Syntheses of methylated catechins and theaflavins using 2-nitrobenzenesulfonyl group to protect and deactivate phenol

Abstract

An efficient and versatile synthetic method for labile polyphenols was established using 2-nitrobenzenesulfonate (Ns) as a protecting group for phenol. This methodology provides regio- and stereoselective access to a range of methylated catechins, such as methylated epigallocatechin gallates, that are not readily available from natural sources. In addition, biomimetic synthesis of theaflavins from catechins was accomplished using Ns protection to minimize undesired side reactions of electron-rich aromatic rings during oxidation, enabling construction of the complex benzotropolone core in a single-step oxidative coupling reaction. Availability of these compounds will aid detailed structure–biological activity relationship studies of catechins.

Introduction

Synthetic methods for polyphenols have been extensively studied, because these compounds possess an array of interesting biological activities, including anticancer, antiviral and antimicrobial activities. Nevertheless, only a few efficient and versatile synthetic methods are available, both because the highly polar nature of polyphenols makes handling difficult, and because of the susceptibility of the compounds to oxidation. Protection of the hydroxyl groups of polyphenol is indispensable during usual chemical transformations and also during purification. Thus, selection of a suitable protecting group is critical. In this context, the 2-nitrobenzenesulfonate (Ns) group¹ should be an excellent protecting group for labile polyphenols, because it can be easily removed under mild conditions. Furthermore, its electron-withdrawing nature should enhance the stability of polyphenols during synthetic manipulations. Herein, we report efficient syntheses of a range of methylated catechins (2 and 3) and theaflavins (4 and 5) by exploiting the Ns group for protection of phenols.

Result and discussion

Synthesis of methylated cathechins

Epigallocatechin gallate (EGCg: 1), which has various biological activities, including cancer-preventive, antiviral and antimicrobial activities, is a major component of catechin derivatives derived from tea (Figure 1).^{2, 3, 4} Recently, various methylated derivatives, such as (–)-3′-methyl-epigallocatechin gallate (3′-Me-EGCg: 2), have been identified as minor catechins in natural tea leaves and as mammalian metabolites of tea catechins.⁴ Because 2 and its regioisomer (4′-Me-EGCg: 3) exhibit potent inhibitory activities towards type I allergic reactions in mice^{5, 6} and matrix metalloproteinases,^{7, 8} it seems likely that other methylated catechin derivatives may also have therapeutic potential.^{9, 10, 11}

Figure 1

EGCg (1) and methylated catechins.

Compounds 2 and 3 are readily available from natural and synthetic sources,^{12, 13} and investigations of structure–activity relationships have so far been limited to these compounds. However, synthesis of all possible regio- and stereoisomers of the naturally available methylated catechins (EGC: epigallocatechin, GC: gallocatechin, EC: epicatechin and CC: catechin) would allow systematic evaluation of the structure–biological activity relationships. Hence, we are interested in concise synthesis of methylated catechins (2, 3 and 6–13). Although synthetic investigations of the catechin skeleton have been reported by many groups,² including ours,^{14, 15} derivation of methylated catechins from natural catechins, such as EGC¹⁶ and other derivatives (GC, EC and CC), which are inexpensive and readily available, should be a convenient and effective strategy.

Our synthetic plan is illustrated in Scheme 1. A key issue is selecting a suitable protecting group for phenol. Although benzyl ether has been employed for catechin synthesis because it is readily deprotectable under hydrogenolysis conditions, ether formation of phenol is often troublesome: for example, epimerization of the 2-position can occur under basic conditions (Scheme 2). To make matters worse, electron-rich aromatics readily undergo undesired electrophilic substitution and unexpected oxidation at the benzylic position. Thus, a major concern in polyphenol synthesis is how to avoid these problems.

The Ns group should be an excellent protecting group for labile polyphenols because it can be easily deprotected under mild conditions.^{1, 17, 18, 19} Furthermore, the electron-withdrawing nature of the Ns group should improve the stability of polyphenol during synthetic manipulations. A preliminary investigation of deprotection of 4-(((2-nitrophenyl)sulfonyl)oxy)benzyl acetate (17) showed that selective deprotection of the Ns group could be achieved in the presence of the ester group (Scheme 3). Thus, protection of phenols with Ns group should be effective for the synthesis of methylated catechins.

Therefore, we next investigated selective incorporation of the methyl group at 3- and 4-OH of allyl gallate (20), as shown in Scheme 4. Gallic acid (19) was converted to allyl ester 20 by reaction with allyl alcohol and EDCI. Upon treatment of 20 with Li₂CO₃ and methyl iodide, selective deprotonation and alkylation of the most acidic 4-OH proceeded smoothly to give 21. On the other hand, 3-OH selective alkylation was achieved by utilizing a bridged boronic ester intermediate²⁰ between the o-phenolic hydroxyl groups. After formation of the boronic ester 23 by treating 20 with borax in the presence of NaOH, methylation with Me₂SO₄ and subsequent acidic hydrolysis of the boronic ester exclusively provided 24. Ns groups were incorporated into the resultant phenols 20, 21 and 24 by treatment with NsCl and Et₃N. Treatment of the allyl esters with catalytic amounts of Pd(PPh₃)₄ and p-tolSO₂Na²¹ resulted in smooth deprotection of the allyl group to afford the desired 26, 22 and 25, respectively.

Next, we focused on incorporating gallate derivatives 22 and 25 into protected epigallocatechin derivatives and deprotection of the Ns group (Scheme 5). Protection of EGC (27) with the Ns group was carried out with NsCl and Et₃N to provide 28. Condensation reaction of 28 with 25 and EDCI in the presence of a catalytic amount of DMAP proceeded smoothly to provide the desired 29 in high yield. Similar condensation of 28 and 22 provided the 4′-methylated EGCg derivative 30. Deprotection of the Ns groups of 29 and 30 was accomplished with the use of thiophenol and cesium carbonate to provide 3′-methylated EGCg (2) and 4′-methylated EGCg (3), respectively. During this transformation, neither epimerization at the 2-position of the benzopyran ring nor decomposition of gallate ester was observed. A similar protocol provided the desired methylated gallate catechin derivatives 8–13 from natural catechin derivatives GC, EC and CC (Table 1).²²

Table 1 Versatile synthesis of methylated catechins

Then, we turned our attention to selectively introducing a methyl group into the B-ring (Scheme 6). To our knowledge, (–)-EGCg derivatives methylated at the B-ring have not yet been reported, so an SAR study of these compounds should be interesting. We found that a bridged boronic ester intermediate effectively distinguishes the hydroxyl groups at the A-ring and B-ring. Treatment of 27 with three equivalents of NsCl and excess H₃BO₃ in the presence of NaOH²³ resulted in regioselective sulfonylation to afford predominantly 3′,5,7-Ns-EGCg (32).

Next, selective incorporation of the TBDPS group at the less hindered hydroxyl group (5′-OH) was accomplished by treating 32 with TBDPSCl and Et₃N to give 33 (Scheme 7). The 4′-Me-EGCg derivative was prepared by methylation of 33 with diazomethane, condensation of 35 with Ns-protected gallic acid 26,²⁴ and stepwise deprotection of TBDPS group and Ns group, affording 4′-Me-EGCg (7).

3′-Me-EGCg (6) and 3′,3′-diMe-EGCg (38) were also synthesized from 33. Protection of 33 with Ns proceeded at the 4′-hydroxyl group. Deprotection of the TBDPS group and incorporation of a methyl group afforded 37. Although condensation of 37 with 26 and deprotection of Ns groups readily provided 3′-Me-EGCg (6), we chose to employ a modified preparation with double-methylated derivatives. After condensation of 37 and 25, deprotection of Ns groups was accomplished using 2-aminothiophenol (39) instead of thiophenol to afford 3′,3′-diMe- EGCG (38; Table 1).^{25, 26} For a review on recent progress in the synthesis of the advantage of this method is that 39 is odorless compared with thiophenol. Furthermore, the by-product, 2-(2-nitrophenylthio)aniline (40), can be easily removed by washing the ethereal layer with 1 m HCl solution.

Combining the selective methylation strategies for the B- and D-rings of EGCg should provide access to several types of double-methylated EGCg derivatives. Furthermore, this regioselective modification of EGCg should be applicable for alkylation as well as acylation; thus, it should be possible to apply this synthetic strategy to other natural catechins (GC, EC and C) to construct a diverse catechin library.

Synthesis of theaflavins

Theaflavin (4) is an oxidative dimer of catechin derivatives (Figure 2),^{27, 28, 29, 30} which is found in black tea. It has a number of biological activities.³¹ Although many synthetic studies of catechin derivatives have been reported,^{32, 33, 34} there are only a few reports of the synthesis of 4 by means of enzymatic oxidation.^{32, 35}

Figure 2

Structures of theaflavine (4) and neotheaflavine (5).

Recently, Nakatsuka and Yanase’s group reported a novel oxidative coupling of o-quinone 45 and pyrogallol derivative 46 based on their proposed biosynthetic pathway,³⁵ as shown in Scheme 8. Although their model reaction proceeded in excellent yield, its application to the synthesis of theaflavin has not been reported to date. This is probably because oxidation precursors and theaflavin itself are unstable under strongly oxidizing conditions. We envisioned that the application of our Ns group^{16, 17, 18, 19} for protecting reactive phenols would enable efficient synthesis of theaflavins from catechins.

For the synthesis of theaflavin, we initially investigated selective incorporation of the Ns group into the A-ring of CC (49), EC (50) and EGC (27), as shown in Table 2.

Table 2 Regioselective incorporation of Ns group into the A-ring of catechins

Regioselective protection of the A-ring with a Ns group was performed utilizing the bridged boronic ester intermediate 54¹¹ between neighboring phenolic hydroxyl groups on the B-ring (Scheme 9). Thus, after formation of the boronic ester by treatment of 27 with boronic acid in the presence of NaOH, reaction with two equivalents of NsCl and subsequent acidic hydrolysis of boronic ester exclusively provided 53 (Table 2, entry 3). Although the boronic ester intermediate of 27 possesses a remaining phenolic hydroxyl group on the B-ring, steric hindrance appears to prevent reaction with NsCl. Similar reactions of 49 and 50 proceeded smoothly to provide 51 and 52 (entries 1 and 2).

Having succeeded in selective protection of the A-ring, the next challenge is oxidation of the catechol group in 51 and 52. First, we optimized the oxidation conditions using 51, which is derived from less expensive 49. As shown in Scheme 10, the best result was obtained by oxidation with Pb(OAc)₄ in MeCN at 0 °C, affording the desired quinone 55 in good yield. Utilizing Pb(OAc)₄ as an oxidant has the advantage that lead derivatives can be easily removed from the reaction medium by celite filtration after completion of the reaction. Furthermore, the electron-withdrawing nature of the Ns group would enhance the stability of the A-ring during the reaction with the strong oxidant Pb(OAc)₄. Although other various oxidants (such as Fetizon reagent and PhI(OAc)₂) were tested, they did not efficiently provide the o-quinone for the next reaction without the need for purification.

Next, we tested the coupling reaction of quinone 55 with pyrogallol derivative 53 (Scheme 11). As quinone 55 was labile during purification, crude 55 was used directly for the coupling reaction. Gratifyingly, treatment of three equivalents of 55 with 53 in a mixture of MeCN and CH₂Cl₂, followed by addition of H₂O, provided the desired 56 in moderate yield. Considering the reaction mechanism shown in Scheme 12, at least two equivalents of o-quinone should theoretically be consumed in the two oxidation steps (58–59 and 61–62). Furthermore, addition of MS3A to the reaction mixture before the addition of H₂O was essential for efficient conversion. MS3A might have a significant role in the oxidation step from 58 to 59, although the mechanism involved remains to be established. After separation from 51 (generated by reduction of 55), deprotection of the Ns group of 56 was accomplished by treatment with thiophenol and cesium carbonate to provide neotheaflavin (5). No decomposition of the reactive benzotropolone ring was observed during the coupling and deprotection processes.

This benzotropolone ring-forming reaction was also applicable to the synthesis of theaflavin (4) and its derivatives, as shown in Scheme 13. Upon treatment of Ns-protected epicatechin (52) with Pb(OAc)₄, the desired oxidation reaction proceeded smoothly to provide the o-quinone 63. The coupling reaction with 53 was carried out without purification of the o-quinone intermediate 63 to give benzotropolone intermediate 64. Finally, deprotection of Ns group afforded theaflavin (4).³⁶ The lower yield of 4 in comparison with 5 might be a result of instability of the o-quinone intermediate derived from cis-benzopyran 52.

