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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Org Chem. Author manuscript; available in PMC 2010 October 2.
Published in final edited form as:
PMCID: PMC2756647

Evidence for π-Stacking as a Source of Stereocontrol in the Synthesis of the Core Pyranochromene Ring System common to Calyxin I, Calyxin J, and Epicalyxin J


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A diastereoselective synthesis of the tetrahydropyranochromene ring system common to several natural product isolates of Alpinia blepharocalyx is reported. We have shown that a stereochemical preference exists for a syn configuration between the anomeric aryl substituents, representative of the C-7 and C-7′ substituents in the natural products. Further, our results show that stereocontrol is under kinetic control, and calculations suggest that a favorable π-stacking interaction may be the source of this stereocontrol.

More than fifty polyphenolic constituents of the seeds of Alpinia blepharocalyx have been isolated by Kadota and coworkers,1 and several of them have been shown to possess significant antiproliferative activity against colon 26-L5 carcinoma and HT-1080 fibrosarcoma cells. Not surprisingly, these compounds have attracted the attention of several groups, resulting in both partial2 and total3 syntheses of a number of analogues. Calyxin I (1) along with the epimeric analogues calyxin J (2) and epicalyxin J (3) comprise a subset of isolates that are characterized by the presence of a novel bis-C-arylpyranoside moiety embedded in a tetrahydropyranochromene framework. To date, synthetic work in this area has been sparse. Li and coworkers have reported stereoselective syntheses of compounds 4 and 5 using the Prins cyclization,4 but they did not report the formation of bis-aryl derivatives by their route. We therefore chose compound 6 as a model synthetic target to see if a stereochemical preference exists for the aryl substituents to be syn to each other as indicated, analogous to the C-7 and C-7′ positions in the natural products. The nature of the interaction between the two aromatic rings at these positions would be important, and the possibility of a favorable π-stacking effect was not ruled out as a controlling factor.5

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Our route began with the racemic lactone 8, which was prepared in 56% yield by a palladium-catalyzed addition of 2-benzyloxy-iodobenzene 76 to 5,6-dihydro-2H-pyran- 2-one (Scheme 1). A directed aldol reaction of lactone 8 with p-methoxybenzaldehyde, via its boron enolate, then gave alcohol 9 in a 91% yield as a single isomer,7 which was cleanly converted to the diol 10 in 94% yield under standard hydrogenation conditions. Exposure of diol 10 to Lewis acid then provided compound 11 diastereomerically pure (79% from compound 9). The stereochemistry of compound 11 was easily assignable based on proton NMR coupling constants. A doublet at δ5.22 (J = 10 Hz) established the trans-diaxial relationship between Ha and Hb, while a doublet of doublets at δ3.08 (J = 10, 13 Hz) confirmed the same relationship between Ha and Hc. Although the formation of 11 from diol 10 proceeded with complete inversion of configuration, establishment of the newly-formed ring stereocenter in this reaction, with a pseudoequatorial aryl substituent, is most likely the result of an SN1 mechanism involving formation of a stabilized benzyl carbocation. Unfortunately, attempts to open the lactone ring of 11 by reaction with commercially-available p-methoxyphenyl magnesium bromide gave only starting material. However, use of the corresponding aryl lithium reagent provided 12 in 72% yield. The final ring closure was accomplished in two steps (81%) by treatment of 12 with NaBH4 followed by exposure of the crude mixture of diols 13 to p-TsOH. To our surprise, compound 6 was formed diastereomerically pure by NMR analysis. The stereochemistry was confirmed by assignments of the alicyclic ring protons, which were supported by GIAO calculations of the chemical shifts. Both anomeric protons Hb and Hd appeared as doublets with coupling constants of 9.7 Hz, thereby confirming the trans-diaxial relationship between Ha and Hd. A final verification of the stereochemistry was provided by the NOESY spectrum, which showed the expected cross peaks for Hb-Hc, Hb-Hd, and Hc-Hd, but not for Ha (see Supporting Information).

We considered the possibility that both anomeric stereocenters in 6 were formed under equilibrating conditions, given their potential acid lability.8 Formation of benzyl carbocation 14 from the diol mixture 13 would be expected to be facile by virtue of the stabilizing effect of the para-methoxy group. However, the question of whether this effect was sufficient to allow its formation reversibly from the the pyranochromene product remained to be addressed. To test for thermodynamic control in the formation of compound 6, the mixture of diols 13 was converted to an equal mixture of 6 and its anomer 16 via the primary tosylate 15 (Scheme 2), and the two diastereomers were separated by column chromatography. However, treatment of compound 16 with p-TsOH, TiCl4, or BF3·OEt2 failed to yield any of the syn isomer 6, suggesting that its formation from intermediate 14 is most likely under kinetic control.

