Synthesis and absolute configuration of the naturally occurring cyano glucoside simmondsin

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1992 Synthesis and Absolute Configuration of the Naturally Occurring Cyano Glucoside Simmondsin Noritaka Chida, Ken Yamada and Seiichiro Ogawa" Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223, Japan The synthesis of the naturally occurring cyano glucoside simmondsin, 1, is reported. An optically active cyclitol, L-quebrachitol 2, was stereoselectively converted into the aglycone 19, which was condensed with D-glucose, followed by deprotection to provide simmondsin 1. This synthesis successfully determined the absolute configuration of the natural product. Simmondsin 1 was first isolated by Elliger et al. in 1973 from seeds of the jojoba plant, Simmondsia californica, and was reported to exhibit feeding inhibitory activity in animals.' The structural study of simmondsin 1, with spectral analysis and degradation studies, by Elliger's group showed that simmondsin 1 consists of D-glucose bonded to a substituted cyclohexane derivative bearing an a,P-unsaturated nitrile group via a p-glycosidic After the discovery of simmondsin, a number of similar cyano glucosides possessing interesting bio- logical activities, uiz.griff~nin,~menisdaurin? lithospermoside and its epimer,6 were isolated from plants.However, in spite of its intriguing structure as well as its unique biological activity, there has been no report of the total synthesis of simmondsin 1, and the absolute configurations of simmondsin 1 and of other natural products in this class have not been elucidated.In this article we document a total synthesis and absolute structure of simmondsin 1 with full experimental detail^.^ .. OH OH 1 Simmondsin 2 L-Quebrachtd Although the absolute configuration of the aglycone moiety of simmondsin was not clear, the relative structural similarity of the aglycone to the naturally occurring opticalIy active cyclitol L-quebrachitol, compound 2,8*9led us to choose compound 2 as the starting material for the synthesis of the aglycone moiety. Thus, four asymmetric centres (C-1,-2, -4 and -6) of compound 2 were envisaged to correlate with C-4, -5, -1 and -3 of the aglycone, respectively. The hydroxy group in the known di-0- isopropylidene derivative 3,9bprepared in one step from L-quebrachitol 2, was O-methylated to give the fully protected derivative 4 in 96 yield.The trans 0-isopropylidene group in compound 4 was selectively cleaved by mild acid hydrolysis to afford the diol5, which was treated with an equimolar quantity of benzoyl chloride in pyridine to give two mono-0-benzoyl derivatives in a ratio of -,5 :1 in 60 yield from compound 4 (Scheme 1). 'H NMR analysis of the major benzoate with spin-spin decoupling revealed that the proton attached to the carbon bearing the benzoyloxy group (6 4.95) was coupled with 5-H (6 4.51, J4,5 5.3 Hz) and there was observed no coupling between the proton at 6 4.95 and 2-H (6 3.62), indicating that the major benzoate should be 4-0-benzoate 6. Reaction of com- pound 6 with methanesulfonyl chloride provided mesylate 7 in 83 yield, which was then treated with sodium methoxide to afford the epoxide 8.Lithium aluminium hydride reduction of epoxide 8 afforded the single alcohol 9 in 91 yield. In the 'H NMR spectrum of the alcohol 9, there was observed no coupling between the signal at 6 4.03 (5-H) and 1-H (6 3.80), and the signal at 6 4.03 was coupled with 4-H (6 4.29) and the C-6 methylene, supporting the assigned structure of compound 9. The predominant formation of compound 9 might be rational- ized by the presence of a cis-0-isopropylidene group at C-5 and -6 in compound 8, which would not have allowed the approach of the reagent to C-1, due to stereoelectronic effects.The hydroxy group in compound 9 was protected as its p-methoxy- benzyl ether to afford compound 10, whose 0-isopropylidene group was removed by acid hydrolysis to provide diol 11 in 75 yield from the alcohol 9. An equatorial hydroxy group in diol 11 was selectively acylated with benzoyl chloride to give monoester 12 (87). After tetrahydropyranylation of the re- maining hydroxy function to give the tetraether 13, the 4-OH group was regenerated by basic hydrolysis to afford the alcohol 14 in 87 yield from compound 12. Oxidation of the alcohol 14 with pyridinium chlorochromate (PCC) gave ketone 15 in 87 yield. The crucial cyanomethylenation of ketone 15 was achieved by Horner-Emmons alkenation using diethyl cyano- methylphosphonate and Bu'OK in toluene, and the desired acylonitrile 16E and its 2-isomer 162 were isolated in 43 and 37 yield, respectively.To establish the geometry of the double bonds in products 16E and 162, they were converted into butenolides 22 and 25, respectively (Scheme 2). Hence, treatment of isomer 16E with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(DDQ) in wet di- chloromethane lo afforded compound 20, whose THP group was removed under acidic conditions to give