This oxidation–coupling strategy was also applied to the coupling between pyrogallol (65) and gallate 66 to give 67 and 68, respectively (Table 3). As compounds similar to 68, which is derived from oxidative coupling with gallate derivatives, have been isolated from tea,⁸ this method would be useful to synthesize derivatives for SAR study.

Table 3 Synthesis of benzotropolone derivatives

In summary, we have shown that the Ns group is an excellent protecting group for labile polyphenols; it can be easily deprotected under mild conditions, and its electron-withdrawing nature improves the stability of polyphenol during synthetic manipulations. Utilizing the Ns group to protect phenols and to block undesired oxidation reactions, we were able to develop an efficient and practical method for regio- and stereoselective methylation of catechins and theaflavins. Further applications, as well as structure–biological activity relationship studies of the synthesized derivatives, are under investigation in our laboratory.

Experimental section

General experimental details

NMR [¹H NMR (270 MHz), ¹³C NMR (68 MHz)] spectra were determined on a JEOL EX-270 instrument (Tokyo, Japan), and [¹H NMR (500 MHz), ¹³C NMR (125 MHz)] spectra were determined on JEOL α-500 instrument (Tokyo, Japan). Chemical shifts for ¹H NMR were reported in p.p.m. downfields from tetramethylsilane (δ) as the internal standard and coupling constants are in hertz (Hz). The following abbreviations are used for spin multiplicity: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad. Chemical shifts for ¹³C NMR were referenced to solvent peaks: δ_C 77.0 for CDCl₃, δ_C 29.8 for acetone-d₆, δ_C 118.3 for CD₃CN and δ_C 49.0 for CD₃OD. HR-MS were obtained on either JEOL MStation JMS-700 or JMS-GCmate II (Tokyo, Japan). Fast atom bombardment (FAB) mass spectra were obtained with a mixture of 3-nitrobenzylalcohol and magic bullet as a matrix.

Analytical TLC was performed on Merck (Tokyo, Japan) precoated analytical plates, 0.25-mm thick, silica gel 60 F₂₅₄. Preparative TLC separations were made on 7 × 20-cm plates prepared with a 0.25-mm layer of Merck silica gel 60 F₂₅₄. Compounds were eluted from the adsorbent with 10% methanol in chloroform. Column chromatography was carried out with KANTO CHEMICAL (Tokyo, Japan) Silica Gel 60 N (spherical, neutral) 63–210 μm. Reagents and solvents were commercial grades and were used as supplied with following exceptions: dichloromethane, diethylether, n-hexane, tetrahydrofuran and toluene, dried over molecular sieves 4A. All reactions sensitive to oxygen or moisture were conducted under an argon atmosphere.

Experimental procedures and characterization data

Allyl gallate (20)

To a mixture of gallic acid monohydrate (50.0 g, 266 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (61.2 g, 319 mmol) and 4-Dimethylaminopyridine (DMAP) (3.25 g, 26.6 mmol) was added allyl alcohol (200 ml) at room temperature, then heated at 60 °C for 4 h. The resulting mixture was quenched with 2 n HCl and extracted with ethyl acetate. The combined organic phases were washed with saturated NaHCO₃, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to afford 20 (48.7 g, 87%) as a light tan solid. HR-MS (FAB) calculated for C₁₀H₁₁O₅ [M+H]⁺211.0606, found 211.0593; IR (neat) 3367, 1701, 1610, 1388, 1256, 1198 cm⁻¹; ¹H NMR (270 MHz, acetone-d₆) δ 7.13 (2H, s), 5.97–6.11 (1H, m), 5.37 (1H, dq, J_1,2=17.1, 1.8 Hz), 5.22 (1H, dq, J_1,2=10.6, 1.8 Hz), 4.71 (2H, dt, J_1,2=5.5, 1.8 Hz); ¹³C NMR (68 MHz, acetone-d₆) δ 166.3, 146.0, 138.8, 133.9, 121.7, 117.6, 109.8, 65.4.

Allyl 3,5-dihydroxy-4-methoxybenzoate (21)

To a suspension of 20 (1.50 g, 7.15 mmol) in N,N-dimethylformamide (DMF) (20 ml) were added Li₂CO₃ (1.32 g, 17.9 mmol) and methyl iodide (1.11 ml, 17.9 mmol) at 50 °C. The mixture was stirred at 50 °C for 20 h. The reaction mixture was quenched with 2 m HCl and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (1–3% MeOH in CH₂Cl₂) to afford 21 (1.83 g, 68%) as a colorless solid. HR-MS (FAB) calculated for C₁₁H₁₂O₅ [M]⁺ 224.0685, found 224.0705; IR (neat) 3369, 1701, 1597, 1524, 1375, 1234, 1193 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.26 (2H, s), 5.97–6.05 (1H, m), 5.40 (1H, dq, J_1,2=17.2, 1.4 Hz), 5.22 (1H, dq, J_1,2=10.4, 1.4 Hz), 4.79 (2H, dt, J_1,2=5.5, 1.4 Hz), 3.97 (3H, s); ¹³C NMR (68 MHz, acetone-d₆) δ 166.1, 151.3, 133.8, 126.4, 117.8, 109.9, 109.8, 65.7, 60.6.

3,5-Di(2-nitrobenzenesulfoxy)-4-methoxybenzoic acid (22)

To a solution of 21 (400 mg, 1.79 mmol) in MeCN (4 ml) were added triethylamine (1.12 ml, 8.04 mmol) and 2-nitrobenzenesulfonyl chloride (872 mg, 3.93 mmol) at 0 ºC. The mixture was stirred at 0 °C for 1.5 h. The reaction mixture was quenched with 2 m HCl and extracted with CH₂Cl₂. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (CH₂Cl₂) to afford crude (954 mg) as a colorless amorphous. To a suspention of p-toluenesulfinic acid (343 mg, 1.92 mmol) in H₂O (16 ml) were added a solution of the crude and tetrakis(triphenylphosphine) palladium(0) (92.0 mg, 800 μmol) in THF (32 ml) at room temperature. The mixture was stirred at room temperature for 1 h. To the resulting mixture were added CH₂Cl₂ and H₂O, and then organic layer was extracted with H₂O. The combined aqueous phases were acidified with 2 m HCl (up to pH 3.0) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 22 (743 mg, 82%, two steps) as a colorless solid. HR-MS (FAB) calculated for C₂₀H₁₅N₂O₁₃S₂ [M+H]⁺555.0016, found 555.0017; IR (neat) 3026, 1703, 1546, 1392, 1307, 1190, 1006 cm⁻¹; ¹H NMR (270 MHz, acetone-d₆) δ 7.94–8.18 (8H, m), 7.78 (2H, s), 3.72 (3H, s); ¹³C NMR (68 MHz, acetone-d₆) δ 164.8, 150.5, 143.4, 137.7, 132.6, 128.5, 127.0, 126.2, 125.6, 62.7.

Allyl 4,5-dihydroxy-3-methoxybenzoate (24)

To a suspension of 20 (300 mg, 1.43 mmol) in H₂O (20 ml) was added sodium tetraborate decahydrate (1.40 g, 3.67 mmol), then the mixture was stirred at room temperature for 1 h. After stirring, dimethyl sulfate (0.523 ml, 5.53 mmol) and 6.5 m NaOH (25 ml) were added to the reaction mixture, which was stirred at room temperature for 12 h. The reaction mixture was acidified with concentrated H₂SO₄ (up to pH 2.0) and stirred at room temperature for 1 h. The resulting mixture was poured into water and extracted with CH₂Cl₂. The organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated to afford 24 (320 mg, 85%) as a colorless solid. HR-MS (FAB) calculated for C₁₁H₁₂O₅[M+H]⁺224.0685, found 224.0705; IR (neat) 3371, 1710, 1602, 1531, 1382, 1246, 1192 cm⁻¹; ¹H NMR (270 MHz, acetone-d₆) δ 7.23 (1H, d, J=2.0 Hz), 7.16 (1H, d, J =2.0 Hz), 5.98–6.10 (1H, m), 5.36 (1H dq, J_1,2=17.1, 1.5 Hz), 5.21 (1H, dq, J_1,2=10.4, 1.5 Hz), 4.73 (2H, dt, J_1,2=5.5, 1.5 Hz), 3.87 (3H, s); ¹³C NMR (68 MHz, acetone-d₆) δ 166.3, 148.5, 145.8, 139.7, 133.8, 121.6, 1177.8, 111.6, 105.7, 65.6, 56.5.

4,5-Di(2-nitrobenzenesulfoxy)-3-methoxybenzoic acid (25)

In a similar manner to that used to prepare 22, treatment of 24 gave 25 (95%, two steps) as a colorless solid. HR-MS (FAB) calculated for C₂₀H₁₅N₂O₁₃S₂ [M+H]⁺555.0016, found 555.0017; IR (neat) 3008, 1705, 1556, 1385, 1194, 1078, 970 cm⁻¹; ¹H NMR (270 MHz, acetone-d₆) δ 7.90–8.13 (8H, m), 7.68 (1H, d, J=2.0 Hz), 7.52 (1H, d, J=2.0 Hz), 3.72 (3H, s); ¹³C NMR (68 MHz, acetone-d₆) δ 165.4, 154.5, 143.3, 137.8, 137.0, 133.9, 133.6, 132.2, 131.5, 130.5, 128.5, 126.2, 125.9, 117.2, 113.7, 57.1.

3,4,5-Tri(2-nitrobenzenesulfoxy)benzoic acid (26)

In a similar manner to that used to prepare 22, treatment of 20 gave 26 (86%) as a colorless solid. HR-MS (FAB) calculated for C₂₅H₁₅N₃O₁₇S₃Na [M+Na]⁺747.9461, found 747.9468; IR (neat) 3437, 1701, 1541, 1400, 1305, 1193, 1091, 1014 cm⁻¹; ¹H NMR (500 MHz, acetone-d₆) δ 8.15–7.85 (14H, m); ¹³C NMR (125 MHz, acetone-d₆) δ 163.5, 148.5, 148.1, 143.0, 138.2, 137.4, 137.1, 133.3, 132.0, 131.8, 131.2, 128.3, 126.9, 125.6, 124.0.

5-((2R,3R)-3-Hydroxy-5,7-bis(2-nitrophenylsulfonyloxy)chroman-2-yl)benzene-1,2,3-triyl tris(2-nitrobenzenesulfonate) (28)

To a solution of 27 (100 mg, 0.327 mmol) in MeCN (20 ml) were added triethylamine (0.453 ml, 3.27 mmol) and 2-nitrobenzenesulfonyl chloride (362 mg, 1.63 mmol) at −20 ºC. The mixture was stirred at −20 °C for 1.5 h. The reaction mixture was quenched with 2 m HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by flash column chromatography (CH₂Cl₂) to afford 28 (377 mg) as a colorless amorphous. HR-MS (FAB) calculated for C₄₅H₃₀N₅O₂₇S₅ [M+H]⁺1231.9732, found 1231.9751; [α] ^D ₂₀=−5.33 (c 1.00, acetone); IR (neat) 3406, 1701, 1618, 1589, 1542, 1421, 1388, 1362, 1305, 1222, 1193, 1114, 1008 cm⁻¹; ¹H NMR (270 MHz, CD₃CN) δ 7.70–8.05 (20H, m), 7.24 (2H, s), 6.66 (1H, d, J=2.6 Hz), 6.44 (1H, d, J=2.6 Hz), 5.01 (1H, m), 4.05 (1H, m), 3.04 (1H, br s), 2.88–2.72 (2H, m); ¹³C NMR (68 MHz, CD₃CN) δ 156.5, 149.5, 149.2, 148.9, 148.3, 143.5, 141.1, 138.0, 137.9, 137.7, 135.2, 134.1, 134.1, 134.0, 133.8, 133.1, 133.0, 132.8, 132.6, 129.3, 128.2, 127.9, 127.5, 126.4, 126.3, 122.1, 118.3, 115.7, 110.7, 109.9, 78.3, 64.2, 29.3.