In an attempt to determine the origin of the stereocontrol in the formation of 6 from 14, we decided to calculate the relative energies of the syn and anti conformers of carbocation 14, leading to the formation of 6a and 16a, respectively (see Figure 1). These two conformations have been labeled 14-syn and 14-anti to designate the syn and anti relationship, respectively, between the two 4-methoxyphenyl groups. Calculations were carried out using the MP2/cc-pVDZ approach, as this method takes into account the possibility of weak interactions such as π-stacking effects.9 We felt that this could be a significant factor in carbocation 14, as there is the potential for a donor-acceptor interaction, given that one aromatic ring is electron deficient by virtue of the benzylic cationic center. Indeed, our calculations show that conformer 14-syn is 5.7 kcal/mol lower in energy than conformer 14-anti, and that the corresponding ring-closed product, 6a, is 5.0 kcal/mol more stable than 16a. Interestingly, the smaller distances separating the two 4-methoxyphenyl rings in 14-syn indicate that attractive forces are involved. The interatomic separation between carbon atoms 1 and 1′, for example, is 3.07 Å, while carbon atoms 4 and 4′ are separated by a distance of 3.30 Å. This suggests that the stabilization calculated for this conformer might be due to a favorable π-stacking interaction that is obviously absent in 14-anti. Based on these calculations, stereocontrol in the formation of compound 6 (see Scheme 1) can be explained by making the reasonable assumptions that carbocation conformer 14-syn is formed from both diastereomers of diol 13 at a faster rate than 14-anti, and that ring closure from 14-syn is fast relative to conformational interchange. Efforts are currently underway to apply these results to the enantioselective syntheses of both calyxin J and epicaylyxin J.

Figure 1
MP2/cc-pVDZ optimized structures and energies (in Hartrees) of syn (top) and anti (bottom) conformers of carbocation 14 (left), as well as initial ring-closed products 6a and 16a (right). Relative energies (kcal/mol) of the syn-anti pairs are given in ...

Experimental Section

4-(2-Benzyloxyphenyl)-tetrahydropyran-2-one (±8)

A mixture of 1-benzyloxy-2-iodobenzene 76 (174 mg, 0.56 mmol), 5,6-dihydro-2H-pyran-2-one (50 mg, 0.51 mmol), tetra-kis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol), and triethylamine (57 mg, 0.56 mmol) was purged with N2 gas and heated to 80 °C for 10 hours. The solution was quenched with 10% HCl and extracted with EtOAc. The organic layer was washed with water then dried over anhydrous MgSO4. The crude oil was subjected to column chromatography using ethyl acetate/hexane mixture as the eluting solvent to afford the product (81 mg, 56%) as a crystalline white solid (mp: 82–84 °C). 1H NMR (600 MHz, CDCl3): δ 7.42-7.36 (m, 5H), 7.24 (t, J = 7.3 Hz, 1H), 7.15 (d, J = 7.1 Hz, 1H), 7.00-6.96 (m, 2H), 5.09 (s, 2H), 4.43-4.25 (m, 2H), 3.65-3.55 (m, 1H), 2.90 (dd, J = 5.9 and 17.3 Hz, 1H), 2.67 (dd, J = 10.2, 17.3 Hz, 1H), 2.10-2.00 (m, 1H); 13C NMR (150 MHz, CDCl3): δ 171.4, 155.9, 136.7, 131.1, 128.6, 128.0, 127.2, 126.8, 121.1, 112.0, 70.1, 68.4, 35.8, 31.8, 28.5; FT-IR (CHCl3): 3033, 2904, 1736, 1234, 752 cm−1. HRMS: calculated for C18H18O3 282.1255 and found 282.1256.

