.8

+34.8 +40.1 +20 $7.2 +9.6

-

- $112 $82

+I18 - 10 - 26 + 43 $52 +53

CHCls

CHCla CHCL CHClo CHCla CHCla

-

- CHCla CHCls CHCls CHCla CaHsN CHCla CHC4 CHC13

342 342 157 343 343 343 344 185 185 341 341 341 182 182 182 182

(342) F. Weygand, E. Klieger, and H. J. Bestmann, Chem. Ber., 90, 645 (1957). (343) E. J. Bourne and R. Stephens, J . Chem. Soc., 4009 (1954). (344) D. L. MacDonald and H. 0. L. Fucher, J . Am. Chem. Soc., 77, 4348 (1965).

TABLE IX Methyl Ethers of D-Fructose

m.p.9 Rotation Refer- Methyl ether of D-fructose "C. degrees solvent ences

1,3,4,5-Tetra-O-methyl- methyl fl-D-fructoside

1 ,3,4-Tri-O-methyl-

methyl 6O-trityl-~- fruc toside

1,4,5-Tri-O-methyl- 2,3-O-isopropylidene- phenylosazone

2,3-0-isopropylidene- methyl D-fructoside

3-O-ptolylsulfonyl-

1 ,4,6-Tri-O-methyl-

3,4,5-Tri-O-methyl- 3,4,6-Tri-O-methyl-

I , 2-O-isopropylidene-

1,2-0-cyclohexylidene- methyl D-fructoside

phenylosazone 3, PDi-O-methyl-

methyl 1,6-di-O-p-tolyl-

1-O-p-tolylsulfonyl-

sulf onyl-D-fructoside 4, SDi-O-methyl-

l,>O-isopropylidene- 3-O-p-tolylsulfonyl-

pheny losaz one (2, Sdichloropheny1)-

hydrazone 1-0-Methyl-

methyl fl-D-fructoside - H20 3,4,5-tri-O-acetyl-

methyl a-D-fructoside 3,4,5-tri-O-acetyl-

pheny lhydrazone (2,Pdinitrophenyl)hydrazone

98-99 33-34

75 72-73

sirup sirup sirup 66-67 sirup sirup sirup sirup sirup sirup sirup sirup 101

sirup 80-82

sirup

sirup

sirup 104-105 64-65 84-85 67-68

102 76-78

78.5 70

113 109 107 133

185-187

-121 -+ -118 -149.1 -56.2 -49.6

+9.2 - 143 +35 -

+24 --f +27 +10 +44 + 28

-121 -+ -128 +27 + $29

+10.8 +15.7

+67.6 +32

-

-62.5 -+ +5 - 62

+20 - 167 - 169 - 121

-27.5 + -8.2

- 45 -111-+ -52.7 -88.5- -82.3

-138.5 - 125 +34.1 +14.7 $14.9 -

HzO HzO HzO HzO

MeOH Hz0 EtOH

HzO EtOH MeOH MeOI1 Hz0 HzO MeOH

-

CHCIa -

MeOH MeOH EtOH Hz0

MeOH HzO MeOH MeOH EtOH

HzO MeOH Hz0 Hz0

HzO CHCb HzO

CHCla

- -

267 267 176 138

176 176 176 176 176 176 176 176 267 267 267 130 130 176 176 176 176

176 176 176 176 176

176 180 180 190a 1908 209 209 190a 180 345

- 180 40-Methyl- sirup -43+ - G l MeOH 176

- 9 3 4 -97 HzO 176 2,3-O-isopropylidene- sirup +6.5 EtOH 176

1,6-di-O-p-tolylsulfony1- 112-1 13 +23 EtOH 176 phenylhy drazone 157-158 -35- -14 HzO 176

(2,5-dichlorophenyl)hydrazone 139 -

(345) M. L. Wolfrom, E. P. Swan, K. S. Ennor, and A. Chaney, J . Am. Chem. Soc., 81,

294 5701 (1959).