5-(2R,3R)-5,7-Bis(2-nitrophenylsulfonyloxy)-2-(3,4,5-tris(2-nitrophenylsulfonyloxy)phenyl) chroman-3-yl-3-methoxy-4,5-bis(2-nitrophenylsulfonyloxy)benzoate (29)

28 (700 mg, 0.568 mmol), 25 (628 mg, 1.14 mmol), EDCI (327 mg, 1.70 mmol) and DMAP (13.9 mg, 0.114 mmol) were dissolved in CH₃CN (3 ml) and stirred at room temperature for 16 h. The resulting mixture was quenched with saturated NH₄Cl and extracted with CH₂Cl₂. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (25% hexane in CH₂Cl₂) to afford 29 (925 mg, 92%) as a colorless amorphous. [α]^D₂₀=−73.1 (c 0.85, acetone); HR-MS (FAB) calculated for C₆₅H₄₁N₇O₃₉S₇Na [M+Na]⁺1789.9383, found 1789.9386; IR (neat) 1708, 1618, 1593, 1545, 1419, 1394, 1366, 1305, 1193, 1121, 1001 cm⁻¹; ¹H NMR (270 MHz, acetone-d₆) δ 7.80–8.14 (28H, m), 7.54 (2H, s), 7.34 (1H, d, J=2.0 Hz), 7.23 (1H, d, J=2.0 Hz), 6.97 (1H, d, J=2.6 Hz), 6.66 (1H, d, J=2.6 Hz), 5.73–5.78 (1H, m), 5.65 (1H, s), 3.59 (3H, s), 3.30 (1H, dd, J_1,2=17.5, 4.3 Hz), 3.23 (1H, dd, J_1,2=17.5, 3.3 Hz); ¹³C NMR (68 MHz, acetone-d₆) δ 162.1, 155.6, 150.2, 148.7, 148.4, 147.8, 142.6, 141.0, 140.8, 138.5, 137.1, 137.0, 136.9, 133.1, 133.0, 133.0, 132.9, 132.3, 132.0, 131.9, 131.8, 127.6, 127.5, 127.4, 127.2, 126.9, 126.7, 125.4, 125.4, 125.3, 124.8, 124.7, 124.7, 122.5, 113.7, 110.4, 109.7, 76.4, 67.7, 62.0, 26.0.

(2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 4,5-dihydroxy-3-methoxybenzoate (2)

To a suspension of Cs₂CO₃ (3.61 g, 11.3 mmol) in MeCN (6 ml) were added thiophenol (1.16 ml, 5.75 mmol) and 29 (800 mg, 0.452 mmol) at 0 ºC. The mixture was stirred at room temperature for 3.5 h. The reaction was quenched with sat. NH₄Cl and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (7% MeOH in CH₂Cl₂) to afford 2 (174 mg, 81%) as a colorless amorphous. HR-MS (FAB) calculated for C₂₃H₂₀O₁₁Na [M+Na]⁺495.0904, found 495.0873; [α]^D₂₀=−186.2 (c 1.00, 50% acetone in H₂O); IR (neat) 3327, 1701, 1610, 1340, 1229 cm⁻¹; ¹H NMR (270 MHz, CD₃OD) δ 7.05 (1H, d, J=1.9 Hz), 7.01 (1H, d, J=1.9 Hz), 6.50 (2H, s), 5.96 (1H, d, J=2.6 Hz), 5.95 (1H, d, J=2.6 Hz), 5.49 (1H, m), 5.00 (1H, s), 3.81 (3H, s), 2.99 (1H, dd, J_1,2=17.5, 4.3 Hz), 2.86 (1H, dd, J_1,2=17.5, 3.0 Hz); ¹³C NMR (68 MHz, CD₃OD) δ 167.7, 157.9, 157.8, 157.2, 149.0, 146.8, 146.0, 140.6, 133.7, 130.9, 121.5, 111.9, 106.8, 106.3, 99.4, 96.5, 95.8, 78.5, 70.4, 56.6, 26.6.

5-(2R,3R)-5,7-Bis(2-nitrophenylsulfonyloxy)-2-(3,4,5-tris(2-nitrophenylsulfonyloxy)phenyl) chroman-3-yl-4-methoxy-3,5-bis(2-nitrophenylsulfonyloxy)benzoate (30)

In a similar manner to that used to prepare 29, treatment of 28 with 22 gave 30 (97%) as a colorless amorphous. HR-MS (FAB) calculated for C₆₅H₄₁N₇O₃₉S₇Na [M+Na]⁺1789.9383, found 1789.9386; [α]^D₂₀=−73.1 (c 0.85, acetone); IR (neat) 1708, 1618, 1593, 1545, 1419, 1394, 1366, 1305, 1193, 1121, 1001 cm⁻¹; ¹H NMR (500 MHz, acetone-d₆) δ 7.80–8.14 (28H, m), 7.57 (2H, s), 7.46 (2H, s), 6.98 (1H, d, J=2.6 Hz), 6.66 (1H, d, J=2.6 Hz), 5.74 (1H, m), 5.60 (1H, s), 3.63 (3H, s), 3.28 (1H, dd, J_1,2=17.5, 4.3 Hz), 3.10 (1H, dd, J_1,2=17.5, 3.3 Hz); ¹³C NMR (126 MHz, acetone-d₆) δ 162.2, 155.3, 150.2, 148.8, 148.4, 148.2, 147.7, 142.9, 142.7, 138.7, 137.2, 136.9, 136.9, 134.4, 133.2, 133.1, 133.1, 133.0, 132.3, 132.1, 132.0, 131.7, 131.6, 128.3, 127.8, 127.1, 126.9, 126.6, 125.5, 125.5, 125.4, 124.9, 124.8, 121.2, 113.8, 110.4, 109.9, 75.9, 67.4, 61.9, 26.0.

(2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,5-dihydroxy-4-methoxybenzoate (3)

In a similar manner to that used to prepare 2, treatment of 30 gave 3 (81%) as a colorless amorphous. HR-MS (FAB) calculated for C₂₃H₂₀O₁₁Na [M+Na]⁺495.0904, found 495.0896; [α]^D₂₀=−171.5 (c 1.20, 50% acetone in H₂O); IR (neat) 3367, 1701, 1604, 1348, 1236 cm⁻¹; ¹H NMR (270 MHz, CD₃OD) δ 6.91 (2H, s), 6.49 (2H, s), 5.95 (2H, s), 5.53 (1H, m), 4.97 (1H, s), 3.81 (3H, s), 2.99 (1H, dd, J_1,2=17.5, 4.6 Hz), 2.84 (1H, dd, J_1,2=17.5, 2.3 Hz); ¹³C NMR (125 MHz, CD₃OD) δ 167.2, 157.9, 157.8, 157.2, 151.5, 146.7, 141.1, 133.8, 130.7, 126.6, 110.3, 106.8, 99.3, 96.5, 95.9, 78.5, 70.3, 60.7, 26.8.

(2R,3R)-2-(3,4-Dihydroxy-5-(2-nitrophenylsulfonyloxy)phenyl)-3-hydroxychroman-5,7-diyl bis(2-nitrobenzenesulfonate) (32)

To a solution of boric acid (4.64 g, 80.3 mmol) and NaOH (800 mg) in H₂O (160 ml) was added 27 (492 mg, 1.61 mmol) and the resulting solution was adjusted to pH 9.0. Then, 2-nitrobenzenesulfonyl chloride (1.06 g, 4.83 mmol) in toluene (16 ml) was added dropwise over 30 min and stirred at room temperature for 3 h. The reaction was quenched with 2 m HCl and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (1–3% MeOH in CH₂Cl₂) to afford 32 (560 mg, 40%) as a pale yellow solid. HR-MS (FAB) calculated for C₃₃H₂₃N₃O₁₉S₃Na [M+Na]⁺883.9986, found 883.9965; [α]^D₂₀=+10.6 (c 1.28, acetone); IR (neat) 3422, 1701, 1618, 1591, 1541, 1440, 1388, 1358, 1305, 1191, 1111, 995 cm⁻¹; ¹H NMR (270 MHz, acetone-d₆) δ 7.80–8.20 (12H, m), 6.99 (1H, d, J=2.3 Hz), 6.71 (1H, d, J=2.3 Hz), 6.62 (1H, d, J=2.3 Hz), 6.50 (1H, d, J=2.3 Hz), 4.99 (1H, m), 4.22 (1H, m), 2.80–2.98 (2H, m); ¹³C NMR (68 MHz, acetone-d₆) δ 157.3, 149.5, 148.2, 147.3, 138.9, 138.2, 137.8, 137.0, 133.9, 133.6, 133.3, 133.0, 132.9, 132.6, 130.2, 129.5, 128.4, 127.7, 126.3, 126.2, 125.8, 116.0, 114.1, 113.4, 110.3, 109.1, 79.4, 64.8, 29.6.

(2R,3R)-2-(3-tert-Butyldiphenylsilyloxy-4-hydroxy-5-(2-nitrophenylsulfonyloxy)phenyl)-3-hydroxychroman-5,7-diyl bis(2-nitrobenzenesulfonate) (33)

To a solution of 32 (200 mg, 0.182 mmol) in MeCN (0.4 ml) were added triethylamine (0.196 ml, 1.09 mmol) and TBDPSCl (197 mg, 0.545 mmol) at −20 ºC, then the resulting solution was stirred at −20 °C for 3 h. The reaction mixture was quenched with 2 m HCl and extracted with CH₂Cl₂. The combined organic phases were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (50% ethyl acetate in hexane) to afford 33 (211 mg, 83%) as a pale yellow solid. HR-MS (FAB) calculated for C₃₃H₂₃N₃O₁₉S₃Na [M+Na]⁺1122.1163, found 1122.1191; [α]^D₂₀=−0.68 (c 1.35, acetone); IR (neat) 3448, 1707, 1618, 1591, 1544, 1441, 1388, 1364, 1305, 1193, 1112, 997 cm⁻¹; ¹H NMR (270 MHz, CDCl₃) δ, 7.36–8.13 (23H, m), 6.77 (1H, d, J=2.0 Hz), 6.51 (1H, d, J=2.0 Hz), 6.43 (1H, d, J=2.0 Hz), 6.37 (1H, d, J=2.0 Hz), 4.58 (1H, m), 3.73 (1H, m), 2.82–2.86 (2H, m), 1.09 (9H, s); ¹³C NMR (68 MHz, CDCl₃) δ 155.4, 148.3, 147.1, 144.4, 140.1, 136.4, 135.9, 135.8, 135.5, 135.4, 135.3, 132.6, 132.3, 132.3, 132.1, 130.6, 130.6, 128.1, 127.7, 125.0, 124.9, 124.8, 116.0, 114.3, 113.9, 110.0, 109.1, 64.6, 28.0, 26.6, 19.5.

(2R,3R)-2-(3-tert-Butyldiphenylsilyloxy-4-methoxy-5-(2-nitrophenylsulfonyloxy)phenyl)-3-hydroxychroman-5,7-diyl bis(2-nitrobenzenesulfonate) (35)

To a solution of 33 (125 mg, 0.110 mmol) in MeCN (1 ml) were added diazomethane (Et₂O solution) until color of the solution became yellow at 0 ºC. The resulting solution was stirred at 0 °C for 10 min. The reaction was quenched with acetic acid and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (50% ethyl acetate in hexane) to afford 35 (115 mg, 91%) as a pale yellow solid. HR-MS (FAB) calculated for C₃₃H₂₃N₃O₁₉S₃Na [M+Na]⁺1136.1320, found 1136.1298; [α]^D₂₀=−9.17 (c 1.25, acetone); IR (neat) 3420, 1709, 1618, 1591, 1550, 1441, 1391, 1360, 1308, 1196, 1113, 997 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ, 8.08–7.36 (22H, m), 6.71 (1H, d, J=2.4 Hz), 6.50 (1H, d, J=2.4 Hz), 6.43 (1H, d, J=2.4 Hz), 6.40 (1H, d, J=2.4 Hz), 4.58 (1H, m), 3.84 (3H, s), 3.71 (1H, m), 2.89 (1H, dd, J_1,2=17.7, 2.4 Hz), 2.89 (1H, dd, J_1,2=17.7, 4.0 Hz), 1.09 (9H, s); ¹³C NMR (68 MHz, CDCl₃) δ 155.3, 150.3, 148.6, 148.3, 147.1, 143.1, 135.9, 135.8, 135.5, 135.4, 135.3, 132.6, 132.3, 132.3, 132.1, 132.0, 131.9, 131.8, 130.4, 130.3, 128.2, 128.0, 128.0, 125.0, 124.9, 124.7, 117.8, 114.1, 113.9, 110.0, 109.1, 64.5, 61.3, 28.0, 26.4, 19.5.

