THE SYNTHESIS OF @-D-GLUCOPYRANOSYL 2-DEOXY-a-D-ARABINO-HEXOPYRANOSIDE1

R. U. LEMIEUX AND A. R. MORGAN^ Departmeltl of Chenzistry, University of Alberta, Edmonton, Alberta

Received January 25, 1965

ABSTRACT

D-Glucal triacetate reacted with iodoniurn and brornoniurn di-sym-collidine perchlorate complexes in the presence of 2,3,4,6-tetra-O-acetyl-j3-~-glucopyranose to yield, after deacetyla- tion, crystalline P-D-glucopyranosyl 2-deoxy-2-halogeno-a-D-mannopyranosides. The halogen was hydrogenolyzed catalytically to yield 8-D-glucopyranosyl 2-deoxy-a-D-arabino-hexopyran- oside (2-deoxy-neotrehalose) isolated as the crystalline heptaacetate. A correction of the literature is made regarding the preparation of 142,3,4,6-tetra-0-acetyl-a-D-glucopyranose".

INTRODUCTION

Lemieux and Levine (I)* proved that the reaction of D-glucal triacetate with iodine and silver benzoate in dry benzene (2) formed an approximately equimolar mixture of the products of trans-addition to the double bond, namely, 1-0-benzoyl-2-deoxy-2-iodo-~-~- glucopyranose triacetate and the stereoisomer with the a-D-manno-configuration. In a later paper (3), they extended this type of reaction to the preparation of glycosides by reacting D-gl~cal triacetate in benzene with equimolar amounts of an alcohol, iodine, silver perchlorate, and sym-collidine.

In view of the limited solubility of silver perchlorate in inert, non-polar solvents, i t seemed probable that the conditions for the glycoside synthesis u~ould be improved by the use of preformed positive halogen complexes with sym-collidine. For example, Carlsohn (4) prepared salts containing cationic iodine con~plexes with sym-collidine such as the hydrox- ide corresponding to the formula [I (sym-collidine) 3.JOH. In a later paper ( 5 ) , he described the preparation of bromonium dipyridine perchlorate and referred to iodonium di-2,6- lutidine nitrate. The analogous complex with sym-collidine was given the fornlula [I(sym- collidine)3.~]N03. We accordingly prepared a number of coillplexes of "halonium perchlo- rates" with pyridine and substituted pyridines.

The general methods used may be sulnlnarized as follows:

where B is the pyridine base and Xz is the halogen. The first stage was carried out in aqueous solution and quantitative yields of the com-

plexed silver perchlorate were obtained. As expected from the highly reactive state of positive halogens, the second stage, in which the halonium complex was produced, was more difficult to carry out. The stabilities and solubilities of the complexes varied widely. Colorless crystalline preparations of the brornonium and iodoniuin con~plexes with

'Presented by R. U. Lenzieux at the I?zternational Synzposiz~nz on Carbohydrate Chemistry sponsored by the Chemical Society and the University of Birt)zingI~am (Clzelem. Ind . 1703 (1962)) .

2Sub?nitted by A. R. M. iin a thesis i n partialfulfillt~zent ofthe requirements for the degree of Doctor of Philosophy, University of Alberta, 1964.

*The rotations reporled i n ref. 1 for methyl 2-deosy-2-iodo-P-D-glucopyranoside and its triacetate are erroneous. The specific rotations at room tenzperature are [ a ] ~ + 3 l 0 (c, 0.9 i n methanol) and [ a ] ~ $61" (c , 2 i n clzloroform) ( l o ) , respectively. I n a private communication, P. W. Kent reported [a]~25 $25.4 (c, 0.92 in ?tzethanol) for the fornzer conzpoz~nd.

Canadian Journal of Chemistry. Volume 43 (19G5)

2190

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LEMIEUX AND MORGAN: SYNTHESIS OF A HEXOPYRANOSIDE 2191

pyridine, 2-methylpyridine, and sym-collidine were readily obtained. The analyses always corresponded closely to 2 molecules of the base per positive halogen, even in the case of sym-collidine con~plexes, compounds for which Carlsohn (4, 5 ) usually obtained 3.5 molecules. Uschakow and Tchistow prepared various haloniuin con~plexes and later they isolated chloronium dipyridine nitrate (6). When me attempted to prepare chloroniuin di-sym-collidine perchlorate, all that was obtained was a mixture of sym-collidinium perchlorate and chlorinated sym-collidine.

