Carbohydrate Boronates

CARBOHYDRATE BORONATES BY ROBERTJ . FEFWER Department of Chemistry. Victoria University of Wellington.Wellington.New Zealand

I . Introduction .......................................................... I1. Synthesis of Boronates ................................................ 1. Direct Condensation of Carbohydrates with Boronic Acids . . . . . . . . . . . . 2 . From Borinates .................................................... I11. Structures of Carbohydrate Boronates .................................. 1. Alditol Boronates .................................................. 2 . Sugar Boronates .................................................... 3 . Boronates of Glycosides, Nucleosides. and Related Compounds . . . . . . . IV . Boronates in Chemical Reactions ...................................... 1. Boronates in Aqueous Systems ...................................... 2 . Removal of Boronate Groups ........................................ 3. Stability of Boronates during Chemical Reactions .................... V Separations of Carbohydrates by Use of Their Boronates ................ 1. Use of Isolated Boronates ........................................... 2 . Use in Paper Chromatography ...................................... 3 Use in Electrophoresis ............................................. 4 . Use in Column Chromatography .................................... 5 . Use in Gas-Liquid Chromatography ................................. VI . Mass Spectrometry of Boronates ....................................... VII . Nuclear Magnetic Resonance Spectroscopy of Boronates ................ VIII . Borinates ............................................................ IX . Tables ............................................................... X . Addendum ...........................................................

.

.

31 37 37 39 41 42 43 45 48 48 52 53 57 57 58 62 63 65 65 70 70 71 80

I . INTRODUCTION Condensation between D-ghCOSe and boric acid in acetone. in the presence of a strong-acid catalyst. gives the discrete. cyclic ester 1.2-0 . isopropylidene-a-D-glucofuranose3.5.boratel (1). which may be used in the preparation of 6-substituted derivatives of D.glucose . Such instances of the isolation and syntheti.c application of specific carbohydrate borates are. however. few. because of the complexity of boric acid as an esterifying agent As well as affording the 3.5.cyclic ester 1. the aforementioned reaction could have led to ( a ) a dimeric

.

(1) L . Vargha. Ber., 66. 704-707 (1933). 31

32

ROBERT J. FERRIER

product containing boron-oxygen-boron linkages: (b) various dimers linked by one boric acid unit, or (c) an intramolecular triester. With a view to exploiting the clear potential of boric acid derivatives in preparative, carbohydrate chemistry, but with reagents not subject to such diverse means of reaction, the present autho9 began, in 1961, a study of the condensation undergone between phenylboronic acid [PhB(OH),I and the diol systems of various glycosides. At that time, it had been found that free sugars interact with this acid in aqueous soluti0n,4-~and several boronates of free sugars’ and alditols8.9 had been isolated, but, despite initial efforts,s no discrete glycoside derivatives had been reported, no successful structural work had been carried out, and the esters had not found application in carbohydrate chemistry. In the ensuing fifteen years, a wide range of specific boronates, for example, 1,2-O-isopropylidene-a-D-g~ucofuranose 3,5phenylboronate (2), have been prepared, and many workers have

1 R=OH 2 R=Ph

shown how useful they can be as suitable crystalline derivatives, as intermediates in synthesis, in a range of separatory techniques, and as reaction catalysts. The present article surveys the progress made during this time. The role of boronic acids in carbohydrate biochemistry is not dealt with, although, in plants, they have been found to influence the storage of polysaccharides and aspects of their growth5 (2)W.Gerrard, M.F. Lappert, and B. A. Mountfield,J. Chem. SOC., 1529-1535 (1959);N. N. Greenwood, in “Comprehensive Inorganic Chemistry,” J. C. Bailar,H. J. Eniekus, R. Nyholm, and A. F. Trotman-Dickenson,eds., Pergamon Press, Oxford, 1973,Vol. 1, p. 895. (3)R. J. Ferrier,]. Chem. SOC., 2325-2330 (1961). (4)K. Torssell, Ark. Kemi, 10, 541-547 (1957);Chem. Abstr., 52, 14,555(1958). (5)K. Torssell, J. H. McClendon, and G. F. Somers,Acta Chem. Scand., 12,1373-1385 (1958). (6)J. P. Lorand and J. 0. Edwards,]. Org. Chem., 24,769-774 (1959). (7)M.L.Wolfrom and J. Solms,J. Org. Chem., 21,815-816 (1956). (8)H.G. Kuivila, A. H. Keough, and E. J. Soboczenski, J. Org. Chem., 19, 780-783 (1954). (9)J. M.Sugihara and C. M. Bowman,]. Am. Chem. SOC., SO, 2443-2446 (1958).

CARBOHYDRATE BORONATES

33

Boron, having the electronic configuration ls22s22p,has 3 valence electrons, and forms planar, tricovalent derivatives that are electron deficient, and which, as Lewis acids, accept two electrons from bases to complete the boron outer-shell octet and give tetrahedral adducts. Boric acid exemplifies this behavior by ionizing, in aqueous solution, not by direct deprotonation, but by hydration and subsequent ionization, to give the symmetrical borate anion:

B(OH)B+ H 2 0

-

B(OH)4+ H+.

Wide attention has been given to the interaction of carbohydrates with these ions,l’Jdespite the complexity of the systems produced; reaction of a conformationally unrestricted, contiguous trio1 could, for instance, result in the formation of many species exemplified by the following.

B B O H

PfoH ’ ‘OH

0 ‘

With boronic acids, formation of dimeric species is essentially precluded, but cyclic products having different ring-sizes and electronic configuration at boron can b e formed, and it is here suggested that isomerization of certain cyclic boronates may consequently occur much more readily than has been recognized. In the case of the general triols (3, the five-membered boronates (4) could conceivably rearrange to the six-membered structures (5) by way of accessible ionic intermediates (6),and thus 4 and 5 may be thought of as (10) J. Boeseken,Adu. Carbohydr. Chem., 4,189-210 (1949);A. B. Foster, ibid.,12,81115 (1957); T. E. Acree,Adu. Chem. Ser., 117, 208-219 (1973); J. Dale,./. Chem. SOC., 922-930 (1961); E. W. Malcolm, J. W. Green, and H. A. Swenson, ihid., 4669-4676 (1964).

ROBERT J. FERRIER

34

4

5

6

tautomers, as well as isomers, bearing the same relationship to each other as do furanose and pyranose forms of free sugars, and thereby presenting classically difficult problems of structural analysis. In the chemistry of alditol boronates, this issue is potentially of wide significance (see, for example, the inconsistencies reported in the chemistry of glycerol phenylboronate; Section III,l), but fortunately, boronates of cyclic carbohydrates are not susceptible (except, conceivably, in such compounds as ribopyranoside esters), and most of the work described in this Chapter relates to discrete compounds of tricovalent boron-all of which can, however, form tetrahedral complexes with Lewis bases. The relevant bond-lengths and bond-angles associated with trigonal and tetrahedral boron in boronates are as shown. Consequently, both

can be accommodated in strainless, six-membered rings formed from l,Sdiols, whereas five-membered, cyclic boronates are free from angle strain only when the boron is tetrahedral. Thus, esters formed from vicinal diols are more strained,ll and exhibit a stronger tendency to react with bases12 (which frequently leads to relatively easy hydroly s i P ) , than their six-membered counterparts. These characteristics (11) A. Finch, P. J. Gardner, P. M. McNamara, and G. R. Wellum,J. Chem. Soc., A, 33393345 (1970). (12) A. Finch and J. C. Lockhart,J. Chem. SOC., 3723-3726 (1962). (13) R. A. Bowie and 0. C. Musgrave,J. Chem. SOC., 3945-3949 (1963).

CARBOHYDRATE BORONATES

35

therefore parallel, as expected, those of five- and six-membered, cyclic borates.14 Apart from this generalization, however, the question of stabilities of carbohydrate boronates is complex, because, not only are they dependent upon ring size but also upon the carbon-bonded radicals (ring strain in alkylboronates being substantially higher than in aryl analogs1'), and, notably, upon the presence and type of substituent groups on the ester rings and elsewhere in the molecules. Groups that inhibit coordination of water with boron stabilize the esters towards hydrolysis,l3 as, especially, do groups which can themselves act as fourth ligands. As, in carbohydrate boronic esters, oxygen atoms are frequently available for this function, this specific means of stabilization is of great importance; for example, in determining the degree of complexing of polyhydroxy compounds in aqueous systems and, consequently, their mobility as boronates on chromatograms or electrophoretograms (see Section V). Specific solvation, such as occurs15 in the complex 7, is also likely to influence ester stability to some extent.

Cyclic boronic esters can be formed readily from simple, acyclic 1,2-, 1,3-, and 1,4-diolsYand five-, six-, and, to a lesser extent, sevenmembered esters are, consequently, frequently encountered. Initial attempts9 to obtain an eight-membered, cyclic product from 1,5pentanediol were not successful, presumably because linear diesters or macrocyclic products preponderated, but it has been shown by massspectrometric methods16 that some of the cyclic phenylboronate can be formed and, furthermore, 1,6-hexanediol affords some nine-membered, cyclic phenylboronate. In model, cyclic systems, cis-lY2-diols on cyclopentane and cyclohexane rings readily give bicyclic boronates, whereas trans-related analogs react with two molar equivalents of boronic acids, to give seven-membered, cyclic diesters (for example, 8 (14) A. J . Hubert, B. Hartigay, and J. Dale,J. Chem. SOC., 931-936 (1961). (15)J. D. Morrison and R. L. Letsinger,J. Org. Chem., 29, 3405-3407 (1964). (16)E. J. Bourne, I. R. McKinley, and H. Weigel, Carbohydr. Res., 35,141-149 (1974)

36

ROBERT J. FERRIER

and 9) of diboronic acids.9 In the case of 1,3- and 1,4-cis-cyclohexanediols, forcing conditions permit the synthesis of cyclic boronate s.l 7

8 n=l 9 n=2

Esters may be prepared from a range of boronic acids that vary widely in their properties, including their aciditiesls (boric acid K, 6.53 x 10-10, phenylboronic acid, 13.7 x and butylboronic acid, 0.18 x 10-10), but most of the known carbohydrate boronates are phenyl esters, although substituted-aryl compounds have received some slight attention. Butyl, ethyl, and methyl analogs, although seldom crystalline compounds, unlike the majority of carbohydrate phenylboronates, have been utilized mainly because of their enhanced volatility and their consequent value in gas-liquid chromatography and mass spectrometry. Naming of carbohydrate boronates may be based on three principles: ( a ) ,the central use of the ester heterocyclic rings: 1,3,2-dioxaborolane (five-membered), lY3,2-dioxaborinane(six-membered), and 1,3,5,2,4trioxadiborepane (seven-membered, for example, 8 and 9); (b),the use of radical prefixes: “borylene” (Chem. Abstr.) or “boranediyl” (Z.U.P.A.C.) for )BH; or (c), ester terminology. Thus, for example, according to these respective procedures, the glycerol derivative 10

may be named ( a ) 5-hydroxy-2-phenyl-l,3,2-dioxaborinane, ( b ) 1,3-0(phenylborylene)glycerol,or 1,3-0-(phenylboranediyl)glycerol,or ( c ) glycerol lY3-phenylboronate.In this Chapter, the third method will be adopted, and, in accordance with current, Chemical Abstracts usage, (17) W. V. Dahlhoff and R. Koster,Justus Liebigs Ann. Chem., 1625-1636 (1975). (18) G. E. K. Branch, D. L. Yabroff, and B. Bettman,]. Am. Chem. SOC., 56,1850-1857 (1934).

CARBOHYDRATE BORONATES

37

alkyl- and aryl-boronate (rather than alkane- and arene-boronate) terminology will b e used. A brief summary is included of carbohdyrate borinates-acyclic esters derived from borinic acids (R,BOH)-which have received less attention than the related boronates. Earlier, short reviews have dealt with m o n o ~ a c c h a r i d eand ~~ nucleoside phenylboronates,20 and the application of phenylboronic acid in carbohydrate chemistry.21 11. SYNTHESIS OF BORONATES 1. Direct Condensation of Carbohydrates with Boronic Acids

Boronic acids readily undergo self-condensation to give cyclic anhydrides, and either these trisubstituted boroxins (ll),or the acids themselves, react spontaneously, but not necessarily completely, in solution, with suitable diols, to give cyclic boronates 12 (see Scheme l),

\

/

12

11

Scheme 1

for the isolation of which the water and solvent have simply to be removed. Frequently, a suitable procedure involves treatment of the carbohydrate with the required number of molar equivalents of the acid or anhydride in boiling benzene, and azeotropic removal of the water formed (which can conveniently be collected in a Dean-Stark distillation head, and, provided that sufficient quantities are evolved, measured, in order to monitor the progress of the reaction). Methyl p-Dxylopyranoside (16.8 g) treated in this way with triphenylboroxin (10.6 g, 0.33 mol. equiv.) liberates water (1.8ml) during conversion into its (19) A. M. Yurkevich and S. G. Verenikina, Vitam. Vitam.Prep., 247-256 (1973);Chem. Abstr., 80, 48,2474 (1974). (20) I. I. Kolodkina and A. M. Yurkevich, Vitam. Vitam. Prep., 257-268 (1973);Chem. Abstr., 79, 146,774h (1973). (21) R. J . Ferrier, Methods Carbohydr. Chem., 6,419-426 (1972).