(2R,3R)-2-(3-tert-Butyldiphenylsilyloxy-4-methoxy-5-(2-nitrophenylsulfonyloxy)phenyl)-5,7-bis(2-nitrophenylsulfonyloxy)-chroman-3-yl-3,4,5-tris(2-nitrophenylsulfonyloxy)benzoate (69)

In a similar manner to that used to prepare 29, treatment of 35 with 26 gave 69 (86%) as a colorless solid. HR-MS (FAB) calculated for C₇₅H₅₆N₆O₃₅SiS₆Na [M+Na]⁺1843.0778, found 1843.0771; [α]^D₂₀=−42.3 (c 1.00, acetone); IR (neat) 1711, 1618, 1591, 1545, 1442, 1391, 1364, 1308, 1193, 1114, 1005 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.34–8.03 (34H, m), 6.68 (1H, d, J=1.9 Hz), 6.67 (1H, d, J=1.9 Hz), 6.60 (1H, d, J=2.0 Hz), 6.26 (1H, d, J=2.0 Hz), 5.04 (1H, m), 4.64 (1H, m), 3.70 (3H, s), 2.95 (1H, dd, J_1,2=18.0, 4.6 Hz), 2.80 (1H, dd, J_1,2=18.0, 1.5 Hz), 1.02 (9H, s); ¹³C NMR (68 MHz, CDCl₃) δ 161.4, 155.1, 150.1, 148.6, 148.4, 148.2, 148.2, 148.0, 147.4, 143.6, 143.1, 143.1, 139.0, 136.3, 136.3, 136.1, 135.9, 135.4, 135.3, 133.0, 132.9, 132.7, 132.6, 132.3, 132.1, 131.9, 131.9, 131.7, 131.1, 130.4, 130.4, 129.2, 128.9, 128.0, 128.0, 127.8, 127.7, 127.4, 125.4, 125.1, 125.0, 124.8, 124.1, 117.6, 114.3, 112.4, 110.2, 110.0, 67.4, 61.3, 26.5, 26.3, 19.5.

(2R,3R)-2-(3-Hydroxy-4-methoxy-5-(2-nitrophenylsulfonyloxy)phenyl)-5,7-bis(2-nitrophenylsulfonyloxy)-chroman-3-yl-3,4,5-tris(2-nitrophenylsulfonyloxy)benzoate (70)

To a solution of 69 (400 mg, 0.220 mmol) and acetic acid (0.0377 ml, 0.661 mmol) in tetrahydrofuran (THF) (4.6 ml) was added TBAF (1.0 m solution in THF, 0.266 ml, 0.266 mmol) at 0 °C, then the resulting solution was stirred at 0 °C for 15 min. The reaction mixture was poured into water and extracted with CH₂Cl₂. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford crude 70 (320 mg) as a colorless solid. The crude 70 was used in the next step without further purification. ¹H NMR (500 MHz, acetone-d₆) δ 7.62–8.07 (24H, m), 7.57 (2H, s), 6.83 (1H, d, J=1.8 Hz), 6.82 (1H, d, J=1.8 Hz), 6.69 (1H, d, J=1.8 Hz), 6.65 (1H, d, J=1.8 Hz), 5.50 (1H, m), 4.06 (1H, m), 3.80 (3H, s), 3.19 (1H, dd, J_1,2=18.3, 4.3 Hz), 3.03 (1H, dd, J_1,2=18.3, 4.3 Hz)

(2R,3R)-2-(3,5-Dihydroxy-4-methoxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate (7)

In a similar manner to that used to prepare 2, treatment of crude 70 gave 7 (77%, 2 steps) as a colorless amorphous. HR-MS (FAB) calculated for C₂₃H₂₀O₁₁Na [M+Na]⁺ 495.0904, found 495.0942; [α]^D₂₀=−147.6 (c 1.00, 50% acetone in H₂O); IR (neat) 3346, 1701, 1608, 1357, 1234 cm⁻¹; ¹H NMR (270 MHz, CD₃OD) δ 6.84 (2H, s), 6.43 (2H, s), 5.87 (2H, s), 5.44 (1H, m), 4.89 (1H, m), 3.66 (3H, s), 2.90 (1H, dd, J_1,2=17.1, 4.6 Hz), 2.75 (1H, dd, J_1,2=17.1, 2.3 Hz); ¹³C NMR (68 MHz, CD₃OD) δ 167.6, 157.8, 157.0, 151.3, 146.2, 136.3, 136.0, 135.8, 129.8, 121.5, 110.3, 107.1, 99.4, 96.6, 95.9, 78.4, 69.8, 60.8, 26.8.

(2R,3R)-2-(3-tert-Butyldiphenylsilyloxy-4,5-bis(2-nitrophenylsulfonyloxy)phenyl)-3-hydroxychroman-5,7-diyl bis(2-nitrobenzenesulfonate) (71)

In a similar manner to that used to prepare 28, treatment of 33 gave 71 (95%) as a colorless amorphous. HR-MS (FAB) calculated for C₅₆H₄₄N₄O₂₃SiS₄Na [M+Na]⁺1307.0946, found 1307.0963; [α]^D₂₀=−9.25 (c 0.84, acetone); IR (neat) 1709, 1618, 1591, 1548, 1440, 1391, 1360, 1306, 1196, 1113, 997 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ, 7.36–8.13 (26H, m), 6.60 (1H, d, J=2.0 Hz), 6.43 (1H, d, J=2.0 Hz), 6.42 (1H, d, J=2.0 Hz), 6.35 (1H, d, J=2.0 Hz), 4.51 (1H, m), 3.58 (1H, m), 2.88 (2H, m), 2.76 (1H, dd, J=17.5, 4.0 Hz), 1.08 (9H, s); ¹³C NMR (125 MHz, CDCl₃) δ 154.9, 150.7, 148.5, 148.3, 148.3, 148.2, 146.9, 142.4, 136.5, 136.0, 136.0, 135.9, 135.5, 135.4, 135.3, 132.8, 132.6, 132.6, 132.4, 132.4, 132.2, 132.1, 132.0, 131.7, 131.2, 131.0, 130.5, 130.4, 130.1, 128.0, 127.5, 125.1, 124.9, 124.6, 117.5, 113.8, 112.6, 109.9, 64.2, 60.4, 27.9, 26.0, 19.4.

(2R,3R)-2-(3-Hydroxy-4,5-bis(2-nitrophenylsulfonyloxy)phenyl)-3-hydroxychroman-5,7-diyl bis(2-nitrobenzenesulfonate) (36)

In a similar manner to that used to prepare 70, treatment of 71 gave 36 (86%) as a colorless amorphous. HR-MS (FAB) calculated for C₃₉H₂₆N₄O₂₃S₄Na [M+Na]⁺1068.9768, found 1068.9788; [α]^D₂₀=−1.41 (c 1.80, acetone); IR (neat) 3429, 1701, 1612, 1591, 1543, 1438, 1389, 1364, 1194, 1113, 999 cm⁻¹; ¹H NMR (270 MHz, acetone-d₆) δ, 8.13–7.86 (16H, m), 7.17 (1H, d, J=2.0 Hz), 6.78 (1H, d, J=2.0 Hz), 6.74 (1H, d, J=2.0 Hz), 6.50 (1H, d, J=2.0 Hz), 5.12 (1H, m), 4.29 (1H, m), 2.98–2.90 (2H, m); ¹³C NMR (125 MHz, acetone-d₆) δ 156.2, 151.6, 148.7, 148.6, 148.5, 148.4, 147.4, 142.3, 139.2, 137.1, 136.8, 136.0, 133.1, 132.9, 132.9, 132.8, 132.2, 132.2, 132.1, 131.9, 131.4, 130.1, 130.0, 127.8, 127.4, 126.8, 125.5, 125.5, 125.3, 125.1, 115.2, 114.9, 112.2, 109.7, 108.6, 78.3, 63.7, 29.8.

(2R,3R)-2-(3-Methoxy-4,5-bis(2-nitrophenylsulfonyloxy)phenyl)-3-hydroxychroman-5,7-diyl bis(2-nitrobenzenesulfonate) (37)

In a similar manner to that used to prepare 35, treatment of 36 gave 37 (91%) as a colorless amorphous. HR-MS (FAB) calculated for C₄₀H₂₈N₄O₂₃S₄Na [M+Na]⁺1082.9925, found 1082.9946; [α]^D₂₀=−3.18 (c 0.56, acetone); IR (neat) 3451, 1701, 1618, 1591, 1541, 1439, 1389, 1356, 1306, 1194, 1113, 999 cm⁻¹; ¹H NMR (270 MHz, acetone-d₆) δ 8.13–7.90 (16H, m), 7.30 (1H, d, J=2.0 Hz), 6.94 (1H, d, J=2.0 Hz), 6.77 (1H, d, J=2.6 Hz), 6.51 (1H, d, J=2.6 Hz), 5.21 (1H, m), 4.37 (1H, m), 3.64 (3H, s), 2.98–2.94 (2H, m); ¹³C NMR (68 MHz, acetone-d₆) δ 156.2, 153.3, 148.7, 148.6, 148.5, 148.3, 147.4, 142.2, 139.6, 137.1, 137.0, 136.8, 136.0, 133.1, 133.0, 132.9, 132.7, 132.2, 132.0, 131.9, 131.3, 130.8, 130.0, 127.9, 127.5, 126.8, 125.5, 125.5, 125.4, 125.1, 115.1, 113.4, 110.7, 109.8, 108.7, 78.5, 63.6, 54.2, 29.8.

(2R,3R)-2-(3-Methoxy-4,5-bis(2-nitrophenylsulfonyloxy)phenyl)-5,7-bis(2-nitrophenylsulfonyloxy)-chroman-3-yl 3-methoxy-4,5-bis(2-nitrophenylsulfonyloxy)benzoate (72)

37 (20.0 mg, 0.0188 mmol), 25 (20.9 mg, 0.0377 mmol), EDCI (10.8 mg, 0.0563 mmol), DMAP (0.2 mg, 1.9 μmol) were dissolved in MeCN (0.25 ml) and the resulting solution was stirred at room temperature for 17 h. Then, the reaction mixture was quenched with saturated NH₄Cl and extracted with CH₂Cl₂. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford crude 72 as a colorless solid. The crude 72 was used in the next step without further purification. ¹H NMR (270 MHz, acetone-d₆) δ, 8.17–7.81 (28H, m, 28H), 7.37 (1H, d, J=2.0 Hz, 1H), 7.31 (1H, d, J=2.0 Hz), 7.24 (1H, d, J=2.0 Hz), 7.04 (1H, d, J=2.0 Hz), 6.96 (1H, d, J=2.0 Hz), 6.66 (1H, d, J=2.0 Hz), 5.82–5.77 (1H, m, 1H), 5.59–5.56 (1H, m, 1H), 3.60 (3H, s), 3.48 (3H, s), 3.32 (1H, dd, J_1,2=17.8, 4.0 Hz), 3.15 (1H, dd, J_1,2=17.8, 2.0 Hz).

(2R,3R)-2-(4,5-Dihydroxy-3-methoxyphenyl)-5,7-dihydroxychroman-3-yl 3,4-dihydroxy-5-methoxybenzoate (38)

In a similar manner to that used to prepare 2, treatment of 72 with 2-aminothiophenol gave 38 (63%) as a colorless amorphous. HR-MS (FAB) calculated for C₂₄H₂₃O₁₁ [M+H]⁺487.1240, found 487.1229; [α]^D₂₀=−218.1 (c 0.04, 50% acetone in H₂O); IR (neat) 3285, 1701, 1605, 1364, 1221; ¹H NMR (500 MHz, CD₃OD) δ 7.10 (1H, d, J=2.0 Hz), 7.02 (1H, d, J=2.0 Hz), 6.61 (1H, d, J=2.0 Hz), 6.58 (1H, d, J=2.0 Hz), 5.96 (2H, s), 5.52 (1H, m), 5.23 (1H, m), 3.79 (3H, s), 3.58 (3H, s), 3.01 (1H, dd, J_1,2=17.1, 4.6 Hz), 2.86 (1H, dd, J_1,2=17.1, 1.7 Hz); ¹³C NMR (125 MHz, CD₃OD) δ 165.9, 156.5, 156.5, 148.0, 147.7, 144.9, 144.8, 139.2, 133.4, 129.3, 119.8, 110.6, 107.3, 104.9, 101.7, 98.1, 95.2, 94.4, 77.5, 68.9, 55.1, 54.9, 25.4.

