Sulfonic Esters of Carbohydrates: Part I

SULFONIC ESTERS OF CARBOHYDRATES: PART I

BY D . H . BALL AND F. W. PARRISH Pioneering Research Laboratory. U. S . Army Laboratories. Natick. Massachusetts

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I Introduction ........................................................... I1 Methods for Sulfonylation of Carbohydrates ............................. 1 The Use of Sulfonyl Halides .......................................... 2 The Use of Sulfonic Anhydrides ..................................... 3. The Use of Methanesulfonic Acid .................................... 4 The Use of Silver Methanesulfonate ................................. 5 Other Methods ..................................................... I11. Relative Reactivity of Hydroxyl Groups in Sulfonylation 1 Preferential Reaction at a Primary Hydroxyl Group .................... 2 Relative Reactivity at Secondary Hydroxyl Groups ..................... IV Physical Properties and Chemical Stability .............................. 1 Some Physical Properties of Sulfonic Esters .......................... 2 Chemical Stability of Sulfonic Esters ................................. V Removal of Sulfonic Ester Groups with Lithium Aluminum Hydride 1 Primary Sulfonic Esters of Pyranoid Sugars ........................... 2 Primary Sulfonic Esters of Furanoid Sugars ........................... 3. Primary Sulfonic Esters of Acyclic Sugars ............................ 4 Secondary Sulfonic Esters ........................................... 5 Tertiary Sulfonic Esters ............................................. VI . Action of Some Alkaline Reagents on Sulfonic Esters ......................

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233 236 236 238 239 239 239

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240 244 253 253 257 269 269 273 274 275 279 279

I . INTRODUCTION

Fifteen years ago. when the chemistry of sulfonic esters of carbohydrates was reviewed in this Series. the importance of these esters for preparative work had been firmly established Adequate methods for sulfonylation existed. and an introduced sulfonyl group provided a protecting group stable under acidic. neutral. and slightly basic conditions. Removal of the sulfonyl protecting group was known to be readily achieved by the use of sodium amalgam. Raney nickel. or lithium aluminum hydride. The last-named reductant. in contrast to the other two. was known to give. on reaction with a primary sulfonyloxy group. the corresponding o-deoxy derivative through alkyloxygen fission; reaction with a secondary sulfonate had been found

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(1) R S . Tipson. Adoan Carbohydrate Chem., 8. 107 (1953)

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generally to regenerate the alcohol group.* The action of alkaline reagents on sulfonic esters had also received much attention, and the nature of the products from derivatives containing isolated or nonisolated, primary or secondary sulfonyloxy groups was well known. The formation of anhydro rings from nonisolated sulfonyloxy groups with alkaline reagents is of considerable importance, and one aspect of this subject, namely, sugar epoxides, has been reviewed by N e ~ t h . ~ The use of Finkelstein's reagent4 (a solution of anhydrous sodium iodide in anhydrous acetone) with sulfonic esters of sugars provided another reaction of considerable utility; the resulting replacement of primary and secondary sulfonyloxy groups with iodine in a variety of sugars has been reviewed in detail.' The reaction was shown to be diagnostic for primary sulfonyloxy groups of cyclic sugar molecules,5 although Levene and Tipsod showed, and later workers have confirmed, the absence of reactivity of sulfonyloxy groups at the primary carbon atom nearest the anomeric carbon atom of cyclic ketoses. Displacement of a sulfonyloxy group by iodide ion, followed b y catalytic reduction of the resulting iodo sugar was known to provide' a convenient synthesis of deoxy sugars; these occur widely as components of natural products.8 Another reaction of Finkelstein's reagent having importance in preparative work was the formation of a glycenose from acyclic sugar derivatives containing a secondary sulfonyloxy group contiguous to a primary sulfonyloxy group. This reaction was discovered by Tipson and Cretcher,O who found that 1,2,3,4-tetra-Op-tolylsulfonylerythritol yields 1,3-butadiene. Nucleophilic displacements of sulfonyloxy groups by reagents other than halide ions had also been observed in sugar chemistry. As early as 1922, a 3-deoxy-3-hydrazino derivative had been obtained'O by the action of hydrazine on 1,2:5,6-di-O-isopropylidene-3-O-p-tolylsulfonyl-a-D-glucofuranose,and this derivative was later characterized'Oa as 3-deoxy-3-hydrazino-1,2: 5,6-di-O-isopropylidene-a-~-a1lofuranose. (2) H. Schmid and P. Karrer, Helw. Chim. Acta, 32, 1371 (1949). (3) F. H. Newth, Quart. Rev. (London), 13,30 (1959). (4) H. Finkelstein, Ber., 43, 1528 (1910). (5) J. W. H. Oldham and J. K. Rutherford,]. Am. Chem. Soc., 54,366 (1932). (6) P. A. Levene and R. S . Tipson,]. Btol. Chem., 120,607 (1937). (7) H. Miiller and T. Reichstein, Helw. Chim. Acta, 21,263 (1938). (8) S. Hanessian, Advan. Carbohydrate Chem., 21, 143 (1966). (9) R. S. Tipson and L. H. Cretcher,]. Org. Chem., 8,95 (1943). (10) K. Freudenberg and F. Brauns, Ber., 55,3233 (1922). (10a) R. U. Lemieux and P. Chu,]. Am. Chem. SOC., 80,4745 (1958).

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Similarly, reaction of 1,2:3,4-di-O-isopropylidene-6-O-p-tolylsulfonylD-galactose with hydrazine gave" the corresponding 6-deoxy-6-hydrazino derivative, and, with ammonia,I2 the corresponding 6-amino-6deoxy derivative. Later, sodium or potassium acetate in boiling acetic anhydride was shown to replace primary or secondary p-tolylsulfonyl groups of alditols,I3 and primary sulfonyl groups of cyclic sugars," by acetyl groups. The use of potassium thi~lacetate'~ was known to cause replacements analogous to those obtained with potassium acetate. Other sulfur-containing nucleophiles had been studied; Raymondi6 found that 1,2-O-isopropylidene-~-O-p-to~y~su~fony~-~-xy~ose with potassium methanethioxide in acetone gave 1,2-O-isopropylidene-5-S-methyl-5-thio-~-xylose, whereas the same reagent caused desulfonylation of an isolated, secondary sulfonyloxy Use had also been made of potassium thiocyanate in acetone to replace primary sulfonyloxy groups in cyclic sugars; for example, 1,2,3,4tetra-O-acety~-6-O-p-to~y~sulfony~-~-D-g~ucose gavel8 the corresponding 6-deoxy-6-thiocyano derivative. Since 1953,' continued interest has been shown in sugar sulfonates for use in the types of reaction mentioned above; however, the present article will be concerned primarily with newer developments in the chemistry of sugar sulfonates that have served to accentuate the utility of these esters. Of particular importance is the large number of nucleophilic displacement reactions of sulfonates for a variety of carbohydrate systems, especially when these reactions are performed in dipolar, aprotic solvents. An understanding of the mechanisms of these reactions is due largely to the pioneering work of Winstein, Baker, and Goodman, and their collaborators. Consideration of these reactions has been deferred until the next volume in this Series. Such reactions, developed initially with alditol and glycoside systems, were soon applied to transformations of the biologically important nucleosides, and in structural elucidation studies on antibiotic components and other natural products. Much of the stimulus for work on sulfonic (11) K. Freudenberg and R. M. Hixon, Ber., 56,2119 (1923). (12) K. Freudenberg and A. Doser, Ber., 58,294 (1925). (13) A. Miiller and L. von Vargha, Ber., 66, 1165 (1933). (14) B. Helferich and A. Gnuchtel, Ber., 71, 712 (1938). (15) J. H. Chapman and L. N. Owen,]. Chem. SOC., 579 (1950). (16) A. L. Raymond,]. Blol. Chem., 107,85 (1934). (17) B. Iselin and T. Reichstein, Helu. Chim. Acta, 29, 508 (1946). (18) A. Miiller and A. Wilhelms, Ber., 74, 698 (1941).

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esters of sugars has arisen from their use in the synthesis of compounds having possible chemotherapeutic activity. 11. METHODS FOR SULFONYLATION OF CARBOHYDRATES 1. The Use of Sulfonyl Halides

The most common procedure for the sulfonylation of sugars entails the use of a sulfonyl halide in pyridine and, in most applications, methanesulfonyl or p-toluenesulfonyl chloride have been the sulfonylation reagent of choice. Few of the many experimental innovations suggested by Tipsod appear to have been examined; this is somewhat disappointing, especially on considering how advances made in isolation procedures have facilitated such studies. It is surprising that, in view of the side reactions that may be encountered with the use of a sulfonyl halide in pyridine, more use has not been made of sulfonic anhydrides. Particularly troublesome is the contamination of the desired sulfonic esters with products containing chlorine. (Incidentally, many sulfonates give a positive Beilstein test, even when the compound is chlorine-free.*O)Although chlorination is generally the more prevalent, the higher the temperature at which sulfonylation is performed,2O some chlorination of sucrose was found when using methanesulfonyl chloride in pyridine, evenz1 at -30". The continued use of pyridine as the usual solvent for sulfonylations is justified by the well known catalytic effect of pyridine on esterification of alcohols. A discussion of such reactions has been presented by Foster and coworkers22in which the possibility is considered that complexes of pyridine with sulfonyl chlorides are responsible for the catalytic effect of pyridine. In a study of the reaction of 1,2:5,6-di-O-isopropylidene-a-~-glucofuranose with methanesulfonyl chloride, the corresponding 3-methanesulfonate was formed in 88% yield with pyridine as solvent, but in only 45% yield with triethylamine or t r i b ~ t y l a m i n e .In ~ ~some methanesulfonylations of methyl glycopyranosides, mixtures of pyridine and triethylamine, and of pyridine and Nfl-dimethylformamide, have been usedz4 to (19)H. B. Wood, Jr., and H. G . Fletcher, Jr.,J. Am. Chem. SOC., 80,5242 (1958). (20)K. Hess and R. Pfleger, Ann., 507,48 (1933). (21)J. H. Westwood, unpublished results. (22)K. W. Buck, J. M. Duxbury, A. B. Foster, A. R.Perry, and J. M. Webber, Carbohyd. Res., 2, 122 (1966). (23)H. H.Stroh, D. Dargel, and R. Haeussler,J. Prakt. Chem., 23,309 (1964). (24)R. C. Chalk, D. H. Ball, and L. Long, Jr.,J. Org. Chem., 31, 1509 (1966).

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permit reactions to be performed at -60°, at which temperature solutions in pyridine would be frozen. However, the results obtained with these mixed solvents were not different from those obtained when pyridine was used alone. Indeed, the use of solvent mixtures containing N,N-dimethylformamide may be inadvisable; EdingtonZ5has shown that its use in the p-toluenesulfonylation of bis(2-hydroxyethyl) terephthalate promotes side reactions that include 0-formylation and chlorination. These side reactions occurred at temperatures as low as -5", but, at a higher temperature (SSO), almost complete chlorination occurred. The use of methanesulfonyl chloride in N,"-dimethylformamide permits selective chlorination of a primary hydroxyl group to be performed in high yield for a variety of carbohydrates and nucleosides.2s Some of the results that have been reported for sulfonylation reactions are attributable to steric effects. Roberts2' was able to obtain a degree of substitution (D.S.) of 2.97 in the methanesulfonylation of mercerized cotton at 28", 2.70 of which was due to methylsulfonyl groups, and the remainder, to chlorination. Under the same conditions, p-toluenesulfonylation gave a product having a D.S. (p-tolylsulfonyl) of 2.14. When re-treated with p-toluenesulfonyl chloride, this product was essentially unchanged, but, with methanesulfonyl chloride, gave a product having a total D.S. of 3.0.These results support the hypothesis that complete p-toluenesulfonylation is prevented when one of the secondary hydroxyl groups is substituted. A byproduct of the methanesulfonylation reaction was identified2' as pyridinium methanesulfonate, but attempts to effect esterification of cellulose with this salt were not successful (compare Ref. 22). Pretreatment of cellulose with ammonia or ethylamine was found2*to be more effective than mercerization in improving the yield of sulfonic esters of cellulose with sulfonyl chlorides in pyridine. Similarly, cycloheptaamylose (Schardinger p-dextrin) can be methanesulfonylated c0mpletely,2~but only two p-tolylsulfonyl groups can be introducedSoper D-glucose residue. Another p-toluenesulfonylation reaction made difficult by a steric effect is that with methyl 2,3-di-O-benzoyl-6-deoxy-a-~-mannopyranoside, which required treatment at 100" for 21 hours to give the 4-p(25)R. A. Edington,]. Chem. SOC.,3499 (1964). (26)M. E. Evans, L. Long, Jr., and F. W. Parrish, Abstracts Papers Am. Chem. SOC. Meeting, 154,253(1967);J. Org. Chem.,33,1074(1968). (27)R. W.Roberts,J. Am. Chem. SOC., 79,1175 (1957). (28)E. Klein and J. E. Snowden, Ind. Eng. Chem., 50,80 (1958). (29)F. W.Parrish, unpublished results. (30)W. J. Whelan, unpublished results.

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tol~enesulfonate~'; the need for forcing conditions was attributed to steric hindrance by the (large) benzoyloxy group on C-3. However, no difficulty was reported3, in preparing the 4-p-toluenesulfonate of methyl 2,3-di-0-benzoyl-6-0-trityl-a-~-glucopyranoside. It was established that no benzoate migration had o ~ c u r r e d , ~whereas, ' under similar conditions of p-toluenesulfonylation of 1,4,5,6-tetra-Oacetyl acetyl-myo-inositol and 1,3,4,5,6-penta-O-acetyl-myo-inositol, migration occurs,33 to give 2,4,5,6-tetra-O-acetyl-l,3-di-O-p-tolylsulfonyl-myo-inositoland 1,2,4,5,6-penta-0-acetyl~-O-p-tolylsulfonylmyo-inositol, respectively. The resistance of the tertiary hydroxyl group of methyl 3,4-0isopropylidene-2-O-methyl-/3-~-arabinopyranoside to esterification with p-toluenesulfonyl chloride in pyridine at room temperature was overcome34by first forming the sodio derivative in ether and then treating this with p-toluenesuIfony1 chloride in ether. 2. The Use of Sulfonic Anhydrides

Only two cases of the use of sulfonic anhydrides were reported previously'; one claimed the p-toluenesulfonylation of alkali-cellulose with p-toluenesulfonic anhydride35and could not be repeated by later and the other example,14 in which methyl WDglucopyranoside was treated with methanesulfonic anhydride in pyridine, gave no experimental procedure. Jeanloz and Jeanloz3' have described the unimolar esterification of methyl 4,6-O-benzylidene-a-D-glucopyranoside with p-toluenesulfonic anhydride (or p-toluenesulfonyl chloride), whereby a preponderance of the 2-ptoluenesulfonate is obtained. An Austrian patenP claims the preparation of compounds having the general formula (RSO,OCH,CH,NH),C,H,(OH),, in which R is an alkyl group containing 1 to 3 carbon atoms, n = 3- 6, and (m p) = 2n, when an alkanesulfonic anhydride or an alkanesulfonyl chloride reacts with the corresponding alcohol in acetonitrile.

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(31) A. C. Richardson and J. M. Williams, Tetrahedron, 23, 1641 (1967). (32) J. W. H. Oldham and G . J. Robertson,J. Chem. Soc., 685 (1935). (33) S. J. Angyal, P. T. Gilham, and G . J. H. Melrose,]. Chem. Soc., 5252 (1965). (34) J. S. Burton, W. G . Overend, and N. R. Williams,]. Chem. Soc., 3433 (1965). (35) G . W. Rigby (to E. I. duPont deNemows & Co.), U. S . Pat. 2,123,806 (July 12, 1938); Chem. Abstracts, 32,7263 (1938). (36) A. L. Bernoulli and H. Stauffer, Helu. Chim. Acta,23,627 (1940). (37) R. W. Jeanloz and D. A. Jeanloz,]. Am. Chem. Soc., 78,2579 (1956). (38) T. Horvath, E. Csanyi, L. Vargha, and B. Dumbovich, Austrian Pat. 236,930 (Nov. 25, 1964); Chem. Abstracts, 62,2709 (1965).

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3. The Use of Methanesulfonic Acid The preparation of a number of a,o-dimethanesulfonates of alditols has been described.39 For example, by treating 1,2: S76-dianhydro3,4-di-O-isopropylidene-~-mannitol with methanesulfonic acid, 1,6di-O-(methylsulfonyl)-D-mannitolwas formed. It is noteworthy that with p-toluenesulfonic treatment of 1,2-anhydro-3-deoxy-~~-glycero1 acid gaveI5s4O 3-deoxy-l-O-p-toly~su~fony1-DL-g~ycero~ and 3-deoxy2-O-p-tolylsulfonyl-~~-glycerol. A novel reaction used by H ~ r v a t hfor ~~ the preparation of 1,4-di-O(methylsulfony1)erythritol involves the treatment of diepoxybutadiene with methanesulfonic acid. 4. The Use of Silver Methanesulfonate

The few, more recent examples of the use of silver methanesulfonate3s*42*43 are analogous to that15 reported in the earlier review.' a,w-Dibromo-apdideoxyalditols were treated with silver methanesulfonate, with the objective of obtaining methanesulfonates possessing carcinostatic activity. 5. Other Methods

Three patents have been issued in which two novel methods for forming sulfonic esters are described. A water-soluble derivative, sodium mono-0-(propylsulfonyl)rutin,was prepared44by sequential treatment of rutin with sodium in ethanol, followed by propane sultone in N,N-dimethylformamide. The second method45 employed methyl p-toluenesulfonate in N,N-dimethylformamide, with potassium carbonate as a catalyst, for transesterification of the hemiacetal group of aldoses or ketoses. (39)S. S. Brown and C. M.Timmis,]. Chem. Soc., 3656 (1961). (40)G. A. Haggis and L. N. Owen,]. Chem. Soc., 2250 (1950). (41)T. Horvath, Hungarian Pat. 147,586 (Oct. 1, 1960);Chem. Abstracts, 58, 6918 (1963). (42)P. W.Feit and 0. T. Nielsen,]. Med. Chem., 9,416 (1966). (43)Chinoin Cyogyszer es Vegyeszeti Termekek Gyara R. T., French Pat. M2114 (Dec. 2, 1963);Chem. Abstracts, 60, 14598 (1964);Belgian Pat. 613,335(Feb. 15,1962);Chem. Abstracts, 58,2502 (1963). (44)Societe Anon. des Laboratoires Robert et Carriere, French Pat. 1,445,465(July 15,1966);Chem. Abstracts, 66,55713 (1967);French Pat. M3779 (Jw. 24,1966); Chem. Abstracts, 66,55716 (1967). (45)K. Knoevenagel (to C. F. Spiess und Sohn), U. S. Pat. 3,103,507(Sept. 10,1963); Chem. Abstracts, 60,3081 (1964).