38

ROBERT J. FERRIER

2,4-phenylboronate7 which may be isolated in excellent yield by removal of most of the solvent and addition of dry, light petroleum.22 Some carbohydrate derivatives are too insoluble in benzene to be so esterified, and, for them, a suitable, alternative solvent is 174-dioxane, the water azeotrope of which may, by careful, fractional distillation be removed before the solvent, and the water evolved in the reaction determined, if desired, by the Karl Fischer method. Whereas methyl a-D-glucopyranoside can be esterified by the benzene procedure, the analogous a-D-mannoside ester must be prepared by use of 1,Cdioxane or by some other variation.3 A further method applicable to benzene-insoluble carbohydrates involves the addition of the compounds, in water, to triphenylboroxins (preferably in methanoP), and, under these conditions, some boronic esters have been found to precipitate. Otherwise, the reactants may be fused under vacuum7 (a procedure not in current use, and not recommended) or treated in such solvents as acet0ne,~*23,24 or 2methoxyethanol.25~28Particularly for the formation of nucleoside boronates, pyridine has often been used as the solvent, and the reactants have been heated at the boiling point, or in sealed tubes27-30; on occasion, N7N-dimethylformarnide2s*31has been employed. A feature of the use of pyridine is the occasional isolation-not surprisingly-of the products as pyridine complexes.32 A slight modification of the reaction in acetone incorporates use of sulfuric acid as a catalyst and provides, from the corresponding, free sugars, moderately efficient, one-step procedures for obtaining 1,2-0isopropylidene-a-D-xylofuranose3,5-phenylboronate and the D-glU(22) R. J. Ferrier, D. Prasad, A. Rudowski, and I. Sangster,]. Chern. SOC.,3330-3334 (1964). (23) E. J. Bourne, E. M. Lees, and H. Weigel,]. Chem. Soc., 3798-3802 (1965). (24) A. M. Yurkevich, S. G . Verenikina, E. G . Chauser, and N. A. Preobrazhenskii, Zh. Obshch. Khim., 36,1746-1749 (1966). (25) S. G. Verenikina, A. M. Yurkevich, and N. A. Preobrazhenskii, Zh. Obshch. Khim., 37,2181-2184 (1967). (26) A. S. Guseva, S. G . Verenikina, S. F. Dymova, and A. M. Yurkevich, Zh. Obshch. Khim., 44,2327-2331 (1974). (27) A. M. Yurkevich, L. S. Varshavskaya, I. I. Kolodkina, and N. A. Preobrazhenskii,Zh. Obshch. Khim., 37,2002-2006 (1967). (28) A. M. Yurkevich, I. I. Kolodkina, L. S. Varshavskaya, V. I. Borodulina-Shvetz, I. P. Rudakova, and N. A. Preobrazhenskii, Tetrahedron, 25,477-484 (1969). (29) J. J. Dolhun and J. L. Wiebers,J. Am. Chem. SOC.,91, 7755-7756 (1969). (30) S. A. Ermishkina and A. M. Yurkevich, Zh. Obshch. Khim., 40,652-655 (1970). (31) A. M. Yurkevich, V. I. Borodulina-Shvetz, I. I. Kolodkina, and N. A. Preobrazhenskii, Zh. Obshch. Khim., 37,21762180 (1967). (32) P. J. Wood and I. R. Siddiqui, Carbohydr. Res., 36,247-256 (1974).

39

CARBOHYDRATE BORONATES

cose analog, 1,2-0-isopropylidene-~-~-arabinopyranose 3,4-phenylboronate and the a-D-galactose analog, and 2,3-0-isopropylidene-Dmannohranose 5,6-~henylboronate.~~ Koster and Dahlhoff introducedsa a variation by using, as the esterifying agent, the ethylboronic anhydride derivative (Me,CCO,BEt),O. 2. From Borinates

1,2-Ethanediol undergoes reaction at 380” with trimethylborane, to give 2-methyl-1,3,2-dioxaborolane34 (14), presumably by way of the intermediate dimethylborinate (13) (see Scheme 2), and Russian workers unexpectedly encountered an analogous reaction during CH,OH

I CH,OH

+

-

H,COBMe,

Me,B

I

CH,OH 13

-Hzlo\BMe H, 0’ 14

Scheme 2

heating of ribonucleosides in pyridine with equimolar amounts of isobutyl diphenylborinate, as, instead of the borinic esters anticipated (presumably 5’), they obtained almost quantitative yields of the 2’,3’phenylboronate~.35-~* The procedure may be used for preparative purposes, and has the advantage of not producing water as the byproduct. German workers independently found that 1,2- 1,3-, and some 1,4diols can be converted into bis(diethy1borinates) which, on heating to -200°, lose triethylboron to give cyclic ethylboronates. Otherwise, these boronates can be prepared directly from the diols by heating with triethylboron in the presence of diethylboryl pivalate, or by dismutation from equimolar proportions of diols and their bis(diethylbori(33) B. E. Stacey and B. Tierney, Carbohydr. Res., 49, 129-140 (1976). (33a) R. Koster and W. V. Dahlhoff, Justus Liebigs Ann. Chem., 1925-1936 (1976). (34) D. W. Wester, F. Longcor, and L. Barton, Synth. Inorg. Met.-Org. Chem.,3,115-123 (1973). (35) A. M. Yurkevich, L. S. Varshavskaya, and I . I. Kolodkina, Zh. Obshch. Khim., 38, 21 15 (1968). (36) I . I. Kolodkina, A. S. Guseva, E. A. Ivanova, L. S. Varshavskaya, and A. M. Yurkevich, 2%. Obshch. Khim., 40,2489-2493 (1970). (37) V. N. Rekunova, I. P. Rudakova, and A. M. Yurkevich,Zh. Obshch. Khim., 44,11821187 (1974). (38) V. N. Rekunova, I. P. Rudakova, and A. M. Yurkevich, Tetrahedron Lett., 281 1-2814 (1973).

ROBERT J. FERRIER

40

nates), and these procedures have been used to obtain ethylboronates of simple diols,17 triols and tetrols,39 alditols,40-42 and the cis-isomers of 1,2-, 1,3-, and 1,4-cyclohexanediol.~~ Pyrolysis of acyclic 1,4- and 1,5diols as their diethylborinates did not give seven- and eightmembered, cyclic products but, instead,l7 the macrocycles 15 and 16.

Et

15 n = 4 l6n=5

In the case of the alditols, the per(diethylboriny1) derivative may be selectively converted into mixed borinate-boronates, the D-mannitol derivative giving D-mannitOl 1,2,5,6-tetrakis(diethylborinate) 3,4ethylboronate (17), which can be isolated prior to its conversion into the 1,2:3,4:5,6-triboronate,4'and the galactitol ester giving galactitol 1,6-bis(diethylborinate) 2,3:4,5-bis(ethylboronate)(18) prior to the (19) having an formation of galactitol 176:2,3:4,5-tris(ethylboronate)

%

%

BEt,

Et,BOCH,

,OBEt,

Et,BOCH,

,OBEt,

18

17

Ef 19

(39) W. V. Dahlhoff and R. Koster, Justus Liebigs Ann. Chem., 1914-1925 (1975). (40) W. V. Dahlhoff and R. Koster,Justus Liebigs Ann. Chem., 1926-1933 (1975). (41) W. V. Dahlhoff, W. Schussler, and R. Koster,Justus Liebigs Ann. Chem., 387-394 (1976). (42) W. V. Dahlhoff and R. KosterJ. Org. Chem., 41, 2316-2320 (1976).

CARBOHYDRATE BORONATES

41

unusual, nine-membered ring.42 Selective deborination provides a means of obtaining, from compounds 17 and 18, D-mannitol 3,4e t h y l b ~ r o n a t and e ~ ~ galactitol 2,3:4,5-bi~(ethylboronate).~* Koster and Dahlhoff have reviewed their work with carbohydrate ethylboron esters.qa From this work, it follows that boronates of polyhydric alcohols can be prepared directly by heating with trialkyl- or triaryl-boranes. Galactitol heated with triphenylborane in refluxing toluene gives the same tris(phenylboronate), in 93%yield22 as can be prepared by use of phenylboronic acid.9 It seems probable that a fundamental distinction may exist between the two methods available for the synthesis of carbohydrate boronates, in that, under dehydration conditions, esterifications may be reversible, whereas boronate formation from borinates is not. In the first, therefore, products may be thermodynamically controlled, whereas kinetic control will operate in the second. It is noteworthy, however, that products obtained from several glycopyranosides (a) by use of an ethylboronate derivative, and (b) by way of the per(diethy1borinates) had the same

111. STRUCTURES OF CARBOHYDRATE BORONATES Chemical methods for determining boronate structures usually involve the substitution of unesterified hydroxyl groups, and the characterization of the products, either by examination of the compounds obtained after removal of the boronate groups, or by independent synthesis of the fully substituted compounds by boronation of known derivatives. Occasionally, the positions of sulfonic ester groups in fully substituted boronates have been determined by means of nucleophilic displacement-reactions. Although these methods are often well suited to derivatives containing one boronate group, they cannot always be applied unambiguously if more than one boronate group is present. The most useful physical methods of structural analysis, apart from X-ray diffraction, are nuclear magnetic resonance (n.m.r.) spectroscopy and mass spectrometry. Newer applications of 13C- and 'lB-n.m.r. spectroscopy (see Section VII) indicate their value in the determination of the ring size of boronates, and mass spectrometry (see Section VI) is of importance largely for the same reason. Proton n.m.r. (p.m.r.) spectroscopy is of

(42a) R . Koster and W. V. Dahlhoff,Am. Chem. SOC. Symp. Ser., 39, 1-21 (1977).

42

R O B E R T J. FERRIER

great, general significance, and on occasion, infrared spectroscopy has been a useful structural tool, as it can offer means of determining the nature of the intramolecular hydrogen-bonding in which unsubstituted hydroxyl groups may be engaged, and this may permit structural assignment.

1. Alditol Boronates For some properties of alditol boronates, see Table V. Glycerol phenylboronate (m.p. 75.5-76.5') is obtainable in high yield,l3 and was assigned the 1,2-cyclic structure on examination of the glycerol N-phenylcarbamate formed from it by treatment with phenyl isocyanate, followed by removal of the boronate ring.23 Consistent with this conclusion are the characteristics of hydrolysis of the parent ester13 and the fact that phenylboronic acid complexes more strongly with 1,2- than with 1,3-diols.6 However, a re-inve~tigation~~ of the glycerol phenylcarbamate revealed that it reduces 0.84 molar equivalent of periodate, instead of the 1 molar equivalent expected, which was taken to indicate that it was contaminated with some of the unoxidized, 2-substituted isomer. A new procedure for structural analysis was then developed to check this conclusion. Glycerol phenylboronate was methylated with diazomethane in dichloromethane containing boron trifluoride etherate, the boronate ring was removed, and the resultant diols were acetylated, to give two mono-0methylglycerol diacetates which were characterized, after g.1.c. separation, by mass spectrometry. Surprisingly, this method revealed that the initial phenylboronate was a mixture comprising the sixmembered ester as the main product. In the present author's opinion, the control experiment conducted on the critical methylation step within the foregoing procedure may not have been sufficiently rigorous, on the grounds that methylation of a-Dglucofuranose 1,2:3,5-bis(phenylboronate)with diazomethane-boron trifluoride may not establish that all boronates react without change under these conditions. As was indicated in the Introduction, chemical methods may be seriously deficient for characterizing such compounds, and techniques that do not disturb delicate chemical states may have to be used in just such cases. However, when applied to glycerol phenylboronate, "B-n.m.r.-spectral analysis did not unambiguously resolve the issue either, because, at 20', the boron chemicalshift indicated the presence of a six-membered ring, whereas, at 80', it moved to a position indicative of a five-membered ring.26 Chemical procedures have to be used with the greatest care, and (43) I. R. McKinley and H. Weigel, Carbohydr. Res., 31, 17-26 (1973).

CARBOHYDRATE BORONATES

43

McKinley and Weigel's results43 with other triols should also be considered with this in mind. By applying the diazomethane methylation procedure, they also investigated the phenylboronates obtained from 3-deoxy-~~-glycero-tetritol, 4-deoxy-~-erythritol,and 1,5-dideoxy-~-arabinitol,-ribitol, and -xylitol, and found that all except that derived from the last trio1 were mixtures. Their conclusion was that, where six-membered rings that do not have axial substituents can be formed, their production is favored (glycerol, 3-deoxy-~~-glycerotetritol, 4-deoxy-~-erythritol,and 175-dideoxyribitol);in other cases, substantial proportions of five-membered ring esters are produced. However, other points that appear to increase suspicion of the validity of the methylation procedure are: (i) the inconsistency between the periodate and the methylation results, as applied to glycerol phenylboronate, ( i i ) the finding of the formation, from some triols, of some thermodynamically unfavored, five-membered, cyclic products, and ( i i i ) the conclusion that the phenylboronate obtained from 4deoxy-L-erythritol comprises all three possible isomers, despite its being a sharp-melting compound. Glycerol ethylboronate produced by the borinate method39 has the five-membered, cyclic structure, consistent with its being a kinetically controlled product, whereas that obtained from 3-deoxy-D~-glycerotetritol contains a six-membered ring. From these findings with triols, it follows that, apart from the expectation that formation of five- and six-membered rings would be favored (see, however, the exceptional compound 19), no general conclusions can be drawn regarding the structures of boronates derived from more-complex polyhydric alcohols. In Table V, alditol boronates are listed with structures when these can be concluded either from the method of synthesis, from physical studies, or by deduction (as with the 1,2:5,6-diesters formed from 3,4-di-O-substituted mannitols).