(2R,3R)-2-(3-Methoxy-4,5-bis(2-nitrophenylsulfonyloxy)phenyl)-5,7-bis(2-nitrophenylsulfonyloxy)-chroman-3-yl-3,4,5-tris(2-nitrophenylsulfonyloxy)benzoate (73)

In a similar manner to that used to prepare 29, treatment of 37 with 26 gave 73 (86%) as a colorless solid. HR-MS (FAB) calculated for C₆₅H₄₁N₇O₃₉S₇Na [M+Na]⁺1789.9383, found 1789.9396; [α]^D₂₀=−37.4 (c 0.38, acetone); IR (neat) 1709, 1618, 1593, 1545, 1442, 1391, 1364, 1308, 1196, 1116, 1006 cm⁻¹; ¹H NMR (270 MHz, acetone-d₆) δ 8.20–7.80 (28H, m), 7.69 (2H, s), 7.31 (1H, d, J=1.3 Hz), 7.00 (1H, d, J=1.3 Hz), 6.96 (1H, d, J=2.0 Hz), 6.67 (1H, d, J=2.0 Hz), 5.81 (1H, m), 5.56 (1H, m), 3.49 (3H, s), 3.33 (1H, dd, J_1,2=17.8, 4.0 Hz), 3.13 (1H, dd, J_1,2=17.8, 2.0 Hz); ¹³C NMR (68 MHz, acetone-d₆) δ 162.3, 156.4, 154.4, 149.2, 149.1, 148.6, 143.9, 143.3, 138.8, 138.1, 137.9, 137.7, 136.9, 134.1, 133.8, 133.7, 133.4, 133.0, 132.8, 132.5, 132.1, 130.6, 130.4, 129.2, 128.4, 128.0, 127.9, 127.6, 126.4, 126.3, 126.1, 125.8, 124.7, 114.4, 114.0, 111.2, 110.8, 110.5, 77.4, 69.0, 56.9, 26.8.

(2R,3R)-2-(4,5-Dihydroxy-3-methoxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate (6)

In a similar manner to that used to prepare 2, treatment of 73 gave 6 (63%) as a colorless amorphous. HR-MS (FAB) calculated for C₂₃H₂₀O₁₁Na [M+Na]⁺ 495.0904, found 495.0938; [α]^D₂₀=−148.9 (c 0.325, 50% acetone in H₂O); IR (neat) 3332, 1703, 1618, 1365, 1244 cm⁻¹; ¹H NMR (270 MHz, CD₃OD) δ 7.05 (1H, d, J=2.0 Hz), 7.01 (1H, d, J=2.0 Hz), 6.51 (2H, s), 5.97 (1H, d, J=2.0 Hz), 5.95 (1H, d, J=2.0 Hz), 5.49 (1H, m), 4.99 (1H, m), 3.80 (3H, s), 2.99 (1H, dd, J_1,2=17.1, 4.6 Hz), 2.86 (1H, dd, J_1,2=17.1, 3.0 Hz); ¹³C NMR (68 MHz, CD₃OD) δ 166.6, 157.1, 156.5, 148.6, 145.6, 145.3, 135.2, 134.0, 129.8, 129.0, 120.7, 109.5, 108.0, 102.6, 98.6, 95.8, 95.2, 78.2, 69.2, 55.6, 26.2.

(2R,3R)-2-(3,4-Bis(2-nitrophenylsulfonyloxy)phenyl)-3-hydroxychroman-5,7-diyl bis(2-nitrophenylsulfonate) (41)

In a similar manner to that used to prepare 28, treatment of (–)-Epicatechin gave 41 (92%) as a colorless amorphous. HR-MS (FAB) calculated for C₃₉H₂₆N₄O₂₂S₄ [M+H]⁺ 1052.9819, found 1052.9816; [α]^D₂₀=+3.83 (c 1.06, acetone); IR (neat) 3404, 1705, 1620, 1591, 1550, 1440, 1394, 1346, 1306, 1182, 1110, 999 cm⁻¹; ¹H NMR (500 MHz, acetone-d₆) δ 8.15–7.86 (16H, m), 7.57 (1H, dd, J_1,2=8.6, 2.0 Hz), 7.39 (1H, d, J=8.6 Hz), 7.38 (1H, d, J=2.0 Hz), 6.77 (1H, d, J=2.4 Hz), 6.51 (1H, d, J=2.4 Hz), 5.26 (1H, s), 4.33–4.26 (1H, m), 3.03–2.85 (2H, m); ¹³C NMR (126 MHz, acetone-d₆) δ 156.2, 148.7, 148.5, 147.4, 140.8, 140.5, 140.1, 137.1, 137.0, 136.9, 136.9, 133.1, 133.1, 133.0, 132.9, 132.2, 132.0, 131.9, 131.7, 127.9, 127.7, 127.5, 127.3, 126.8, 125.5, 125.5, 125.4, 124.2, 122.9, 115.1, 109.7, 108.7, 78.2, 63.7, 29.3.

(2R,3R)-2-(3,4-Bis(2-nitrophenylsulfonyloxy)phenyl)-5,7-bis(2-nitrophenylsulfonyloxy) chroman-3-yl 3-methoxy-4,5-bis(2-nitrophenylsulfonyloxy)benzoate (74)

In a similar manner to that used to prepare 29, treatment of 41 with 25 gave 74 (97%) as a colorless amorphous. HR-MS (FAB) calculated for C₆₅H₄₁N₇O₃₉S₇Na [M+Na]⁺ 1566.9831, found 1566.9817; [α]^D₂₀=−32.1 (c 1.00, acetone); IR (neat) 1712, 1618, 1591, 1552, 1423, 1394, 1368, 1304, 1198, 1117, 1009 cm⁻¹; ¹H NMR (270 MHz, acetone-d₆) δ 8.15–7.80 (28H, m), 7.62 (1H, dd, J_1,2=8.6, 2.0 Hz), 7.49 (1H, d, J=2.0 Hz), 7.35 (1H, d, J=2.0 Hz), 7.32 (1H, d, J=8.6 Hz), 7.22 (1H, d, J=2.0 Hz), 6.98 (1H, d, J=2.0 Hz), 6.66 (1H, d, J=2.0 Hz), 5.74 (1H, m), 5.63 (1H, s), 3.61 (3H, s), 3.33 (1H, dd, J_1,2=17.8, 4.0 Hz), 3.23 (1H, dd, J_1,2=17.8, 2.6 Hz); ¹³C NMR (125 MHz, acetone-d₆) δ 162.1, 155.6, 150.2, 148.7, 148.4, 147.8, 142.6, 141.0, 140.8, 138.5, 137.1, 137.0, 136.9, 133.1, 133.0, 133.0, 132.9, 132.3, 132.0, 131.9, 131.8, 127.6, 127.5, 127.4, 127.2, 126.9, 126.7, 125.5, 125.4, 125.4, 125.3, 124.8, 124.7, 124.7, 122.5, 113.7, 110.4, 109.7, 76.4, 67.7, 62.0, 26.0.

(2R,3R)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4-dihydroxy-5-methoxybenzoate (8)

In a similar manner to that used to prepare 2, treatment of 74 gave 8 (87%) as a colorless amorphous. HR-MS (FAB) calculated for C₂₃H₂₀O₁₀Na [M+Na]⁺ 479.0954, found 479.0906; [α]^D₂₀=−194.4 (c 1.10, 50% acetone in H₂O); IR (neat) 3366, 1701, 1608, 1363, 1232 cm⁻¹; ¹H NMR (270 MHz, CD₃OD) δ 7.07 (1H, d, J=2.0 Hz), 7.02 (1H, d, J=2.0 Hz), 6.96 (1H, d, J=2.0 Hz), 6.80 (1H, dd, J=7.9, 2.0 Hz), 6.70 (1H, d, J=7.9 Hz), 5.98 (1H, d, J=2.6 Hz), 5.97 (1H, d, J=2.6 Hz), 5.51 (1H, m), 5.06 (1H, s), 3.81 (3H, s), 3.01 (1H, dd, J=17.1, 4.6 Hz), 2.88 (1H, dd, J=17.1, 2.6 Hz); ¹³C NMR (68 MHz, CD₃OD) δ 167.6, 157.9, 157.8, 157.2, 149.0, 146.1, 146.0, 146.0, 140.6, 131.5, 121.5, 119.2, 116.0, 115.1, 111.9, 106.2, 99.3, 96.6, 95.8, 78.5, 70.4, 56.6, 26.7.

(2R,3R)-2-(3,4-Bis(2-nitrophenylsulfonyloxy)phenyl)-5,7-bis(2-nitrophenylsulfonyloxy) chroman-3-yl 4-methoxy-3,5-bis(2-nitrophenylsulfonyloxy)benzoate (75)

In a similar manner to that used to prepare 29, treatment of 41 with 22 gave 75 (99%) as a colorless amorphous. HR-MS (FAB) calculated for C₆₅H₄₁N₇O₃₉S₇Na [M+Na]⁺ 1566.9831, found 1566.9839; [α]^D₂₀=−35.4 (c 1.00, acetone); IR (neat) 1714, 1619, 1591, 1557, 1425, 1398, 1368, 1311, 1201, 1111, 1007 cm⁻¹; ¹H NMR (270 MHz, acetone-d₆) δ 8.15–7.80 (28H, m, 28H), 7.59 (1H, dd, J_1,2=8.6, 2.0 Hz), 7.56 (2H, s), 7.40 (1H, d, J=2.0 Hz), 7.32 (1H, d, J=8.6 Hz), 6.98 (1H, d, J=2.0 Hz), 6.65 (1H, d, J=2.0 Hz), 5.71 (1H, m), 5.59 (1H, s), 3.69 (3H, s), 3.32 (1H, dd, J_1,2=17.8, 4.0 Hz), 3.10 (1H, dd, J_1,2=17.8, 2.0 Hz); ¹³C NMR (125 MHz, acetone-d₆) δ 162.1, 155.6, 150.2, 148.8, 148.5, 147.8, 142.6, 141.0, 140.8, 138.5, 137.0, 136.9, 133.1, 133.0, 132.9, 132.9, 132.3, 132.0, 131.9, 131.8, 127.6, 127.5, 127.4, 127.1, 126.9, 126.7, 125.5, 125.4, 125.3, 125.3, 124.8, 124.7, 124.7, 122.5, 113.7, 110.4, 109.7, 76.4, 67.7, 61.9, 26.0.

(2R,3R)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,5-dihydroxy-4-methoxybenzoate (9)

In a similar manner to that used to prepare 2, treatment of 75 gave 9 (84%) as a colorless amorphous. [α]^D₂₀=−217.3 (c 0.75, 50% acetone in H₂O); IR (neat) 3367, 1705, 1605, 1371, 1240 cm⁻¹; HR-MS (FAB) calculated for C₂₃H₂₀O₁₀Na [M+Na]⁺ 479.0954, found 479.0906; ¹H NMR (270 MHz, CD₃OD) δ 6.93 (1H, d, J=2.0 Hz), 6.92 (2H, s), 6.80 (1H, dd, J_1,2=8.0, 2.0 Hz), 6.70 (1H, d, J=8.0 Hz), 5.97 (2H, s), 5.54 (1H, m), 5.04 (1H, s), 3.83 (3H, s), 3.01 (1H, dd, J_1,2=17.8, 4.6 Hz), 2.85 (1H, dd, J_1,2=17.8, 2.6 Hz); ¹³C NMR (68 MHz, CD₃OD) δ 167.1, 157.9, 157.8, 157.2, 151.5, 146.0, 141.1, 131.4, 126.5, 119.3, 116.0, 115.0, 110.3, 99.3, 96.6, 95.9, 78.5, 70.3, 60.7, 26.8.

5-((2S,3R)-3-Hydroxy-5,7-bis(2-nitrophenylsulfonyloxy)chroman-2-yl)benzene-1,2,3-triyl tris(2-nitrobenzenesulfonate) (42)

In a similar manner to that used to prepare 28, treatment of (–)-gallocatechin gave 42 (94%) as a colorless amorphous. HR-MS (FAB) calculated for C₄₅H₃₀N₅O₂₇S₅ [M+H]⁺ 1231.9732, found 1231.9717; [α]^D₂₀=−1.61 (c 1.00, acetone); IR (neat) 3406, 1701, 1618, 1589, 1542, 1421, 1388, 1362, 1305, 1222, 1193, 1114, 1008 cm⁻¹; ¹H NMR (500 MHz, acetone-d₆) δ 8.15–7.85 (20H, m), 7.32 (2H, s), 6.74 (1H, d, J=2.6 Hz), 6.55 (1H, d, J=2.6 Hz), 5.00 (1H, d, J=7.3 Hz), 4.75 (1H, d, J=5.1 Hz), 3.90–3.97 (1H, m), 2.82 (1H, dd, J_1,2=16.8, 5.4 Hz), 2.66 (1H, dd, J_1,2=16.8, 8.6 Hz); ¹³C NMR (125 MHz, acetone-d₆) δ 155.2, 148.7, 148.5, 148.2, 148.0, 147.6, 142.8, 140.2, 137.2, 137.2, 137.1, 136.9, 134.6, 133.2, 133.2, 133.1, 132.9, 132.2, 132.1, 131.9, 131.6, 128.6, 127.3, 127.1, 126.7, 125.5, 121.5, 115.7, 109.7, 109.3, 80.2, 65.6, 27.8.