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111. RELATIVEREACTMTY OF HYDROXYL GROUPS IN SULFONYLATION

1. Preferential Reaction at a Primary Hydroxyl Group Selective p-toluenesulfonylation of a primary hydroxyl group on a furanoid ring was shown by Ohle and DickhauseP in 1925; since then, more than thirty reactions have been reported in which preferential, unimolar p-toluenesulfonylation or methanesulfonylation occurs to form an w-sulfonic ester of a sugar derivative, the majority of these reactions being with pyranoid derivatives. Brimacombe and coworkers achieved selective p-toluenesulfonylation at 0-6 in methyl 3-O-ben~yl-2-0-methyl-~' and methyl 3-0-methyl-2-0-p-tolylsulfonyla-~-allopyranoside,~~ to obtain intermediates in the synthesis of 6-deoxy-2-O-methyl-~-allose and 6-deoxy-3-O-methyl-~-allose, respectively. With another derivative possessing free hydroxyl groups at C-4 and C-6, namely, methyl 3-0-methyl-2-0-p-tolylsulfonyl-a-Dglucopyranoside, p-toluenesulfonylation gave the corresponding 6-ptoluenesulfonate in 70% yield.4gThe resistance to derivative formation at the C-4 hydroxyl group in galactopyranosides was demonstrated by the formation of the 6-p-toluenesulfonates only from methyl 2,3-di-O-meth~l-a-~~ and -P-D-galactopyranosides,5land was ascribed51 to the axial disposition at C-4 and the influence of the adjacent methyl ether group at (3-3.CrameP2 has described preferential sulfonylation at 0-6, to give benzyl 6-O-p-tolylsulfonyl-~-~-g~ucopyranoside, methyl 6-O-p-tolylsu~fony~-a-~-glucopyranoside, and methyl 6-0(methylsulfony1)-a-D-glucopyranoside.The formation of the lastnamed ester was although it was obtained in somewhat lower yield than the other two. Similarly, 6-p-toluenesulfonates were prepared from various deoxy sugars, including methyl 2-deoxy-a-Darabino-he~opyranoside,5~ methyl 3-deoxy-~-xyZo-hexopyranoside,5~ methyl 3-deoxy-~-lyxo-hexopyranoside,5~ methyl 4-deoxy-a-D-xylo(46) H. Ohle and E. Dickhauser, Ber., 58,2593 (1925). (47) J. S. Brimacombe and A. Husain, Chem. Commun., 630 (1966). (48) J. S. Brimacombe and D. Portsmouth,J. Chem. Soc. (C), 499 (1966). (49) N. K. Kochetkov and A. I. Usov, Izu. Akad. Nauk SSSR, Ser. Khim., 492 (1965). (50) N. K. Kochetkov and A. I. Usov, Zsu. Akad. Nauk S S S R , Ser. Khim., 475 (1964). (51) N. R. Williams and R. W. Jeanloz,J. Org. Chem., 29,3434 (1964). (52) F. Cramer, H. Otterbach, and H. Springmann, Chem. Ber., 92,384 (1959). (53) S. A. Brooks and W. G . Overend, Chem. Ind. (London), 471 (1960). (54) C. Fouquey, E. Lederer, 0. Liideritz, J. Polonsky, A. M. Staub, S. Stirm, R. Tinelli, and 0. Westphal, Compt. Rend., 246,2417 (1958).

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he~opyranoside,5~and ethyl 2,3-dideoxy-a-~-erythro-hexopyranoside.5s Derivatives of amino sugars have also been selectively p toluenesulfonylated at 0-6; these examples include methyl 2-(benzyloxycarbonyl)amino-2-deoxy-a-~-glucopyranoside,~' methyl 3-acetamido-3-deoxy-a-~-mannopyranoside,~~ and phenyl 2-acetamido-2deoxy-a-~-mannopyranoside.~~ The 6-p-toluenesulfonates of the last two glycosides were used as intermediates in the preparation of (a derivamethyl 3-acetamido-3,6-dideoxy-a-~-mannopyranoside~~ tive of mycosamine) and 2,6-diamino-2,6-dideoxy-~-mannose,5~ respectively. Other studies of selective sulfonylation at a primary hydroxyl group of sugars were made with 5-deoxy-l,2-0-isopropylidene-a-~xyZo-hexofuranosesOat -12" to give the 6-p-toluenesulfonate and 6methanesulfonate. On warming the reaction mixture to 25", these derivatives were converted into 3,6-anhydro-5-deoxy-l,2-O-isopropylidene-a-D-xylo-hexofuranose. The formation of 2,5-anhydridess1 on p-toluenesulfonylation of dialkyl dithioacetals of pentoses probably proceeds similarly, through the 5-p-toluenesulfonates. Similar findings have been reported with nucleosidess2 and with acetals of alditols.63 It appears that sulfonylations of carbohydrates invariably result in preferential reaction at a primary hydroxyl group. Selective sulfonylation of primary hydroxyl groups has also been demonstrated in oligosaccharides and polysaccharides. Thus, Umezawa and coworkerssq used sequential p-toluenesulfonylation and acetylation to obtain crystalline 1,2,2 ,3,3,4 '-hexa-O-acetyl-6,6'-di0-p-tolylsulfonyl-p-maltose in 45% yield. From methyl p-maltoside, Wolfrom and coworkerss5 prepared crystalline methyl 6,6'-di-O-ptolylsulfonyl-p-maltoside in 86% yield. Crystalline derivatives have (55)S. McNally and W. G . Overend, Chem. Znd. (London), 2021 (1964). (56)C.L. Stevens, P. Blumbergs, and D. L. Wood,J. Am. Chem. SOC., 86,3592(1964). (57)A. B. Foster, M. Stacey, and S. V. Vardheim, Acta Chem. Scand., 13,281 (1959). (58)M. H. Von Saltza, J. Reid, J. D. Dutcher, and 0. Wintersteiner,J . Am. Chem. SOC.,83,2785 (1961). (59)M. L.Wolfrom, P. Chakravarty, and D. Horton, J. Org. Chem., 30,2728 (1965). (60)R.L. Whistler and B. Urbas,J. Org. Chem., 30,2721(1965). (61)J. Defaye, Bull. SOC. Chim. France, 2686 (1964). (62)J. P. Horwitz, J. Chua, and M. Noe1,J. Org. Chem., 29,2076 (1964). (63) T. I. Orlova, A. N. Anikeeva, and S. N. Danilov, Zh. Obshch. Khlm., 35, 649 (1965). (64) S. Umezawa, T. Tsuchiya, S. Nakada, and K. Tatsuta, Bull. Chem. SOC.Japan, 40,395 (1967). (65)M. L. Wolfrom, Y.-L. Hung, P. Chakravarty, G. U. Yuen, and D. Horton,J. Org. Chem., 31,2227 (1966).

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also been isolatedss in high yield by sulfonylation of Schardinger a- and fl-dextrins; these derivatives contain one sulfonyl group per D-glucose residue, and were assumed to be substituted at 0-6, an assumption that appears valid in view of the results cited above with other carbohydrates, and that is supported67by the quantitative conversion of the acetylated sulfonates into the corresponding 6-amino6-deoxy derivatives with methanolic ammonia. A detailed study of the reaction conditions leading to maximal substitution of primary hydroxyl groups and minimal substitution of secondary hydroxyl groups in amylose has been made by Whistler and Hirase.O8The best procedure was dimolar p-toluenesulfonylation of a 5% suspension of amylose in dry pyridine for 1 hour at 35"; the p-toluenesulfonyl chloride was added in one portion. The product contained 0.86 primary p-tolylsulfonyl group and 0.13 secondary p-tolylsulfonyl group. It was establishedss that p-tolylsulfonyl groups on primary hydroxyl groups of the amylose derivative are removed with sodium methoxide in methanol to form 3,6-anhydro rings quantitatively. Considerable attention has been paid to the selective p-toluenesulfonylation of sucrose. Hockett and Ziefsgtreated sucrose with 3 molar proportions of p-toluenesulfonyl chloride in pyridine at O", and obtained an amorphous product that had an elementary analysis agreeing with that calculated for a tri-0-p-tolylsulfonylsucrose. In view of the greater reactivity of primary as compared with secondary hydroxyl groups, the compound was designated as 6,1',6'-tri-O-ptolylsulfonylsucrose. However, the authors statedsg that the degree of homogeneity and the structure had not been determined by rigid methods. The amorphous acetate derived from the tri-0-p-tolylsulfonylsucrose was shown by elementary analysis to be a pentaacetate, and was described as 2,3,4,3',4'-penta-O-acetyl-6,1 ',6'-tri-Op-tolylsulfonylsucrose. Treatment of the amorphous tri-o-p-tolylsulfonylsucrosesg with sodium ethoxide in ethanol gave70 a crystalline trianhydrosucrose, in 3.5% yield, that was later shown7' to be 1',2:3,6:3',6'-trianhydrosucrose. The low yield of the trianhydrosucrose prompted a chromatographic e x a m i n a t i ~ nof ~ ~the tri-0-p(66)W. Lautsch, R. Wiechert, and H. Lehmann, Kolloid-Z., 135,134 (1954). (67)W. Lautsch and R. Wiechert, Kolloid-Z., 153,103 (1957). (68)R. L. Whistler and S. Hirase,]. Org. Chem., 26,4600(1961). (69)R. C.Hockett and M. Zief,J. Am. Chem. SOC., 72,1839(1950). (70)R. U. Lemieux and J. P. Barrette,J. Am. Chem. Soc., 80,2243(1958). (71)R.U.Lemieux and J. P. Barrette, Can. J . Chem., 37, 1964 (1959). (72)R. U. Lemieux and J. P. Barrette, Can. J . Chem., 38,656 (1960).

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tolylsulfonylsucrose6son paper impregnated with silicic acid, and the presence of four zones was observed. By column chromatography, these zones were separated and found to correspond to di-, tri-, tetra-, and penta-O-p-tolylsulfonylsucrose in the molar ratios 20: 20:6.6: 1. In addition, the tri-O-p-tolylsulfonylsucrose fraction was subdivided into two fractions constituting 29% and 13% by weight of the original “tri-O-p-tolylsulfonylsucrose.”The larger fraction, mainly 1’,6,6‘-tri-O-p-tolylsulfony~sucrose, was converted, in 77.4% yield, on treatment with sodium into 1’,2:3,6: 3’,6’-trianhydrosu~rose~~ methoxide in methanol; further evidence that this fraction was mainly (78%) 1‘,6,6’-tri-O-p-tolylsulfonylsucrose came from measurement of the uptake of periodate (2.82 moles of periodate per mole) and from reaction with sodium iodide in acetone to replace 1.87 p-tolylsulfonyloxy groups (a sulfonyloxy group at position 1’ is not replaced6) with iodine. The smaller of the two tri-O-p-tolylsulfonylsucrose fractions afforded analytical data consistent with a tri-O-p-tolylsulfonylsucrose, consumed 1.75 moles of periodate per mole, and underwent replacement of 1.63 p-tolylsulfonyloxy groups on treatment with sodium iodide in acetone; this fraction was clearly a mixture, and was not further separated. The di-O-p-tolylsulfonylsucrosefraction gave crystalline 6,6‘-di-O-p-tolylsulfonylsucrose in 10% yield (by weight), and the mother liquor contained di-O-p-tolylsulfonylsucroses in which 1.1of the p-tolylsulfonyloxy groups were replaceable by iodine on treatment with sodium iodide in acetone. It was considered that the di-O-p-tolylsulfonylsucrose fraction was composed of almost equal amounts of 1’,6-, 1’,6’-, and 6,6’-di-O-p-tolylsulfonylsucrose. The product formed on dimolar p-toluenesulfonylation of sucrose was examined similarly, and was found to contain di-, tri-, and tetraO-p-tolylsulfonylsucrose in the molar ratios 50:40:1. Of the di-0-ptolylsulfonylsucrose fraction, 42% was 6,6‘-di-O-p-tolylsulfonylsucrose, indicating that the 6- and 6’- hydroxyl groups undergo p toluenesulfonylation somewhat more readily than the 1’-hydroxyl group. Dimolar p-toluenesulfonylation gave nearly as much 1’,6,6‘tri-O-p-tolylsulfonylsucrose as did trimolar p-toluenesulfonylation, indicating the greater reactivity of the three primary hydroxyl groups of sucrose over the secondary ones. Prior to Lemieux and Barrette’s work,72 Bragg and Jones73 had examined tri-O-p-tolylsulfony1sucroseasby methylation, followed by de-p-tolylsulfonylation and hydrolysis, and separation of the partially methylated D-glucose and D-fructose derivatives thus formed. The (73) P.D.Bragg and J. K. N. Jones, Can.J . Chem., 37,575 (1959).

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c o n c l ~ s i o nthat ~ ~ the tri-0-p-tolylsulfonylsucrose was mainly 6,l ’,6’tri-0-p-tolylsulfonylsucrosewas c r i t i ~ i z e das~having ~ no basis. Crystalline 6,1’,6‘-tri-O-p-tolylsulfonyllactose has been ~repared,’~ and the derived pentaacetate is ~ r y s t a l l i n e To . ~ ~explain the above sulfonylation results, we quote Lemieux and Barrette,” who stated that “undoubtedly, non-bonded interactions in the transition state are important and probably mainly responsible for the generally greater reactivity of primary positions.” 2. Relative Reactivity at Secondary Hydroxyl Groups a. Secondary Hydroxyl Groups on a Furanoid Ring. - Differences in reactivity between secondary hydroxyl groups in aldohexosides have long been known.’ Dimolar p-toluenesulfonylation of lY2-O-isopropylidene-a-D-glucofuranose gave the 5,6-di-p-toluenesulfonate, and unimolar p-toluenesulfonylation of 6-O-benzoyl-l,2-O-isopropylidene-a-D-glucofuranose gave the 5-p-toluenes~lfonate.~~ Both compounds could be fully p-toluenesulfonylated with an excess of p toluenesulfonyl chloride; thus, the decreasing order of the reactivity of the hydroxyl groups is 0-6 > 0-5 > 0-3. We have found only one example of a more recent sulfonylation of a glycofuranoside. Siddiqui and U r b a ~ treated ~ ~ methyl 6-0-trityl-p-~galactofuranoside with 1.5 molar proportions of p-toluenesulfonyl chloride in pyridine at 100”for 10 hours. The syrupy product, obtained in 75% yield, contained four products and unchanged starling-material, and was fractionated by column chromatography on silica gel to give the 2-, 3-, and 5-0-p-tolylsulfonyl and 2,5-di-O-p-tolylsulfonyl derivatives in the molar ratios of 6: 5: 9: 8. The recovery of fractionated products was 50% (by weight) of the syrupy p-toluenesulfonylation product; the amount of unchanged starting material was not reported. The products were characterized by successive methylation, de-ptolylsulfonylation, detritylation, and hydrolysis, to give methyl ethers of D-galactose. These results show that 0-2 and 0-5 are of comparable reactivity and that they are about three times as reactive as 0-3. When D-erythrono-1,4-lactone was treated with 3.5 equivalents of p-toluenesulfonyl chloride in pyridine at 0” for 30 min., a mono-0(74) I. R. Rominskii, Z . B. Shaposhnikova, N. N. Lisovskaya, and 1. V. Alekseeva, Ukr. Khfm. Zh., 29,420 (1963). (75) Z . B. Shaposhnikova, N. N. Lisovskaya, I. V. Alekseeva, and I. R. Rominskii, Ukr. Khim. Zh., 28,858 (1962). (76)1. R. Siddiqui and B. Urbas, Carbohyd. Res., 5,210 (1967).

