PAPER
Enantioselective Synthesis of Flavan-3-ols
785
1H NMR (200 MHz, CDCl3): d = 2.51 (dd, J = 14.8, 7.3 Hz, 1 H, 3-
Ha), 2.60 (dd, J = 14.8, 3.2 Hz, 1 H, 3-Hb), 3.68 (s, 3 H, OCH3),
3.77 (s, 3 H, OCH3), 3.93 (m, 1 H, 2-H), 4.29 (d, J = 7.8 Hz, 1 H, 1-
H), 6.33 (dd, J = 8.3, 2.5 Hz, 1 H, 5¢-H), 6.44 (d, J = 2.6 Hz, 1 H, 3¢-
H), 6.61 (d, J = 8.3 Hz, 1 H, 6¢-H), 6.84 (dt, J = 7.0, 1.8 Hz, 2 H, 3¢¢-
H, 5¢¢-H), 7.28 (dt, J = 7.0, 1.7 Hz, 2 H, 2¢¢-H, 6¢¢-H).
13C NMR (50 MHz, CDCl3): d = 34.1 (C-3), 55.22 (OCH3), 55.26
(OCH3), 76.1 (C-2), 77.3 (C-1), 102.3 (C-3¢), 106.0 (C-5¢), 113.9
(C-1¢), 114.0 (C-3¢¢), 114.3 (C-5¢¢), 128.2 (C-2¢¢), 128.4 (C-6¢¢),
131.9 (C-6¢), 132.2 (C-1¢¢), 156.3 (C-2¢), 159.5 (C-4¢), 159.8 (C-4¢¢).
MS (EI): m/z (%) = 304 (34) [M+], 286 (54), 167 (32), 137 (100),
109 (33), 65 (6).
HRMS: m/z [M]+ calcd for C17H20O5: 304.13107; found:
304.13115.
wise to the reaction mixture. After stirring for 3 h at r.t. (reaction
monitored by TLC), the reaction mixture was diluted with EtOAc
(40 mL) and washed with H2O (30 mL) and brine (30 mL). The or-
ganic phase was dried over MgSO4, filtered and concentrated under
reduced pressure to give a brown residue. The residue obtained was
purified by silica gel column chromatography (EtOAc–PE, 1:3) to
afford of the cyclized products 13a–d as white solids.
2,3-trans-Flavan-3-ol (13a)28
Yield: 75%; mp 107–109 °C; 91.2% ee (HPLC); [a]D –7.9 (c 1.0,
CH2Cl2).
IR (KBr): 3403, 3031, 2911, 1583, 1488, 1301, 1247, 1114, 1037,
750, 701 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.86 (d, J = 3.8 Hz, 1 H, 3-OH),
2.93 (dd, J = 16.1, 8.8 Hz, 1 H, 4-Ha), 3.09 (dd, J = 16.1, 5.3 Hz,
1 H, 4-Hb), 4.12 (m, 1 H, 3-H), 4.65 (d, J = 7.8 Hz, 1 H, 2-H), 6.87–
6.95 (m, 2 H, 6-H, 8-H), 7.11–7.20 (m, 2 H, 5-H, 7-H), 7.33–7.46
(m, 5 H, ArH).
13C NMR (50 MHz, CDCl3): d = 32.8 (C-4), 68.6 (C-3), 81.9 (C-2),
116.5, 120.1, 121.0, 127.1, 127.7, 128.6, 128.8, 129.6, 130.0, 131.0,
138.2 (Ar), 154.0 (C-8a).
MS (EI): m/z (%) = 226.17 (44) [M+], 177 (8), 176 (48), 149 (56),
107 (100), 91 (78), 57 (28), 43 (42).
HRMS: m/z [M]+ calcd for C15H14O2: 226.09938; found:
226.09947.
(1S,2S)-3-(4-Benzyloxy-2-hydroxyphenyl)-1-(4-benzyloxy-
phenyl)propane-1,2-diol (12c)
Yield: 95%; mp 122–124 °C; [a]D –1.28 (c 1.0, CHCl3).
IR (KBr): 3426, 3033, 2892, 1614, 1509, 1440, 1286, 1168, 1024
cm–1.