5-(2S,3R)-5,7-Bis(2-nitrophenylsulfonyloxy)-2-(3,4,5-tris(2-nitrophenylsulfonyloxy)phenyl) chroman-3-yl-3-methoxy-4,5-bis(2-nitrophenylsulfonyloxy)benzoate (76)

In a similar manner to that used to prepare 29, treatment of 42 with 25 gave 76 (93%) as a colorless amorphous. HR-MS (FAB) calculated for C₆₅H₄₁N₇O₃₉S₇Na [M+Na]⁺ 1789.9383, found 1789.9375; [α]^D₂₀=+4.03 (c 1.25, acetone); IR (neat) 1717, 1618, 1591, 1550, 1419, 1391, 1362, 1305, 1188, 1105, 1000 cm⁻¹; ¹H NMR (500 MHz, acetone-d₆) δ 8.20–7.75 (28H, m), 7.56 (1H, d, J=2.0 Hz), 7.39 (2H, s), 7.33 (1H, d, J=2.0 Hz), 6.87 (1H, d, J=2.0 Hz), 6.66 (1H, d, J=2.0 Hz), 5.63 (1H, d, J=5.8 Hz), 5.44–5.40 (1H, m), 3.65 (3H, s), 3.06 (1H, dd, J_1,2=17.8, 6.3 Hz), 2.81 (1H, dd, J_1,2=17.8, 4.6 Hz); ¹³C NMR (125 MHz, acetone-d₆) δ 162.7, 154.5, 153.7, 148.7, 148.4, 148.2, 148.2, 148.1, 148.0, 143.2, 142.6, 138.8, 137.4, 137.3, 137.2, 137.0, 136.4, 133.2, 133.2, 133.0, 132.9, 132.2, 132.1, 132.0, 131.9, 131.7, 131.4, 129.6, 129.4, 128.2, 127.66, 127.1, 126.8, 126.6, 125.6, 125.5, 125.4, 125.2, 121.4, 116.4, 113.8, 113.0, 110.0, 109.9, 76.9, 68.7, 56.4, 23.1.

(2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-dihydroxy-5-methoxybenzoate (10)

In a similar manner to that used to prepare 2, treatment of 76 gave 10 (81%) as a colorless amorphous. HR-MS (FAB) calculated for C₂₃H₂₀O₁₁Na [M+Na]⁺ 495.0904, found 495.0873; [α]^D₂₀=+13.9 (c 0.30, 50% acetone in H₂O); IR (neat) 3369, 1701, 1611, 1375, 1240 cm⁻¹; ¹H NMR (270 MHz, CD₃OD) δ 7.07 (1H, d, J=2.0 Hz), 7.01 (1H, d, J=2.0 Hz), 6.43 (2H, s), 5.96 (1H, d, J=2.0 Hz), 5.94 (1H, d, J=2.0 Hz), 5.35–5.25 (1H, m), 4.99 (1H, d, J=6.6 Hz), 3.81 (3H, s), 2.90 (1H, dd, J_1,2=16.5, 4.6 Hz), 2.70 (1H, dd, J_1,2=16.5, 6.0 Hz); ¹³C NMR (68 MHz, CD₃OD) δ 167.6, 158.1, 157.7, 156.6, 149.1, 147.0, 146.2, 140.7, 134.1, 130.9, 121.5, 111.9, 106.6, 106.2, 99.7, 96.5, 95.6, 79.7, 71.7, 56.7, 24.7.

5-(2S,3R)-5,7-Bis(2-nitrophenylsulfonyloxy)-2-(3,4,5-tris(2-nitrophenylsulfonyloxy)phenyl) chroman-3-yl-4-methoxy-3,5-bis(2-nitrophenylsulfonyloxy)benzoate (77)

In a similar manner to that used to prepare 29, treatment of 42 with 22 gave 77 as a crude colorless amorphous. The crude 77 was used in the next step without further purification. ¹H NMR (500 MHz, acetone-d₆) δ 8.20–7.80 (28H, m), 7.68 (2H, s), 7.33 (2H, s), 6.86 (1H, d, J=2.3 Hz), 6.64 (1H, d, J=2.3 Hz), 5.63 (1H, d, J=5.8 Hz), 5.37–5.42 (1H, m), 3.67 (3H, s), 3.01 (1H, dd, J_1,2=18.4, 5.2 Hz), 2.71 (1H, dd, J_1,2=18.4, 4.6 Hz).

(2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,5-dihydroxy-4-methoxybenzoate (11)

In a similar manner to that used to prepare 2, treatment of crude 77 gave 11 (71%, two steps) as a colorless amorphous. HR-MS (FAB) calculated for C₂₃H₂₀O₁₁Na [M+Na]⁺ 495.0904, found 495.0885; [α]^D₂₀=+13.7 (c 0.25, 50% acetone in H₂O); IR (neat) 3300, 1701, 1604, 1377, 1238 cm⁻¹; ¹H NMR (270 MHz, CD₃OD) δ 6.95 (2H, s), 6.41 (2H, s), 5.96 (2H, s), 5.42–5.35 (1H, m), 5.04 (1H, d, J=5.9 Hz), 3.84 (3H, s), 2.80 (1H, dd, J_1,2=16.5, 5.3 Hz), 2.71 (1H, dd, J_1,2=16.5, 5.3 Hz); ¹³C NMR (68 MHz, CD₃OD) δ 167.1, 158.1, 158.0, 157.6, 157.5, 156.3, 151.6, 147.0, 141.3, 134.0, 130.9, 126.5, 110.2, 106.4, 99.5, 79.2, 71.4, 60.7, 23.9.

(2R,3S)-2-(3,4-Bis(2-nitrophenylsulfonyloxy)phenyl)-3-hydroxychroman-5,7-diyl bis(2-nitrophenylsulfonate) (43)

In a manner similar to that used to prepare 28, treatment of (+)-catechin gave 43 (94%) as a colorless amorphous. HR-MS (FAB) calculated for C₃₉H₂₆N₄O₂₂S₄ [M+H]⁺ 1052.9819, found 1052.9843; [α]^D₂₀=+8.54 (c 1.00, acetone); IR (neat) 3498, 1713, 1618, 1595, 1545, 1419, 1392, 1350, 1304, 1191, 1112, 1015 cm⁻¹; ¹H NMR (270 MHz, CD₃CN) δ 8.07–8.01 (4H, m), 7.91–7.71 (12H, m), 7.33–7.23 (3H, m), 6.74 (1H, d, J=2.5 Hz), 6.57 (1H, d, J=2.5 Hz), 4.83 (1H, d, J=7.3 Hz), 3.98 (1H, m), 2.98 (1H, dd, J_1,2=17.0, 5.0 Hz), 2.80 (1H, dd, J_1,2=17.0, 8.0 H); ¹³C NMR (68 MHz, CD₃CN) δ 156.1, 149.3, 149.1, 148.9, 148.5, 141.8, 141.6, 140.7, 137.8, 137.7, 133.9, 133.8, 133.7, 133.1, 132.8, 132.7, 132.6, 128.4, 128.2, 128.0, 127.4, 126.2, 126.2, 125.4, 123.2, 116.3, 110.6, 110.1, 81.1, 66.1, 27.7.

(2R,3S)-2-(3,4-Bis(2-nitrophenylsulfonyloxy)phenyl)-5,7-bis(2-nitrophenylsulfonyloxy) chroman-3-yl 3-methoxy-4,5-bis(2-nitrophenylsulfonyloxy)benzoate (78)

In a similar manner to that used to prepare 29, treatment of 43 with 25 gave 78 (74%) as a colorless amorphous. HR-MS (FAB) calculated for C₆₅H₄₁N₇O₃₉S₇Na [M+Na]⁺ 1566.9831, found 1566.9819; [α]^D₂₀=+22.4 (c 1.07, acetone); IR (neat) 1718, 1618, 1591, 1554, 1417, 1385, 1356, 1304, 1184, 1119, 1000 cm⁻¹; ¹H NMR (500 MHz, acetone-d₆) δ 8.17–7.85 (28H, m), 7.54 (1H, d, J=2.3 Hz), 7.49 (1H, dd, J=8.6, 2.3 Hz), 7.39 (1H, d, J=8.6 Hz), 7.32 (1H, d, J=2.3 Hz), 7.31 (1H, d, J=2.3 Hz), 6.89 (1H, d, J=2.0 Hz), 6.65 (1H, d, J=2.0 Hz), 5.59 (1H, d, J=5.8 Hz), 5.46–5.42 (1H, m), 3.65 (3H, s), 3.04 (1H, dd, J_1,2=17.2, 5.2 Hz), 2.77 (1H, dd, J_1,2=17.2, 4.6 Hz); ¹³C NMR (125 MHz, acetone-d₆) δ 162.7, 154.8, 153.8, 148.7, 148.5, 148.4, 148.2, 148.1, 148.0, 142.6, 141.3, 141.1, 138.6, 137.2, 137.2, 137.1, 137.0, 136.4, 135.2, 133.2, 133.1, 133.0, 133.0, 132.9, 132.3, 131.9, 131.9, 131.8, 131.4, 129.6, 129.5, 127.6, 127.5, 127.3, 127.1, 126.9, 126.6, 125.6, 125.5, 125.5, 125.4, 125.4, 125.2, 125.1, 122.3, 116.3, 113.9, 112.9, 110.1, 109.8, 77.1, 68.9, 56.4, 23.2.

(2R,3S)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4-dihydroxy-5-methoxybenzoate (12)

In a similar manner to that used to prepare 2, treatment of 78 gave 12 (99%) as a colorless amorphous. HR-MS (FAB) calculated for C₂₃H₂₀O₁₀Na [M+Na]⁺ 479.0954, found 479.0994, [α]^D₂₀=+142.5 (c 0.34, 50% acetone in H₂O); IR (neat) 3331, 1705, 1612, 1385, 1231 cm⁻¹; ¹H NMR (270 MHz, CD₃OD) δ 7.07 (1H, d, J=2.0 Hz), 7.01 (1H, d, J=2.0 Hz), 6.86 (1H, d, J=2.0 Hz), 6.71–6.76 (2H, m), 5.97 (1H, d, J=2.0 Hz), 5.94 (1H, d, J=2.0 Hz), 5.28–5.37 (1H, m), 5.03 (1H, d, J=6.6 Hz), 3.82 (3H, s), 2.92 (1H, dd, J_1,2=16.5, 5.3 Hz), 2.71 (1H, dd, J_1,2=16.5, 7.3 Hz); ¹³C NMR (68 MHz, CD₃OD) δ 167.4, 158.2, 157.7, 156.7, 149.0, 146.4, 146.2, 140.7, 131.4, 121.4, 119.4, 116.2, 114.7, 111.9, 106.2, 99.8, 96.5, 95.6, 79.7, 71.2, 56.7, 25.1.

(2R,3S)-2-(3,4-Bis(2-nitrophenylsulfonyloxy)phenyl)-5,7-bis(2-nitrophenylsulfonyloxy) chroman-3-yl 4-methoxy-3,5-bis(2-nitrophenylsulfonyloxy)benzoate (79)

In a similar manner to that used to prepare 29, treatment of 43 with 22 gave 79 (89%) as a colorless amorphous. HR-MS (FAB) calculated for C₆₅H₄₁N₇O₃₉S₇Na [M+Na]⁺ 1566.9831, found 1566.9825; [α]^D₂₀=+21.0 (c 1.10, acetone); IR (neat) 1705, 1618, 1593, 1554, 1418, 1395, 1365, 1315, 1177, 1119, 1011 cm⁻¹; ¹H NMR (500 MHz, acetone-d₆) δ 8.18–7.88 (28H, m), 7.67 (2H, s), 7.45 (1H, dd, J=8.6, 2.3 Hz), 7.39 (1H, d, J=8.6 Hz), 7.26 (1H, d, J=2.3 Hz), 6.88 (1H, d, J=2.0 Hz), 6.65 (1H, d, J=2.0 Hz), 5.58 (1H, d, J=5.2 Hz), 5.43–5.39 (1H, m), 3.69 (3H, s), 3.00 (1H, dd, J_1,2=17.8, 5.8 Hz), 2.66 (1H, dd, J_1,2=17.8, 4.6 Hz); ¹³C NMR (125 MHz, acetone-d₆) δ 162.2, 154.7, 150.3, 148.8, 148.5, 148.5, 148.4, 148.1, 148.1, 142.6, 141.3, 141.1, 138.5, 137.2, 137.2, 137.1, 137.1, 137.0, 133.1, 133.0, 132.9, 132.3, 132.0, 131.9, 131.8, 131.8, 127.6, 127.5, 127.3, 127.0, 126.9, 126.6, 125.6, 125.5, 125.4, 125.1, 124.8, 122.1, 113.8, 110.1, 109.9, 77.0, 68.6, 61.9, 22.9.

