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Synthesis of (±)-trans-cyclohexa-3,5-diene-1,2-diolderivatives from myo-inositol |
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Journal of the Chemical Society, Perkin Transactions 1,
Volume 1,
Issue 11,
1997,
Page 1755-1758
Hari Babu Mereyala,
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J. Chem. Soc. Perkin Trans. 1 1997 1755 Synthesis of (±)-trans-cyclohexa-3,5-diene-1,2-diol derivatives from myo-inositol Hari Babu Mereyala * and Madhavi Pannala Organic Division III Indian Institute of Chemical Technology Hyderabad 500007 India myo-Inositol 8 has been converted to biscyclohexylidene ketals 9–11. The inseparable mixture of isomers 9 and 11 has been utilised as such to obtain the synthetically useful (±)-trans-cyclohexa-3,5-diene-1,2-diol derivative 24 via the intermediates 14 and 15. The trans-diol derivative 24 has also been converted to synthetically useful epoxide derivative 25 in high yield and selectivity. Introduction Metabolism of aromatic compounds by bacteria was studied at the beginning of this century by Stormer.1 Oxidation of benzene to catechol was subsequently reported as early as 1913.2 cis-Cyclohexadiene-1,2-diol 1 was isolated for the first time by Gibson in 1968 from the metabolism of benzene by certain soil bacteria 3–5 and likewise was chiral cis-diol 2 from toluene.6,7 Subsequently several alkylbenzenes halogenobenzenes and other aromatics were oxidised to chiral cis-diols 3–5.8–10 Extensive use of cis-diol 1 as a building block in enantiospecific syntheses is best known from the work of Ley and his group.11,12 On the other hand the utility of bacteria to produce the analogous enantiomerically pure trans-cyclohexa-3,5-diene-1,2- diols (1)- and (2)-6 from benzene has not been very good.Metabolism of benzene oxide with liver microsomes in vivo is known to result in the formation of isomer (1)-6 at an estimated optical purity of 50%.13,14 Enzyme-catalysed hydrolysis of trans-diol diacetate (±)-7 was selected for resolution to obtain isomers (2)-6 and (1)-6 (97% ee) in an overall yield of 15 and 47% respectively.15 The absolute stereochemistry of isomers (2)-6 and (1)-6 was determined by converting them to the known (2)- and (1)-trans-1,2-dihydroxycyclohexane,13,16,17 respectively.Enantiomerically pure isomers (1)-7 and (2)-7 have also been obtained from lipase-effected enantioselective hydrolysis of (±)-4,5-diacetoxycyclohex-1-ene.18 Racemic transcyclohexa- 3,5-diene-1,2-diol diacetate (±)-7 has been prepared synthetically from benzene via successive Birch reduction bromination trans-hydroxylation dehydrobromination and acetylation.19 Diol (±)-6 was synthetically exploited for the synthesis of racemic conduramines,20 conduritols,21 inosamine,22 fortamine,23 aminocyclitol antibiotics of the 2-deoxystreptamine type,24 chiro-inositol 2,3,5-trisphosphate,25 myo-inositol 1,4,5-trisphosphate 26 and fluoroinositol phosphate analogues.27 Results and discussion We felt the need to develop a chemical route to obtain enantiomerically pure trans-cyclohexa-3,5-diene-1,2-diol derivatives from (meso)-myo-inositol 28 in large quantities because of their utility in the total synthesis of natural products (Scheme 1).myo-Inositol 8 was converted to a mixture of bis-cyclohexylidene ketals 9 10 11 in 38 26 and 19% yield respectively by reaction with cyclohexanone in N,N-dimethylformamide (DMF) at 100 8C for 12 h containing toluene-p-sulfonic acid (p-TsOH).29 Alternatively it could be made by reaction of myoinositol 8 with 1-ethoxycyclohexene containing a catalytic amount of p-TsOH in DMF at 100 8C for 2 h.30 From the soobtained bis-ketals 9–11 crystalline 1,4-diol 10 was separated by crystallisation 29 to leave a residue containing diastereoisomeric 1,2-diols 9 and 11 in the ratio 2 1 (by 1H NMR spectroscopy).Reaction of 1,2-diols 9 and 11 with Ph3P (3 mol equiv.) imidazole (3 mol equiv.) and iodine (3 mol equiv.) in toluene at reflux for 6 h gave the cyclohexene bis-cyclohexylidene ketals 12 and 13 (mp 66–68 8C) in 74% yield; 31 formation of the cyclohexene double bond was evident from the appearance of multiplets in the 1H NMR spectrum between d 5.6–6.25 integrating for two protons. Compounds 12 and 13 were allowed to react further at 0–5 8C with a catalytic amount of p-TsOH in CH2Cl2 for 4 h to obtain the cyclohexene diols 14 and 15 in 78% yield as a solid (mp 96–98 8C) due to selective deprotection of the trans-cyclohexylidene ketal.Products 14 and 15 were characterised from the 1H NMR spectrum where cyclohexylidene protons appeared between d 1.2–1.8 integrating for ten protons. From a mixture of compounds 14 and 15 we planned to obtain the trans-cyclohexa-3,5-diene-1,2-diols. Diols 14 and 15 were therefore treated with Ac2O–pyridine to obtain the di-O-acetyl derivatives 16 and 17 in quantitative yield. However attempted selective deprotection of the ciscyclohexylidene protecting group of compounds 16 and 17 by reaction with p-TsOH in CH2Cl2 at 0 8C resulted in the formation of phenolic compounds. Attempts to deprotect the cyclohexylidene ketal in ethylene glycol–p-TsOH and HCl– methanol also met with failure.It was hence decided to protect the alcohols 14 and 15 as their benzyl ethers by reaction with C6H5CH2Br–NaH–DMF at 0 8C to obtain the dibenzyl ether derivatives 18 and 19 in 98% yield. The mixture of compounds 18 and 19 was then subjected to deprotection of the cyclohexylidene ketal in p-TsOH–CH2Cl2–methanol at 0 8C to room temp. for 4 h to obtain the diol derivatives 20 and 21 in 90% yield which were characterised from their 1H NMR spectrum. The mixture of diols 20 and 21 was further treated with 1,19- thiocarbonyldimidazole 32 in toluene at reflux for 1 h to obtain the cyclic thiocarbonate derivatives 22 and 23 in high yield and these were subsequently subjected to syn elimination by being refluxed in trimethyl phosphite for 2 h to obtain trans-(±)- cyclohexa-3,5-diene-1,2-diol bisbenzyl ether 24 as a syrup in X OH OH 1 OH OH X = H 2 X = CH3 3 OH X = Et 5 OH X = CI OH X = Pri (±)–6 OH 4 OAc (+)–6 (±)–7 OAc (–)–6 1756 J.Chem. Soc. Perkin Trans. 1 1997 Scheme 1 Reagents and conditions i cyclohexanone DMF p-TsOH 100 8C 12 h; ii PPh3 I2 imidazole toluene reflux 6 h iii p-TsOH (cat.) CH2Cl2 5 8C 4 h; iv BnBr NaH DMF; v p-TsOH CH2Cl2–MeOH; vi 1,19-thiocarbonyldiimidazole toluene reflux 1 h; vii P(OMe)3 reflux 2 h; viii MCPBA CH2Cl2 NaHCO3 room temp. 4h OH OH HO OH HO OH OH OH O O O O OH O O HO O O O O O HO O OH O O O O O O O O O RO O OR O O OR OR O BnO O OBn O O OBn OBn OH HO OBn BnO OH HO OBn OBn 8 9 10 i 11 O BnO O OBn ii 12 iii 13 15 17 S O O 14 16 19 iv 18 v S 16 17 R = Ac OBn OBn 14 15 R = H 20 OBn OBn 21 vi vii OBn OBn 22 23 O viii 24 25 90% yield.Compound 24 was characterised from the appearance of cyclohexadiene protons (4 H) at d 5.83 as a singlet and the H-5 H-6 protons at d 4.37 as a singlet in the 1H NMR spectrum. The trans-1,2-diol derivative 24 on reaction with mchloroperbenzoic acid (MCPBA) in CH2Cl2 at room temperature for 4 h gave the epoxide 25 due to stereoselective epoxida- J. Chem. Soc. Perkin Trans. 