摘要:
1977 643Synthesis of Derivatives of Methyl 2,6-Dideoxy-4-0-methyl-a-~-ribo-hexopyranoside : on the Structure of VarioseBy John S. Brimacombe,' Annalee S. Mengech, and Leslie C. N. Tucker, Chemistry Department,The Univer-sity, Dundee DD1 4HNMethyl ~3-0-benzoyl-2,6-dideoxy-4-O-methyl-a-~-~i~o-hexopyranoside (10) has been synthesised by anunambiguous route from methyl 4,6-0-benzylidene-2-deoxy-ot-~-ribo-hexopyranoside (2). The benzoate (1 0)differs from benzoylated methyl varioside (obtained by way of methanolysis of the antibiotic variiimycin) ~ which isclaimed to have the same structure.METHANOLYSIS of the antibiotic variamycin yieldsmethyl varioside, which has been identified as methyl2,6-dideoxy-4-0-methyl-~-~-r~bo-hexopyranos~de (9)principally from its n.m.r.spectrum and that of thederived monobenzoate (10). However, certain featuresof the n.m.r. spectra of these derivatives are not readilyreconciled with structures (9) and (10); in particular,the signal assigned to H-5 of the monobenzoate appearsat uncharacteristically low field ( 5 ca. 4.8; see Figure)for such a proton in a pyranoid derivative. We havesynthesised methyl 3-0-benzoyl-2,6-dideoxy-4-0-methyl-a-D-ribo-hexopyranoside (10) by an unambiguousroute and have shown that its n.m.r. spectrum differsfrom that reported for methyl varioside monobenzoate.Reduction of methyl 4,6-0-benzylidene-2-deoxy-a-~-erythro-hexopyranosid-3-ulose (1) with sodium boro-hydride in methanol-NN-dimethylformamide furnishedmethyl 4,6-0-benzylidene-2-deoxy-a-~-ribo-hexopyrano-side (2), whose physical constants readily distinguishedit from the epimeric ~-arabirto-compound.~ Overendet aL4 have found that reduction of the hexopyrano-sidulose (1) with lithium aluminium hydride also givesV.I . Sheichenko, Khim. prirod. Soedinenii, 1973, 9, 418.Overend, J . Chern. SOC. ( C ) , 1966, 1131.SOC. (C). 1966, 398.G. B. Lokshin, Yu. V. Zhdanovich, A. D. Kuzovkov, andP. J . Beynon, P. M. Collins, P. T. Doganges, and W. G.B. Flaherty, W. G. Overend, and N. R. Williams, J . Chem.the D-ribo-hexopyranoside (2) preferentially. Benzyl-ation5 of compound (2) gave the 3-O-benzyl derivativeP h C H 2' 0 PhCHjO R O(4) R=H (6) R=Ts (9) R=H(5) R=Ts (7) R=H (10) H =Bz(8) R=Me(3), which was converted into methyl 3-0-benzyl-2-deoxy-4,6-di-O-~-tolylsulphonyl- a-D-ribo-hexopyranoside(5) by consecutive treatment with dilute hydrochloricP.J. Beynon, P. M. Collins, and W. G. Overend, J . Chem.J . S . Brimacombe, B. D. Jones, M. Stacey, and J . J . Willard,SOC. (C), 1969, 272.Carbohydrate Rcs., 1966, 2, 167644 J.C.S. Perkin Iacid and toluene-p-sulphonyl chloride in pyridine. Theditosylate (5) was transformed into methyl 3-O-benzyl-2,6-dideoxy-a-~-ribo-hexopyranoside (7) in two steps :first, reduction to the monotosylate (6) with lithiumaluminium hydride in tetrahydrofuran, and then solvo-lysis of the monotosylate (6) with methanolic sodiummethoxide. Attempts to convert the ditosylate (5) intocompound (7) by prolonged treatment with lithiumaluminium hydride6 gave a product mixture of un-expected complexity.Methylation of compound (7)afforded the 4-O-methyl derivative (€9, which was4 5 6 7 8 9 TParts of the 90 MHz n.m.r. spectra (solvent [2H]chloroform) of (a)methyl O-benzoylvarioside (ref. 1) and (b) methyl 3-O-ben.zoy1-2,6-dideoxy-4-O-methyl-a-~-ribo-hexopyranoside (10)converted into