As expected (3), reaction of D-glucal triacetate with equiniolar amounts of methanol and either iodonium or br01noniuin di-sym-collidine con~plexes dissolved in chloroform gave virtually quantitative yields of acetylated methyl 2-deoxy-2-halogenoglycosides. Mihen these haloniuni coinplexes were reacted with D-glucal triacetate in absence of the alcohol, only a very slow disappearance of the olefin took place leading to intractable materials. On the other hand, the haloniuin coinplexes with either pyridine or 2-methylpyridine rapidly gave rise to the N-(tri-0-acety-2-deoxy-2-halogenoglycosyl) pyridiniuin or 2- methylpyridiniunl perchlorates (7). Thus, the steric hindrance to N-glycoside forination provided by the methyl groups a t the 2- and 6-positions of sym-collidine is required for a successful 0-glycoside synthesis using these pyridine bases as buffers.

In view of the high yields obtained in the preparation of 2-deoxy-2-halogenoglycosides of siinple alcohols, it was believed of interest to attempt the synthesis of non-reducing disaccharides and, for this purpose, 2,3,4,6-tetra-0-acetyl-fl-D-glucose (8) was used as the "alcohol". The 2-deoxy-2-halogenodisaccharide heptaacetates (mainly I1 and 111) were not obtained crystalline but deacetylation with triethylamine in aqueous inethanol (9) yielded crystalline samples of both 0-D-glucopyranosyl 2-deoxy-2-iodo-a-~-inannop~ran- oside (IV) and the corresponding bromide (V). The structures of these compounds were deterinined as follows.

AcO

Compound IV was hydrogenolyzed with palladium on charcoal as the catalyst, and acetylation of the product yielded the crystalline heptaacetate (VI). The deacetplated product was rapidly hydrolyzed by dilute hydrochloric acid (typical of 2-deoxpglycosides), to give D-glucose and 2-deoxy-D-arabino-hexose as shown by paper chromatography. A compound identical to VI was obtained on hydrogenolysis followed by acetylation of the

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2102 C.ANAD1AN JOUllNAL OF CllEMISTRY. VOL. 43. 1965

bromo-compound V. Therefore, compounds IV and V have identical anoincric con- figurations. The n.1n.r. spectruin of IV in deuterium oxide had signals of intensity one a t T 4.35 (spacing, < I c.p.s.) and T about 5.25 (obscured by another signal) which call be assigned to anoineric protons. The n.m.r. spectruin of V in deuterium oxide containing a little pyridinc had signals of intensity one a t T 4.7 and T 5.52 \\Tit11 spacings of < 1 c.p.s. and 8 c.p.s., respectively. The low field signals in these spectra show very sinall coupling of the anoineric protoil \vith the H-2 proton. This is characteristic of compounds with the a- manno- or p-nzanno- configurations (10). Since the 2-deoxy-disaccharide (VI) forined on l~ydrogenolysis of both IV and V was found to have the deoxyglucose residue in the a- configuration, both coinpounds IV and V inust have the residue containing the halogen atoll1 in the a-D-ffZan?Z~- configuration. This conclusioil is in accord with expectations based on the experience of Lemieux and Levine as to the preferred stereochemical route in these halogenoallcoxylation reactions. The configuration of the deoxyglycoside obtained on deacetylation of \TI was clearly evident from its n.1n.r. spectrum in deuterium oxide. The signals for the anolneric protons appeared as two "doublets" a t T 4.6 and T 5.3. The latter signal had a spacing of 7.0 c.p.s. and can be assigned to the 0-D-glucopyranosyl portion of the compound. The low field signal was actually an ill-defined "doublet" resembling closely the signal for the anomeric proton of 2-deoxy-a-D-arabino-hexopyranosidcs (3). Well-resolved quartets are obtained for the p-D-isomers (3). Also, the structures of the signals for the protons a t the 2-position were very similar to those observed for 2-deoxy- a-D-arabino-hexopyranosides (3). The inolar rotations of compounds IV, V, and VI are approxiinately those which would be expected from rotations of closely related compounds. I-Iowever, i t is of interest to note that, according to Bre\vster7s rules of atomic and con- formational asymmetry (11), the bromo compound V should be Inore dextrorotatory than the iodo analog IV. In fact, V ([lid], +140°) was inore dextrorotatory than IV ([ilf], +123"). I-Iowever, caution must be exercised in extending Brcwster's rules to screnr patterns involving atoins of high rotational ranl;. For example, according to Brewster's rules, methyl P-D-glucopyranoside ([lla, -66") and inetl~yl 2-deox)r-2-iodo-P-~-gluco- pyranoside ([A%f]D +94") (I) should have the same rotation.