TABLE X

Anhydrides of D-Fructose

m.p.9 [a]D, Rotation Refer- Derivative "C. degrees solvent ences

2,3-Anhydro-~-fructofuranose 1 4,6-tri-O-acetyl- 1,4,6-trinitrate 1 ,6-di-O-p-tolylsulfonyl-

1 ,Bdi-O-trityl-

1 , 3 Ptri-O-acetyl- 1 3,Ptri-0-benaoyl- 1 ,3,4-tri-O-methyl- 1-0-methyl-

3, Pdi-0-acetyl- 1,6(?)-di-O-trityl- 1-0-trityl-

tri-0-acetyl- pyruvaldehyde acetal

.CHsOH solvate

2 6-Anhydro-#?-D-fructofuranose

1 (f) ,2-Anhydro-~-fructofuranose

1,4:3,6-Dianhydro-~-frueto- furanose

(2,4-dinitrophenyl) hydrazone

hexanitrate dimorph

Di-D-fructose dianhydride I

Diheterolevulosan I hexa-0-methyl-

Diheterolevulosan I1 hexa-0-methy 1-

Diheterolevulosan I11 hexa-0-acetyl-

Diheterolevulosan I V hexa-0-acet yl- hexa-0-methy 1-

arnorph.

80.5 112

156 147 165

118-1 19 sirup

amorph. sirup sirup 74

224-226 150-155

sirup 203-205

sirup 156-157

140 138

146-147

100-100.5 240-242 130-131 279-281 268-269

122-122.5

+79.4 +57.4 +34.5 - - -

- 107 - 108 - 163 -54.5 -88.5

-38.5 -43.7

-10.7 +15.6

$91.9

-114

-

+49 +47.6

-

-21 - 183 - 159 - 309 - 199 - 243

EtOH EtOH EtOH - - -

HzO CHC13 CHCls H2O Hzo CHCla CHC13 CHCli

CeHe Hz0

Hz0 -

MeOH MeOH

-

CHC4 HzO CHCla HzO CHC13 CHCI,

189 189 189 189 189 189 138 138 138 137a 137a 137a 138 138

195 195

202 202

194 194

198

1 98 346 346 346 346 346

(346) B. Lindberg and B. Wickberg, Acta Chem. Scand., 7, 969 (1953).


TABLE XI

D-Fructosyl Halides, and Their Esters and Ethers

m.p., [a]D, Rotation Refer- Compound "C. degrees solvent ences

P-D-Fruc topyranosyl bromide 3,4,5-tri-O-acetyI-l-O-methyl- 1,3,4,5-tetra-O-benzoyl-,

&D-Fructopyranosyl chloride 3,4 , 5-tri-0-acetyl-1-0-methyl-

fl-D-Fructopyranosyl fluoride l13,4,5-tetra-O-acetyl- 3,4 I 5-tri-0-acetyl- 3,4,5-tri-O-methyl- 1-0-methyl-

0.25 AcOH

a-D-Fructopyranosyl fluoride 3,4,5-tri-O-acetyl-l-O-methyI- 1-0-methyl-

63 (dec.)

101-104

84 110-119

112 136135

85 102-109

54-56 amorph.

- 202

- 181

-167.3 -119 -90.4

-128.8 -90.6

-110 + -82

+52.9 -12.6 -45.2

CHCls

CHCla

CHCla H20 CHCI, CHCls CHC1, HzO

Hz0

HzO

209

206

209 208 208 209 209 209

209

209

D-FRUCTOSE AND ITS DERIVATIVES

TABLE XI1

Hydrazones of and Osazones from D-Fructose

297

m.p.9 [a]D, Rotation Refer- Derivative of n-Fructose “C. degrees solvent ences

N-(Methylbenzothiazoly1)- hydrazone

penta-0-acetyl-

hydrazone N-(Dithiocarbomethoxy)-

Hydrazone Isonicotinoylhydrazone Phen ylhydrazone

p-bromo-a-methyl- p-carbethoxy-

a-methyl- p-carboxy- 2,3-dichloro- 2, Pdichloro- a-methyl-

tetra-0-acetyl- 2, Pdinitro-, p-dioxane

pyridme Phthalazinylhydraeone Pyridy l-3-hydrazone Pyridyl-4hydrazone o-Toly lhy drezone Phenylosazone