1 1997 1757 tion of the double bond anti to the adjacent benzyl ether. Compound 25 was fully characterised from the 1H NMR spectrum. Experimental 1H NMR spectra were measured with a Varian Gemini (200 MHz) spectrometer with tetramethylsilane as internal standard for solutions in deuteriochloroform; coupling constants (J) are given in Hz. IR spectra were taken with a Perkin-Elmer 283 spectrometer.UV spectra were measured with a Shimadzu 160- A spectrometer. Organic solutions were dried over anhydrous Na2SO4 and concentrated below 40 8C on rotary evaporator. (±)-(3·,4‚,5·,6·)-3,4 5,6-Bis(cyclohexylidenedioxy)cyclohexene 12 and (±)-(3·,4·,5·,6‚)-3,4 5,6-bis(cyclohexylidenedioxy) cyclohexene 13 To a solution of diols 9 and 11 (5.0 g 4.7 mmol) in toluene (40 cm3) were added triphenylphosphine (11.55 g 44.1 mmol) and imidazole (2.29 g 44.1 mmol) and the mixture was heated to 60 8C. Iodine (11.2 g 44.1 mmol) was added portionwise during 15 min and the reaction mixture was refluxed for 4 h when TLC (hexane–ethyl acetate 3 1) indicated completion of the reaction from the appearance of a faster moving spot; it was then cooled to room temperature a further batch of iodine (14.94 g 58.8 mmol) was added followed by aq.NaOH (1 M; 50 cm3) and the mixture was stirred for 30 min at room temperature. The toluene phase was washed successively with water 5% aq. sodium thiosulfate saturated aq. NaHCO3 and water dried (Na2SO4) and concentrated to obtain a solid residue which was filtered on a bed of silica gel (eluted with 25% ethyl acetate in hexane) to obtain the title compounds (3.33 g 74%) which solidified on storage mp 66–68 8C (Found C 70.45; H 8.46. C18H26O4 requires C 70.56; H 8.55%); dH 1.3–1.8 (20 H m cyclohexylidene) 3.35–4.8 (4 H m 3- 4- 5- and 6-H) and 5.6– 6.25 (2 H m 1- and 2-H). (±)-(1·,2‚,5·,6·)-5,6-(Cyclohexylidenedioxy)cyclohex-3-ene- 1,2-diol 14 and (±)-(1‚,2·,5·,6·)-5,6-(cyclohexylidenedioxy)- cyclohex-3-ene-1,2-diol 15 To a solution of compounds 12 and 13 (3.30 g 10.8 mmol) in CH2Cl2 (10 cm3) was added catalytic amount of p-TsOH (30 mg) and the mixture was stirred at 0–5 8C for 4 h.After completion of the reaction the mixture was neutralised with triethylamine. The reaction mixture was concentrated and filtered on a bed of silica gel (eluted with 50% ethyl acetate in hexane) to obtain the title compounds 14 and 15 (1.91 g 78%) as an inseparable mixture of solids mp 96–98 8C (Found C 63.65; H 7.95. C12H18O4 requires C 63.70; H 8.02%); nmax(CHCl3) 3500 cm21 (OH); dH 1.2–1.8 (10 H m cyclohexylidene) 3.4–4.7 (4 H m 1- 2- 5- and 6-H) and 5.5–6.0 (2 H m 3- and 4-H). (±)-(3·,4‚,5·,6·)-3,4-Bis(benzyloxy)-5,6-(cyclohexylidenedioxy) cyclohexene 18 and (±)-(3‚,4·,5·,6·)-3,4-bis(benzyloxy)- 5,6-(cyclohexylidenedioxy)cyclohexene 19 To hexane-washed NaH (0.35 g 14.4 mmol) in DMF (10 cm3) was added a solution of compounds 14 and 15 (1.3 g 5.75 mmol) in DMF (5 cm3) at 0 8C.The reaction mixture was stirred for 15 min at 0 8C and benzyl bromide (2.24 g 14.4 mmol) was added dropwise. The reaction mixture was stirred for 30 min at room temperature. After completion of the reaction the mixture was quenched with methanol followed by ice– water and extracted into CH2Cl2. The organic phase was washed with water dried (Na2SO4) and concentrated to obtain title compounds 18 and 19 (2.28 g 98%) as a syrup (Found C 76.39; H 7.84. C26H30O4 requires C 76.82; H 7.44%); dH 1.3– 1.7 (10 H m cyclohexylidene) 3.5–4.6 (4 H m 3- 4- 5- and 6-H) 4.6–4.85 (4 H m C6H5CH2 × 2) 5.5–5.9 (2 H m 1- and 2-H) and 7.25–7.45 (10 H m ArH).(±)-(1·,2·,5·,6‚)-5,6-Bis(benzyloxy)cyclohex-3-ene-1,2-diol 20 and (±)-(1·,2·,5‚,6·)-5,6-bis(benzyloxy)cyclohex-3-ene-1,2-diol 21 To a solution of compounds 18 and 19 (2.2 g 5.4 mmol) in CH2Cl2–CH3OH (60 and 10 cm3) was added a catalytic amount of p-TsOH (20 mg) and the mixture was stirred for 3 h at 0 8C before being warmed to room temperature and stirred for another 1 h. The reaction mixture was neutralised with triethylamine and concentrated to obtain a residue which was filtered on a bed of silica gel (eluted with 50% ethyl acetate in hexane) to obtain the title compounds (1.65 g 90%) as a syrup (Found C 73.06; H 7.26. C20H24O4 requires C 73.14; H 7.37%); dH 2.5–2.8 (2 H br s OH) 3.55–4.3 (4 H m 1- 2- 5- and 6-H) 4.45–4.95 (4 H m C6H5CH2 × 2) 5.7–5.9 (2 H m 3- and 4-H) and 7.2–7.35 (10 H m ArH).(±)-(3a·,6·,7‚,7a·)-6,7-Bis(benzyloxy)-3a,6,7,7a-tetrahydrobenzo[ d][1,3]dioxole-2-thione 22 and (±)-(3a·,6‚,7·,7a·)-6,7- bis(benzyloxy)-3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxole-2- thione 23 To a solution of compounds 20 and 21 (1.6 g 4.91 mmol) in dry toluene (10 cm3) was added 1,19-thiocarbonyldiimidazole (1.31 g 7.36 mmol) and the mixture was refluxed under nitrogen for 1 h. After completion of the reaction the mixture was diluted with toluene (20 cm3) and then concentrated to obtain a residue which was filtered on a bed of silica gel (eluted with 25% ethyl acetate in hexane) to obtain the title compounds (1.71 g 95%) as a syrup (Found C 67.99; H 5.86. C21H20O4S requires C 68.47; H 5.47%); dH 3.7–4.2 (2 H m 6- and 7-H) 4.6–5.3 (6 H m 3a- and 7a-H C6H5CH2 × 2) 5.8–6.2 (2 H m 4- and 5-H) and 7.2–7.35 (10 H m ArH).(±)-trans-5,6-Bis(benzyloxy)cyclohexa-1,3-diene 24 Thiocarbonate derivatives 22 and 23 (1.65 g 4.48 mmol) were refluxed for 2 h in trimethyl phosphite (0.94 g 6.72 mmol) under nitrogen. After completion of the reaction the mixture was made alkaline by the addition of aq. NaOH and was extracted into CH2Cl2. The organic phase was washed with water (50 cm3 × 3) dried (Na2SO4) and concentrated to obtain the title compound (1.17 g 90%) as a syrup (Found C 82.03; H 6.81. C20H20O2 requires C 82.15; H 6.89%); M1 292; lmax(Me- OH) 259 nm; dH 4.37 (2 H s 5- and 6-H) 4.55 (4 H s C6H5CH2 × 2) 5.83 (4 H s 1- 2- 3- and 4-H) and 7.2–7.35 (10 H m ArH). (±)-(3‚,4·,5‚,6‚)-3,4-Bis(benzyloxy)-5,6-epoxycyclohexene 25 To a solution of compound 24 (1.0 g 3.42 mmol) in CH2Cl2 (200 cm3) were added MCPBA (0.59 g 3.42 mmol) and NaHCO3 (0.28 g 3.42 mmol) and the mixture was stirred at room temperature for 4 h.After completion of the reaction the mixture was diluted with CH2Cl2 (50 cm3) and washed successively with saturated aq. NaHCO3 and water. The organic phase was dried (Na2SO4) and concentrated to obtain the title compound (0.97 g 92%) as a syrup (Found C 77.83; H 6.47. C20H20O3 requires C 77.90; H 6.54%); dH 3.2–3.5 (2 H m 5- and 6-H) 3.84 (1 H d J3,4 7.7 3-H) 4.19 (1 H d J3,4 7.7 4-H) 4.65–4.95 (4 H m C6H5CH2 × 2) 5.92 (2 H AB-type doublet J 8.8 1- and 2-H) and 7.25–7.4 (10 H m ArH). Acknowledgements M. P. thanks the University Grants Commission New Delhi for financial support in the form of a Junior Research Fellowship.References 1 K. Stormer Zentralbl. Bakteriol. Parasitenk. Infek. 1908 20 282. 2 N. L. Sohngen Centr. Bakteriol. Parasitenk. Abt. II. 1913 37 595 (Chem. Abstr. 1913 7 3348); T. Weiland G. Griss and B. Haccius Arch. Microbiol. 1958 28 383; B. Haccius and O. Helfrich Arch. Microbiol. 1958 28 394. 1758 J. Chem. Soc. Perkin Trans. 1 1997 3 D. T. Gibson and V. Subramanian in Microbial Degradation of Organic Compounds ed. D. T. Gibson Microbiology Series Marcel Dekker New York 1984 vol. 13 ch. 7–13 inclusive. 4 T. Hudlicky and J. W. Reed Advances in Asymmetric Synthesis JAI Press 1995 vol. 1 p. 271. 5 D. T. Gibson J. R. Koch and R. E. Kallio Biochemistry 1968 7 2653. 6 D. T. Gibson M. Hensley H. Yoshioka and T. J. Mabry Biochemistry 1970 9 1626. 7 D.T. Gibson G. E. Cardini F. C. Maseles and R. E. Kallio Biochemistry 1970 9 1631. 8 D. T. Gibson J. R. Koch C. L. Schuld and R. E. Kallio Biochemistry 1968 7 3795. 9 D. T. Gibson B. Gschwendt W. K. Yeh and V. M. Kobal Biochemistry 1973 12 1520. 10 J. J. DeFrank and D. W. Ribbons J. Bacteriol. 1977 129 1356; G. J. Wigmore and D. W. Ribbons J. Bacteriol. 1980 143 816. 11 S. V. Ley and F. Sternfeld Tetrahedron 1989 45 3463. 12 S. V. Ley and A. J. Redgrave Synlett 1990 393. 13 D. M. Jerina H. Ziffer and J. W. Daly J. Am. Chem. Soc. 1970 92 1056. 14 T. Sato T. Fukuyama T. Suzuki and H. Yoshikawa J. Biochem. (Tokyo) 1963 53 23. 15 M. V. Ganey R. E. Padykula and G. A. Berchtold J. Org. Chem. 1989 54 2787. 16 T. Posternak D. Reymond and H. Friedli Helv. Chim. Acta 1955 38 205. 17 N. A. B.Wilson and J. Read J. Chem. Soc. 1935 1269. 18 H. Suemune A. Hasegawa and K. Sakai Tetrahedron Asymmetry 1995 6 55. 19 K. L. Platt and F. Oesch Synthesis 1977 449. 20 B. Beier K. Schurrle O. Werbitzky and W. Piepersberg J. Chem. Soc. Perkin Trans. 1 1990 2255. 21 H. Secen Y. Sutbeyaz and M. Balci Tetrahedron Lett. 1990 31 1323. 22 G. Kresze and W. Dittel Liebigs Ann. Chem. 1981 610. 23 C. H. Kuo and N. L. Wendler Tetrahedron Lett. 1984 25 2291. 24 K. Schurrle B. Beier O. Werbitzky and W. Piepersberg Carbohydr. Res. 1991 212 321. 25 H. A. J. Carless and K. Busia Tetrahedron Lett. 1990 31 1617. 26 H. A. J. Carless and K. Busia Tetrahedron Lett. 1990 31 3449. 27 H. A. J. Carless and K. Busia Carbohydr. Res. 1992 234 207. 28 H. B. Mereyala and M. Pannala Tetrahedron Lett. 1995 36 2121.29 D. J. R. Massy and P. Wyss Helv. Chim. Acta 1990 73 1037. 30 J. P. Vacca S. J. deSolms J. R. Hoff D. C. Billington R. Baker J. J. Kulagowski and I. M. Mawer Tetrahedron 1989 45 5679. 31 P. J. Garegg and B. Samuelsson Synthesis 1979 469. 