In preliminary experiments, when Celite chromatography (12) was used to isolate the deacetylated 2-deoxy-2-halogenodisaccharides, 110 crystalline material with the 2-deoxy- 2-iodo-P-D-glzlco-configuration could be obtained. Paper chromatograins also sho\ved no evidence for the forination of stereoisomcrs other than the 2-deoxy-2-iodo-a-D-manno isomer. On the other hand, both the 2-deoxy-2-iodo- and 2-bromo-2-deoxy-disaccharides IV and V crystallized extremely slo\vly and incompletely froin the crude syrup, possibly suggesting an impurity. Only trace anlounts of glucose could be detected chrornatographi- callp as an impurity of the crude syrup. I t is therefore likely that these compounds were forined in substantially higher yields than those (30-40%) calculated on the basis of the ainounts of crystalline products obtained.

I11 attempting to extend the reaction to the forination of the a,a-linked disaccharide, i t was necessary to prepare 2,3,4,6-tetra-0-acetyl-a-D-glucose.

Schlubach and Wolf (13) reacted ~,3,4,6-tetra-0-acetyl-~-D-glucopyranosy chloride with silver carbonate in either ether or acetone containing a little water to obtain a product inelting a t 107-log0, [a], +138.g0, (c, 0.9 in chloroforin). The compound was assigned the structure of 2,3,4,6-tetra-0-acetyl-a-D-glucose.

Georg (14) treated tetra-0-acetyl-a-D-glucopyranosyl bromide with silver nitrate in ether containing a little water. He isolated material of 1n.p. 99-loo0, [a], +13j0 (c, 4 in chloroforin), and claimed its structure to be 2,3,4,6-tetra-0-acetyl-a-D-glucose. The

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LEMIEUS AXD MORGAN: SYNTI-IESIS OF A HESOPYRAKOSIDE 2193

n1echanisin for its for~nation was postulated as Walclen inversion a t the anomeric center of the glucosyl bromide with replacement of bromide by the nitrate, follotvecl by a second Walden inversion as \t7ater attaclts the P-nitrate. Georg could not raise the melting point of his product to that of Schlubach and Wolf's inaterial in spite of repeated recrystalliza- tioil from ether - petroleuin ether. Georg obtained a sainple of Schlubach's material and 011

recrystallizatio~l froin ether - petroleun~ ether the inelti~lg point fell to 98-99', but \\:hen he recrl-stallized the co~npound froin ether alone, the lnelting point rose i inn~edia te l~ to 112-113". I~Ie then obtained the same result with his own sample. Georg therefore coilcluded that dimorphic forins had been obtained.

Leinieux and Brice (15) reacted tetra-0-acetyl-P-D-glucopyranosyl chloride with silver acetate in 90% aqueous acetic acid and isolated crystals of 1n.p. 93-98', [a], +138' (c, 0.44 in cl~loroform). The ~llutarotation displayed by an aqueoussolution of the compound and the good agreeineilt with Georg's values for the physical constants led thein to assuine they had prepared the 2,3,4,6-tetra-0-acetyl-a-D-glucose.

\Ye repeated Lemieux and Brice's directions to obtain a product of m.p. 110-111°, [a], +149' (c, 1 in chloroform), and the n.1n.r. spectruin shown in Fig. 1. The saine spectrum was obtained for a product, inelting in the range 90-95" obtained in second preparation. I t was possible to raise the inelti~lg point to 110-111' by recrystallization from ether - Sltellysolve B and seeding with the crystals of 1n.p. 110-111'.

The n.1n.r. spectruin (Fig. 1) requires (16) the coinpound to be 1,3,4,6-tetra-0-acetyl- a-D-glucopyranose. The spacing of 3.75 c.p.s. in the signal for the anomeric proton a t T 3.77 is characteristic of protons in gaz~che orieiltation (17). Therefore, the anoineric configuration is a-D. The chemical shift of the proton requires the presence of an acetoxy group a t the 1-position ; for example, a-D-glucopyranose pentaacetate gives a signal for the anomeric protoil a t T 3.63, spacing 3.3 c.p.s. The presence of a signal for an acetyl group a t T 7.82 is indicative of an axial acetoxy group. The doublet a t T 6.77 and wit11 a spacing of 7.5 c.p.s. is assigned to the hydroxyl proton since the signal was not present in the spectrum after the chloroforlll solution had been shalten with deuteriu~u oxide. The coupling of the hydroxyl proton with the 2-proton was not always observed. The signal for the 2-proton was in the region T 5.7-6.3 and superimposed by the signals froin the protons a t the 5- and 6-positions.