diol21. Treatment of diol 21 with aq. acid provided the known butenolide2 22, previously obtained from natural simmondsin by acid hydro- lysis, in 11 overall yield from 16E. The physical (m.p. 138- 139 "C; lit.,2 138-140deg;C) and spectral properties of the butenolide 22 were in good accord with those of an authentic sample' reported by Elliger.On the other hand, removal of THP group in compound 162 gave the alcohol 23, which was then treated with DDQ to afford diol24. Acid treatment of diol 24 generated another butenolide, 25, in 9 overall yield from 162. The 'H NMR data as well as the mass spectrum (see Experimental section) supported the assigned structure. From these results, the geometries of the double bonds in compounds 16E and 162 were unambiguously determined. The 'H NMR analysis of compounds having an a,p-unsatur- ated nitrile function suggested that the conformations of these compounds are strongly influenced by the geometry of the 1132 J. CHEM. SOC. PERKIN TRANS. 1 1992 OMe OMe 3 R=H 5 R'=R2=H 4 R=Me 6 R'=H,R2=Bz 7 R' = Ms,R2 = BZ I 9 R=H 8 10 R=MPM 1 OMe OR' 0 11 R' = R2= H 15 12 R' = BZ, R~ = H 13 R' = Bz,R2= THP 14 R' = H, R2 = THP + CN 16E R' = MPM, R2 = THP 16Z 17 R' = MPM, R2 = H 18 R' = MPM, R~= AC 19 R' = H, R~= AC Scheme 1 Bz = PhCO, Ms = MeSO,, MPM = p-MeOC,H,CH,, THP = tetrahydropyran-2-yl, Ac = MeCO double bond.Compounds with a trans (to the C-2-C-3 bond) olefin always adopt conformation i whereas those having a cis (to C-242-3 bond) olefin adopt conformation ii. In the 'H NMR spectrum of compound 18, for example, 3-H was ob- served at 6 5.96 as dd (J3,48.8 and J3,vinyl1.8 Hz). The large coupling constant between 3-H and 4-H revealed that the acetoxy group at C-3 has an equatorial orientation, and the relatively large long-range coupling between 3-H and the vinyl proton suggested that the C-3-H bond is parallel to the n orbital.' ' The signal of 1-H in compound 18 appeared at 6 4.56 with J, ,6 4.8 and J,,6' 3.7 Hz, indicating that 1-H is equatorially oriented, and the lack of coupling between the vinyl proton suggested that the C-1-H bond is orthogonal to the n orbital,'' supporting our hypothesis that compound 18 adopts con- formation i.On the other hand, in the 'H NMR of the compounds having a cis-olefin to C-2-C-3 bond (compounds '0 2220 R' = H, R2= THP 21 R'=R~=H 23 R' = MPM, R~= 25H 24 R' = R2= H Scheme 2 Me0 Me0..CN4 0 Me0 'R2 H OR2 i ii 162, 23 and 24), large coupling constants (-11 Hz) between 1-H and 6-H, and long-range couplings ( -2 Hz) between 1-H and the vinyl proton, were observed.These results, as well as the small coupling constants J3,4 5.2 Hz, and lack of coupling between 3-H and the vinyl protons, suggested the structure ii for these compounds. This significant conformational change be- tween trans- and cis-olefins should probably be ascribed to steric factors. The severe allylic 1,3 strainI2 between the hydroxy and cyano groups would make conformation i and ii preferable for trans- and cis-olefins, respectively. It is noteworthy that conformation i is stable for trans-olefin compounds in spite of the presence of a 1,3-diaxial interaction of hydroxy functions. It has been reported by Elliger '*'that natural simmondsin also adopts conformation i.AcO OMe 19 + I OAc "0R 26 'OR 27 R=Ac 1 R=H Scheme 3 Removal of the 0-THP group in compound 16E to give the alcohol 17,and acetylation gave compound 18 in 97 yield. The MPM protecting group was then removed to provide the aglycone 19, suitable for condensation, in 72 yield. P-Glucos- idation of aglycone 19 was successfully achieved by Schmidt's protocol.' Thus, treatment of compound 19 with trichloro- acetimidate derivative 2614in the presence of BF,-OEt, and molecular sieves (1,2-dichIoroethane) afforded the P-glucoside 27in 27 yield (Scheme 3). The Koenigs-Knorr condensation of compound 19 with glucopyranosyl bromides or chlorides with various metal salts as catalysts gave less satisfactory J.CHEM. SOC. PERKIN TRANS. i 1992 6,(270 MHz; CDCI,) 1.37, 1.43, 1.44 and 1.51 (each 3 H, 4 s, HO /OH 2 x CMe,), 3.44 (1 H, m, 2-H), 3.53 and 3.54 (each 3 H, 2 s, 2 x OMe), 3.61-3.78 (2 H, m, 3- and 4-H), 3.84 (1 H, m, 1-H) and 4.29-4.40 (2 H, m, 5-and 6-H). 1,2-di-O-rnethyf-chiro-inositof1~-5,6-O-Zsopropyfidene-6 5.-To a stirred solution of compound 4 (26 mg, 0.088 mmol) in OH H methanol (0.5 cm3) at 0 "C, was added toluene-p-sulfonic acid monohydrate (PTSA) (0.2 mg), and the mixture was stirred at 1 Fig. 1 Absolute configuration of simmondsin 1 results, and the low yield of the condensation might be attributable to the relative instability of substrate 19 towards acidic reaction conditions. The 'H NMR spectrum, as well as the m.p., of product 27 were in good accord with those of an authentic sample, reported by Elliger m-p.164-165 "C (lit.,' 165-166 "C), and the P-glucosidic linkage was confirmed from the 'H NMR data (J 7.8 Hz at the anomeric centre). Finally, 0-acetyl groups were removed by treatment of compound 27 with sodium methoxide in methanol to provide simmondsin 1, quantitatively. The spectral ('H, I3C NMR and IR) and physical properties (m.p. 94-95 "C; alp -69 * (MeOH)) were in good accord with those of natural simmondsin {m.p. 98- 99 "C; a;' -73 (MeOH)}. From this synthesis, therefore, the absolute configuration of simmondsin was determined to be (22)-( 1R,3 S,4 R,5S)-2-cyanome thylene- 3- hydroxy-4,5-dime th- oxycyclohexyl P-D-glucopyranoside as depicted in Fig.1. Experimental M.p.s were determined on a Mitamura-riken micro hot stage and are uncorrected. 