(2R,3S)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,5-dihydroxy-4-methoxybenzoate (13)

In a similar manner to that used to prepare 2, treatment of 79 gave 13 (89%) as a colorless amorphous. HR-MS (FAB) calculated for C₂₃H₂₀O₁₀Na [M+Na]⁺ 479.0954, found 479.0994; [α]^D₂₀=+110.6 (c 0.80, 50% acetone in H₂O); IR (neat) 3367, 1701, 1604, 1367, 1234 cm⁻¹; ¹H NMR (270 MHz, CD₃OD) δ 6.94 (2H, s), 6.83 (1H, s), 6.72 (2H, s), 5.97–5.93 (2H, m), 5.41–5.34 (1H, m), 5.05 (1H, d, J=5.9 Hz), 3.84 (3H, s), 2.85 (1H, dd, J_1,2=16.5, 5.3 Hz), 2.71 (1H, dd, J_1,2=16.5, 6.6 Hz); ¹³C NMR (68 MHz, CD₃OD) δ 167.1, 158.2, 157.6, 156.5, 151.6, 146.3, 146.3, 131.3, 126.5, 119.3, 116.2, 114.4, 110.2, 99.6, 96.5, 95.6, 79.3, 71.5, 60.7, 24.5.

5,7–Di-O-(2–nitrobenzenesulfonyl)catechin (51)

To a solution of boric acid (100 g, 1.6 mol) and NaOH (20 g) in H₂O (1300 ml) was added 49 (10.0 g, 34.5 mmol) and the resulting solution was adjusted to pH 9.0 by the addition of 1 m NaOH. Then, 2-nitrobenzenesulfonyl chloride (15.3 g, 69.0 mmol) in toluene (220 ml) was added dropwise over 30 min and the mixture was stirred at room temperature for 7 h. The reaction was quenched with 1 m HCl and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (1–3% MeOH in CH₂Cl₂) to afford 51 (15.9 g, 70%) as a pale yellow amorphous solid. HR-MS (ESI) calculated for C₂₇H₂₀N₂O₁₄S₂Na [M+Na]⁺ 683.0248, found 683.0281; [α]²⁰_D=+13.3 (c 1.0, acetone) IR (neat) 3398, 1701, 1618, 1591, 1545, 1439, 1389, 1366, 1196, 1110, 1032, 997, 780 cm⁻¹; ¹H NMR (500 MHz, acetone-d₆) δ 8.09–8.00 (3H, m), 7.98–7.75 (5H, m), 6.78 (1H, d, J=8.0 Hz), 6.73 (1H, dd, J_1,2=6.5, 2.0 Hz), 6.60 (1H, dd, J_1,2=8.0, 2.0 Hz), 6.55 (1H, d, J=2.0 Hz), 4.85 (1H, d, J=6.0 Hz), 4.39 (1H, d, J=4.0 Hz), 4.10–4.05 (1H, m), 2.66 (1H, dd, J_1,2=17.0, 7.5 Hz), 2.53 (1H, dd, J_1,2=17.0, 5.0 Hz); ¹³C NMR (126 MHz, acetone-d₆) δ 157.1, 149.5, 149.2, 149.0, 148.5, 148.4, 145.9, 145.8, 137.8, 137.7, 133.8, 133.6, 133.0, 132.5, 130.8, 128.2, 127.6, 126.2, 126.2, 119.1, 116.5, 116.0, 114.5, 110.3, 109.3, 82.7, 66.2, 27.6.

5,7–Di-O-(2–nitrobenzenesulfonyl)epicatechin (52)

In a similar manner to that used to prepare 51, treatment of 50 (5.0 g) gave 52 (7.1 g, 63%) as a pale yellow amorphous solid. HR-MS (ESI) calculated for C₂₇H₂₀N₂O₁₄S₂Na [M+Na]⁺ 683.0248, found 683.0255; [α]²⁰_D=+6.5 (c 1.00, acetone); IR (neat) 3421, 1691, 1617, 1385, 1195, 1110, 997, 781 cm⁻¹; ¹H NMR (500 MHz, acetone-d₆) δ 8.17-8.08 (4H, m, 4H), 8.06–8.01 (2H, m, 2H), 8.00–7.91 (2H, m), 7.91 (1H, br s), 7.88 (1H, br s), 7.00 (1H, br s), 6.79 (2H, br s), 6.77 (1H, d, J=2.0 Hz), 6.47 (1H, d, J=2.0 Hz), 5.02 (1H, br s), 4.30–4.20 (1H, m), 4.06 (1H, d, J=4.5 Hz), 3.00–2.85 (2H, m); ¹³C NMR (126 MHz, acetone-d₆) δ 157.0, 148.7, 148.5, 147.5, 144.8, 144.7, 136.9, 133.1, 132.9, 132.2, 131.8, 130.0, 127.6, 126.9, 125.5, 125.4, 118.5, 115.3, 114.8, 114.4, 109.6, 108.2, 79.5, 64.3, 29.1.

5,7–Di-O-(2–nitrobenzenesulfonyl)epigallocatechin (53)

In a similar manner to that used to prepare 51, treatment of 27 (4.0 g) gave 53 (4.6 g, 52%) as a brown amorphous solid. HR-MS (ESI) calculated for C₂₇H₂₀N₂O₁₅S₂Na [M+Na]⁺ 699.0197, found 699.0191; [α]²⁰_D=+4.1 (c 1.00, acetone); IR (neat) 3342, 1701, 1620, 1591, 1547, 1441, 1385, 1368, 1194, 1111, 997, 781 cm⁻¹; ¹H NMR (500 MHz, acetone-d₆) δ 8.20–7.75 (8H, m), 7.34 (1H, s), 7.00 (1H, br s), 6.75 (1H, d, J=2.5 Hz), 6.51 (2H, s), 6.47 (1H, d, J=2.0 Hz), 4.96 (1H, br s), 4.26–4.20 (1H, m), 4.01 (1H, d, J=4.5 Hz), 2.93 (1H, dd, J_1,2=16.5, 4.0 Hz), 2.53 (1H, dd, J_1,2=16.5, 4.0 Hz); ¹³C NMR (126 MHz, acetone-d₆) δ 157.7, 149.4, 148.2, 146.1, 137.7, 133.8, 133.6, 133.2, 133.0, 132.6, 130.0, 128.3, 127.6, 126.2, 126.2, 110.3, 108.9, 106.7, 80.1, 65.1, 30.0.

(2R,3R)-5,7,5,7-Tetra-O–(2-nitrobenzenesulfonyl)neotheaflavin (56)

To a solution of 50 (1.0 g, 1.5 mmol) in MeCN (15 ml) was added Pb(OAc)₄ (806 mg, 4.5 mmol) at 0 °C. The resulting suspension was stirred for 10 min at 0 °C. The reaction mixture was added to benzene, and then the mixture was filtered through a pad of celite. Then, the filtrate was evaporated under reduced pressure, and the resulting crude product was used in the next reaction without further purification.

The crude product 55 was dissolved in MeCN/CH₂Cl₂ (1:4, 25 ml). To this solution were added MS3A (1.0 g) and Ns-epigallocatchin (53) (342 mg, 505 μmol) in MeCN/CH₂Cl₂ (1:4, 10 ml) at 0 °C. The resulting suspension was stirred for 20 min at 0 °C. After the addition of H₂O, the mixture was stirred for 5 min at room temperature. The reaction mixture was filtered, and then the filtrate was extracted with AcOEt, the organic phase was washed with H₂O, and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (CH₂Cl₂:MeOH=98:2) to afford 56 (327 mg, 50%) as an orange amorphous solid. HR-MS (ESI) calculated for C₅₃H₃₆N₄O₂₈S₄Na [M+Na]⁺ 1327.0291, found 1327.0284; [α]²⁰_D=–6.6 (c 0.20, acetone); IR (neat) 3352, 1701, 1618, 1591, 1541, 1477, 1437, 1384, 1361, 1232, 1190, 1106, 1058, 1030, 995 850, 775, 736 cm⁻¹; ¹H NMR (500 MHz, acetone-d₆) δ 8.18–7.86 (16H, m), 7.51 (1H, s), 7.47 (1H, s), 6.88 (1H, s), 6.83 (1H, br s), 6.63 (1H, d, J=2.0 Hz), 6.53 (1H, d, J=2.0 Hz), 5.85 (1H, br s), 5.17 (1H, s), 4.49 (1H, s), 4.31–2.98 (1H, m), 3.10 (1H, dd, J_1,2=17.5, 2.5 Hz), 3.05 (1H, dd, J_1,2=17.5, 2.5 Hz), 2.80 (1H, dd, J_1,2=17.0, 7.5 Hz), 2.65–2.50 (1H, br s); ¹³C NMR (125 MHz, acetone-d₆) δ 184.8, 156.9, 156.7, 154.5, 151.2, 149.2, 149.2, 149.1, 149.0, 148.8, 148.4, 148.1, 146.3, 137.6, 137.6, 137.5, 133.8, 133.7, 133.7, 133.6 132.9, 132.8, 132.5, 132.3, 130.4, 129.7, 128.1, 128.0, 127.9, 127.5, 127.3, 126.2, 126.1, 126.1, 126.1, 121.6, 118.6, 116.3, 115.7, 110.5, 110.3, 109.7, 109.4, 82.0, 69.7, 66.5, 64.7, 55.2, 29.6, 29.5.

Neotheaflavin (5)

To a suspension of Cs₂CO₃ (223 mg, 0.17 mmol) and thiophenol (0.17 ml, 1.7 mmol) in MeCN/DMF(1:2, 2.7 ml) was added the solution of 56 in MeCN (3.0 ml) at 0 °C and the reaction mixture was stirred at the same temperature for 2.0 h. The reaction was quenched with 1 m HCl aqueous and extracted with AcOEt. The organic phase was evaporated under reduced pressure. The residue was purified by preparative TLC (CH₂Cl₂:MeOH=9:1) to afford 5 (53.1 mg, 55%) as a orange amorphous solid. HR-MS (ESI) calculated for C₂₉H₂₄O₁₂Na [M+Na]⁺ 587.1159, found 587.1130; [α]²⁰_D=–122.1 (c 0.20, acetone); IR (neat) 3362, 1699, 1622, 1607, 1506, 1472, 1429, 1361, 1236, 1193, 1143, 1099, 1076, 1046, 1012, 823 cm⁻¹; ¹H NMR (500 MHz, acetone-d₆) δ 8.80 (1H, br s), 8.26 (1H, s), 7.77 (1H, s), 7.66 (1H, s), 6.06 (1H, s), 6.03 (1H, s), 5.95 (1H, s), 5.94 (1H, s), 5.60 (1H, d, J=5.0 Hz), 5.01 (1H, s), 4.36 (1H, br s), 4.12–4.06 (1H, m), 3.00–2.75 (3H, m), 2.63 (1H, dd, J_1,2=16.0, 9.0 Hz); ¹³C NMR (125 MHz, acetone-d₆) δ 184.9, 157.7, 157.5, 157.4, 157.1, 156.7, 156.6, 154.4, 150.6, 146.3, 134.9, 132.3, 130.9, 128.7, 122.4, 121.7, 119.3, 100.8, 99.3, 96.4 96.3, 95.6, 95.4, 81.7, 79.3, 69.5, 66.7, 30.6, 29.4. Analytical data for neotheaflavin (5) in ref. 16.

(2R,3R)-5,7,5,7-Tetra-O–(2-nitrobenzenesulfonyl)theaflavin (64)

To a solution of 52 (500 mg, 757 mmol) in MeCN (7 ml) was added Pb(OAc)₄ (268 mg, 605 mmol) at 0 °C. The resulting suspension was stirred for 10 min at the same temparature. The reaction mixture was added benzene (20 ml), and then the mixture was filtered with celite pad. Then the filtrate was evaporated under reduced pressure, and the resulting crude product was used in the next reaction without further purification.