Lemieux and I-Iuber (18) prepared 1,3,4,6-tetra-0-acetyl-a-D-glucose, [a], +14j0 (in chloroform), 1n.p. 97-98', by reacting 3,4,6-tri-0-acetyl-P-D-glucopyranosyl chloride with silver acetate in acetic acid. NIatsuda (19) has s~~bst i tuted mercuric acetate for the silver acetate. Elis lnaterial n~elted a t 98-loo0, [a], +143' (c, 3 in chloroform). Recently, I-Ielferich and Zirner (20) prepared 1,3,4,6-tetra-0-acetyl-a-D-glucose 1n.p. 98-100°, [&ID +141.1° (c, 3.2 in cl~loroform), by a new route. Alt11oug.h I-Ielferich and Ziriler reported their compound to depress the melting point of Georg's material, it seems probable tha t the compounds were identical.

The forinatioil of 1,3,4,6-tetra-0-acetyl-a-D-glucose from 2,3,4,6-tetra-0-acetyl-P-D- glucosyl chloride is most readily understood in terms of participation of the 2-acetoxy group in the solvolysis of the chloride to yield in the presence of water a transient ortho- acid, 1~11ich can then rearrange to either the 1,3,4,6- or 2,3,4,6-tetra-0-acetyl-a-D-glucose. Our results indicate that, in the glucose series a t any rate, the inajor first product is the 1,3,4,6-tetraacetate. That 1,3,4,6-tetra-0-acetyl-a-D-glucose in aqueous solution is thermo- dyila~nically less stable than the 2,3,4,6-isomer was established as follo~vs. Although the 1,3,4,6-tetraacetate did not ~llutarotate in dry pyridine, the specific rotation of an aqueous solutioll changed from 147.5' to 71" in 12 11. That the product consisted essentially of

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CANADIAN JOURNAL OF CHEMISTRY. VOL. 43. 1965

Aco AcO

AcO

FIG. 1. A. The n.m.r. spectrum of 1,3,4,6-tetra-0-acetyl-a-D-glucopyranose in chlorofor~n solution. B. The n.nl.r. spectrum of the equilibrium mixture of the anomeric 2,3,4,6-tetra-0-acetyi-~-glucoses in pyridine solution.

2,3,4,6-tetra-0-acetyl-a- and -P-D-glucose in about equal amounts was evident from the n.m.r. spectrum in chloroform. The signal for the anomeric proton a t T 3.77 disappeared, and no trace of the signal a t T 7.82 characteristic of the 1-0-acetyl group of the 1,3,4,6- tetraacetate was present. The equilibrium mixture obtained when 2,3,4,6-tetra-0-acetyl- 0-D-glucose was dissolved in water had the same spectrum and rotation. That the mutarotation was due to acetyl group migration followed by a P interconversion was evident since the intensity of the signals for acetyl groups required the product to be a mixture of tetraacetates.

A solution of 2,3,4,6-tetra-0-acetyl-P-D-glucose in pyridine displayed mutarotation. The n.m.r. spectrum (see Fig. 1) of the product in pyridine solution after equilibrium was achieved, showed a triplet with spacings of 9.5 c.p.s. a t T 3.92, and a doublet with a spacing of 3.0 c.p.s. a t T 4.16. In view of its spacing and chemical shift, the doublet is assigned to the anomeric proton of the a-anomer. This configuration is supported by the position of the triplet which is assigned to the 3-proton and which is 0.7 7-values to lower field than the signals for the protons a t the 2- and 4-positions. This decreased shielding of

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LEMIEUS AND MORGAS: SYNTHESIS OF A HESOPYRANOSIDE 2195

the 3-proton is expected for the a-anomer wherein the 1-hydroxyl group is in axial orientation (21). The intensities of these signals relative to the total of the intensities of the other signals in the spectrunl indicated that the equilibrium mixture contained about 8OY0 of the a-anomer. The greater abundance of this isomer in the equilibrium mixture obtained froin pyridine as coinpared to water was expected (22). Benzoylation of the product gave an 80-85yo yield of 2,3,4,6-tetra-0-acetyl-1-0-benzoyl-a-D-glucose. The isomerizatioi~ of the 1,3,4,6-tetraacetate of a-D-glucose in aqueous solution was inde- pendently established by Helferich and Zirner (20) during the course of this investigation.