'H NMR spectra were measured with a JEOL JNM EX-90 (90 MHz) and a JEOL JNM-GSX 270 (270 MHz) spectrometer, with tetramethylsilane as internal standard for solutions in deuteriochloroform, unless otherwise noted; J-values are given in Hz. 13C NMR spectra were taken on a JEOL JNM-GSX 270 (67 MHz) spectrometer with l3CDC1, as in- ternal standard (6, 77.0 ppm) for solutions in deuteriochloro- form. High-resolution mass spectra were measured by a JEOL JMS-DX-302 spectrometer with EI mode (70 eV). Optical rotations were measured with a JASCO DIP-370 instrument. IR spectra were taken with a JASCO IR-810 spectrometer.Organic solutions were dried over anhydrous Na2S04 and concentrated below 40 "C under reduced pressure. pH Values were measured using pH paper. 1~-3,4:5,6-Di-O-isopropyfidene-1,2-di-O-rnethyf-chiro-inos-itof t 4.-To a stirred solution of 1 ~-3,45,6-di-O-isopropyl-idene-2-O-methyl-chiro-inositol$3(35 mg, 0.13 mmol) in N,N-dimethylformamide (DMF) (0.6 cm3) at 0 "C was added 60 sodium hydride (6.1 mg, 0.15 mmol). After the mixture had been stirred at 0 "C for 40 min, iodomethane (0.016 cm3, 0.26 mmol) was added and the resulting mixture was stirred at room temperature for 30 min. After addition of methanol at 0 "C, the mixture was concentrated, and then diluted with EtOAc. The organic layer was washed with brine, then dried. Evaporation of the solvent left an oil which was chromatographed on a column of silica gel (1 g) with EtOAc-toluene (1 :10, v/v) as eluent to give compound 4 (35 mg, 96) as a syrup (Found: C, 58.0 H, 8.1.C14H2406 requires C, 58.3; H, 8.4); Calk8 -16 (c 1.0, CHCl,); * Units for .ID are now lo-' deg cm2 g-'. t Systematically: 1L-I ,2:3,4-di-O-isopropylidene-5,6-di-O-methyl-chi-inositol. Systematically: 1 L-1,2:3,4-di-O-isopropylidene-5-O-methyl-chiro-ino-sitol. 0deg;C for 7 h. The reaction mixture was then neutralized by addition of triethylamine (pH 7 -8), and was then concentrated to give a residue, which was chromatographed on a column of silica gel (1 g) with methanol-chloroform (1:20) as eluent to give compound5 (18 mg, 81) as a syrup (Found: C, 52.9; H, 7.9.CI1H2,O, requires C, 53.2; H, 8.1); Cali8 -68 (c 1.0, CHCl,); v,,,(neat)/cm-' 3430 (OH); 6,(270 MHz; CDCI,) 1.37 and 1.49 (each 3 H, 2 s, CMe,), 3.31 (1 H br s, OH), 3.33-3.68 (3 H, m, 2-, 3-, 4-H), 3.53 and 3.57 (each 3 H, 2 s, 2 x OMe), 3.73 (1 H, br s, OH),3.82(1 H,dd,J1,22.8,J1,63.9, l-H),4.15(1 H,dd,J4,56.1, J5,66.1, 5-H) and 4.34 (1 H, dd, 6-H). 1 L-4-0- Benzoyf-5,6-O-isopropyfidene-1,2-di-O-methyl-chiro-inositoffl 6.-To a stirred solution of the diol 5 (40 mg, 0.16 mmol) in pyridine (0.6 cm3) at 0 "C was added benzoyl chloride (0.026 cm3, 0.23 mmol). After the mixture had been stirred at 0deg;C for 27 h, methanol was added and the mixture was concentrated to give a residue, which was dissolved in EtOAc.The organic solution was washed successively with 0.5 mol dmd3 aq. HCI, saturated aq. sodium hydrogen carbonate, and brine, then dried. Removal of the solvent left a syrup, which was chromatographed on a column of silica gel (1 g) with EtOAc- toluene (1 :10)as eluent to give a 5:1 mixture of compound 6and its regioisomer (34 mg, 60) as a syrup. This compound was used in the next step without further purification. A part of this syrup was further purified with silica gel chromatography and used as an analytical sample (Found: C, 61.15; H, 6.7. CIS- H2407 requires C, 61.4; H, 6.9); aamp;7 -94 (c 0.9, CHCl,); v,,,(neat)/cm-' 3470 (OH) and 1730 (ester); 6,(270 MHz; CDCl,) 1.39 and 1.53 (each 3 H, 2 s, CMe,), 3.50 and 3.56 (each 3 H, 2 s, 2 x OMe), 3.62 (1 H, dd, J1,,2.4, J2,,4.9,2-H), 3.83 (1 H, dd, Ji.6 4.9, 1-H), 3.95 (1 H, m, 3-H),4.45 (1 H, dd, J5.6 6.4,5-H), 4.51 (1 H, dd, J4,58.3,5-H),4.95 (1 H, dd, J3,47.3,4-H) and 7.45-8.13 (5 H, m, Ph).1 L-4-0- Benzoyf-5,6-O-isopropyfidene-1,2-di-O-methyi-3-0-rnethyfsulfonyf-chiro-inositof11 7.