2,4:3,5-di-O-benzylidene-D -glucitol

Cmbohydrate Research Elsevier Publishing Cornpay,Amsterdam Printed in Belgium

2,4:3,5-DI-O-BENZYLIDENE-D-GLUCITOL T. G. IWINNER, E. J.

BOUFCNE, AND

Chemistry

Department,

Englefield

Green,

Surrey

Royal (Great

D. LEWIS

Hollorvay

CoIlege

(University

of London),

Britain)

(Received March Ist, 1966)

INTRODUCTION

The diacetal obtained by condensing r,6-di-O-benzoyl-D-glucitol with benzaldehyde, in the presence of zinc chloride, was assumed to have a 2,4:3,5_arrangement of acetal ring+. Recently, this assignment of acetal groups was confirmed by n.m.r. spectroscopys. The chemical evidence below provides an independent proof of the structure. RESULTSAND DISCUSSION The parent diacetal tl),obtained by saponification of the dibenzoate, yielded a diacetate and a dimethyl ether, both crystalline. Proof that the two free hydroxyl groups of the diacetal were at the I- and 6-positions was obtained as follows. Its dimethyl ether, on mild, acid hydrolysis, yielded a syrupy D-glucitol dimethyl ether (2) which, in turn, afforded a crystalline tetra-acetate. The tetra-acetate, after deacetylation, consumed 2.8 mol. of periodate, liberating 2.0 mol. of formic acid and methoxyacetaldehyde, characterised as its knownp-nitrophenylhydrazone (1.5 mol.). The dimethyl ether (2) migrated on molybdate ionophoresis as expecteds for a r,6_disubstituted glucitol. The positions and sizes of the acetal rings in the diacetal (1) were not determined by partial, acid hydrolysis, because this reaction was shown to lead to acetal migration4. Instead, partial hydrogenolysis was used; this reaction was shown to avoid migration. Chromatography on alumina of the reaction mixture yielded a glassy solid and the known 2,4-O-benzylidene-D-glucitol (3). The a,+acetal (3) was shown to be identical with an authentic sample prepared, in good yield, by directly condensing D-gh3CitOl and

benzaldehyde

(cz

preparation

Acetylation of the glassy solid gave a compound

of

2,4-O-furfurylidene-D-@ucitoF).

which gave correct elemental anal-

yses for a tetra-O-acetyl-mono-O-benzylidenehexitol. Acid hydrolysis of the saponified tetra-acetate showed the hexitol to be D-glucitol (isolated as its hexa-acetate); benzaldehyde was obtained as its dimedone (5,5-dimethylcyclohexane-r,pdione) derivative. That the benzylidene group was in fact spanning the 3,5-positions (4) was shown by periodate oxidation (I -02 mol. of oxidant being consumed and 0.94 mol. of formaldehyde being liberated)_ Mild, acid hydrolysis of the main oxidation fission product yielded D-arabinose, which was characterised as its bisphenylboronate. Carbohydrate

Res.,

z (1966)

421-425

T. G. BONNER, E. J. BOURNE,

422

D. LEWIS

Borohydride reduction of 2,4-0-benzylidene-aldehydo-D-arabinose oxidation yielded 2,4-0-benzylidene-D-arabinitol, isolated as its crystalline

from the triacetate.

Saponification, followed by mild, acid arabinitol on paper chromatography.

moved

hydrolysis,

gave material

which

as

4

A 3,5-acetal of D-glucitol (4) and 2,gacetals of D-arabinose and D-arabinitol are less thermodynamically stable than other monoacetals which can be formed by the parent unsubstituted compounds (cJ MiW). In particular, the D-arabinose acetal must exist with the sugar moiety in the open-chain form. Hydrogenolysis thus provides a synthetic route to thermodynamically unstable benzylidene acetals not readily accessible by acid hydrolysis or synthesis_ Di- and tri-acetals are liable to isomerise during treatment with acid and, in cases of this sort, evidence from hydrogenolysis is likely to be a more reliable indication of structure. EXPERIMENTAL

Whatman No. I paper was used for paper chromatography. Solvent (A) was butan-I-al-ethanol-water (40: I I: Ig, v/v). Potassium periodate-silver nitrate-sodium were used for detection. Quantitative hydroxide or 2,4-dinitrophenylhydrazine’ and formic acid determination+ were periodate oxidationss, and formaldehydegJO performed by standard procedures. 2,4:3,5-Di-0-benzylidene-D-glucitol (m.p. 205207~) was prepared by the method12 of Haworth et al., who recorded m-p. 208“.