When the syrup containing about 80% of 2,3,4,6-tetraacetyl-a-D-glucose was used as the "alcohol" in an attempt to form an a,a-linked isomer of coinpound IV, only IV was obtained and the yield was about the same as when pure 2,3,4,6-tetra-0-acetyl-p-D- glucose was used. Presumably, therefore, mutarotation took place more rapidly than did the reaction of the a-anomer, and the a-anomer reacted only very slowly as compared to the P-anomer in the iodoalkoxylation reaction.

With regard to the formation of 1,3,4,6-tetra-0-acetyl-a-D-glucose, it is of interest to note that Perlin (23) found the acid hydrolysis of the diastereoisoineric P-D-inannose 1,2-(benzyl orthoacetates) yielded 2-0-acetyl-D-mannose. Evidently, the configuration is important in determining whether the acetyl group materializes a t the 1- or the 2-poisiton. Ness and Fletcher (24) showed that 1,3,5-tri-0-benzoyl-a-D-ribose is formed both on hydrolysis of tri-0-benzoyl-D-ribofuranosyl bromide and on hydrogenolysis of 3,4-di-0- benzoj.1-a-D-ribose 1,2-(benzoyl orthobenzoate). The 1-0-benzoyl group was found to migrate to the 2-position in alkaline solution. The isolation by Antia (25) of 1,3,4-tri-0- acetyl-a-D-xylose as a product of the reaction of tri-0-acetyl-a-D-xylopyranosyl bromide in aqueous acetone and in the presence of silver carbonate is noteworthy.

EXPERIMENTAL

The melting points were talien on a heating stage and are uncorrected. The rotations were measured a t room temperature, 23-25'.

The nuclear magnetic resonance (n.m.r.) spectra were determined, unless otherwise stated, in deuterium oxide with a Varian A60 spectrometer and the chemical shifts are reported in tau (7) values with tetramethyl- silane (TMS) as external standard.

Deacetylated niaterial was chro~natographed on Whatman No. 1 paper and developed with the lighter phase of I-butanol, ethanol, and water mixture (5:1:4) (26). Silver nitrate C27), periodate-permanganate (28), p-anisidine hydrochloride (29), and aniline hydrogen phthalate (30) sprays were used. The RG numbers refer to the Rr values relative to that of glucose.

Chloroform, when used in preparative procedures, was purified by passing down a colu~nn of activated alumina. A column 1.9 cm X 28 cm gave 400 ml chloroform with no trace of hydroxyl absorption in the infrared.

I t is important to realize that perchlorates are potentially powerful explosives. Although none of the preparations described below caused trouble, the compounds detonated on strong heating. Due precautions nus st be taken (31).

Silver Di-synt-collidi?ze Perchlorate synt-Collidine, 20 1111, was added with vigorous stirring to a solution of silver nitrate, 9 g, and sodium

perchlorate, 11 g, in 100 ml of water to give a white curdy precipitate. After washing repeatedly with water, the product was washed with ethanol and ether and finally dried under vacuum over phosphorus pentoxide. The yield was 24 g (100yo).

Iodoniz~nt Di-sym-collidine Perchlorate I t is important in the preparation of halonium complexes to make sure the conditions are anhydrous.

Otherwise, the halogen tends to be reliberated. Powdered iodine, 20.2 g (79.5 mmoles), was added to a suspension of the silver di-sym-collidine perchlorate, 35.7 g (78.5 mmoles), in about 200 ml of chloroform and 5 ml of syiii-collidine. After shaking for 15 min, the yellow precipitate of silver iodide was removed by filtration through a bed of Celite, and the iodoniurn complex crystallized directly from the filtrate on standing in the cold. The mother licluors gave further fine white crystals on the addition of ether. The combined crystals were dried under high vacuum and analyzed for positive iodine by titration of the iodine liberated in

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2196 CANADIAN JOURNAL O F CI-IElMISTRY. VOL. 43. 1065

the reaction with potassium iodide in aqueous acid. The yield of iodine was 97.5% of theoretical based on the formula ( C ~ M I I N ) ~ I C I O ~ .