-To a solution of a 5:1 mixture of compound 6 and its regioisomer (29 mg, 0.083 mmol) in pyridine (0.5 cm3) at 0 "C was added methanesulfonyl chloride (0.013 cm3, 0.17 mmol). After being stirred at room temperature for 6 h, the mixture was treated with methanol and the resulting mixture was concentrated to give a residue. This was diluted with EtOAc and then washed successively with 0.5 mol dm-, aq. HCl, saturated aq.sodium hydrogen carbonate, and brine, and dried. Evaporation of the solvent left a crystalline residue, which was purified on preparative TLC (PLC) with ethyl acetate-toluene (1 :4) to give pure compound 7 (30 mg, 83) as needles, m.p. 140.5-141.5 "C (from EtOH) (Found: C, 52.7; H, 6.05. C,,H,,O,S requires C, 53.0; H, 6.1); a;7 -46 (c 0.98, CHCl,); v,,,(KBr)/cm-' 1730 (ester); 6,(270 MHz; CDCl,) 1.36 and 1.59 (each 3 H, 2 s, CMe,), 2.94 (3 H, s, SO,Me), 3.56 and 3.58 (each 3 H, 2 s, 2 x OMe), 3.77 (1 H, dd, J,,22.4, J2.3 642-H), 3.94 (1 H, dd, J1,63.4, 1-H), 4.37-4.44 (2 H, m, 5-and 6-H), 5 Systematically: 1L-1,2-O-isopropylidene-5,6-di-0-methyl-chio-inosi-tol. 7 Systematically: 1L-3-0-benzoyl-1,2-di-O-isopropylidene-5,6-di-O-methyl-chiro-inositol.11 Systematically: 1 L-3-0-benzoyl-1,2-O-isopropylidene-5,6-di-O-meth-y l-4-O-meth ylsulfonyl-chiro-inositol. 4.98 (1 H, dd, J3,48.8, 3-H), 5.48 (1 H, dd, J4,57.8, 4-H) and 7.44-8.1 1 (5 H, m, Ph).1D-1,2-Anhydro-5,6-O-isopropy~idene-3,4-di-O-methyl-a110-inositol8.-To a stirred solution of the mesyl ester 7 (85 mg, 0.20 mmol) in methanol (1.5 cm3) at 0deg;C was added 1 mol dm-, sodium methoxide in methanol (0.30 cm3; 0.30 mmol) and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was neutralized by addition of IR-120B resin (H+-form)and insoluble materials were removed by filtration. The filtrate was concentrated to give a residue, which was diluted with EtOAc. The organic solution was washed suc- cessively with saturated aq.sodium hydrogen carbonate and brine, and dried. Removal of the solvent gave a syrup, which was chromatographed on a silica gel column (2 g) with EtOAc- toluene (1 :5) as eluent to afford compound 8 (38 mg, 84) as a crystalline residue, m.p. 63-64 "C (from EtOH) (Found: C, 57.3; H, 7.6. CllH1805 requires C, 57.4; H, 7.9); alp +30 (c 1.0, CHCl,); S,(270 MHz; CDCl,) 1.37 and 1.45 (each 3 H, 2 s, CMe2), 3.24 (1 H, dd, J1,22.9, J1.5 1.0, 1-H), 3.42 (1 H, ddd, J2.3 2.0, J2,41.0,2-H), 3.52 and 3.54 (each 3 H, 2 s, 2 x OMe), 3.72 (1 H,ddd,J3,44.4,J4,54.4,4-H),3.94(1H,dd,3-H),4.41(1H,ddd, J5,65.9,5-H) and 4.55 (1 H, d, 6-H). 1D-( 1,2,5/3,4)-3,4-0-Isopropylidene-1,2-di-O-methylcyclohex-anepentaol 9.-To a stirred suspension of lithium aluminium hydride (31 mg, 0.83 mmol) in tetrahydrofuran (THF) (1 an3)at 0 "C was added a solution of the epoxide 8(38 mg, 0.17 mmol) in THF (1 cm3) dropwise.After the mixture had been stirred at room temperature for 3 h, water was added and the product was extracted with EtOAc. The organic layer was washed with brine and dried. Removal of the solvent left a syrup, which was chromatographed on a silica gel column (1 g), with EtOAc- toluene (1 :2) as eluent, to give compound 9 (35 mg, 91) as a syrup (Found: C, 56.6; H, 8.6. C12H1806 requires C, 56.9; H, 8.7); Calk7 +48 (c 0.97, CHC1,); v,,,(neat)/cm-' 3480 (OH); 6,(270 MHz; CDCl,) 1.38 and 1.49 (each 3 H, 2 s, CMe,), 1.91 (1 H, ddd, J,,6 3.4, J5.6 4.9, J6,6*14.7,6-H), 2.09 (1 H, ddd, J1.6' 4.4, J5,6,4.4, 6-H'), 3.35 (1 H, dd, J1,,2.9, J2,,6.4, 2-H), 3.47 and 3.53 (each 3 H, 2 s, 2 x OMe), 3.80 (1 H, m, 1-H), 4.03 (1 H, m, 5-H), 4.29 (1 H, dd, J3,45.9, J4,54.4, 4-H) and 4.36 (1 H, dd, 3-H).1D-( 1,2,5/3,4)-3,4-0-Isopropyiidene-5-O-(p-methoxybenzyi)-1,2-di-O-rnethylcyciohexanepentaol10.-To a stirred solution of compound 9 (18 mg, 0.066 mmol) in DMF (0.5cm3) at 0 "Cwas added 60 sodium hydride (12 mg, 0.31 mmol). After the mixture had been stirred at 0 "C for 45 min, p-methoxybenzyl chloride (0.042 cm', 0.31 mmol) was added, and the resulting mixture was stirred at room temperature for 12 h before being poured into ice-water and stirred for 1 h, and the product was extracted with EtOAc.The extract was washed successively with saturated aq. sodium hydrogen carbonate and brine, then dried over anhydrous sodium carbonate and sodium sulfate. Removal of the solvent afforded a syrup, which was purified by PLC with acetone-toluene (1 :5) to give compound 10 (22 mg, 81) as a syrup (Found: C, 64.5; H, 7.7. C19H2806 requires C, 64.75; H, 8.0); v,,,(neat)/cm-' 1610 (para-substituted phenyl); 6,(90 MHz; CDCl,) 1.37 and 1.43 (each 3 H, 2 s, CMe,), 1.69- 2.18 (2 H, m, 6-H2), 3.38 (3 H, s, OMe), 3.42-3.68 (3 H, m, 1-, 2- and 5-H), 3.51 and 3.80 (each 3 H, 2 s, 2 x OMe), 4.19 (1 H, dd, J3,4 6.3,4-H), 4.33 (1 H, dd, J2.3 3.8,3-H), 4.54 and 4.72 6.3, J4,5 (each 1 H, 2 d, J 11.O, ArCH2) and 6.79-7.38 (4 H, m, ArH). 1D-( 1,2,5/3,4)- 5-O-(p-Methoxybenzyi)- 1,2-di-O-methyicycio- hexanepentaoi 11.-A solution of compound 10 (89 mg, 0.25 mmol) and PTSA (10 mg, 0.053 mmol) in methanol (2 cm3) was stirred at room temperature for 4 h.The reaction mixture was J. CHEM. SOC. PERKIN TRANS. 1 1992 neutralized by addition of triethylamine (pH 7-8), and was then concentrated to give a residue, which was chromatographed on a silica gel column (3 g), with EtOAc-hexane (2: 3) as eluent, to give compound 11(72 mg, 92) as a syrup (Found: C, 61.1; H, 7.7. C16H2406 requires C, 61.5; H, 7.7); a',' -65 (c 0.87, CHCl,); v,,,(neat)/cm-' 3430 (OH) and 1610 (para-substituted phenyl); 6,(270 MHz; CDC13) 1.71 (1 H, ddd, J1.6 11.7,J5.6 11.7, J6.6' 11.7,6-H), 2.21 (1 H, ddd,J,,,, 3.9, J5,6,3.9,6-H'), 3.41 and 3.48 (each 3 H, 2 s, 2 x OMe), 3.52-3.61 (2 H, m, 1- and 5-H), 3.71 (1 H,dd, Jl,,3.4, J2.3 3.4,2-H), 3.80(1 H, m,4-H), 3.81 (3 H, s, OMe), 4.21 (1 H, dd, J3,43.4,3-H), 4.38 and 4.64 (each 1 H, 2 d, J 10.7, ArCH2) and 6.87-7.30 (4 H, m, ArH).1D-( 1,2,5/3,4)-4-0-BenzoyZ-5-O-(p-methoxybenzyl)-1,2-di-0-methyicyclohexanepentaoZl2.