2. Sugar Boronates For some properties of boronates of sugars, see Table 111. Although boronates of sugars were amongst the first such carbohydrate esters to be prepared,' little structural work was performed until the advent of n.m.r.-spectroscopic and mass-spectrometric methods. The high-yielding condensations undergone by D-xylose and Larabinose with phenyl- and butyl-boronic acid have thus been shown to give a-D-xylose 1,2:3,5-bis(phenyl-and butyl-boronate) (20)and p-Larabinose 1,2:3,4-bis(phenyl- and butyl-boronate)44 (21). (44) P. J. Wood and I. R. Siddiqui, Curbohydr. Res., 33,97-104 (1974).

ROBERT J. FERRIER

44

20

R

= Bu or Ph

21

In 1956, a ribose diphenylboronate (map.140-142") was prepared in modest yield by a fusion method,' but it was later shown26 that an almost quantitative yield of a mono-ester was obtainable by conducting the condensation in hot 2-methoxyethanol, and this was a-D-ribose 2,4phenylboronate (22), as indicated by p.m.r. and "B-n.m.r. and conversion by selective substitution into the S-p-toluenesulf~ n a t eIt. ~is ~here suggested that the 2,4-ester (22) might be very sus-

22

ceptible to structural change, as it could give the 1,2-, 1,3-, 2,3-, and 3,4-isomers by a set of tautomeric rearrangements by way of the accessible, boronate anions (23 and 24).

23

24

Condensation of D-ribose with two molar equivalents of phenylboronic acid in 2-methoxyethanol gave a diester to which was assigned the 1,5:2,3-P-furanose structure (25) on the basis of as-yet-unreported n.m.r. data.26 (45) M. G. Edelev, T. M. Filippova, V. N. Robos, I. K. Shmyrev, A. S. Guseva, S. G. Verenikina, and A. M. Yurkevich, Z h . Obshch. Khim., 44,2321-2327 (1974). (46) A. S. Guseva, I. P. Rudakova, S. G. Verenikina, and A. M. Yurkevich, Zh. Obshch. Khim., 44, 1187-1193 (1974).

CARBOHYDRATE BORONATES

45

D-Glucose gives a crystalline 172:3,5-bis(phenylboronate)(26) Ph

phAFGy &H

0

b-hPh

B Ph 26

25

( ~ . m . r . ~and * * 13C-n.m.r.45 ~~ evidence) which can b e used to prepare 6substituted esters32.4' and ethers** of the sugar. Likewise, 1,2-0isopropylidene-a-D-glucose gives a crystalline 3,5-phenylboronate724. 32*33 and, with two molar equivalents of the boronating agent, a further When a crystalline derivative, characterized as the 5,6-dib0ronate.~~ substituent is present at C-3, as in 3-deoxy-3-fluoro-1,2-O-isopropylidene-a-~-glucofuranose,4~ direct boronation takes place, as expected, at the 5,6-diol. D-Fructose reacts in the P-pyranose form, to give the 2,3:4,5bis(phenylboronate)32 (27), and 6-deoxy-a-~-galactoseaffordP the stereochemically related 1,2:3,4-die ster (28).

Phb-0

27 R' = H, R2 = CH,OH 28 R' = Me. Rz = H

Little structural work has been performed on derivatives of other hexoses, or higher sugars. 3. Boronates of Glycosides, Nucleosides, and Related Compounds

For some properties of boronates of glycosides, nucleosides, and related compounds, see Tables IV, VI, and VII. Glycosides and related compounds tend to give boronates easier to (47) L. G. Mogel and A. M. Yurkevich, Zh. Obshch. Khim., 39, 1882-1886 (1969). (48) E. J. Bourne, I. R. McKinley, and H. Weigel, Carbohydr. Res., 25,516-517 (1972). (49) A. B. Foster, R. Hems, and J. M . Webber, Carbohydr. Res., 5,292-301 (1967).

ROBERT J. FERRIER

46

characterize than corresponding derivatives of alditols and sugars, because of the specific diol systems they present to the boronating reagents. Most interestingly, cis-173-related diols on pyranoid rings condense to give cyclic boronates [for example, methyl a-D-xylopyranoside 2,4-phenylboronate (29) and N-(p-bromopheny1)-a-D-ribopyronosylamine 2,4-phenylboronate (30)] which, in the ~ y l o s e ~ ~ , ~ ~ ~

Ph 29

Ph 30

and ribose51 series, afford useful means for obtaining 3-substituted derivative~2~*~~.52 and glycosid-3-uloses.53 The specific complexing that occurs between boronic acids and contiguous cis,cis-triols (as in ribopyranosides; see Section V) is postulated as resulting from stabilization of the cyclic esters formed from 1,3-related7axial hydroxyl groups by coordination from the oxygen atom of the central hydroxyl groups. However, although the crystal structure of N-(p-bromopheny1)-a-D-ribopyranosylamine 2,4-phenylboronate (30) indicates that the pyranoid ring is in the expected IC4conformation with the ester oxygen bonds axial, it also reveals that the boron is trigonal and that 0 - 3 is too far from it (305 pm; 3.05 A)* for coordination. The propensity for this oxygen atom to co-ordinate is, however, satisfied by hydrogen bonding with the N-bonded proton of an adjacent molecule.54 The a r a b i n o p y r a n ~ s i d e sand ~ ~ ~lyxopyranosides are esterified, as expected, at the 3,4- and 2,3cis-diols7 respectively5’; in the ribofuranosyl series, esterification occurs at 0-2’,0-3’, and a range of nucleoside phenylboronates is known, mainly through the work of Yurkevich and his associates (see Table VII). In the hexopyranoside series, 4,6-phenylboronates [for example, methyl a-D-glucopyranoside 4,6-phenylboronate (31)l are obtainR. J. Ferrier, D. Prasad,and A. Rudowski, Chern. lnd. (London), 1260-1261 (1964). R. J. Ferrier and D. Prasad,J. Chem. Soc., 7425-7428 (1965). R. J. Ferrier and D. Prasad,J. Chern. Soc., 7429-7432 (1965). B. Lindberg and K. N. Slessor, Curbohydr. Res., 1,492-493 (1966); Actu Chern. S c u d . , 21, 910-914 (1967). (54) H. Shimanouchi, N. Saito, and Y. Sasada, Bull. Chern. SOC.Jpn., 42, 1239-1247 (1969).

(50) (51) (52) (53)

*Calculated by Dr. J. H. Johnston of this Department.

CARBOHYDRATE BORONATES

47

able,3.33a,55 and residual diols may react further, to lead to fully substituted compounds [for example, methyl a-D-glucopyranoside 4,6-phenylboronate 2,3-(diphenyl~yclodiboronate)~*~~ (32)l. Chemical

PCHa

p""'

OHOMe

PhBQ

O,

Ph\&PhB

Me

b-B, 31

Ph

32

analyses55 indicated that the galactopyranosides likewise give 4,6esters in preference to the five-membered-ring derivatives that might have been formed from the cis-related 3,4-diols. However, the situation appears to be delicately balanced in compounds containing such 3,4,6-triol groupings, as some undergo reaction to give 4,6-esters (33), whereas others (presumably different in flexibility and timeaveraged conformation) afford mainly the five-membered derivatives (34). Later work, based on mass spectrometry,56 suggested that the esterifications of the methyl galactopyranosides are not so unambiguous as suggested by the chemical methods,55and revealed that 3,4- as well as 4,6-esters are produced. Here, again, it is possible that facile isomerization of the initial products might have occurred during their isolation or subsequent analysis, and, for this reason, the available information should be considered with reservation.

"0

Phl3/OcH,

R'

h.1

Rs

R4 R' H OH H OMe OH H H OMe H H H OMe O H H H H H H H H R2

33

R' H

R2 RS R4 H OMe H

34

(55) R. J. Ferrier, A. J . Hannaford, W. G. Overend, and B. C. Smith, Carbohydr. Res., 1, 38-43 (1965). (56) V. N. Reinhold, F. Wirtz-Peitz, and K. Biemann, Carbohydr. Res., 37, 203-221 (1974).

ROBERT J. FERRIER

48

Methyl a-D-mannopyranoside appears to give mixed monoesters (presumably 2,3- and 4,6-), but reacts readily to afford the 2,3:4,6d i e ~ t e P . ~ (35) ~ * ~with ~ * two ~ ' molar equivalents of acid, whereas, in the 6-deoxyhexoside series, reaction occurs at vicinal, cis-diol sites (2,3 for methyl 6-deoxy-a-~-mannopyranoside,58 and 3,4 for methyl 6-deoxy-a~-galactopyranoside),5Bbut, again, a compound having a cis-related, diol grouping at C-2 and C-4 gives a six-membered, cyclic ester. For methyl 6-deoxy-/3-~-allopyranoside,this is somewhat surprising, in view of the diaxial relationship between the groups at C-1 and C-5 in the product58,60 (36).Methyl 6-deoxy-a-glucopyranosidelikewise gives59 the 2,4-ester (37).

/b

ph\

@

Q o

dB,o

Me

Me

35

Ph B/O

-B'

36

Ph

37

With the 1,6-anhydrohexopyranoses,condensation occurs at vicinal at the diaxial cis-diols or, in the case of 1,6-anhydro-/3-~-glucopyranose, 2,4-~ites,~l despite the observation that this anhydride does not readily complex with the acid (see Section V,2).

Iv. BORONATES IN CHEMICAL REACTIONS 1. Boronates in Aqueous Systems

a. Interaction Between Carbohydrates and Boronic Acids in Aqueous Media.-Initial1 y, Torssel14 detected interaction between phenylboronic acid and D-fructose, and, by potentiometric titration with sodium hydroxide solution, determined a formation constant for a 1:1 complex: 0 OH PhB(OH),

+ D-fructose * (D-fructose)/ \ I

(57) D. S. Robinson, J. Eagles, and R. Self, Carbohydr. Res., 26,204-207 (1973). (58)J. S.Brimacombe, F. Hunedy, and A. Husain, Carbohydr. Res., 10,141-151 (1969). (59)J. S.Brimacombe, A. Husain, F. Hunedy, and M. Stacey,Ado. Chem. Ser., 74,56-69 (1968). (60) J. S. Brimacombe and D. Portsmouth,]. Chem. SOC., C , 499-501 (1966). (61) F. Shafizadeh, G.D. McGinnis, and P. S. Chin, Carbohydr. Res., 18,357-361(1971).

CARBOHYDRATE BORONATES

49

With colleagues,5 he then proceeded to examine this complexing for a range of substituted phenylboronic acids (as part of a study of their influence in certain aspects of plant biochemistry), and found that, as expected, electron-withdrawing groups on the aromatic ring increased the stability of the complexes formed. By examining pH depressions, other workers6 determined formation constants for the phenylboronate complexes formed with various diols and polyhydroxy compounds, and found that, of several sugars examined, D-frUCtOSe formed much the most stable complex. Fourteen years later, S. A. Barker and his colleagues62 conducted a detailed, polarimetric analysis of the complexing undergone between Dglucose, D-mannose, and D-fructose (separately) and phenylboronic acid and its m-nitro and p-methoxy derivatives, respectively, and showed that the favored complexing with the ketose is pH-dependent. Their observations indicated that, with phenylboronic acid, D-glucose is uncomplexed up to pH 6, and fully complexed beyond pH 9, whereas D-fructose begins to form a complex near pH 5 and, in the experiment reported, is -30% complexed before D-glucose begins to react. The ketose is also fully complexed at, and above, pH 9. Similar effects were observed for the substituted acids, the pH ranges within which partial complexing occurs going to lower values with the m-nitrated acid and to higher values with the p-methoxy compound. It was then demonstrated63 that these arylboronic acids displace, in favor of the ketose, the D-glucose-D-mannose-D-fructose pseudoequilibrium that is established in alkaline solution, so that the usual, single-step, conversion efficiency of D-glUCOSe to D-fructose of -30% may be increased to as high as 81%. A detailed investigation of the effects of pH, temperature, and concentration on this phenomenon was undertaken with a view to optimizing a commercial preparation of Dfructose. This displacement may also be effected with polymeric arylboronic acids which, as expected, also show differential binding of the ketose.64 Yurkevich and coworkers,65 using the pH-depression procedure, reported complexing constants of nucleosides and nucleotides, and showed that the depressions are themselves pH-dependent, adenosine exhibiting maximal effects near pH 7.8, 7.3, and 8.2 on mixing with S. A. Barker, A. K. Chopra, B. W. Hatt, and P. J. Somers,Carbohydr. Res., 26,33-40 (1973). S. A. Barker, B. W. Hatt, and P. J. Somers, Carbohydr. Res., 26,41-53 (1973). S. A. Barker, B. W. Hatt, P. J. Somers, and R. R. Woodbury, Carbohydr.Res., 26,5564 (1973). E. A.Ivanova, I. I. Kolodkina, and A. M. Yurkevich,Zh. Obshch. Khim., 41,455-459 (1971).

