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A highly diastereoselective total synthesis of (±)-heritonin and (±)-heritol
Tetrahedron 68 (2012) 8509e8514
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A highly diastereoselective total synthesis of ()-heritonin and ()-heritol Subhash P. Chavan *, Sumanta Garai, Uttam R. Kalkote Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 February 2012 Received in revised form 6 July 2012 Accepted 9 July 2012 Available online 24 July 2012
A highly diastereoselective synthesis of heritol and heritonin by intramolecular cyclization on a preformed sensitive butenolide functionality is described. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: FriedeleCrafts acylation Butenolide Tetralone Dihydroxylation Cyclization
1. Introduction Different parts of the world produce a wide range of interesting natural products having important biological activity of considerable pharmacological interest. Miles and co-workers have isolated cadinane sesquiterpene lactones heritol (1)1 and heritonin (2)2 (Fig. 1) from the sap of the mangrove plant Heritiera littoralis of Philippines and other tropical countries, which were shown to possess ichthyotoxicity in parts per million quantities to Tilapia nilotica fingerlings and is used by native fishermen to kill fish. These compounds represent a new and novel class of sesquiterpene and possess unusual oxygenation pattern not generally encountered in cadinane family. Until date three racemic syntheses by others3a,b and us3c and one enantioselective synthesis by us4 of heritol 1 and heritonin 2 are reported in literature. We were the first to report the enantioselective
synthesis of heritol 1 and assign the correct absolute configuration. All reported syntheses involve first construction of tetralin unit of heritol followed by the installation of the sensitive butenolide ring at a later stage3a,c,4 or begin with substituted tetralone as the starting material and then involve the synthesis of butenolide ring.3b,d However, most of the reported syntheses have drawbacks, involving lengthy routes and/or expensive starting materials, hazardous reagents or harsh reaction conditions and/or proceed in low overall yields. To overcome these problems there still exists a need to develop a simple, practical and efficient synthesis of heritol 1 and heritonin 2. The potential interesting biological activity and unique structural features of heritol and heritonin and our interest in butenolides prompted us to develop an efficient strategy for the synthesis of heritol 1 and heritonin 2.
2. Results and discussion
Fig. 1. Structure of heritol and heritonin.
* Corresponding author. Fax: þ91 20 5892629; e-mail address: sp.chavan@ ncl.res.in (S.P. Chavan). 0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2012.07.020
As a part of our continuing interest in synthesis of terpenes,5 we report herein a conceptually different, convenient and efficient synthesis of () heritonin 2 and () heritol 1 via butenolide ring formation followed by tetralin unit. Retrosynthetic analysis of heritonin 2 and heritol 1 (Scheme 1) revealed that heritonin 2 and heritol 1 can be obtained from tetralone unit 3, which in turn could be obtained from acid 4 via intramolecular FriedeleCrafts acylation. The acid 4 having a,b-unsaturated lactone can be synthesized from keto compound 5. The keto compound 5 can be accessed from cheap and commercially available starting material 6. According to retrosynthetic analysis, synthesis of heritol 1 and heritonin 2 began with FriedeleCrafts acylation of o-cresol methyl
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ether 6 with allylacetyl chloride in dichloromethane (DCM) at room temperature to furnish the corresponding allylic keto compound 5
BF3$OEt2, PTSA in DCM at room temperature (Table 1). Gratifyingly, use of excess BF3$OEt2 proved to be an ideal condition, which furnished compound 9 and 10 in 9.5:1 ratio. This may be attributed to BF3$OEt2 acting as a monodentate Lewis acid with two molecules of BF3$OEt2 complexing separately with the ethereal oxygen and C16eOH leading to the formation of benzylic carbocation, which on loss of acidic proton a to ester group leads to the formation of butenolide 9 (Scheme 2).
Scheme 1. Retrosynthetic analysis of ()-heritonin 2 and ()-heritol 1.
in 95% yield. Reformatsky reaction on 5 with ethyl 2bromopropionate using activated Zn in benzene/diethylether (1:1) as the solvent at reflux condition gave b-hydroxy ester, which without further purification was treated with PTSA in DCM at room temperature to afford selectively b,g-unsaturated ester 7 as an inseparable mixture of geometrical isomers (82:18) in 85% yield (over two steps). The b,g-unsaturated ester 7 was subjected to exhaustive dihydroxylation of both the double bonds with OsO4. It was observed that the reaction did not go to completion even after five to six days and also after sequential/portionwise addition of OsO4 over 2e3 days due to the presence of tri-substituted highly sterically congested double bond. The exact reason as to why the reaction does not go to completion is not clear to us but we believe that the active dihydroxylation catalyst gets ‘poisoned’ and is not available for further dihydroxylation. So it was decided to perform stepwise dihydroxylation. Thus selective dihydroxylation of monosubstituted olefin of b,g-unsaturated ester 7 by using OsO4, NMO as a co-oxidant in acetonitrile/water (9:1) as solvent system furnished the diol 8 in 99% yield. Further dihydroxylation of sterically crowded tri-substituted olefin of diol 8 was successfully carried out under same reaction conditions for three days. The crude tetrol mixture on treatment with PTSA furnished the desired a,b-unsaturated lactone 9 along with undesired cyclized product 10 in 1:1.2 ratio. The structure of undesired bicyclic compound was confirmed by single crystal XRD spectroscopy (Fig. 2).6 In an attempt to get the desired compound 9 as the sole product, the crude mixture was treated with different stoichiometric amounts of
Scheme 2. Reagents and conditions: (a) allylacetyl chloride, CF3SO3H, DCM, rt, 4 h, 95%; (b) (i) ethyl 2-bromopropionate, activated Zn, benzene/ether (1:1), reflux, 3 h; (ii) PTSA, DCM, rt, 12 h, 85% (over two steps); (c) OsO4, NMO, acetonitrile/water (9:1), 30 min, 99%; (d) (i) OsO4, NMO, acetonitrile/water (9:1), 3 days; (ii) BF3$OEt2, DCM, rt, 1 h, 76% (9), 8% (10).
Table 1 Optimization for butenolide synthesis Entry no
Conditions
Ratio 9:10
1 2 3
PTSA BF3$OEt2 (2.5 equiv) BF3$OEt2 (excess)
1:1.2 1.02:1 9.5:1
The undesired bicyclic compound 10 was subjected to standard iodination reaction conditions, but surprisingly it was observed that the allylic lactone 11 was formed under the reaction conditions. The mechanism of this reaction is uncertain and is under investigation. The proposed mechanism leading to the formation of 11 is depicted in Scheme 4. It seems likely that similar to the iodoepoxide opening by Zn7 and I2, PPh3,8 specifically, iodolactone 12 was formed in our case as an intermediate. On iodine elimination followed by dehydration, it gave rise to allylic lactone 11. Several attempts were made to cyclize the allylic lactone 11 to achieve target molecule 2 via acid catalyzed cyclization and via epoxide formation but unfortunately those efforts were unsuccessful. Then we converted allylic lactone 11 to desired diol 9 in very good yield by treatment with OsO4, NMO as a co-oxidant in acetonitrile/water (9:1) as solvent (Scheme 3).
Scheme 3. Reagents and conditions: (a) PPh3, I2, imidazole, toluene, reflux, 6 h, 95%; (b) OsO4, NMO, acetonitrile/water (9:1), 24 h, 75%.
Fig. 2. ORTEP diagram of the bicyclic compound 10.
After successful synthesis of compound 9 having butenolide ring using our own developed methodology,3d next task was to construct the tetralin unit of heritol via cyclization. Toward this end,
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stereochemistry of the compound 13 was confirmed by 2D NOESY spectral analysis. The hydroxy compound 13 was subjected to deoxygenation using triethylsilane,11 BF3$OEt2 in DCM. Interestingly and gratifyingly, it afforded only the desired diastereomer 2 in 96% yield. This may be attributed to the steric hindrance of the butenolide moiety, which direct the hydride from the face opposite to it thereby resulting in cis stereochemistry (Fig. 3).
Scheme 4. Proposed mechanism for transformation of compound 10 to compound 11. Fig. 3. Face selectivity of deoxygenation reaction.
our efforts to cyclize compound 9 to get tetralin unit using a variety of conditions involving acid catalyzed cyclization of diol, and also via epoxide formation were not successful. This result illustrated that the meta position (C5 position, heritol numbering) of the ring is deactivated due to the long conjugation of ring electron with the butenolide ring. This finding, however allowed us to attempt the cyclization by FriedeleCrafts acylation because the intermediate acyl cation would be highly electrophilic, thus facilitating cyclization at the deactivated C5 position. Based on this hypothesis, the compound 9 was subjected to oxidative cleavage by using NaIO4 to afford aldehyde. The crude aldehyde was subjected to oxidation9 using NaClO2 to afford acid 4 in 78% yield (over two steps). Acid 4 was converted to its acid chloride using oxalyl chloride in DCM solvent at room temperature. After distillation of excess oxalyl chloride and solvent, the crude acid chloride was treated with triflic acid10 in DCM at reflux condition to furnish the key intermediate 3 in 95% yield (over two steps, based on starting acid 4 with recovered, 36% conversion from acid 4) (Scheme 5). Having key intermediate tetralone 3 in hand, the remaining task was introduction of methyl group. Grignard reaction of 3 with methyl magnesium bromide furnished the corresponding hydroxy compound 13 in 97% yield as a single diastereomer. The relative
Scheme 5. Reagents and conditions: (a) (i) NaIO4, acetone/H2O (3:1), 0 C-rt, 15 min; (ii) NaClO2, NaH2PO4, H2O2, acetonitrile, rt, 4 h, 78% (over two steps); (b) (i) oxalyl chloride, DCM, overnight; (ii) CF3SO3H, DCM, reflux, 3 h, 95% (after two steps, based on starting material recovered); (c) MeMgBr (1.5 equiv), THF, 78e0 C, 5 h, 97%; (d) Et3SiH, BF3$OEt2, DCM, 78 C, 96%; (e) AlCl3, EtSH, DCM, rt, 12 h, 80%.
