Methylation of carbohydrates bearing base-labile substituents, with diazomethane-boron trifluoride etherate. III. New syntheses of 4-O-methyl-d -galactose and 4,6-di-O-methyl-d -galactose

318

CARBOHYDRATE RESEARCH

Note

Methylation of carbohydrates bearing base-labile substituents, with diazomethane-boron trifluoride etherate. Ial*. New syntheses of 4-O-methyl-D-galactose and 4,6-di-0-methyl-D-galactose E. G.

GROS**

AND

I.

0.

MASIRONARDI

Departamento de Q&mica Orgdnica. Facaltadde Ciencias Evaeras y Narurales, y Facultadde Ingenierfa, Uniuersidad de Buenos Aires, Perti 222, Buenos Aires (Argentina)

(Received October 29th, 1968) It has previously been shown’ that monosaccharides having base-labile substituents can readily be methylated by the use of diazomethane in the presence of a catalytic proportion of boron trifiuoride etherate, without migration of the labile substituents. In our previous experiments, the stability of 0-acetyl groups towards the action of the methylating reagents has been tested. We now report an extension of the method in which the reagents are empIoyed with monosaccharides having U-benzoyl groups in the molecule. Bacon er al.’ submitted methyl 2,3,6-tri-O-benzoyl-/I-D-galactopyranoside (2) to the action of Purdie’s reagents in an attempt to prepare the USmethyl derivative, but methyl 2-0-methyl-3,4,6-tri-O-benzoyl-B-D-galactopyranoside was obtained instead; this result clearly indicated that an 0-benzoyl group had migrated during the reaction, showing that 0-benzoyl groups, as well as 0-acetyl groups, are unstable in the alkaline medium of Purdie’s reagents.’ When our methylating reagent was applied to compound 2, the expected methyl 2,3,6-tri-U-benzoyI-CO-methyi-j3-D-galactopyranoside (3) was readily formed. This product was debenzoyIated with sodium methoxide in methanol to the hithertounknown methyl 4-0-methyl-j&D-galactopyranoside (4), which, upon acid hydrolysis, yielded 4-0-methyl-8-D-galactopyranose (5) whose physical properties were in agreement with values reported in the literature3 - 5. In order to obtain compound 2, it was necessary to prepare methyl 2,3-di-Obenzoyl-)3-D-galactopyranoside (1). This compound offered the opportunity to evaluate the methylating reagent with a partially benzoylated monosaccharide having , R-R’= Bz , R”= R’b Flu0 CyOR”

R’Ok%

0th~

P

R=

R’=R%

4’

;:;:p”,‘;

6 ,

R=R’=Bz, R= R’=,-,

OR

Bz,

H

;z”,:

,

Me0

Me0

RI=” HobaoH

HsoH

Rm=RR-=Me R”= R-=Me

HO 5

8

*For Part II, see ref. 1. **Research member of the Consejo National de Investigaciones Cientificas y Tt5cnica.s. Carbohyd. Res., 10 (1969) 318-321

NOTE

319

two hydroxyl groups free. When compound 1 was treated with diazomethane-boron trifluoride etherate, methyl 2,3-di-O-be~oy:-4,~di-O-methyl-B_D-gaiactopyranoside (6) was obtained. This product failed to crystallize, but it was readily purified by high-vacuum distillation. Upon debenzoylation with sodium methoxide in methanol, compound 6 yielded methyl 4,6-di-0-methyl-/3-D-galactopyranoside (7) having essentially the same physical properties as the product described in the literature6. Acid hydrolysis of 7 gave 4,6-di-0-methyl-D-galactose (8) having physical constants in accordance with reported values6g7. It has thus been proved that the new methylation method is effective with monosaccharides having O-benzoyl substituents, and does not cause migration of the 0-acyl groups. Not only one but two hydroxyl groups can be methylated in one step. EXPERIMENTAL