50

ROBERT J. FERRIER

phenylboronic acid and its p-nitro and p-methyl derivatives, respectively. Here, it may safely be assumed that the 2’,3’-diol is involved in complex-formation; in all of the other work referred to in this Section, no specific evidence is available regarding the structures of the complexes.

b. Hydrolysis of Boronates-There is very little good information available on the stability to hydrolysis of an adequate range of carbohydrate boronates. Some evidence indicates that at least certain esters are stable in aqueous systems: phenylboronates of sugars and alditols may be isolated by crystallization from aqueous m e t h a n ~ l ~ , ~ ~ ; p-tolylboronates of various diols and of 1,2-0-(trichloroethylidene)-aD-glucofuranose can be precipitated by acidification of aqueous alkaline solutions66; and 1,3-O-benzylidene-~-arabinitol gives a phenylboronate that is apparently unchanged on heating in aqueous sodium hydr0xide.6~It has been suggested9 that the first of these points does not establish the stability, but rather the insolubility of the esters in water, and the second point conceivably reflects the insolubility of trigonal esters relative to their tetrahedral, anionic analogs. In the case of the L-arabinitol derivative, after the hydrolysis, the solution was extracted continuously with chloroform for several hours, and it is here suggested that, during this treatment, phenylboronic acid and the benzylidene acetal may have been separately taken into the chloroform, to recondense during the subsequent removal ofthis solvent. The finding that phenylboronic acid could be removed at room temperature by chromatographic separation on an anionic resin or on neutral alumina adds support to the conjecture that hydrolysis had occurred in the alkaline medium. It is, therefore, suggested that none of this evidence establishes the stability of any ofthe esters in aqueous media. All other evidence indicates that carbohydrate boronates readily undergo hydrolysis on addition of water to their solutions in organic solvents. Thus, early in the history of the compounds, it was found that very mild hydrolysis of L-arabinose bis(phenylboronate)7 and Dmannitol tri~(pheny1boronate)~ gave the respective starting-materials, which could readily be separated from each other. In all cases, when water has been added to solutions of boronates in dry solvents, optical rotational changes in magnitude occur in directions consistent with their being caused by hydrolysis. In this way, Hannaf0rd5~468 (66)Brit. Pat. 885,766(1960);Chem. Abstr., 56, 15,546f(1962). (67)A.B.Foster, A. H. Haines, T. D. Inch, M. H. Randall, and J. M. Webber, Carbohydr. Res., 1, 145-155 (1965). (68)A. J. Hannaford, Ph.D. Thesis, University of London, 1964.

CARBOHYDRATE BORONATES

51

calculated the equilibrium constants for the reaction

0

Carbohydrate

/ \ \ / 0

BPh

+ H 2 0 * carbohydrate + PhB(OH),

to be 0.2 k O . 1 for methyl a- and P-D-glucopyranoside and their 2,3-diO-methyl derivatives and for D-glucal. This means that -4% of water caused complete hydrolysis of the esters dissolved (2%)in 1,cdioxane. Similar, semiquantitative work on methyl xyloside phenylboronates revealed much more variable susceptibilities, the percentages of water needed to cause complete hydrolysis ofthe esters (29,38,39,and 40) of OMe

0 \/O

JpQ( OH

Ph

38

39 R’ = H. R* = OMe 40 R1 = OMe, RZ = H

the a- and p-pyranoside and a- and p-furanoside (1%, in 174-dioxane) being 1,3,9, and 30, r e s p e c t i ~ e l yAs . ~ expected, ~ therefore, the highly strained, pyranoside derivatives are highly susceptible to hydrolysis, whereas the furanoside analogs, particularly the p anomers, are appreciably more stable. Although the trans-relationships of the groups at C-1 and C-2 of the p-furanoside (40) make it thermodynamically the more stable, it does not seem likely that its marked hydrolytic stability can be attributed to this factor alone (see later). Other compounds examined by this type of procedure are the 2’,3’phenylboronates of nu~leosides,~7~28~3~ and the butyl- and phenylboronates of D-xylose and L-arabinose,” and these, also, are hydrolytically unstable. It is here concluded that carbohydrate boronic esters should normally be treated as being readily susceptible to hydrolysis and, presumably, alcoholysis, and that their occasional isolation in crystalline form from aqueous solvents**23.70or ethanol67 should be (69) R. J. Ferrier, D. Prasad, and A. Rudowski,J. Chem. SOC.,858-863 (1965). (70)R. J. Ferrier and L. R. Hatton, Carbohydr. Res., 5, 132-139 (1967).

52

ROBERT J. FERRIER

viewed as evidence of their insolubility and not of their stability in these solvents. Although it might have been expected that such solvents as pyridine could stabilize the esters by co-ordination with the boron atoms, this does not appear to be so44; however, intramolecular co-ordination by suitably oriented oxygen atoms does stabilize them considerably, and it is probably this factor that is responsible for the observed character (see earlier) of methyl /3-D-xylofuranoside 3,5phenylboronate (40), in which 0 - 1 can specifically bond to boron. Although no formal studies of hydrolyses of carbohydrate derivatives stabilized in this way appear to have been reported, their stability as revealed by their behavior in chromatography and electrophoresis is well recognized; this is discussed in Section V,2 and 3. Products of the partial hydrolysis of complex esters have not often been isolated, but the very labile, seven-membered ring of the diphenyldiboronate 32 can be selectively removed, to give methyl aD-ghcopyranoside 4,6-phenylboronate (31)in good yield.3 In their work with alditol derivatives containing ethylboronate and diethylborinate groups, Dahlhoff and K o ~ t e r ~ O found - ~ ~ that the latter may be selectively removed by treatment with either methanol or 2,4pentanedione and, in the case of xylitol 2-diethylborinate 1,3:4,5bi~(ethylboronate),4~ they were able to remove the six-membered ring selectively. This is against expectations (see Section I), and may result from intramolecular stabilization of the smaller ring by co-ordination from 0-2.

2. Removal of Boronate Groups When boronic esters are utilized as protecting groups in the synthesis of specifically substituted, or otherwise modified, carbohydrate derivatives, the cleavage of the esters must be followed by removal of the by-products liberated. With esters of strongly hydrophilic, carbohydrate compounds, the boronic acids can be specifically extracted from aqueous into organic solvents, and, in this way, alditolss and free sugars' have been recovered from their phenylboronates, but a more widely applicable procedure involves exchanging the boronic acids from the carbohydrate to 1,e-ethanedio140,41*71 or, more usually, 1,3-propanediol,22*58~72 with which they condense to give volatile, cyclic derivatives. Addition of 1,3-pro(71)A. A. Amagaeva, A. M. Yurkevich, I. P. Rudakova, L. V. Khristenko, I. M. Kustanovich, and N. A. Preobrazhenskii, Khim. Prfr. Soedfn., 4, 304-307 (1968); Chem. Abstr., 70, 115,471s(1969). (72)L.G.Mogel and A. M. Yurkevich, Zh. Obshch. Khim., 40,708(1970).

CARBOHYDRATE BORONATES

53

panediol to a solution of a carbohydrate boronate in acetone, and removal of the volatile products, usually offers a very efficient method of deboronation. Column separations of the products of hydrolysis of carbohydrate boronates by use of anionic resins provides an alternative, efficient means of deb0ronation,~~,67,69 and other similar separations have used columns of cellulose,48 alumina,67 and, for carbonyl-containing In compounds, anion-exchange resins in the hydrogensulfite special cases, e l e c t r o p h o r e ~ i sand ~ ~ direct crystallizationz3 have been employed. An interesting, alternative procedure, applicable at least to the removal of phenylboronic acid, involves its conversion, by treatment with bromine-water, into bromobenzene and boric acid, and the removal of these by distillation-the latter as its trimethyl ester.43

3. Stability of Boronates during Chemical Reactions a. Esterificatioa-Successful acetylation of unsubstituted hydroxyl groups in carbohydrate boronates has been reported on several occasions. Acetyl chloride in pyridine has usually been used as the acetylating agent, and the products have frequently been distilled prior to crystallization. Acetates of boronates of glycosides,3~22*51*~5~~9 a l d i t o l ~and , ~ ~ nucleosides3" have been reported. Benzoylation is, likewise, usually a satisfactory process, but the products are insufficiently volatile for distillation. Fully substituted aldito1,41,67 and nucleoside36 esters have been prepared, and, sometimes, the boronate groups have been removed without isolation of the (benzoylated) first products. An instance of the use of an insoluble poly(styry1boronic acid) in the preparation of methyl 2,3-di-0-benzoy~-a-D-ghcopyranoside and -galactopyranoside has been reported.72aUsually, benzoyl chloride is the reagent used, but, with this, methyl a-D-xylopyranoside 2,4phenylboronate gave only 37% of the 3-benzoate7 whereas the yield was doubled by use of benzoic anhydride.22 p-Toluenesulfonylation of methyl a-D-glucopyranoside 4,6-phenylboronate did not give an isolable product, although the bis-ptoluenesulfonate could be prepared by boronation of the appropriate Dglucoside derivatives; othersZ3 have reported failure to esterify galactitol bis( phenylboronate). Despite these findings, there is little reason to doubt that p-toluenesulfonylation of boronates can be satisfactorily achieved. Thus, direct products have been obtained from (72a) E. Seymour and J. M. J. Frechet, Tetrahedron Lett., 1149-1152 (1976).

54

ROBERT J . FERRIER

alditol67 and sugar47 boronates having free primary-hydroxyl groups, and secondary p-toluenesulfonates from 1,6-anhydroaldohexose boronates61 (although the D-gdo compound was slow to react); D-ribose 2,4-phenylboronate gave,"6 selectively, the 3-p-toluenesulfonate at -10". Several reports have appeared on the preparation of 5'-ptoluenesulfonates of nucleoside 2',3'-phenylb0ronates,37,7~*73*74 but these still remain poorly characterized derivatives. The preparation of N-phenylcarbamates from incompletely substituted, carbohydrate boronates is, perhaps, the least destructive of esterifying reactions, requiring only that the compounds be heated with phenyl isocyanate in dry benzene or toluene. Several reports have sugar,47and appeared on successful application to aldito123 derivatives. By using the 2',3'-phenylboronate protecting-group, Yurkevich and his colleagues prepared 5'-phosphates of adeno~ine~28.75-77 uridine, 27,76 cytidineYz7 and g ~ a n o s i n e Usually, .~~ 2-rnorpholino-1,ldiphenylpyrophosphorochloridate has been used as the phosphorylating reagent, but the morpholinophosphorodichloridate and 2-cyanoethyl phosphate-N,N'-dicyclohexylcarbodiimide procedures have also been employed.28 Nucleoside 2',3'-phenylboronates may also be used in the synthesis of dinucleoside phosphates.30 Chloroacetylation can be effected by use of chloroacetic anhydride in pyridine, and, in this way, the 6- and 3-esters of l,%O-isopropylidene-a-D-glucofuranose were prepared, in good yield, by using the 3,5phenylboronate and 5,6-(diphenylcyclodiboronate), respectively, as starting materials, and, from the chloroacetates, trimethylammonioacetyl salts were prepared.24In further work, connected with pangamic acid, 6-O-(N,N-dimethylglycyl)-~-glucose was synthesized by use of N,N-dimethylglycine and N,N'-dicyclohexylcarbodiimide in acetonitrile-pyridine,25 and pangamolactone [6-0-(N,N-dimethylglycyl)-~glucono-1,4-lactone] by a similar procedure from D-glucono-1,4lactone 3,5-phenylboronate.78 (73) A. M. Yurkevich, A. A. Amagaeva, I. P. Rudakova, and N. A. Preobrazhenskii, Zh. Obshch. Khim., 39,434-440 (1969). (74) I. P. Rudakova,T. A. Pospelova, and A. M. Yurkevich,Zh. Obshch. Khim., 40,24932499 (1970). (75) A. M. Yurkevich, I. I. Kolodkina, and N. A. Preobrazhenskii, Dokl. Akad. Nauk S S S R , 164,828-830 (1965);Chem. Abstr., 64,3661g (1966). (76) I. I. Kolodkina, L. S. Varshavskaya,A. M. Yurkevich, and N. A. Preobrazhenskii,Zh. Obshch. Khim., 37,1996-2002 (1967). (77) A. M. Yurkevich, I. I. Kolodkina, G. S. Evdokimova, E. T. Bazhanova, and N. A. Preobrazhenskii, Khim. Org. Soedin. Fosfora, Akad. Nauk SSSR, Otd. Obshch. Tekh. Khim., 215-220 (1967);Chem. Abstr., 69, 10,667m (1968). (78) K. Murase and M. Murakami, Yamanouchi Seiyaku Kenkyu Hokoku, 2, 62-65 (1974); Chem. Abstr., 83, 179,446p (1975).

CARBOHYDRATE BORONATES

55

Methacrylic anhydride in pyridine, applied to 1,6-anhydro-~glucose 2,4-phenylboronate, gave the 3-methacrylate7from which an addition polymer was prepared.79

b. Etherification.-Successful methylation of hydroxyl groups in partially substituted carbohydrate boronates has not often been reported. The first attempt, in which methyl iodide, silver oxide, and a drying agent were applied to methyl a-D-glucopyranoside 4,6phenylboronate, gave,3 after distillation of the product, a poor yield of the diether, chromatographic evidence being obtained that some triether (but no tetraether) was formed during the reaction. Applied .to methyl P-D-xylopyranoside 3,5-phenylboronate in N,N-dimethylformamide, the same reagent gavez2only 18% of the 2-ether7 which could be purified by sublimation. Other workers have reported no success on attempted methylation of galactitol bi~(pheny1boronate)~~ and methyl 6-deoxy-/3-~-allopyranoside2,4-phenylboronate.60 The first, satisfactory methylation appears to have been effected by Bourne and his colleague^,^* who prepared 6-0-methyl-D-glucose in high yield from the 1,2:3,5-bis(phenylboronate),using diazomethane and boron trifluoride etherate in dichloromethane for methylation, and a final separation on a column of cellulose powder. It is this procedure which the same group used for structural analysis of trio1 phenylboronate^^^ (see Section 111,l); others60have attempted to use it, but without success. The phenylboronate group has been shown to be stable under Koenigs-Knorr glycosylation conditions, and, from benzyl p-D-xylopyand 3ranoside 2,4-phenylboronate73-0-~-D-g~ucopyranosy~-D-xy~ose 0 - a - and p-D-xylopyranosyl-D-xylose have been synthesized52by using nitromethane as the solvent. The anomer of the initial boronate was less reactive under these conditions, conceivably because its 3hydroxyl group cannot become hydrogen-bonded intramolecularly and thereby gain enhanced nucleophilicity. Tritylation of the nucleoside 2’,3’-phenylboronate has been used to obtain 5’-O-trityladenosine,’T and trimethylsilyl ethers of glycoside phenyl-, methyl-, and butyl-boronates have been produced by use of chlorotrimethylsilane and trifluorobis(trimethy1silyl)acetamide in pyridine for mass-spectrometric studies56 (see Section VI). c. Nucleophilic Displacement Reactions-Several reports have appeared on the introduction of nucleophilic groups into carbohydrate (79) S . P. Valueva, E. P. Cherneva, V. A. Kargin, and N. M. Merlis, Vysokomol. Soedin. Ser., 13, 468-470 (1971); Chern. Abstr., 75, 152,153~(1971).

