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Synlett 2008(20): 3234-3238  
DOI: 10.1055/s-0028-1087371
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Efficient Synthesis of Optically Active Gallocatechin-3-gallate Derivatives via 6-endo-Cyclization

Yasuo Hirooka, Mariko Nitta, Takumi Furuta, Toshiyuki Kan*
School of Pharmaceutical Sciences, University of Shizuoka and Global COE Program, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Fax: +81(54)2645745; e-Mail: kant@u-shizuoka-ken.ac.jp;
Further Information

Publication History

Received 1 September 2008
Publication Date:
26 November 2008 (online)

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Abstract

Optically active dihydrobenzopyran derivatives are synthesized by 6-endo cyclization of corresponding epoxy-phenol, which is readily derived from the enantioselective epoxidation of 1,3-diarylpropene. Synthetic dihydrobenzopyrans are converted into (-)-5,7-dideoxy-gallocatechin gallate as well as (-)-5,7-dideoxy-epigallocatechin derivative.

Key words

dihydrobenzopyran - 6-endo cyclization - enantioselective epoxidation - (-)-5,7-dideoxy-gallocatechin gallate

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1

Present Address: Fine Organic Synthesis, Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.

9

Although HWE reaction of 10 and phosphonate 24 provided 8a in good stereoselectivity, it resulted in a low yield (Scheme  [7] ).

Scheme 7

10

In acidic conditions, epoxide 16 was readily converted into quinone methide intermediate 25, and sequential attack by MCBA to benzyl position of 25 afforded 26 (Scheme  [8] ).

Scheme 8

11

Experimental Procedure for Shi Epoxidation
To a solution of 15 (77.0 mg, 0.255 mmol) in MeCN-DMM (dimethyl methylether) (1:2, 2.7 mL) were successively added 8a (100 mg, 0.156 mmol), Bu4N+HSO4 - (2.4 mg, 7.0 µmol), phosphorus buffer (pH 9.18, 4 mL), Oxone (376 mg, 0.611 mmol), and K2CO3 (125 mg, 0.90 mmol) at 0 ˚C. After being stirred for 25 min at 0 ˚C, H2O was added to the reaction mixture, extracted with EtOAc, dried over anhyd MgSO4, and evaporated. The residue was purified by chromatography on silica gel column (n-hexane-EtOAc, 10:1) to afford 16 (71.5 mg, 70%) as a yellow oil. The ee of 16 was determined by HPLC analysis on a chiral stationary phase under the conditions described below.
Spectral Data for 16 [α]D ²0 +14.1 (c 1.0, CHCl3). IR (neat): 1116, 1253, 1591, 2927, 3030 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 0.24 (s, 6 H), 1.01 (s, 9 H), 2.93 (dd, J = 14.3, 5.2 Hz, 1 H), 3.04 (dd, J = 14.3, 5.2 Hz, 1 H), 3.15 (td, J = 5.2, 2.0 Hz, 1 H), 3.58 (d, J = 2.0 Hz, 1 H), 5.02 (s, 2 H), 5.07 (s, 4 H), 6.57 (s, 2 H), 6.82 (dd, J = 7.9, 1.2 Hz, 1 H), 6.92 (td, J = 7.9, 1.2 Hz, 1 H), 7.13 (td, J = 7.9, 1.2 Hz, 1 H), 7.31-7.42 (m, 15 H). ¹³C NMR (68 MHz, CDCl3): δ = -4.0, 18.3, 25.8, 33.0, 58.6, 62.2, 71.2, 75.2, 105.0, 118.4, 121.2, 127.4, 127.7, 127.8, 128.1, 128.5, 128.6, 130.7, 133.3, 137.0, 137.8, 153.0, 153.7. MS-FAB: m/z = 659 [M + H]+. HRMS: m/z calcd for C42H47O5Si [M + H]+: 659.3193; found: 659.3167. HPLC analysis: Daicel Chiralpak AD-H 0.46 cm ø x 25 cm, eluent: 7% IPA-hexane, flow rate: 0.5 mL/min, t R = 98.7 min (96.2%), 109.7 min (3.7%).