2,3-dichloro- 2,4-dichloro- 2,5-dichloro- 3(?) ,Pdichloro-

(4Phenylthiazol-2-y1)osazone

15S160 156

164 (dec.) 136-137

90

146 (dec.) 197-198 196-197 201-202

161 127

169-170 151-153

119 176-178 173-174

118 (dec.) 156 186 146

202 226 242 199 223

347 348

227 349 350

216 216 216 216 218 218 35 1 352 351 212 212 353 295 295 219

218 218 218 218 354

(347) R. Riemschneider, Monatsh., 89, 683 (1958). (348) R. Riemschneider, Monatsh., 91, 639 (1960). (349) A. Miyake, Pharm. Bull. (Tokyo), 1, 89 (1953). (350) H. H. Fox, J . Org. Chem., 18, 990 (1953). (351) H. Ohle, G. Henseke, and A. Cryzenick, Chem. Ber., 86, 316 (1953). (352) 5. Akija and S. Suzuki, Yakugaku Zasshi, 76, 126 (1956). (353) E. Menziani, Boll. Sci. Fac. Chim. Znd. Bologna, 12, 162 (1954). (354) H. Beyer, G. Henseke, and W. Liebenow, Chem. Ber., 86, 10 (1953).


TABLE XI11

D-Fructosylamine Derivatives

m.p.9 [.ID, Rotation Refer- D-Fructosylamine O C . degrees solvent ences

N-Bensy 1-

mono-0-isoprop ylidene- tri-0-benzoyl-

N- (o-Carboxypheny1)-

N-(p-Hy droxypheny1)- N-(pMethoxypheny1)-

N-Ethyl-

tetra-o-acetyl- N-(p-Phenetidin0)- N-Phenyl-

1 3,4,5-tetra-O-acetyl- 1,3,4,5-tetra-O-bensoyl-

N-P-Tolyl-

1 ,3 4,5-tetra-O-acetyl- 1 3 4,5-tetra-O-benaoyl-

107-108

124-125 125-125.5 139-140

100 151 152

127 140 149

152-153 151 147 151

10a-102 138

155-156 129 167.5

141-142

-42.5+ +6.3 -140+ -2.2

-64.5 --* +14.6 -5.0 - 18

-4.4+ -77.2 -i99 + -132 -165-t -118

-195.5 -114 -179.8

-209 + -164 -196.7 -186-t -175 -200+ -100

-149.6 - 132

-207.7 + -177 -190.4 - 141 -131.4

240 240 240 240 355 241 231 231 232 23 1 232 241 232 356 233 230 230 230 232 230 230

(355) Y. Inoue, K. Onodera, and S. Kitaoka, Nippon Nogeikagaku Kuishi, 26, 291

(350) T. Miwa, M. Takeshita, and S. Nakamura, Koso Kagaku Shimpoziumu, 13, 92 (1952).

(1958); Chem. Abstracts, 63, 13226 (1959).


TABLE XIV

1-Amino Derivatives of 1-Deoxy-D-fructose

Derivative of l-deoxy- map., Gal% Rotation D-frUc tose "C. degrees solvent

I-L- Alanino- 184 (dec.) - 62 HzO 153 -56.9 HzO

I-Amino-, acetate 145-1 46 - 63 HzO 137 -69.8 HzO

143-145 - -

hexa-0-acetyl- 139-140 -7 CHCla I-Anilino- 128-129 -83-1 -45 C6HbN I-(N-Methylani1ino)- 163-164 -37 -+ -24 C6H6N

hydrochloride 120-121 - -

1-(p-Ethylani1ino)- 154 - 45 CsHsN I-(o-Anisidmo)- I50 - 43 C6HsN 1-(m-Anisidin0)-, oxalate 124 (dec.) -36.5 C&N/&O 1-tbrginino- amorph. - 13 HzO 1-(o-Anthranilin0)- 100-102 +43.3 MeOH I-(tAsparagin0)- 154 (dec.) -52 -+ -61 HzO 1-(Benzy1amino)- 113-115 -34.4 MeOH