56

ROBERT J. FERRIER

derivatives carrying boronic ester groups. In the most straightforward, D-glucose 1,2:3,5-bis(phenylboronate)was separately treated with triphenylphosphine in bromoform and carbon tetrachloride, and the initial products were deboronated, to give 6-bromo- and 6-chloro-6deoxy-D-glucose in 81 and 79% yield, r e ~ p e c t i v e l y .Although ~~ displacements of the sulfonyloxy groups of 1,3-O-benzylidene-5-OO-ptolylsulfonyl-L-arabinitol 2,Cphenylboronate and 6-deoxy-3,4-0-isopropylidene-5-0-p-tolylsulfonyl-~-mannitol 1,2-phenylboronate did not occur so readily when the esters were heated in refluxing N , N dimethylformamide with sodium benzoate and sodium azide, respectively, direct substitution did occur, to give products whose structures were used to establish the sites of bor0nation.~7 Yurkevich and coworkers46 used 3-0-p-tolylsulfonyl-D-ribose 2,4phenylboronate to prepare a cobalt-containing carbohydrate compound which, without reported evidence, they claimed has a C-3cobalt bond and the D-XY~O configuration. Similarly,74 they prepared, from the 5’-p-toluenesulfonates, nucleoside derivatives having C-5’cobalt bonding, and, in related work, they obtained nucleoside derivatives bonded directly to cobalt at C-5’ by use of an intermediate which, on the basis of carbon and hydrogen analytical data, they proposed had structure 41 (R = H). Synthesis of this compound was a~hieved71.8~ by treatment of 5’-O-p-tolylsulfonyladenosine2’,3’phenylboronate with lithium bromide in acetic anhydride at 100’conditions that would be expected81to yield the acetylated analog (41, R = Ac). As such a compound would have carbon and hydrogen compositions similar to those of the monoboronate (41, R = H), the two NHAc

I

b

b

PhBOR, Ac

41

(80) I. P. Rudakova, V. I. Sheichenko, T. A. Pospelova, and A. M. Yurkevich,Zh. Obshch. Khim., 37, 1748-1753 (1967). (81) B. C. Maiti, 0.C. Musgrave, and D. Skoyles,]. Chem. SOC. Chem. Commun., 244245 (1976).

CARBOHYDRATE BORONATES

57

would not be readily distinguishable on this basis. The same 5’-bromo5‘-deoxy intermediate was also used to obtain 5’-thioadenosine derivatives .73

d. Oxidation Reactions.-The phenylboronate group has been found to be stable during acetic anhydride-dimethyl sulfoxide oxidation of hydroxyl groups, and this has made possible53the synthesis of methyl a-D-erythro-pentopyranosid-3-ulose in 50-60% yield from methyl Q-Dxylopyranoside 2,4-phenylboronate (29); the P-glycosidulose was obtained similarly from the p-ester 38 in 80% yield. Oxidations were effected at 40°, and the stability of the esters during the reactions was indicated by polarimetry, as the first product obtained from the boronate 29 is levorotatory, whereas the derived, deboronated ketone is dextrorotatory. Furthermore, the oxidations were highly specific, indicating that the readily oxidized, ketonic products remained protected during the reactions. The oxidized boronates were not, however, isolated, the de-esterified products being obtained by column chromatography. Other worker@ reported the unreactivity of methyl 6-deoxy-P-D-allopyranoside2,4-phenylboronate under these conditions. Oxidation of phenylboronates with the periodate ion has been used in structural analysis,3*22*23,56as, in aqueous 1,4-dioxane7 they are hydrolyzed to release diols that are susceptible to oxidation only when they are vicinally related. Thus, the esters of mOnO-O-aCetyl-D-glUCal and -D-galactal were found to reduce 0.09 and 1.07 molar equivalents of periodate, respectively, and were, therefore, assigned55 the we have found it structures 42 and 43. Whereas, in our lab0ratory,3*2~*~5 unnecessary in these analyses to correct for oxidation of reaction components other than the carbohydrates, other workers23 have reported the use of substantial corrections. $!H,OAc

42

43

v. SEPARATIONS OF CARBOHYDRATES BY USE OF THEIRBORONATES 1. Use of Isolated Boronates As only the cis isomers of 1,2-, 1,3-, and 1,4-cyclohexanediols can form simple, cyclic boronates, whereas the trans compounds give

58

ROBERT J. FERRIER

polymeric diesters, the epimeric diols may be separated by distillation of their boronates, and this procedure has been applied by using butylboronates prepared directly with butylboronic acid,82 and ethylboronates obtained by thermal cyclization of bis(diethy1borinates).17 The anomeric methyl 3,5-O-isopropylidene-~-xylofuranosides are separable by distillation,83 and, therefore, the corresponding 3,5cyclic boronates (for example, 39 and 40) could also afford means of separating the methyl xylofuranosides by this method. This procedure has, apparently, not yet been attempted, but the intramolecular hydrogen-bonding responsible for making a anomers in this series relatively volatile makes them, also, very much more soluble in nonpolar solvents, and this characteristic has been usefully applied to the isolation of the anomeric methyl D - x y l o f u r a n o s i d e ~Their . ~ ~ ~ ~3,5~ phenylboronates prepared from a glycoside mixture rich in furanosides can be fractionally crystallized from light petroleum [solubilities (g/lOO ml): a, 17.3; /3, 0.641, thus providing a means of obtaining the unsubstituted a- and P-glycosides in 21 and 29% yield, respectively. With the methyl D-xylopyranosides, it is the ester (38) of the P anomer that has the intramolecular, strongly hydrogen-bonded hydroxyl group, making it the more soluble anomer [solubilities50 (g/lOO ml in light petroleum): a,0.07; P, 531. By virtue of this great difference, methyl a-D-xylopyranoside 2,4-phenylboronate can readily be separated from its isomers, to provide a convenient means of isolating this glycoside, which is otherwise difficult to obtain.69Methyl a-and /3-D-~ylopyranoside-5-~~0 have both been prepared by application of this procedure,83aand the stereoisomers of cis-3,4-thiolanediol l-oxide have been separated as their p h e n y l b ~ r o n a t e s . ~ ~ ~ 2. Use in Paper Chromatography

It has been shown by two groups of w0rkers84-8~that phenylboronic acid incorporated into paper-chromatographic solvents specifically (82) H. C. Brown and G . Zweifel,]. Org. Chem., 27,4708-4709 (1962). (83) B. R. Baker, R. E. Schaub, J. P. Joseph, and J. H. Williams,]. Am. Chem. Soc., 76, 4044-4045 (1954). (83a) W. D. Hitz, D. C. Wright, P. A. Seib, M. K. Hoffman, and R. M. Caprioli, Carbohydr. Res., 46, 195-200 (1976). (83b) J. E. McCormick and R. S. McElhinney,]. Chem. Soc. Perkin Trans. 1 , 25332540 (1976). (84) H. M. Wall, M.Sc. Thesis, University of London, 1964. (85) R. J. Ferrier, W. G. Overend, G. A. Rafferty, H. M. Wall, and N. R. Williams, Proc. Chem. Soc., 133 (1963). (86) E. J. Bourne, E. M. Lees, and H. Weigel,]. Chrornatogr., 11,253-257 (1963).

CARBOHYDRATE BORONATES

59

TABLEI Enhancement Factors for Paper-chromatographic Mobility of Free Sugars by Phenylboronic Acid sugar GIycerose Erythrose Threose Ribose Arabinose Xylose Lyxose Allose Altrose Glucose Mannose Gulose Idose Galactose Talose

Enhancement factora 1.05: 2.7b 1.7,b 2.0,b 0.9,b 1.0: 1.0:

1.0'

1.0' 2.0e 0.7' 0.7" 0.8' 1.4" 0.95" 1.0,* 0.75" l . l , b 0.7' 2.l,* 2.1' 1.8: 2.0' 1.3: 1.0" 2.7'

Sugar G1ycerone glycero-Tetrulose erythro- Pentulose threo-Pentulose Fructose Sorbose gluco- Heptulose 2-Deoxy-erythro-pentose 2-Deoxy-ribo- hexose 2-Deoxy-arabino-hexose 2-Deoxy-lyxo-hexose 3-Deoxy-ribo-hexose 3-Deox y-xylo-hexose 4-Deoxy-xylo-hexose 6-Deoxytalose

Enhancement factor" 1.oc 1.0'

1.8= 2.3" 1.1: 0.9' 1.6b 2.2' 0Bc 0.8' 0.8e 1.3c

0.9' 1,4c 0.8''

2.0e

"Ratios of RF values in solvents (ii) and (i).The enhancement factors determined in the butanol-containing solvents are frequently somewhat less than unity, presumably because the solvents differed slightly in their ethanol content (see footnote c). bDescending chromatograms with solvents (i) 9:2:2 ethyl acetate-acetic acid-water, and (ii) the same, but with phenylboronic acid (0.55%) added.86'Descending chromatograms with solvents (i) butanol-ethanol-water (4:1:5, upper phase), and (ii) the same, but with phenylboronic acid (5%) added. This caused slight phase-separation, and so ethanol (2.5%) was then also added.84

enhances the mobilities of compounds that possess trio1 systems from which particularly stable, boronic esters are formed (see Tables I and 11). From work with six-membered-ring compounds, it was concluded that this stabilization arises from contiguous cis&-triols on such rings, which use 1,3-related, axial hydroxyl groups to give six-membered, cyclic esters (44) stabilized to hydrolysis by the intervening, equatorial

44

ROBERT J. FERRIER

60

TABLEI1 Enhancement Factorsa for Paper-chromatographic Mobility of Alditols, Inositols, and Anhydro Compounds by Phenylboronic Acid Enhancement factop

Inositols and anhydro compounds

Enhancement factop

Glycerol Erythritol Ribitol Arabinitol Xylitol Allitol Alhitol

1.1; 0.85' 1.4; 1.6' 3.4," 2.85' 3.6,b3.3c 3.2,b4.2' 2.5' 3.2b

2.7b 4.0b 0.7b 1.06 1.@ LO* 1.0; 0.9'

Glucitol

5.6,b7.8'

Mannitol

5.4," 4.6c

Galactitol

6.7," 5.7'

2-Deoxy-erythropentitol 1-Deoxygalactitol

1.46 2.26

1,6-Dideoxygalactitol

1.5b

d o - Inositol epi-Inositol chiro-Inositol muco-Inositol myo-Inositol scyZZo- Inositol l,6-Anhydro-Paltropyranose 1,6-Anhydro-pglucopyranose 1,6-Anhydro-Pmannopyranose 1,6-Anhydro-Pgulopyranose 1,6-Anhydro-Pgalactopyranose Methyl 3,B-anhydro-aglucopyranoside Methyl 3,6-anhydro-Pglucopyranoside

Alditol

1 . 0 , b 0.9"

1.2: 2.w 1.0; 1.w l.lb

1.2" 1.2'

aFootnotes as for Table I.

hydroxyl group. Of the pentoses, ribose alone has such a triol grouping (P-D-lyxopyranose is excluded, because of its instability in the lC4 conformation) and is specifically affected (see Table I and Fig. 1).In the aldohexose series, allose, gulose, and talose show enhancements, presumably because, in the pyranose modifications, they contain the required cis,cis-trio1 groupings, but mannose does not, and is thus analogous to lyxose. Idose does not possess a cis,cis-trio1 grouping but shows marked boronate enhancement, suggesting that either its boronate is formed at 0-2,O-4 of a pyranose form, and the ester is stabilized by the ring-oxygen atom, or else a furanoid form presents a suitable triol grouping to the reagent. Other than glycerol, the alditols (see Table 11) all form strong complexes, so the technique is usually suitable for separations of free sugars from their reduction products.86 Removal of oxygen atoms from these derivatives, as expected, lessens their association with the acid.

CARBOHYDRATE BORONATES

61

FIG. 1.-Paper Chromatograms of the Aldopentoses (1, Arabinose; 2, Lyxose; 3, Ribose, and 4, Xylose). [Solvent: A, butanol-ethanol-water (4:1:5, upper phase); B, the same, but containing 2% of phenylboronic acid.]