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p-tolylsulfonyl derivative was formed in 85% yield,77but attempts to prepare a di-p-toluenesulfonic ester were unsuccessful; similarly, with ~-ribono-1,4-lactone,a di-p-toluenesulfonic ester could be prepared, but not a mono- or tri-p-toluenesulfonate. Several examples of selective sulfonylation at secondary hydroxyl groups are to be found for nucleosides protected at 0-5‘. Brown and coworkers achieved selective p-toluenesulfonylation at 0-2‘ of 5’O-a~etyluridine,~~ 5’-deo~y-5‘-iodouridine,’~ and 1-(5-O-acetyl-B-Dribofuranosyl)thymine.80 Subsequently 5’-0-acetyl-3’-O-p-tolylsulfonyluridine was obtained8’ as a minor product of the p-toluenesulfonylation of 5’-O-acetyluridine. Concurrently with this work, Fox with and coworkersa2treated 1-(5-O-trityl-p-~-ribofurano~yl)thymine 2.5 molar proportions of methanesulfonyl chloride to give (presumably) a 2’-methanesulfonate in not more than 25% yield (based on analysis for sulfur). Use of a larger excess of methanesulfonyl chloride did not increase the sulfur content of the crude product. The 1-[2O-(methylsulfonyl)-5-O-trityl-~-~-ribofuranosyl]thymine was treated with methanolic ammonia, thereby forming a 2,2’-anhydronucleoside which, on acid hydrolysis, gave 1-p-D-arabinofuranosylthymine. The absence of any significant proportion of 1-[3-0-(methylsulfonyl)-5-0trityl-p-~-ribofuranosyl]thymine was inferred, as no l-/ii-D-xylofuranosylthymine could be found. Similarly, 1-(5-O-trityl-p-D-ribofuranosyl) derivatives of uracil, thymine, and 5-fluorouracil were p-toluenesulfonylated preferentiallyw. at 0-2’ in yields of 40-60%. Other examples of preferential sulfonylation at 0-2’ are known; methanesulfonylation of 8-bromoguanosineeJ gave 8-bromo-2‘,5’-di0-(methylsulfony1)guanosinein 42% yield, and unimolar p-toluenesulfonylation of 5-fluoro-5’-O-trityluridinees gave 5-fluoro-2’ - 0 - p (77)D.L. Mitchell, Can.J . Chem., 41,214 (1963). (78)D.M. Brown, A. R. Todd, and S. Varadarajan,J. Chem. SOC., 2388 (1956). (79)D. M. Brown, W. Cochran, E. H. Medlin, and S. Varadarqjan,]. Chem. SOC., 4873 (1956). (80) D. M. Brown, D. B. Parihar, C. B. Reese, and A. R. Todd,J. Chem. Soc., 3035 (1958). (81)D. M. Brown, D. B. Parihar, A. R. Todd, and S. Varadarajan, J . Chem. SOC., 3028 (1958). (82)J. J. Fox, N. Yung, and A. Bendich,J. Am. Chem. Soc., 79,2775(1957). (83)J. F. Codington, I. Doerr, D. V. Praag,A. Bendich, and J. J. Fox,]. Am. Chem. SOC., 83,5030 (1961). (84)J. F. Codington, I. L. Doerr, and J. J. Fox, J . Org. Chem., 29,558 (1964). (85)M. Ikehara, H.Tada, and K. Muneyama, Chem. Phorm. Bull. (Tokyo), 13,639 (1965). (86)N. C. Yung, J. H. Burchenal, R. Fecher, R. Duschinsky, and J. J. FoxJ. Am. Chem. SOC., 83,4060 (1961).

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tolylsulfonyl-5’-O-trityluridinein 52% yield, and no 3‘-p-toluenesulfonate was detected. Unimolar methanesulfonylation of 5-fluoro-5’0-trityluridine gavess only the 2’,3’-di-O-(methylsulfonyl) derivative. This is one of the few examples of a marked difference in reactivity between methanesulfonyl and p-toluenesulfonyl chlorides. The methanesulfonylation was performed at O”, and it is possible that, had the reaction been conducted at a lower t e m p e r a t ~ r e ?preferential ~ methanesulfonylation at 0-2’ would have occurred. In one of the few sulfonylations not involving methanesulfonyl or p-toluenesulfonyl chloride performed in recent years, Todd and UlbrichtS7 treated 5‘-O-acetyladenosine with p-nitrobenzenesulfonyl chloride, and isolated crystalline 2’-and 3’-p-nitrobenzenesulfonatesin the ratio 2: 1. An interesting result was observeds8 in the unimolar p-toluenesulin which 945fonylation of 9-(5-deoxy-/3-~-xylofuranosyl)adenine, deoxy-3-O-p-to~ylsulfony~-~-~-xylofuranosyl)adenine was formed. The position of p-toluenesulfonylation was unambiguously determined by use of proton magnetic resonance spin-decoupling. This result is surprising in view of the generally greater reactivity at 0-2’, compared with 0-3’ in nucleosides,86 and the steric hindrance at the 3’-hydroxyl group by the aglycon and the methyl group on C-4’ in these nucleosides having the D-XYZO configuration. A possible explanationes is that hydrogen bonding between the 3’-hydroxyl group and N-3 of adenine renders the C-3 hydroxyl group more basic and hence more reactive. A similar explanation had previously been proposed by Lemieux and M c I n n e P (see p. 252)in a study of the p-toluenesuland the role of intramolfonylation of 1,4:3,6-dianhydro-~-glucitol, ecular hydrogen-bonding in esterification reactions has been discussed by Foster and coworkers.22Removal of the hydrogen bonding in 9-(5-deoxy-/3-~-xylofuranosyl)adenine by the use of sodium hydride, to form a dianion, eliminated the electronic advantage of 0-3‘ for the p-toluenesulfonylation reaction,8’ and steric factors predominated, resulting in preferential p-toluenesulfonylation at 0-2’. This 2‘-O-p-tolylsulfonyl substituent was then attacked by the anion at 0-3’, to form 9-(2,3-anhydro-5-deoxy-~-~-lyxofuranosyl)adenine. Further p-toluenesulfonylation of 9-(5-deoxy-3-0-p-tolylsulfonylP-D-xylofuranosyl)adenine to give a 2‘,3’-di-O-p-tolylsulfonyl derivative was foundss to be exceedingly difficult. This is one of the few (87) A. R. Todd and T. L. V. Ulbricht,J. Chern. Soc., 3275 (1960). (88) E. J. Reist, V. J. Bartuska, D. F. Calkins, and L. Goodman, J . Org. Chem., 30, 3401 (1965). (89) R. U. Lemieux and A. G . McInnes, Can. J . Chem., 38,136 (1960).

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studies in which information is found on the relative rates for sulfonylation of the starting material and of the initial product of sulfonylation; such a consideration is of importance in sulfonylationseg (or any other type of substitution reaction) of polyhydroxy compounds. b. Secondary Hydroxyl Groups on a Pyranoid Ring. -In most cases, selective sulfonylation has been observed incidentally, as part of a synthetic program, and few systematic studies have been reported in which the selectivity of sulfonylation was the primary interest. From a dimolar methanesulfonylationgoof methyl-a-D-glucopyranocrystalside, methyl 2,6-di-O-(methylsulfonyl)-a-D-glucopyranoside lized out in 51% yield; no starting material or mono-substituted products were detected in the reaction mixture by paper chromatography, but isolation of other methanesulfonylated products was not attempted. However, the greater reactivity during methanesulfonylation of the C-2 hydroxyl group, compared with that of the other secondary hydroxyl groups, was demonstrated. This result was expected,g0 in view of the formation of 2,6-di-O-benzoyl,9l 2,6-di-0p a l m i t ~ y l ,and ~ ~ 2,6-di-O-p-tolylsulfonyls2derivatives from methyl a-D-glucopyranoside by dimolar esterification. The last-named derivative was also obtained by Jary and coworkersg3in 69% yield. Uni-, di-, and tri-molar methanesulfonylations were then performed24on methyl /3-D-glucopyranoside, methyl a- and /3-D-galactopyranoside, and methyl a-D-mannopyranoside. The mixtures of products so obtained were subjected to separation by column chromatography on silica gel; however, from a preparative standpoint, the results were disappointing when compared with the high yield of the 2,6-di-0methylsulfonyl derivative obtained from methyl a-D-glucopyranoside. The respective, major products from di- and tri-molar methanesulfonylation of methyl a-D-galactopyranoside were the 2,6-di-O-methylsulfonyl (20% yield), and 2,3,6-tri-O-methylsulfonyl (30% yield) derivatives. The latter compound was also obtained as the only product of unimolar methanesulfonylation of methyl 2,6-, methyl 3,6-, and methyl 2,3-di-O-(methylsulfonyl)-a-~-galactopyranoside. The formation of methyl 2,6-di-O-(methylsulfony1)-a-D-galactopyranosidecould be expected, in view of the prior isolation of the 2,6-di-p-toluenesulfonate from an analogous reaction.g4 These results clearly indicate (90) A. K. Mitra, D. H. Ball, and L. Long, Jr.,J. Org. Chem., 27, 160 (1962). (91) T. Lieser and R. Schweizer, Ann., 519,271 (1935). (92) J. Asselinevau, Bull. SOC. Chi?. France, 937 (1955). (93) J. Jar$, K. Capek, and J. KO&, Collection Czech. Chem. Commun.,29,930 (1964). (94) P. A. Rao and F.Smith, J . Chem. SOC., 229 (1944).

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that the order of decreasing reactivity of the secondary hydroxyl groups in methyl a-D-galactopyranoside is 0-2 > 0-3 > 0-4. Methyl 2,3,6-tri-0-(methylsulfony~)-a-~-mannopyranoside was the major product isolated from the dimolar (14% yield) and trimolar (41% yield) methanesulfonylations of methyl a-D-mannopyranoside. Thus, for all of the a-D-glycopyranosides discussed, the hydroxyl group on C-4 is the least reactive. The high reactivity at 0-2 of methyl a - ~ gluco- and -galacto-pyranosides may be explained by hydrogen bonding between the C-2 hydroxyl group and the methoxyl group on C-1, but, obviously, this is not the explanation with methyl a-D-mannopyranoside, which also exhibits high reactivity on the axially attached hydroxyl group on C-2, On dimolar methanesulfonylation of methyl /3-D-gl~copyranoside,2~ a mixture of products was obtained which, on fractionation, gave methyl 4,6-di-O-(methylsulfonyl)-~-~-glucopyranoside as the major product, isolated in 13% yield; the 2,6- and 3,6-di-O-methylsulfonyl derivatives were each obtained in 4% yield. These results indicate that the 4-hydroxyl group is the most reactive of the secondary hydroxyl groups. Similarly, dimolar methanesulfonylation of methyl P-D-ga1actopyranosidez4gave the 3,6-di-O-methylsulfonyl derivative in 26% yield, indicating that the greatest reactivity among the secondary hydroxyl groups is for that on C-3. Other examples can be cited in which enhanced reactivity of one of the secondary hydroxyl groups has been demonstrated. Thus, Brimacombe and Portsmoutha5 performed a dimolar p-toluenesulfonylation of methyl 2-deoxy-a-~-2yxo-hexopyranoside, and obtained the corresponding 3,6-di-O-p-tolylsulfonyl derivative in high yield, together with a small proportion of tri-ester. In all of the examples already discussed, the favored conformation of the starting glycoside was C ~ ( D )With . methyl 3-amino-3,6-dideoxy-a-~-glucopyranoside, for which the favored conformation is the same (in mirror image), namely, 1C(L), methanesulfonylation or acetylation was foundm to occur predominantly at the hydroxyl group on C-2. In this example, a cis-arrangement of the methoxyl group on C-1 and the hydroxyl group on C-2 occurs, permitting hydrogen bonding between the two oxygen atoms. Few examples have been reported of selective sulfonylation of methyl pentopyranosides. Reist and coworkersa7 obtained methyl (95)J. S. Brimacopbe and D. Portsmouth, Carbohyd. Res., 1, 128 (1965). Collection Czech. Chem. Commun., 31,1854 (96)K. Capek, J. SteffkovB, and J. (1966). (97)E.J. Reist, L. V. Fisher, and D. E. GuefFroy,]. Org. Chem., 31,226(1966).

Je,

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2-O-benzoyl-3-O-p-tolylsulfonyl-~-~-arabinopyranoside by unimolar p-toluenesulfonylation of methyl 2-O-benzoyl-/3-~-arabinopyranoside, which was stated to illustrate the preferential sulfonylation of an equatorially, as compared with an axially, attached hydroxyl group. Unimolar p-toluenesulfonylation of methyl a-D-xylopyranoside gavese the 2-0-p-tolylsulfonyl derivative in 47% yield, together with 4% of the 4-p-toluenesulfonate and 0.2% of the 3-p-toluenesulfonate. A similar result was obtained by Chalkss for the unimolar methanesulfonylation of methyl a-D-xylopyranoside, but the 2,4-dimethanesulfonate was also isolated (in 10%yield). Dimolar methanesulfonylation of methyl a-D-xylopyranoside afFordedeeJW56% of the 2,4-diester, 10% of the 2,3,4-triester, 4% of the 2-monoester, and 3% of the 2,Sdiester; the product from dimolar methanesulfonylation of methyl P-D-xylopyranoside could not be resolved.lWMethyl a-D-xylopyranoside and methyl a-D-glucopyranoside, which possess the same stereochemistry at the carbon atoms bearing secondary hydroxyl groups, show the same high reactivity to methanesulfonylation at 0-2; surprisingly, no information is available concerning the relative reactivities towards sulfonylation of the hydroxyl groups on C-3 and C-4 of the D-glucopyranoside, to determine whether the D-glucoside behaves analogously to the D-xyloside, that is, whether 0-4 is the more reactive. However, it seems probable that 0-3 is more reactive than 0 - 4 in sulfonylation, because selective tribenzo ylation of methyl a-D-glucopyranoside affords'O' the 2,3,6- and 2,4,6-tribenzoates in the ratio of 7:3. An explanation has been proposed'O' for the greater reactivity of the hydroxyl group on C-3 compared with that on (2-4, in the benzoylation of the D-ghcopyranoside, in terms of the gauche interactions experienced by the hydroxyl groups at these carbon atoms. In the 2,6-dibenzoate, the major product of dimolar benzoylation, the 3-hydroxyl group interacts with neighboring benzoyloxy and hydroxyl groups, whereas the 4-hydroxyl group is flanked by the larger 5-(benzoyloxymethyl) group and a hydroxyl group. Consequently, formation of the tribenzoates will occur preferentially at the sterically less-hindered C-3 hydroxyl group. The same considerations were applied to explain the formation of methyl 2,3,6-tri-Obenzoyl-a-D-mannopyranosideas the major product of trimolar benzoylation of methyl a-D-mannopyranoside, for which the major product from dimolar benzoylation is methyl 3,6-di-O-benzoyl-a-~(98) J. G. Buchanan and R. Fletcher, I . Chem. SOC. (C), 1926 (1966). (99) R. C. Chalk, unpublished results. (100) A. J. Dick and J. K. N. Jones, unpublished results. (101) J. M. Williams and A. C. Richardson, Tetrahedron, 23, 1369 (1967).

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mannopyranoside. In the case of methyl a-D-galactopyranoside, the 2,3,6-tribenzoate is the major product of trimolar benzoylation, but dimolar benzoylation shows low selectivity, and only the 3,6-dibenzoate was identified . The similarity of the data for benzoylationI0' to those obtained by methanes~lfonylation~~ justifies the assumption that the hydroxyl group on C-3 should be more reactive than that on C-4 in methyl a-D-glucopyranoside. The influence of hydrogen bonding on the rate of benzoylation has been discussed'Ol; it was considered unlikely that intramolecular hydrogen-bonding would occur in pyridine, because of the strong intermolecular hydrogen-bonding which occurs between pyridine and alcohols.lo2However, if hydrogen bonding to pyridine is sterically hindered in the transition state, intramolecular hydrogen-bonding may become a factor of some importance. These considerations of non-bonded interactions and hydrogen bonding in benzoylation should apply equally to sulfonylations. c. Secondary Hydroxyl Groups in Cyclitols. - Little information is as yet available on the relative reactivities, toward sulfonylation, of the hydroxyl groups of cyclitols. In two examples reported by Suami and coworker^,^^^^^^^ selective methanesulfonylation occurred at an equatorial hydroxyl group when an axial hydroxyl group was also on methanepresent. Thus,103(~)-1,4,5,6-tetra-0-acetyl-myo-inositol, sulfonylation in pyridine, gave crystalline (k)-1,4,5,6-tetra-O-acetyl3-O-(methylsulfonyl)-myo-inositol; this compound was acetylated, and the product was different from that obtained b y methanesulfonIn addition to estabylation of 1,3,4,5,6-penta-0-acetyl-myo-inositol. lishing the position of methanesulfonylation in these compounds, the absence of acetate migration during methanesulfonylation was demonstrated. In the second example,'" (k)-4,5,6-tri-O-acetyl-l-deoxymyo-inositol was shown to be esterified selectively at the equatorially attached hydroxyl group on C-3, instead of at the axially attached hydroxyl group on C-2, on unimolar methanesulfonylation or unimolar benzoylation. d. Secondary Hydroxyl Groups in Bicyclic Systems. - Unimolar p-toluenesulfonylation of several 4,6-O-benzylidene derivatives of methyl glycopyranosides has been reviewed previous1y.l Methyl 4,6-O-benzylidene-a-~-glucopyranoside gave105*'0smainly the 2-p(102) G. C. Pimentel and A. L. McClellan, "The Hydrogen Bond," Freeman and Co., San Francisco, 1960, p. 91. (103) T. Suami and S. Ogawa, Bull. Chem. Soc.Japan, 37, 1238 (1964). (104) T. Suami and K. Yabe, Bull. Chem. SOC.Japan, 39,1931 (1966). (105) G . J. Robertson and C. F. Griffith,]. Chem. SOC., 1193 (1935). (106) H. R. Bolliger and D. A. Prins, Helu. Chim. Acta,28,465 (1945).