Spectral data of compound 2 matched with literature data.4 This result indicates that the stereochemistry at the C8 position directs the stereochemistry at the C10 position because the beta face is sterically crowded by lactone ring. Finally, compound 2 was subjected to demethylation with AlCl3/EtSH at room temperature to afford heritol 1 in 80% yields. Spectral data for heritol 1 was in complete agreement with data reported by us eariler.4 3. Conclusions and summary In conclusion, we have achieved the highly diastereoselective total synthesis of racemic heritonin 2 and heritol 1 from cheap and commercially available starting materials in eight and nine purification operation in 43% and 33% overall yield, respectively, which is highest overall yield reported so far. Currently work on asymmetric synthesis of heritonin, heritol, and other cadinane sesquiterpene lactones is in progress, which will be reported in due course. 4. Experimental section 4.1. General Melting points are recorded using Buchi B-540 or M-560 melting point apparatus in capillary tubes and are uncorrected and the temperatures are in centigrade scale. IR spectra were recorded on a PerkineElmer Infrared Spectrophotometer Model 68B or on a PerkineElmer 1615 FT Infrared spectrophotometer. 1H (200 and 400 MHz) and 13C (50 and 100 MHz) NMR spectra were recorded on Bruker and Bruker Advance 400 spectrometers, using a 1:1 mixture of CDCl3 and CCl4 as solvent. The chemical shifts (d ppm) and coupling constants (hertz) are reported in the standard fashion with reference to chloroform, d 7.26 (for 1H) or the central line (77.0 ppm) of CDCl3 (for 13C). In the 13C NMR spectra, the nature of the carbons (C, CH, CH2, or CH3) was determined by recording the DEPT-135 spectra. Microanalytical data were obtained using a Carlo-Erba CHNSeO EA 1108 elemental analyzer, within the limits of accuracy (0.4%). The reaction progress was monitored by the TLC analysis using thin layer plates precoated with silica gel 60 F254 (Merck) and visualized by fluorescence quenching or iodine or by charring after treatment with p-anisaldehyde. Merck’s flash silica gel (300e400 mesh) was used for column chromatography. All small scale dry reactions were carried out using standard syringeseptum technique. Low temperature reactions were carried out using a bath made of sodium chloride and ice. Dry THF was
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obtained by distillation over sodium/benzophenone ketyl. Dry DCM was prepared by distillation over phosphorous pentoxide or calcium hydride. Dry benzene was obtained by distillation over sodium. All other reagents and solvents were used as received from the manufacturer, unless otherwise specified. All air and water sensitive reactions were performed in flasks flame dried under positive flow of argon and conducted under an argon atmosphere.
[MþNa]þ. Anal. Calcd for C18H24O3: C, 74.97; H, 8.39. Found: C, 75.03; H, 8.34.
4.1.1. 1-(4-Methoxy-3-methylphenyl)-pent-4-en-1-one (5). To a cold (0 C), magnetically stirred solution of o-cresol methyl ether 6 (1 g, 8.2 mmol) and freshly prepared allylacetyl chloride (1 mL, 9.02 mmol) in anhydrous DCM (10 mL) was added catalytic amount (0.1 mL) of trifluoromethanesulphonic acid and stirred for 4 h at room temperature. The reaction was quenched with saturated NaHCO3 solution (10 mL) and extracted with DCM (310 mL). The combined organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4 and filtered. Evaporation of the solvent under reduced pressure and purification of the resultant residue on a silica gel column using ethyl acetate/hexane (0.5:9.5) as eluent furnished the keto compound 5 (1.54 g, 95%) as a colorless oil. Rf (10% EtOAc/hexane) 0.6; IR (CHCl3) 2924, 1676, 1640, 1602, 1503 cm1; 1H NMR (200 MHz, CDCl3þCCl4): d 2.25 (s, 3H), 2.42e2.54 (m, 2H), 3.02 (t, J¼7.1 Hz, 2H), 3.90 (s, 3H), 4.97e5.14 (m, 2H), 5.80e6.01 (m, 1H), 6.84 (d, J¼8.9 Hz, 1H), 7.78 (d, J¼2.5 Hz, 1H), 7.83 (dd, J¼2.3, 8 Hz, 1H). 13C NMR (50 MHz, CDCl3þCCl4): d 16.21, 28.37, 37.19, 55.32, 109.06, 115.04, 126.55, 128.04, 129.47, 130.52, 137.51, 161.56, 197.77. MS (EI): m/z 205 [MþH]þ, 227 [MþNa]þ. Anal. Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C, 76.31; H, 8.04.
4 .1. 3 . ( E ) a n d ( Z ) - E t h yl 6 , 7 - d i h y d r o x y - 3 - ( 4 - m e t h o x y - 3 methylphenyl)-2-methylhept-3-enoate (8). To a cold (0 C), magnetically stirred solution of b,g-unsaturated ester 7 (1 g, 3.5 mmol) in acetonitrile/water (9:1) (10 mL), catalytic amount OsO4 (0.1 mL, 0.1 M solution in toluene) was added in presence of N-methylmorpholine-N-oxide (NMO) (472 mg, 3.5 mmol) as a co-oxidant and stirred for 30 min at room temperature. The reaction was quenched with saturated Na2SO3 (10 mL) solution and again stirred for 30 min. The solvent was evaporated and the residue was extracted with ethyl acetate (310 mL). The combined organic layer was washed with brine (7 mL) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue on a silica gel column using ethyl acetate/ hexane (5:5) as eluent furnished the diol compound 8 (1.11 g, 99%) as yellowish oil. Rf (100% EtOAc) 0.8; IR (CHCl3) 3444, 2939, 1732, 1605, 1502 cm1; 1H NMR (200 MHz, CDCl3þCCl4, mixture of geometrical isomers): d 1.18e1.26 (m, 6H), 2.05e2.17 (m, 2H), 2.19 (s, 3H), 3.36e3.71 (m, 2H), 3.81 and 3.82 (s, 3H), 4.05e4.16 (m, 2H), 5.57e5.69 (m, 1H), 6.68e6.76 (m, 1H), 6.84e6.98 (m, 2H). 13C NMR (50 MHz, CDCl3þCCl4, mixture of geometrical isomers): d 14.13, 14.18, 16.29, 33.01, 47.91, 47.95, 55.04, 55.11, 60.30, 60.53, 66.15, 71.97, 72.00, 109.35, 124.29, 124.32, 126.09, 127.04, 130.85, 130.95, 131.00, 142.09, 142.16, 156.67, 174.70, 174.75. MS (EI): m/z 323 [MþH]þ, 345 [MþNa]þ. Anal. Calcd for C18H26O5: C, 67.06; H, 8.13. Found: C, 67.36; H, 8.18.
4.1.2. (E) and (Z)-Ethyl 3-(4-methoxy-3-methylphenyl)-2methylhepta-3,6-dienoate (7). To a magnetically stirred solution of allylic keto compound 5 (1 g, 4.9 mmol) and activated Zn (961 mg, 14.7 mmol) and in the presence of catalytic amount of iodine in anhydrous diethylether and benzene (1:1) (5 mL), was slowly added a solution of ethyl 2-bromopropionate (0.96 mL, 7.35 mmol) in anhydrous diethylether and benzene (1:1) (5 mL) over a period of 15 min and further refluxed (80 C) for 3 h in an argon atmosphere. The reaction mixture was cooled to 0 C and quenched with 10% HCl (10 mL) and extracted with ethyl acetate (38 mL). The combined organic layer was washed with brine (7 mL) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude alcohol was used as such in the next reaction without further purification. Catalytic amount PTSA was added to a magnetically stirred solution of b-hydroxy ester (1.45 g, 4.7 mmol) obtained above in dry DCM (15 mL) and stirred for 12 h at room temperature in an argon atmosphere. Saturated NaHCO3 solution (10 mL) was added to the reaction mixture and extracted with DCM (310 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4 and filtered. Evaporation of the solvent and purification of the residue on a silica gel column using ethyl acetate/hexane (0.2:9.8) as eluent furnished the mixture of geometrical isomers (80:20, confirmed by GC and GC-mass analysis) of 7 (1.19 g, 85%) as colorless oil, which were found to be inseparable by column chromatography on silica gel as well as on silver nitrate impregnated silica gel.12 Rf (10% EtOAc/hexane) 0.6; IR (CHCl3) 2986, 2837, 1731, 1607, 1504 cm1; 1H NMR (200 MHz, CDCl3þCCl4, 8:2 mixture of geometrical isomers): d 1.16e1.31 (m, 6H), 2.20 (s, 3H), 2.63e2.70 and 2.93e3.10 (m, 2H), 3.39 (q, J¼7.1 Hz, 1H), 3.82 and 3.83 (s, 3H), 4.06e4.16 (m, 2H), 4.94e5.07 (m, 2H), 5.53e5.88 (m, 2H), 6.70e6.78 (m, 1H), 6.89e7.07 (m, 2H). 13C NMR (50 MHz, CDCl3þCCl4, 8:2 mixture of geometrical isomers): d 14.07, 14.15, 15.86, 16.24, 16.53, 32.06, 33.15, 40.83, 47.69, 55.04, 55.10, 60.26, 60.48, 109.22, 114.70, 115.18, 125.49, 125.58, 125.86, 125.92, 126.93, 127.73, 127.75, 130.85, 131.19, 134.19, 136.25, 137.06, 140.17, 141.02, 156.69, 156.77, 174.31, 174.36. MS (EI): m/z 289 [MþH]þ, 311