Evidence of complexing was obtained with the anomeric methyl 3,6anhydro-D-glucopyranosides(see Table II), which suggests that the oxygen atoms on the pyranoid ring can play a role in ester stabilization (45); but, with 1,6-anhydro-/3-~-glucopyranose (46), no complex was

45

62

ROBERT J. FERRIER

formed, because of the splayed relationship of its carbon-oxygen bonds at C-2 and C-4. The 0-2-0-4 distances in these compounds87 of 276 and 330 pm (2.76 and 3.30 A) are in agreement with these observations, but it should be noted that the 1,6-anhydride can be converted into an unstable 2,4-phenylb0ronate.~l The complexes formed by the methyl 3,6-anhydroglucosides and 1,6anhydro-P-mannopyranose (see Table 11) establish that cyclic systems other than that depicted in formula 44 may give rise to mobility enhancements, but, nevertheless, this chromatographic technique can be used in certain cases to detect cis&-triols and, thereby, in configurational analysis, The configurations of 2-C-methyl-~-arabinose and -L-ribose have thus been ascertained by determination of the mobilities of the free sugars and their methyl P-pyranosides. The epimer and the glycoside that showed enhanced mobilities in solvents containing phenylboronic acid were assigned the ribo structure.88 3. Use in Electrophoresis

Sulfonylated phenylboronic acid (mainly the ortho isomer) shows selective, complexing abilities with carbohydrates, and may thus be used in electrophoresis to permit separations of alkali-sensitive compounds at neutral pH values .89 Complexing occurs with all alditols other than glycerol, that is, they migrate on the electrophoretograms, and the relative degrees of complexing are related to the enhancement values found during chromatography with phenylboronic acid (see Tables I and 11). (For example, relative mobilities are: ribitol, 0.3; arabinitol, 0.6; xylitol, 0.9; glucitol, 1.3; mannitol, 1.0; and galactitol, 1.0). Observations with free sugars indicate, however, that the two procedures are basically different, because all aldopentoses, for example, migrate on the electrophoretograms (mobilities relative to glucose as unity: ribose, 4.7; arabinose, 2.4; xylose, 1.8; and lyxose, 2.3), whereas only ribose shows chromatographic enhancement. Likewise, fructose showed no complexing during chromatography, but underwent an extremely strong interaction with sufonylated phenylboronic acid. With the information available at present, the two methods cannot be accurately compared; both, however, appear to be selective for cis&-trio1 groupings on six-membered rings, and the (87) Borje Lindberg, Bengt Lindberg, and S. Svensson,Actu Chem. Scand., 27,373-374 (1973). (88) R. J. Fernier, W. G. Overend, G.A. Rafferty, H. M. Wal1,andN. R. Williams,J. Chem. SOC.,C, 1091-1095 (1968). (89) P. J. Garegg and B. Lindberg, Actu Chem. Scund., 15, 1913-1922 (1961).

63

CARBOHYDRATE BORONATES

electrophoresis results also reveal interaction with cis-1,2-diol groupings in furanoid systems.

4. Use in Column Chromatography From the known, differential complexing between boronic acids and polyhydroxy compounds, it follows that carbohydrate mixtures may be separated b y column-chromatographic methods that exploit the differences. Nucleoside and nucleotide boronates have been separated on columns of anion-exchange resinsFOand sugars and alditols have been shown to be differentially retained on such resins in the sulfonated phenylboronic acid form,64but perhaps the best uses of column chromatography in this connection have incorporated the resolving powers of insoluble polymers to which boronic acid groups have been covalently bonded. Such insoluble forms of boronates have been synthesized either by substitution of polysaccharide derivatives, or by polymerization of suitable arylboronic acids. In the first approach, O-(carboxymethy1)cellulose (47) has been converted into the acyl azide (48) and thence, by treatment with maminophenylboronic acid, into the borylated form 49, to give a polymer

47

48

49

on columns of which the alditols had the relative retention-times: erythritol, 51; ribitol, 56; arabinitol, 76; xylitol, 93; glucitol, 182; mannitol, 109; and galactitol, 111(eluted with acetate buffer, pH 7.5).91 These values indicate that the complexing that results in enhancements of paper-chromatographic mobilities of alditols when phenylboronic acid is added to solvents (see Table 11) operates in a closely similar fashion, to determine their retention by the borylated cellulose. In the same work, it was showng1that nucleosides could be separated on this stationary phase, and that they have retention volumes that depend on the pH and ionic strengths of the buffers used, and on the heterocyclic bases, but, especially, on the presence ofthe 2’,3’-diols. At high pH-values, binding of the purine ribonucleosides was so strong (90) I. I. Kolodkina, E. A. Ivanova, and A. M. Yurkevich, Khim. Prir. Soedin., 6,612-616 (1970); Chem. Abstr., 74, 112,363e (1971). (91) H. L. Weith, J. L. Wiebers, and P. T. Gilham, Biochemistry, 9,4396-4401 (1970).

64

ROBERT J. FERRIER

that they could not be eluted. Yurkevich and coworkers prepared similar column-materials (50)by treatment of 0-(2-diethylaminoethyl)-

so

Sephadex and O-(2-diethylaminoethyl)cellulose with a-bromotolylboronic acid, and studied the separation of free sugarse2~93and nucleosides and nucleotidess3~94on them at various pH values and with different eluants. Compounds containing cis-172-diol groupings were, again, the most strongly bound. Solms and Deuelg5initially prepared a wholly synthetic, borylated polymer by using m-phenylenediamine, p-aminophenylboron dichloride, and formaldehyde, and they investigated carbohydrate separations on it, but addition polymers have usually been favored. Thus, ribonucleosides and deoxyribonucleosides have been efficiently separated on a column of a mixed copolymer of the methacroyl derivativesee 51 and 52, and the method has been extended to

oligonucleotides, including free transfer-ribonucleic acids (t-RNA). The strong complexing that again occurs with compounds containing 2’,3’cis-diol groupings makes it possible to retain ribonucleoside 5’phosphates, 3‘-ribonucleoside-terminatedoligo(deoxynucleotides), and t-RNA’s on the columns, while deoxynucleotides and their oligomers, ribonucleoside 2’-or 3’-phosphates and aminoacyl t-RNA’s (92) E. A. Ivanova, S. I. Panchenko, I. I. Kolodkina, and A. M. Yurkevich, Zh. Obshch. Khim., 45,208-212 (1975). (93) A. M. Yurkevich, I. I. Kolodkina, E. A. Ivanova, and E. I. Pichuzhkina, Carbohydr. Res., 43, 215-224 (1975). (94)E. A. Ivanova, I. I. Kolodkina, and A. M. Yurkevich,Zh.Obshch. Khim., 44,430-434 ( 1974). (95) J. Solms and H. Deuel, Chimia, 11,311 (1957). (96) H. Schott, Angew. Chem. Int. Ed. Engl., 11,824-825 (1972).

CARBOHYDRATE BORONATES

65

are eluted, and this represents97 a significant development in techniques available for the purification of t-RNA’s. Similar polymers have been used by S . A. Barker a n d his colleague^.^^ Radical-induced copolymerization of iminodiethyl (4vinylphenyl)boronate, divinylbenzene, and ethylvinylbenzene gave a polymer on which free sugars can be differentially eluted with distilled water. It is noteworthy that ribose was specifically bound by the polymer (compare, Table I). Separations-particularly those of Dglucose and D-fructose-were shown to be temperature- and pHdependent. 5. Use in Gas-Liquid Chromatography

Separations were first achieved with butylboronates of sugars and alditols, many of which were shown to be separable at 200”. In the earliest report,f’8 it was recognized that products obtained by direct esterification of some sugars in pyridine were chromatographically homogeneous, whereas others were not-glucose giving, for example, three resolvable products. A concurrent study,99 however, showed that glucose gave a single ester if the butylboronation was allowed to proceed to equilibrium, and, similarly, lyxose, fucose, arabinose, xylose, fructose, galactose, and mannose gave essentially homogeneous products (eluted in that order); ribose, rhamnose, erythritol, arabinitol, xylitol, and glucitol did not give single esters. This workggdiffered from that reported in the first paper98 by trimethylsilylation of the unsubstituted hydroxyl groups of the esters prior to g.1.c. examination. A fuller report,loOwhich included mass-spectral results on the main products obtained from D-glUCOSe, D-mannose, D-galactose, and D-fructose showed them to be bis(buty1boronate) trimethylsilyl ethers. Similar substitutions, involving methylboronation followed by trimethylsilylation, have been performed in a g.1.c.-m.s. investigationS8 of the structures of esters of several glycosides and sugars (see Section VI). VI. MASSSPECTROMETRY OF BORONATES

Although, in the mass spectrometer, several fragmentationpathways are followed by carbohydrate boronates, those which result (97) H. Schott, E . Rudloff, P. Schmidt, R. Roychoudhury, and H. Kossel, Biochemistry, 12,932-938 (1973). (98) F. Eisenberg, Carbohydr. Res., 19, 135-138 (1971). (99) P. J. Wood and I. R. Siddiqui, Carbohydr. Res., 19,283-286 (1971). (100) P. J. Wood, I. R. Siddiqui, and J. Weisz, Carbohydr. Res., 42, 1-13 (1975).

ROBERT J. FERRIER

66

in the formation ofthe cyclic, boron-containing ions shown in Scheme 3

‘p):’

‘PR

Bu

Ph

84

126

146

98

140

160

’ 0 ‘

Jb

R’

Ion masses

R = Me

i t k 3 R (R‘=H)

Scheme 3

are of the greatest value in structural analysis. The formation, structures, and masses of such ions formed from five- and six-membered methyl-, butyl-, and phenyl-boronates are shown, together with those of the ions derived from analogous a-diol cyclodiboronates. In the case of the six-membered species, loss of hydrogen atoms can readily occur, to give intense, conjugated ions of one mass unit less than those given in Scheme 3. Boronates of vicinal diols are, therefore, recognizable by the ions derived by direct excision of the two carbon atoms involved, together with their ester substituents, whereas boronates of 173-related diols give ions having a neighboring group (R’) attached. In terminal systems of this type (derived, for example, from 4,6-diols of aldopyranosides), ions having R’ = H are produced, and are, therefore, readily recognized by having the mle values given in Scheme 3. The bis(pheny1boronates) of the tetritols and pentitols produced by the dehydration procedure all gave ions with mle 159 and 160, and were therefore assigned 173:2,4-bicylostructures; for the D-arabinitol derivative, however, the 2,4:3,5-isomeric structure cannot be excluded.101On the other hand, the bis(boronate) obtained from xylitol per(diethy1borinate) was shown in this way to have the 1,2:3,5-structure.40 With the bis(pheny1boronates) of D-glucitol, galactitol, and D-mannitol, the first two were each determined to contain two-fused, six-membered (101) I. R. McKinley and H. Weige1,J. Chem. Soc. Chem. Commun., 1051-1052 (1972).

CARBOHYDRATE BORONATES

67

ring-systems (and a five-membered ring), whereas the third gave no ions indicative of a similar structure.101 Applied on a micro scale, and without isolation of the esters, to products derived from mixtures of phenylboronic acid and methyl a-D-glucopyranoside, methyl a-D-galactopyranoside, and methyl a-Dmannopyranoside, the procedure indicated that the D-ghcoside and D-galactoside derivatives contained 4,6-ester rings (mle 160) and 2,3-(diphenylcyclodiboronate)systems (mle 250), whereas the Dmannoside gave the 2,3:4,6-bis(phenylboronate)structure (mle 160; mle 146; no rnle 250).57 Molecular-ion masses confirmed these conclusions, which are in agreement with the results ofchemical analysis (see Section 111). Analogous results were obtained from the eight methyl amino-4,6-O-benzylidenedeoxy-a-~-hexopyranosides~~~; when the hydroxyl and amino groups at C-2 (C-3) and C-3 (C-2) were cis-related, 2-phenyl-1,3,2-oxazaborolane(53) rings were formed, whereas 2,4diphenyl-1,3,5,2,4-dioxazadiborepaneproducts (54) were obtained from the trans-related glycoside derivatives (compare Section I),so the method provides a means for determining the relative configurations of a-diols and vicinal amino-alcohol groups on cyclic structures.

53

54

For free sugars, the procedure has been applied with isolated est e r ~ ? and ~ * with ~ ~ samples prepared on a micro-scale and purified by g.l.c.563esL-Arabinose gave a bis(buty1boronate) and a bis(pheny1boronate) displaying ions mle 126 and 146, respectively, indicative of their containing five-membered ester groups.44 No ions of mle 140 or 160 were detected (indicating the absence of six-membered rings), and thus, 1,2:3,4-structures were assigned. On the other hand, D-XylOSe bis(buty1boronate) and bis(pheny1boronate) gave ions having rnle 126 and 146 respectively, and also others having mle 140 (139) and 160 (159), respectively, indicating their 1,2:3,5-furanoid structures. Care has to be taken, however, with analytical work of this type, as is illustrated by the spectra given by the bis(methy1boronates) of these two sugars?e which are distinguishable mainly on the basis of ion inten(102) I. R. McKinley, H. Weigel, C. B. Barlow, and R. D. Guthrie, Carbohydr. Res., 32, 187-193 (1974).