oxalate 146-148 -51.3 HzO 165 (dec.) -48+ -39 HzO

I-(N-Butyl-N-benzy1amino)- 106-107 - 94 CsHaN 1-(N-Cyanomethyl-N-

benzy1amino)- 145-147 -56.6 C&N 1-(N-Ethylbenzy1amino)- 119-120 - 99 CaHsN

acetate 144-146 - 33 H2O 1-(N-Methylbenzy1amino)- 143-144 -74.9 CaH6N

acetate 152-153 - 58 Hz0 hydrochloride 160-162 -78.8 HzO

l-(Butylamino)- 88-90 -40.2 MeOH hydrochloride 134-135 00.0 HzO oxalate 118-120 -20.4 HzO

I-(Dibenav1amino)- 161-162 -89 -+ -35 CaH6N 1- (Di-2-hydroxyethy1amino)-

2 , 3 : 4 , 5-di-O- - - isopropylidene- 191-193

l-(Di-2-chloroethylamino)- 2 ,3 : 4,5-di-O-isopropyl-

2,3-O-isopropylidene- 111-113 $16.3 H20 1-(Dodecy1amino)- 103-104 - - I-L-Glycino- 145-146 -68.8 Ha0

157 (dec.) -65.8 Ha0 1-(p-Hydroxypheny1amino)- 108 -42+ -37 HC1

1- (L-a-Lysino)- sirup - 27 Ha0

idene 159-161 -3 CHCli

penta-o-acetyl- 134 $15.5 CHCb

Refer- ences

254 357 277 275,282 358 277 277,358 260 260 359 359 257 360 361 238,254 259 258,259 276 261,362

261,362 261,362 261 261,362 261 , 362 261,362 259 261 258,259 248,363

269

269 269 364 357 254 23 1 23 1 360


TABLE XIV-Continued

Derivative of l-deoxy- m.p., ral% Rotation Refer- D-fructose "C. degrees solvent ences

amorph. 104107 105-106

170 (dec.) 127

135-150

- 28 - - -

- 33 - 57

-115 + -50 - 92 - 86 - 82 -44.6 - 33 - 40

HzO 360 360,365 242,364 365 238 363 358 249 249 249 259 258,259 257

l-(Ir?-Lysino)- 1-(0ctadecylamino)-

oxalate 1-tPhenylalanino- I-Piperidino-

1-IrProlino- HzO CHsOH

1- (Propylamin0)- oxalate hydrogen oxalate

1-(2,6-Dihydroxy-5-nitro- Ppyrimid iny1amino)-

oxime

3,4,5-tri-O-acetyl-, I-Sarcosino-

lactone 1-cSerino- 1-cThreonino- 1- (m-Toluidino) -

1-(N-p-Bromophenylazo-p

1-(N-2,5-Dichlorophenylazo-

1- (N-p-Nitrophenylaso-

1-(N-Phenylazo-p-to1uidino)- 1- (N-pMethylphenylazo-

2,3,4,5-tetra-O-acetyl- I-(N-Methyl-p-to1uidno)-

p henylhydrazone I-tTryptophano- 1-IrValino-

oxalate

to1uidino)-

p-to1uidino)-

p-to1uidino)-

p-to1uidino)-

137 (dec.) 119 (dec.)

80-81 78-80

118-120 138 (dec.)

291 amorph.

-49.8 0.05 N NaOH -48+ -51 Hz0

282 366

198-199 amorph. amorph. 140-141

110 (dec.)

156-158

- 176 CHCla -50.2 H20 -53.4 HzO

-63.9 --t -21.9 CaHsN - -

366 254 254 275 257

+60.7+ -8 CSHKB

-12.7 --t +63.5 CsH6N

280

179-180 280

144-146 147-148

+129.5 + -29.9 C6HsN +167.6 -+ 0.0 CIHfiN

280 280

+235 --f +32.6 +118

-36.5 -+ -30 -16.7 -7.2 - 47 -47.6

128-130 114-115

148 168-169 amorph.