32 D. H. R. Barton P. Dalko and S. D. Gero Tetrahedron Lett. 1991 32 2471; H. A. Staab and G. Walther Justus Liebigs Ann. Chem. 1962 657 104. Paper 6/05576A Received 9th August 1996 Accepted 20th February 1997 © Copyright 1997 by the Royal Society of Chemistry J. Chem. Soc. Perkin Trans. 1 1997 1755 Synthesis of (±)-trans-cyclohexa-3,5-diene-1,2-diol derivatives from myo-inositol Hari Babu Mereyala * and Madhavi Pannala Organic Division III Indian Institute of Chemical Technology Hyderabad 500007 India myo-Inositol 8 has been converted to biscyclohexylidene ketals 9–11.The inseparable mixture of isomers 9 and 11 has been utilised as such to obtain the synthetically useful (±)-trans-cyclohexa-3,5-diene-1,2-diol derivative 24 via the intermediates 14 and 15. The trans-diol derivative 24 has also been converted to synthetically useful epoxide derivative 25 in high yield and selectivity. Introduction Metabolism of aromatic compounds by bacteria was studied at the beginning of this century by Stormer.1 Oxidation of benzene to catechol was subsequently reported as early as 1913.2 cis-Cyclohexadiene-1,2-diol 1 was isolated for the first time by Gibson in 1968 from the metabolism of benzene by certain soil bacteria 3–5 and likewise was chiral cis-diol 2 from toluene.6,7 Subsequently several alkylbenzenes halogenobenzenes and other aromatics were oxidised to chiral cis-diols 3–5.8–10 Extensive use of cis-diol 1 as a building block in enantiospecific syntheses is best known from the work of Ley and his group.11,12 On the other hand the utility of bacteria to produce the analogous enantiomerically pure trans-cyclohexa-3,5-diene-1,2- diols (1)- and (2)-6 from benzene has not been very good.Metabolism of benzene oxide with liver microsomes in vivo is known to result in the formation of isomer (1)-6 at an estimated optical purity of 50%.13,14 Enzyme-catalysed hydrolysis of trans-diol diacetate (±)-7 was selected for resolution to obtain isomers (2)-6 and (1)-6 (97% ee) in an overall yield of 15 and 47% respectively.15 The absolute stereochemistry of isomers (2)-6 and (1)-6 was determined by converting them to the known (2)- and (1)-trans-1,2-dihydroxycyclohexane,13,16,17 respectively.Enantiomerically pure isomers (1)-7 and (2)-7 have also been obtained from lipase-effected enantioselective hydrolysis of (±)-4,5-diacetoxycyclohex-1-ene.18 Racemic transcyclohexa- 3,5-diene-1,2-diol diacetate (±)-7 has been prepared synthetically from benzene via successive Birch reduction bromination trans-hydroxylation dehydrobromination and acetylation.19 Diol (±)-6 was synthetically exploited for the synthesis of racemic conduramines,20 conduritols,21 inosamine,22 fortamine,23 aminocyclitol antibiotics of the 2-deoxystreptamine type,24 chiro-inositol 2,3,5-trisphosphate,25 myo-inositol 1,4,5-trisphosphate 26 and fluoroinositol phosphate analogues.27 Results and discussion We felt the need to develop a chemical route to obtain enantiomerically pure trans-cyclohexa-3,5-diene-1,2-diol derivatives from (meso)-myo-inositol 28 in large quantities because of their utility in the total synthesis of natural products (Scheme 1).myo-Inositol 8 was converted to a mixture of bis-cyclohexylidene ketals 9 10 11 in 38 26 and 19% yield respectively by reaction with cyclohexanone in N,N-dimethylformamide (DMF) at 100 8C for 12 h containing toluene-p-sulfonic acid (p-TsOH).29 Alternatively it could be made by reaction of myoinositol 8 with 1-ethoxycyclohexene containing a catalytic amount of p-TsOH in DMF at 100 8C for 2 h.30 From the soobtained bis-ketals 9–11 crystalline 1,4-diol 10 was separated by crystallisation 29 to leave a residue containing diastereoisomeric 1,2-diols 9 and 11 in the ratio 2 1 (by 1H NMR spectroscopy).Reaction of 1,2-diols 9 and 11 with Ph3P (3 mol equiv.) imidazole (3 mol equiv.) and iodine (3 mol equiv.) in toluene at reflux for 6 h gave the cyclohexene bis-cyclohexylidene ketals 12 and 13 (mp 66–68 8C) in 74% yield; 31 formation of the cyclohexene double bond was evident from the appearance of multiplets in the 1H NMR spectrum between d 5.6–6.25 integrating for two protons. Compounds 12 and 13 were allowed to react further at 0–5 8C with a catalytic amount of p-TsOH in CH2Cl2 for 4 h to obtain the cyclohexene diols 14 and 15 in 78% yield as a solid (mp 96–98 8C) due to selective deprotection of the trans-cyclohexylidene ketal. Products 14 and 15 were characterised from the 1H NMR spectrum where cyclohexylidene protons appeared between d 1.2–1.8 integrating for ten protons.From a mixture of compounds 14 and 15 we planned to obtain the trans-cyclohexa-3,5-diene-1,2-diols. Diols 14 and 15 were therefore treated with Ac2O–pyridine to obtain the di-O-acetyl derivatives 16 and 17 in quantitative yield. However attempted selective deprotection of the ciscyclohexylidene protecting group of compounds 16 and 17 by reaction with p-TsOH in CH2Cl2 at 0 8C resulted in the formation of phenolic compounds. Attempts to deprotect the cyclohexylidene ketal in ethylene glycol–p-TsOH and HCl– methanol also met with failure. It was hence decided to protect the alcohols 14 and 15 as their benzyl ethers by reaction with C6H5CH2Br–NaH–DMF at 0 8C to obtain the dibenzyl ether derivatives 18 and 19 in 98% yield. The mixture of compounds 18 and 19 was then subjected to deprotection of the cyclohexylidene ketal in p-TsOH–CH2Cl2–methanol at 0 8C to room temp.for 4 h to obtain the diol derivatives 20 and 21 in 90% yield which were characterised from their 1H NMR spectrum. The mixture of diols 20 and 21 was further treated with 1,19- thiocarbonyldimidazole 32 in toluene at reflux for 1 h to obtain the cyclic thiocarbonate derivatives 22 and 23 in high yield and these were subsequently subjected to syn elimination by being refluxed in trimethyl phosphite for 2 h to obtain trans-(±)- cyclohexa-3,5-diene-1,2-diol bisbenzyl ether 24 as a syrup in X OH OH 1 OH OH X = H 2 X = CH3 3 OH X = Et 5 OH X = CI OH X = Pri (±)–6 OH 4 OAc (+)–6 (±)–7 OAc (–)–6 1756 J. Chem. Soc. Perkin Trans. 1 1997 Scheme 1 Reagents and conditions i cyclohexanone DMF p-TsOH 100 8C 12 h; ii PPh3 I2 imidazole toluene reflux 6 h iii p-TsOH (cat.) CH2Cl2 5 8C 4 h; iv BnBr NaH DMF; v p-TsOH CH2Cl2–MeOH; vi 1,19-thiocarbonyldiimidazole toluene reflux 1 h; vii P(OMe)3 reflux 2 h; viii MCPBA CH2Cl2 NaHCO3 room temp.4h OH OH HO OH HO OH OH OH O O O O OH O O HO O O O O O HO O OH O O O O O O O O O RO O OR O O OR OR O BnO O OBn O O OBn OBn OH HO OBn BnO OH HO OBn OBn 8 9 10 i 11 O BnO O OBn ii 12 iii 13 15 17 S O O 14 16 19 iv 18 v S 16 17 R = Ac OBn OBn 14 15 R = H 20 OBn OBn 21 vi vii OBn OBn 22 23 O viii 24 25 90% yield. Compound 24 was characterised from the appearance of cyclohexadiene protons (4 H) at d 5.83 as a singlet and the H-5 H-6 protons at d 4.37 as a singlet in the 1H NMR spectrum. The trans-1,2-diol derivative 24 on reaction with mchloroperbenzoic acid (MCPBA) in CH2Cl2 at room temperature for 4 h gave the epoxide 25 due to stereoselective epoxida- J.Chem. Soc. Perkin Trans. 