methyl 3-0-benzoyl-2,6-dideoxy-4-0-methyl-a-D-ribo-hexopyranoside (10) on catalytic de-benzylation and treatment of the debenzylated com-pound (9) with benzoyl chloride in pyridine.Comparison of the n.m.r. spectrum of the syntheticcompound (10) with that of benzoylated methyl varioside(Figure) establishes that these compounds are notidentical. The same conclusion has been reached byTakai, Yuki, and T a k i ~ r a , ~ who recently described analternative synthesis of methyl 3-0-benzoyl-2,6-dideoxy-R. S.Tipson, A d v . Cavbohydrate Chem., 1963, 8, 107.H. Takai, H. Yuki, and K. Takiura, Tetrahedron Letters,1975, 3647.4-O-methyl-a-~-r~bo-hexopyranoside (10). The n.m .r.spectrum of our compound was indistinguishable fromthat of the compound synthesised by the Japaneseworkers,' who have suggested that methyl varioside isprobably a methyl 2,6-dideoxy-3-0-methylhexofurano-side; this suggestion is in keeping with the shift of theH-5 n.m.r. signal to low field in the spectrum of thebenzoylated derivative, although it remains for theabsolute configuration of variose to be determined.EXPERIMENTALT.1.c. was performed on Kieselgel G; spots were locatedwith vanillin-sulphuric acid.8 1.r.spectra were routinelyrecorded for Nujol mulls on a Perkin-Elmer Infracordspectrophotometer ; in all cases, the spectra are compatiblewith the structures assigned. N.m.r. spectra were usuallymeasured with a Perkin-Elmer R-10 (60 MHz) spectro-meter for solutions in deuteriochloroform with tetramethyl-silane as internal reference. Optical rotations weremeasured at ambient temperature with a Perkin-Elmer141 automatic polarimeter. Light petroleum refers t o thefraction having b.p. 60-80 "C, unless otherwise stated.Methyl 4,6-O-Benzylidene-2-deoxy-a-~-ribo-hexo~yranoside(2).--Sodium borohydride (25.3 g) was added in smallportions over 2 h to a stirred solution of methyl 4,6-0-benzylidene- 2-deoxy-a-~-erythro-hexopyranosid- 3-ulose(10 g) in methanol (500 ml) and NN-dimethylformamide(20 ml) ; stirring was continued for 1 h at room temperatureand the solvents were then removed.The solid residuewas partitioned between chloroform and water, and theseparated aqueous layer was washed with chloroform(3 x 50 ml) . The combined and dried (MgSO,) chloroformlayers were evaporated, and the crystalline residue was re-crystallised (twice) from chloroform-light petroleum t o givethe product (2) (8.7 g), m.p. 124-126", [a], +140° (c 1.2 inCHC1,) (lit.,, m.p. 124-125', [bl], f145' (c 1 in CHCl,))( c j . methyl 4,6-O-benzylidene-2-deoxy-a-~-arabino-hexo-pyranoside, m.p. 151-152", [a&, +90" (c 1 in Me,CO),}.Methyl 3-0-BenzyZ-4,6-O-benzylidene-2-deoxy-a-~-ribo-Jiexopyranoside' (3) .-Sodium hydride (2.1 g) was added t o astirred solution of compound (2) (ca.10 g) in NN-dimethyl-formamide (200 ml) at room temperature. After 45 min,freshly distilled benzyl bromide (10.1 g, 1.6 mmol) wasadded dropwise. Stirring was continued for 22 h, afterwhich time t.1.c. (ethyl acetate-light petroleum, 1 : 1)revealed two products, one of which predominated.Methanol (100 ml) was carefully added to decompose theexcess of reagents and, after 1 h, the solvents were removed.The residue was extracted with chloroform (150 ml), whichwas then washed with water (3 x 50 ml), dried (MgSO,),and evaporated. Recrystallisation (twice) of the residuefrom chloroform-light petroleum gave the benzyl ether (3)(8.35 gl 63%), m.p.96.5-98', [a], +64" (c 0.7 in CHCl,)(Found: C, 70.9; H, 6.5. C21H240, requires C, 70.8; H,6.8%); 7 ca. 2.6 (10 H, aromatic), 4.38 ( 1 H, s, PhCH),5.14 (2 H, s, CH,Ph), and 6.57 (3 H, s, OMe).Methyl 3-O-Benzyl-2-deoxy-4,6-bis-O-p-tolylsul~honyl-ac-~-ribo-hexopyranoside (5) .