141 (dec.) 155-160

185-186

280 280 260 260 367 238 254 238 phenylhydrazone

1- (N-m-Dichlorophenylazo-

1- (N-Nitroso-o-xylidino)- l-(6-m-Dichloropheny?azo-

o-xylidino)-

o-xylidino) -

186-187 139-140

-27.5 + +56.5 CSHIN +6.4 C&N

281 281

145-146 281


TABLE XIV-Continued

1-Amino Derivatives of 1-Deoxy-D-Fructose

Derivative of l-deoxy- m.p., CQID, Rotation Refer- D-fructose "C. degrees solvent ences

l-Deoxy-&D-fructopyranose

1-Amino-, HCl

I-(pTo1uidino)- 3,4,5-tri-O-methyl-

1-N , 2-0-benzylidene-

3,4,5-tri-O-methyl- I-N ,2-0-(p-nitro-

benzy1idene)- 3,4,5-tri-O-methyl-

methyl D-fructoside 4,5-O-isopropylidene-

156-157 153-1 54 196-198 198-200

198 151-153

210-212 133-134 sirup

123-1 24

- 106 -64 --+ -21 - 148 -142.6

- 122 -

-79.7 -58.3 .--t -54.7

-8.3 - 95

267

267 268 257 267

250,256,363

268 267 267 368

1-Deoxy-cY-D-fructopyranose

1-(p-To1uidino)- 3,4,5-tri-O-methyl- 126 (dec.) +49 --* +37.7 HzO 267

4,6-O-Benzylidene Derivatives

I-DL-Alanino-, bopropy1 ester 149 1- Anilino- 195 1- (N-Met hy lanilino) - 158-159 1-(o-Anisidin0)- 151-152

1-(o-Anthranilin0)- 192-194 1-(m-Anisidin0)- 142

benz ylisothiouronium 128-129 1- (m-Anthranilin0)- 147 1-(Benaylamino)- 130

1- (Buty1amino)- 106 binoxalate 170 (dec.)

oxalate 164 (dec.)

dibenzyl ester 12&122

diisopropyl ester 107 1-Glycocol, beneyl ester 87

isobutyl ester 99

isopropyl ester 118

I-bGlutamino- 157-158

oxalate 90-95 (dec.)

oxalate 130 (dec.)

oxalate 132 1-Piperidino- 130

- 57 - 97

-116 - 92 - 94

-119.3

- 95 -67.6 -6 - 75 - 73 -47.5 - 49

- 54 - 59 - 64 - 54 -69.5 -38 - 57

-

-

257 260 260 257 257 272 361 257 369 369 257 257 259 259 259 259 257 257 257 255,257 255 257


TABLE XIV-Continued

Derivative of 1-deoxy- m.p., COrlDY Rotation Refer- D-fructose "C. degrees solvent ences

I-Propylamino- 106-108 oxalate 170 (dec.)

1-(3-Methoxypropylamino)- 172 1-DL-Serino-, isopropyl ester 164

1- (pToluidino) - 152 oxime 162

1-(N-Methyl-p-to1uidino)- 171 4,6-Di-O-methyl Derivatives 127-129

1-(benaylamino)-, oxalate 9'7-98

1-(m-To1uidino)- 147-148

1 - (buty lamino) - 1-(propy1amino)- 102- 104

97-98

6-0-Methyl Derivatives

l,%Dideoxy-D-fructose 1-(propy1amino)-, oxalate 100 (dec.)