1 1997 1757 tion of the double bond anti to the adjacent benzyl ether. Compound 25 was fully characterised from the 1H NMR spectrum. Experimental 1H NMR spectra were measured with a Varian Gemini (200 MHz) spectrometer with tetramethylsilane as internal standard for solutions in deuteriochloroform; coupling constants (J) are given in Hz. IR spectra were taken with a Perkin-Elmer 283 spectrometer. UV spectra were measured with a Shimadzu 160- A spectrometer. Organic solutions were dried over anhydrous Na2SO4 and concentrated below 40 8C on rotary evaporator. (±)-(3·,4‚,5·,6·)-3,4 5,6-Bis(cyclohexylidenedioxy)cyclohexene 12 and (±)-(3·,4·,5·,6‚)-3,4 5,6-bis(cyclohexylidenedioxy) cyclohexene 13 To a solution of diols 9 and 11 (5.0 g 4.7 mmol) in toluene (40 cm3) were added triphenylphosphine (11.55 g 44.1 mmol) and imidazole (2.29 g 44.1 mmol) and the mixture was heated to 60 8C.Iodine (11.2 g 44.1 mmol) was added portionwise during 15 min and the reaction mixture was refluxed for 4 h when TLC (hexane–ethyl acetate 3 1) indicated completion of the reaction from the appearance of a faster moving spot; it was then cooled to room temperature a further batch of iodine (14.94 g 58.8 mmol) was added followed by aq. NaOH (1 M; 50 cm3) and the mixture was stirred for 30 min at room temperature. The toluene phase was washed successively with water 5% aq. sodium thiosulfate saturated aq. NaHCO3 and water dried (Na2SO4) and concentrated to obtain a solid residue which was filtered on a bed of silica gel (eluted with 25% ethyl acetate in hexane) to obtain the title compounds (3.33 g 74%) which solidified on storage mp 66–68 8C (Found C 70.45; H 8.46.C18H26O4 requires C 70.56; H 8.55%); dH 1.3–1.8 (20 H m cyclohexylidene) 3.35–4.8 (4 H m 3- 4- 5- and 6-H) and 5.6– 6.25 (2 H m 1- and 2-H). (±)-(1·,2‚,5·,6·)-5,6-(Cyclohexylidenedioxy)cyclohex-3-ene- 1,2-diol 14 and (±)-(1‚,2·,5·,6·)-5,6-(cyclohexylidenedioxy)- cyclohex-3-ene-1,2-diol 15 To a solution of compounds 12 and 13 (3.30 g 10.8 mmol) in CH2Cl2 (10 cm3) was added catalytic amount of p-TsOH (30 mg) and the mixture was stirred at 0–5 8C for 4 h. After completion of the reaction the mixture was neutralised with triethylamine. The reaction mixture was concentrated and filtered on a bed of silica gel (eluted with 50% ethyl acetate in hexane) to obtain the title compounds 14 and 15 (1.91 g 78%) as an inseparable mixture of solids mp 96–98 8C (Found C 63.65; H 7.95.C12H18O4 requires C 63.70; H 8.02%); nmax(CHCl3) 3500 cm21 (OH); dH 1.2–1.8 (10 H m cyclohexylidene) 3.4–4.7 (4 H m 1- 2- 5- and 6-H) and 5.5–6.0 (2 H m 3- and 4-H). (±)-(3·,4‚,5·,6·)-3,4-Bis(benzyloxy)-5,6-(cyclohexylidenedioxy) cyclohexene 18 and (±)-(3‚,4·,5·,6·)-3,4-bis(benzyloxy)- 5,6-(cyclohexylidenedioxy)cyclohexene 19 To hexane-washed NaH (0.35 g 14.4 mmol) in DMF (10 cm3) was added a solution of compounds 14 and 15 (1.3 g 5.75 mmol) in DMF (5 cm3) at 0 8C. The reaction mixture was stirred for 15 min at 0 8C and benzyl bromide (2.24 g 14.4 mmol) was added dropwise.The reaction mixture was stirred for 30 min at room temperature. After completion of the reaction the mixture was quenched with methanol followed by ice– water and extracted into CH2Cl2. The organic phase was washed with water dried (Na2SO4) and concentrated to obtain title compounds 18 and 19 (2.28 g 98%) as a syrup (Found C 76.39; H 7.84. C26H30O4 requires C 76.82; H 7.44%); dH 1.3– 1.7 (10 H m cyclohexylidene) 3.5–4.6 (4 H m 3- 4- 5- and 6-H) 4.6–4.85 (4 H m C6H5CH2 × 2) 5.5–5.9 (2 H m 1- and 2-H) and 7.25–7.45 (10 H m ArH). (±)-(1·,2·,5·,6‚)-5,6-Bis(benzyloxy)cyclohex-3-ene-1,2-diol 20 and (±)-(1·,2·,5‚,6·)-5,6-bis(benzyloxy)cyclohex-3-ene-1,2-diol 21 To a solution of compounds 18 and 19 (2.2 g 5.4 mmol) in CH2Cl2–CH3OH (60 and 10 cm3) was added a catalytic amount of p-TsOH (20 mg) and the mixture was stirred for 3 h at 0 8C before being warmed to room temperature and stirred for another 1 h.The reaction mixture was neutralised with triethylamine and concentrated to obtain a residue which was filtered on a bed of silica gel (eluted with 50% ethyl acetate in hexane) to obtain the title compounds (1.65 g 90%) as a syrup (Found C 73.06; H 7.26. C20H24O4 requires C 73.14; H 7.37%); dH 2.5–2.8 (2 H br s OH) 3.55–4.3 (4 H m 1- 2- 5- and 6-H) 4.45–4.95 (4 H m C6H5CH2 × 2) 5.7–5.9 (2 H m 3- and 4-H) and 7.2–7.35 (10 H m ArH). (±)-(3a·,6·,7‚,7a·)-6,7-Bis(benzyloxy)-3a,6,7,7a-tetrahydrobenzo[ d][1,3]dioxole-2-thione 22 and (±)-(3a·,6‚,7·,7a·)-6,7- bis(benzyloxy)-3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxole-2- thione 23 To a solution of compounds 20 and 21 (1.6 g 4.91 mmol) in dry toluene (10 cm3) was added 1,19-thiocarbonyldiimidazole (1.31 g 7.36 mmol) and the mixture was refluxed under nitrogen for 1 h.After completion of the reaction the mixture was diluted with toluene (20 cm3) and then concentrated to obtain a residue which was filtered on a bed of silica gel (eluted with 25% ethyl acetate in hexane) to obtain the title compounds (1.71 g 95%) as a syrup (Found C 67.99; H 5.86. C21H20O4S requires C 68.47; H 5.47%); dH 3.7–4.2 (2 H m 6- and 7-H) 4.6–5.3 (6 H m 3a- and 7a-H C6H5CH2 × 2) 5.8–6.2 (2 H m 4- and 5-H) and 7.2–7.35 (10 H m ArH). (±)-trans-5,6-Bis(benzyloxy)cyclohexa-1,3-diene 24 Thiocarbonate derivatives 22 and 23 (1.65 g 4.48 mmol) were refluxed for 2 h in trimethyl phosphite (0.94 g 6.72 mmol) under nitrogen.After completion of the reaction the mixture was made alkaline by the addition of aq. NaOH and was extracted into CH2Cl2. The organic phase was washed with water (50 cm3 × 3) dried (Na2SO4) and concentrated to obtain the title compound (1.17 g 90%) as a syrup (Found C 82.03; H 6.81. C20H20O2 requires C 82.15; H 6.89%); M1 292; lmax(Me- OH) 259 nm; dH 4.37 (2 H s 5- and 6-H) 4.55 (4 H s C6H5CH2 × 2) 5.83 (4 H s 1- 2- 3- and 4-H) and 7.2–7.35 (10 H m ArH). (±)-(3‚,4·,5‚,6‚)-3,4-Bis(benzyloxy)-5,6-epoxycyclohexene 25 To a solution of compound 24 (1.0 g 3.42 mmol) in CH2Cl2 (200 cm3) were added MCPBA (0.59 g 3.42 mmol) and NaHCO3 (0.28 g 3.42 mmol) and the mixture was stirred at room temperature for 4 h. After completion of the reaction the mixture was diluted with CH2Cl2 (50 cm3) and washed successively with saturated aq.NaHCO3 and water. The organic phase was dried (Na2SO4) and concentrated to obtain the title compound (0.97 g 92%) as a syrup (Found C 77.83; H 6.47. C20H20O3 requires C 77.90; H 6.54%); dH 3.2–3.5 (2 H m 5- and 6-H) 3.84 (1 H d J3,4 7.7 3-H) 4.19 (1 H d J3,4 7.7 4-H) 4.65–4.95 (4 H m C6H5CH2 × 2) 5.92 (2 H AB-type doublet J 8.8 1- and 2-H) and 7.25–7.4 (10 H m ArH). Acknowledgements M. P. thanks the University Grants Commission New Delhi for financial support in the form of a Junior Research Fellowship. References 1 K. Stormer Zentralbl. Bakteriol. Parasitenk. Infek. 1908 20 282. 2 N. L. Sohngen Centr. Bakteriol. Parasitenk. Abt. II. 1913 37 595 (Chem. Abstr. 1913 7 3348); T. Weiland G. Griss and B. Haccius Arch. Microbiol. 1958 28 383; B.Haccius and O. Helfrich Arch. Microbiol. 1958 28 394. 1758 J. Chem. Soc. Perkin Trans. 1 1997 3 D. T. Gibson and V. Subramanian in Microbial Degradation of Organic Compounds ed. D. T. Gibson Microbiology Series Marcel Dekker New York 1984 vol. 13 ch. 7–13 inclusive. 4 T. Hudlicky and J. W. Reed Advances in Asymmetric Synthesis JAI Press 1995 vol. 1 p. 271. 5 D. T. Gibson J. R. Koch and R. E. Kallio Biochemistry 1968 7 2653. 6 D. T. Gibson M. Hensley H. Yoshioka and T. J. Mabry Biochemistry 1970 9 1626. 7 D. T. Gibson G. E. Cardini F. C. Maseles and R. E. Kallio Biochemistry 1970 9 1631. 8 D. T. Gibson J. R. Koch C. L. Schuld and R. E. Kallio Biochemistry 1968 7 3795. 9 D. T. Gibson B. Gschwendt W. K. Yeh and V. M. Kobal Biochemistry 1973 12 1520. 10 J. J. DeFrank and D. W. Ribbons J.Bacteriol. 1977 129 1356; G. J. Wigmore and D. W. Ribbons J. Bacteriol. 1980 143 816. 11 S. V. Ley and F. Sternfeld Tetrahedron 1989 45 3463. 12 S. V. Ley and A. J. Redgrave Synlett 1990 393. 13 D. M. Jerina H. Ziffer and J. W. Daly J. Am. Chem. Soc. 1970 92 1056. 14 T. Sato T. Fukuyama T. Suzuki and H. Yoshikawa J. Biochem. (Tokyo) 1963 53 23. 15 M. V. Ganey R. E. Padykula and G. A. Berchtold J. Org. Chem. 1989 54 2787. 16 T. Posternak D. Reymond and H. Friedli Helv. Chim. Acta 1955 38 205. 17 N. A. B. Wilson and J. Read J. Chem. Soc. 1935 1269. 18 H. Suemune A. Hasegawa and K. Sakai Tetrahedron Asymmetry 1995 6 55. 19 K. L. Platt and F. Oesch Synthesis 1977 449. 20 B. Beier K. Schurrle O. Werbitzky and W. Piepersberg J. Chem. Soc. Perkin Trans. 1 1990 2255. 21 H. Secen Y.Sutbeyaz and M. Balci Tetrahedron Lett. 1990 31 1323. 22 G. Kresze and W. Dittel Liebigs Ann. Chem. 1981 610. 23 C. H. Kuo and N. L. Wendler Tetrahedron Lett. 1984 25 2291. 24 K. Schurrle B. Beier O. Werbitzky and W. Piepersberg Carbohydr. Res. 1991 212 321. 25 H. A. J. Carless and K. Busia Tetrahedron Lett. 1990 31 1617. 26 H. A. J. Carless and K. Busia Tetrahedron Lett. 1990 31 3449. 27 H. A. J. Carless and K. Busia Carbohydr. Res. 1992 234 207. 28 H. B. Mereyala and M. Pannala Tetrahedron Lett. 1995 36 2121. 29 D. J. R. Massy and P. Wyss Helv. Chim. Acta 1990 73 1037. 30 J. P. Vacca S. J. deSolms J. R. Hoff D. C. Billington R. Baker J. J. Kulagowski and I. M. Mawer Tetrahedron 1989 45 5679. 31 P. J. Garegg and B. Samuelsson Synthesis 1979 469. 