-To a stirred solution of the diol 11(241 mg, 0.772 mmol) in pyridine (4 cm3) was added benzoyl chloride (0.099 cm3, 0.85mmol) and the resulting mixture was stirred at 70 "C for 13 h. After addition of methanol at 0 "C, the reaction mixture was concentrated to give a residue, which was dissolved in EtOAc and washed successively with 1 mol dm-, aq. HCl, saturated aq. sodium hydrogen carbonate, and brine, then dried.Removal of the solvent left a syrup, which was chromato- graphed on a silica gel column (10 g) with EtOAc-toluene (1 :7) as eluent, to give benzoate 12 (281 mg, 87) as a crystalline residue, m.p. 77-78 "C (from EtOH) (Found: C, 66.4; H, 6.7. C23H2807requires C, 66.3; H, 6.8); Calk7 -47 (c 1.7, CHCl,); v,,,(KBr)/cm-' 3440 (OH), 1710 (ester) and 1605 (para- substituted phenyl); 6,(270 MHz; CDCl,) 1.58 (1 H, br s, OH), 1.94 (1 H, ddd,J1,6 11.2, J5.6 11.2, J6.6, 11.2,6-H), 2.21 (I H, m, 6-H'), 3.42 and 3.53 (each 3 H, 2 s, 2 x OMe), 3.67 (1 H, ddd, J1.2 3-47J1.6' 3.4, I-H), 3.74 (1 H, dd, J2,3 3.4,2-H), 3.76 (3 H, S, OMe), 3.90 (1 H, ddd, J4,5 4.4, 5-H), 4.42 (1 H, dd, J3,49.3, J5,6 2.9,3-H), 4.49 and 4.60 (each 1 H, 2 d, J 11.7, ArCH,), 5.38 (1 H, dd, 4-H) and 6.74-8.04 (9 H, m, ArH).1D-( 1,2,5/3,4)-4-0-Benzoyi-5-0-(p-methoxybenzyl)-1,2-di-0-methyl-3-0-(tetrahydropyran-2-yl)cyciohexanepentaol13.-A mixture of compound 12 (1.59 g, 3.82 mmol), 3,4-dihydro-2H- pyran (1.05 cm3, 11.5 mmol) and PTSA (15 mg, 0.079 mmol) in dichloromethane (20 cm3) was stirred at room temperature for 30 min. After neutralization with triethylamine (pH 7-8), the reaction mixture was concentrated, and then diluted with EtOAc. The organic solution was washed successively with saturated aq. sodium hydrogen carbonate and brine, and dried. Removal of the solvent left a residue, which was chromato- graphed on a silica gel column (60g) with EtOAc-toluene (1 :8) to give compound 13(1.87 g, 98) as a syrup (Found: C, 66.8; H, 7.2.C28H3608 requires C, 67.2; H, 7.25); Calk6 -53 (c 1.1, CHCl,); v,,,(neat)/cm-' 1720 (ester) and 1610 (para-substituted phenyl); 6,(90 MHz; CDCl,) 1.33-1.71 (4 H, m, 2 methylenes of THP), 1.73-2.42 (4 H, m, methylene of THP and 6-H2), 3.30- 4.08 (5 H, m, 1-, 2- and 5-H, and OCH, of THP), 3.41,3.54 and 3.77 (each 3 H, 3 s, 3 x OMe), 4.40 (1 H, dd, J2.3 4.3, J3,43.3,3-H), 4.50-4.66 (3 H, m, ASH, and -0CHO- of THP), 5.36 (1 H, dd, J4.59.8,4-H) and 6.67-8.13 (9 H, m, ArH). 1D-( 1,2,5/3,4)-5-0-(p-Methoxybenzyl)-1,2-di-O-methyl-3-0-(tetrahydropyran-2-yl)cyciohexanepentaoi14.-To a stirred solution of compound 13 (1.61 g, 3.22 mmol) in methanol (25 cm3) at room temperature was added 1 mol dm-3 sodium methoxide in methanol (6.44 cm3, 6.44 mmol).After being stirred at 50 "C for 9 h, the reaction mixture was neutralized with resin (pH 7; IR 120B, H+-form) and the insoluble materials were removed by filtration. The filtrate was concentrated to give a residue, which was chromatographed on a silica gel column (40 g) with EtOAc-toluene (1 :3) as eluent, to give compound 14 (1.13 g, 89) as a syrup (Found: C, 63.7; H, 7.85. C2lH~207 requires C, 63.6; H, 8.1); a;' -20 (c 1.9, CHCl,); J. CHEM. SOC. PERKIN TRANS. I 1992 v,,,(neat)/cm-' 3450 (OH) and 1610 (para-substituted phenyl); 6,(270 MHz; CDCl,) 1.48-1.58 (4 H, m, 2 methylenes of THP), 1.631.82 (3 H, m, methylene of THP and 6-H), 2.22 (1 H, m, 6- H'), 3.40 and 3.48 (each 3 H, 2 s, 2 x OMe), 3.51-3.84 (5 H, m, 1-, 2-, 5-H, and OCH, of THP), 3.80 (3 H, s, OMe), 4.18-4.66 (4 H, m, ArCH, and 3- and 4-H), 4.82 (1 H, m, -0CHO- of THP) and 6.85-7.34 (4 H, m, ArH).2~-(2/3,4,6)-6-O-(p-Methoxybenzyf)-3,4-di-O-rnethyf-2-0-(tetrahydropyran-2-y1)-2,3,4,6-tetrahydroxycyclohexanone 15.-To a stirred suspension of PCC (3.07 g, 14.3 mmol) and molecular sieves 4 A (powder; 3.0 g) in dichloromethane (30 cm3) at 0 "C was added a solution of compound 14 (1.13 g, 2.85 mmol) in dichloromethane (10 cm3) dropwise. After being stirred at room temperature for 6 h, the reaction mixture was partially concentrated and chromatographed on a silica gel column (60 g), with diethyl ether as eluent, to give the ketone 15 (973 mg, 87) as a syrup (Found C, 63.9; H, 7.4.C21H30O7 requires C, 63.9; H, 7.7); Calk6 +68 (c 0.58, CHCl,);v,-(neat)/cm-' 1740 (M)and 1610 (para-substituted phenyl); 6,(270 MHz; CDCI,) 1.45-1.82 (6 H, m, 3 methylenes of THP), 2.04-2.37 (2 H, m, 5-H2), 3.38-4.78 (9 H, m, 2-, 3-, 4-, 6-H, ArCH,, and OCH, and -0CHO- of THP), 3.43,3.47 and 3.80 (each 3 H, 3 s, 3 x OMe) and 6.82-7.38 (4 H, m, ArH). (2E)-(1R,3S,4S,5S)-2-Cyanomethyfene-4,5-dimethoxy-1 -(p- methoxybenzyfoxy)- 3 -(tetrahydropyran-2-yZoxy)cycZohexane 16E and its 2Z-Isomer 16Z.