-A solution of the benzylideneacetal (3) (5 g) in aqueous methanol (900 ml; 1 : 8 v/v)containing O.OlM-hydrochloric acid (100 ml) was heatedunder reflux at 75-80 "C for 6.5 h ; t.1.c. (ethyl acetate-light petroleum-ethanol, 2 : 4 : 1) then showed that all theE. Merck AG, Chromatography,' Darmstadt, 2nd edn.,p. 301977 645starting material had reacted to give one principal andseveral minor products. The acidic solution was neutralised(PbCO,) and the solvents were aremoved to give a paleyellow syrup that was chromatographed on silica gel(elution with ethyl acetate-light petroleum-ethanol,2 : 14 : 1) to give the diol (4) (3.1 g, 82y0), [a], + l O l " (c 1in CHCI,); T 2.64 ( 5 H, aromatic), 5.40 (2 H, ABq, J A B12 Hz, PhCH,), and 6.67 (3 H, s, OMe).To a cooled (0 "C) solution of the diol (4) (3.7 g) in drypyridine ( 15 ml) was added toluene-fi-sulphonyl chloride(10.5 g) in pyridine (30 ml), and the mixture was set asideovernight a t room temperature.Water (3 ml) was addedto destroy the excess of reagent and the solvents wereremoved. The residue was dissolved in chloroform (200ml), which was then washed with aqueous 5% sodiumhydrogen sulphite (3 x 150 ml), M-hydrochloric acid(2 x 150 ml), saturated aqueous sodium hydrogen carbonate(3 x 100 ml), and water (2 x 150 ml).Evaporation of thedried (MgSO,) organic extract gave the crude ditosylate(5) (7.91 g, ca. 99%) as a dark yellow syrup. Chromato-graphy of a portion on silica gel (elution with benzene-ether, 4 : 1) gave the pure ditosylate ( 5 ) , m.p. 115-117°[from benzene-light petroleum (b.p. 80-100 "C)], [a],+67" (c 0.75 in CHCl,) (Found: C, 58.35; H, 5.6; S, 11.1.C28H,,0,S, requires C, 58.3; H, 5.6; S, 11.1%): 7 ca. 2.4(13 H, aromatic), 6.74 (3 H, s, OMe), and 7.58 (6 H, s,2 x ArMe).Methyl 3-0-Benzyl-2,6-dideoxy-4-O-p-tolylsul~honyl-a-~-ribo-hexopyranoside (6) .-To a stirred solution of theditosylate (5) (2.3 g) in dry tetrahydrofuran (10 nil) wasgradually added a solution of lithium aluminium hydride(0.91 g) in dry tetrahydrofuran (10 ml); the mixture wasthen heated under gentle reflux for 75 min.The excess ofreagent was destroyed by addition of moist ethyl acetate(20 ml) to the cooled solution, followed by water (20 ml).The separated organic layer was washed with water (2 x100 ml) and combined with one obtained by washing theaqueous layer with chloroform (6 x 50 ml). Concen-tration of the combined and dried (MgSO,) extracts left asyrup that t.1.c. (light petroleum-ethyl acetate, 2 : 1)showed t o contain a number of products and some startingmaterial. Chromatography on silica gel (elution withlight petroleum-ethyl acetate, 4 : l), gave, inter alia, themonotosylate (6) (0.8 g, 49y0), [a], $114" (c 0.72 in CHCI,),as a syrup that could not be induced to crystallise; t ca.2.6(9 HI aromatic), 6.63 (3 H, s, OMe), 7.57 (3 H, s, ArMe),and 8.72 ( 3 H, d, J5,6 6 Hz, HCMe).Methyl 3-0-Benzyl-2,6-dideoxy-a-~-ribo-hexopyranoside(7).