4.1.4. 5-(2,3-Dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)-3methylfuran-2(5H)-one (9). To a cold (0 C), magnetically stirred solution of diol 8 (1 g, 3.1 mmol) in acetonitrile/water (9:1) (10 mL), catalytic amount of OsO4 (0.1 mL, 0.1 M solution in toluene) was added in presence of N-methylmorpholine-N-oxide (NMO) (838 mg, 6.2 mmol) as a co-oxidant and stirred for 3 days at room temperature. The reaction was quenched with saturated Na2SO3 solution (10 mL) and again stirred for 30 min. Evaporation of the solvent furnished a residue, which was extracted with ethyl acetate (38 mL). The combined organic layer was washed with brine (7 mL) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was used as such in the next reaction without further purification. Catalytic amount of PTSA was added to a magnetically stirred solution of tetrol (300 mg, 0.96 mmol) in dry DCM (3 mL) and stirred for 12 h at room temperature in an argon atmosphere. Saturated NaHCO3 solution (10 mL) was added to the reaction mixture and extracted with CH2Cl2 (38 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered. Evaporation of the solvent under reduced pressure and purification of the residue thus obtained on a silica gel column gave mixture of lactone 9 (120 mg, 42%) and bicyclic compound 10 (146 mg, 52%) in 0.82:1 ratio. To a magnetically stirred solution of tetrol (2.1 g, 6.77 mmol) in dry DCM (20 mL), excess BF3$OEt2 (4.2 mL) was added and the reaction mixture was stirred for 12 h at room temperature in an argon atmosphere. Saturated NaHCO3 solution (10 mL) was added to the reaction mixture and extracted with CH2Cl2 (38 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4 and filtered. Evaporation of the solvent under reduced pressure furnished a residue. Purification of the residue on a silica gel column gave mixture of lactone 9 (1.5 g, 76% yield) and bicyclic compound 10 (0.15 g, 8%) in 9.5:1 ratio. Compound 9: white solid, melting point 102e105 C; Rf (80% EtOAc/hexane) 0.4; IR (CHCl3) 3421, 3019, 2927, 1741, 1647, 1607, 1508 cm1; 1H NMR (200 MHz, CDCl3): d 1.77e1.89 (m, 1H), 2.02 (s, 3H), 2.17e2.20 (m, 1H), 2.23 (s, 3H), 3.30e3.39 (m, 1H), 3.50e3.61
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(m, 2H), 3.85 (s, 3H), 5.48e5.65 (m, 1H), 6.85e6.90 (d, J¼8.6 Hz, 1H), 7.18e7.24 (m, 2H). 13C NMR (50 MHz, CDCl3þCCl4): d 9.99, 10.05, 16.15, 37.11, 37.54, 55.25, 65.74, 66.61, 68.71, 69.33, 78.69, 79.36, 110.01, 120.41, 120.68, 122.89, 122.99, 127.11, 127.28, 130.08, 158.93, 160.23, 160.28, 175.09, 175.33. MS (EI): m/z 293 [MþH]þ, 315 [MþNa]þ. Anal. Calcd for C16H20O5: C, 65.74; H, 6.90. Found: C, 65.84; H, 6.86. Compound 10: white solid, melting point 90e116 C (mixture of diastereomers); Rf (80% EtOAc/hexane) 0.8; IR (CHCl3) 3444, 2978, 1774, 1610, 1504 cm1; 1H NMR (200 MHz, CDCl3þCCl4, mixture of two diastereomers): d 1.18 and 1.21 (d, J¼7.2 Hz, 1H), 1.90e2.30 (m, 2H), 2.24 (s, 3H), 2.83e2.95 (q, 1H), 3.58e3.70 (m, 2H), 3.84 and 3.85 (s, 3H), 4.34e4.41 (m, 1H), 5.08e5.17 (m, 1H), 6.82 and 6.86 (d, J¼8 Hz, 1H), 7.17e7.25 (m, 2H). 13C NMR (50 MHz, CDCl3, mixture of two diastereomers): d 7.40, 7.65, 16.19, 32.45, 32.59, 47.57, 48.56, 55.12, 64.04, 65.00, 79.56, 80.10, 86.58, 87.49, 90.82, 91.79, 109.60, 109.76, 123.56, 123.58, 126.67, 126.84, 127.01, 127.15, 128.74, 131.09, 157.16, 157.32, 177.08, 177.39. MS (EI): 315 [MþNa]þ. Anal. Calcd for C16H20O5: C, 65.74; H, 6.90. Found: C, 65.59; H, 6.95. 4.1.5. 2-(3-(4-Methoxy-3-methylphenyl)-4-methyl-5-oxo-2,5dihydrofuran-2-yl)acetic acid (4). To a magnetically stirred solution of lactone 9 (270 mg, 0.92 mmol) in acetone/water (3:1), NaIO4 (556 mg, 2.6 mmol) was added portion wise and stirred for 15 min at room temperature. The solid residue was separated by filtration. The filtrate was extracted with DCM (35 mL). The combined organic layer was washed with brine (7 mL) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude aldehyde was used in the next reaction without further purification. A solution of NaClO2 (230 mg, 2.5 mmol) in water (2 mL) was added dropwise to a stirred mixture of crude aldehyde (210 mg, 0.81 mmol) in acetonitrile (5 mL) and NaH2PO4 (324 mg, 2.13 mmol) in water (2 mL) and 2.13 mL of 35% H2O2, keeping the temperature at 10 C with water cooling. Oxygen evolved from the solution and the reaction was monitored by TLC until the end of the reaction (about 4 h). A small amount (100 mg) of Na2SO3 was added to destroy the unreacted HOCl and H2O2. After acidification with 10% aqueous HCl (3 mL), it was extracted with ethyl acetate (35 mL). The combined organic layer was washed with brine (3 mL) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue was done on a silica gel column using ethyl acetate/hexane (5:5) as eluent to furnish the acid 4 (200 mg, 78%) as a white solid, melting point 135e137 C. Rf (80% EtOAc/hexane) 0.6 (long tail); IR (CHCl3) 3456, 3020, 2950, 1747, 1651, 1606, 1507 cm1; 1H NMR (200 MHz, CDCl3þCCl4): d 2.07 (d, J¼1.5 Hz, 3H), 2.27 (s, 3H), 2.41 (dd, J¼9.6, 18 Hz, 1H), 2.83 (dd, J¼2.5, 17 Hz, 1H), 3.90 (s, 3H), 5.75 (m, 1H), 6.93 (d, J¼8.4 Hz, 1H), 7.17 (d, J¼2 Hz, 1H), 7.23 (dd, J¼8, 2 Hz, 1H). 13C NMR (50 MHz, CDCl3þC2D6SO): d 10.05, 16.20, 38.68, 55.33, 77.75, 110.20, 121.33, 122.44, 127.02, 127.26, 129.79, 158.18, 158.96, 171.36, 174.13. MS (EI): m/z 277 [MþH]þ, 299 [MþNa]þ. Anal. Calcd for C15H16O5: C, 65.21; H, 5.84. Found: C, 65.31; H, 5.89. 4.1.6. 7-Methoxy-1,8-dimethyl-3a,4-dihydronaphtho[2,1-b]furan2,5-dione (3). To a magnetically stirred solution of acid 4 (110 mg, 0.4 mmol) in DCM (3 mL), was added dropwise excess oxalyl chloride (1.0 mL) and stirred overnight at room temperature. Excess oxalyl chloride and solvent was distilled out at 120 C (oil bath temperature). The crude acid chloride was used in the next reaction without further purification. To the stirred solution of crude acid chloride (100 mg) in DCM (3 mL) under reflux was added catalytic amount (0.02 mL) of trifluoromethanesulphonic acid. The reaction mixture was heated to reflux for 3 h and it was diluted with water and extracted with DCM (33 mL). Combined organic layers were then washed with brine
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(3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography using ethyl acetate/hexane (1.5:8.5) as eluent to furnish the tetralone 3 (40 mg, 95% based on the recovery 54 mg of acid 4) as a white solid with melting point 203e205 C. Compound 3: Rf (15% EtOAc/hexane) 0.7; IR (Nujol) 2923, 2853, 1745, 1702, 1636, 1602, 1508 cm1; 1H NMR (200 MHz, CDCl3): d 2.21 (d, J¼2 Hz, 3H), 2.36 (s, 3H), 2.62 (dd, J¼16, 12 Hz, 1H), 3.51 (dd, J¼16, 6 Hz, 1H), 3.95 (s, 3H), 5.17e5.31 (m, 1H), 7.53 (s, 1H), 7.56 (s, 1H). 13C NMR (50 MHz, CDCl3): d 9.82, 16.94, 45.24, 55.80, 76.76, 107.67, 120.86, 125.25, 129.23, 131.88, 135.35, 152.65, 159.83, 174.17, 192.61. MS (ESI): m/z 259 [MþH]þ, 281 [MþNa]þ. Anal. Calcd for C15H14O4: C, 69.76; H, 5.46. Found: C, 69.44; H, 5.39. 4.1.7. 5-Hydroxy-7-methoxy-1,5,8-trimethyl-4,5-dihydronaphtho [2,1-b]furan-2(3aH)-one (13). To a dry round bottom flask under argon was added tetralone 3 (100 mg, 1.4 mmol) in dry THF (2 mL). The solution was cooled to 78 C and MeMgBr (1.4 M, Aldrich make) (0.43 mL, 0.6 mmol) was added dropwise. The reaction was stirred at same temperature for 1 h, then slowly allowed to come room temperature and further stirred at room temperature for 5 h. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate (33 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and, concentrated under reduced pressure. The crude product was purified by flash column chromatography (20% EtOAc/hexane) to provide the product 13 (103 mg, 97% yield) as a white semisolid compound. Rf (50% EtOAc/ hexane) 0.5; IR (Nujol) 3529, 2925, 2855, 1739, 1646, 1613 cm1; 1H NMR (200 MHz, CDCl3þCCl4): d 1.63 (s, 3H), 1.85 (t, J¼11.4 Hz, 1H), 2.12 (d, J¼2 Hz, 3H), 2.26 (s, 3H), 2.81 (dd, J¼11, 4 Hz, 1H), 3.93 (s, 3H), 4.88e4.97 (m, 1H), 7.19 (s, 1H), 7.39 (s, 1H). 13C NMR (50 MHz, CDCl3þCCl4): d 9.84, 16.16, 29.68, 31.65, 46.32, 55.48, 71.57, 77.11, 96.11, 107.66, 116.92, 118.74, 127.26, 129.00, 145.15, 155.74, 160.09, 175.21. MS (ESI): m/z 275 [MþH]þ, 297 [MþNa]þ. Anal. Calcd for C16H18O4: C, 70.06; H, 6.61. Found: C, 70.26; H, 6.69. 4.1.8. (3aS,5R)-7-Methoxy-1,5,8-trimethyl-4,5-dihydronaphtho[2,1b]furan-2(3aH)-one [heritonin, 2]. To a magnetically stirred solution of hydroxy compound 13 (30 mg, 0.11 mmol) in DCM (3 mL) at 78 C was added BF3$OEt2 (0.07 mL, 0.55 mmol) and Et3SiH (0.1 mL, 0.66 mmol) dropwise. The reaction was allowed to warm up to room temperature over 30 min and stirred at room temperature for 3 h and quenched by adding saturated NaHCO3 solution (3 mL) and extracted with DCM (35 mL). The organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4 and filtered. Evaporation of the solvent and purification of the residue on a silica gel (5% EtOAc/hexane) to provide the product heritonin 2 (27 mg, 96% yield) as a white solid, melting point 115e117 C (lit. 115e116 C). IR (Nujol) 2926, 2854, 1747, 1659, 1611 cm1; 1H NMR (CDCl3, 200 MHz): d 1.46 (d, J¼7 Hz, 3H), 1.36e1.64 (m, 1H), 2.14 (d, J¼1.6 Hz, 3H), 2.25 (s, 3H), 2.58e2.69 (m, 1H), 3.04e3.22 (m, 1H), 3.89 (s, 3H), 4.85e4.94 (m, 1H), 6.84 (s, 1H), 7.41 (s, 1H). 13C NMR (CDCl3, 50 MHz): d 9.88, 15.98, 21.70, 31.95, 38.62, 55.32, 78.14, 108.32, 115.86, 120.65, 125.70, 129.57, 142.21, 156.71, 159.53, 175.63. MS (ESI): m/z 259 [MþH]þ, 281 [MþNa]þ. 4.1.9. (3aS,5R)-7-Hydroxy-1,5,8-trimethyl-4,5-dihydronaphtho[2,1b]furan-2(3aH)-one4 [heritol, 1]. Ethanethiol (1 mL) was added to a magnetically stirred solution of methyl ether 2 (20 mg, 0.078 mmol) and anhydrous aluminum chloride (50 mg, 0.375 mmol) in DCM (1 mL) at room temperature. The reaction mixture was allowed to stir for 12 h. Water was added to the reaction mixture and the separated solid was extracted with DCM (35 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to furnish
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a white solid, melting point 270e271 C (lit. 271e272 C). Purification of the solid by flash column chromatography using 20% ethyl acetate/hexane as an eluent afforded heritol 1 (18 mg, 94% yield) as a white solid. IR (CHCl3) 3595, 2960, 2360, 1749, 1654, 1559 cm1; 1 H NMR (CDCl3þCD3OD, 500 MHz): d 1.41 (d, J¼7 Hz, 3H), 1.43e1.48 (m, 1H), 2.11 (d, J¼1.5 Hz, 3H), 2.26 (s, 3H), 2.58e2.62 (m, 1H), 3.04e3.10 (m, 1H), 4.91e4.95 (m, 1H), 6.88 (s, 1H), 7.40 (s, 1H). 13C NMR (CDCl3þCD3OD, 125 MHz): d 9.38, 15.36, 21.00, 31.39, 38.34, 78.57, 113.01, 114.41, 120.65, 119.58, 123.59, 130.00, 142.16, 157.63, 157.95, 175.53. MS (ESI): m/z 245 [MþH]þ, 267 [MþNa]þ. 4.1.10. 5-Allyl-4-(4-methoxy-3-methylphenyl)-3-methylfuran-2(5H)one (11). A mixture of bicyclic lactone 10 (146 mg, 0.5 mmol), PPh3 (262 mg, 1.0 mmol), imidazole (34 mg, 0.5 mmol), and iodine (262 mg, 1.0 mmol) in anhydrous toluene (5 mL) was stirred and refluxed under nitrogen atmosphere for 6 h. After completion of reaction, it was diluted with water and extracted with ethyl acetate (35 mL). Combined organic layers were then washed with saturated solution of Na2S2O3 (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography using ethyl acetate/hexane (2:8) as eluent to furnish the allylic lactone 11 (96 mg, 95% yield) as a yellowish white semisolid compound. Rf (30% EtOAc/hexane) 0.7; IR (CHCl3) 3020, 2800, 1750, 1646, 1606, 1508 cm1; 1H NMR (200 MHz, CDCl3þCCl4): d 1.92e2.09 (m, 4H), 2.15e2.24 (m, 1H), 2.27 (s, 3H), 3.90 (s, 3H), 4.95e5.09 (m, 2H), 5.34e5.39 (m, 1H), 5.56e5.76 (m, 1H), 6.91 (d, J¼8.2 Hz, 1H), 7.14e7.24 (m, 2H). 13C NMR (50 MHz, CDCl3þCCl4): d 10.06, 16.38, 37.02, 55.37, 80.53, 110.04, 119.07, 122.22, 123.41, 126.91, 127.64, 129.97, 131.15, 158.46, 158.93, 174.61. MS (EI): m/z 259 [MþH]þ, 281 [MþNa]þ. Anal. Calcd for C16H18O3: C, 74.39; H, 7.02. Found: C, 74.54; H, 7.09. 4.1.11. 5-(2,3-Dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)-3methylf uran -2(5 H) -on e ( 9) f rom 5-allyl -4- (4-methox y-3methylphenyl)-3-methylfuran-2(5H)-one (11). To a cold (0 C), magnetically stirred solution of allylic lactone 11 (100 mg, 0.4 mmol) in acetonitrile/water (9:1) (10 mL), catalytic amount of OsO4 (0.1 mL, 0.1 M solution in toluene) was added in presence of N-methylmorpholine-N-oxide (NMO) as a co-oxidant and stirred for 1 h at room temperature. The reaction was quenched with saturated Na2SO3 solution (5 mL) and again stirred for 0.5 h. Evaporation of the solvent furnished the residue, which was
extracted with ethyl acetate (38 mL). The combined organic layer was washed with brine (7 mL) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue on a silica gel column using ethyl acetate/hexane (1:1) as eluent furnished the diol compound 9 (85 mg, 75% yield) as white solid. Acknowledgements S.G. thanks CSIR, New Delhi, India, for a fellowship and S.P.C. acknowledges funding from NCL inhouse project [MLP 012726]. Supplementary data Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.tet.2012.07.020. References and notes 1. Miles, D. H.; Lho, D.-S.; de la Cruz, A. A.; Gomez, E. D.; Weeks, J. A.; Atwood, J. L. J. Org. Chem. 1987, 52, 2930e2932. 2. Miles, D. H.; Maria Ly, A.; Chittawong, V. J. Nat. Prod. 1989, 52, 896e898. 3. (a) Irie, H.; Matsumoto, R.; Nishimura, M.; Zhang, Y. Chem. Pharm. Bull. 1990, 38, 1852e1856; (b) Silveira, C. C.; Machado, A.; Braga, A. L.; Lenardao, E. J. Tetrahedron Lett. 2004, 45, 4077e4080; (c) Zubaidha, P. K.; Chavan, S. P.; Racherla, U. S.; Ayyangar, N. R. Tetrahedron 1991, 47, 5759e5768; (d) Chavan, S. P.; Zubaidha, P. K.; Ayyangar, N. R. Tetrahedron Lett. 1992, 33, 4605e4608. 4. Chavan, S. P.; Thakkar, M.; Kalkote, U. R. Tetrahedron Lett. 2007, 48, 643e646. 5. (a) Chavan, S. P.; Ravindranathan, T.; Patil, S. S.; Dhondge, V.; Dantale, S. W. Tetrahedron Lett. 1996, 37, 2629e2630; (b) Chavan, S. P.; Ravindranathan, T.; Patil, S. S. Tetrahedron 1999, 40, 4733e4734; (c) Chavan, S. P.; Thakkar, M.; Kharul, R. K.; Pathak, A. B.; Bhosekar, G. V.; Bhadbhade, M. M. Tetrahedron 2005, 61, 3873e3879; (d) Chavan, S. P.; Kharul, R. K.; Kale, R. R.; Khobragade, D. A. Tetrahedron 2003, 59, 2737e2741; (e) Chavan, S. P.; Dhawane, A. N.; Kalkote, U. R. Tetrahedron Lett. 2007, 48, 965e966; (f) Chavan, S. P.; Dhawane, A. N.; Kalkote, U. R. Synthesis 2007, 3827e3830. 6. Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 866165. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: þ44-(0)1223 336033 or e-mail: [email protected]). 7. Hayashi, N.; Mine, T.; Fujiwara, K.; Mural, A. Chem. Lett. 1994, 2143e2146. 8. Takemura, A.; Fujiwara, K.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2004, 45, 7567e7571 and references therein. 9. Dalcanale, E. J. Org. Chem. 1986, 51, 567e569. 10. Epple, G.; Effenberger, F. Angew. Chem., Int. Ed. Engl. 1972, 11, 300e301. 11. Fry, J.; Adlington, M. G.; Orfanopoulos, M. Tetrahedron Lett. 1976, 17, 2955e2958. 12. Williams, C. M.; Lewis, N.; Mander, L. N. Tetrahedron 2001, 57, 425e447.