-To a stirred solution of ketone 15 (992 mg, 2.5 1 mmol) and diethyl cyanomethylphosphonate (2.03 cm', 12.5 mmol) in toluene (15 cm') under Ar was added potassium tert-butoxide (704 mg, 6.28 mmol), and the resulting mixture was stirred at room temperature for 6 h.The reaction mixture was then diluted with E~OAC, washed with brine, and dried. Removal of the solvent left a residue, which was chromatographed on a silica gel column (25 g) with EtOAc- toluene (1 : 12) as eluent to give, first, compound 162 (388 mg, give compound 17 (36 mg, 97) as a syrup (Found: M', 333.1560. C18H2,N05 requires M, 333.1576); Cali6 -12 (c 1.1, CHCl,); v,,,(neat)/cm-' 3380 (OH), 2180 (CN), and 1630 (para-substituted phenyl); SH(270 MHz; CDC1,) 1.46 (1 H, m, 6-H), 1.65 (1 H, br s, OH), 2.64 (1 H, ddd, J1.6' 2.6, J5,6,2.9,J6,6, 16.1,6-H'), 2.99 (1 H, dd, J3,410.3,J4,52.9,4-H), 3.44,3.48 and 3.80 (each 3 H, 3 s, 3 x OMe), 3.93 (1 H, ddd, J5,62.9,5-H), 4.36 and 4.50 (each 1 H, 2 d, J 11.4, ArCH,), 4.67 (1 H, dd, J1.6 3.7, 1-H),4.87 (1 H, dd, J3,viny,2.2,3-H), 5.84 (1 H, d, vinyl) and 6.84- 7.29 (4 H, m, ArH).(2E)-(1 R,3S,4S,5S)-3- Acetoxy-2-cyanomethyfene-4,5-dimeth-oxy- 1 -@-methoxybenzyfoxy)cycfohexane 18.-A mixture of compound 17 (8.9 mg, 0.027 mmol) and acetic anhydride (0.5 cm3) in pyridine (0.5 cm3)was stirred at room temperature for 2 h. After addition of methanol, the mixture was concentrated to give a residue, which was chromatographed on a silica gel column (1 g) with EtOAc-toluene (1 :3) as eluent to give acetate 18(10.8 mg, 100) as a crystalline residue, m.p. 70-73 "C(from EtOH) (Found: C, 63.6; H, 6.65; N, 3.85. C20H,5N06 requires C, 64.0; H, 6.7; N, 3.7); a;2 -2 (C 0.54, CHCl,); v,,,(KBr)/cm-' 2150 (CN), 1780 (M)and 1650 (para- substituted phenyl); SH(270 MHz; CDCl,) 1.63 (1 H, ddd, J1.6 3.7, J5.6 3.7, J6.6, 15.0, 6-H), 2.15 (3 H, S, OAC), 2.46 (1 H, ddd, J1.60 4.8,J5,6'4.8,6-H'), 3.28 (I H,dd, J3.4 8.8, J4.5 2.9,4-H), 3.42, 3.47 and 3.80 (each 3 H, 3 s, 3 x OMe), 3.82 (1 H, m, 5-H), 4.35 (1 H, d, J 11.4, ArCHH), 4.56 (1 H, m, 1-H),4.60 (1 H, d, J 11.4, ArCHH), 5.47 (1 H, d, JJ,vinyl1.8, vinyl), 5.96 (1 H, dd, 3-H) and 6.88-7.32 (4 H, m, ArH).(2E)-(1 R,3S,4S,5S)-3- Acetoxy-2-cyanomethylene-1 -hydroxy- 4,5-dimethoxycycZohexane19.-To a stirred mixture of com- pound 18(164 mg, 0.438 mmol) in dichloromethane (12 cm3)- water (1.5 cm3)was added DDQ (149 mg, 0.657 mmol), and the mixture was stirred at room temperature for 18 h.The reaction mixture was diluted with CH,Cl,, washed with water, and 37) as a syrup (Found: C, 66.0; H, 7.4; N, 3.5. CZ~H~~NO~dried. Removal of the solvent left a residue, which was requires C, 66.2; H, 7.5; N, 3.35); a;' -36 (c 0.25, CHCl,); v,,,(neat)/cm-' 2210 (CN) and 1610 (para-substituted phenyl); 6,(270 MHz; CDC13) 1.45-1.63 (5 H, m,2 methylenes of THP and 6-H), 1.66-1.80 (2 H, m, methylene of THP), 2.33 (1 H, ddd, J1.6, 5.2, J5,6* 4.8, J6.6, 11.4, 6-H'), 3.41 and 3.52 (each 3 H, 2 S, 2 x OMe), 3.53 (1 H, m, 4-H), 3.54 (1 H, m, OCH of THP), 3.68 (1 H, ddd, J4,53.3, J5,612.1,5-H), 3.81 (3 H, s, OMe), 3.91 (1 H, m, OCH ofTHP),4.10(1 H,ddd,J1,6 11.9, Jl,viny,2.4, l-H),4.40 1 H, m, -0CHO- of THP), 4.46 and 4.59 (each 1 H, 2 d, J 11.7, ArCH,),5.11(1H,d,J3,43.4,3-H),5.82(1H,d,vinyl)and6.8~ 7.25 (4 H, m, ArH).The second fraction gave regioisomer 16E (45 1 mg, 43) as a syrup (Found: C, 66.0; H, 7.45; N, 3.3); a;, -28 (c 0.92, CHCI,); v,,(neat)/cm-' 2180 (CN) and 1630 (para-substituted phenyl); 6,(270 MHz; CDC1,) 1.44-1.64 (5 H, m, 2 methylenes of THP and 6-H), 1.73-1.84 (2 H, m, methylene of THP), 2.50 (1 H, ddd, J1.6, 3.4, J5.6, 3.4,16,6, 15.6,6-H'), 3.13 (1 H, dd, J3.4 9.3, J4,53.4,4-H), 3.41 (3 H, s, OMe), 3.44 (1 H, m, OCH of THP), 3.48 (3 H, s,OMe), 3.74(1 H,m, 5-H), 3.80(3 H, s, OMe), 3.83 (1 H, m, OCH of THP), 4.33 and 4.52 (each 1 H, 2 d, J 11.7, ArCH,), 4.64 (1 H, dd, J1.6 3.4, 1-H),4.82 (1 H, m,-OCHO-of THP), 4.83 (1 H, m, 3-H), 5.88 (1 H, d, J3,viny,1.5, vinyl) and 6.83-7.30 (4 H, m, ArH).chromatographed on a silica gel column (5 g) with EtOAc- toluene (1 :6) as eluent to afford compound 19 (80.2 mg, 72) as a syrup (Found: C, 56.2; H, 6.6; N, 5.4. C12H17N05 requires C, 56.5; H, 6.7; N, 5.5); ab8 -9 (c 0.35, CHCl,); v,,,(neat)/cm-' 3400 (OH), 2160 (CN) and 1780 (C=O);6,(270 MHz; CJXl,) 1.60 (1 H, ddd, J1.6 2.9, J5,6 2.9, J6.6' 15.1, 6-H), 2.19 (3 H, S, OAC), 2.48 (1 H, ddd, J1,6*3.4, J5,6*3.4,6-H'), 3.17 (1 H, dd, J3.4 9.8,J4,52.7,4-H), 3.46 and 3.59 (each 3 H, 2 s, 2 x OMe), 4.01 (1 H, m, 5-H),4.23 (1 H, d, J1,OH 9.8, OH), 4.92 (1 H, m, 1-H), 5.32 (1 H, d, J3,viny, 9.8,3-H); amp;(67 2.0, vinyl) and 6.15 (1 H, dd, J3,4 MHz; CDClj) 20.7, 32.9, 58.7, 59.8, 69.2, 70.2, 77.4, 84.7, 93.7, 115.1, 161.5 and 169.0 (2E)-(1R,3S,4S,SS)-2-CyanomethyZene-1 -hydroxy-4,5-dimeth- oxy-3-(tetrahydropyran-2-yfoxy)cyclohexane2O.