32 D. H. R. Barton P. Dalko and S.D. Gero Tetrahedron Lett. 1991 32 2471; H. A. Staab and G. Walther Justus Liebigs Ann. Chem. 1962 657 104. Paper 6/05576A Received 9th August 1996 Accepted 20th February 1997 © Copyright 1997 by the Royal Society of Chemistry J. Chem. Soc. Perkin Trans. 1 1997 1755 Synthesis of (±)-trans-cyclohexa-3,5-diene-1,2-diol derivatives from myo-inositol Hari Babu Mereyala * and Madhavi Pannala Organic Division III Indian Institute of Chemical Technology Hyderabad 500007 India myo-Inositol 8 has been converted to biscyclohexylidene ketals 9–11. The inseparable mixture of isomers 9 and 11 has been utilised as such to obtain the synthetically useful (±)-trans-cyclohexa-3,5-diene-1,2-diol derivative 24 via the intermediates 14 and 15. The trans-diol derivative 24 has also been converted to synthetically useful epoxide derivative 25 in high yield and selectivity.Introduction Metabolism of aromatic compounds by bacteria was studied at the beginning of this century by Stormer.1 Oxidation of benzene to catechol was subsequently reported as early as 1913.2 cis-Cyclohexadiene-1,2-diol 1 was isolated for the first time by Gibson in 1968 from the metabolism of benzene by certain soil bacteria 3–5 and likewise was chiral cis-diol 2 from toluene.6,7 Subsequently several alkylbenzenes halogenobenzenes and other aromatics were oxidised to chiral cis-diols 3–5.8–10 Extensive use of cis-diol 1 as a building block in enantiospecific syntheses is best known from the work of Ley and his group.11,12 On the other hand the utility of bacteria to produce the analogous enantiomerically pure trans-cyclohexa-3,5-diene-1,2- diols (1)- and (2)-6 from benzene has not been very good.Metabolism of benzene oxide with liver microsomes in vivo is known to result in the formation of isomer (1)-6 at an estimated optical purity of 50%.13,14 Enzyme-catalysed hydrolysis of trans-diol diacetate (±)-7 was selected for resolution to obtain isomers (2)-6 and (1)-6 (97% ee) in an overall yield of 15 and 47% respectively.15 The absolute stereochemistry of isomers (2)-6 and (1)-6 was determined by converting them to the known (2)- and (1)-trans-1,2-dihydroxycyclohexane,13,16,17 respectively. Enantiomerically pure isomers (1)-7 and (2)-7 have also been obtained from lipase-effected enantioselective hydrolysis of (±)-4,5-diacetoxycyclohex-1-ene.18 Racemic transcyclohexa- 3,5-diene-1,2-diol diacetate (±)-7 has been prepared synthetically from benzene via successive Birch reduction bromination trans-hydroxylation dehydrobromination and acetylation.19 Diol (±)-6 was synthetically exploited for the synthesis of racemic conduramines,20 conduritols,21 inosamine,22 fortamine,23 aminocyclitol antibiotics of the 2-deoxystreptamine type,24 chiro-inositol 2,3,5-trisphosphate,25 myo-inositol 1,4,5-trisphosphate 26 and fluoroinositol phosphate analogues.27 Results and discussion We felt the need to develop a chemical route to obtain enantiomerically pure trans-cyclohexa-3,5-diene-1,2-diol derivatives from (meso)-myo-inositol 28 in large quantities because of their utility in the total synthesis of natural products (Scheme 1).myo-Inositol 8 was converted to a mixture of bis-cyclohexylidene ketals 9 10 11 in 38 26 and 19% yield respectively by reaction with cyclohexanone in N,N-dimethylformamide (DMF) at 100 8C for 12 h containing toluene-p-sulfonic acid (p-TsOH).29 Alternatively it could be made by reaction of myoinositol 8 with 1-ethoxycyclohexene containing a catalytic amount of p-TsOH in DMF at 100 8C for 2 h.30 From the soobtained bis-ketals 9–11 crystalline 1,4-diol 10 was separated by crystallisation 29 to leave a residue containing diastereoisomeric 1,2-diols 9 and 11 in the ratio 2 1 (by 1H NMR spectroscopy).Reaction of 1,2-diols 9 and 11 with Ph3P (3 mol equiv.) imidazole (3 mol equiv.) and iodine (3 mol equiv.) in toluene at reflux for 6 h gave the cyclohexene bis-cyclohexylidene ketals 12 and 13 (mp 66–68 8C) in 74% yield; 31 formation of the cyclohexene double bond was evident from the appearance of multiplets in the 1H NMR spectrum between d 5.6–6.25 integrating for two protons.Compounds 12 and 13 were allowed to react further at 0–5 8C with a catalytic amount of p-TsOH in CH2Cl2 for 4 h to obtain the cyclohexene diols 14 and 15 in 78% yield as a solid (mp 96–98 8C) due to selective deprotection of the trans-cyclohexylidene ketal. Products 14 and 15 were characterised from the 1H NMR spectrum where cyclohexylidene protons appeared between d 1.2–1.8 integrating for ten protons. From a mixture of compounds 14 and 15 we planned to obtain the trans-cyclohexa-3,5-diene-1,2-diols. Diols 14 and 15 were therefore treated with Ac2O–pyridine to obtain the di-O-acetyl derivatives 16 and 17 in quantitative yield. However attempted selective deprotection of the ciscyclohexylidene protecting group of compounds 16 and 17 by reaction with p-TsOH in CH2Cl2 at 0 8C resulted in the formation of phenolic compounds.Attempts to deprotect the cyclohexylidene ketal in ethylene glycol–p-TsOH and HCl– methanol also met with failure. It was hence decided to protect the alcohols 14 and 15 as their benzyl ethers by reaction with C6H5CH2Br–NaH–DMF at 0 8C to obtain the dibenzyl ether derivatives 18 and 19 in 98% yield. The mixture of compounds 18 and 19 was then subjected to deprotection of the cyclohexylidene ketal in p-TsOH–CH2Cl2–methanol at 0 8C to room temp. for 4 h to obtain the diol derivatives 20 and 21 in 90% yield which were characterised from their 1H NMR spectrum. The mixture of diols 20 and 21 was further treated with 1,19- thiocarbonyldimidazole 32 in toluene at reflux for 1 h to obtain the cyclic thiocarbonate derivatives 22 and 23 in high yield and these were subsequently subjected to syn elimination by being refluxed in trimethyl phosphite for 2 h to obtain trans-(±)- cyclohexa-3,5-diene-1,2-diol bisbenzyl ether 24 as a syrup in X OH OH 1 OH OH X = H 2 X = CH3 3 OH X = Et 5 OH X = CI OH X = Pri (±)–6 OH 4 OAc (+)–6 (±)–7 OAc (–)–6 1756 J.Chem. Soc. Perkin Trans. 1 1997 Scheme 1 Reagents and conditions i cyclohexanone DMF p-TsOH 100 8C 12 h; ii PPh3 I2 imidazole toluene reflux 6 h iii p-TsOH (cat.) CH2Cl2 5 8C 4 h; iv BnBr NaH DMF; v p-TsOH CH2Cl2–MeOH; vi 1,19-thiocarbonyldiimidazole toluene reflux 1 h; vii P(OMe)3 reflux 2 h; viii MCPBA CH2Cl2 NaHCO3 room temp. 4h OH OH HO OH HO OH OH OH O O O O OH O O HO O O O O O HO O OH O O O O O O O O O RO O OR O O OR OR O BnO O OBn O O OBn OBn OH HO OBn BnO OH HO OBn OBn 8 9 10 i 11 O BnO O OBn ii 12 iii 13 15 17 S O O 14 16 19 iv 18 v S 16 17 R = Ac OBn OBn 14 15 R = H 20 OBn OBn 21 vi vii OBn OBn 22 23 O viii 24 25 90% yield.Compound 24 was characterised from the appearance of cyclohexadiene protons (4 H) at d 5.83 as a singlet and the H-5 H-6 protons at d 4.37 as a singlet in the 1H NMR spectrum. The trans-1,2-diol derivative 24 on reaction with mchloroperbenzoic acid (MCPBA) in CH2Cl2 at room temperature for 4 h gave the epoxide 25 due to stereoselective epoxida- J. Chem. Soc. Perkin Trans. 1 1997 1757 tion of the double bond anti to the adjacent benzyl ether. Compound 25 was fully characterised from the 1H NMR spectrum.Experimental 1H NMR spectra were measured with a Varian Gemini (200 MHz) spectrometer with tetramethylsilane as internal standard for solutions in deuteriochloroform; coupling constants (J) are given in Hz. IR spectra were taken with a Perkin-Elmer 283 spectrometer. UV spectra were measured with a Shimadzu 160- A spectrometer. Organic solutions were dried over anhydrous Na2SO4 and concentrated below 40 8C on rotary evaporator. (±)-(3·,4‚,5·,6·)-3,4 5,6-Bis(cyclohexylidenedioxy)cyclohexene 12 and (±)-(3·,4·,5·,6‚)-3,4 5,6-bis(cyclohexylidenedioxy) cyclohexene 13 To a solution of diols 9 and 11 (5.0 g 4.7 mmol) in toluene (40 cm3) were added triphenylphosphine (11.55 g 44.1 mmol) and imidazole (2.29 g 44.1 mmol) and the mixture was heated to 60 8C. Iodine (11.2 g 44.1 mmol) was added portionwise during 15 min and the reaction mixture was refluxed for 4 h when TLC (hexane–ethyl acetate 3 1) indicated completion of the reaction from the appearance of a faster moving spot; it was then cooled to room temperature a further batch of iodine (14.94 g 58.8 mmol) was added followed by aq.NaOH (1 M; 50 cm3) and the mixture was stirred for 30 min at room temperature. The toluene phase was washed successively with water 5% aq. sodium thiosulfate saturated aq. NaHCO3 and water dried (Na2SO4) and concentrated to obtain a solid residue which was filtered on a bed of silica gel (eluted with 25% ethyl acetate in hexane) to obtain the title compounds (3.33 g 74%) which solidified on storage mp 66–68 8C (Found C 70.45; H 8.46. C18H26O4 requires C 70.56; H 8.55%); dH 1.3–1.8 (20 H m cyclohexylidene) 3.35–4.8 (4 H m 3- 4- 5- and 6-H) and 5.6– 6.25 (2 H m 1- and 2-H).