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toluenesulfonate, together with some of the 2,3-diester. In contrast, methyl 4,6-O-benzylidene-a(or 0)-D-galactopyranoside gavelo7 the 3-p-toluenesulfonate, together with small proportions of the 2-monoand 2,3-di-ester, and methyl 4,6-O-benzylidene-~-~-glucopyranoside gave108the 2-and 3-mono-and 2,3-di-sulfonic esters in the molar ratio of 5.6: 7.3: 1. I n an analogous reaction, Aspinall and ZweifePogobtained methyl 4,6-0-ethylidene-3-0-p-tolylsulfonyl-a-~-mannopyranoside in 60% yield, and the 2-p-toluenesulfonate was not found. The higher reactivity of the equatorially attached hydroxyl group on C-3 was explained on stereochemical grounds. The same workers performed unimolar p-toluenesulfonylations on 1,6-anhydro-p-~mannopyranose and its 4-methyl ether, resulting in preferential sulfonylation at the equatorially attached hydroxyl group on C-2 in both compounds.loQSeveral other examples of preferential sulfonylation of 1,6-anhydro-/3-~-glycopyranoses have been reported. 1,6-Anhydro-pD-glucopyranose gives the 2,4-di-p-toluenesulfonate in high yield when one mole of it is treatedl10with three moles of p-toluenesulfonyl chloride at 15-20" for 100 hours, and, from the mother liquors, some tri-p-toluenesulfonate was obtained. A more informative study of the same reaction was made by Jeanloz and coworkersll'; unimolar p-toluenesulfonylation of 1,6-anhydro-~-~-glucopyranose for 29 hours at 0" and then for 16 hours at room temperature, followed by column chromatography, gave"' the 2,4-di-p-toluenesulfonic ester (30% yield), a mixture of the 2- and 4-p-toluenesulfonic esters in the ratio of 2: 1 (30% yield), and the 2,3,4-tri-p-toluenesulfonate (2% yield); dimolar p-toluenesulfonylation gave"' the same derivatives in yields of 69,13.5, and 7%, respectively. These results show that the order of decreasing reactivity of these axially attached, secondary hydroxyl groups is 2 > 4 > 3. Surprisingly, no reaction occurred when the 2and 4-0-p-tolylsulfonyl derivatives of 1,6-anhydro-~-~-glucopyranose were subjected"' to unimolar p-toluenesulfonylation at room temperature for 16 hours; however, with an excess of p-toluenesulfonyl chloride, the 2- and 4-p-toluenesulfonic esters were converted mainly into the 2,4-di- and 2,3,4-tri-p-toluenesulfonicesters, respectively. Similarly, reaction of 1,6-anhydro-2-O-benzoyl-/3-~-glucopyranose with an excess of p-toluenesulfonyl chloride afforded"' the 4-p-toluenesulfonate, whereas unimolar p-toluenesulfonylation (107) E. Sorkin and T. Reichstein, Helu. Chim. Acta, 28, 1 (1945). (108) S. Stirm, 0. Luderitz, and 0. Westphal, Ann., 696,180 (1966). (109) G. Aspinall and G. Zweifel, J . Chem. SOC., 2271 (1957). (110) M. Cern);, V. Gut, and J. Pacik, Collection Czech. Chem. Commun., 26,2542 (1961). (111) R. W. Jeanloz, A. M. C. Rapin, and S. Hakomori, J . Org. Chem., 26,3939(1961).

2.

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resulted in recovery of 90% of the starting material. With the 4- and the use 2,4-di-benzoic esters of 1,6-anhydro-~-~-glucopyranose, of an excess of p-toluenesulfonyl chloride gavelll the corresponding 2- and 3-p-toluenesulfonates, but in low yield; again, unimolar p-toluenesulfonylation was unsuccessful. Clearly, the introduction of a substituent on one hydroxyl group in 1,6-anhydro-P-oglucopyranose can alter the reactivity of other hydroxyl groups; whereas the effect of a sulfonate group on 0 - 2 or 0-4on the reactivity at 0-4 or 0-2, respectively, may be explained by steric considerations, it is difficult to rationalize the greater reactivity on p-toluenesulfonylation (judged by the yield of reaction products) when the substituent is changed from a benzoate on 0-4 of 1,6-anhydro-~-~-glucopyranose to a p-toluenesulfonate group. Methanesulfonylation1l2 of 2-acetamido-1,6-anhydro-2-deoxy-~-~-galactopyranose and p-toluenesulresulted in preff~nylation"~ of 1,6-anhydro-2-O-benzoyl-~-~-altrose erential sulfonylation at the equatorial hydroxyl group in each compound, to give the 4-0-methylsulfonyl and 3-0-p-tolylsulfonyl derivatives, respectively. Reaction of one mole of 1,Sanhydro-gD-gulOpy~anOSewith 6 moles of p-toluenesulfonyl chloride gave114 a di-ester, tentatively identified as the 2,3-di-O-p-tolylsulfonyl derivative; in addition, 1,6-anhydro-2,3,4-tri-O-p-tolylsulfonyl-~-~-gulopyranose was isolated. These results for sulfonylations of 1,6-anhydro-~-~-glycopyranoses indicate that the order of decreasing reactivity of the hydroxyl groups is 2 (axial or equatorial) > 3 (equatorial) > 4 (axial or equatorial) > 3 (axial). In a study of the preferential p-toluenesulfonylation of 1,4:3,6dianhydro-D-glucitol, Lemieux and McInnessOfound that the sterically shielded and hydrogen-bonded endo-hydroxyl group on C-5 is esterified substantially more rapidly than the exo-hydroxyl group on (2-2; unimolar p-toluenesulfonylation at 5" for 46 hours gave the 5-p-toluenesulfonic ester (in 45% yield) and the 2-p-toluenesulfonic ester (in 15% yield), together with approximately 40% of the 2,5-di-ptoluenesulfonate. In a study of the rates of p-toluenesulfonylation of several monosubstitution products of 1,4: 3,6-dianhydro-~-glucitol, LeMaistre and coworkers115confirmed that the hydroxyl group on C-5 is more reactive than that on C-2. In addition, the results showed that (112) (113) (114) (115)

R. W. Jeanloz,J.Am. Chem. SOC., 81,1956 (1959). F. H. Newth, J . Chem. SOC., 441 (1956). L. C. Stewart and N. K. Richtmyer,J. Am. Chem. SOC., 77, 1021 (1955). G. C. Gatos, J. D. Zech, and J. W. LeMaistre, Abstracts Papers Am. Chem. SOC. Meeting, 141, 2D (1962).

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the reactivity is markedly influenced by the nature and size of the substituent already present. Other interesting examples of preferential sulfonylation of fusedring systems have been provided by studies by Newth116and Wolfrom and ~ o w o r k e r s .Unimolar ~~ p-toluenesulfonylation of 13-anhydro4,6-O-benzylidene-~-glucitol afforded,l16selectively, the 2-p-toluenesulfonate, and this result was interpreted to mean that the substituent at C-1 does not influence the reactivity of the hydroxyl group on C-2. However, the latter hydroxyl group is sterically less hinderedlO1than that on C-3, both groups being equatorially attached in the favored conformation. On unimolar p-toluenesulfonylation of methyl 3,6anhydro-a-D-glucopyranoside, which is locked in the I C(D)conformation and has axially attached hydroxyl groups on C-2 and C-4, Wolfrom and coworkersa5 found that reaction occurs preferentially at 0-4. Methyl 3,6-anhydro-4-0-p-tolylsulfonyl-a-~-glucop~anoside was isolated in 11% yield; this compound, unlike the corresponding 2-p-toluenesulfonic ester, was found to be unstable, because it decomposed when stored for a few weeks at room temperature, even after careful purification.

IV. PHYSICALPROPERTIESAND CHEMICALSTABILITY 1. Some Physical Properties of Sulfonic Esters In the years since the last review1of sulfonic esters of carbohydrates, there have been many developments in physical methods for isolation of organic compounds and for their structural elucidation. Column ~hromatography~~'."'*~~~ on a variety of adsorbents has found wide application in the separation and isolation24of esters of carbohydrates. Caution should be exercised in the use of alumina as the adsorbent for primary sulfonates; on neutral or basic alumina of activity I, selective hydrolysis of the primary sulfonate group occurred"* with methyl 3,4 - di- 0 -methyl-2,6-di-O-(methylsulfonyl)-a-~-glucopyranoside, methyl 2,3-di-O-methyl-4,6-di-O-(methylsulfony1)-P-D-glucopyranoside, and methyl 4-0-rnethyl-2,3,6-tri-O-( methylsulfonyl)-cr-~-mannopyranoside in benzene or ethanol-free chloroform. Analogous results (116)F. H.Newth,J. Chem. SOC., 2717 (1959). (117)W.W.Binkley, Aduan. Carbohvdrate Chem., 10,55(1955). (118)M. L. Wolfrom, R. M. de Lederkremer, and L. E. Anderson, Anal. Chem., 35, 1357 (1963). (119)F. W.Parrish, R. C. Chalk, and L. Long, Jr.,J. Org. Chem., 33,3165(1968).

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were obtained with p-toluenesulfonic esters, and, by operating at 50°, this reaction provides a useful, preparative method for the selective hydrolysis of primary sulfonates. Little hydrolysis occurred with alumina of activity 11, and none with alumina of activity 111. When solvents containing alcohols or esters were used, the corresponding ether was formed at 0-6, in addition to the hydrolysis product. When the reaction was extended to acid alumina (activity I), selective reaction again occurred2Qwith the primary sulfonate, with the formation of the corresponding 6-chloro-6-deoxy derivative, because acid alumina is prepared by treating sodium aluminate with hydrochloric acid. Thin-layer chromatography120is frequently employed for following the course of chemical reactions and for small-scale, preparative purposes. Often, it may be advantageous to employ a fluorescent adsorbent and to use a p-toluenesulfonic ester instead of the corresponding methanesulfonic ester, since p-toluenesulfonic esters can then be located by examination of a chromatoplate under ultraviolet light. Gas - liquid chromatography121has proved a useful analytical technique in carbohydrate chemistry, particularly for methyl ethers and acetic esters. By forming trimethylsilyl ethers of relatively nonvolatile sulfonates of sugars,122gas - liquid chromatography can be performed. Application of mass spectrometry to carbohydrate derivatives has been reviewed in this Series.123Although no example of its application to sugar sulfonates was cited, such experiments have undoubtedly been performed; samples having very low volatility may be examined after direct introduction into the ion-source chamber. Sulfonates of 6-chloro-6-deoxy sugars were first identified2' in this way, and interpretation of the mass spectra was aided by the presence of fragments containing 35Cland 37Cl. An isolated example of the use of x-ray diffraction analysis is provided by the work of Camerman and c o w o r k e r ~ . ~Hydroformyl~~J~ ation of 3,4,6-tri-O-acetyl-D-glucal gave 4,5,7-tri-O-acetyl-2,6-anhydro3-deoxy-~-gluco-and -D-manno-heptitols, which were converted into the corresponding 1-p-bromobenzenesulfonates. One of these sulfonates was shown by x-ray analysis to have the C1(D) conformation in which all of the substituents are oriented equatorially; hence, this sulfonate was the D-gluco isomer. (120) M. E. Tate and C. T. Bishop, Can.J . Chern., 40, 1043 (1962). (121) C. T. Bishop, Aduan. Carbohydrate Chem., 19, 95 (1964). (122) C. C. Sweeley, R. Bentley, M. Makita, and W. W. Wells,]. Am. Chem. Soc., 85, 2497 (1963). (123) N. K. Kochetkov and 0. S . Chizhov, Adoan. Carbohydrate Chern., 21,39 (1966). (124) A. Camerman, H. J. Koch, A. Rosenthal, and J. Trotter, Can.]. Chern., 42,2630 (1964). (125) A. Camennan and J. Trotter, Acta Cryst., 18, 197 (1965).

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Two techniques that have found routine application in carbohydrate chemistry, namely, infraredlZ6 and nuclear magnetic resonance',' spectroscopy, were reviewed in 1964;in combination, these methods can provide much of the information required for structural elucidation of an unknown compound. The first infrared study of sugar sulfonates was made'28 with 1,2,3,4-tetra-0-p-tolylsulfonylerythritoland l-O-p-tolylsulfonylglycerol; absorption bands near 1600 and 810 cm.-' were assigned to the aromatic ring vibration and the out-of-plane C - H deformation mode in a puru-substituted phenyl ring, respectively. The p-tolylsulfonyloxy group also contributes bands, at 1360and 1180cm.-', due to asymmetric and symmetric -SO,- stretching. Guthrie and Spedding',@obtained infrared spectra for a number of methyl 4,6-0-benzylidene-~-glycosides containing nitrate and sulfonate groups, and found the asymmetric and symmetric -SO,- stretching frequencies to lie in the ranges 1337- 1372 cm.-' and 1168- 1194 cm.-', respectively. Onodera and coworkers'30have examined the 800-900 cm-' region in the infrared spectra of several sugar sulfonates and their parent compounds, and have reported a characteristic difference in this region between axial and equatorial sulfonyloxy groups. An axial sulfonyloxy group showed a strong absorption band at 890cm.-', and equatorial groups absorbed at 840-850 cm.-'. These frequencies were present in sulfonates having allo, gluco, and galacto configurations, where the favored conformation is IC(L), that is, C ~ ( D )in ; addition, the nature of the sulfonyloxy group (p-tolylsulfonyloxy, benzylsulfonyloxy, or methylsulfonyloxy) and the phase used for the measurement (Nujol, chloroform, or potassium bromide) did not alter these characteristic frequencies, which were assigned to the C - 0-S vibration mode. However, only two compounds having an axial sulfonyloxy group were discussed, and these were the closely related methyl 2-acetamido-2-deoxy-3-O-(methylsulfonyl)-a-~-allopyranoside and its 4,6benzylidene acetal. Furthermore, no compounds containing an axial sulfonyloxy group on C-2 or C-4 of a pyranoid ring were studied. Numerous examples are to be f o ~ n d ~ which ~ ~ J support ~ ~ J ~the ~ assignment130of the 840-850 cm.-' band to an equatorial sulfonyloxy group, but exceptions to the postulate130 that the 880-890 (126)H. Spedding, Aduan. Carbohydrate Chem., 19,23 (1964). (127)L.D.Hal1,Aduan. Carbohydrate Chem., 19, 51 (1964). (128)R. S. Tipson,]. Am. Chem. Soc., 74,1354 (1952). (129)R. D.Guthrie and H. Spedding,]. Chem. Soc., 953 (1960). (130)K. Onodera, S. Hirano and N. Kashimura, Carbohyd. Res., 1,208 (1965). (131)J. Honeyman and J. W. W. Morgan,]. Chem. Soc., 3660 (1955). (132)J. Honeyman, J . Chem. Soc., 2586 (1958).

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cm.-' band is characteristic of an axial sulfonate also occur. No strong band in the 890-cm.-I region occurs in the infrared spectra of methyl 4,6-0-benzylidene-2-O-(methylsulfonyl)-~-~-altropyranoside 3-11itrate,'~~ the corresponding 2-p-toluenesulfonic ester,129or methyl 4-0-methyl-2,3,6-tri-O-(methy~sulfonyl)-cr-~-mannopyranoside~~ all of which have an axially attached sulfonyloxy group on (2-2. An equatorial sulfonyloxy group was indicated130by the infrared spectrum of 1,2:3,4-di-O-isopropylidene-6-O-p-tolylsulfonyl-~-~-galactopyranose; from its nuclear magnetic resonance spectrum, this compound exists133 in a conformation intermediate between a skew &,,J and a boat (B2E) form,134(a) and, as earlier s u g g e ~ t e d , l ~the ~ ( ~substituents ) cannot be described as being equatorially or axially attached. The use of high-resolution, proton magnetic resonance spectroscopy provides information on the configuration of unknown compounds and on the conformation of known substances; this information is obtained from a chemical shift that reflects the electronic and geometric environment of a proton, and the splitting of the signal, which depends on spin - spin interactions between a proton and its neighboring protons. A feature of value in nuclear magnetic resonance spectra, infrequently employed with infrared spectra, is that of peak integration, the area being proportional to the number of protons in the resonance signal. In the first nuclear magnetic resonance study of carbohydrates, Lemieux and found that the methyl protons of an axially attached acetoxy group on a pyranoid ring have chemical shifts that are lower than those of an equatorially attached group. This correlation of chemical shift with orientation was not found with methylsulfonyloxy s u b s t i t u e n t ~ .Introduction '~~ of a sulfonyloxy group causes a shift to lower field in the signal of the proton on the ring carbon atom to which the sulfonyloxy group is attached; this effect is often helpful in interpretation of the nuclear magnetic resonance spectra of sugar sulfonates. The dependence of the numerical value of a coupling constant on the orientation of the protons involved in the coupling was observed'35 in the spectra of pyranose acetates; an equation has been derived by (133)C.Cone and L. Hough, Carbohyd. Res., 1, 1 (1965). (134)(a) H. S. Isbell and R. S. TipsonJ. Res. Natl. Bur. Std., MA, 171 (1960);(b) R. S. Tipson, H. S. Isbell, and J. E. Stewart, ibid., 62,257(1959). (135)R.U.Lemieux, R. K. Kullnig, H. J. Bemstein, and W. G. SchneiderJ. Am. Chem. Soc., 80,6098 (1958). (136)L. D.Hall and M. B. Perry, unpublished results.