Brotttoni.r~??t Di-sy~iz-collidi?ze Perchlorate Silver di-synt-collidine perchlorate, 13.47 g (30 mmoles), was suspended in 150 ml pure chlorofor~n and 1 ml

syln-collidine, and 1.65 ml bromine (30 mmoles) was added. Silver bromide was rapidly precipitated and was collected by filtration on Celite. The clear faint-yellow filtrate gave a fine, white crystalline precipitate on the addition of ether. A 70% yield was obtained of a product which, on analysis contained 03y0 of the positive bromine expected (CsI-InX)zBrC1O.i. The n.m.r. spectrum in methylene chloride was that espected for complexed syw-collidine. The intensities of the signals a t T 2.72, 7.15, and 7.57 were 2:6:3, respectively. sy111-Collidine in methylene chloride gave signals of corresponding relative intensities a t higher field T 3.22, 7.59, and 7.77, respectively. The melting point was ill-defined but a clear liquid was obtained a t 230°.

Methyl S,.~,6-tr~-O-~cetyl-2-deo~y-~-~odo-a-~-?izannoyranosde a?zd the Correspondi?tg 8-G1.ucoside Anhydrous methanol, 0.12 ml (2.8 mmoles), and 1.3 g of the iodonium comples (titration gave S6T5 of the

theoretical iodine) were added to D-glucal triacetate, 0.755 g (2.78 mmoles), dissolved in 15 ml of pure chloroform. A homogeneous faint-yellow solution was obtained from which, almost immediately, sy??~- collidinium perchlorate separated. The mixture was filtered after a 20 min reaction time, and the filtrate was washed first with water, then with 2 N sulfuric acid, and finally with water. -4fter drying by filtration through chloroform-wetted paper, the solution was evaporated a t high vacuum to a syrup, 1.115 g (93c0 yield of methyl tri-0-acetyl-2-deoxy-2-iodoglycosides). The n.m.r. spectrum was almost identical to that obtained by Lemieux and Levine (3) except that integration of the methosyl peaks indicated 82% of the a-liza?zrzo and 18% of the 8-glzico-configurations.

8-D-Glr~copyra?zosyl 2-Deo.vy-2-iodo-a-~-n1annopyranoside ( I V ) The iodonium complex, 12.17 g (23.7 mmoles of positive iodine as determined by titration) was added to

D-glucal triacetate, 6.45 g (23.7 mmoles), and 8.25 g (23.7 mmoles) of 2,3,4,6-tetra-0-acetyl-~-~-~copyranose dissolved in 50 ml of pure chloroform. As the iodonium salt dissolved on stirring the mixture, sy~lt-collidinium perchlorate was precipitated. After 20 min, a sanlple of the solution was added to aqueous potassiunl iodide solution containing soluble starch. A strong blue color developed. After 6 h, the brownish solution was filtered to remove the synt-collidiniurn perchlorate and the filtrate was washed with 0.1 dd sodium thiosulfate, 60 ml, to give a light-brown chloroforn~ layer. Iodine was liberated 011 standing. On passing the chlorofor~n layer down a silicic acid column (1.8 cm X 19.5 cm), a band with the violet color of iodine moved down the column followed by a brown band from which a syrup was isolated. The syrup was deacetylated by allowing a solution, in 20 ml of methanol containing 2 ml of triethylamine and water added to turbidity, to stand overnight a t room temperature. )\ paper chronlatogram of the deacetylated syrup showed a spot with RG = 1.19 and a trace of glucose (aniline hydrogen phthalate as spray reagent). The compound, 2.84 g, crystallized fro111 water oil seeding with crystals obtained in an earlier experiment from a chromatographic purification on a Celite column using 1-butanol-water (12). A further 0.5 g was obtained by crystallizatio~l of the residual syrup from methanol. The total yield was 33y0. Recrystallization from ethanol-water gave material which decomposed around loo0, [ a ] ~ f26.3" (c, 2 in water).

Anal. Calcd. for C~211r101oI.1.5MzO: C, 30.08; H, 5.05; I, 26.48. Found: C, 30.19; 11, 5.00; I, 27.94. Further elution of the silicic acid column gave 0.6 g of syrup which, on deacetylation, gave spots corre-

sponding to glucose and glucal on paper chromatograms.