4-(2-Benzyloxyphenyl)-3-[hydroxy-(4-methoxyphenyl)-methyl]-tetrahydropyran-2-one (9)

Dibutylboron tri-fluoromethanesulfonate (1M solution in dichloromethane, 6.6 mL, 6.6 mmol) and N,N-diisopropylethylamine (1.4 mL, 8.25 mmol) were added to a solution of lactone 8 (930 mg, 3.3 mmol) in dichloromethane (20 mL) at −78 °C. The resultant mixture was stirred at the same temperature for 2 hours and then p-methoxy benzaldehyde (0.8 mL, 6.6 mmol) was added to the mixture and stirred for another 2 hours. After being stirred an additional 2 hours at 0 °C, phosphate buffer solution (pH= 7.0, 8 mL), methanol (15 mL), and H2O2 (30 wt. % solution in water, 8 mL) were added and stirred overnight at room temperature. The solvent was removed in vacuo and the residue was extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/hexane mixture as eluting solvent to give the product (1.25 g, 91%) as a crystalline white solid (mp: 122–124 °C). 1H NMR (600 MHz, CDCl3): δ 7.43-7.36 (m, 5H), 7.33 (dt, J = 1.6 and 8.3 Hz, 1H), 7.11 (d, J = 8.5 Hz, 3H), 6.95 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.75 (d, J = 8.7 Hz, 2H), 5.07 (d, J = 11.2 Hz, 1H), 5.04 (d, J = 11.2 Hz, 1H), 4.72 (s (broad), 1H), 4.24-4.19 (m, 1H), 4.08-4.04 (m, 1H), 3.81-3.80 (m, 1H), 3.76 (s, 3H), 3.56-3.49 (m, 2H), 2.18-2.11 (m, 1H), 2.05-1.99 (m, 1H); 13C NMR (150 MHz, CDCl3): δ 174.2, 158.7, 155.8, 136.3, 133.8, 130.7, 129.7, 128.7, 128.3, 128.2, 127.7, 127.3, 121.1, 113.4, 112.0, 72.6, 70.2, 67.0, 55.1, 50.3, 36.0, 29.1; FT-IR (CHCl3): 3445 (broad), 2935, 1716, 1512, 1248, 752 cm−1

3-[Hydroxy-(4-methoxyphenyl)-methyl]-4-(2-hydroxy-phenyl)-tetrahydropyran-2-one (10)

Lactone 9 (700 mg, 1.7 mmol) was dissolved in 15 mL of EtOAc:EtOH (2:1) and 10 mol % Pd/C was added to the solution. The resultant mixture was stirred overnight at room temperature under H2 gas atmosphere. The reaction mixture was filtered and the solvent was removed in vacuo. The crude product was purified by flash column chromatography using ethyl acetate/hexane mixture as eluting solvent to provide the product (515 mg, 94%) as a crystalline white solid (mp: 48–50 °C). 1H NMR (600 MHz, CDCl3): δ 7.15 (d, J = 8.7 Hz, 2H), 7.08-7.02 (m, 2H), 7.00-6.97 (m, 1H), 6.79 (t, J = 7.0 Hz, 1H), 6.76 (d, J = 8.7 Hz, 2H), 4.80 (s (broad), 1H), 4.41 (ddd, J = 4.2, 7.2 and 11.3 Hz, 1H), 4.07-4.02 (m, 1H), 3.73 (s, 3H), 3.53 (dd, J = 4.2 and 9.1 Hz, 1H), 3.47-3.40 (m, 1H), 2.11-2.05 (m, 2H); 13C NMR (150 MHz, CDCl3): δ 174.5, 158.8, 153.7, 133.4, 129.3, 128.2, 127.2, 120.7, 116.4, 114.2, 113.5, 72.9, 67.6, 55.2, 51.4, 35.6, 29.1; FT-IR (CHCl3): 3362 (broad), 2933, 1705, 1513, 1249, 755 cm−1. HRMS: calculated for C19H20O5 328.1305 and found 328.1311.

5-(4-Methoxyphenyl)-1,4a,5,10b-tetrahydro-2H-pyrano-[3,4-c]chromen-4-one (11)

To a solution of diol 10 (130 mg, 0.39 mmol) in dichloromethane (10 mL) was added crushed 4Å molecular sieves and BF3·OEt2 (24μl, 0.2 mmol, 0.5 equiv.) at 0 °C. The resulting mixture was stirred at the same temperature for one hour and then quenched with water and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/hexane mixtures as eluting solvent to give the product (102 mg, 84%) as a crystalline white solid (mp: 218–220 °C). 1H NMR (600 MHz, CDCl3): δ 7.43 (d, J = 8.6 Hz, 2H), 7.20-7.14 (m, 2H), 6.98 (t, J = 7.1 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.1 Hz, 1H), 5.22 (d, J = 10.0 Hz, 1H), 4.50 (ddd, J = 3.6, 7.5, and 11.4 Hz, 1H), 4.40 (ddd, J = 6.3, 9.5 and 11.9 Hz), 3.82 (s, 3H), 3.37 (td, J = 8.9 and 13.0 Hz, 1H), 3.08 (dd, J = 10.0 and 13.0 Hz, 1H), 2.82-2.74 (m, 1H), 2.14-2.08 (m, 1H); 13C NMR (150 MHz, CDCl3): δ 170.8, 159.7, 153.9, 132.0, 129.0, 128.3, 126.1, 123.9, 121.1, 117.1, 113.7, 77.3, 65.4, 55.2, 44.4, 33.2, 27.0; FT-IR (CHCl3): 2910, 1737, 1230, 754 cm−1. HRMS: calculated for C19H18O4 310.1199; found 310.1196.