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Karplus13' relating the coupling constant J to the projected valenceangle Id, namely,

+

J =Jocos2 (3 K where the parameter K has a value of-0.28 andJo is 8.5 for Id= 0-90", or 9.5 for 9, = 90- 180". The J o values were derived from a valencebond approach, and, in order to obtain reasonable and meaningful results for a carbohydrate ring-system, some modification of the original Karplus parameters was found necessary. The modified parameters were obtained13*from an analysis of the C-5 to C-6 portion of the nuclear magnetic resonance spectra of 3,6-anhydro-1,2-0isopropylidene-a-D-ghcofuranose and its 5-p-toluenesulfonic ester. From the coupling constants between the protons on C-5 and C-6, and on the assumption that the angle between the protons on C-6 is 120", the J o parameters were changed to 9.3 for Id= 0- 90" and 10.4 for P, = 90- 180". An extensive study by C o x ~ nof ' ~the ~ nuclear magnetic resonance spectra of thirty-six methyl 4,6-O-benzylidene-a-~-aldohexopyranosides having the D - d t r o , manno no, and D-gluco configurations included five p-toluenesulfonates. Values of coupling constants for ) these acetals supported the assignment of the C ~ ( D conformation to these pyranosides. An ultraviolet spectrophotometric method for following reactions of arylsulfonates has been described,140but no example of its use with carbohydrate p-toluenesulfonates has yet been reported. 2. Chemical Stability of Sulfonic Esters

Sulfonic esters are frequently prepared as intermediates in carbohydrate chemistry, and their widespread use in synthetic work may be attributed to several factors; adequate methods are available for sulfonylation in good yield, and sulfonyloxy groups exhibit high stability under the conditions used for acetalation, glycosidation, esterification, etherification, and mercaptalation. In many cases, the substituents introduced by these reactions may also be removed with(137) M. Karplus, J . Chem. Phys., 30, 11 (1959). (138) R. J. Abraham, L. D. Hall, L. Hough, and K. A. McLauchlanJ. Chem. SOC.,3699 (1962). (139) B. Coxon, Tetrahedron, 21, 3481 (1965). (140) C. G . Swain and C. R. Morgan,J. Org. Chem., 29, 2097 (1964).

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out affecting sulfonate groups. Furthermore, desulfonylation may be accomplished by reductive methods or by the use of alkaline reagents to regenerate the original hydroxyl group, and a variety of nucleophilic displacement reactions of sulfonyloxy groups are of value. Much information on the chemical stability of sulfonic esters was provided in a previous review'; this section is concerned mainly with up-dating that information by including more-recent applications of sulfonic esters in carbohydrate syntheses. Several methods have been reported for the oxidation of alcohols to their corresponding carbonyl derivative^'^'-'^^; the latter compound~~ are ~ 'useful as intermediates in the synthesis of branchedchain carbohydrate^,'^^ amino sugars,149and epimeric s ~ g a r s . ' ~ ~ J ~ ~ When these oxidations are performed on free hydroxyl groups of carbohydrate sulfonates, no loss of sulfonyl groups occurs, and no adverse effects of the presence of the sulfonic ester group have been reported. With N,N'-dicyclohexylcarbodiimide and phosphoric acid in methyl sulfoxide (Pfitzner- Moffatt reagentl4I), 1,2:5,6-di-Oisopropylidene-3-0-(methylsulfonyl)-~-mannitol gave'42 1,2:5,6-di-Oisopropylidene -4 -0-( methylsulfonyl)-D-arab i no -3-hexdose in 74 5% yield; similarly, methyl 4,6-0-benzylidene-2-O-p-tolylsulfonyl-a-~glucopyranoside was oxidized142to methyl 4,6-0-benzylidene-2-O-ptolylsulfonyl-a-~-ribo-hexopyranosid-3-ulose which, by stereospecific reduction with sodium borohydride, gave methyl 4,6-O-benzylidene2-O-p-to~ylsu~fonyl-a-D-a~lopyranoside. Overend and coworkers'43 have employed ruthenium tetraoxide in carbon tetrachloride for the oxidation of single hydroxyl groups in acetals of methyl glycosides. Similar oxidations may be performed144 in the presence of sulfonic ester groups, the oxidant being continuously regenerated with potassium metaperiodate. Oxidations of hexofuranose derivatives have been performed145 over Adams platinum catalyst, and a protective effect of a primary p-tolylsulfonyloxy group against oxidation at an adjacent C-5 hydroxyl group has been demonstrated. 3-Deoxy-l,2-0-isopropylidene-6-0-p(141) K. E. Pfitzner and J. G. Moffatt, J . Am. Chem. Soc., 85, 3027 (1963). (142) B. R. Baker and D. H. Buss, J . Org. Chem., 30, 2304 (1965). (143) P. J. Beynon, P. M. Collins, and W. G . Overend, Proc. Chem. Soc., 342 (1964). (144) B. Lawton and J. K. N. Jones, unpublished results. (145) K. Antonakis, F. Leclercq, and M. J. Arvor, Compt. Rend., 264, 524 (1967). (146) K. Heyns, A. L. Baron, and H. Paulsen, Chem. Ber., 97, 921 (1964). (147) 0. Theander, Aduan. Carbohydrate Chem., 17,223 (1962). (148) J. S. Burton, W. G. Overend, and N. R. Williams, J . Chem. Soc., 3433 (1965). (149) B. Lindberg and 0. Theander,Acta Chem. Scand., 13, 1226 (1959). (150) 0. Theander, Acta Chem. Scand., 18,2209 (1964).

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tolylsulfonyl-a-D-xybhexofuranosedid not give the hexofuranos-5ulose derivative expected, and from 1,2-O-isopropylidene-6-0-ptoIylsulfony1-a-D-glucofuranose,only the corresponding 3-keto sugar derivative was obtained. From 6-deoxy-l,2-0-isopropylidene-a-Dglucofuranose and 3,6-dideoxy-l,2-O-isopropylidene-a-~-xyZo-hexofuranose, under the conditions used for the above 6-p-toluenesulfonic esters, the products expected from oxidation at the C-5 hydroxyl group were obtained. No interference with oxidation at C-5 was found145when the 6-p-toluenesulfonic esters were oxidized with acetic anhydride in methyl su1f0xide.l~~Heyns and coworkers146 oxidized methyl W p t o l ylsulfon yle-~galactopyranosidewith Adams catalyst in aqueous p-dioxene; the product was reduced with lithium aluminum hydride in tetrahydrofuran, and the product was hydrolyzed to yield 6-deoxy-~-glucoseand 6-deoxy-~-galactose,showing that oxidation had occurred at the axial hydroxyl group on C-4. Boron trichloride and tribromide have been used e x t e n s i ~ e l y ~ ~ ~ * ' ~ ~ for the removal of acetal, acyl, and methyl ether protecting groups from carbohydrate derivatives; with methyl 4,6-0-benzylidene-2-0p-tolylsulfonyl-a-D-glucopyranosideunder conditions that cleave acetals, the reaction product with boron trichloride was not D-glUCOSe, and it may be inferred that it was 2-O-p-tOlylSUlfOnyl-D-glUCOSe.'53 This finding, if substantiated, could make boron trichloride a useful reagent for the cleavage of glycosides bearing a sulfonic ester group on a neighboring carbon atom, as these glycosides are hydrolyzed with difficultyby aqueous acid.lgWhen 3,4:5,6-di-O-cyclohexylidene2-O-methyl-l-O-p-tolylsulfonyl-(-)-inosito1 was treatedlS4with boron trichloride, the product obtained depended on the proportion of boron trichloride used in the reaction; the acetal and methyl ether groups could be removed by treatment with 43 moles of boron trichloride per mole, in dichloromethane at -SO0, to give l-o-p-tolylsulfonyl-(-)-inositol, but, with a lower proportion of boron trichloride, 2-O-methyl-l-O-p-tolylsulfonyI-(-)-inositol was obtained. Resistance to deacetalation was foundlS2with 2,4-0-methylene-1,6-di-O-p-tolylsulfonyl-D-glucitol under the usual reaction conditions. Many examples were earlier reported' of acid hydrolysis of acetals and glycosides of sugar sulfonates in which no loss of a sulfonate group occurred; in addition, by suitable choice of acidic conditions, deacetalation may be performed without concurrent hydrolysis of a (151) J. D. Albright and L. Goldman,J . Am. Chem. SOC., 87,4214 (1965). (152) T. G. Bonner and N. M. Saville,]. Chem. SOC., 2851 (1960). (153) T. C.Bonner, E. J. Bourne, and S. McNally, J. Chem. Soc., 2929 (1960). (154) S . D. Gero, Tetrahedron Letters, 591 (1966).

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glycosidic group. In some instances, low yields have been obtained on deacetalation; for example, Jones and Nicholson'ss hydrolyzed methyl 3,4-O-isopropylidene-2-O-(methylsulfonyl)-~~~-arabinopyranoside in boiling M sulfuric acid for 24 hours and obtained 2-O-(methylsulfonyl)-D-arabinose in a yield of only 8%.The sulfonyloxy group on C-2 stabilize^'^ the glycoside, and the vigorous conditions required for effecting hydrolysis of the glycoside caused destruction of the sugar sulfonate liberated. The compound obtained (in 75% yield) on treatment of methyl 3,4-0-isopropylidene-2-O-(methylsu~fony~)-~-Darabinopyranoside with boiling 0.5 M sulfuric acid for 4 hours was shownIg to be methyl 2-O-(methylsulfonyl)-~-~-arabinopyranoside, and not 2-O-(methylsulfonyl)-~-arabinose (as r e p ~ r t e d previously). '~~ This result indicates that the stabilizing effect of the 2-0-(methylsulfonyl) group is confined to the glycoside group, and does not extend to the 3,4-acetal. Another interesting effect of the presence of a 2-0(methylsulfonyl) substituent is contained in Wood and Fletcher's work.lgWhen treated at 50" for 12 hours with methanol containing4% of hydrogen chloride, 2-O-(methylsulfonyl)-~-arabinose afforded methyl 2-O-(methylsulfonyl)-~-arabinofuranosides, as shown by the transformation of the latter mixture to crystalline 1,3,5-tri-O-benzoyl2-O-(methylsulfonyl)-a- and -P-D-arabinofuranose; unsubstituted aldoses are converted into methyl pyranosides under these conditions of acid concentration and temperature, and the unexpected formation of furanosides from 2-O-(methylsulfonyl)-~-arabinose was attributed to the influence of the methanesulfonic group. The high yield of methyl 2-04methy~su~fony~)-~-~-arabinopyranoside ~ b t a i n e d 'from ~ the 3,4-O-isopropylidene acetal with boiling 0.5 M sulfuric acid contrasts with the low yield of methyl 2-O-(methylsulfony1)-p-L-arabinopyranoside~btained'~' from its 3,4-O-isopropylidene acetal in boiling, 50% acetic acid; the suggestion' that demethanesulfonylation might have occurred in the latter reaction does not appear to have been examined. When methyl 3,4-O-isopropylidene-2-O-p-tolylsulfonyl-~-~-arabinopyranoside was treated for 8 hours with boiling methanol containing 0.3% of hydrogen chloride, methyl 2-O-p-tolylsulfonyl-~-~-arabinopyranoside was isolated in 88% yield; however, the corresponding 3,4-O-benzylidene acetal was unchangedIJ8 by prolonged boiling with methanol containing 0.45% of hydrogen chloride. (155)J. K. N.Jones and W. H. Nicholson,J. Chem. SOC., 3050 (1955). (156)W.G.Overend and M. Stacey, J. Chem. SOC., 1235 (1949). (157)J. K. N.Jones, P. W. Kent, and M. Stacey,]. Chem. SOC., 1341 (1947). (158)J. Honeyman, J. Chem. SOC., 990 (1946).

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Hydrolysis of 1,2:3,4-di-O-isopropylidene-6-0-( methylsulfonyl)a-D-galactopyranoside with 0.05 M sulfuric acid in 50% aqueous crystalline 6-0-(methylsulfony1)ethanol at 80" for 3 hours a-D-galactose in a yield of 40%; the corresponding 6-p-toluenesulfonate of the acetal required15emore vigorous conditions of hydrolysis, namely, 0.125 M sulfuric acid in 75% aqueous ethanol at 80" for 4 hours, to produce 6-O-p-toly~su~fony~-fi-D-ga~actose in 30% yield, as compared to the 70% yield obtained by Ohle and ThiePO by use of 75% aqueous acetic acid at 100" for 2 days. The resistance of glycosides to hydrolysis by acids is not confined to compounds containing a sulfonic ester group adjacent to the glycosidic linkage. D. C. C. Smith1s1 reported, without experimental details, that the glycosidic group in methyl 4,6-0-benzylidene-2-0methyl-3-O-(methy~su~fony~)-fi-~-glucopyranoside is resistant to acid hydrolysis. However, acetolysis of the compound is complete in 2 hours at room temperature, to give 1,4,6-tri-O-acetyl-2-O-methyl-3-0(methylsulfony1)-a-D-glucopyranose. When 1,3:4,6-di-0-(1-chloroethylidene)-2,5-di-O-p-tolylsulfonylgalactitol was treatedlB2with 1.25 M sulfuric acid in ethanol for 16 hours under reflux, unchanged starting material was recovered; reaction occurred in 6 M sulfuric acid, but the product was an intractable syrup. The acetal groups were eventually cleaved by acetolysis under reflux for 30 minutes with 10:5: 1(vlv)acetic anhydride - glacial acetic acid -concentrated sulfuric acid, affording 1,3,4,6-tetra-O-acetyl-2,5di-0-p-tolylsulfonylgalactitol in 18% yield. Acetolysis of 1,3:4,6-di-0benzylidene-2,5-di-O-p-tolylsulfonylgalactitol was achievedlg3more readily; after treatment at 100" for 1 hour in 50:20: 1 (vlv) acetic anhydride -acetic acid-concentrated sulfuric acid, 1,3,4,6-tetra-Oacetyl-2,5-di-O-p-tolylsulfonylgalactitol was isolated in 78 % yield. Foster and treated 1,5-anhydro-4,6-O-benzylidene-2deoxy-3-O-p-tolylsulfonyl-~-urubino-hexitol with 0.05 M methanolic hydrogen chloride under reflux for 2 hours, and obtained 1,5-anhydro2-deoxy-3-O-p-tolylsulfonyl-~-urubino-hexitol in a yield of 66%. The differences in reactivity of acetals of sugar sulfonates demonstrate the need for care in the choice of acetal protecting groups in preparative work. (159) D. L. Mitchell, Can. J . Chem., 41, 1837 (1963). (160) H. Ohle and H. Thiel, Ber., 66, 525 (1933). (161) D. C. C. Smith, J . Chem. SOC., 2690 (1957). (162) H. B. Sinclair and W. J. Wheadon, Carbohyd. Res.,4,292 (1967). (163) N. K. Matheson and S. J. AngyalJ. Chem. SOC., 1133 (1952). (164) A. B. Foster, M. Stacey, and S. Vardheim, Acta Chem. Scand., 12,1819 (1958).

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An interesting result has been reported185 for the treatment of under 1,6: 3,4-dianhydro-2-0-p-tolylsulfonyl-~-~-galactopyranose acidic conditions. With methanolic hydrogen chloride, a mixture of products was obtained,lB5probably by cleavage of the 1,6-anhydro ring followed by undirected opening of the epoxide. However, in boiling methanol in the presence of a sulfonic acid, ion-exchange resin (Dowex 50) for 16 hours, 1,6-anhydro-4-O-methyl-2-O-ptolylsulfonyl-P-D-glucopyranose was produced in 49% yield, whereas the same conditions with 1,6-anhydro-P-~-glucopyranose led to methyl D-ghcopyranosides in quantitative yield. However, it is noteworthy that hydrolysis of 1,6:3,4-dianhydro-2-0-p-tolylsulfonyl-~-Dgalactopyranose was accomplished186in 30 minutes in boiling 2.5 M sulfuric acid in 50% aqueous p-dioxane, to give 1,6-anhydro-2-O-pto~y~su~fony~-~-D-glucopyranose in 47% yield. Jeanloz112has reported a similar reaction, wherein the 3,4-0-acetal group of 1,6-anhydro3,4-O-isopropy~idene-2-O-(methylsulfonyl)-~-~-ga~actopyranose is cleaved selectively and quantitatively in 1 hour by boiling 0.085 M sulfuric acid in 70% aqueous ethanol. Clearly, these further examples of the stabilizing effect of a sulfonyl group on an acetal under acidic conditions show the importance of the reagent chosen for hydrolysis and the conditions under which it is used. The stability of sugar sulfonates to conditions of methanolysis has been used in establishing the structures of some members of the chromomycin group of antibiotic substances. p-Toluenesulfonylation of chromomycins A2 and A3 followed by methanolysis atFordedl8' separable mixtures of known methyl glycosides of unsubstituted chromose sugars and their p-toluenesulfonic esters, permitting determination of the structures of chromomycins A2 and & (except for anomeric configurations). A novel ring-expansion occurred188on treating methyl 2-0-benzoyl3-O-(methylsulfonyl)-5-O-tri~l-a- or -@-D-xylofuranoside with 80% acetic acid at 100" for 30 minutes; in addition to detritylation to the corresponding furanoside, some 13-18% of the latter product was converted into the pyranosides with retention of anomeric configuration, as evidenced by the isolation of crystalline methyl 3-amino-3deoxy-a- or -P-D-xylopyranoside on successive treatment of the (165)L. JLCarlson,J. Org. Chem., 30, 3953 (1965). (166)M.Can$, J. Pa&, and J. Stangk, Collection Czech. Chem. Commun., 30, 1151 (1965). (167)M. Miyamoto, Y. Kawamatsu, K. Kawashima, M. Shinohara, and K. Nakanishi, Tetrahedron Letters, 545 (1966). (168)R. E. Schaub and M. J. Weiss, J . Am. Chem. SOC.,80, 4683 (1958).