1H NMR (500 MHz, CDCl3): d = 2.55 (dd, J = 15.2, 8.3 Hz, 1 H, 3-
Ha), 2.71 (dd, J = 14.2, 6.1 Hz, 1 H, 3-Hb), 4.07 (br, 1 H, 2-H), 4.41
(d, J = 7.2 Hz, 1 H, 1-H), 5.04 (s, 2 H, OCH2Ph), 5.11 (s, 2 H,
OCH2Ph), 6.47 (dd, J = 8.3, 2.4 Hz, 1 H, 5¢-H), 6.62 (d, J = 2.4 Hz,
1 H, 3¢-H), 6.69 (d, J = 8.7 Hz, 1 H, 6-H), 7.04 (d, J = 8.7 Hz, 2 H,
3¢¢-H, 5¢¢-H), 7.24–7.46 (m, 12 H, 2¢¢-H, 6¢¢-H, ArH).
13C NMR (125 MHz, CDCl3): d = 34.6 (C-3), 70.4 (OCH2Ph), 70.5
(OCH2Ph), 76.1 (C-2), 76.1 (C-1), 104.1 (C-3¢), 107.3 (C-5¢), 115.5
(C-3¢¢, C-5¢¢), 117.1 (C-1¢), 127.9 (C-1¢), 127.6, 127.8, 127.7, 128.3,
128.5, 128.9, 129.0, 132.7, 133.8, 137.1, 137.5 (Ar), 157.1 (C-2¢),
159.4 (C-4¢), 159.6 (C-4¢¢).
2,3-trans-7,4¢-Dimethoxyflavan-3-ol (13b)26,29
Yield: 82%; mp 89–90 °C (Lit.26 86–88 °C); 75.7% ee [>98% after
one recrystallization (EtOAc–PE, 1:7)]; [a]D –9.2 (c 1.0, CH2Cl2).
IR (KBr): 3440, 2933, 1619, 1506, 1398, 1247, 1157 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.01 (br, 1 H, 3-OH), 2.81 (dd,
J = 15.7, 8.9 Hz, 1 H, 4-Ha), 3.01 (dd, J = 15.7, 5.3 Hz, 1 H, 4-Hb),
3.75 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 4.06 (m, 1 H, 3-H), 4.72
(d, J = 8.0 Hz, 1 H, 2-H), 6.48 (d, J = 2.5 Hz, 1 H, 8-H), 6.53 (dd,
J = 8.4, 2.5 Hz, 1 H, 6-H), 6.94 (dt, J = 6.7, 2.0 Hz, 2 H, 3¢-H, 5¢-H),
7.00 (d, J = 8.4 Hz, 1 H, 5-H), 7.36 (dt, J = 6.7, 2.0 Hz, 2 H, 2¢-H,
6¢-H).
13C NMR (50 MHz, CDCl3): d = 32.4 (C-4), 55.3 (OCH3), 68.6 (C-
3), 81.7 (C-2), 101.3 (C-8), 108.0 (C-6), 112.1 (C-4a), 114.2 (C-3¢,
C-5¢), 127.6, 128.5, 130.1, 130.3, 130.6 (Ar), 154.9 (C-8a), 159.4
(C-4¢), 159.9 (C-7).
MS (EI): m/z (%) = 456 (10) [M+], 438 (60), 362 (16), 243 (36), 213
(97), 137 (50), 123 (58), 91 (100), 65 (25).
HRMS: m/z [M]+ calcd for C29H28O5: 456.1937; found: 456.1934.
(1S,2S)-3-[2,4-Bis(benzyloxy)-6-hydroxyphenyl]-1-[3,4,5-
tris(benzyloxy)phenyl]propane-1,2-diol (12d)27
Yield: 92%; mp 144–145 °C (no mp given in Lit.27); [a]D +11.61 (c
1.0, CHCl3) [Lit.10 +11.54 (c 1.0, CHCl3)].