68

ROBERT J . FERRIER

sities. All of the structurally significant fragment-ions appear in both spectra. Biemann and coworkers56 extended the g.1.c.-mass spectrometric analysis of boronates by studying the trimethylsilyl ethers of compounds which, after methylboronation, still retain unsubstituted hydroxyl groups. On such treatment, D-fUCOSe gives a product showing a molecular ion mle 212, establishing that it contains two boronic ester and no trimethylsilyl groups, whereas the isomer L-rhamnose is converted into a derivative having one cyclic ester group and two ether substituents (mle 332). The esterification process therefore occurred at one diol site only. In this way, the xylose and arabinose results (see the preceding) were confirmed, and the diesters respectively formed from D-ghcose, D-mannose, and D-galaCtOSe were shown to have the 1,2:3,5, 2,3:4,6, and 1,2:3,4 structures, respectively. Similar work was performed with several methyl aldopyranosides and, with an excess of methylboronic acid, methyl a-D-mannopyranoside gave the 2,3:4,6diester, as expected, and, with limiting amounts of the reagent, a mixture of the 2,3- and 4,g-esters (compare Section 111,3).Methyl a - ~ galactopyranoside was shown to be esterified to give both the 3,4- and 4,6-cyclic esters, in contrast to the conclusion drawn from chemical evidence (see Section 111,3). One feature of this analysis that merits comment is the failure to detect evidence for trioxadiborepane ringstructures with such compounds as methyl a-D-glucopyranoside, despite the use of a 20-fold molar excess of the reagent. A study of the 3-0-a-D-glucopyranosyl-, 3-0-P-D-glucopyranosyl-, 3-0-a-D-galactopyranosyl-, 3-0-~-D-ga~actopyranosy~-, and 3 - 0 - m ~ mannopyranosyl-L-glycerols as phenylboronates, prepared in submilligram quantities, illustrates ( a ) the value of the method in structural analysis, and ( b ) the diversity of the fragmentation reactions that can occur.1o3In Scheme 4, the full degradation pattern of the derivative of 3-0-a-D-glucopyranosy~-L-glycero~ is illustrated; all except the mannosy1 isomer gave the same ions, but having different intensities. Initial work with nucleoside 2’,3’-phenylboronates and their 5’trimethylsilyl ethers was conducted by Dolhun and Wiebers,l04 who identified the main fragmentation-pathways as including rupture of the C-l‘-N and C-4’-C-5’ bonds. They then showed29 that phenylboronated and then trimethylsilylated dinucleotides undergo fragmentation in a way that identifies their sequence, and the method has potential for characterizing the 3’-terminal base of oligo(ribonucleotides). (103) S. G . Batrakov, E. F. Il’ina, B. V. Rozynov, V. L. Sadovskaya,and L. D. Bergel’son, Izu. Akad. Nauk S S S R , Ser. Khim., 821-828 (1975). (104) J. J. Dolhun and J. L. Wiebers, Org. Mass Spectrom., 3,669-681 (1970).

CARBOHYDRATE BORONATES

69

pq

OH

146

159

I

P

h

t

O?

q

160

phB%+-

353

4 51

250

Ph 306

1

phQ 410

Ph

459

ss5

438

334

1

Ph

Ph 141

Ph 305

409

Scheme 4

Carbohydrate phosphates have been examined as the methyl- and butyl-boronates of their dimethyl esters.105 Procedures involved methylation of the enzymically prepared phosphates, and conversion into the dimethyl esters with diazomethane, followed by the usual boronation. Fragmentation patterns were identified for the following: a-D-glucofuranose 172:3,5-bis(butylboronate) 6-(dimethyl phosphate), a-D-galaCtOpyranOSe 1,2:3,4-bis(butylboronate) 6-(dimethyl phosphate), P-D-fructopyranose 2,3:4,5-bis(butylboronate)1-(dimethyl phosphate), and methyl D-gluconate 2,3:4,5-bis(butylboronate) 6-(dimethyl phosphate). In the case of the D-mannose &(dimethyl phosphate), the bis(buty1boronate) obtained was assigned the 1,2:3,5furanoid structure, which contrasts with the 2,3:4,6-structure of boronates derived from the unsubstituted ~ u g a r . ~ 6 With the boronate phosphates,l05 provided that stereochemical factors permit, the phosphate groups stabilize species formed by loss of (105) J. Wiecko and W. R. Sherman, Org. Mass Spectrom., 10, 1007-1020 (1975).

70

ROBERT J. FERRIER

the radicals attached to the boron atoms. Similarly, in acetates of sugar boronic ester~,105~ the acetyl groups stabilize ions produced from neighboring boronate rings, and this behavior can be used, for example, to distinguish between a-D-glucofuranose 1,2-butylboronate 3,smethylboronate and the isomeric 3,5-butylboronate 1,2-methylboronate; an acetyl group on 0-6 interacts only with the boron of the adjacent 3,5-ester. VII. NUCLEARMAGNETIC RESONANCE SPECTROSCOPY OF BORONATEs Several proton-, W - , and l'B-n.m.r. studies have been reported, and all provide means for elucidating the structures of boronates. Results from p.m.r. work26.32,33.44.45.108 were interpreted in the conventional way, and gave information on the molecular structure and the conformation of the carbohydrate portions of the molecules. The 13C shifts of the ortho-aromatic carbon atoms of phenylboronates may provide a means of determining the ester ring-sizes,32 but, on the basis of studies of five compounds, Yurkevich and his ~olleagues4~ pointed out that all three aromatic-carbon resonances (the signal from C-1 is not observed, because of relaxation caused by bonding to boron) occur at lower fields (0.5-1 p.p.m.) in the case of five-membered boronates. Following the work of Cragg and Lockhart,l07 they also demonstrated that broad-line, "B-n.m.r. spectra allow distinction between five- and six-membered, cyclic phenylboronates.26 The former give resonances 4 p.p.m. upfield of those of the latter, and similar findings have been reported for e t h y l b o r o n a t e ~ . ~This ~*3~ observation has assisted in the structural analysis of cyclic ethylboronates of ~ y l i t o lD-mannitol>l ,~~ and galactit01.4~ VIII. BOFUNATES The reaction undergone by alcohols with trialkyl- and triarylboranes in the presence of pivalic acid, to give borinic esters, and the thermal cyclization of bis(dialky1borinates) to boronates, are discussed briefly in Section 11. Many borinates have been prepared in quantitative yield from mono-, di-, oligo-, and poly-sa~charides,3~~J~* and mixed (105a) J. Wiecko and W. R. Sherman,J. Am. Chem. Soc., 98,7631-7637 (1976). (106) A. B. Foster, R. Hems, and L. D. Hall, Can. J. Chem., 48,3937-3945 (1970). (107) R. H. Cragg and J. C. Lockhart,J. Inorg. Nucl. Chem., 31,2282-2284 (1969). (108) R. Koster, K.-L. Amen, and W. V. Dahlhoff,Justus Liebigs Ann. Chem., 752-788 (1975).

CARBOHYDRATE BORONATES

71

borinic-boronic esters have been reported.17*33a*40-42 Treatment of all of these compounds with methanol or 2,4-pentanedione causes deesterification, the borinic esters of mixed compounds being selectively removable, to provide a means, for example, of preparing D-mannitol 3,4-ethylboronate41 and galactitol 2,3:4,5-bi~(ethylboronate)~ (see also, Ref. 33a). At pH 10, diphenylborinic acid gives a tetrahedral anion that complexes with various diol systems, and thus it can be used in electrophoresis like borate.lo9 I n a more detailed study of such complexing,llO diols were examined by 13C-n.m.r. spectroscopy, before and after addition of sodium diphenylborinate, and complexes were detected, and their spectra observed, for a variety of carbohydrate derivatives. 1,2-Diol groupings in acyclic and cis-cyclic compounds, lY3-relateddiols at C-4,C-6 of hexopyranosides, the 3,s-diols of glucofuranoses, and 2,4-diols of the anomeric methyl 3,6-anhydro-~glucopyranosides were all found to react. No interaction occurred with 1,6-anhydro-/3-~-glucopyranose (compare Section V,2).

IX. TABLES The following Tables record some physical properties of boronates of sugars, glycosides, C- and N-glycosyl compounds including nucleosides, alditols, and anhydro sugars,

(109) P.J. Garegg and K. Lindstrom, Acta Chem. Scand., 25, 1559-1566 (1971). (110) P.A. J. Gorin and M. Mazurek, C a n . J .Chem., 51,3277-3286 (1973).

TABLEI11 Boronates of Sugars sugar

Arabinopyranose, 8-L1,2-0-isopropylidene3,4-O-isopropylidene2-Deoxy-~erythro-pentose 1-0-p-tolylsulfonylFructopyranose, 8-D14-benzoylGalactopyranose, a - ~ 1,2-0-isopropylideneGalactopyranose, a - ~ 6-deoxyGlucohranose, Q-D6-0-benzoyl1,24-isopropylidene3-deoxy-3-fluoro6-0-(N-phenylcarbamoyl)6-0-p- tolylsulfonyl6-0-(N-phenylcarbamoy1)6-0-p- tolylsulfonyl1,2-0-(trichloroethylidene)-

Boronate

Melting point

(“C)

-

[QI,

(degrees)

+19

Rotation solvent

1,2:3,4bis(butyl1,2:3,4bis(phenyl3,4phenyll,&phenyl3,4-phenyl3,Pphenyl2,3:4,5-bis(phenyl2,3:4,5-bis(phenyl-

166 130-131 80-82 146147 117-1 18 89-98 139-142

+8.5

CHCI3 CsH6

-25.4 +77.4 - 17 -26

CHC13 CHCl, CsHa

3,4-phenyl-

143-145

-

1,2:3,4-bis(butyl1,2:3,4-bis(phenyl1,2:3,5bis(phenyl1,2:3,5-bis(phenyl3,s-phenyl5,6-(diphenylcyclodi5,gphenyl3,Sphenyl3,Sphenyl1,2:3,5-bis(phenyl1,2:3,5bis(phenyl3,5-p-tolyl-

108.5-109.5 161-162 142-144 116-1 17 4648 115-116 6669 93-94 78-80 120-122 95

-

c6b

44 7.44 33 33 26 46 32 32

-

33

-

+24 +29 +22 +81 + 14

CHCl, C,H,

-2

CHCl,

+24.4

CHCl,

+42.4

CHCl, -

-

-

References

c 6 b

CsHs CHCI,

-

-

32 7,32 23,25,32,48 32 24,32,33 24 49 47 47 47 47 66

sm P

s 4

?

m P

z!

!L

Lyxose, D Mannofuranose, a-D 2,3OisopropylideneMannose, L6-deoxyRibofuranose, 8-D Ribopyranose, a-D3-09- tolylsulfonylRibose, D Xylofuranose, a-D1,20isopropylidene3,5-di-O-methylXylose, D, dibutyl acetal diethyl a c e d ethylene acetal di-isobutyl acetal dimethyl acetal dipropyl acetal

7

bis(pheny1-

109-110

-60.4

5,Gphenyl-

171-173

-

bis(pheny11,5:2,3-bis(phenyl2,4phenyl2,4-phenylbis(pheny11,2:3,5-bis(butyl1,2:3,5-bis (phenyl3,Sphenyl1,Bphenyl-

107.5 124-126 90-92 57-58 140-142 142-142.5 126-127 54-55

+87 +82.8 -44.1 -6.9 +116 +34 -10 - 14 -9

CHCll C6Kl 1,Cdioxane 1P-dioxane

7,44 32,33,69 69

bis(pheny1bis(pheny1bis(pheny1bis(pheny1bis(pheny1bis(pheny1-

114-115 150-151 180-181 130-132 168-169 135-136

+25 +28 +1 +23 +30 +22

l,.l-dioxane 1,4dioxane 1,4-dioxane 1,Pdioxane 1,Pdioxane 1,4-dioxane

70 70 70 70 70 70

-

C&

CiHs CHCl, CHCI, CHCl, c6&

33 7 26 26 46 7

44

TABLEIV

2

Boronates of Glycosides and C-and N-Glycosyl Compounds Glycoside or glycosyl compound Allopyranoside, methyl p-D 6deoxy3-O-(N-phenylcarbamoyl)Arabinopyranoside, methyl p-L2 0benzoylGalactopyranoside, methyl a-D 2,3-di-O-acetyl6-deoxyGalactopyranoside, methyl p-D 2,Sdi-O-acetyl2,3-di-O- benzoylGlucopyranoside, benzyl p-D 2,3,6-tri-O-acety1-4-0(2,3-di-O-acetyl-p-~ glucopyranosy1)Glucopyranoside, methyl a-D

2,3-di-O-acetyl2,3-di-O-benzoyl6-deoxy2,3-di-O-methyl2,3-di-0-p- tolylsulfonyl-

Boronate

Melting point

(“C)

[ffID

(degrees)

2,4phenyl2,Pphenyl3,4-phenyl3,4-ethyl3,4-phenyl4,6-phenyl4,Gphenyl3,4phenyl4,6-phenyl4,gphenyl4,Gphenyl4,Cphenyl-

145-146 154-155 73-74

176-177 145 161-162 177- 178

-76 -74 +117 + 27 +184 +147 +232 -28 +75 +125 -91

4‘,6’-phenyl4,6-p-chlorophenyl3,4-ethyl4,6-m-nitrophenyl4,g-phenyl4,6-phenyl 2,3(diphenylcyclodi4,6-phenyl4,6-phenyl2,4-phenyl4,6-phenyl4,g-phenyl-