SULFONIC ESTERS OF CARBOHYDRATES: PART I

263

detritylation product with methanolic sodium methoxide at 5" for 3-5 days and with aqueous ammonia at 100"for 18 hours. Prolonged heating with 80%'acetic acid lowered the yield of detritylation products, and did not ultimately produce increased yields of methyl aminodeoxy-D-xylopyranosidgs.A mechanism was proposed16' for the ring expansion with retention of configuration. Protonation of the

OMe

- H@ bcoc,H,

ring-oxygen atom is followed by rupture of the 0-5-C-1 bond by attack on C-1 of the carbonyl oxygen atom of the 2-0-benzoyl group to form a cyclic carbonium ion; the latter ion may then be attacked intramolecularly at C-1 by the C-4 hydroxyl group to regenerate the furanoside, or by the C-5 hydroxyl group to give a pyranoside having the same anomeric configuration. In an alternative synthesis of the anomeric methyl 3-amino-3-deoxyD-xylofuranosides starting from 1,2-O-isopropylidene-5-O-(methoxycarbonyl)-3-O-(methylsulfonyl)(or p-tOlylSUlfOnyl)-a-D-XylOf~anOSe, better results were obtainedlB9when deacetonation was performed by acetolysis than by acetobrominolysis, prior to glycoside formation with 1% methanolic hydrogen chloride at room temperature. Under these conditions, no loss of the 5-O-(methoxycarbonyl) group occurred, but concurrent deacetonation and glycoside formation by use of refluxing, 1%methanolic hydrogen chloride caused significant loss of the protecting group on 0-5, permitting isomerization of the desired furanosides to methyl 3-O-(methylsulfonyl) (or p-tOlylSUlfOnyl)-Dxylopyranosides. (169) C. D. Anderson, L. Goodman, and B. R. BakerJ. Am. Chem. SOC.,835247 (1f.68).

264

D. H. BALL AND F. W. PARRISH

More examples have been reported in which a glycosyl halide containing a sulfonyl group is used in glycoside formation by the Koenigs -Kn~rr'~Oprocedure. Methanesulfonylation of 1,3,4,6-tetra-O-acetyla-D-gluco- and -galacto-pyranosides gave171the corresponding 2-0(methylsulfonyl) derivatives in 85% yield; the derived 3,4,6-tri-Oacety~-2-O-(methylsu~fony~)-a-D-g~ucosyl bromide was treated171with methanol in acetonitrile containing mercuric cyanide and mercuric bromide, to form methyl 3,4,6-tri-O-acetyl-2-0-(methylsulfonyl)-~D-glucopyranoside in 42% yield. Treatment of 3,4,6-tri-O-acety1-2-0p-tolylsulfonyl-~-D-glucosylchloride with a mixture of silver carbonate, silver perchlorate, and Drierite in methanol dorded'" a single product which, on reductive desulfonylation and acetylation, gave methyl tetra-0-acetyl-a-D-glucopyranosidein 72% yield. However, in an attempt to synthesize disaccharides containing an a-D-glucosidic chloride linkage, 3,4,6-tri-0-acety~-2-~-p-to~y~su~fony~-~-D-g~ucosy~ in chloroform was treated172 with 1,2,3,4-tetra-O-acetyl-~-~-glucopyranose in the presence of silver carbonate, silver perchlorate, and Drierite. The reaction mixture was acetylated, and the acetates separated by chromatography on Magnesollls into P-gentiobiose octaacetate (6% yield) and a compound which, on reductive desulfonylation and acetylation, afforded p-isomaltose octaacetate (9% yield). The cleavage of the 2-0-p-tolylsulfonyl group in the formation of pgentiobiose octaacetate indi~ated'~' that this group was not a nonparticipating group. When the corresponding 2-O-(methylsulfonyl) derivative was treated17*similarly, but in tetrahydrofuran - ether instead of chloroform, P-gentiobiose octaacetate was again isolated; difficulty was experienced in removing the methylsulfonyl group from the sulfur-containing fraction with sodium amalgam, and no p-isomaltose octaacetate was isolated. When the reaction was perf~rmed'~'in acetonitrile containing mercuric cyanide and mercuric bromide, crystalline 0-(3,4,6-tri-~-acety~-2-0-p-to~y~su~fony~-~-~-g~ucopyranos (1~6)-tetra-O-acety~-~-D-g~ucopyranose was isolated; reductive desulfonylation and acetylation of this compound produced P-gentiobiose octaacetate (4.5% yield), and no isomaltose derivative was isolated. Other syntheses of p-D-glucosyl halides containing a sulfonate group have been described. Treatment of 1,2,3,4-tetra-O-acetyl-6-0p-tolylsu~fonyl-~-D-glucose in phosphorus pentachloride with hydro(170) W. Koenigs and E. Knorr, Ber., 34,957 (1901). (171) B. Helferich and J. Zirner, Chem. Ber., 95, 2604 (1962). (172) M.L. Wolfrom, K. Igarashi, and K. Koizumi,J. Org. Chem., 30,3841 (1965).

SULFONIC ESTERS OF CARBOHYDRATES: PART I

265

gen chloride at 100" gave1732,3,4-tri-O-acetyl-6-O-p-tolylsulfonyl-~D-glucopyranosyl chloride. treated 5,6-di-0-acetyl-1,2-0-isopropyliHelferich and ~oworkers'7~ dene-3-O-(methy~sulfonyl)-a-D-glucofuranose with glacial acetic acid containing dry hydrogen bromide and isolated 2,5,6-tri-O-acetyl3-04methylsu~fonyl)-cr-D-glucofuranosy~ bromide in 50 90' yield; subsequently, the product was described'75 as 5,6-di-O-acetyl-l,2-0(1- bromoethylidene)- 3- 0-(methylsulfonyl) -a-D- glucofuranose, because its reaction with methanol in pyridine afforded the corresponding (1-methoxyethylidene) acetal, in which only two alkali-labile acetate groups are present. The problem has been re-examined by Heyns and coworkers,17swho measured the nuclear magnetic resonance spectrum of the acetobrominolysis product from 5,6-di-0acetyl-l,2-O-isopropylidene-3-0-( methylsulfony1)-a-D-glucofuranose, and found signals at 2.07-2.17 p.p.m. corresponding to 9 protons of 3 acetyl groups; also, a coupling constant forJl,z of 4.7Hz was found. These values are consistent with the acetobrominolysis products' brobeing ~,~,6-tr~-~-acety~-~-~-(methy~su~fony~)-a-D-g~ucofuranos mide, as originally formulated by Helferich and coworker^.'^^ Reaction of this bromide with ethanol in pyridine gave1765,6-di-O-acetyl-172-0( l-ethoxyethylidene)-3-0-( methy~sulfony~)-a-~-glucofuranose, as indicated by the expected singlet at 1.63 p.p.m. for the C-methyl of the orthoacetyl group and aJ1,z value of 3.6 Hz. On treating the acetylglycosyl bromide with silver acetate, the corresponding &acetate was obtained,176and this had 0 Hz, as expected. Similarly, from nuclear magnetic resonance data, the product from 1,2-0-isopropylidene-3,5,6-tri-O-p-tolylsulfonyl-a-~-glucofuranose was formulated176 as an acetylglycosyl bromide, not as an orthoester. Osazone and (p-nitropheny1)hydrazone formation without desulfonylation has been a c c ~ m p l i s h e din ' ~ aqueous ~ ethanolic acetic acid with 3,6-anhydro-5-0-p-tolylsulfonyl-~-glucofranose. With 6-0-(methylsulfony1)-and 6-0-p-tolylsulfonyl-D-galactosein methanol at room temperature for 2 days, the corresponding (Z,l-dinitro-, (N-benzyl-, and (2,5-dichloro-phenyl)hydrazoneswere readily obtained.150How(173)F. Garrido Espinosa, Anales Uniu. Catolica Val-Paralso, 4-5, 245 (1957-8); Chenz. Abstracts, 55,20066 (1961). (174)B. Helferich, H. Dressler, and R. Griebel, J . Prakt. Chem., 153,285(1939). (175)B. Helferich and H. Jochinke, Ber., 74,719 (1941). (176)K. Heyns, W. P. Trautwein, F. Garrido Espinosa, and H. Paulsen, Chem. Ber., 99,1183 (1966). (177)H. Ohle and E. Euler, Ber., 63, 1796 (1930).

266

D. H. BALL AND F. W. PARRISH

ever, when the reaction was p e r f ~ r m e d "at ~ 45-50' for 1 hour, and the mixture was then kept for 48 hours at room temperature, phenylhydrazone derivatives of 3,6-anhydro-~-galactosewere formed. Attempts phenylosazone in acetateto prepare 6-O-(methylsulfonyl)-~-galactose buffered aqueous acetic acid at 80" 3,6-anhydro-~-Zyxohexose phenylosazone. A procedure, devised by Kuhn and coworkers,178that employs methyl iodide and silver oxide in N,N-dimethylformamide is frequently used for the permethylation of carbohydrates. When applied to sulfonic esters of carbohydrates, two side-reactions are found24if appropriate structures are present, namely 3,6-anhydro ring formation, and conversion of a primary methylsulfonyloxy group into a methoxyl group. These side reactions were minimized by conducting the methylation at 0" instead of at room temperature, and by processing the reaction mixture as soon as the reaction was complete, as shown by thin-layer chromatography. With methyl 2,3-di-O-p-tolylsulfonyl-60-trityl-a-D-glucopyranoside,methylation was effe~ted"~in 86% yield with methyl iodide and silver oxide in hot acetone, without occurrence of desulfonylation. Removal of a nitrate group, without desulfonylation, may be performed5 by reduction with a mixture of zinc dust and iron dust in boiling, glacial acetic acid; the same result may be achievedlsOby use of hydrazine in ethanol, hydrazine in ethanol-chloroform, or sodium nitrite. Thus, treatment of methyl 4,6-0-benzylidene-3-0(methylsulfony1)-a-D-ghcopyranoside2-nitrate with hydrazine gave methyl 4,6-O-benzylidene-3-O-(methylsulfonyl)-a-~-glucop~anoside in 87% yield. When methyl 4,6-O-benzylidene-a-~-altropyranoside 2,Sdinitrate was treated with sodium nitrite in aqueous ethanol for 16 hours, the corresponding 3-nitrate was obtained in 55% yield; the stable, 3-nitrate group could be removed with sodium nitrite when it was activated by the presence of a 2-O-(methylsulfonyl) group. Sequential esterification of methyl a-D-mannopyranoside with p toluenesulfonyl chloride, phosgene, and benzoyl chloride afforded181 methyl 4-0-benzoyl-2,3-0-carbonyl-6-O-p-tolylsulfonyl-a-~-mannoside in 37% yield, without isolation of intermediate products. The compound was used as an intermediate in the synthesis of two 1,2(178) R. Kuhn, H. Trischmann, and I. Low, Angew. Chem., 67,32 (1955). (179) C. P'ang and C. M. Hu, Sci. Sinica (Peking), 13, 441 (1964); Chem. Abstracts, 61,5740 (1964). (180) K. S . Ennor, J. Honeyman, and T. C. Stening, Chem. Znd. (London), 1308 (1956). (181) W. W. Zorbach and W. H. Gilligan, Carbohyd. Res., 1,274 (1965).

SULFONIC ESTERS OF CARBOHYDRATES: PART I

267

cis-cardenolides, and may offer a new and improved route to Drhamnose. 182,183 Whereas reaction of equimofar amounts of methyl 2,3-di-O-p-tolylsulfonyl-a-D-ghcopyranoside and benzeneboronic acid in refluxing benzene gavels4 the corresponding 4,6-benzeneboronate in good yield, treatment of methyl a-D-glucoside 4,6-benzeneboronate with p-toluenesulfonyl chloride in pyridine liberated pyridinium chloride, but failed to afford a crystalline glycoside derivative. However, benzoylation and acetylation of methyl a-D-ghcopyranoside 4,6benzeneboronate was readily effectedls4by use of the corresponding acyl chloride in pyridine. Selective transformation of 0-benzylidene acetals into o-bromosubstituted benzoic esters in high yield has been d e ~ c r i b e d , ' ~ J ~ and may be performed equally successfully in the presence of a sulpfonic ester group. Thus, methyl 4,6-0-benzylidene-2-deoxy-2-( tolylsulfonamido)-3-O-p-tolylsulfonyl-a-~-altrop~anosidewith N bromosuccinimide (and benzoyl peroxide) in refluxing benzene gavels6 methyl 4-O-benzoyl-6-bromo-2,6-dideoxy-2-(p-tolylsulfonamido)-3-O-p-tolylsu~fonyl-c~-~-altropyranoside in 88 % yield. Analogous results have been obtained'% by use of N-bromosuccinimide in the absence of a radical initiator in refluxing carbon tetrachloride containing barium carbonate. These oxidative methods cause removal of 0-benzylidene group under non-acidic conditions, without any effect on free hydroxyl groups that may be present; the resulting 6-bromo6-deoxy sugars may be readily convertedl6 into the corresponding 6deoxy sugars. A possible side-reaction with N-bromosuccinimide in carbon tetrachloride is186a Baeyer -Villiger oxidation; thus, methyl 2,3,4,6-tetra-O-methyl-a,~-~-g~ucopyranoside afforded a product which was homogeneous by thin-layer chromatography and which showed infrared absorption at 1720 cm-' characteristic of a S-lactonic or acyclic ester carbonyl. A similar oxygen-insertion reaction has been observedls7 on prolonged oxidation with ruthenium tetraoxide; with ruthenium tetra1,2: 5,6-di-O-isopropylidene-a-~-glucofuranose oxide in carbon tetrachloride at 20" for 1-4 hours gave'43 1,2:5,6-diO-isopropylidene-cu-~-ribo-3-hexulofuranose in 80% yield, but, after (182)W.T.Haskins, R. M. Hann, and C. S. HudsonJ. Am. Chem. SOC., 68,628(1946). (183)W.W.Zorbach and C. Tio,J. Org. Chem., 26, 3543 (1961). (184)R. J. Ferrier, J . Chem. SOC., 2325 (1961). (185)S. Hanessian, Carbohyd. Res., 2, 86 (1966). (186)D. L. Failla, T. L. Hullar, and S. B. Siskin, Chem. Commun., 716 (1966).

268

D. H. BALL AND F. W. PARRISH

48 hours, the major product was18' 1,2:6,7-di-O-isopropylidene-3-oxaa-D-~ibo-4-heptulopyranose.

Kochetkov and Usov49~50~188 have utilized triphenyl phosphite complexes containing halogens to replace primary or secondary sulfonyloxy groups by halogen in carbohydrate sulfonates. Methyl 3-0methyl-2,6-di-O-p-tolylsulfonyl-a-~-glucopyranoside with triphenyl phosphite methiodide in benzene for 5 hours at 55" gave49methyl 4-deoxy-4-iodo-3-0-methyl-2,6-di-O-p-tolylsulfonyl-a-~-g~actopyranoside in 83.5% yield; however, with a higher proportion of the iodinating reagent, reaction of the latter compound 0ccurred,4~by displacement of the primary p-tolylsulfonyloxy group, to form methyl 4,6-dideoxy-4,6-diiodo-3-O-methyl-2-O-p-tolylsulfonyl-a-~-galactopyranoside in 85% yield. Possibly, analogous displacements can occur with 4-sulfonates having the gluco or galacto configuration. Similarly, methyl 2,3-di-0-methyl-6-0-p-tolylsulfonyl-a-~-galactoand -glucopyranoside a f f ~ r d e d ~the ~ J corresponding ~~ 4-deoxy-4-iodo-~-gluco and -D-galaCtO derivatives in 58 and 80 % yield, respectively. In addition to the sulfonyloxy displacement reaction which may occur on halogenation with triphenyl phosphite complexes, the possibility of acetal migration (with appropriate structure) should not be overlooked. Thus, 1,2:5,6-di-O-isopropylidene-a-~-glucofuranose with triphenyl phosphite dibromide in benzene for 48 hours affordedls8 (presumably) 6-bromo-6-deoxy-l,2: 3,5-di-O-isopropylidenea-D-ghcofuranose, which was hydrolyzed to 6-bromo-6-deoxy-~glucose in 10% overall yield. In some compounds, steric factors may prevent the introduction of halogen.lS8With vicinal glycols and triphenyl phosphite methiodide, phosphonic ester formation occurs18g instead of halide production, but this reaction may be eliminated189 by use of triphenylphosphine in carbon tetrachloride. Hydroboration'" of a terminal olefin group in a sugar methanesulfonate has been performedis1 without affecting the sulfonate substituent; 5,6 - dideoxy - 1,2- 0- isopropylidene - 3- 0- (methylsulfony1)-a-~xylo-hex-5-enose, treated with diborane in tetrahydrofuran at room temperature for 1.5 hours, affordedlgl the expected 5-deoxy-1,2-0in 74 % yield. isopropylidene-3-0-(methy~sulfonyl)-a-D-glucofranose (187) R. F. Nutt, B. Arison, F. W. Holly, and E. Walton, J . Am. Chem. Soc., 87,3273 (1965). (188) N. K. Kochetkov and A. I. Usov, Tetrahedron, 19, 973 (1963). (189) J. B. Lee and T. J. Nolan, C a n . ] . Chem., 44, 1331 (1966). (190) G. Zweifel and H. C. Brown, Org. Reactions, 13, 1 (1963). (191) K. J. Ryan, H. Arzoumanian, E. M. Acton, and L. Goodman,J. Am. Chem. SOC., 86, 2503 (1964).