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A highly diastereoselective total synthesis of ()-heritonin and ()-heritol Subhash P. Chavan *, Sumanta Garai, Uttam R. Kalkote Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 February 2012 Received in revised form 6 July 2012 Accepted 9 July 2012 Available online 24 July 2012
A highly diastereoselective synthesis of heritol and heritonin by intramolecular cyclization on a preformed sensitive butenolide functionality is described. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: FriedeleCrafts acylation Butenolide Tetralone Dihydroxylation Cyclization
1. Introduction Different parts of the world produce a wide range of interesting natural products having important biological activity of considerable pharmacological interest. Miles and co-workers have isolated cadinane sesquiterpene lactones heritol (1)1 and heritonin (2)2 (Fig. 1) from the sap of the mangrove plant Heritiera littoralis of Philippines and other tropical countries, which were shown to possess ichthyotoxicity in parts per million quantities to Tilapia nilotica fingerlings and is used by native fishermen to kill fish. These compounds represent a new and novel class of sesquiterpene and possess unusual oxygenation pattern not generally encountered in cadinane family. Until date three racemic syntheses by others3a,b and us3c and one enantioselective synthesis by us4 of heritol 1 and heritonin 2 are reported in literature. We were the first to report the enantioselective
synthesis of heritol 1 and assign the correct absolute configuration. All reported syntheses involve first construction of tetralin unit of heritol followed by the installation of the sensitive butenolide ring at a later stage3a,c,4 or begin with substituted tetralone as the starting material and then involve the synthesis of butenolide ring.3b,d However, most of the reported syntheses have drawbacks, involving lengthy routes and/or expensive starting materials, hazardous reagents or harsh reaction conditions and/or proceed in low overall yields. To overcome these problems there still exists a need to develop a simple, practical and efficient synthesis of heritol 1 and heritonin 2. The potential interesting biological activity and unique structural features of heritol and heritonin and our interest in butenolides prompted us to develop an efficient strategy for the synthesis of heritol 1 and heritonin 2.
2. Results and discussion
Fig. 1. Structure of heritol and heritonin.
* Corresponding author. Fax: þ91 20 5892629; e-mail address: sp.chavan@ ncl.res.in (S.P. Chavan). 0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2012.07.020
As a part of our continuing interest in synthesis of terpenes,5 we report herein a conceptually different, convenient and efficient synthesis of () heritonin 2 and () heritol 1 via butenolide ring formation followed by tetralin unit. Retrosynthetic analysis of heritonin 2 and heritol 1 (Scheme 1) revealed that heritonin 2 and heritol 1 can be obtained from tetralone unit 3, which in turn could be obtained from acid 4 via intramolecular FriedeleCrafts acylation. The acid 4 having a,b-unsaturated lactone can be synthesized from keto compound 5. The keto compound 5 can be accessed from cheap and commercially available starting material 6. According to retrosynthetic analysis, synthesis of heritol 1 and heritonin 2 began with FriedeleCrafts acylation of o-cresol methyl
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ether 6 with allylacetyl chloride in dichloromethane (DCM) at room temperature to furnish the corresponding allylic keto compound 5
BF3$OEt2, PTSA in DCM at room temperature (Table 1). Gratifyingly, use of excess BF3$OEt2 proved to be an ideal condition, which furnished compound 9 and 10 in 9.5:1 ratio. This may be attributed to BF3$OEt2 acting as a monodentate Lewis acid with two molecules of BF3$OEt2 complexing separately with the ethereal oxygen and C16eOH leading to the formation of benzylic carbocation, which on loss of acidic proton a to ester group leads to the formation of butenolide 9 (Scheme 2).
Scheme 1. Retrosynthetic analysis of ()-heritonin 2 and ()-heritol 1.
in 95% yield. Reformatsky reaction on 5 with ethyl 2bromopropionate using activated Zn in benzene/diethylether (1:1) as the solvent at reflux condition gave b-hydroxy ester, which without further purification was treated with PTSA in DCM at room temperature to afford selectively b,g-unsaturated ester 7 as an inseparable mixture of geometrical isomers (82:18) in 85% yield (over two steps). The b,g-unsaturated ester 7 was subjected to exhaustive dihydroxylation of both the double bonds with OsO4. It was observed that the reaction did not go to completion even after five to six days and also after sequential/portionwise addition of OsO4 over 2e3 days due to the presence of tri-substituted highly sterically congested double bond. The exact reason as to why the reaction does not go to completion is not clear to us but we believe that the active dihydroxylation catalyst gets ‘poisoned’ and is not available for further dihydroxylation. So it was decided to perform stepwise dihydroxylation. Thus selective dihydroxylation of monosubstituted olefin of b,g-unsaturated ester 7 by using OsO4, NMO as a co-oxidant in acetonitrile/water (9:1) as solvent system furnished the diol 8 in 99% yield. Further dihydroxylation of sterically crowded tri-substituted olefin of diol 8 was successfully carried out under same reaction conditions for three days. The crude tetrol mixture on treatment with PTSA furnished the desired a,b-unsaturated lactone 9 along with undesired cyclized product 10 in 1:1.2 ratio. The structure of undesired bicyclic compound was confirmed by single crystal XRD spectroscopy (Fig. 2).6 In an attempt to get the desired compound 9 as the sole product, the crude mixture was treated with different stoichiometric amounts of
Scheme 2. Reagents and conditions: (a) allylacetyl chloride, CF3SO3H, DCM, rt, 4 h, 95%; (b) (i) ethyl 2-bromopropionate, activated Zn, benzene/ether (1:1), reflux, 3 h; (ii) PTSA, DCM, rt, 12 h, 85% (over two steps); (c) OsO4, NMO, acetonitrile/water (9:1), 30 min, 99%; (d) (i) OsO4, NMO, acetonitrile/water (9:1), 3 days; (ii) BF3$OEt2, DCM, rt, 1 h, 76% (9), 8% (10).
Table 1 Optimization for butenolide synthesis Entry no
Conditions
Ratio 9:10
1 2 3
PTSA BF3$OEt2 (2.5 equiv) BF3$OEt2 (excess)
1:1.2 1.02:1 9.5:1
The undesired bicyclic compound 10 was subjected to standard iodination reaction conditions, but surprisingly it was observed that the allylic lactone 11 was formed under the reaction conditions. The mechanism of this reaction is uncertain and is under investigation. The proposed mechanism leading to the formation of 11 is depicted in Scheme 4. It seems likely that similar to the iodoepoxide opening by Zn7 and I2, PPh3,8 specifically, iodolactone 12 was formed in our case as an intermediate. On iodine elimination followed by dehydration, it gave rise to allylic lactone 11. Several attempts were made to cyclize the allylic lactone 11 to achieve target molecule 2 via acid catalyzed cyclization and via epoxide formation but unfortunately those efforts were unsuccessful. Then we converted allylic lactone 11 to desired diol 9 in very good yield by treatment with OsO4, NMO as a co-oxidant in acetonitrile/water (9:1) as solvent (Scheme 3).
Scheme 3. Reagents and conditions: (a) PPh3, I2, imidazole, toluene, reflux, 6 h, 95%; (b) OsO4, NMO, acetonitrile/water (9:1), 24 h, 75%.
Fig. 2. ORTEP diagram of the bicyclic compound 10.
After successful synthesis of compound 9 having butenolide ring using our own developed methodology,3d next task was to construct the tetralin unit of heritol via cyclization. Toward this end,
S.P. Chavan et al. / Tetrahedron 68 (2012) 8509e8514
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stereochemistry of the compound 13 was confirmed by 2D NOESY spectral analysis. The hydroxy compound 13 was subjected to deoxygenation using triethylsilane,11 BF3$OEt2 in DCM. Interestingly and gratifyingly, it afforded only the desired diastereomer 2 in 96% yield. This may be attributed to the steric hindrance of the butenolide moiety, which direct the hydride from the face opposite to it thereby resulting in cis stereochemistry (Fig. 3).
Scheme 4. Proposed mechanism for transformation of compound 10 to compound 11. Fig. 3. Face selectivity of deoxygenation reaction.
our efforts to cyclize compound 9 to get tetralin unit using a variety of conditions involving acid catalyzed cyclization of diol, and also via epoxide formation were not successful. This result illustrated that the meta position (C5 position, heritol numbering) of the ring is deactivated due to the long conjugation of ring electron with the butenolide ring. This finding, however allowed us to attempt the cyclization by FriedeleCrafts acylation because the intermediate acyl cation would be highly electrophilic, thus facilitating cyclization at the deactivated C5 position. Based on this hypothesis, the compound 9 was subjected to oxidative cleavage by using NaIO4 to afford aldehyde. The crude aldehyde was subjected to oxidation9 using NaClO2 to afford acid 4 in 78% yield (over two steps). Acid 4 was converted to its acid chloride using oxalyl chloride in DCM solvent at room temperature. After distillation of excess oxalyl chloride and solvent, the crude acid chloride was treated with triflic acid10 in DCM at reflux condition to furnish the key intermediate 3 in 95% yield (over two steps, based on starting acid 4 with recovered, 36% conversion from acid 4) (Scheme 5). Having key intermediate tetralone 3 in hand, the remaining task was introduction of methyl group. Grignard reaction of 3 with methyl magnesium bromide furnished the corresponding hydroxy compound 13 in 97% yield as a single diastereomer. The relative
Scheme 5. Reagents and conditions: (a) (i) NaIO4, acetone/H2O (3:1), 0 C-rt, 15 min; (ii) NaClO2, NaH2PO4, H2O2, acetonitrile, rt, 4 h, 78% (over two steps); (b) (i) oxalyl chloride, DCM, overnight; (ii) CF3SO3H, DCM, reflux, 3 h, 95% (after two steps, based on starting material recovered); (c) MeMgBr (1.5 equiv), THF, 78e0 C, 5 h, 97%; (d) Et3SiH, BF3$OEt2, DCM, 78 C, 96%; (e) AlCl3, EtSH, DCM, rt, 12 h, 80%.