The diacetal(o.50 g) gave needles of the diacetate (0.41 g, 66%),m.p. I88.5-Igo (c 1.8,chloroform). (Found: C, 65.1; H, 5.8; (from IO parts of benzene), [c&s -10.9~ Ac, 19.15. C24HZsQs talc.: C, 65.15; H, 5.9; AC, 19.5%).

The diacetal (3-o g), dry methyl iodide (4.7 N,N-dimethylformamide (g ml) were shaken for silver salts and volatile material were removed in was purified on alumina (75 g), using benzene as roq-Iog”) in fraction I (50 ml) could not be purified material Carbohp+ate

from Res.,

the column 2

(x966)

gave the dimethyl

421-425

ml), silver oxide (3 g), and dry 27 h at room temperature. The the usual way, and the product eluent. The material (0.6 g, m-p. by crystallisation. The remaining

ether

(o-98

g, 30x),

m.p.

I tg-I~o”,

423

2,4:&s-DI-O-BENZYLIDENE-D-GLUCITOL

[c&f t0.5” (c 2.1, chloroform), as needles from 8 parts of ethanol (Found: C, 68.2; H, 6.8: OMe, 16.3. CZSH~SOScaIc.: C, 68.35; H, 6.8; OMe, 16.1%).

2,4:3,5-Di-O-benzylidene-r,6-di-O-methyl-~-glucitol (0.30 g) was refluxed for 15 min with a mixture of ethanol (I ml) and o. IN hydrochloric acid (I ml). The mixture was concentrated. The acid treatment and concentration were repeated, and then sodium hydrogen carbonate (0.02 g) was added and the whole evaporated to dryness. I$-Di-O-methyl-D-glucitol had RF 0.51 in solvent (A) and MS (rate relative to glucitol) 0.94 on molybdates ionophoresis. Acetylation of the residue yielded, after crystallisation from a mixture of light petroleum (3 ml) and ethanol (0.3 ml), the q&4,5-tetra-acetate (0.20 g, 68x), m-p. 72-74”, [a]~*’ f24.0” (c r-5, chloroform) (Found: C, 50.7; H, 6.7; OMe, 16.5; AC, 45.8. C1sHssOre talc.: C, 50.8; H, 6.9; OMe, 16.4; Ac, 45.55%). Periodate oxidation of I,6-ni-0-metflyl-D-glucitol Tetra-0-acetyl-r,6-di-0-methyl-D-glucitol (I mol.) was deacetylated with methanolic sodium methylate. The methanol was removed, and the residue consumed 2.7, 2.8, and 2.8 mol. of periodate (7-55 mol. initially present) (theor., 3.0) after 0.5, 2.0, and 7.3 h, respectively, and gave 2.0 mol. of formic acid (corrected for methoxide) (theor., 2.0). The tetra-acetate (0.036 g) was deacetylated as above, and the solvent-free residue was treated with sodium periodate (0.08 g) in water (2 ml). After 0.5 h, the solution was concentrated, more water (1.5 ml) was added, and the solution was concentrated. The total distillate was treated with a warm solution of p-nitrophenylhydrazine13. Crystallisation of the precipitate from aqreous ethanol gave methoxyacetaldehyde p-nitrophenylhydrazone (0.030 g, 1.5 mol.), m-p. and mixed m-p. 113I 16”. Partial hydrogenolysis