(±)-(1·,2‚,5·,6·)-5,6-(Cyclohexylidenedioxy)cyclohex-3-ene- 1,2-diol 14 and (±)-(1‚,2·,5·,6·)-5,6-(cyclohexylidenedioxy)- cyclohex-3-ene-1,2-diol 15 To a solution of compounds 12 and 13 (3.30 g 10.8 mmol) in CH2Cl2 (10 cm3) was added catalytic amount of p-TsOH (30 mg) and the mixture was stirred at 0–5 8C for 4 h. After completion of the reaction the mixture was neutralised with triethylamine. The reaction mixture was concentrated and filtered on a bed of silica gel (eluted with 50% ethyl acetate in hexane) to obtain the title compounds 14 and 15 (1.91 g 78%) as an inseparable mixture of solids mp 96–98 8C (Found C 63.65; H 7.95. C12H18O4 requires C 63.70; H 8.02%); nmax(CHCl3) 3500 cm21 (OH); dH 1.2–1.8 (10 H m cyclohexylidene) 3.4–4.7 (4 H m 1- 2- 5- and 6-H) and 5.5–6.0 (2 H m 3- and 4-H).(±)-(3·,4‚,5·,6·)-3,4-Bis(benzyloxy)-5,6-(cyclohexylidenedioxy) cyclohexene 18 and (±)-(3‚,4·,5·,6·)-3,4-bis(benzyloxy)- 5,6-(cyclohexylidenedioxy)cyclohexene 19 To hexane-washed NaH (0.35 g 14.4 mmol) in DMF (10 cm3) was added a solution of compounds 14 and 15 (1.3 g 5.75 mmol) in DMF (5 cm3) at 0 8C. The reaction mixture was stirred for 15 min at 0 8C and benzyl bromide (2.24 g 14.4 mmol) was added dropwise. The reaction mixture was stirred for 30 min at room temperature. After completion of the reaction the mixture was quenched with methanol followed by ice– water and extracted into CH2Cl2. The organic phase was washed with water dried (Na2SO4) and concentrated to obtain title compounds 18 and 19 (2.28 g 98%) as a syrup (Found C 76.39; H 7.84.C26H30O4 requires C 76.82; H 7.44%); dH 1.3– 1.7 (10 H m cyclohexylidene) 3.5–4.6 (4 H m 3- 4- 5- and 6-H) 4.6–4.85 (4 H m C6H5CH2 × 2) 5.5–5.9 (2 H m 1- and 2-H) and 7.25–7.45 (10 H m ArH). (±)-(1·,2·,5·,6‚)-5,6-Bis(benzyloxy)cyclohex-3-ene-1,2-diol 20 and (±)-(1·,2·,5‚,6·)-5,6-bis(benzyloxy)cyclohex-3-ene-1,2-diol 21 To a solution of compounds 18 and 19 (2.2 g 5.4 mmol) in CH2Cl2–CH3OH (60 and 10 cm3) was added a catalytic amount of p-TsOH (20 mg) and the mixture was stirred for 3 h at 0 8C before being warmed to room temperature and stirred for another 1 h. The reaction mixture was neutralised with triethylamine and concentrated to obtain a residue which was filtered on a bed of silica gel (eluted with 50% ethyl acetate in hexane) to obtain the title compounds (1.65 g 90%) as a syrup (Found C 73.06; H 7.26.C20H24O4 requires C 73.14; H 7.37%); dH 2.5–2.8 (2 H br s OH) 3.55–4.3 (4 H m 1- 2- 5- and 6-H) 4.45–4.95 (4 H m C6H5CH2 × 2) 5.7–5.9 (2 H m 3- and 4-H) and 7.2–7.35 (10 H m ArH). (±)-(3a·,6·,7‚,7a·)-6,7-Bis(benzyloxy)-3a,6,7,7a-tetrahydrobenzo[ d][1,3]dioxole-2-thione 22 and (±)-(3a·,6‚,7·,7a·)-6,7- bis(benzyloxy)-3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxole-2- thione 23 To a solution of compounds 20 and 21 (1.6 g 4.91 mmol) in dry toluene (10 cm3) was added 1,19-thiocarbonyldiimidazole (1.31 g 7.36 mmol) and the mixture was refluxed under nitrogen for 1 h. After completion of the reaction the mixture was diluted with toluene (20 cm3) and then concentrated to obtain a residue which was filtered on a bed of silica gel (eluted with 25% ethyl acetate in hexane) to obtain the title compounds (1.71 g 95%) as a syrup (Found C 67.99; H 5.86.C21H20O4S requires C 68.47; H 5.47%); dH 3.7–4.2 (2 H m 6- and 7-H) 4.6–5.3 (6 H m 3a- and 7a-H C6H5CH2 × 2) 5.8–6.2 (2 H m 4- and 5-H) and 7.2–7.35 (10 H m ArH). (±)-trans-5,6-Bis(benzyloxy)cyclohexa-1,3-diene 24 Thiocarbonate derivatives 22 and 23 (1.65 g 4.48 mmol) were refluxed for 2 h in trimethyl phosphite (0.94 g 6.72 mmol) under nitrogen. After completion of the reaction the mixture was made alkaline by the addition of aq. NaOH and was extracted into CH2Cl2. The organic phase was washed with water (50 cm3 × 3) dried (Na2SO4) and concentrated to obtain the title compound (1.17 g 90%) as a syrup (Found C 82.03; H 6.81.C20H20O2 requires C 82.15; H 6.89%); M1 292; lmax(Me- OH) 259 nm; dH 4.37 (2 H s 5- and 6-H) 4.55 (4 H s C6H5CH2 × 2) 5.83 (4 H s 1- 2- 3- and 4-H) and 7.2–7.35 (10 H m ArH). (±)-(3‚,4·,5‚,6‚)-3,4-Bis(benzyloxy)-5,6-epoxycyclohexene 25 To a solution of compound 24 (1.0 g 3.42 mmol) in CH2Cl2 (200 cm3) were added MCPBA (0.59 g 3.42 mmol) and NaHCO3 (0.28 g 3.42 mmol) and the mixture was stirred at room temperature for 4 h. After completion of the reaction the mixture was diluted with CH2Cl2 (50 cm3) and washed successively with saturated aq. NaHCO3 and water. The organic phase was dried (Na2SO4) and concentrated to obtain the title compound (0.97 g 92%) as a syrup (Found C 77.83; H 6.47. C20H20O3 requires C 77.90; H 6.54%); dH 3.2–3.5 (2 H m 5- and 6-H) 3.84 (1 H d J3,4 7.7 3-H) 4.19 (1 H d J3,4 7.7 4-H) 4.65–4.95 (4 H m C6H5CH2 × 2) 5.92 (2 H AB-type doublet J 8.8 1- and 2-H) and 7.25–7.4 (10 H m ArH).Acknowledgements M. P. thanks the University Grants Commission New Delhi for financial support in the form of a Junior Research Fellowship. References 1 K. Stormer Zentralbl. Bakteriol. Parasitenk. Infek. 1908 20 282. 2 N. L. Sohngen Centr. Bakteriol. Parasitenk. Abt. II. 1913 37 595 (Chem. Abstr. 1913 7 3348); T. Weiland G. Griss and B. Haccius Arch. Microbiol. 1958 28 383; B. Haccius and O. Helfrich Arch. Microbiol. 1958 28 394. 1758 J. Chem. Soc. Perkin Trans. 1 1997 3 D. T. Gibson and V. Subramanian in Microbial Degradation of Organic Compounds ed. D. T. Gibson Microbiology Series Marcel Dekker New York 1984 vol. 13 ch. 7–13 inclusive.4 T. Hudlicky and J. W. Reed Advances in Asymmetric Synthesis JAI Press 1995 vol. 1 p. 271. 5 D. T. Gibson J. R. Koch and R. E. Kallio Biochemistry 1968 7 2653. 6 D. T. Gibson M. Hensley H. Yoshioka and T. J. Mabry Biochemistry 1970 9 1626. 7 D. T. Gibson G. E. Cardini F. C. Maseles and R. E. Kallio Biochemistry 1970 9 1631. 8 D. T. Gibson J. R. Koch C. L. Schuld and R. E. Kallio Biochemistry 1968 7 3795. 9 D. T. Gibson B. Gschwendt W. K. Yeh and V. M. Kobal Biochemistry 1973 12 1520. 10 J. J. DeFrank and D. W. Ribbons J. Bacteriol. 1977 129 1356; G. J. Wigmore and D. W. Ribbons J. Bacteriol. 1980 143 816. 11 S. V. Ley and F. Sternfeld Tetrahedron 1989 45 3463. 12 S. V. Ley and A. J. Redgrave Synlett 1990 393. 13 D. M. Jerina H. Ziffer and J. W. Daly J. Am. Chem. Soc. 1970 92 1056.14 T. Sato T. Fukuyama T. Suzuki and H. Yoshikawa J. Biochem. (Tokyo) 1963 53 23. 15 M. V. Ganey R. E. Padykula and G. A. Berchtold J. Org. Chem. 1989 54 2787. 16 T. Posternak D. Reymond and H. Friedli Helv. Chim. Acta 1955 38 205. 17 N. A. B. Wilson and J. Read J. Chem. Soc. 1935 1269. 18 H. Suemune A. Hasegawa and K. Sakai Tetrahedron Asymmetry 1995 6 55. 19 K. L. Platt and F. Oesch Synthesis 1977 449. 20 B. Beier K. Schurrle O. Werbitzky and W. Piepersberg J. Chem. Soc. Perkin Trans. 1 1990 2255. 21 H. Secen Y. Sutbeyaz and M. Balci Tetrahedron Lett. 1990 31 1323. 22 G. Kresze and W. Dittel Liebigs Ann. Chem. 1981 610. 23 C. H. Kuo and N. L. Wendler Tetrahedron Lett. 1984 25 2291. 24 K. Schurrle B. Beier O. Werbitzky and W. Piepersberg Carbohydr. Res. 1991 212 321. 25 H. A. J. Carless and K.Busia Tetrahedron Lett. 1990 31 1617. 26 H. A. J. Carless and K. Busia Tetrahedron Lett. 1990 31 3449. 27 H. A. J. Carless and K. Busia Carbohydr. Res. 1992 234 207. 28 H. B. Mereyala and M. Pannala Tetrahedron Lett. 1995 36 2121. 29 D. J. R. Massy and P. Wyss Helv. Chim. Acta 1990 73 1037. 30 J. P. Vacca S. J. deSolms J. R. Hoff D. C. Billington R. Baker J. J. Kulagowski and I. M. Mawer Tetrahedron 1989 45 5679. 31 P. J. Garegg and B. Samuelsson Synthesis 1979 469. 32 D. H. R. Barton P. Dalko and S. D. Gero Tetrahedron Lett. 1991 32 2471; H. A. Staab and G. Walther Justus Liebigs Ann. Chem. 1962 657 104. Paper 6/05576A Received 9th August 1996 Accepted 20th February 1997 © Copyright 1997 by the Royal Society of Chemistry J. Chem. Soc. Perkin Trans. 