5378 J . Org. Chem., Vol. 65, No. 17, 2000
Kozikowski et al.
129.81, 119.02, 110.93, 109.37, 100.22, 92.90, 91.79, 77.69,
77.48, 55.78, 55.36, 55.29, 23.24, 18.88.
3.61 (s), 3.26 (s), 2.91-2.75 (m), 2.75-2.56 (m), 2.30-1.82 (m),
1.80-1.63 (m); 13C NMR (CDCl3, TMS, excluding δ 129-126
region) δ 158.02, 157.73, 157.02, 156.87, 156.37, 156.25, 155.36,
153.39, 149.07, 149.01, 148.86, 148.42, 148.29, 148.23, 148.10,
137.61, 137.40, 137.32, 137.23, 136.18, 135.96, 135.00, 134.43,
119.66, 119.55, 118.03, 117.82, 115.62, 115.12, 114.48, 113.48,
113.34, 110.75, 110.24, 109.31, 108.84, 107.87, 107.50, 103.99,
103.95, 94.52, 93.75, 92.63, 92.31, 90.66, 88.02, 77.98, 74.84,
74.50, 71.40, 71.36, 70.06, 69.57, 69.51, 69.26, 56.89, 55.85,
55.74, 55.58, 55.49, 55.36, 38.97, 37.79, 30.56, 29.99, 26.60,
26.37, 20.33, 19.82. Anal. Calcd for C62H58O10: C, 77.33; H,
6.07. Found: C, 77.33; H, 6.09.
(2S)-5,7,3′,4′-Tetr a m eth oxyfla va n (7).18 A stirred solution
of 4.17 g (9.55 mmol) of intermediate 6 in 150 mL of anhydrous
toluene was heated to reflux under N2, and a solution of 10.3
mL (38.2 mmol) of nBu3SnH and 0.31 g (1.9 mmol) of AIBN in
80 mL of anhydrous toluene was added dropwise through the
reflux condenser over a period of 4.25 h. Reflux was continued
for 4 h. The cooled reaction mixture was directly chromato-
graphed on SiO2. A forerun was eluted using toluene, and then
a mixture of 7 and a slightly more polar impurity 8 using
toluene/EtOAc (12:1). A late fraction containing mostly 8 was
set aside for the isolation of this impurity (see Supporting
Information); from the remaining mixture, 7 was isolated by
further CC on SiO2 with EtOAc/CHCl3/hexane 1:7:12. Evapo-
ration and drying in vacuo yielded 2.52 g (80%) of 7 as a
colorless glass: 1H NMR δ 7.00-6.85 (m, 3 H), 6.14, 6.08 (ABq,
2 H, J ) 2.5 Hz), 4.91 (dd, 1 H, J ) 2, 10.5 Hz), 3.91 (s, 3 H),
3.89 (s, 3 H), 3.80 (s, 3 H), 3.76 (s, 3 H), 2.77, 2.64 (ABq, 2 H,
J ) 16.5 Hz, both parts dd with J ) 2.5, 5.5 Hz and 6.5, 11.5
Hz, respectively), 2.17, 2.02 (ABq, 2 H, J ) 13.5 Hz, both parts
dt with J ) 2.5 Hz (t), 6.5 Hz (d) and 5.5 Hz (d), 11 Hz (t),
respectively); 13C NMR δ 159.24, 158.47, 156.26, 148.96,
148.62, 134.16, 118.46, 110.97, 109.28, 103.22, 93.30, 91.28,
77.72, 55.85, 55.78, 55.32, 55.21, 29.45, 19.39.