Melting points were determined with a Fisher-Johns block, and are uncorrected. 1.r. spectra were recorded with a Perkin-Elmer “Infracord” spectrophotometer. N.m.r. spectra were recorded in deuterium oxide or chloroform-d, with a Varian A-60 n.m.r. spectrometer. Microanalyses were performed by A. Bernhardt (Mulheim-Ruhr, Germany). Solvents were removed under diminished pressure below 50”. Methyl 2,3,6-tri-O-bensoyI~-O-methyZ-~-D-galactopyranoside (3). Methyl 2,3,6-tri-O-benzoyl-B-D-galactopyranoside’ (2) (2.13 g) was dissolved in dichloromethane (20 ml), and the solution was cooled to 0”; boron trifluoride etherate (0.08 ml) was added, and, while the temperature was kept at O”, diazomethane in dichloromethane was added until a faint, yellow color persisted in the solution. After 30 min at O’, a white solid (polymethylene) was filtered off, and the filtrate was evaporated. The crystalline residue (2.20 g) was recrystallized (twice) from ethanoi, to give pure 3 (1.09 g), m-p. 135-136”, [LY]~’ +29. I” (c 1.9, chloroform). The i-r. spectrum showed no absorption in the hydroxyl region; n.m.r. data: T 4.13 (I-proton quartet, J, .2 7 Hz, J2.3 10 Hz, H-2), 7 4.59 (l-proton quartet, J3,4 3 Hz, H-3), 7 5.33 (l-proton doublet, axial H-l of 8-D form); z 5.35 (broad signal, H-6), o 5.90 (unresolved signal, H-4 and H-5), z 6.42 (OMe at C-l), and 7 6.45 (OMe at C-4). Anal. Calc. for C,,H2,0,: C, 66.91; H, 5.42. Found: C, 67.25; H, 5.50. Methyl 4-0-methyl-p-D-galactopyranoside (4). - Compound 3 (915 mg) was dissolved in methanol (50 ml), and the solution was treated with ht methanolic sodium methoxide (1 ml) and kept for 12 h at room temperature. The solution was neutralized with Dowex-SOW ion-exchange resin, the solid was filtered off, and the titrate was evaporated. The crystalline residue (490 mg) was recrystallized (twice) from absolute ethanol to give pure 4 (263 mg), m.p. 175-176O, [c# -39.9” (c 1.3, ethanol); n.m.r. data: ‘t 5.71 (1 proton doubIet, JIw27 Hz, axial H-l Of B-D form), 7 6.45 (OMe at C-l), and z 6.49 (OMe at C-4). Anal. Calc. for CsH1606: C, 46.14; H, 7.74. Found: C, 46.31; H, 7.80. 4-O-Methyl-/3-D-galactose (5). Compound 4 (200 mg) was dissolved in hf HCl, and the solution was kept for 2.5 h at 100”. When cool, it was neutralized with Dowex-1 resin, the solid was filtered off, and the filtrate was evaporated. The Carbohyn. Res., 10 (1969)318-321