1 1997 1755 Synthesis of (±)-trans-cyclohexa-3,5-diene-1,2-diol derivatives from myo-inositol Hari Babu Mereyala * and Madhavi Pannala Organic Division III Indian Institute of Chemical Technology Hyderabad 500007 India myo-Inositol 8 has been converted to biscyclohexylidene ketals 9–11.The inseparable mixture of isomers 9 and 11 has been utilised as such to obtain the synthetically useful (±)-trans-cyclohexa-3,5-diene-1,2-diol derivative 24 via the intermediates 14 and 15. The trans-diol derivative 24 has also been converted to synthetically useful epoxide derivative 25 in high yield and selectivity. Introduction Metabolism of aromatic compounds by bacteria was studied at the beginning of this century by Stormer.1 Oxidation of benzene to catechol was subsequently reported as early as 1913.2 cis-Cyclohexadiene-1,2-diol 1 was isolated for the first time by Gibson in 1968 from the metabolism of benzene by certain soil bacteria 3–5 and likewise was chiral cis-diol 2 from toluene.6,7 Subsequently several alkylbenzenes halogenobenzenes and other aromatics were oxidised to chiral cis-diols 3–5.8–10 Extensive use of cis-diol 1 as a building block in enantiospecific syntheses is best known from the work of Ley and his group.11,12 On the other hand the utility of bacteria to produce the analogous enantiomerically pure trans-cyclohexa-3,5-diene-1,2- diols (1)- and (2)-6 from benzene has not been very good.Metabolism of benzene oxide with liver microsomes in vivo is known to result in the formation of isomer (1)-6 at an estimated optical purity of 50%.13,14 Enzyme-catalysed hydrolysis of trans-diol diacetate (±)-7 was selected for resolution to obtain isomers (2)-6 and (1)-6 (97% ee) in an overall yield of 15 and 47% respectively.15 The absolute stereochemistry of isomers (2)-6 and (1)-6 was determined by converting them to the known (2)- and (1)-trans-1,2-dihydroxycyclohexane,13,16,17 respectively.Enantiomerically pure isomers (1)-7 and (2)-7 have also been obtained from lipase-effected enantioselective hydrolysis of (±)-4,5-diacetoxycyclohex-1-ene.18 Racemic transcyclohexa- 3,5-diene-1,2-diol diacetate (±)-7 has been prepared synthetically from benzene via successive Birch reduction bromination trans-hydroxylation dehydrobromination and acetylation.19 Diol (±)-6 was synthetically exploited for the synthesis of racemic conduramines,20 conduritols,21 inosamine,22 fortamine,23 aminocyclitol antibiotics of the 2-deoxystreptamine type,24 chiro-inositol 2,3,5-trisphosphate,25 myo-inositol 1,4,5-trisphosphate 26 and fluoroinositol phosphate analogues.27 Results and discussion We felt the need to develop a chemical route to obtain enantiomerically pure trans-cyclohexa-3,5-diene-1,2-diol derivatives from (meso)-myo-inositol 28 in large quantities because of their utility in the total synthesis of natural products (Scheme 1).myo-Inositol 8 was converted to a mixture of bis-cyclohexylidene ketals 9 10 11 in 38 26 and 19% yield respectively by reaction with cyclohexanone in N,N-dimethylformamide (DMF) at 100 8C for 12 h containing toluene-p-sulfonic acid (p-TsOH).29 Alternatively it could be made by reaction of myoinositol 8 with 1-ethoxycyclohexene containing a catalytic amount of p-TsOH in DMF at 100 8C for 2 h.30 From the soobtained bis-ketals 9–11 crystalline 1,4-diol 10 was separated by crystallisation 29 to leave a residue containing diastereoisomeric 1,2-diols 9 and 11 in the ratio 2 1 (by 1H NMR spectroscopy).Reaction of 1,2-diols 9 and 11 with Ph3P (3 mol equiv.) imidazole (3 mol equiv.) and iodine (3 mol equiv.) in toluene at reflux for 6 h gave the cyclohexene bis-cyclohexylidene ketals 12 and 13 (mp 66–68 8C) in 74% yield; 31 formation of the cyclohexene double bond was evident from the appearance of multiplets in the 1H NMR spectrum between d 5.6–6.25 integrating for two protons. Compounds 12 and 13 were allowed to react further at 0–5 8C with a catalytic amount of p-TsOH in CH2Cl2 for 4 h to obtain the cyclohexene diols 14 and 15 in 78% yield as a solid (mp 96–98 8C) due to selective deprotection of the trans-cyclohexylidene ketal.Products 14 and 15 were characterised from the 1H NMR spectrum where cyclohexylidene protons appeared between d 1.2–1.8 integrating for ten protons. From a mixture of compounds 14 and 15 we planned to obtain the trans-cyclohexa-3,5-diene-1,2-diols. Diols 14 and 15 were therefore treated with Ac2O–pyridine to obtain the di-O-acetyl derivatives 16 and 17 in quantitative yield. However attempted selective deprotection of the ciscyclohexylidene protecting group of compounds 16 and 17 by reaction with p-TsOH in CH2Cl2 at 0 8C resulted in the formation of phenolic compounds. Attempts to deprotect the cyclohexylidene ketal in ethylene glycol–p-TsOH and HCl– methanol also met with failure.It was hence decided to protect the alcohols 14 and 15 as their benzyl ethers by reaction with C6H5CH2Br–NaH–DMF at 0 8C to obtain the dibenzyl ether derivatives 18 and 19 in 98% yield. The mixture of compounds 18 and 19 was then subjected to deprotection of the cyclohexylidene ketal in p-TsOH–CH2Cl2–methanol at 0 8C to room temp. for 4 h to obtain the diol derivatives 20 and 21 in 90% yield which were characterised from their 1H NMR spectrum. The mixture of diols 20 and 21 was further treated with 1,19- thiocarbonyldimidazole 32 in toluene at reflux for 1 h to obtain the cyclic thiocarbonate derivatives 22 and 23 in high yield and these were subsequently subjected to syn elimination by being refluxed in trimethyl phosphite for 2 h to obtain trans-(±)- cyclohexa-3,5-diene-1,2-diol bisbenzyl ether 24 as a syrup in X OH OH 1 OH OH X = H 2 X = CH3 3 OH X = Et 5 OH X = CI OH X = Pri (±)–6 OH 4 OAc (+)–6 (±)–7 OAc (–)–6 1756 J.Chem. Soc. Perkin Trans. 1 1997 Scheme 1 Reagents and conditions i cyclohexanone DMF p-TsOH 100 8C 12 h; ii PPh3 I2 imidazole toluene reflux 6 h iii p-TsOH (cat.) CH2Cl2 5 8C 4 h; iv BnBr NaH DMF; v p-TsOH CH2Cl2–MeOH; vi 1,19-thiocarbonyldiimidazole toluene reflux 1 h; vii P(OMe)3 reflux 2 h; viii MCPBA CH2Cl2 NaHCO3 room temp. 4h OH OH HO OH HO OH OH OH O O O O OH O O HO O O O O O HO O OH O O O O O O O O O RO O OR O O OR OR O BnO O OBn O O OBn OBn OH HO OBn BnO OH HO OBn OBn 8 9 10 i 11 O BnO O OBn ii 12 iii 13 15 17 S O O 14 16 19 iv 18 v S 16 17 R = Ac OBn OBn 14 15 R = H 20 OBn OBn 21 vi vii OBn OBn 22 23 O viii 24 25 90% yield.Compound 24 was characterised from the appearance of cyclohexadiene protons (4 H) at d 5.83 as a singlet and the H-5 H-6 protons at d 4.37 as a singlet in the 1H NMR spectrum. The trans-1,2-diol derivative 24 on reaction with mchloroperbenzoic acid (MCPBA) in CH2Cl2 at room temperature for 4 h gave the epoxide 25 due to stereoselective epoxida- J. Chem. Soc. Perkin Trans. 1 1997 1757 tion of the double bond anti to the adjacent benzyl ether. Compound 25 was fully characterised from the 1H NMR spectrum. Experimental 1H NMR spectra were measured with a Varian Gemini (200 MHz) spectrometer with tetramethylsilane as internal standard for solutions in deuteriochloroform; coupling constants (J) are given in Hz. IR spectra were taken with a Perkin-Elmer 283 spectrometer.UV spectra were measured with a Shimadzu 160- A spectrometer. Organic solutions were dried over anhydrous Na2SO4 and concentrated below 40 8C on rotary evaporator. (±)-(3·,4‚,5·,6·)-3,4 5,6-Bis(cyclohexylidenedioxy)cyclohexene 12 and (±)-(3·,4·,5·,6‚)-3,4 5,6-bis(cyclohexylidenedioxy) cyclohexene 13 To a solution of diols 9 and 11 (5.0 g 4.7 mmol) in toluene (40 cm3) were added triphenylphosphine (11.55 g 44.1 mmol) and imidazole (2.29 g 44.1 mmol) and the mixture was heated to 60 8C. Iodine (11.2 g 44.1 mmol) was added portionwise during 15 min and the reaction mixture was refluxed for 4 h when TLC (hexane–ethyl acetate 3 1) indicated completion of the reaction from the appearance of a faster moving spot; it was then cooled to room temperature a further batch of iodine (14.94 g 58.8 mmol) was added followed by aq.NaOH (1 M; 50 cm3) and the mixture was stirred for 30 min at room temperature. The toluene phase was washed successively with water 5% aq. sodium thiosulfate saturated aq. NaHCO3 and water dried (Na2SO4) and concentrated to obtain