of z&.$:3,5-di-O-benzylidene-D-giucizol

The diacetal (4 g) in methanol (170 ml) was added to pre-hydrogenated palladium black (3-4 g) in methanol_ The suspension was allowed to stand, with occasional shaking, until ca. 0.5 1 of hydrogen was consumed (1-6 days). The catalyst was removed, and the solution was concentrated. The residue, dissolved in absolute ethanol (200 ml), was passed through alumina (IOO g). Fraction I, eluted with absolute ethanol (0.6 l), gave unchanged diacetal (1.3 g), RF in solvent (A) o.gr ; using dimethyl sulphoxide-benzene (1:50, v/v) on dimethyl sulphoxider*, RF 0.38 (1,3:2,4-di-0-benzylidene-D-glucitolla, RF 0.43, was absent). Increasing amounts of water (up to 5%, v/v) in the eluent gave 3,5-0-benzylidene-D-glucitol (2,4-O-benzylidene-L-gulitol), Rp 0.71 in solvent (A>_Industrial methylated spirit-water (g8:2, v/v) gave 2,4-0-benzylidene-D-glucitol (ca. 0.2 g), m.p. and mixed m.p. with the sample prepared below, 172-174-5”~ RF 0.74 in solvent (A)_ The 3,5-benzylidene acetal yielded a tetra-acetate (0.4-0.6 g), m-p. 98-99” (from ethanol), [& - 13.8” (c 1.55, Cdmhydrare

Res.,

2 (1966)

421-425

424

T.G.BONNER,E.J.BOURNE,D.I;E\NIS

&loroform), Ac, 39.3%).

(Found: C, 57-q;

H, 5.9; AC, 39.3.

hH26010

cak.:

C,

57-5; H, 6.0;

2,q-0-Benzylidene-D-glucitol

The acetal was prepared by using a modification of the preparations of 2,4-0furfurylidene-D-glucitol. D-Glucitol (g g). dissolved in 3~ sulphuric acid (2.5 ml), was treated with benzaldehyde (5 ml) and warmed to 70”. After cooling and standing overnight, the mixture was crystallised from water (50 ml) containing sodium hydrogen carbonate (0.8 g), any insoluble material being removed by filtration. The product (5.6 g,42%) had m.p. 173-175" (&.ls, 176-177"). Hydroiysis of 3,5-0-benzylidene-D-glucitol

Tetra-O-acetyl-3,5-O-benzylidene-D-glucitol(o.o281 g) was saponified, and the but using residue was hydrolysed, as described 1’ for 4,6-0-butylidene-D-glucitol, 0.1~ acid (3 ml). The benzaldehyde bisdimedone derivative (65%) had m.p. and mixed m.p. Ig4-196”. The D-glucitol hexa-acetate (78%) had m-p. and mixed m-p. 97-100”.

Periodate oxidation of 3,5-0-benzylinene-D-glucitol

Tetra-0-acetyl-3,5-0-benzylidene-D-glucitol (I mol.) was deacetylated with methanolic sodium methyIate. The methanol was remuved, and the residue consumed 0.80, 0.87, 0.95, and 1.02 mol. of periodate (3.4 mol. initially present) (theor., 1.0) after 0.5, 5.5, 12.5, and 23 h, respectively, and gave 0.94 mol. of formaldehyde (theor., 1.0) after 25 h. Under similar conditions, tetra-0-acetyl-2,4-O-benzylideneD-glucitol, after deacetylation, consumed 0.99 mol. of periodate (theor., 1.0). Tetra-0-acetyl-3,5-0-benzylidene-D-glucitol (0.58 g) was treated with 0.2~ methanolic sodium methylate (0.8 ml). The methanol was removed, and a solution of sodium periodate (0.4 g) in water was added. After 3 h, the suspension was freezedried, and the residue was extracted with boiling ethyl acetate. Part (0.08 g) of the extracted material [cu. 0.28 g, RF 0.87 (single spot) in solvent (A)] was hydrolysed as described above for the acid hydrolysis of 3,5-0-benzylidene-D-glucitol. The dry, neutralised residue, which moved as arabinose, but not xylose, in solvent (A), was treated with phenylboronic anhydride (0.08 gj in boiling methanol. The methanol was evaporated, and the residue was extracted with boiling light petroleum. Four crystallisations from light petroleum gave D-arabinose bisphenylboronate (0.012 g, II%), m.p. 157-159”, mixed m.p. with authentic D-arabinose bisphenylboronate (see below, m.p. 159-161.5~), 157-158”; the infrared spectra (KBr discs) were identical. D-Arabinose bisphenylboronate

This C, 63.7; H, Co.3 g), in m-p. 166”,

compound, m.p. r5g-16r.5”, [& -8.4” (c 1.8, dry benzene). (Found: 5. I. Cl7Hl6&05 talc.: C, 63.4; H, 5.0%), was prepared from D-arabinose 75% yield, as described above. L-Arabinose bisphenylboronate18 has [a]g +8-s” in benzene.