Spectral data of compound 2 matched with literature data.4 This result indicates that the stereochemistry at the C8 position directs the stereochemistry at the C10 position because the beta face is sterically crowded by lactone ring. Finally, compound 2 was subjected to demethylation with AlCl3/EtSH at room temperature to afford heritol 1 in 80% yields. Spectral data for heritol 1 was in complete agreement with data reported by us eariler.4 3. Conclusions and summary In conclusion, we have achieved the highly diastereoselective total synthesis of racemic heritonin 2 and heritol 1 from cheap and commercially available starting materials in eight and nine purification operation in 43% and 33% overall yield, respectively, which is highest overall yield reported so far. Currently work on asymmetric synthesis of heritonin, heritol, and other cadinane sesquiterpene lactones is in progress, which will be reported in due course. 4. Experimental section 4.1. General Melting points are recorded using Buchi B-540 or M-560 melting point apparatus in capillary tubes and are uncorrected and the temperatures are in centigrade scale. IR spectra were recorded on a PerkineElmer Infrared Spectrophotometer Model 68B or on a PerkineElmer 1615 FT Infrared spectrophotometer. 1H (200 and 400 MHz) and 13C (50 and 100 MHz) NMR spectra were recorded on Bruker and Bruker Advance 400 spectrometers, using a 1:1 mixture of CDCl3 and CCl4 as solvent. The chemical shifts (d ppm) and coupling constants (hertz) are reported in the standard fashion with reference to chloroform, d 7.26 (for 1H) or the central line (77.0 ppm) of CDCl3 (for 13C). In the 13C NMR spectra, the nature of the carbons (C, CH, CH2, or CH3) was determined by recording the DEPT-135 spectra. Microanalytical data were obtained using a Carlo-Erba CHNSeO EA 1108 elemental analyzer, within the limits of accuracy (0.4%). The reaction progress was monitored by the TLC analysis using thin layer plates precoated with silica gel 60 F254 (Merck) and visualized by fluorescence quenching or iodine or by charring after treatment with p-anisaldehyde. Merck’s flash silica gel (300e400 mesh) was used for column chromatography. All small scale dry reactions were carried out using standard syringeseptum technique. Low temperature reactions were carried out using a bath made of sodium chloride and ice. Dry THF was
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obtained by distillation over sodium/benzophenone ketyl. Dry DCM was prepared by distillation over phosphorous pentoxide or calcium hydride. Dry benzene was obtained by distillation over sodium. All other reagents and solvents were used as received from the manufacturer, unless otherwise specified. All air and water sensitive reactions were performed in flasks flame dried under positive flow of argon and conducted under an argon atmosphere.
[MþNa]þ. Anal. Calcd for C18H24O3: C, 74.97; H, 8.39. Found: C, 75.03; H, 8.34.
4.1.1. 1-(4-Methoxy-3-methylphenyl)-pent-4-en-1-one (5). To a cold (0 C), magnetically stirred solution of o-cresol methyl ether 6 (1 g, 8.2 mmol) and freshly prepared allylacetyl chloride (1 mL, 9.02 mmol) in anhydrous DCM (10 mL) was added catalytic amount (0.1 mL) of trifluoromethanesulphonic acid and stirred for 4 h at room temperature. The reaction was quenched with saturated NaHCO3 solution (10 mL) and extracted with DCM (310 mL). The combined organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4 and filtered. Evaporation of the solvent under reduced pressure and purification of the resultant residue on a silica gel column using ethyl acetate/hexane (0.5:9.5) as eluent furnished the keto compound 5 (1.54 g, 95%) as a colorless oil. Rf (10% EtOAc/hexane) 0.6; IR (CHCl3) 2924, 1676, 1640, 1602, 1503 cm1; 1H NMR (200 MHz, CDCl3þCCl4): d 2.25 (s, 3H), 2.42e2.54 (m, 2H), 3.02 (t, J¼7.1 Hz, 2H), 3.90 (s, 3H), 4.97e5.14 (m, 2H), 5.80e6.01 (m, 1H), 6.84 (d, J¼8.9 Hz, 1H), 7.78 (d, J¼2.5 Hz, 1H), 7.83 (dd, J¼2.3, 8 Hz, 1H). 13C NMR (50 MHz, CDCl3þCCl4): d 16.21, 28.37, 37.19, 55.32, 109.06, 115.04, 126.55, 128.04, 129.47, 130.52, 137.51, 161.56, 197.77. MS (EI): m/z 205 [MþH]þ, 227 [MþNa]þ. Anal. Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C, 76.31; H, 8.04.
4 .1. 3 . ( E ) a n d ( Z ) - E t h yl 6 , 7 - d i h y d r o x y - 3 - ( 4 - m e t h o x y - 3 methylphenyl)-2-methylhept-3-enoate (8). To a cold (0 C), magnetically stirred solution of b,g-unsaturated ester 7 (1 g, 3.5 mmol) in acetonitrile/water (9:1) (10 mL), catalytic amount OsO4 (0.1 mL, 0.1 M solution in toluene) was added in presence of N-methylmorpholine-N-oxide (NMO) (472 mg, 3.5 mmol) as a co-oxidant and stirred for 30 min at room temperature. The reaction was quenched with saturated Na2SO3 (10 mL) solution and again stirred for 30 min. The solvent was evaporated and the residue was extracted with ethyl acetate (310 mL). The combined organic layer was washed with brine (7 mL) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue on a silica gel column using ethyl acetate/ hexane (5:5) as eluent furnished the diol compound 8 (1.11 g, 99%) as yellowish oil. Rf (100% EtOAc) 0.8; IR (CHCl3) 3444, 2939, 1732, 1605, 1502 cm1; 1H NMR (200 MHz, CDCl3þCCl4, mixture of geometrical isomers): d 1.18e1.26 (m, 6H), 2.05e2.17 (m, 2H), 2.19 (s, 3H), 3.36e3.71 (m, 2H), 3.81 and 3.82 (s, 3H), 4.05e4.16 (m, 2H), 5.57e5.69 (m, 1H), 6.68e6.76 (m, 1H), 6.84e6.98 (m, 2H). 13C NMR (50 MHz, CDCl3þCCl4, mixture of geometrical isomers): d 14.13, 14.18, 16.29, 33.01, 47.91, 47.95, 55.04, 55.11, 60.30, 60.53, 66.15, 71.97, 72.00, 109.35, 124.29, 124.32, 126.09, 127.04, 130.85, 130.95, 131.00, 142.09, 142.16, 156.67, 174.70, 174.75. MS (EI): m/z 323 [MþH]þ, 345 [MþNa]þ. Anal. Calcd for C18H26O5: C, 67.06; H, 8.13. Found: C, 67.36; H, 8.18.
4.1.2. (E) and (Z)-Ethyl 3-(4-methoxy-3-methylphenyl)-2methylhepta-3,6-dienoate (7). To a magnetically stirred solution of allylic keto compound 5 (1 g, 4.9 mmol) and activated Zn (961 mg, 14.7 mmol) and in the presence of catalytic amount of iodine in anhydrous diethylether and benzene (1:1) (5 mL), was slowly added a solution of ethyl 2-bromopropionate (0.96 mL, 7.35 mmol) in anhydrous diethylether and benzene (1:1) (5 mL) over a period of 15 min and further refluxed (80 C) for 3 h in an argon atmosphere. The reaction mixture was cooled to 0 C and quenched with 10% HCl (10 mL) and extracted with ethyl acetate (38 mL). The combined organic layer was washed with brine (7 mL) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude alcohol was used as such in the next reaction without further purification. Catalytic amount PTSA was added to a magnetically stirred solution of b-hydroxy ester (1.45 g, 4.7 mmol) obtained above in dry DCM (15 mL) and stirred for 12 h at room temperature in an argon atmosphere. Saturated NaHCO3 solution (10 mL) was added to the reaction mixture and extracted with DCM (310 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4 and filtered. Evaporation of the solvent and purification of the residue on a silica gel column using ethyl acetate/hexane (0.2:9.8) as eluent furnished the mixture of geometrical isomers (80:20, confirmed by GC and GC-mass analysis) of 7 (1.19 g, 85%) as colorless oil, which were found to be inseparable by column chromatography on silica gel as well as on silver nitrate impregnated silica gel.12 Rf (10% EtOAc/hexane) 0.6; IR (CHCl3) 2986, 2837, 1731, 1607, 1504 cm1; 1H NMR (200 MHz, CDCl3þCCl4, 8:2 mixture of geometrical isomers): d 1.16e1.31 (m, 6H), 2.20 (s, 3H), 2.63e2.70 and 2.93e3.10 (m, 2H), 3.39 (q, J¼7.1 Hz, 1H), 3.82 and 3.83 (s, 3H), 4.06e4.16 (m, 2H), 4.94e5.07 (m, 2H), 5.53e5.88 (m, 2H), 6.70e6.78 (m, 1H), 6.89e7.07 (m, 2H). 13C NMR (50 MHz, CDCl3þCCl4, 8:2 mixture of geometrical isomers): d 14.07, 14.15, 15.86, 16.24, 16.53, 32.06, 33.15, 40.83, 47.69, 55.04, 55.10, 60.26, 60.48, 109.22, 114.70, 115.18, 125.49, 125.58, 125.86, 125.92, 126.93, 127.73, 127.75, 130.85, 131.19, 134.19, 136.25, 137.06, 140.17, 141.02, 156.69, 156.77, 174.31, 174.36. MS (EI): m/z 289 [MþH]þ, 311