2,3,/t,6-Tetra-O-acety~-~-~-glucopyra?zosyl 2-Deory-5,/t,6-tli-O-acetyl-a-~-arabino-hexopyranoside ( V I ) The above described compound (IV), 0.163 g (0.36 mmoles), dissolved in 2.5 ml water and 0.3 ml triethyl-

anline, was hydrogenolyzed with a lOYo palladium-on-charcoal catalyst. After stirring for 2 h under hydrogen a t slightly above atmospheric pressure, the theoretical quantity of hydrogel1 was talcen up. The catalyst was removed by filtration using Celite. Silver carbonate, 10 inmoles, was added to the filtrate to precipitate the iodide ion. Filtration followed by passage of hydrogen sulfide to remove traces of silver salts and evaporation of the clarified solution left 0.135 g of brown residue which was acetylated in 5 ml pyridine and 5 1x1 acetic anhydride. After standing overnight, the solvents were evaporated to leave 0.207 g of a semicrystalline syrup. Two recrystallizations from ethanol gave fine crystals, n1.p. 163.5" and [a]= f66.5' (c, 0.8 in chloroforn~).

Anal. Calcd. for C261<3~01,: C, 50.25; H, 5.80. Found: C, 50.25; H, 5.79. The compound was deacetylated with sodium rnethoxide in methanol to give a fine, white amorphous

powder, RG = 0.43. The n.m.r. spectrum in deuterium oxide had signals of intensity one (relative to the intensity of a broad band in the T 5.6-6.9 region and taken as arising froin 11 protons) a t T 4.60, 5.28, about 7.6, and about 8.2. The structures of the signals a t T 4.60, 7.6, and 8.2 were very similar to those with similar chemical shifts in the spectrum of methyl 2-deoxy-a-D-arabino-hesopyranoside (3). The signal a t T 5.28 was a doublet with a spacing of 7.0 c.p.s. as expected for the anomeric proton of the 8-D-glucosyl portion of VII. A 0.05 g sample of the deacetylated product was dissolved in 5 ml of 0.2 N hydrochloric acid. The observed rotation of 0.65" (1 dm tube) after 0.5 h fell to 0.55'after 1 day. The reaction was also followed chromatog- raphically and after 1 d essentially all the starting material, RG = 0.43, had hydrolyzed to glucose and 2-deoxy-D-arabhro-hexose as seen by direct comparison with authentic samples on a paper chromatogram.

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L E M I E U S A S D MORGAS: SYSTIIESIS O F A IIEXOPYR.1SOSIDE 2197

Methyl 5,4,6-Tr~-O-acety~-Z-bro~?zo-,~-deoxy-or-~-nlannopyuanoside and the Correspol~ding (3-D-Glilcoside 'The bromonium complex, 0.965 g (2.12 ~nmoles of positive bromine as determined by titration), n-ns added

to D-glucal triacetate, 0.576 g (2.12 mmoles), and 0.2 1111 1netha110l (4.9 1n1noIes) in 5 ml chloroform. 'The reaction mas exothermic and a rapid precipitation of synz-collidinium perchlorate was obtained. After stirring for 10 min, the solution was washed with dilute hydrochloric acid containing potassiuln iodide. Iodine was liberated, but 6 ml of 0.1 M thiosulfate solution rendered both phases colorless. The chloroform layer was then washed with sodium bicarbonate, filtered, and evaporated overnight i11 a high vacuum. The residue, 0.818 g (quantitative yield) of a light-yellow syrup, had an n.m.r. spectrum which showed the presence of three methyl glycosides. From the chemical shifts of the methoxy-group signals, the colnpounds were identified a s the methyl tri-0-acetyl-2-bro1~~0-2-deoxy-~-glycopyraosides with the 0-glzlco- (2570), a-mal~no- (about 65%), a-gl~ico- (about loyo) (32) configurations.

fi-~-Glzlcopy?anosyl 2-Bromo-2-deoxy-a-~-~~lnnnopyranoside ( V ) The brotnoniunl di-sym-collidine perchlorate, 13.5 g (27.3 mnl~oles of bromonium ion by titration), was

added to D-glucal triacetate, 7.17 g (26.4 mmoles), and 2,3,4,6-tetra-0-acetyl-(3-~-glucopyranose 9.17 g (26.4 mmoles), in chloroforn~. There resulted an exothermic reaction with precipitation of sy?n-collidinium perchlorate. After 5 min, a sample did not liberate iodine when shaken with potassium iodide solution. The reaction mixture was cooled to 0' and about 6 g (27 ~nmoles) of sym-collidi~lium perchlorate mas obtained on filtration. The chlorofor~n filtrate was washed with dilute acid and then sodiurn bicarbonate.