The crude product 63 was dissolved in MeCN/CH₂Cl₂ (1:4, 12 ml). The solution was added MS3A (300 mg), Ns-epigallocatchin 53 (171 mg, 252 mmol) in MeCN/CH₂Cl₂ (1:4, 4 ml) at 0 °C. The resulting suspension was stirred for 20 min at 0 °C. After the addition of H₂O, the mixture was stirred for 5 min at room temperature. The reaction mixture was filtered, and then the filtrate was extracted with AcOEt, the organic phase was washed with H₂O, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel column (CH₂Cl₂:MeOH=9:1) to afford mixture of 64 and 52 as an orange amorphous solid, and the mixture of product was used in the next reaction without further purification. HR-MS (ESI) calculated for C₅₃H₃₆N₄O₂₈S₄Na [M+Na]⁺ 1327.0291, found 1327.0245.

Theaflavine (4)

To a solution of the crude 64 (249 mg) in MeCN/DMF (1:2, 3.0 ml) were added Cs₂CO₃ (257 mg, 789 mmol) and thiophenol 39 (0.09 ml, 879 mmol) at 0 °C and the reaction mixture was stirred for 3 h at the same temperature. The reaction was quenched with 1 n HCl aqueous and extracted with AcOEt. The organic layer was evaporated under reduced pressure and the residue was purified by HPLC to afford Theaflavin (4) (16 mg, 11% for two steps) as an orange amorphous solid. HR-MS (ESI) calculated for C₂₉H₂₄O₁₂Na [M+Na]⁺ 587.1159, found 587.1164; [α]²⁰_D=–274.8 (c 0.20, acetone); IR (neat) 3275, 1691, 1624, 1600, 1507, 1460, 1419, 1352, 1230, 1197, 1138, 1089, 1060, 1041, 1010, 891, 805, 706 cm⁻¹; ¹H NMR (500 MHz, CD₃OD) δ 7.94 (1H, s), 7.81 (1H, s), 7.33 (1H, s), 6.00 (1H, d, J=2.0 Hz), 5.97 (1H, d, J=2.0 Hz), 5.95 (1H, d, J=2.0 Hz), 5.94 (1H, d, J=2.0 Hz), 5.62 (1H, s), 4.86 (1H, s), 4.47–4.41 (1H, m), 4.32–4.25 (1H, m), 2.96 (1H, dd, J_1,2=17.0, 4.0 Hz), 2.93 (1H, dd, J_1,2=17.0, 4.0 Hz), 2.82 (1H, br d, J=16.0 Hz), 2.80 (1H, br d, J=16.0 Hz); ¹³C NMR (126 MHz, CD₃OD) δ 184.7, 157.0, 156.9, 156.6, 156.4, 156.1, 156.1, 155.4, 149.8, 145.2, 133.4, 130.2, 127.7, 125.0, 122.7, 120.9, 117.1, 99.0, 98.4, 95.5, 94.8, 94.3, 80.0, 75.9, 65.3, 64.4, 28.6, 28.1. Analytical data for theaflavin (4) in ref. 16.

(2R,3S)-3-Hydroxy-2-(3,4,6-trihydroxy-5-oxo-5H-benzo[7]annulen-1-yl)chroman-5,7-diyl bis(2-nitrobenzenesulfonate) (80)

To a solution of 51 (100 mg, 152 μmol) in MeCN (2 ml) was added Pb(OAc)₄ (53.7 mg, 121 μmol) at 0 °C. The resulting suspension was stirred for 10 min at 0 °C. To the reaction mixture was added benzene (6.7 ml), and then the mixture was filtered through a pad of celite. Then, the filtrate was evaporated under reduced pressure, and the resulting crude product was used in the next reaction without further purification.

The crude product 55 was dissolved in MeCN/CH₂Cl₂ (1:4, 1.65 ml). To this solution were added MS3A (30 mg) and pyrogallol 65 (19 mg, 150 μmol) in MeCN/CH₂Cl₂ (1:4, 0.50 ml) at 0 °C. The resulting suspension was stirred for 20 min at 0 °C. After the addition of H₂O, the mixture was stirred for 5 min at room temperature. The reaction mixture was filtered, and then the filtrate was extracted with AcOEt, the organic phase was washed with H₂O and evaporated under reduced pressure. The residue was purified by preparative TLC (CH₂Cl₂:MeOH=98:2) to afford 80 (19.5 mg) as a orange amorphous solid. HR-MS (ESI) calculated for C₃₂H₂₂N₂O₁₆S₂Na [M+Na]⁺ 777.0320, found 777.0269; [α]²⁰_D=+52.9 (c 0.20, acetone); IR (neat) 3420, 1554, 1384, 1195, 1111, 997 cm⁻¹; ¹H NMR (500 MHz, methanol-d₄) δ 8.15–7.90 (8H, m), 7.88 (1H, d, J=12.0 Hz), 7.47 (1H, s), 7.25 (1H, d, J=9.2 Hz), 6.90 (1H, dd, J_1,2=12.0, 9.2 Hz), 6.79 (1H, d, J=2.3 Hz), 6.60 (1H, d, J=2.3 Hz), 5.75 (1H, d, J=6.2 Hz), 4.31–4.24 (1H, m), 2.82 (1H, dd, J_1,2=16.9, 7.7 Hz), 2.65 (1H, dd, J_1,2=16.9, 4.3 Hz); ¹³C NMR (126 MHz, acetone-d₆) δ 157.0, 148.9, 148.4, 145.8, 145.8, 137.7, 137.6, 133.7, 133.6, 133.0, 132.5, 130.8, 128.1, 127.5, 126.2, 126.1, 119.1, 116.5, 116.0, 114.4, 110.3, 109.3, 82.6, 66.1, 27.5.

3,4,6-Trihydroxy-1-((2R,3S)-3,5,7-trihydroxychroman-2-yl)-5H-benzo[7]annulen-5-one (67)

To a suspension of Cs₂CO₃ (40.0 mg, 53.0 μmol) and thiophenol (55 μl, 0.53 mmol) in MeCN/DMF(1:2, 0.9 ml) was added solution of the crude of 80 in MeCN (1.0 ml) at 0 °C and the reaction mixture was stirred at the same temperature for 2 h. The reaction was quenched with 1 m HCl aqueous and extracted with AcOEt. The organic phase was evaporated under reduced pressure. The residue was purified by preparative TLC (CH₂Cl₂:MeOH=9:1) to afford 67 (15.9 mg, 78%) as a orange amorphous solid. HR-MS (ESI) calculated for C₂₀H₁₆O₈Na [M+Na]⁺ 407.0737, found 407.0748; [α]²⁰_D=–24.8 (c 0.20, acetone); IR (neat) 3319, 1602, 1411, 1327, 1253, 1070, 825 cm⁻¹; ¹H NMR (500 MHz, methanol-d₄) δ 7.84 (1H, d, J=12.5 Hz), 7.60 (1H, s), 7.15 (1H, d, J=9.1 Hz), 6.80 (1H, dd, J_1,2=12.5, 9.1 Hz), 6.79 (1H, d, J=2.3 Hz), 6.60 (1H, d, J=2.3 Hz), 5.75 (1H, d, J=6.2 Hz), 4.20–4.13 (1H, m), 2.86 (1H, dd, J_1,2=16.3, 5.3 Hz), 2.62 (1H, dd, J_1,2=16.1, 8.5 Hz); ¹³C NMR (126 MHz, methanol-d₄) δ 186.3, 158.0, 157.7, 156.7, 156.6, 151.9, 147.1, 131.5, 130.0, 124.1, 122.9, 122.6, 118.6, 100.7, 96.7, 95.5, 80.2, 68.9, 49.7, 28.9.

Methyl 3,4,6-trihydroxy-1-((2R,3S)-3-hydroxy-5,7-bis(((2-nitrophenyl)sulfonyl)oxy) chroman-2-yl)-5-oxo-5H-benzo[7]annulene-8-carboxylate (81)

To a solution of 51 (200 mg, 303 μmol) in MeCN (3 ml) was added Pb(OAc)₄ (161 mg, 363 μmol) at 0 °C. The resulting suspension was stirred for 10 min at 0 °C. The reaction mixture was added to benzene, and then the mixture was filtered through a pad of celite. Then, the filtrate was evaporated under reduced pressure, and the resulting crude product was used in the next reaction without further purification.

The crude product 55 was dissolved in MeCN/CH₂Cl₂ (1:4, 5.0 ml). To the solution were added MS3A (200 mg) and methyl gallate (66) (18.6 mg, 101 μmol) in MeCN/CH₂Cl₂ (1:4, 2.0 ml) at 0 °C. The resulting suspension was stirred for 20 min at 0 °C. After the addition of H₂O, the mixture was stirred for 5 min at room temperature. The reaction mixture was filtered, and then the filtrate was extracted with AcOEt, the organic phase was washed with H₂O and evaporated under reduced pressure. The residue was purified by preparative TLC (CH₂Cl₂:MeOH=98:2) to afford 81 (40.6 mg, 50%) as a orange amorphous solid. HR-MS (ESI) calculated for C₃₄H₂₄N₂NaO₁₈S₂ [M+Na]⁺ 835.0358, found 835.0343; [α]²⁰_D=+9.6 (c 0.20, acetone); IR (neat) 3369, 1701, 1385, 1248, 1195, 1111, 999, 781 cm⁻¹; ¹H NMR (500 MHz, acetone-d₆) δ 8.88 (1H, s), 8.12–7.93 (8H, m), 7.76 (1H, s), 7.58 (1H, s), 6.82 (1H, d, J=2.3 Hz), 6.61 (1H, d, J=2.3 Hz), 5.62 (1H, d, J=7.5 Hz), 4.33–4.26 (1H, m), 3.84 (1H, s), 2.90 (1H, m), 2.74 (1H, dd, J_1,2=17.2, 8.6 Hz);¹³C NMR (126 MHz, acetone-d₆) δ 186.8, 168.5, 157.6, 155.4, 153.1, 150.3, 150.1, 149.9, 149.7, 149.4, 138.7, 134.7, 134.5, 134.3, 133.9, 133.6, 133.5, 129.1, 129.0, 128.3, 127.2, 127.1, 125.1, 123.6, 123.1, 117.5, 116.8, 111.4, 110.8, 82.1, 67.5, 54.3, 31.4.

Methyl 3,4,6-trihydroxy-5-oxo-1-((2R,3S)-3,5,7-trihydroxychroman-2-yl)-5H-benzo[7] annulene-8-carboxylate (68)

To a suspension of Cs₂CO₃ (52.1 mg, 64.1 μmol) and thiophenol (66 μl, 641 μmol) in MeCN/DMF(1:2, 0.9 m;) was added solution of 81 in MeCN (1.0 ml) at 0 °C and the reaction mixture was stirred at the same temperature for 30 min. The reaction was quenched with 1 m HCl aqueous and extracted with AcOEt. The organic phase was evaporated under reduced pressure. The residue was purified by preparative TLC (CH₂Cl₂:MeOH=9:1) to afford 68 (13.4 mg, 47%) as a orange amorphous solid. HR-MS (ESI) calculated for C₂₂H₁₈O₁₀Na [M+Na]⁺ 465.0792, found 465.0795; [α]²⁰_D=–44.6 (c 0.20, acetone); IR (neat) 3346, 1701, 1608, 1225 cm⁻¹; ¹H NMR (500 MHz, methanol-d₄) δ 8.92 (1H, s), 7.69 (1H, s), 7.62 (1H, s), 5.97 (1H, d, J=1.7 Hz), 5.91 (1H, d, J=1.7 Hz), 5.34 (1H, d, J=8.0 Hz), 4.35–4.13 (1H, m), 3.82 (1H, s), 2.97 (1H, dd, J_1,2=16.1, 5.7 Hz), 2.61 (1H, dd, J_1,2=16.0, 9.2 Hz); ¹³C NMR (126 MHz, methanol-d₄) δ 186.8, 181.9, 158.1, 157.7, 156.6, 155.0, 152.4, 149.7, 134.6, 134.4, 128.7, 124.0, 123.5, 112.8, 115.9, 100.8, 96.7, 95.5, 81.3, 69.1, 53.5, 29.7.

Plan for practical synthesis of methylated catechins.

Potential issues in catechin synthesis.

Selective deprotection of O-Ns group.

Synthesis of selectively methylated gallic acids.

Synthesis of 3′-Me-EGCg (2) and 4′-Me-EGCg (3).

Selective incorporation of Ns group via bridged boronic ester intermediate.

Synthesis of selectively methylated epigallocatechin.

Coupling reaction of o-quinone 45 and pyrogallol derivative 46 reported by Nakatsuka and Yanase.

Regioselective incorporation of Ns group into the A-ring.

Oxidation of 51 to o-quinone 55.

Synthesis of neotheaflavin (5) by oxidative coupling reaction of 53 and 55.

Proposed mechanism of the coupling reaction of quinone and pyrogallol according to Nakatsuka and Yanase.

Synthesis of theaflavin (4).