199-200 164-165 46-47 168-169 166-167 162-163 116-117 203-204

-

119-120 166-167

-

-

120-122 180-181

Rotation solvent

References

1,4-dioxane 1,Cdioxane 1,4-dioxane 1,4-dioxane

58,60 58 51 33a 51 55 55 59 55 55 55 3

-58.9 +59 + 80 +49 +59

CHC& 1,4-dioxane 1,4-dioxane 1P-dioxane 1,Pdioxane

111 3 33a 3 3

-31 +74 +94 +61 - 15

1P-dioxane 1,4-&oxane 1,Pdioxane 1,Cdioxane 1,4dioxane

3 3 3 59 3 3

GH,

1,Pdioxane 1,4-dioxane MezSO 1,4-dioxane 1,4-dioxane I,4-dioxane

-

Glucopyranoside, methyl p-D2,3-di-O-acetyl2,3-di-O-benzoyl Hex-2-enopyranoside,p-nitrophenyl 2,3-dideoxy-a-~erythroHexopyranoside, methyl 2-deoxy-a-~arabinoHexopyranoside, methyl 2-deoxy-a-~-lyxo6-0-acetylHexopyranoside, methyl 2-deoxy-P-~-lyxo3-0-acetylLyxopyranoside, methyl a-D 4-0-acetylMannopyranoside, methyl a-DMannopyranoside, methyl a - ~ 6-deoxy4-0-(N-phenylcarbamoyl)Psicofuranoside, methyl p-D l-chloro-l-deoxyRibofuranoside, methyl p-D Benzene 2,4,6-trimethoxy-l-p--~ ribofuranosylRibopyranoside, methyl p-D3-0-acetyl3-0-(N-phenylcarbamoyl)-

4,6-phenyl4,6-phenyl-2,3(diphenylcvclodi4,g-phenyl4,Gphenyl-

188-189

-82

1,4-dioxane

3,55

185- 186 123-124 123-124

-127 -99 -2.6

l,4-dioxane 1,4-dioxane 1,Pdioxane

55 55

4,6-phenyl-

180-181

+265

1,4-dioxane

3

4,g-phenyl-

142-143

+63

1,4-dioxane

3

3,4phenyl3,4-phenyl-

159 132-133

+114 +39

1,Cdioxane 1,4-dioxane

55 55

4,g-phenyl4,g-phenyl2,3-phenyl2,3-phenyl2,3:4,Gbis(phenyl2,3:4,6-bis(ethyl-

188 131 66-69 116-117 -

-71 -87 +36 +13 - 118 - 39

1,Pdioxane 1,4-dioxane 1P-dioxane 1,4-dioxane 1,Pdioxane CCl,

55 55 51 51

2,3-phenyl2,3-phenyl3,4-phenyl3,4-phenyl2,3-phenyl-

-34

184-185 123-124 95-96 87.5

1,4-dioxane 1,4-dioxane C& -

-

58 58 112 113 113

2,3-phenyl2,4-phenyl2,4-phenyl2,4-phenyl-

136-137 149-150 82-83 163-164.5

1,4-dioxane 1,4-dioxane 1,4-dioxane

114 51 51 51

-

+ 13

- 136

-111.8 -64.6 -113 -118 -94

55

3 33a

(Continued)

8

4

TABLEIV (Confinued) Glycoside or glycosyl compound Ribopyranosylamine,N-(pbromopheny1)-a-DXylofuranoside, ethyl 1-thio-a-D Xylofuranoside, ethyl 6-Dl-thioXylofuranoside, methyl a - ~ 2-0-(N-phenylcarbamoyl)Xylofuranoside, methyl p-D20acetylXylopyranoside, benzyl a - ~ Xylopyranoside, benzyl p-D 3-0- (tetra-0-acety l-p-D glucopyranosy1)Xylopyranoside, ethyl CY-D l-thioXylopyranoside, ethyl l-thioP-D-

Xylopyranoside, methyl a-D 3-0-acetyl3-0-benzo ylXylopyranoside, methyl p-D3-0-acetyl3-0-benzoyl3-0-methyl3-0-(N-phenylcarbamoyl)-

Borunate

Melting point

("C)

2,4-phenyl-

-

3,Sphenyl3,Sphenyl3,5-phenyl3,Sphenyl3,5-phenyl3,Sphenyl3,5-phenyl2,4-phenyl2,Pphenyl-

102-104 157-158 83-84 215-216 122-123 99-100 152-153 77-78

2,4phenyl2,4-phenyl2,4phenyl-

151-152 137-138 143-145

2,4-phenyl2,4-phenyl2,4-phenyl2,Pphenyl2,Pphenyl2,4-ethyl2,Pphenyl2,4-phenyl2,4phenyl2,4-phenyl-

109-110 175- 176 119-121 138-140 85-86 122-123 99-100 82-84 146-147

110-111

0)

(degrees)

1.13.

Rotation solvent

References

-

-

54

+27 - 146 -254 +21 +97 - 158 -88 -4 - 144 -97 +11 +79.5 -233

+ 10 + 13 + 18

- 104 - 113 - 127 -82 -114 -90

1,4-dioxane 1,Pdioxane 1,Pdioxane 1,4-dioxane 1,4-dioxane 1,4dioxane 1P-dioxane 1,Pdioxane 1,4-dioxane

115 116 116 50,69 69 50,69 69 52 52

1,cdioxane 1,4dioxane 1,4-dioxane

52 116 115

1,4-dioxane 1,4dioxane 1,4-dioxane 1,4-dioxan e 1,Cdioxane CCl, 1P-dioxane 1,4-dioxane 1,Pdioxane 1,cdioxane

115 22,50 22 22 22,50 33a 22 22 22 22

5

TABLEV Boronates of Alditols Alditol

Boronate

L-Arabinitol 5-0-benzoyl1,3-O-benzylidene5-0-ptolylsulfonylErythritol 1,3-O-butylideneDErythritol l-deoxyGalactitol

bis(pheny12,4-phenyl2,4-phenyl2,4-phenylbis(phenyl2,4-phenyl-

2,5-di43-(N-phenylcarbamoyl)-

DGlucitol 2,4di-0- benzoyl2,402-butenylidene2 , 4 0 butylidene1,3:2,4-dia-ethylidene2,4-O-furylidene-

phenyl2,3:4,5-bis(ethyl1,6:2,3:4,5tris(ethyl1,3:4,6-bis(phenyltris(pheny1bis(pheny1tris(pheny11,3:5,&bis(phenyl1,3:5,6bis(phenyl1,3:5,6bis(phenyl5,6phenyl1,3:5,6-bis(phenyl-

Melting point

(“C)

114-1 16 141-142 120-121 141-142 88 60.5-62

DI.[

(degrees)

-

+12 +ll + 16 +28

Rotation solvent

CHCl, CHCl, CHC13

-

CHCl,

75-76 97-98

-

125-130 162-163 223-224 187-190 199 129-131 82-84.5 88 177- 178

+39.6 -

-

+18.6

CHCI, CHC&

+40.5

CHCl,

-6.1 -

-

~~~

(111) H. Kuzuhara and S. Emoto, Agric. Biol. Chem., 30,122-125 (1966);Chem. Abstr., 64, 19,736h (1966). (112) H. Hiehnhecky and J. FarkaS, Collect. Czech. Chem. Commun., 39, 1093-1106 (1974). (113) J. Farkas’, Collect. Czech. C h e p . Commun., 31, 1535-1543 (1966). (114) L. Kalvoda, J. Farkag, and F. Sorm, Tetrahedron Lett., 2297-2300 (1970). (115) R. J. Femer, L. R. Hatton, and W. G. Overend, Carbohydr. Res., 6,87-96 (1968). (116) R. J. Femer and L. R. Hatton, Carbohydr. Res., 6,75-86 (1968).

References 23

67 67 67 23 117 43 42 42 23,42 9,42 23 8,9,23 23

118

119 23 120

~

(Continued)

4

-l

4

TABLEV (Continued)

Alditol Glycerol DMannitol

1,2,5,6-tetra-O-acetyl1,6-di-O-benzoyl3,4-di-O-benzoyl1,3-O-butylidene3,4-0- butylideneL-Mannitol 6-deoxy3,4-O-isopropylidene5-0-ptolylsulfonylPentaerythritol Xylitol 4-0-acetyl4-0- benzoyl3,4,5-tri-O-acetyl-

Boronate phenyl3,4-ethyltris(p-bromophenyltris(p-chlorophenyl1,2:3,4:5,6-tris(ethyl1,2:3,4:5,6tris(phenyltris(p-tolyl3,4-ethylbis(pheny11,2:5,6bis(phenylphenyl1,2:5,6bis(phenyl-

Melting point (“C) 76-78 128 204-205 184-185

-

134-135 162-164

-

150 149-150 116118 69-72

W

Iff1

(degrees) +28.2 +35.1 +45.4 +9.7 +53.4 +45.9 +48.6 -

-

-10.8 +45

Rotation solvent

CCI, -

-

CCI, -

-

CCl,

-

CHCl, CHCI,

References 13,23,26,43 41 8 8 41 8,9,23,123 8 41 23 9 121 121

!=

m

!= 4 ?

m P 1,e-phenyl1,e-phenylbis(pheny11,2:3,5bis(ethyl1,2:3,5-bis(ethyl1,e-ethyl1,2:3,5-bis(ethyl1,e-ethyl-

78-80 124-126 207-208 -

-

-27 -23

-

-

(117) T. G. Bonner, E. J. Bourne, and D. Lewis,]. Chem. Soc., 7453-7458 (1965). (118) T. G. Bonner, E. J. Bourne, and D. Lewis, J . Chem. Soc., 3375-3381 (1963). (119) T. G. Bonner, E. J. Bourne, S. E. Harwood, and D. Lewis,J. Chem. SOC., 121-126 (1965). (120) T. G. Bonner, E. J. Bourne, S. E. Harwood, and D. Lewis,]. Chem. SOC., C , 2229-2233 (1966). (121) T. G. Bonner, E. J. Bourne, D. G. Gillies, and D. Lewis, Carbohydr. Res., 9,463-470 (1969).

CHCl, CHCl,

-

-

-

67 67 8 40 40 40 40 40

22

m

!=

TABLEVI Boronates of Anhydro Sugar Derivatives (Including a Lactone) Anhydro compound

Boronate

Altropyranose, 1,6-anhydro-p-~ 3,4-phenyl2-0-p- tolylsulfonyl3,4-phenylGalactitol, 1,5-anhydro-~4,Gphenyl4,6-phenyl-2,3-(diphenylcyclodi2,3-diOacetyl4,6-phenylGalactopyranose, 1,6-anhydro3,4-phenylP-D3,4-phenyl2-0-p- tolylsulfonyl4,g-phenylGlucitol, 1,5-anhydro-~4,6-phenyl-2,3-(diphenylcyclodiD-Glucono-l,4-lactone 3,5-phenylGlucopyranose, 1,6-anhydro2,4-phenylp-DGulopyranose, 1,6-anhydro-p-~- 2,3-phenyl2,3-phenyl4-0-p- tolylsulfonylHex-1-enitol, 1,5-anhydr0-2deoxy-Darabino- (D-glucal) 4,Gphenyl4,6-phenyl3-0-acetylHex-1-enitol, 1,5-anhydro-23,4-phenyldeoxy-Dlyxo- (D-galactal) 3,4-phenyl6-0-acetylHexitol, 1,5-anhydro-2-deoxy4,g-phenylD-lyX04,6-phenyl3-0-acetylMannopyranose, 1,6-anhydro2,3-phenylp-D2,3-phenyl4-0-p- tolylsulfonyl-

Melting point (“C)

166-167 173- 175 141-142 201-203 143-144

[&I,

(degrees)

Rotation solvent

- 129.6

-

-112 +69

+ 177 +177

References

1,4-dioxane

61 61 55

1,4-dioxane 1,Cdioxane

55 55

-

61 61 3

169- 170 135-136 176- 177

-114 +50 -80

1,4-dioxane

188-189

-121

1,4-dioxane

3 78

-

61 61 61 55

-

122-124 212-216 140-141

-

-70.4 +43.7 +83.9

-

128 88-89

-53 -90

1,4-dioxane 1,4-dioxane

104 98-99

-87 -74

1,4-dioxane 1P-dioxane

55

114-115 89

+ 172

+60

1,Cdioxane 1,4-dioxane

55

149-150 157-158

- 104.9 - 104

-

-

55 55

55

61 61

03

TABLEVII

0

Boronates of Nucleosides Nucleoside Adenosine N6-benzoyl5'-phosphate 5'4-p-tolylsulfonyl5'4-t~itylCytidine N-acetylN-benzoyl5'-O-p-tolylsulfonylGuanosine N- benzoylInosine 5'-O-p-tolylsulfonylUridine 5'-O-p-tolylsulfonyl-

Boronate 2',3'-phenyl2',3'-m-nitrophenyl2',3'-p-tolyl2',3'-phenyl2',3'-phenyl2',3'-phenyl2',3'-phenyl2',3'-phenyl2',3'-phenyl2',3'-phenyl2',3'-phenyl2',3'-phenyl2',3'-phenyl2',3'-phenyl2',3'-phenyl2',3'-phenyl2',3'-phenyl-

Melting point ("C)

[ffl

(degrees)

Rotation solvent

223-224 235-237 226229 187- 188 170

-

78 140 110 175-177

-

270 160,168-170 196, 178-179

-

221-222

-

References 28,35,36,75,77 36 36 122 36 71,80 36 27,28 36 30 74 35,36 35,36 28,35,36 37 27,28 73

(122) S. G. Verenikina, E. G. Chauser, and A. M. Yurkevich, Zh. Obshch. Khim., 41, 1630-1632 (1971).

X. ADDENDUM An X-ray structural study of D-mannitol1,2:3,4:5,6-tris(phenylboronate) has been reported.123 (123) A. Gupta, A. Kirfel, G. Will, and G. Wulff,Acta Crystallogr., Sect. B, 33,637-641 (1977).