-A solution of the monotosylate (6) (0.59 g) inmethanolic sodium methoxide [lo ml; from sodium (0.46 g)]was heated under reflux for 3 h; t.1.c. (light petroleum-ethyl acetate, 2 : 1) then showed that the starting materialhad not reacted completely, so more sodium methoxide(10 ml) was added and heating was continued for a further18 h. Dry methanol (50 ml) was added to the cooledsolution, which was then neutralised (CO,) and concen-trated. The residue was partitioned between chloroformand water; the separated organic layer was washed withwater (2 x 50 ml) and dilute hydrochloric acid (50 ml)before drying (MgSO,).Removal of the solvent left amobile yellow syrup that furnished the alcohol ( 7 ) (0.24 g,65.5y0), b.p. ca. 145" (bath) a t 0.5 mmHg, [a], $134"(c 2.5 in CHCl?), following chromatography on silica gel(elution with light petroleum-ethyl acetate, 4 : 1). Slightdecomposition of the product occurred on distillation andon storage so that satisfactory analytical data could not beobtained. However, the structure (7) is readily reconciledwith the following data: 7 2.58 ( 5 H, aromatic), 5.40 (2 H,ABq, Jas 12 Hz, PhCH,), 6.65 ( 3 H, s, OMe), and 8.75(2 H, d, J5.6 6 Hz, HCMe); vlnax. 3 540 and 3 450 cm-l (OH).Methyl 3-O-Benzyl-2,6-dideoxy-4-O-methyZ-a-~-ribo-hexo-9yranoside (8).-To a stirred solution of compound ( 7 )(0.24 g) in dry Nhr-dimethylforniamide (10 ml) containingsodium hydride (0.14 g) was gradually added freshlydistilled methyl iodide (0.58 g) ; stirring was then continuedfor 1 h, after which t.1.c.(light petroleum-ethyl acetate-ethanol, 50 : 10 : 1) showed that a little starting materialstill remained. More methyl iodide (0.09 g) was addedand the mixture was stirred for 4 h. Work-up in theusual way and chromatography on silica gel (elution withhexane-ethyl acetate, 5 : 1) gave the methyl ether (8) (0.18 g,71%), b.p. 120" (bath) a t 0.7 mmHg, [u], +162" (c 1 inCHCI,) (Found: C, 67.9; H, 8 . 5 . CI5H2,O4 requires C,67.7; H, 8.3o/b); T 2.57 (5 H, aromatic), 5.30 (2 H, ABq,JAB 12 Hz, CH,Ph), 6.52 and 6.56 (6 H, each s, 2 x OMe),and 8.75 (3 H, d, J5,* 6 Hz, HCiWe).Methyl 3-0-Benzoyl-2,6-dideoxy-4-O-nzethyZ-u-~-rib~~-hexo-pyranoside (10) .--A solution of the benzylated compound(8) (51 mg) in dry ethanol (10 ml) containing Adamscatalyst (230 mg) was shaken under a slight overpressure ofhydrogen a t room temperature for 22 h, during which timecomplete reaction occurred.The catalyst and solventwere removed, and the resulting syrup in pyridine (5 ml)was treated overnight a t room temperature with benzoylchloride (0.11 g). Work-up in the usual way and chromato-graphy on silica gel (elution with carbon tetrachloride-ether, 5 : 1) gave, inter alia, the benzoate (10) (27 mg, 509/0),[a], f174 f 2" (c 0.9 in CHCI,) (Found: C, 64.6; H, 7 . 1 .C,,H,,O, requires C, 64.3; H, 7.1%); T 4.32 ( 1 H, q,H-1), ca. 5.75 ( 1 H, m, H-5), 6.63 (6 H, s, 2 x OMe), 6.95H-2eq), 8.03 ( 1 H, sext, JBn.r.3 ca. 3 Hz, H-~ux), and 8.67(3 H, d, J 5 . 6 6 Hz, HCMe). The n.m.r. spectrum of thebenzoate ( 10) was indistinguishable from that recorded byTakai et ul.,' although i t was easily distinguished from then.m.r. spectrum reported for benzoylated methyl variosidei1it.l [a], f 6 0Ja.4 3 Hz, H-3), 5.27 (1 H, d, J1.Zaz CU. 4 Hz, J1,2eq CU. 0 Hz,( 1 HI q, J 4 . 5 CU. 10 Hz, H-4), 7.75 ( 1 H, 9, Jzeq,3 CU. 0 Hz,2" ( c 0.2 in CHCI,)}.[6/1711 Received, 8th September, 1976
ISSN:1472-7781
DOI:10.1039/P19770000643
出版商:RSC
年代:1977
数据来源: RSC