320

NOTE

crystalline residue (150 mg) was recrystallized from ethanol. Pure 5 (98 mg) had m.p. 215-217”, [IX];’ + 54.5 (5 min) --, +82.3” (final, c 1.1, water); n.m.r. data: 5 min after dissolution, H-l gave a doublet at z 5.41 (J1 ,* 7.5 Hz) indicating the pure B-D anomer ; 8 h later, the previous doublet had decreased and another doublet (H-l of CC-Dform) at T 4.71 (J1 ,2 3 Hz) had appeared. The OMe signal appeared at z 6.46. i&tJzyZ 2,3-di-O-benzoyl-4,6-di-O-methyl-8_~-galac~opyranoside (6). - Methyl 2,3-di-U-benzoyl-8-Dgalactopyranoside’ (1) (1.23 g) in dichloromethane (30 ml) was treated with boron trifluoride etherate (50 ~1) and with diazomethane in dichloromethane (as described for the preparation of compound 3). In this case, the residue (1.32 g) obtained after evaporation of the solvent failed to crystallize, and was purified by distillation (165-170”/10-3 torr). The hard, gummy product had [a];’ +63.8” (c 1.5, chloroform); the i.r. spectrum showed no hydroxyl absorption; n.m.r. data: 7 4.18 (l-proton quartet, J,,, 7 Hz, J2,3 10 Hz, H-2), 7 4.62 (l-proton quartet, J3,4 3 Hz, H-3), 7 5.37 (l-proton doublet, axial H-l of B-D form), z 6.05 (l-proton triplet, J4,5 3 Hz, H-4), ‘t 6.26 (unresolved signal, H-5 and H-6), T 6.47 (OMe at C-l and C-4), and z 6.56 (OMe at C-6). Anal. Calc. for C,,H,,O,: C, 64.17; H, 6.08. Found: C, 64.32; H, 6.01. Methyl 4,6-di-0-methyl-/3-D-galactopyranoside (7). - Compound 6 (1.05 g) in methanol (50 ml) was treated with M methanolic sodium methoxide, and the solution was kept for 12 h at room temperature, and processed as described for compound 4. The crystalline residue (520 mg) obtained by removal of the solvent was recrystallized from absolute ethanol; pure 7 had m-p. 139-140”, [a];’ -38.9” (c 1.3, water); n.m.r. data: ‘c 5.72 (l-proton doubIet, J1,2 7 Hz, H-l of B-D form), T 6.45 (OMe at C-l), r 6.49 (OMe at C-4), and 7 6.58 (OMe at C-6). 4,6-Di-0-methyl-a-D-galactose (8). - Compound 7 (100 mg) in M HCl(l0 ml) was hydrolyzed as described for compound 5. The crystalline residue (56 mg) obtained by removal of the solvent was recrystallized from methanol-ethyl acetate to yield pure 8, m-p. 145-147”, [c&O + 128.8 (6 min) + +76.2” (final, c 1.3, water). When recrystallized from absolute ethanol, compound 8 showed m-p. 148-150”; the specific rotation was unchanged_ N.m.r. data: 5 min after dissolution, z 4.74 (l-proton doubIet, J,., 3 Hz, H-l of a-~ form), z 6.48 (OMe at C-4), and 7 6.59 (OMe at C-6). After 8 h, the intensity of the H-l signal had decreased, and another doublet, at 7 5.43 (J1 ,* 7.5 Hz, equatorial H-l of the /I-Dform) had appeared. ACKNOWL.EDG-

We thank Mr. J. J. Ferrer for the measurement of the i-r. and n.m.r. spectra, and the Consejo National de Investigaciones Cientificas y Tecnicas (Buenos Aires) and FORGE (New York) for financial support. REFERENCES 1 J. 0. DEFERRARI, E. G. GROS, AND I.0. MASTRONARDI,Carboltyd. Res., 4 (1967) 432, and previous papers cited therein. See also, W. E. DICK, JR.,B. G. BAKER,AND J. E. HODGE, ibid., 6 (1968) 52; C!. P. J. GLAUDEMANS AND H. G. FLETCHER,JR.,ibid., 7 (1968) 480; P. A.S~1~,ibid.,8 (1968) 101. Carbohyd.

Res., 10 (1969) 318-321

321

NOTE 2 3 4 5 6 7

J. S. BACON, D. J. BELL, AND H. W. KOSTERLITZ, J. Chem. Sot., (1939) 1248. R. W. JEANLOZ, J. Amer. Chem. Sot., 76 (1954) 5684. H. BOUVENGAND B. LENDBERG, Acta Chem. Stand., 10 (1956) 1283. M. i.%mQ, I. BUBEN, AND J. PACAK, Collect. Czech. Chem. Commun., 28 (1963) 1569. J. S. BACON, D. J. BELL, AND J. LORFSER, J. Chem. Sot., (1940) 1147. R. KUHN, I. Law, AND H. TRISCHMANN, Chem. Ber., 88 (1955) 1492. Carbohyd. Res-, 10 (1969) 318-321