IR (film): 3426, 2965, 1436, 1376, 1272, 1112, 879, 777, 694 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.75 (dd, J = 14.8, 8.4 Hz, 1 H, 3-
Ha), 2.90 (dd, J = 14.8, 3.6 Hz, 1 H, 3-Hb), 3.92 (ddd, J = 8.4, 5.6,
3.6 Hz, 1 H, 2-H), 4.43 (d, J = 5.6 Hz, 1 H, 1-H), 4.89 (s, 2 H,
OCH2Ph), 4.95–5.05 (m, 8 H, OCH2Ph), 6.21 (d, J = 2.0 Hz, 1 H,
5¢-H), 6.26 (d, J = 2.0 Hz, 1 H, 3¢-H), 6.59 (s, 2 H, 2¢¢-H, 6¢¢-H),
7.25–7.45 (m, 25 H, ArH).
13C NMR (125 MHz, CDCl3): d = 26.9 (C-3), 70.0 (OCH2Ph), 71.3
(OCH2Ph), 75.3 (OCH2Ph), 76.9 (OCH2Ph), 77.1 (OCH2Ph), 79.4
(C-1), 82.1 (C-2), 93.9 (C-3¢), 98.5 (C-5¢), 105.9 (C-2¢¢, C-6¢¢),
112.1 (C-1¢), 127.3, 127.4, 127.4, 127.7, 128.1, 128.4, 128.5, 128.5,
128.7, 128.7, 128.8, 128.9, 128.9, 129.0, 129.6, 130.6, 133.3, 137.1,
137.3, 137.6, 138.0 (Ar), 152.1 (C-4¢¢), 152.8 (C-3¢¢, C-5¢¢), 154.7
(C-6¢), 158.1 (C-4¢), 158.4 (C-2¢).
MS (EI): m/z (%) = 286.12 (78) [M+], 233 (5), 176 (40), 150 (58),
137 (100), 121 (82), 91 (28), 75 (32).
HRMS: m/z [M]+ calcd for C17H18O4: 286.12051; found:
286.12047.
2,3-trans-7,4¢-Bis(benzyloxy)flavan-3-ol (13c)12
Yield: 77%; mp 96–98 °C (no mp given in Lit.12); 97.7% ee after
chromatography (EtOAc–PE, 1:3) and crystallization (EtOAc–PE,
1:7); [a]D –17.38 (c 1.11, CHCl3) [Lit.10 –16.1 (c 1.11, CHCl3)].
1H NMR (500 MHz, CDCl3): d = 2.13 (br, 1 H, 3-OH), 2.94 (dd,
J = 15.6, 9.0 Hz, 1 H, 4-Ha), 3.06 (dd, J = 15.6, 5.3 Hz, 1 H, 4-Hb),
4.13 (m, 1 H, 3-H), 4.65 (d, J = 8.0 Hz, 1 H, 2-H), 5.04 (s, 2 H,
OCH2Ph), 5.13 (s, 2 H, OCH2Ph), 6.67 (dd, J = 8.1, 2.4 Hz, 2 H, 3¢-
H, 5¢-H), 7.08 (m, 3 H, 5-H, 6-H, 8-H), 7.30–7.47 (m, 12 H, ArH).
13C NMR (125 MHz, CDCl3): d = 32.5 (C-4), 68.6 (C-3), 70.4
(OCH2Ph), 82.1 (C-2), 107.6, 137.2, 137.4 (Ar), 155.2 (C-8a),
158.9 (C-4¢), 159.5 (C-7).
MS (EI): m/z (%) = 774 (0.2) [M+], 665 (0.1), 542 (0.1), 450 (0.1),
396 (3), 348 (2), 306 (4), 227 (1), 142 (2), 91 (100), 51 (2).
HRMS: m/z [M]+ calcd for C50H46O8: 774.31927; found:
774.31266.
Mitsunobu Reaction; General Procedure
MS (EI): m/z (%) = 438 (98) [M+], 362 (8), 347 (24), 226 (34), 213
(88), 107 (26), 91 (100), 65 (22).
HRMS: m/z [M]+ calcd for C29H26O4: 438.18311; found:
438.18333.
To a solution of triols 12a–d (0.56 mmol) in anhydrous THF (6
mL), was added Ph3P (225 mg, 0.86 mmol). The mixture was stirred
for 15 min and DEAD (0.13 mL, 0.83 mmol) was then added drop-
Synthesis 2009, No. 5, 779–786 © Thieme Stuttgart · New York