4.1.4. 5-(2,3-Dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)-3methylfuran-2(5H)-one (9). To a cold (0 C), magnetically stirred solution of diol 8 (1 g, 3.1 mmol) in acetonitrile/water (9:1) (10 mL), catalytic amount of OsO4 (0.1 mL, 0.1 M solution in toluene) was added in presence of N-methylmorpholine-N-oxide (NMO) (838 mg, 6.2 mmol) as a co-oxidant and stirred for 3 days at room temperature. The reaction was quenched with saturated Na2SO3 solution (10 mL) and again stirred for 30 min. Evaporation of the solvent furnished a residue, which was extracted with ethyl acetate (38 mL). The combined organic layer was washed with brine (7 mL) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was used as such in the next reaction without further purification. Catalytic amount of PTSA was added to a magnetically stirred solution of tetrol (300 mg, 0.96 mmol) in dry DCM (3 mL) and stirred for 12 h at room temperature in an argon atmosphere. Saturated NaHCO3 solution (10 mL) was added to the reaction mixture and extracted with CH2Cl2 (38 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered. Evaporation of the solvent under reduced pressure and purification of the residue thus obtained on a silica gel column gave mixture of lactone 9 (120 mg, 42%) and bicyclic compound 10 (146 mg, 52%) in 0.82:1 ratio. To a magnetically stirred solution of tetrol (2.1 g, 6.77 mmol) in dry DCM (20 mL), excess BF3$OEt2 (4.2 mL) was added and the reaction mixture was stirred for 12 h at room temperature in an argon atmosphere. Saturated NaHCO3 solution (10 mL) was added to the reaction mixture and extracted with CH2Cl2 (38 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4 and filtered. Evaporation of the solvent under reduced pressure furnished a residue. Purification of the residue on a silica gel column gave mixture of lactone 9 (1.5 g, 76% yield) and bicyclic compound 10 (0.15 g, 8%) in 9.5:1 ratio. Compound 9: white solid, melting point 102e105 C; Rf (80% EtOAc/hexane) 0.4; IR (CHCl3) 3421, 3019, 2927, 1741, 1647, 1607, 1508 cm1; 1H NMR (200 MHz, CDCl3): d 1.77e1.89 (m, 1H), 2.02 (s, 3H), 2.17e2.20 (m, 1H), 2.23 (s, 3H), 3.30e3.39 (m, 1H), 3.50e3.61
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(m, 2H), 3.85 (s, 3H), 5.48e5.65 (m, 1H), 6.85e6.90 (d, J¼8.6 Hz, 1H), 7.18e7.24 (m, 2H). 13C NMR (50 MHz, CDCl3þCCl4): d 9.99, 10.05, 16.15, 37.11, 37.54, 55.25, 65.74, 66.61, 68.71, 69.33, 78.69, 79.36, 110.01, 120.41, 120.68, 122.89, 122.99, 127.11, 127.28, 130.08, 158.93, 160.23, 160.28, 175.09, 175.33. MS (EI): m/z 293 [MþH]þ, 315 [MþNa]þ. Anal. Calcd for C16H20O5: C, 65.74; H, 6.90. Found: C, 65.84; H, 6.86. Compound 10: white solid, melting point 90e116 C (mixture of diastereomers); Rf (80% EtOAc/hexane) 0.8; IR (CHCl3) 3444, 2978, 1774, 1610, 1504 cm1; 1H NMR (200 MHz, CDCl3þCCl4, mixture of two diastereomers): d 1.18 and 1.21 (d, J¼7.2 Hz, 1H), 1.90e2.30 (m, 2H), 2.24 (s, 3H), 2.83e2.95 (q, 1H), 3.58e3.70 (m, 2H), 3.84 and 3.85 (s, 3H), 4.34e4.41 (m, 1H), 5.08e5.17 (m, 1H), 6.82 and 6.86 (d, J¼8 Hz, 1H), 7.17e7.25 (m, 2H). 13C NMR (50 MHz, CDCl3, mixture of two diastereomers): d 7.40, 7.65, 16.19, 32.45, 32.59, 47.57, 48.56, 55.12, 64.04, 65.00, 79.56, 80.10, 86.58, 87.49, 90.82, 91.79, 109.60, 109.76, 123.56, 123.58, 126.67, 126.84, 127.01, 127.15, 128.74, 131.09, 157.16, 157.32, 177.08, 177.39. MS (EI): 315 [MþNa]þ. Anal. Calcd for C16H20O5: C, 65.74; H, 6.90. Found: C, 65.59; H, 6.95. 4.1.5. 2-(3-(4-Methoxy-3-methylphenyl)-4-methyl-5-oxo-2,5dihydrofuran-2-yl)acetic acid (4). To a magnetically stirred solution of lactone 9 (270 mg, 0.92 mmol) in acetone/water (3:1), NaIO4 (556 mg, 2.6 mmol) was added portion wise and stirred for 15 min at room temperature. The solid residue was separated by filtration. The filtrate was extracted with DCM (35 mL). The combined organic layer was washed with brine (7 mL) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude aldehyde was used in the next reaction without further purification. A solution of NaClO2 (230 mg, 2.5 mmol) in water (2 mL) was added dropwise to a stirred mixture of crude aldehyde (210 mg, 0.81 mmol) in acetonitrile (5 mL) and NaH2PO4 (324 mg, 2.13 mmol) in water (2 mL) and 2.13 mL of 35% H2O2, keeping the temperature at 10 C with water cooling. Oxygen evolved from the solution and the reaction was monitored by TLC until the end of the reaction (about 4 h). A small amount (100 mg) of Na2SO3 was added to destroy the unreacted HOCl and H2O2. After acidification with 10% aqueous HCl (3 mL), it was extracted with ethyl acetate (35 mL). The combined organic layer was washed with brine (3 mL) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue was done on a silica gel column using ethyl acetate/hexane (5:5) as eluent to furnish the acid 4 (200 mg, 78%) as a white solid, melting point 135e137 C. Rf (80% EtOAc/hexane) 0.6 (long tail); IR (CHCl3) 3456, 3020, 2950, 1747, 1651, 1606, 1507 cm1; 1H NMR (200 MHz, CDCl3þCCl4): d 2.07 (d, J¼1.5 Hz, 3H), 2.27 (s, 3H), 2.41 (dd, J¼9.6, 18 Hz, 1H), 2.83 (dd, J¼2.5, 17 Hz, 1H), 3.90 (s, 3H), 5.75 (m, 1H), 6.93 (d, J¼8.4 Hz, 1H), 7.17 (d, J¼2 Hz, 1H), 7.23 (dd, J¼8, 2 Hz, 1H). 13C NMR (50 MHz, CDCl3þC2D6SO): d 10.05, 16.20, 38.68, 55.33, 77.75, 110.20, 121.33, 122.44, 127.02, 127.26, 129.79, 158.18, 158.96, 171.36, 174.13. MS (EI): m/z 277 [MþH]þ, 299 [MþNa]þ. Anal. Calcd for C15H16O5: C, 65.21; H, 5.84. Found: C, 65.31; H, 5.89. 4.1.6. 7-Methoxy-1,8-dimethyl-3a,4-dihydronaphtho[2,1-b]furan2,5-dione (3). To a magnetically stirred solution of acid 4 (110 mg, 0.4 mmol) in DCM (3 mL), was added dropwise excess oxalyl chloride (1.0 mL) and stirred overnight at room temperature. Excess oxalyl chloride and solvent was distilled out at 120 C (oil bath temperature). The crude acid chloride was used in the next reaction without further purification. To the stirred solution of crude acid chloride (100 mg) in DCM (3 mL) under reflux was added catalytic amount (0.02 mL) of trifluoromethanesulphonic acid. The reaction mixture was heated to reflux for 3 h and it was diluted with water and extracted with DCM (33 mL). Combined organic layers were then washed with brine
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(3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography using ethyl acetate/hexane (1.5:8.5) as eluent to furnish the tetralone 3 (40 mg, 95% based on the recovery 54 mg of acid 4) as a white solid with melting point 203e205 C. Compound 3: Rf (15% EtOAc/hexane) 0.7; IR (Nujol) 2923, 2853, 1745, 1702, 1636, 1602, 1508 cm1; 1H NMR (200 MHz, CDCl3): d 2.21 (d, J¼2 Hz, 3H), 2.36 (s, 3H), 2.62 (dd, J¼16, 12 Hz, 1H), 3.51 (dd, J¼16, 6 Hz, 1H), 3.95 (s, 3H), 5.17e5.31 (m, 1H), 7.53 (s, 1H), 7.56 (s, 1H). 13C NMR (50 MHz, CDCl3): d 9.82, 16.94, 45.24, 55.80, 76.76, 107.67, 120.86, 125.25, 129.23, 131.88, 135.35, 152.65, 159.83, 174.17, 192.61. MS (ESI): m/z 259 [MþH]þ, 281 [MþNa]þ. Anal. Calcd for C15H14O4: C, 69.76; H, 5.46. Found: C, 69.44; H, 5.39. 4.1.7. 5-Hydroxy-7-methoxy-1,5,8-trimethyl-4,5-dihydronaphtho [2,1-b]furan-2(3aH)-one (13). To a dry round bottom flask under argon was added tetralone 3 (100 mg, 1.4 mmol) in dry THF (2 mL). The solution was cooled to 78 C and MeMgBr (1.4 M, Aldrich make) (0.43 mL, 0.6 mmol) was added dropwise. The reaction was stirred at same temperature for 1 h, then slowly allowed to come room temperature and further stirred at room temperature for 5 h. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate (33 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and, concentrated under reduced pressure. The crude product was purified by flash column chromatography (20% EtOAc/hexane) to provide the product 13 (103 mg, 97% yield) as a white semisolid compound. Rf (50% EtOAc/ hexane) 0.5; IR (Nujol) 3529, 2925, 2855, 1739, 1646, 1613 cm1; 1H NMR (200 MHz, CDCl3þCCl4): d 1.63 (s, 3H), 1.85 (t, J¼11.4 Hz, 1H), 2.12 (d, J¼2 Hz, 3H), 2.26 (s, 3H), 2.81 (dd, J¼11, 4 Hz, 1H), 3.93 (s, 3H), 4.88e4.97 (m, 1H), 7.19 (s, 1H), 7.39 (s, 1H). 13C NMR (50 MHz, CDCl3þCCl4): d 9.84, 16.16, 29.68, 31.65, 46.32, 55.48, 71.57, 77.11, 96.11, 107.66, 116.92, 118.74, 127.26, 129.00, 145.15, 155.74, 160.09, 175.21. MS (ESI): m/z 275 [MþH]þ, 297 [MþNa]þ. Anal. Calcd for C16H18O4: C, 70.06; H, 6.61. Found: C, 70.26; H, 6.69. 4.1.8. (3aS,5R)-7-Methoxy-1,5,8-trimethyl-4,5-dihydronaphtho[2,1b]furan-2(3aH)-one [heritonin, 2]. To a magnetically stirred solution of hydroxy compound 13 (30 mg, 0.11 mmol) in DCM (3 mL) at 78 C was added BF3$OEt2 (0.07 mL, 0.55 mmol) and Et3SiH (0.1 mL, 0.66 mmol) dropwise. The reaction was allowed to warm up to room temperature over 30 min and stirred at room temperature for 3 h and quenched by adding saturated NaHCO3 solution (3 mL) and extracted with DCM (35 mL). The organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4 and filtered. Evaporation of the solvent and purification of the residue on a silica gel (5% EtOAc/hexane) to provide the product heritonin 2 (27 mg, 96% yield) as a white solid, melting point 115e117 C (lit. 115e116 C). IR (Nujol) 2926, 2854, 1747, 1659, 1611 cm1; 1H NMR (CDCl3, 200 MHz): d 1.46 (d, J¼7 Hz, 3H), 1.36e1.64 (m, 1H), 2.14 (d, J¼1.6 Hz, 3H), 2.25 (s, 3H), 2.58e2.69 (m, 1H), 3.04e3.22 (m, 1H), 3.89 (s, 3H), 4.85e4.94 (m, 1H), 6.84 (s, 1H), 7.41 (s, 1H). 13C NMR (CDCl3, 50 MHz): d 9.88, 15.98, 21.70, 31.95, 38.62, 55.32, 78.14, 108.32, 115.86, 120.65, 125.70, 129.57, 142.21, 156.71, 159.53, 175.63. MS (ESI): m/z 259 [MþH]þ, 281 [MþNa]þ. 4.1.9. (3aS,5R)-7-Hydroxy-1,5,8-trimethyl-4,5-dihydronaphtho[2,1b]furan-2(3aH)-one4 [heritol, 1]. Ethanethiol (1 mL) was added to a magnetically stirred solution of methyl ether 2 (20 mg, 0.078 mmol) and anhydrous aluminum chloride (50 mg, 0.375 mmol) in DCM (1 mL) at room temperature. The reaction mixture was allowed to stir for 12 h. Water was added to the reaction mixture and the separated solid was extracted with DCM (35 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to furnish
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a white solid, melting point 270e271 C (lit. 271e272 C). Purification of the solid by flash column chromatography using 20% ethyl acetate/hexane as an eluent afforded heritol 1 (18 mg, 94% yield) as a white solid. IR (CHCl3) 3595, 2960, 2360, 1749, 1654, 1559 cm1; 1 H NMR (CDCl3þCD3OD, 500 MHz): d 1.41 (d, J¼7 Hz, 3H), 1.43e1.48 (m, 1H), 2.11 (d, J¼1.5 Hz, 3H), 2.26 (s, 3H), 2.58e2.62 (m, 1H), 3.04e3.10 (m, 1H), 4.91e4.95 (m, 1H), 6.88 (s, 1H), 7.40 (s, 1H). 13C NMR (CDCl3þCD3OD, 125 MHz): d 9.38, 15.36, 21.00, 31.39, 38.34, 78.57, 113.01, 114.41, 120.65, 119.58, 123.59, 130.00, 142.16, 157.63, 157.95, 175.53. MS (ESI): m/z 245 [MþH]þ, 267 [MþNa]þ. 4.1.10. 5-Allyl-4-(4-methoxy-3-methylphenyl)-3-methylfuran-2(5H)one (11). A mixture of bicyclic lactone 10 (146 mg, 0.5 mmol), PPh3 (262 mg, 1.0 mmol), imidazole (34 mg, 0.5 mmol), and iodine (262 mg, 1.0 mmol) in anhydrous toluene (5 mL) was stirred and refluxed under nitrogen atmosphere for 6 h. After completion of reaction, it was diluted with water and extracted with ethyl acetate (35 mL). Combined organic layers were then washed with saturated solution of Na2S2O3 (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography using ethyl acetate/hexane (2:8) as eluent to furnish the allylic lactone 11 (96 mg, 95% yield) as a yellowish white semisolid compound. Rf (30% EtOAc/hexane) 0.7; IR (CHCl3) 3020, 2800, 1750, 1646, 1606, 1508 cm1; 1H NMR (200 MHz, CDCl3þCCl4): d 1.92e2.09 (m, 4H), 2.15e2.24 (m, 1H), 2.27 (s, 3H), 3.90 (s, 3H), 4.95e5.09 (m, 2H), 5.34e5.39 (m, 1H), 5.56e5.76 (m, 1H), 6.91 (d, J¼8.2 Hz, 1H), 7.14e7.24 (m, 2H). 13C NMR (50 MHz, CDCl3þCCl4): d 10.06, 16.38, 37.02, 55.37, 80.53, 110.04, 119.07, 122.22, 123.41, 126.91, 127.64, 129.97, 131.15, 158.46, 158.93, 174.61. MS (EI): m/z 259 [MþH]þ, 281 [MþNa]þ. Anal. Calcd for C16H18O3: C, 74.39; H, 7.02. Found: C, 74.54; H, 7.09. 4.1.11. 5-(2,3-Dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)-3methylf uran -2(5 H) -on e ( 9) f rom 5-allyl -4- (4-methox y-3methylphenyl)-3-methylfuran-2(5H)-one (11). To a cold (0 C), magnetically stirred solution of allylic lactone 11 (100 mg, 0.4 mmol) in acetonitrile/water (9:1) (10 mL), catalytic amount of OsO4 (0.1 mL, 0.1 M solution in toluene) was added in presence of N-methylmorpholine-N-oxide (NMO) as a co-oxidant and stirred for 1 h at room temperature. The reaction was quenched with saturated Na2SO3 solution (5 mL) and again stirred for 0.5 h. Evaporation of the solvent furnished the residue, which was
extracted with ethyl acetate (38 mL). The combined organic layer was washed with brine (7 mL) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue on a silica gel column using ethyl acetate/hexane (1:1) as eluent furnished the diol compound 9 (85 mg, 75% yield) as white solid. Acknowledgements S.G. thanks CSIR, New Delhi, India, for a fellowship and S.P.C. acknowledges funding from NCL inhouse project [MLP 012726]. Supplementary data Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.tet.2012.07.020. References and notes 1. Miles, D. H.; Lho, D.-S.; de la Cruz, A. A.; Gomez, E. D.; Weeks, J. A.; Atwood, J. L. J. Org. Chem. 1987, 52, 2930e2932. 2. Miles, D. H.; Maria Ly, A.; Chittawong, V. J. Nat. Prod. 1989, 52, 896e898. 3. (a) Irie, H.; Matsumoto, R.; Nishimura, M.; Zhang, Y. Chem. Pharm. Bull. 1990, 38, 1852e1856; (b) Silveira, C. C.; Machado, A.; Braga, A. L.; Lenardao, E. J. Tetrahedron Lett. 2004, 45, 4077e4080; (c) Zubaidha, P. K.; Chavan, S. P.; Racherla, U. S.; Ayyangar, N. R. Tetrahedron 1991, 47, 5759e5768; (d) Chavan, S. P.; Zubaidha, P. K.; Ayyangar, N. R. Tetrahedron Lett. 1992, 33, 4605e4608. 4. Chavan, S. P.; Thakkar, M.; Kalkote, U. R. Tetrahedron Lett. 2007, 48, 643e646. 5. (a) Chavan, S. P.; Ravindranathan, T.; Patil, S. S.; Dhondge, V.; Dantale, S. W. Tetrahedron Lett. 1996, 37, 2629e2630; (b) Chavan, S. P.; Ravindranathan, T.; Patil, S. S. Tetrahedron 1999, 40, 4733e4734; (c) Chavan, S. P.; Thakkar, M.; Kharul, R. K.; Pathak, A. B.; Bhosekar, G. V.; Bhadbhade, M. M. Tetrahedron 2005, 61, 3873e3879; (d) Chavan, S. P.; Kharul, R. K.; Kale, R. R.; Khobragade, D. A. Tetrahedron 2003, 59, 2737e2741; (e) Chavan, S. P.; Dhawane, A. N.; Kalkote, U. R. Tetrahedron Lett. 2007, 48, 965e966; (f) Chavan, S. P.; Dhawane, A. N.; Kalkote, U. R. Synthesis 2007, 3827e3830. 6. Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 866165. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: þ44-(0)1223 336033 or e-mail: [email protected]). 7. Hayashi, N.; Mine, T.; Fujiwara, K.; Mural, A. Chem. Lett. 1994, 2143e2146. 8. Takemura, A.; Fujiwara, K.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2004, 45, 7567e7571 and references therein. 9. Dalcanale, E. J. Org. Chem. 1986, 51, 567e569. 10. Epple, G.; Effenberger, F. Angew. Chem., Int. Ed. Engl. 1972, 11, 300e301. 11. Fry, J.; Adlington, M. G.; Orfanopoulos, M. Tetrahedron Lett. 1976, 17, 2955e2958. 12. Williams, C. M.; Lewis, N.; Mander, L. N. Tetrahedron 2001, 57, 425e447.