Derivatives l-amino- sirup

hydrazone 248 (pnitropheny1)-

Di- (1-deoxy-D-fructose) Derivatives l-hly sino- sirup

l-piperazino- 146 l-glycino- 112

- 100 - 80 -72.5 - 49 -84 - 89 -

-116 $24.4 $28.4 +28.4 $30

-4.8

-

-

- 37 - 78 -88

CsHsN 258

370 -

370 -

HzO 360 HzO 357 HzO 288

(357) E. F. L. J. Anet, Aust~alian J . Chem., 10, 193 (1957). (358) J. Druey and G. Huber, U. S. Pat. 2,903,443 (1959); Chem. Abstracts, 64, 2200

(359) F. Micheel and B. Schleppinghoff, Chem. Ber., 89, 1702 (1956). (360) K. Heyns and H. Noack, Chem. Ber., 96, 720 (1962). (361) F. Lingens and E. Schrauen, Ann., 666, 167 (1962). (362) G. Huber and J. Druey, Brit. Pat. 888,239 (1964); Chem. Abstracrs, 62, 1734

(363) J. E. Hodge, U. S. Pat. 2,715,123 (1955); Chem. Abstracts, 60, 7146 (1956). (364) J. G. Erickson, U. S. Pat. 2,815,399 (1957); Chem. Abstracts, 62, 6824 (1958). (365) G. R. Ames and T. A. King, J . Org. Chem., 27, 390 (1962). (366) A. Klemer and F. Micheel, Chem. Ber., 89, 1242 (1956). (367) K. Heyns and H. Noack, Chem. Ber., 97, 415 (1964). (368) S. Tejima and Y . Oketani, Yakugaku Zasshi, 81, 18 (1961); Chem. Absfracts, 66,

(369) B. Helferich and A. Porck, Ann., 682, 233 (1953). (370) K. Onodera, T. Uehara, and S. Kitaoka, Bull. Agr. Chem. SOC. Japan, 24, '703

(1960).

(1965).

12305 (1961).

(1960).

D-FRUCTOSE AND ITS DERIVATIVES

TABLE XV

1-Amino Derivatives of “1-Deoxy-D-fructuronic Acid”

303

Derivative of “l-deoxy- m.p.9 CUlD, Rotation Refer- D-frUCtUrOniC acid” “C. degrees solvent ences

l-tAlanino- l-.obAlanino- 1-Amino- 1-Aniline

potassium salt 1 - t Asparagino- 1- (Benzy1amh.o)- 1-(Buty1amino)- 1-(Cyclohexv1amino)- 1-(N , N‘-Dibenzy1amino)- l-L-Glycino- 1-I.-?-Lysino- 1-(cPhenyla1anino)- 1-Piperidino-

1-L-Prolino- 1-p-Toluidmo-

1-L-’Valino-

piperidine salt

potassium salt

108 (dec.) 107 (dec.)

amorph. 145 (dec.)

153-1 55

- 128-129

103

148-150 109 (dec.)

157-159

- 139-141 157-158 87-88

110 (dec.) 137-138 139-140

165 (dec.)

“1-Deoxy-D-fructuronamide”

1-p-Anisidino- 145-146 lactol form 78-80

1-p-Phenetidino- 141-142 1-p-Toluidino- 158-159

+16.1 Hz0 $13.9 Hz0 $51.8 HzO

$2.5 He0 t l . 2 HzO

+13.1 HzO +24.3 H20 +24 HzO $11.4 MeOH $13.8 HzO +22.1 HzO $21.7 HzO +33 * 9 HzO $31 MeOH -31.9 Hz0

$2.7 HzO +30.8 HzO

- -

- -

+7.6+ -2.9 Hz0 -16.5+ -13.7 HzO

-9.3 HzO -15.6 Ha0

264 264 263 264 263 266 265 265 265 265 264 266 266 265 265 266 263 263 266

371 371 371 37 1

TABLE XVI

Miscellaneous Derivatives of D-Fructose

m.p., Derivative “C.

D-Fructose azine 44-48

D-Fructazine 237 Deoxy-D-fruc tazbe 162 D-Fructose thiobenzhydrazide 175-176 D-Fructose

deca-0-acetyl- 71-75

6-acetamido-6-deoxy- sirup

C a h degrees

Rotation Refer- solvent ences

- -

-80 - 78 -24.2

-8

295 295

HzO 293 HzO 293 CaHiiN 372

Hz0 292

- -

(371) H. Nakajima, Yakugaku Zasshi, 81, 811 (1961); Chem. Abstracts, 66, 27096 (1961). (372) B. Holmberg, Ark&. Kemi., 4, 33 (1952).