12

Experimental Procedure for 6- endo Cyclization
To a solution of 16 (127 mg, 0.193 mmol) in THF (4.5 mL) were successively added AcOH (33 µL, 0.578 mmol) and TBAF (1 M in THF, 231 µL, 0.231 mmol) at 0 ˚C under an Ar atmosphere. After being stirred for 10 min at 0 ˚C, H2O was added to the mixture and extracted with EtOAc, dried over anhyd MgSO4, and evaporated to the crude product (major constituent: 7; 185 mg) as a yellow oil. The crude 7 (185 mg) and CSA (45.4 mg, 0.193 mmol) were dissolved in CH2Cl2 (4.5 mL) under an Ar atmosphere. After being stirred for 30 min at 0 ˚C, H2O was added to the mixture and extracted with CH2Cl2, dried over anhyd MgSO4, and evaporated. The residue was purified by chromatography on silica gel column (n-hexane-EtOAc, 3:1) to afford 6 (63.7 mg, 61%, 2 steps), containing a small amount of the corresponding cis-isomer, as a yellow oil. The product (20.3 mg) was recrystallized from EtOAc-hexane to afford optically pure trans-isomer 6 (13.7 mg, 67%). The ee of 6 was determined by HPLC analysis on a chiral stationary phase under the conditions described below. Spectral date for 6: [α]D +1.7 (c 0.84, CHCl3). IR (neat): 1132, 1246, 1597, 3032 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 1.63 (d, J = 3.8 Hz, 1 H), 2.89 (dd, J = 15.8, 9.1 Hz, 1 H), 3.07 (dd, J = 15.8, 5.5 Hz, 1 H), 3.99 (dq, J = 15.8, 3.8 Hz, 1 H), 4.65 (d, J = 7.9 Hz, 1 H), 5.11-5.16 (m, 6 H), 6.73 (s, 2 H), 6.91-6.95 (m, 1 H), 7.11 (d, J = 7.3 Hz, 1 H), 7.16 (t, J = 7.3 Hz, 1 H), 7.25-7.44 (m, 16 H). ¹³C NMR (68 MHz, CDCl3): δ = 32.9, 68.1, 71.2, 75.2, 81.9, 106.7, 116.4, 120.2, 121.1, 127.5, 127.7, 127.8, 127.9, 128.2, 128.47, 128.53, 130.0, 133.3, 136.8, 137.7, 138.7, 153.0, 153.9. MS.FAB: m/z = 544 [M]+. HRMS: m/z calcd for C36H32O5 [M]+: 544.2250; found: 544.2264. HPLC analysis: Daicel Chiralcel OD 0.46 cm ø x 25 cm, eluent: 10% IPA-hexane, flow rate: 0.5 mL/min, t R: 77.8 min (>99%).

13

Spectral Data for 4
[α]D ²0 -73.5 (c 1.1, 50% acetone-H2O). IR (neat): 1230, 1336, 1693, 3287 cm-¹. ¹H NMR (270 MHz, acetone-d 6):
δ = 2.79 (dd, J = 16.2, 5.6 Hz, 1 H), 2.93 (dd, J = 16.2, 4.6 Hz, 1 H), 5.11 (d, J = 5.3 Hz, 1 H), 5.30 (q, J = 5.3 Hz, 1 H), 6.34 (s, 2 H), 6.76 (t, J = 7.9 Hz, 2 H), 6.97 (d, J = 6.6 Hz, 1 H), 6.98 (s, 2 H), 7.05 (t, J = 7.6 Hz, 1 H), 7.93 (br s, 6 H). ¹³C NMR (68 MHz, acetone-d 6): δ = 52,1, 70.5, 79.0, 106.3, 110.1, 110.2, 117.1, 120.4, 121.7, 121.8, 128.8, 131.0, 131.1, 133.6, 139.2, 146.2, 146.9, 155.0, 166.3. MS-FAB: m/z = 427 [M + H]+. HRMS: m/z calcd for C22H19O9 [M + H]+: 427.1029; found: 427.1049.

16

Spectral Data for 21 [α]D ²0 -16.7 (c 0.075, CHCl3). IR (neat): 837, 1255, 1608, 3543 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = -0.30 (s, 3 H), -0.08 (s, 3 H), 0.17 (m, 9 H), 0,78-0.98 (m, 30 H), 2.90 (dd, J = 15.8, 5.5 Hz, 1 H), 3.08 (dd, J = 15.8, 5.5 Hz, 1 H), 3.93 (tt, J = 10.7, 3.1 Hz, 1 H), 4.57 (t, J = 8.5 Hz, 1 H), 5.23 (s, 1 H), 6.55 (s, 2 H), 6.87-6.90 (m, 2 H), 7.07 (d, J = 2.0 Hz, 1 H), 7.12 (t, J = 7.2 Hz). ¹³C NMR (68 MHz, CDCl3):
δ = -5.2, -4.8, -4.5, -4.3, -0.01, 1.0, 17.9, 18.3, 25.7, 25.9, 26.2, 35.4, 69.2, 82.0, 107.5, 112.0, 112.3, 116.4, 120.6, 120.7, 127.5, 129.6, 129.8, 138.6, 142.9, 154.3. MS-FAB: m/z = 617 [M + H]+. HRMS: m/z calcd for C33H57O5Si3 [M + H]+: 617.3514; found: 617.3516. HPLC analysis: Daicel Chiralpak AD-H 0.46 cm ø x 25 cm, eluent: hexane, flow rate: 0.7 mL/min, t R: 30.5 min.

18

Experimental Procedure and Separation of Diasteromers
Compounds 22 and 6 (33.5 mg, 61.5 mmol), 18 (81.3 mg, 184 mmol), WSC (29 mg, 154 mmol), and DMAP (0.8 mg, 6.2 mmol) were dissolved in CH2Cl2 (3 mL) under an Ar atmosphere. After being stirred for 3 h at r.t., sat. NH4Cl aq was added to the reaction mixture, extracted with CH2Cl2, dried over anhyd MgSO4, and evaporated. The residue was purified by chromatography on silica gel column (n-hexane-EtOAc, 6:1) to afford 23 (33.3 mg, 56%, R f  = 0.42,
n-hexane-EtOAc, 3:1) and 5 (26.2 mg, 44%, R f  = 0.49,
n-hexane-EtOAc, 3:1).