SULFONIC ESTERS OF CARBOHYDRATES: PART I

v. REMOVAL OF

ESTER GROUPSWITH ALUMINUMHYDRIDE

SULFONIC

269

LITHIUM

1. Primary Sulfonic Esters of Pyranoid Sugars Schmid and Karre? observed that treatment of 1,2:3,4-di-Oisopropylidene-6-O-p-tolylsulfony~-~-galactose with lithium aluminum hydride in boiling ether-benzene (2: 1, by vol) caused desulfonyloxylation, to give 1,2:3,4-di-O-isopropylidene-~-fucose in 55% yield. Analogous results were obtained with 1,2: 3,4-di-O-benzylidene-6-O-p-tolylsulfonyl-~-galactose.~~ This method for removing primary sulfonyloxy groups has frequently been used in the synthesis of w-deoxy sugarsY8many of which occur in Nature. Secondary p tolylsulfonyloxy groups are generally converted into the corresponding alcohol by lithium aluminum hydride.2 Recent applications of this reaction include the reduction of methyl 3-O-benzyl-2-O-methyl-6-O-p-tolylsulfonyl~-~-allopyranoside~ leading to the synthesis of 6-deoxy-2-O-methyl-~-allose,4~ and the reduction of methyl 3-O-methyl-2,6-di-O-p-tolylsulfonyl-cy-~-allopyranoside as a step in the synthesis of 6-deoxy-3-O-methyl-D-allose.48 The last-named compound was also synthesized,4@in lower yield (because of competing side-reactions), starting from methyl 3-0methy~-2,4,6-tri-O-p-to~y~su~fony~-~-~-a~~opyranoside. The effects of solvents in reductions with lithium aluminum hydride have not yet been systematically examined. Generally, the solvent employed is ether or tetrahydrofuran, and the choice is usually dictated by the ease of reaction at the boiling point of the solvent.lS3However, the solvent may affect the course of the reaction and the nature of the end-products. When tetrahydrofuran was usedz1”9 instead of ether -benzeneZin the reduction of 1,2:3,4-di-O-isopropylidene-6-O-p-tolylsu~fony~-~-galactose with lithium aluminum hydride, the conditions of Schmid and KarreP being otherwise unchanged, the only reaction product was 1,2: 3,4-di-O-isopropylidene-~-galactose, instead of 1,2: 3,4-di-O-isopropylidene-~-fucose. The same products were obtained starting from the corresponding 6-methanesulfonate. At 25-66”, in tetrahydrofuran that was 0.06- 1.0 M in lithium aluminum hydride, both sulfonic esters (0.06-0.7 M) afforded 1,2:3,4di-0-isopropylidene-D-galactose; in ether- benzene (2: 1,by vol) over (192) J. Pacak and M. :ern$, Collection Czech. Chem. Commun., 26,2212 (1961). (193) L. F. Fieser, “Experiments in Organic Chemistry,” Heath and Co., Boston, 1955, p. 292.

270

D. H. BALL AND F. W. PARRISH

the same range of reaction conditions, the 6-p-toluenesulfonate gave the D-fucose acetal as the sole product, but the 6-methanesulfonate (0.06 M) with lithium aluminum hydride (concentration greater than 0.25 M) gave mixtures of the D-fucose and D-galactose acetals. Knowledge of this solvent effect in reductions with lithium aluminum hydride permitted the synthesis of 6-deoxy-2,4-di-O-methyl-Dgalactose (labilose) in 60% yield from methyl 2,4-di-O-methyl-3,6di-0-(methylsulfony1)-P-D-galactopyranosidein ether -benzene.” When tetrahydrofuran was used as the solvent, the products were methyl 2,4-di-O-methyl-~-~-galactopyranoside and methyl 3,6-anhydro-2,4-di-O-methyl-~-~-galactopyranoside in the ratio of 2: 1. A step was the reduction, in the synthesis of 6-deoxy-4-O-methyl-~-galactose with lithium aluminum hydride in ether -benzene, of methyl 2,3-diO-benzyl-6-O-p-tolylsulfonyl-~-~-galactopyranoside to methyl 2,3-di0- benzyl- 6 -deoxy -P -D- galactopyranoside in 86% yield.‘% When treated similarly, methyl 4-0-methyl-2,3,6-tri-O-p-to~y~su~fonyl-~-~galactopyranoside gave (presumably) methyl 6-deoxy-4-0-methylP-D-galactopyranoside in 88% yield.IBgOwen and Raggl% treated methylsulfony1)-P-D-galactopyranomethyl 2,3-di-O-methyl-4,6-di-O-( side with lithium aluminum hydride in boiling ether for 13 hours, to obtain methyl 6-deoxy-2,3-di-O-methyl-4-O-(methylsulfonyl)-~-~galactopyranoside in 76% yield. Reduction of methyl 3,4-di-0-methyl-2,6-di-0-(methylsulfonyl)-aD-glucopyranoside with a hydride in boiling tetrahydrofuran for 2 hours methyl 6-deoxy-3,4-di-O-methyl-a-~-glucopyranoside in 90% yield; this glycoside was a minor product when the reduction was performed in boiling ether- benzene (4:l),the major product being tentatively identified as methyl 2,6-dideoxy-3,4-di0-methyl-a-D-arabino-hexopyranoside.Equal amounts of methyl 3,4-di-O-benzyl-a-~-glucopyranoside and the corresponding 6-deoxyD-glucoside were producedw on reduction of methyl 3,4-di-O-benzyl2,6-di-O-(methylsulfonyl)-a-~-glucopyranoside with a hydride in boiling tetrahydrofuran. However, reduction of primary sulfonic esters of D-galaCtOpyranOsides with lithium aluminum hydride in tetrahydrofuran can also result in formation of deoxy sugars. Heyns and coworker^'^' reduced in this methyl ~-~-methy~-6-O-p-to~y~su~fony~-~-~-ga~actopyranoside (194) J. H. Westwood, R. C. Chalk, D. H. Ball, and L. Long, Jr., 1. Org. Chem., 32, 1643 (1967). (195) E. G . Gros, Carbohyd. Res., 2, 56 (1966). (196) L. N. Owen and P. L. Ragg, J . Chem. SOC. (C), 1291 (1966). (197) K. Heyns, G . Ruediger, and H. Paulsen, Chem. Ber., 97,2096 (1964).

SULFONIC ESTERS OF CARBOHYDRATES: PART I

27 1

way to afford methyl 3-O-methyl-/3-~-fucopyranosidein 40% yield. Similarly, the mixture of 6-0-p-tolylsulfonyl and 4,6-di-O-p-tolylsulfonyl derivatives obtained on p-toluenesulfonylation of methyl 2,3-di-O-methyl-/3-~-galactopyranoside, on reduction with lithium aluminum hydride in tetrahydrofuran, gavelgs mainly methyl 2,3-di0-methyl-/3-D-fucopyranoside, together with some methyl 2,3-di-0methyl-P-D-galactopyranosideand a small proportion of methyl 2,3di-O-methyl-4-O-p-tolylsulfonyl-/3-~-fucopyranos ide. Brimacombe and reduced methyl 3,4-0-isopropylidene-2,6di-0-p-tolylsulfonyl-a-D-galactopyranoside with lithium aluminum hydride in tetrahydrofuran, to provide methyl 3,4-O-isopropylidene2-O-p-to~ylsulfonyl-a-~-fucopyranoside in 54% yield. In later reductions of closely related compounds, the solvent chosen was etherbenzene; methyl 3-O-benzyl-2-deoxy-6-O-p-tolylsulfonyl-a-~-Zyxohexopyranoside afforded the corresponding 6-deoxy compound which, on methylation, debenzylation, and acid hydrolysis, gavezm 2,6dideoxy-4-0-methyl-D-Zyxo-hexose(chromose A).167 An improved synthesis of this sugar involvedg5the reduction, in ether- benzene (1:l),of methyl 2-deoxy-4-O-methyl-3,6-di-O-p-tolylsulfonyl-a-~-Zyxohexopyranoside to methyl 2,6-dideoxy-4-O-methyl-a-~-lyxo-hexopyranoside in 25% yield; a synthesis of 3-O-acetyl-2,6-dideoxy-~-Zyxohexose (chromose D)'67was effecteds5by way of reduction in etherbenzene (2: 1) of methyl 2-deoxy-6-O-p-tolylsulfonyl-a-~-lyro-hexopyranoside to the corresponding 6-deoxy compound in 27% yield, followed by partial acetylation and acid hydrolysis. Syntheses of 2,6-dideoxy sugars having the D-&O or D-X& configurations have been described by Bolliger and coworkers.201-203 When methyl 2,3-anhydro-4,6-di-O-p-tolylsulfonyl-a-~-allopyranoside was treated for 6 hours with lithium aluminum hydride in boiling tetrahydrofuran, the product obtained was methyl 2,6-dideoxy-a-~-ribohexopyranoside (methyl a-D-digitoxoside)201;the 4-0-p-tolylsulfonyl derivative of this glycoside could be isolated after reaction for 1hour. When the reduction was performed at 18", only the anhydro ring was cleaved,2O2affording methyl 2-deoxy-4,6-di-O-p-tolylsulfonyl-a-~-allopyranoside. Thus, the order of reactivity in the reaction with lithium aluminum hydride in tetrahydrofuran iszo2 anhydro > primary p (198) M. P. Khare, 0. Schindler, and T. Reichstein, Helu. Chim. Actu, 45,1547 (1962). (199) J. S. Brimacombe and M. J. How, J . Chem. SOC., 5037 (1962). (200) J. S. Brimacombe, D. Portsmouth, and M. Stacey,]. Chem. SOC., 5614 (1964). (201) H. R. Bolliger and P. Ulrich, Helu. Chim. Acta, 35, 93 (1952). (202) H. R. Bolliger and M. Thurkauf, Helu. Chim. Acta, 35, 1426 (1952). (203) H. R. Bolliger and T. Reichstein, Helu. Chim. Acta, 36,302 (1953).

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D. H. BALL AND F. W. PARRISH

tolylsulfonyloxy > secondary p-tolylsulfonyloxy. The product from reduction (in tetrahydrofuran) of methyl 2,3-anhydro-4,6-di-O-ptolylsulfonyl-a-D-gulopyranosidegave, on p-toluenesulfonylation,2°5 methyl 2-deoxy-3,4,6-tri-0-p-tolylsulfonyl-a-~-gulopyranoside and in methyl 2,6-dideoxy-3,4-di-O-p-tolylsulfonyl-~-~-gulopyranoside the molar ratio of 5 2 . It would be of practical value to determine if the 6-deoxy sugar is the sole product of the reduction with lithium aluminum hydride in ether -benzene of methyl 2,3-anhydro-4,6-di0-p-tolylsulfonyl-a-D-gulopyranoside. Reduction in ether of methyl 2,3-anhydro-6-0-p-tolylsulfonyl-a-~-gulopyranoside, and p-toluenesulfonylation of the product, gave203methyl 2,6-dideoxy-3,4-di-O-ptolylsulfonyl-a-D-xylo-hexopyranoside and a small proportion of methyl 2-deoxy-3,4,6-tri-O-p-tolylsulfonyl-a-~-gulopyranoside. Reduction of o-sulfonates has also been employed in syntheses of 3,6-dideoxy-~-hexoses.Methyl 3-deoxy-~-~ibo-hexopyranoside was selectively p-toluenesulfonylated, and the 6-p-toluenesulfonate was reduced with lithium aluminum hydride in ether-benzene (1:1); the product was hydrolyzed, to give 3,6-dideoxy-~-ribo-hexose (para3,6-Dideoxy-~-arabino-hexose (tyvelose) was p ~ e p a r e d ~ ~ 2 ~ tose).2M*205 in a similar manner. More recently, Westphal and coworkers1o8have prepared the methyl glycosides of tyvelose, starting with the individual anomers of methyl 3-deoxy-~-arubino-hexopyranoside, and proceeding by way of the 6-p-toluenesulfonate; methyl 3,6-dideoxy-P-~xylo-hexopyranoside (methyl p-abequoside) was prepared similarly, in 45% yield. Earlier syntheses of abequose from methyl 3-deoxy6-O-p-tolylsulfonyl-~-xy2o-hexopyranoside i n v o l ~ e d ~ displace~”~ ment of the p-tolylsulfonyloxy group by iodine prior to reduction, and hydrolysis with acid; in some cases, an improved yield of deoxy sugar is obtained by hydride reduction of the iodo sugar as compared with direct reduction of the sulfonic ester. Hydride reduction of methyl 2-deoxy-3-C-methyl-6-O-p-tolylsulfonyl-a-~-~ibo-hexopyranoside was unsuccessfu1,2°7but the desired methyl 2,6-dideoxy-3-C-methyl-a-~ribo-hexopyranoside was obtained from the corresponding 6-iodo derivative by treatment with Raney nickel and triethylamine. Methyl 2,6-dideoxy-3-C-methyl-3-O-methyl-a-~-~ib~-hexopyranoside (methyl a-D-cladinoside) was prepared207by a similar procedure. Unexpect(204)C. Fouquey, J. Polonsky, E. Lederer, 0. Westphal, and 0. Liideritz, Nature, 182,944 (1958). (205)C. Fouquey, J. Polonsky, and E. Lederer, Bull. SOC. Chlm. France, 803 (1959). (206)K. Antonakis, Cornpt. Rend., 258, 5911 (1964);Bull. SOC. Chim. France, 2112 (1965). (207)B. Flaherty, W. G . Overend, and N. R. Williams, J . Chem. SOC. (C), 398 (1966).

SULFONIC ESTERS OF CARBOHYDRATES: PART I

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edly, some anomerization of methyl 2-deoxy-3-0-methyl-4,6-di-O-ptolylsulfonyl-a-D-x~Zo-hexopyranosidezw and of methyl 2-deo~y-3~4~6tri-O-p-tolylsulfonyl-a-D-xyZo-hexopyranosidezw occurred with sodium iodide in acetone. Hydride reduction of methyl 3-deoxy-3-(dimethylamino)-2,4,6-tri0-p-tolylsulfonyl-a-D-Tibo-hexopyranoside in tetrahydrofuran gavezo9 the corresponding 6-deoxy sugar which, on hydrolysis, afforded 3,6this was found to be dideoxy-3-(dimethylamino)-~-~-ribo-hexose; identical with mycaminose, a component of an antibiotic substance. Syntheses of 4,6-dideoxy-3-0-methyl-~-x~Zo-hexose (chalcose) have been reported by the intermediate hydride reduction, in tetrahydrofuran, of 6-p-toluenesulfonates; methyl 4-deoxy-6-0-p-tolylsulfonyla-D-xylo-hexopyranoside afforded:§ by such treatment, the corresponding 6-deoxy glycoside, and methyl 4-deoxy-3-0-methyl-2,6-di0-p-tolylsulfonyl-a-D-xybhexopyranosidegave40 a mixture of five products, from which methyl a-D-chalcoside was isolated in 26% yield.

2. Primary Sulfonic Esters of Furanoid Sugars Lithium aluminum hydride reduction of w-sulfonyloxy groups of furanoid sugar derivatives has been used extensively for the preparation of the corresponding o-deoxy sugar derivatives; similar results have been obtained with ether or tetrahydrofuran as the solvent. Hydride reduction in ether of 3,5-O-benzylidene-l,2-O-isopropylidene6-O-p-to~y~sulfonyl-a-D-glucofuranosez10 and of 3-0-benzyl-1,2-0isopropy~idene-6-O-p-to~y~sulfonyl-a-~-g~ucofuranose~~~ afForded the corresponding 6-deoxy derivative; similarly, 1,2-O-isopropylidene3,5-di-O-p-to~ylsulfonyl-a-~-xy~ofuranose gavez1* 5-deoxy-l,2-O-isopropylidene-a-D-xylofuranosein 35% yield. When the 5-mono- and 3,5-di-p-toluenesulfonic esters of 1,2-O-isopropylidene-~-arabinose were reduced in tetrahydrofuran, 5-deoxy-l,2-O-isopropylidene-~arabinose was obtained2l3; similar reduction, in tetrahydrofuran, of a number of methyl 5-0-p-tolylsulfonyl-pentofuranosides to 5-deoxy glycosides has been reported.214 (208) H. Hauenstein and T. Reichstein, Helu. Chim. Acta, 33,446 (1950). (209) A. B. Foster, T. D. Inch, J. Lehmann, M. Stacey, and J. M. Webber,]. Chem. SOC., 2116 (1962). (210) P. Karrer and A. Boettcher, Helu. Chim. Acta, 36, 570 (1953). (211) M. L. Wolfrom and S. Hanessian,J. Org. Chem., 27,2107 (1962). (212) P. Karrer and A. Boettcher, Helu. Chim. Acta, 36, 837 (1953). (213) A. K. Mitra and P. Karrer, Helu. C h h . Acta, 38, 1 (1955). (214) B. Green and H. Rembold, Chem. Ber., 99,2162 (1966).