-To a stirred mixture of compound 16E (5.5 mg, 0.013 mmol) in dichloro- methane (0.9 cm3)-water (0.05 cm3)was added DDQ (6.0 mg, 0.026 mmol), and the mixture was stirred at room temperature for 6 h.The reaction mixture was diluted with EtOAc and washed successively with saturated aq. sodium thiosulfate, saturated aq. sodium hydrogen carbonate, and brine, and dried. Removal of the solvent left a residue, which was chromato- graphed on a silica gel column (0.5 g) with EtOAc-toluene (1 :6) as eluent to afford compound 20 (2.9 mg, 74) as a syrup (22)-(1R,3S,4R,5S)-2-Cyanomethylene-3-hydroxy-4,5-dimeth-(Found: M+, 297.1570.Cl,H17N05 requires M, 297.1576); oxy-1-(p-methoxybenzyfoxy)cycfohexane 17.-A mixture of compound 16E (46 mg, 0.11 mmol) and pyridinium toluene-p- sulfonate (PPTS) (3 mg) in ethanol (1 cm3) was stirred at 50 "C for 4 h. After addition of triethylamine, the mixture was concentrated to give a residue, which was chromatographed on a silica gel column (1 g) with EtOAc-toluene (1 :3) as eluent to ab8 -22 (c 1.2, CHCI,); v,,(neat)/cm-' 3480 (OH) and 2160 (CN); 6,(270 MHz; CDCl,) 1.49-1.65 (5 H, m, 2 methylenes of THP and 6-H), 1.79-1.85 (2 H, m, methylene of THP), 2.47 (1 H, ddd, J1.6P3.3, J5.6~3.3, J6.6, I5.4,6-H'), 3.08 (1 H, dd, J3.4 9.9, J4.5 2.9,4-H),3.49(3H,s,OMe),3.52(1H,m,OCH ofTHP),3.56(3 H, s, OMe), 3.81 (1 H, m, OCH of THP),3.95 (1 H, m, 5-H), 4.19 (1 H, d, J1,OH 9.9, OH), 4.86 (1 H, dd, J3,"inyl 2.2, 3-H), 4.91 (1 H, m, -0CHO- of THP), 4.95 (1 H, m, 1-H) and 5.78 (1 H, d, vinyl).(2 E)-( 1 R,3 S,4 R,5 S)-2- Cyanome thy lene- 1,3 -dihydr oxy -4,5-di-methoxycyclohexane 21.-A mixture of compound 20 (18 mg, 0.061 mmol) and PPTS (2 mg) in ethanol (1 cm3)was stirred at 55 "C for 6 h. After addition of triethylamine, the mixture was concentrated to give a residue, which was chromatographed on a silica gel column (1 g) with EtOAc-toluene (1 :4) as eluent to give diol 21 (8.1 mg, 62) as a syrup (Found: M+, 213.1012. CI8H2,NO5 requires M, 213.1001); a'," + 13 (c 0.55, CHCl,); v,,,(neat)/cm-' 3380 (OH) and 2180 (CN); 6,(270 MHz; CDCI3) 1.55 (1 H, ddd, J1.6 2.9, J5.6 2.9,J6,6, 15.6, 6-H), 2.51 (1 H, ddd, J1.6' 2.9, J5.6, 2.9, 6-H'), 2.83 (1 H, d, J3,oH 2.0, 3-OH), 2.99 (1 H, dd, J3,49.8, J4,52.9,4-H), 3.52 and 3.57 (each 3 H, 3 s, 2 x OMe), 4.03 (1 H, m, 5-H), 4.08 (1 H, d, J1,OH 9.8, 1-OH), 4.84 (1 H, ddd, J3,vinyl2.0,3-H), 4.91 (1 H, ddd, 1-H) and 5.67 (1 H, d, vinyl).(2S,3 R,4S,6R)-2- Hydroxy-3,4-dimethoxy-7-oxabicyclo-4.3.0non-1(9)-en-8-one22.-A mixture of the diol 21 (19.5 mg, 0.092 mmol) in THF (1.5 cm3)-aq. 1 mol dm-3 HCl(0.5 em3) was heated at 55 "C for 5 h. The mixture was then poured into ice-water and then extracted three times with EtOAc. The combined extracts were washed successively with saturated aq. sodium hydrogen carbonate and brine, and dried.Removal of the solvent left a residue, which was chromatographed on a silica gel column (1 g) with acetone-toluene (1 :5) as eluent to afford lactone 22 (4.6 mg, 24) as a crystalline residue, m.p. 138-139 "C (from benzene) (lit.,2 138-140 "C) (Found: C, 56.1; H, 6.6. Calc. for ClOH1405: C, 56.1; H, 6.6); Calk2 -168 (c 0.1, CHCl,); v,,,(KBr)/cm-' 3410 (OH) and 1750 (GO);SH(27O MHz; CDC13) 1.74 (1 H, ddd, J4.5 1 1.2, J5.6 1 1.2, J5.5' 1 1.2,5-H), 2.16 (1 H, d, J2,0H2.9, OH), 2.62 (1 H, m, 5-H'), 3.44 and 3.49 (each3H,2s,2 x OMe),3.77-3.87(2H,m,3-and4-H),4.91(1 H, dd, J2.3 2.9, 2-H), 5.09 (1 H, ddd, J5,,66.3, J6,91.5, 6-H) and 5.98 (1 H, d, 9-H). (2E)-( 1 R,3S,4R,5S)-2-Cyanomethylene-3-hydroxy-4,5-di-methoxy- 1 -(p-rnethoxybenzy1oxy)cyclohexane23.-A mixture of compound 162 (1 15 mg, 0.275 mmol) and PPTS (10 mg) in ethanol (2 cm3) was stirred at 50 "C for 25 h.After addition of triethylamine, the mixture was concentrated to give a residue, which was chromatographed on a silica gel column (1 g) with EtOAc-toluene (1:5) as eluent to give compound 23 (66 mg, 71) as a syrup (Found: C, 64.6; H, 6.9; N, 4.1. C18H2,N05 requires C, 64.85; H, 6.95; N, 4.2); -13 (c 0.78, CHCl,); v,,,(neat)/cm-' 3440 (OH), 2220 (CN) and 1610 (para- substituted phenyl); 6,(90 MHz; CDCl,) 1.84 (1 H, m, 6-H), 2.31 (1 H, m, 6-H'), 3.41 and 3.52 (each 3 H, 2 s, 2 x OMe), 3.61-3.88 (2 H, m,4- and 5-H), 3.82 (3 H, s, OMe), 4.30 (1 H, ddd, J1.6 11.0, J1.6, 5.1, Jl,vinyl2.1, 1-H), 4.45 and 4.61 (each 1 H, 2 d, J 10.4, ArCH,), 5.08 (1 H, d, J3,43.6,3-H), 5.72 (1 H, d, vinyl) and 6.78- 7.32 (4 H, m, ArH).(22)-( 1 R,3S74R,5S)-2-Cyanornethylene-l,3-dihydroxy-4,5-di-methoxycyclohexane 24.-To a stirred mixture of compound 23 (1 32.5 mg, 0.397 mmol) in dichloromethane (9 cm3)-water (1 cm3) was added DDQ (90.2 mg, 0.397 mmol), and the mixture was stirred at room temperature for 32 h. The reaction mixture was diluted with EtOAc and washed successively with saturated aq. sodium thiosulfate, saturated aq. sodium hydrogen carbon- ate, and brine, and dried. Removal of the solvent left a residue, which was chromatographed on a silica gel column (3 g) with acetone-toluene (1 :3) as eluent to afford diol24 (68 mg, 80) as a syrup (Found: C, 56.05; H, 6.9; N, 6.5.C ,H sNO4 requires C, 56.3; H, 7.1; N, 6.6); ag -55 (c 1.1, CHCl,); v,,,(neat)/cm-' J. CHEM. SOC. PERKIN TRANS. I 1992 3410 (OH) and 2220 (CN); 6,(90 MHz; CDCl,) 1.82-2.58 (2 H, m, 6-H2), 3.46 and 3.53 (each 3 H, 2 s, 2 x OMe), 3.63 (1 H, dd, J3.4 5.2, J4.5 2.7,4-H), 3.86 (1 H, ddd, J5.6 4.5, J5,6,9.2,5-H), 4.54 (1 H, m, 1-H), 5.08 (1 H,d, 3-H)and 5.69(1 H,d, Jl,vinyl2.0, vinyl). (2R,4S)-2-Hydroxy-4-methoxy-7-o.xabicyclo4.3.0Jnona-1(9),5-dien-8-one 25.