[4-(2-Hydroxyethyl)-2-(4-methoxyphenyl)-chroman-3-yl]-(4-methoxyphenyl)-methanone (12)

To a solution of lactone 11 (32 mg, 0.10 mmol) in anhydrous THF (2 mL) and HMPA (0.1 mL) was added freshly prepared p-MeOPhLi in a dropwise manner at −78 °C until the disappearance of the lactone was indicated by TLC, and the resulting solution was stirred at the same temperature for 6 hours. The reaction was quenched by the addition of water and warmed to room temperature. The mixture was extracted twice with EtOAc and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the product as an oil (31 mg, 72%). 1H NMR (600 MHz, CDCl3): δ 7.66 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.15 (t, J = 7.4 Hz, 1H), 6.99-6.94 (m, 2H), 6.73 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 4.95 ((d, J = 9.6 Hz, 1H), 4.09 (t, J = 10.1 Hz, 1H), 3.85-3.78 (m, 1H), 3.78 (s, 3H), 3.66 (s, 3H), 3.58-3.50 (m, 2H), 2.03-2.00 (m, 1H), 1.98-1.92 (m,1H); 13C NMR (150 MHz, CDCl3): δ 200.6, 163.5, 159.4, 155.0, 130.7, 128.2, 127.5, 127.3, 125.0, 121.2, 117.2, 113.7, 113.5, 80.5, 60.0, 55.4, 55.2, 52.0, 36.6, 35.5; FT-IR (CHCl3): 3471, 2935, 1660, 1598, 1514, 1251, 1174 cm−1. HRMS: calculated for C26H26O5 418.1774; found 418.1782.

4,5-Bis-(4-methoxyphenyl)-1,4a,5,10b-tetrahydro-2H,4H-pyrano[3,4-c]chromene (6)

To a solution of compound 12 (18.2 mg, 0.04 mmol) in EtOH (2 mL) was added NaBH4 (1.7 mg, 0.044 mmol) at 0 °C and the reaction mixture was stirred for 2 hours at the same temperature. The reaction was quenched with water and the ethanol was evaporated under reduced pressure. The residue was extracted twice with EtOAc and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (2 mL) and a catalytic amount of p-TsOH was added at room temperature. The reaction mixture was stirred until the disappearance of the diol was indicated by TLC. The mixture was filtered and concentrated under reduced pressure, and the crude product was purified by flash column chromatography using ethyl acetate/hexane mixtures as eluting solvent to give the product as an oil (13 mg, 81%). 1H NMR (600 MHz, CDCl3): δ 7.23 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 6.76 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 8.5 Hz, 2H), 6.45 (d, J = 8.5 Hz, 2H), 6.42 (d, J = 8.5 Hz, 2H), 4.83 (d, J = 9.7 Hz, 1H), 4.29 (dd, J = 3.5 and 11.4 Hz, 1H), 4.18 (d, J = 9.6 Hz, 1H), 3.82 (dt, J = 1.9 and 11.9 Hz, 1H), 3.67 (s, 6H), 3.06 (dt, J = 2.8 and 11.3 Hz, 1H), 2.39 (d (broad), J = 12.9 Hz, 1H), 2.34 (q, J = 9.9 Hz, 1H), 1.91 (dq, J = 4.5 and 12.5 Hz, 1H); 13C NMR (150 MHz, CDCl3): δ 158.7, 154.4, 132.6, 132.1129.0, 128.9, 127.7, 126.7, 124.4, 120.6, 116.7, 113.3, 113.2, 83.0, 81.6, 68.1, 55.1, 47.9, 38.1, 28.9; FT-IR (CHCl3): 2952, 2835, 1515, 1246 cm−1. HRMS: calculated for C26H26O4 402.1825; found 402.1822.

Supplementary Material



We thank the National Institutes of Health, through NCI Grant R15 CA122083-01, for financial support of this research. Helpful suggestions from Dr. Bruce Ganem are appreciated.


Supporting Information Available: 1H and 13C spectra for new compounds, and details of the computational studies. This material is available free of charge via the Internet at


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