Carbol?ydmfe Res., 2 (x966) 421-_425

2,4- U-Benzylidene-aZdehD-arabinose (0. I g, from the oxidation) was reduced by borohydride, as described 17 for the reduction of 4,6-O-butylidene-Dglucose. The product was acetylated and yielded, from ethanol, 1,3,5-tri-O-acetyl2,4-0-benzylidene-D-arabinitol (0.05 g), m-p. 79-80~ (Found: C, 58.9; H, 5-gC1sH220s talc.: C, 59.0; H, 6.0%). Hydrolysis of 2,4-0-benzylidene-D-arabinitol The triacetate was deacetylated, and the residue was hydrolysed with O-IN hydrochloric acid in the usual way. The hydrolysate moved as arabinitol (RF 0.27),

and not xylitol (RP o-25), in solvent (A). ACKNOWLEDGMENT

The authors thank Imperial Chemical Industries Limited for financial assistance. SUMMARY

Chemical proof is given that the acetal groups in the known 2,3,4,5-di-Obenzylidene-D-glucitol span the 2,4- and 3,5-positions. REFERENCES I L. VON VARGHA, Ber., 68 (1935) 1377~ 2 N. BAGGETT, K. W. BUCK, A. B. FOSTER, AND

J. M. WEJJEIER, J_ Chem. Sot., (1965) 3401. 3 E. J. BOURNE, D. H. H~TSON, AND H. WEIGEL, J. Chem. Sot., (1960) 4252; H. WEIGEL, Adt;an. Carbohydrate Chem., 18 (1963) 61. 4 T. G. BONNER, E. J. BOURNE, AND D. LEWIS, unpublished results. 5 R. C. HOC-, U. S. Par. 2,584,Izg [Chem. Absrr., 46 (1952) 81481; S. L. RUSKIN AND R. C. HOCKE~~, U. S. Par-, z,853.495 [Chem. Abstr., 53 (1959) 5150]. 6 3. A. MILLS, Aduan. Carbohydrate Chem., IO (1955) I. 7 D. E. BLAND, Numre, 164 (1949) Iog3. 8 G. 0. ASPINALL AND R. J. FERRIER,Chem. Znd. (London), (1957) 1216. g J. MITCHELL, I. M. KOLTHOFF, E. S. PROSKAUSER,AND A. WEISSBERGER,Organic Analy.vis, Vol. I, Interscience, New York, 1953, p. 288. IO W. E. A. MITCHELL AND E. PERCIVAL, J. Chem. SOL, (1954) 1423. II E. L. HIR~T AND J. K. N. JONES, J. Chem. Sot., (1949) 1659. 12 W. N. HA~VORTH, H. GREGORY, AND L. F. WIGGINS, J. Chem. Sot., (1946) 488. 13 J. K. HAI.IILTON, G. W. HUFFMAN, AND F. SMITH, J. Am. Chem. Sot., 81 (1959) 2173. 14 B. WICKBERG, Acfu Chem. ScatId., 12 (1958) 615. 15 J. K. WOLFE, R. M. HANN, AND C. S. HUDSON, J. Am. Chem. Sot., 64 (1942) 1493. 16 S. J. ANGYAL AND J. V. LAWLER, J. Am. Chem. Sot., 66 (194) 837. 17 T. G. BONNER, E. J. BOURNE, AND D. LEWIS, J. Chem. Sot., !Ig65) 7453. 18 M. L. WOLFROM AND J. So~nls, J. Org. C/tern., 21 (1956) 815.

Corbohydrnte Res., 2 (1966) 421-425