a solid residue which was filtered on a bed of silica gel (eluted with 25% ethyl acetate in hexane) to obtain the title compounds (3.33 g 74%) which solidified on storage mp 66–68 8C (Found C 70.45; H 8.46. C18H26O4 requires C 70.56; H 8.55%); dH 1.3–1.8 (20 H m cyclohexylidene) 3.35–4.8 (4 H m 3- 4- 5- and 6-H) and 5.6– 6.25 (2 H m 1- and 2-H). (±)-(1·,2‚,5·,6·)-5,6-(Cyclohexylidenedioxy)cyclohex-3-ene- 1,2-diol 14 and (±)-(1‚,2·,5·,6·)-5,6-(cyclohexylidenedioxy)- cyclohex-3-ene-1,2-diol 15 To a solution of compounds 12 and 13 (3.30 g 10.8 mmol) in CH2Cl2 (10 cm3) was added catalytic amount of p-TsOH (30 mg) and the mixture was stirred at 0–5 8C for 4 h.After completion of the reaction the mixture was neutralised with triethylamine. The reaction mixture was concentrated and filtered on a bed of silica gel (eluted with 50% ethyl acetate in hexane) to obtain the title compounds 14 and 15 (1.91 g 78%) as an inseparable mixture of solids mp 96–98 8C (Found C 63.65; H 7.95. C12H18O4 requires C 63.70; H 8.02%); nmax(CHCl3) 3500 cm21 (OH); dH 1.2–1.8 (10 H m cyclohexylidene) 3.4–4.7 (4 H m 1- 2- 5- and 6-H) and 5.5–6.0 (2 H m 3- and 4-H). (±)-(3·,4‚,5·,6·)-3,4-Bis(benzyloxy)-5,6-(cyclohexylidenedioxy) cyclohexene 18 and (±)-(3‚,4·,5·,6·)-3,4-bis(benzyloxy)- 5,6-(cyclohexylidenedioxy)cyclohexene 19 To hexane-washed NaH (0.35 g 14.4 mmol) in DMF (10 cm3) was added a solution of compounds 14 and 15 (1.3 g 5.75 mmol) in DMF (5 cm3) at 0 8C.The reaction mixture was stirred for 15 min at 0 8C and benzyl bromide (2.24 g 14.4 mmol) was added dropwise. The reaction mixture was stirred for 30 min at room temperature. After completion of the reaction the mixture was quenched with methanol followed by ice– water and extracted into CH2Cl2. The organic phase was washed with water dried (Na2SO4) and concentrated to obtain title compounds 18 and 19 (2.28 g 98%) as a syrup (Found C 76.39; H 7.84. C26H30O4 requires C 76.82; H 7.44%); dH 1.3– 1.7 (10 H m cyclohexylidene) 3.5–4.6 (4 H m 3- 4- 5- and 6-H) 4.6–4.85 (4 H m C6H5CH2 × 2) 5.5–5.9 (2 H m 1- and 2-H) and 7.25–7.45 (10 H m ArH).(±)-(1·,2·,5·,6‚)-5,6-Bis(benzyloxy)cyclohex-3-ene-1,2-diol 20 and (±)-(1·,2·,5‚,6·)-5,6-bis(benzyloxy)cyclohex-3-ene-1,2-diol 21 To a solution of compounds 18 and 19 (2.2 g 5.4 mmol) in CH2Cl2–CH3OH (60 and 10 cm3) was added a catalytic amount of p-TsOH (20 mg) and the mixture was stirred for 3 h at 0 8C before being warmed to room temperature and stirred for another 1 h. The reaction mixture was neutralised with triethylamine and concentrated to obtain a residue which was filtered on a bed of silica gel (eluted with 50% ethyl acetate in hexane) to obtain the title compounds (1.65 g 90%) as a syrup (Found C 73.06; H 7.26. C20H24O4 requires C 73.14; H 7.37%); dH 2.5–2.8 (2 H br s OH) 3.55–4.3 (4 H m 1- 2- 5- and 6-H) 4.45–4.95 (4 H m C6H5CH2 × 2) 5.7–5.9 (2 H m 3- and 4-H) and 7.2–7.35 (10 H m ArH).(±)-(3a·,6·,7‚,7a·)-6,7-Bis(benzyloxy)-3a,6,7,7a-tetrahydrobenzo[ d][1,3]dioxole-2-thione 22 and (±)-(3a·,6‚,7·,7a·)-6,7- bis(benzyloxy)-3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxole-2- thione 23 To a solution of compounds 20 and 21 (1.6 g 4.91 mmol) in dry toluene (10 cm3) was added 1,19-thiocarbonyldiimidazole (1.31 g 7.36 mmol) and the mixture was refluxed under nitrogen for 1 h. After completion of the reaction the mixture was diluted with toluene (20 cm3) and then concentrated to obtain a residue which was filtered on a bed of silica gel (eluted with 25% ethyl acetate in hexane) to obtain the title compounds (1.71 g 95%) as a syrup (Found C 67.99; H 5.86. C21H20O4S requires C 68.47; H 5.47%); dH 3.7–4.2 (2 H m 6- and 7-H) 4.6–5.3 (6 H m 3a- and 7a-H C6H5CH2 × 2) 5.8–6.2 (2 H m 4- and 5-H) and 7.2–7.35 (10 H m ArH).(±)-trans-5,6-Bis(benzyloxy)cyclohexa-1,3-diene 24 Thiocarbonate derivatives 22 and 23 (1.65 g 4.48 mmol) were refluxed for 2 h in trimethyl phosphite (0.94 g 6.72 mmol) under nitrogen. After completion of the reaction the mixture was made alkaline by the addition of aq. NaOH and was extracted into CH2Cl2. The organic phase was washed with water (50 cm3 × 3) dried (Na2SO4) and concentrated to obtain the title compound (1.17 g 90%) as a syrup (Found C 82.03; H 6.81. C20H20O2 requires C 82.15; H 6.89%); M1 292; lmax(Me- OH) 259 nm; dH 4.37 (2 H s 5- and 6-H) 4.55 (4 H s C6H5CH2 × 2) 5.83 (4 H s 1- 2- 3- and 4-H) and 7.2–7.35 (10 H m ArH). (±)-(3‚,4·,5‚,6‚)-3,4-Bis(benzyloxy)-5,6-epoxycyclohexene 25 To a solution of compound 24 (1.0 g 3.42 mmol) in CH2Cl2 (200 cm3) were added MCPBA (0.59 g 3.42 mmol) and NaHCO3 (0.28 g 3.42 mmol) and the mixture was stirred at room temperature for 4 h.After completion of the reaction the mixture was diluted with CH2Cl2 (50 cm3) and washed successively with saturated aq. NaHCO3 and water. The organic phase was dried (Na2SO4) and concentrated to obtain the title compound (0.97 g 92%) as a syrup (Found C 77.83; H 6.47. C20H20O3 requires C 77.90; H 6.54%); dH 3.2–3.5 (2 H m 5- and 6-H) 3.84 (1 H d J3,4 7.7 3-H) 4.19 (1 H d J3,4 7.7 4-H) 4.65–4.95 (4 H m C6H5CH2 × 2) 5.92 (2 H AB-type doublet J 8.8 1- and 2-H) and 7.25–7.4 (10 H m ArH). Acknowledgements M. P. thanks the University Grants Commission New Delhi for financial support in the form of a Junior Research Fellowship.References 1 K. Stormer Zentralbl. Bakteriol. Parasitenk. Infek. 1908 20 282. 2 N. L. Sohngen Centr. Bakteriol. Parasitenk. Abt. II. 1913 37 595 (Chem. Abstr. 1913 7 3348); T. Weiland G. Griss and B. Haccius Arch. Microbiol. 1958 28 383; B. Haccius and O. Helfrich Arch. Microbiol. 1958 28 394. 1758 J. Chem. Soc. Perkin Trans. 1 1997 3 D. T. Gibson and V. Subramanian in Microbial Degradation of Organic Compounds ed. D. T. Gibson Microbiology Series Marcel Dekker New York 1984 vol. 13 ch. 7–13 inclusive. 4 T. Hudlicky and J. W. Reed Advances in Asymmetric Synthesis JAI Press 1995 vol. 1 p. 271. 5 D. T. Gibson J. R. Koch and R. E. Kallio Biochemistry 1968 7 2653. 6 D. T. Gibson M. Hensley H. Yoshioka and T. J. Mabry Biochemistry 1970 9 1626. 7 D. T. Gibson G. E. Cardini F. C.Maseles and R. E. Kallio Biochemistry 1970 9 1631. 8 D. T. Gibson J. R. Koch C. L. Schuld and R. E. Kallio Biochemistry 1968 7 3795. 9 D. T. Gibson B. Gschwendt W. K. Yeh and V. M. Kobal Biochemistry 1973 12 1520. 10 J. J. DeFrank and D. W. Ribbons J. Bacteriol. 1977 129 1356; G. J. Wigmore and D. W. Ribbons J. Bacteriol. 1980 143 816. 11 S. V. Ley and F. Sternfeld Tetrahedron 1989 45 3463. 12 S. V. Ley and A. J. Redgrave Synlett 1990 393. 13 D. M. Jerina H. Ziffer and J. W. Daly J. Am. Chem. Soc. 1970 92 1056. 14 T. Sato T. Fukuyama T. Suzuki and H. Yoshikawa J. Biochem. (Tokyo) 1963 53 23. 15 M. V. Ganey R. E. Padykula and G. A. Berchtold J. Org. Chem. 1989 54 2787. 16 T. Posternak D. Reymond and H. Friedli Helv. Chim. Acta 1955 38 205. 17 N. A. B. Wilson and J. Read J. Chem. Soc.1935 1269. 18 H. Suemune A. Hasegawa and K. Sakai Tetrahedron Asymmetry 1995 6 55. 19 K. L. Platt and F. Oesch Synthesis 1977 449. 20 B. Beier K. Schurrle O. Werbitzky and W. Piepersberg J. Chem. Soc. Perkin Trans. 1 1990 2255. 21 H. Secen Y. Sutbeyaz and M. Balci Tetrahedron Lett. 1990 31 1323. 22 G. Kresze and W. Dittel Liebigs Ann. Chem. 1981 610. 23 C. H. Kuo and N. L. Wendler Tetrahedron Lett. 1984 25 2291. 24 K. Schurrle B. Beier O. Werbitzky and W. Piepersberg Carbohydr. Res. 1991 212 321. 25 H. A. J. Carless and K. Busia Tetrahedron Lett. 1990 31 1617. 26 H. A. J. Carless and K. Busia Tetrahedron Lett. 1990 31 3449. 27 H. A. J. Carless and K. Busia Carbohydr. Res. 1992 234 207. 28 H. B. Mereyala and M. Pannala Tetrahedron Lett. 1995 36 2121. 29 D. J. R. Massy and P. Wyss Helv.Chim. Acta 1990 73 1037. 30 J. P. Vacca S. J. deSolms J. R. Hoff D. C. Billington R. Baker J. J. Kulagowski and I. M. Mawer Tetrahedron 1989 45 5679. 31 P. J. Garegg and B. Samuelsson Synthesis 1979 469. 32 D. H. R. Barton P. Dalko and S. D. Gero Tetrahedron Lett. 1991 32 2471; H. A. Staab and G. Walther Justus Liebigs Ann. Chem. 1962 657 104. Paper 6/05576A Received 9th August 1996 Accepted 20th February 1997 © Copyright 1997 by the Royal Society of Chemistry
ISSN:1472-7781
DOI:10.1039/a605576a
出版商:RSC
年代:1997
数据来源: RSC
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