Evaporation left a syrup which was dissolved in 40 ml of methanol containing 6.5 ml of triethylalninc, and water was added to turbidity. The solution turned green and, on standing overnight, became purple. The deacetylated syrup very slowly deposited crystals from methanol, 3.5 g after a month (33% yield). Recry- stallization from methanol-water mixture gave material which carbonized around lSOO, [ a ] ~ +39.4' (c, 1 in water).

Anal. Calcd. for C1?N21010Br: C, 35.56; 13, 5.32. Found: C, 35.46; 13, 5.32. Since the RG value was 0.95, the compound was difficult to distinguish from glucose in the chrolnatogranl

of the crude deacetylated syrup. The conlpound was hydrogenolyzed for 2 d under the same conditions as described above for compound IV

using palladium-on-charcoal catalyst. The syrup obtained from the reaction was acetylated and worked up exactly a s described for the preparation of the deoxy-glycoside VI. The melting point, 163", was not depressed 011 admixture with VI.

i,S,/t,6-Tetra-0-acetyl-a-~-g~z~cose 2,3,4,6-Tetra-0-acetyl-(3-D-glucopyranosyl chloride, 36.6 g (100 mmoles), was dissolved in about 100 ml of

glacial acetic acid, and 5 ml water (110 mmoles) and 20 g silver acetate (120 mmoles) were added. 'The mixture was shaken vigorously for 2 min and then frozen in a dry ice and acetone mixture. The volatile components were removed in vaczlo. The residue was finally warnled to SOo in vaczlo to remove the last traces of acetic acid. The residue was extracted five times with ether and the silver salts were removed on Celite. T o the ether filtrate was added Sl:ellysolve B just to the point of turbidity. The crystalline precipitate, 13.7 g (40y0 yield), m.p. 90-95' had the n.1n.r. spectru~n expected for the 1,3,4,6-tetraacetate. Recrystallization from ether- Sl<ellysolve R gave material of 111.p. 110-Ill0, [ a ] ~ +14g0 (c, 1 in chloroform). The n.1n.r. spectrum (Fig. 1) is described ill the above discussion.

1,3,4,6-Tetra-0-acetyl-a-~-glucopyranose did not mutarotate in dry pyridine but did in water to a final rotation of [a]D +71° (c, 1.8 in water). 2,3,4,6-Tetra-0-acetyl-(3-D-glucopyranose ~nutarotated in water to an equilibrium point of [ a ] ~ +71° (c, 1.5 in water). The n.1n.r. spectra of the equilibrium products dissolved in chloroforln were identical and it was apparent that the a - and 0-anomers were present in about equal amounts.

When the product from the equilibration in water was dissolved in pyridine further mutarotation occurred and the n.m.r. spectrum in pyridine indicated that about 80y0 of the ~nixture was 2,3,4,6-tetra-0-acetyl- a-D-glucopyranose. This was confirn~ed by benzoylation in the usual Inanner using benzoyl chloride in pyridine. The n.m.r. spectrum of the crude syrupy product, or]^ +93.5O in chloroform, contained a doublet a t 7 3.35, spacing 3.5 c.p.s. This signal is readily assigned to the anomeric proton of 1-0-benzoyl-a-~-gluco- pyranose tetraacetate, which must comprise about 80y0 of the product a s determined from the relative intensities of the signals in the n.m.r. spectrum. The syrup readily provided a 75y0 yield of crystalline product from a solution in ethanol and water, [ a ] ~ +74.3' in chloroform, 1n.p. 65-70', and the n.m.r. spectrum indicated now only 75y0 of the l-0-benzoyl-or-~-gl~1copyra11ose tetraacetate. I-Iowever, a further crop of crystals was obtained from the mother liquors which, after repeated recrystallizations, melted a t 67-68O, [ a ] ~ +132O (c, 0.3 in chloroforn~). The n.nl.r. spectrum was that expected for pure 2,3,4,6-tetra-0-acetyl- l-0-be11zoyl-a-~-glucopyranose and half a molecule of ethanol of solvation. The literature values (33) for 2,3,4,6-tetra-0-acetyl-1-0-benzoyl-a- and -0-D-glucopyra~~oses are, respectively, 111.p. 60-63', [CY]D" +113.5" (c, 3 in chloroform) and 1n.p. 143' [ a ]~20 -28.1" (c, 3 in chlorofornl). Treatment of the benzoate with hydrogen bromide in acetic acid gave a crystalline product identical to tetra-0-acetyl-a-D-glucopyranosyl bromide.

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