274

D. H. BALL AND F. W. PARRISH

Reist and coworkers215reduced 3,5-di-O-acetyl-l,2-O-isopropylidene-6-O-p-to~ylsulfony~-a-~-g~ucofuranose in ether to form 6-deoxy1,2-0-isopropy~idene-a-D-glucofuranose7 possibly through an intermediate 5,6-anhydro-~-gZucoderivative. Reduction of 6-S-benzyl-2,3-0-isopropylidene-6-thio-l-O-p-tolylsu~fonyl-~-D-fructofranose with lithium aluminum hydride in tetrahydrofuran caused2I6desulfonyloxylation to 6-S-benzyl-1-deoxy2,3-O-isopropylidene-6-thio-/3-~-fructofuranose, The sterically morehindered p-tolylsulfonyl group in 2,3:4,5-di-O-isopropylidene-lO-p-tolylsulfonyl-~-D-fructopyranose is simply removed2 on hydride reduction in ether, to give 2,3:4,5-di-O-isopropylidene-/3-~-fructopyranose. The formation of 6,6’-dideo~ysucrose~~ by hydride reduction, in tetrahydrofuran, of “tri-0-p-tolylsulfonylsucrose” warrants further investigation in view of the discovery72 that tri-0-p-tolylsulfonylsucrose is a mixture of compounds. Reduction of 2,3-0isopropy~idene-5-O-p-tolylsulfony~-~-ribono-l,4-lactone in tetrahyin 84% yield. drofuran gave2175-deoxy-2,3-0-isopropylidene-~-ribitol

3. Primary Sulfonic Esters of Acyclic Sugars Many examples have been reported of the hydride reduction of p-toluenesulfonic esters of primary alcohol groups of sugar dithioacetals to the corresponding w-deoxy derivative, but we have found no example of the use of methanesulfonic esters, although some of these esters have been prepared.218 Reduction of 5-O-p-tolylsulfonyl-Darabinose dithioacetals, derived from methane-, ethane-, 2-propane-, butane-, or a-toluene-thiol, in ether -benzene (5:l),gave2**the corresponding 5-deoxy-D-arabinose dithioacetal in 40- 56% yield. A similar procedure, starting from D-mannose dimethyl dithioacetal, provided183a new synthesis of D-rhamnose, albeit in low, overall yield (9%). Applications of this method to the synthesis of dideoxy sugars have been described. Hydride reduction, in ether, of 2-deoxy6-O-p-tolylsulfonyl-D-~rabino-hexose diethyl dithioacetal afForded2I9 the 2,6-dideoxy-~-urabino-hexosedithioacetal. Syntheses of 3,6dideoxy-D-xylo-220and -D-arabino-hexose221involved hydride reduc(215) E. J. Reist, R. R. Spencer, and B. R. Baker, J . Org. Chem., 23, 1753 (1958). (216) M. S. Feather and R. L. Whistler,J. Org. Chem., 28, 1567 (1963). (217) L. Hough, J. K. N. Jones, and D. L. Mitchell, Can. J . Chem., 36, 1720 (1958). (218) H. Zinner, K. Wessely, and H. Kristen, Chem. Ber., 92,1618 (1959). (219) W. W. Zorbach and J. P. Ciaudelli,J. Org. Chem., 30,451 (1965). (220) H. Zinner, B. Ernst, and F. Kreienbring, Chem. Ber., 95,821 (1962). (221) G. Remban,J. Prakt. Chem., 19, 319 (1963).

SULFONIC ESTERS OF CARBOHYDRATES: PART I

275

tion, in p-dioxane, of the corresponding 3-deoxy-6-0-p-tolylsulfonylD-pentose dimethyl dithioacetals. A difference in the behavior of methanesulfonic and p-toluenesulfonic esters of 1,3-O-benzylidene-tetritols on reduction with lithium aluminum hydride in tetrahydrofuran has been described by Foster and coworkers222; 1,3-0-benzylidene-2,4-di-O-p-tolylsulfonyl-~erythritol and -L-threitol gave the corresponding 4-deoxytetritol acetals, whereas 1,3-O-benzylidene-2,4-di-O-(methylsulfonyl)-~threitol was simply demethanesulfonylated to 1,3-O-benzylidene-~threitol. 4. Secondary Sulfonic Esters

In general, on reaction with lithium aluminum hydride, secondary sulfonic esters are desulfonylated, with formation of the corresponding secondary alcohol.2 An exception is provided in an observation by Reist and c o ~ o r k e r s , who 2 ~ ~ treated 6-O-benzoyl-l,2-O-isopropylidene-5-O-p-tolylsu~fonyl-a-D-glucofuranosey with lithium aluminum hydride in ether and obtained a product thought to be 6-deoxy-1,2-0isopropylidene-P-L-idofuranose,derived from an intermediate 5,6anhydro-L-ido derivative; later, Ryan and coworkers191showed, from its nuclear magnetic resonance spectrum, that the product was 5deoxy-1,2-O-isopropylidene-~-~-~yZo-hexofuranose. The problem has been re-examined by Overend and coworker^"^; the repetition experiment under the conditions of Reist and coworkers223afforded 5-deoxy1,2-0-isopropylidene - a - ~ - x y l-hexofuranose o and 6-deoxy-1,2-O-isopropylidene-P-L-idofranose in 62 and 30% yield, respectively. Various conditions were without success, for raising the the yield of 5-deoxy-l,2-O-isopropylidene-a-~-~ylo-hexofuranose; yield was significantly lowered (about 30%) when the hydride reduction was performed in tetrahydrofuran. A mechanism was proposed224 for formation of the two products: namely, that formation of 6-deoxy1,2-O-isopropylidene-P-~-idofuranose occurs by hydride reduction of an intermediate 5,6-anhydride, and that 5-deoxy-l,2-O-isopropylidene-a-D-xylo-hexofranose is produced by formation of a C-3 alkoxyaluminum hydride derivative, followed by intramolecular hydride displacement of the p-tolylsulfonyloxy group on C-5. It would be of interest to study this system with a sugar derivative in which 0-3 is (222) A. B. Foster, A. H. Haines, J. Homer, J. Lehmann, and L. F . Thomas,]. Chem. Soc., 5005 (1961). (223) E. J. Reist, R. R. Spencer, and B. R. Baker,]. Org. Chem.,23,1757(1958). (224) E. J. Hedgley, 0. MBrBsz, and W. G. Overend,J. Chem. SOC. (C), 888 (1967).

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D. H. BALL AND F. W.PARRISH

protected by a substituent that is stable under the conditions of hydride reduction, in order to determine the extent to which direct displacement of the p-tolylsulfonyloxy group on C-5 by hydride can occur. Reduction of methyl 4,6-0-benzylidene-2,3-di-O-p-tolylsulfonyl-crD-glucopyranoside with lithium aluminum hydride in tetrahydrofuran affordsee5methyl 4,6-0-benzylidene-3deoxy-a-~-~bo-hexopyranoside (in 66% yield) by a mechanism analogous to that proposed by Overend and coworkerse” for the formation of 5-deoxy-1,2-O-isopropylidene-cu-D-xylo-hexofuranose.With the corresponding p-D anomer, hydride reduction in tetrahydrofuran proceeds less readily, giving methyl 4,6-0-benzylidene-3-deoxy-~-~-dbo-hexopyranoside in 38% yield.ezeThis compound was also obtained (in 22% yield) when hydride reduction was performed in p-dioxane, together with a second crystalline compound, identified as methyl 4,6-0-benzylidene-2,3dideoxy-p-D-erythroo-hexosideformed by direct displacement at C-2 and C-3 with hydride. Treatment of methyl 3,4-O-isopropylidene-2-O-p-tolylsulfonyl[or (methylsulfonyl)]-p-~-arabinopyranoside with lithium aluminum hydride in ether gaveze7methyl 3,4-0-isopropylidene-~-~-arabinopyranoside; similar treatment of methyl 2-O-p-tolylsulfonyl-~-~-arabinopyranoside afforded mainly methyl P-L-arabinopyranoside, together with methyl 2,3-anhydro-p-~-ribopyranoside, methyl &-deoxy-p-~erythro-pentopyranoside,and methyl 3-deoxy-P-~-eqthro-pentopyranoside in low yield. Direct reduction of methyl 2-09-tolylsulfonylp-L-arabinopyranoside to the 2-deoxy glycoside was postulated:*‘ and the production of both deoxy sugars was ascribed to cleavage of methyl 2,3-anhydro-/3-~-ribopyranoside.Similar results were obta.inedee7 with methyl 2-O-(methylsulfonyl)-~-~-arabinopyranoside, except that more methyl 8-L-arabinoside and less 2deoxy sugar were formed. Reduction of methyl 3,4-di-O-acetyl-2-O-p-tolylsulfonyl-~-~arabinopyranoside in ether gavepL7 methyl 2-deoxy-p-~-erythro-pentopyranoside and methyl /3-L-arabinoside, but the latter sugar was the sole product from the corresponding 2-methanesulfonic ester; direct, reductive cleavage of the p-tolylsulfonyloxy group was suggested, to account for the formation of the 2-deoxy sugar. In all of these experirnentsya7the excess lithium aluminum hydride was decomposed by cautious addition of water; if, in the above com(225)E. Vis and P. h r , Helv. Chfm. Acta, 37,378 (1954). (226) E. J. Hedgley, W. G. Overend, and R. A. C. Rennie,J. C b m . Soc., 4701 (1903). (227) R. Allerton and W. G. Overend,J. Chsrn. Soc., 3629 (1954).

SULFONIC ESTERS OF CARBOHYDRATES: PART I

277

pounds containing a free hydroxyl group at (2-3, cleavage of the sulfonic ester was incomplete, addition of water could result in formation of 2,Sanhydro sugar, together with some reduction of this compound to 2-deoxy and 3-deoxy sugars. The isolation227of methyl 2,3-anhydro-P-L-ribopyranosideafter 72 hours of reaction is otherwise difficultto reconcile with the ready cleavage of 2,3-anhydro rings observed earlier.201-203 A similar explanation may account for the formation2Is of 2,5-anhydro-1,3:4,6-di-O-methylene-~-mannitol (36%), together with 1,3:4,6-di-O-methylene-~-mannitol (39%), on hydride reduction in tetrahydrofuran of the 2,5-di-p-toluenesulfonate of the latter acetal. The axially attached p-tolylsulfonyloxy group of methyl 3deoxy4,6-di-0-methyl-2-0-p-tolylsulfonyl-a-~-u~u~~~o-hexopyranoside was de-p-toluenesulfonylatedZz8when the compound was treated with lithium aluminum hydride in ether. However, removal of the axially attached p-tolylsulfonyloxy group of methyl 4,6-0-benzylidene-3-0methy~-2-O-p-tolylsu~fonyl-a-~-a~tropyranoside~~~ and of methyl 4,6O-ethylidene-3-O-methyl-2-O-p-tolylsulfonyl-a-~-mannopyr~oside with lithium aluminum hydride'" in tetrahydrofuran proceeded with difficulty, but was readily achieved'O0 with sodium amalgam in 90% aqueous methanol. An interesting reaction of a secondary methylsulfonyloxy group has been described briefly by Lehmann22g;the product obtained by treatment of methyl 6-deoxy-2,3-0-isopropylidene-4-0-(methylsulfonyl)a-~-lyxo-hex-5-enopyranoside (1)with lithium aluminum hydride in ether for 30 minutes at room temperature was described as methyl 4,6-dideoxy-2,3-0-isopropylidene -p-~-erythro-hex-4-enopyranoside (2) on the basis of proton magnetic resonance data and elementary analysis. An analogous reaction had previously been observed by Overend and (see compounds 3 and 4, p. 279).

(228) G. Remban, Chen. ber., 95,825 (1962). (229) J. Lehmann, Angew. Chem., 77,863 (1965).

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D. H. BALL AND F. W. PARRISH

A number of epimino sugars have been prepared230-233 by the action of lithium aluminum hydride in tetrahydrofuran on vicinal benzamido sulfonates oriented in the trans relationship. Treated in this way, methyl 3-benzamido-4,6-0-benzylidene-3-deoxy-2-O-(methylsulfony1)-a-D-altropyranosideafForded230,231 methyl 4,6-O-benzylidene2,3-dideoxy-2,3-epimino-a-~-allopyranoside in 53% yield. The Dmanno isomer was similarly prepared, in 60% yield, from methyl 2benzamido-4,6-O-benzylidene -2 -deoxy-3 -0-(methylsulfonyl)- a - ~ altropyranoside, but in only 20% yield from the 2-acetamido analog. The reacting groups in these starting-materials possess a trans-diaxial relationship in the favored, C1(D) conformation; this permits displacement of the methylsulfonyloxy group by rearward participation of the amide-nitrogen atom, with inversion of configuration, to form the epimino sugar. in 51% yield, from the The D-UZZO epimine was also more readily available methyl 2-benzamido-4,6-0-benzylidene-2deoxy-3-O-(methylsulfonyl)-a-~-glucopyranoside by treatment with 11 molar proportions of lithium aluminum hydride in tetrahydrofuran; here, the reacting groups are in the trans-diequatorial relation) but a transition state having ship in the favored, C ~ ( Dconformation, a boat conformation permits assumption of the trans-diaxial relationship required for formation of the epimino sugar. When 5.5 molar proportions of lithium aluminum hydride were used, methyl 2(benzylamino)-4,6-O-benzylidene-2-deoxy-a-~-glucopyranoside was formed in 34% yield, together with the epimino sugar in 35% yield. Reaction of the 2-acetamido analog with 11 molar proportions of lithium aluminum hydride afforded crystalline methyl 4,6-O-benzylidene-2-deoxy-2-(ethy1amino)-a-D-glucopyranosidein 52% yield, and the presence of the D-UZZO epimino sugar was indicated by the results of thin-layer chromatography of the mother liquor. Treatment of methyl 3-benzamido-3,6-dideoxy-2,4-di-0-(methylsulfony1)-a-L-glucopyranosideor methyl 3-benzamido-2-0-benzoyl3,6-dideoxy-4-0-(methylsulfonyl)-a-~-glucopyranoside with lithium aluminum hydride in tetrahydrofuran gave233methyl 3,4,6-trideoxy3,4-epimino-a-~-galactopyranoside in yields of 50 and 66%, respectively. (230) R. D. Guthrie, D. Murphy, D. H. Buss, L. Hough, and A. C. Richardson, Proc. Chem. SOC., 84 (1963). (231) D. H. Buss, L. Hough, and A. C. Richardson,J. Chem. SOC., 5295 (1963). (232) C. F. Gibbs, L. Hough, and A. C. Richardson, Carbohyd. Res., 1, 290 (1965). (233) A. D. Barford and A. C . Richardson, Carbohyd. Res., 4,408 (1967).

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5. Tertiary Sulfonic Esters

In their extensive studies of branched-chain sugars, Overend and coworkers have examined148the reaction of several tertiary p-toluenesulfonic esters with Iithium aluminum hydride in ether, as a method of obtaining branched-chain deoxy sugars. Methyl 3,40-isopropylidene-2-C-methyl-2-O-p-tolylsulfonyl-~-~-arabinopyranoside (3,R = CH3, R’ = OTs) afforded methyl 2-deoxy-3,4-0-isopropylidene-2-C-methyl-P-~-ergthro-pentopyranoside (3, R = CH3,R’ = H) in 50 % yield. Extension of this method to the 2-C-(phenylethynyl) and

\\

CHMe

(9)

(4)

2-C-(cis-phenylethenyl) analogs was unsuccessful, and the tertiary alcohol group was regenerated; methyl 3,4-0-isopropylidene-2-O-ptolylsulfonyl-2-C-vinyl-~-~-arabinopyranoside (3, R = CH=CH2, R’ = OTs) gave a mixture of 70 % of the parent alcohol and 30 % of a deoxy sugar (4) in which the vinyl double bond of compound 3 had

undergone migration, with elimination of the p-tolyIsulfonyIoxy gr0up.234

VI. ACTIONOF SOMEALKALINEREAGENTSON SULFONICESTERS The transformation of sulfonic esters into anhydro sugars has been reviewed extensively.l3 Reaction of 2-0-sulfonyl derivatives of free sugars with sodium methoxide has since received attention; initial formation of a 1,2-anhydro sugar155is followed by production of a methyl glycoside of the C-2 epimeric sugar, in which the hydroxyl group on C-2 is tmns to the methoxyl group on C-1. Saponification of 2-O-(methylsulfonyl)-~-arabinose with sodium methoxide gave181a mixture of methyl pentosides contaminated with (234)W. G . Overend, Chem. Ind. (London), 342 (1963).

D. H. BALL AND F. W. PARRISH

280

free D-arabinose and D-ribose; the free sugars were probably produced by traces of (more reactive) sodium hydroxide present. Methyl pentosides were the sole products (97% yield) from 4-0-formyl-20-(methylsulfony1)-D-arabinose,probably because hydroxyl ions had been removed in saponification of the formic ester; the product consisted of methyl /?-D-ribopyranoside(61 %), methyl /?-D-arabinofuranoside (30%) and methyl a-D-arabinofuranoside (9%). Initial formation of l,Z-anhydro-D-ribopyranose, followed by attack of methoxide ion at C-1, explainslg’ the production of methyl /?-D-ribopyranoside. An intermediate 2,3-anhydro-~-ribose(5) to which addition of methoxide ion could occur at C-1 could afford two stereoisomers (6); the “anomeric” epoxide methyl ethers (7),formed by epoxide migration, could then react with the alkoxide ion generated from C-4, giving the anomeric methyl D-arabinofuranosides (8). H

H ‘OCOMe I

c=o I

HHC’Y b

I HCOH I C%OH (5)

-C

HC’ I HCOH I CHgOH (6)

- ,CHOMe “AH I HCOH I HCOH I CHsOH (7)

HOH,C

’ c H n O M e HO (8)

Similar reactions of 2-methanesulfonic esters with sodium meth~~-~~’; oxide have been described by Fletcher and ~ o ~ o r k e r s ~ 1,3,5tri-O-benzoyl-2-O-(methylsulfonyl)-a-~-ribose affordedz35 methyl a-D-arabinopyranoside. From 1,3,5-tri-O-benzoyl-2-O-(methylsulfonyl)-P-D-arabinose, a mixture of methyl /?a-ribofuranoside and methyl /?-D-ribopyranoside was 0btained,2~~ whereas only the latter glycoside was isolatedz3’ when 2-O-(methylsulfonyl)-173,5-tri-0(p-nitrobenzoy1)-/?-D-arabinose was the starting material. Desulfonylation of 2-0-p-tolylsulfonyl or 2-O-(methylsulfonyl) derivatives of D-arabinose, D-xylose, and L-fucose with aqueous barium hydroxide D-ribose, D-lyxose, and Ci-deoxy-~-talose, respectively, by way of a 1,e-anhydro sugar; similarly, 3-O-(methylSUlfOnyl)-D-fruCtOSe affords D-pSiCOSe. (235) R. K. Ness and H. G . Fletcher, Jr., J . Am. Chem. SOC., 78,4710 (1956). (236) R. K. Ness and H. G . Fletcher, Jr.,J.Am. Chem. SOC., 80, 2007 (1958). (237) C. P. J. Glaudemans and H. G. Fletcher, Jr., J . Org. Chem., 29, 3286 (1964).