TABLE XVII

Sulfur-containing Compounds of D-Fructose

m.p.9 ral% Rotation Refer- Compound “C. degrees solvent ences

D-Fructop yranose 1-S-ethyl-1-thio- 87-88 -71.3 + -62.8 HzO 297

propylidene- sirup -58.4 CHCla 297 2,3 : 4,bdi-0-iso-

D-Fructofuranose 6-S-benz yl-6-thio-

2,3-0-isopropylidene- 95-96 -13.9 MeOH 298 1-0-p-tolylsulfon yl- 120-121 -6.7 CHCla 298

2,3-0-isopropylidene- 76-77 +4.9 MeOH 298

2,3-O-isopropylidene- 93 -34.8 CHCli 298

2,3-0-isopropylidene- 70-72 -2.8 CHCI, 298

6-thio-

6-S-benzyl-l-deoxy-6-thio-

1-deoxy-6thio-

TABLE XVIII

Branched Derivatives of D-Fructose

m.p.9 ra l% Rotation Refer- Derivative “C. degrees solvent ences

-Fructose cyanohydrin

hexa-0-acetyl- “D-Fructoheptose”

phenylhy drazone

(p-nitrophenyl) hydrazone (2, Sdichloropheny1)-

hydrazone “D-Fructoheptitol”

3-0-benzoyl- hepta-o-acetyl-

3-0-benzoyl- “D-Fructoheptonic lactone”

l-Deoxy-l-(p-toluidino)-D- 3-0-benzoyl-

fructose cyanohydri penta-0-acetyl-

105-110 108-109

81-82 174-175 173-174

143 144.5 178.5

188-190 sirup glass 70.5

129.5 150-152

63-67

137-138 136

-3.3

+12.1 +50.3 + 4-43.7 +51.9 + +42.9 +12.8+ +7.6 +9.8+ +1.5

-

-26.3+ -21.6

+7.9 + +5.0 -5.7

+13.7 $31.6 +31

+45.5 -

+17.6+ +8.3

+12.9 -31.8

316 318 316 316 318 316 318 318

318 318 319 318 319 318 319

316 316 316


TABLE XIX

Dicarbonyl Condensation Products of D-Fructose

m.p.9 [a]D, Rotation Refer- Condensation product of "C. degrees solvent ences

Ethyl acetoacetate with

1-Amino-1-deoxy-o-fructose

1-(p-Anisidino)-1-deoxy-D-fructose

1- (p-Anthrani1ino)-1-deoxy-n-

tetra-0-acetyl-

tetra-0-acetyl-

fructose tetra-0-acetyl-

l-Deoxy-l-(p-tohidino)-D-fructose N-Ben2 yl-D-fructosylamine N-Butyl-D-fructosylamine

N-Ethyl-D-fructosyladne tetra-0-acetyl-

tetra-0-acetyl-

2,4-Pentanedione with

1-Amino-1-deoxy-D-fructose

l-(p-Anisidino)-l-deoxy-D-fructose

1- (p-Anthranilino)-l-deoxy-D-

tetra-0-acetyl-

tetra-0-acetyl-

fructose tetra-0-acetyl-

tetra-0-acetyl- 1-Dcoxy-l-(p-tohidmo)-D-fructose

N-Benzyl-D-fructosyladne N-But y 1-D-fruct osyhmine

N-Ethyl-D-fructosylamine tetra-0-acetyl-

tetra-0-acetyl-

139-141 -46.2 - 5657

103 172 -27.9

-

154 -21.8 - 107

160 -36.9 140-141 -15 168-169 -5.5

68-70 -

143-1 44 0 94-95 -

169-171 -38.2 164-165 -

184 - 38 - 117

193 -36.8 150 184 -35.9 160

165-166 -5.3 154-155 -23

74-76 - 149-150 -6.1 129-130 -

-

-

334 334 335 335

335 335 335 336 336 336 336 336

334 334 335 335

335 335 335 335 336 336 336 336 336

[Advances in Carbohydrate Chemistry] Volume 22 || D-Fructose and Its Derivatives

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