-A mixture of the diol 24 (25 mg, 0.12 mmol) in THF (1.5 cm3)-aq. 1 mol dm-3 HCl (0.5 cm3) was heated at 55 "C for 10 h. The mixture was poured into ice-water and then extracted three times with EtOAc. The combined extracts were washed successively with saturated aq.sodium hydrogen carbonate and brine, and dried. Removal of the solvent left a residue, which was chromatographed on a silica gel column (1 g) with acetone-toluene (1:G as eluent to afford lactone 25 (3.4 mg, 16) as a syrup (Found: M+, 182.0586. CgH1004 requires M,182.0579); a"," -117 (c 0.27, CHCl,); v,,,(neat)/cm-' 3400 (OH) and 1770 (C=O);6,(270 MHz; CDCl3) 2.1 2 (1 H, ddd, J2.3 7.8, J3.4 6.8, J3,3*13.2,3-H), 2.32 (1 H, ddd, J2.3, 3.9, J3,,43.9, 3-H'), 3.46 (3 H, s, OMe), 4.26 (1 H, ddd, J4,5 2.0,5-H) and 3.9,4-H), 4.74 (1 H, m, 2-H), 6.03 (1 H, dd, J5,9 6.12 (1 H, m, 9-H). (2E)-( 1 R,3S,4S,5S)-3- Acetoxy-2-cyanomethylene-4,5-dimeth-oxycyclohexyl 2',3',4',6'-Tetra-O-acetyl-P-~-glucopyranoside (Simmondsin Penta-0-acetate) 27.-To a stirred mixture of compound 19 (1 1.8 mg, 0.0462 mmol), 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl trichloroacetimidate l4 26 (3 1.9 mg, 0.0647 mmol), and molecular sieves 4 A (20 mg) in 1,2-dichloroethane (0.5 cm3) at 0deg;C under Ar was added BF3*OEt2 (0.006cm3, 0.023 mmol).After being stirred at 0 "C for 20 min, the reaction mixture was quenched by addition of saturated aq. sodium hydrogen carbonate. The product was extracted with dichloromethane, washed with brine, and dried. Removal of the solvent afforded a residue, which was chromatographed on a silica gel column (1 g) with acetone-hexane (1 :4) as eluent to give the glycoside 27 (7.2 mg, 27) as a crystalline residue, m.p. 164-165 "C from ethyl acetate-hexane (1 :l) (lit.,l 165-166 "C) (Found: C, 53.3; H, 5.9; N, 2.4.Calc. for C26H35N014: C, 53.3; H, 6.0; N, 2.4); aJk2 -24 (c 0.39, CHCl,); v,,,,,(KBr)/cm-' 2220 (CN) and 1760 (M);MHz;6,(270 CDCl3) 1.62 (1 H, ddd, J1.6, 4.4, J5.6, 4.4, J6a,6b 15.1, 6-Ha), 2-00, 2.02,2.04,2.08 and 2.14 (each 3 H, 5 s, 5 x OAc), 2.44 (1 H, ddd, J1,6b 4.4, J5,6b 4.4, 6-Hb), 3.20 (1 H, dd, J3.4 9.3, J4,5 3.4, 4-H), 3.35 and 3.42 (each 3 H, 2 s, 2 x OMe), 3.66 (1 H, ddd, J4t,5r9.8, J5,,6ta 2.4, J5,,61b 3.9, 5'-H), 3.81 (1 H, m, 5-H), 4.03 (I H, dd, J6ca,6'b 12.2, 6'-Hb), 4.25 (1 H, dd, 6'-Ha), 4.70 (1 H, d, J1,,2, 7.8, 1'-H), 4.79 (1 H, dd, 1-H), 5.04-5.23 (3 H, m, 2'-, 3'- and 4'-H), 5.43 (1 H, d, J3,viny,2.0, vinyl) and 6.03 (1 H, dd, 3-H); amp;(67 MHz; CDCI,) 20.6 (3 C), 20.7 (2 C), 30.7, 56.7, 58.4, 61.3, 68.2, 70.8, 71.0, 72.1, 72.9, 74.3, 75.8, 82.7, 95.9, 101.0, 115.6, 159.5, 168.4, 168.9, 169.3, 170.3 and 170.7.(22)-(1R,3S,4R,5S)-2-(Cyanomethylene)-3-hydroxy-4,5-di-methoxycyclohexyl P-D-Glucopyranoside (Simmondsin) 1.-To a stirred solution of simmondsin penta-0-acetate 27 (4.5 mg, 0.0077 mmol) in methanol (0.5 cm3) at 0 "C was added 1 mol dm-3 sodium methoxide in methanol (0.0077 cm3, 0.0077 mmol), and the resulting solution was stirred at 0deg;C for 2 h. The reaction mixture was neutralized by addition of resin (ph 7;IR-120B, H+-form), and the resin was removed by filtration. Removal of the solvent left a syrup, which was chromatographed on a silica gel column (1 g) with methanol-EtOAc (1:lO) as eluent to provide compound 1 (3.2 mg, quantitatively) as a crystalline residue, m.p.94-95 "C from methanol-acetone (1 :l) (natural product 98-99 "C; lit.,' 95-100 "C) (Found: C, 49.9; H, 6.6; N, 3.5. Calc. for C,,H,,N09~0.5H,0: C, 50.0 H, 6.8; N, 3.6); aamp;4 -69 (c0.57, MeOH) natural product, a;' -73 (c 0.86, MeOH); vmax(KBr)/cm-' 3410 (OH) and 2220 (CN); J. CHEM. SOC. PERKIN TRANS. I 1992 6,(270 MHz; C2H4MeOH) 1.69 (1 H, ddd, J1,6a 3.9,3.9, J5,6a J6,,6,15.1,6-Ha),2.51(1 H,ddd,J1,6b3.9,J5,6b3.9,6-Hb),3.14(1 H, dd, J3,49.3, J4,52.9,4-H), 3.20-3.39 (4 H, m, 2'-, 3'-, 4'- and 5'-H), 3.45 and 3.47 (each 3 H, 2 s, 2 x OMe), 3.65 (1 H, dd, J5,,6,a 6.1, Jbza,6,b 12.2, 6'-Ha), 3.83 (1 H, dd, J5,,6*b 2.0, 6'-Hb), 3.91 (1 H, m, 5-H), 4.38 (1 H, d, Jl,,2,7.3, 1'-H), 4.73 (1 H, dd, J3,viny,2.0,3-H), 4.88 (1 H, m, l-H) and 5.70 (1 H, d, vinyl); S,(67 MHz; C2H4MeOH) 32.0, 58.1, 58.5, 62.7, 70.2, 71.3, 74.7, 76.4, 76.7, 78.1,86.3,95.2, 104.0, 117.5 and 166.4.Acknowledgements We express our sincere thanks to Dr. Carl A. Elliger (US Department of Agriculture, California, USA) for the generous gift of natural simmondsin. Financial support from Yokohama Rubber Co. Ltd. (Tokyo, Japan) is gratefully acknowledged. References 1 C. A. Elliger, A. C. Waiss, Jr. and R. E. Lundin, J. Chem. SOC., Perkin Trans. I, 1973,2209. 2 C. A. Elliger, A. C. Waiss, Jr. and R. E. Lundin, J. Org. 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Cook, R. Khan and J. M. Brown, J. Carhohydr. Chem., 1984,3, 343. Paper 1 /06507F Received 30th December 199 1 Accepted 22nd January 1992