5,7,3′,4′-Tet r a -O-b en zyl-3-O-(ter t-b u t yld im et h ylsilyl)-
ep ica tech in (11). A solution of 4.37 g (6.72 mmol) of 1a , 0.69
g (10.1 mmol, 1.5 equiv) of imidazole, and 1.42 g (9.4 mmol,
1.4 equiv) of TBDMS-Cl in 6 mL of anhydrous DMF was stirred
at room temperature in a closed flask for 19.5 h. Direct CC on
SiO2 with EtOAc/hexane 1:5, followed by evaporation and
drying in vacuo gave 5.02 g (98%) of the silyl ether as a
yellowish glass: 1H NMR δ 7.47-7.25 (m, 20 H), 7.11 (s, 1 H),
6.94, 6.90 (ABq, 2 H, J ) 1 Hz), 6.24, 6.22 (ABq, 2 H, J ) 2
Hz), 5.15 (s, 2 H), 5.14 (narrow ABq, 2 H), 5.03 (s, 2 H), 5.02,
4.98 (ABq, 2 H, J ) 11.5 Hz), 4.93 (s, 1 H), 4.18 (narrow m, 1
H), 2.86, 2.77 (ABq, 2 H, J ) 17 Hz, both parts d with J ) 4
Hz), 0.76 (s, 9 H), -0.15 (s, 3 H), -0.30 (s, 3 H); 13C NMR
(CDCl3, TMS) δ 158.49, 157.85, 155.56, 148.69, 148.29, 137.39,
137.36, 137.25, 137.01, 132.75, 128.55, 128.49, 128.41, 127.93,
127.74, 127.69, 127.63, 127.47, 127.31, 127.07, 120.07, 115.03,
114.21, 101.66, 94.49, 93.45, 78.93, 71.47, 71.36, 70.08, 69.88,
67.48, 28.38, 25.78, 18.07, -5.09, -5.12. Anal. Calcd for
(2S )-5,7,3′,4′-Te t r a k is(b e n zyloxy)fla va n -4â,8-[(2S )-
5,7,3′,4′-tetr a m eth oxyfla va n ] (10). To a solution of 519 mg
(520 µmol) of 3d and 254 mg (2.08 mmol, 4 equiv) of DMAP in
2 mL of 1,2-dichloroethane (HPLC grade, 0.002% H2O) was
added dropwise in 7 min with water cooling 252 µL (1.82 mmol,
C
49H52O6Si: C, 76.93; H, 6.85. Found: C, 77.17; H, 6.62.
3.5 equiv) of PhOC(S)Cl. The mixture was stirred in
a
resealable tube at room temperature for 1 h and then at 50
°C for 48 h. After addition of 20 mL of saturated aqueous
NaHCO3 and 50 mL of H2O, the mixture was extracted with
50 + 10 mL of CH2Cl2, and the extract was dried over MgSO4
and evaporated. CC (SiO2, EtOAc/hexane 1:2; Rf approximately
0.35) gave, after evaporation and drying in vacuo, 494 mg
(75%) of the bis[(phenoxy)thiocarbonyl] derivative 9 as a
colorless glass: 1H NMR (major rotamer only) δ 7.48-7.10 (m),
7.10-6.82 (m), 6.76 (d, 1 H, J ) 8.5 Hz), 6.67, 6.51 (ABq, 2 H,
J ) 8.5 Hz, B part br), 6.29 (s, 1 H), 6.07 (s, 1 H), 5.88 (s, 1 H),
5.81 (s, 1 H), 5.64 (d, 1 H, J ) 3.5 Hz), 5.52 (s, 1 H), 5.12 (s, 1
H), 5.07 (s, 2 H), 5.02 (s, 2 H), 4.88 (s, 2 H), 4.64, 4.45 (ABq,
2 H, J ) 11.5 Hz), 4.24 (s, 1 H), 3.92 (s, 3 H), 3.81 (s, 3 H),
3.75 (s, 3 H), 3.52 (s, 3 H), 3.24, 3.02 (ABq, 2 H, J ) 18.5 Hz,
B part d with J ) 4.5 Hz). To a solution of 532 mg (420 µmol)
of 9 in 8.4 mL of anhydrous 1,4-dioxane (distilled over Na/
benzophenone) were added at room temperature 1.46 mL (10.5
mmol, 25 equiv) of Et3N and 0.88 mL (8.4 mmol, 20 equiv) of
50% (approximately 9.6 M) aq H3PO2. The mixture was stirred
and heated under N2 to gentle reflux, and a solution of 138
mg (0.84 mmol, 2 equiv) of AIBN in 2.1 mL of anhydrous 1,4-
dioxane was added in 7 equal portions in 20 min intervals.
Reflux was continued for 1 h, and then the mixture was cooled
and without further treatment filtered over a short SiO2
column with EtOAc/hexane 1:2. The evaporation residue (0.45
g) was taken up in 25 mL of THF, and to this solution were
added sequentially 15 mL of EtOH, 10 mL of 2.5 M aq NaOH,
and 2.5 mL of 35% aq H2O2. After stirring in an room
temperature water bath for 4 h, another 2.5 mL of 35% aq
H2O2 was added, and stirring was continued overnight. Partial
evaporation was followed by addition of 10 mL of H2O,
extraction with 3 × 20 mL of EtOAc, and drying over MgSO4.
After evaporation, CC on SiO2 with EtOAc/CHCl3/hexane
1:12:7 yielded 286 mg (70%) of the product 10 which was
sufficiently pure to be used in the subsequent step. The
analytical sample was obtained by preparative HPLC (column
1, EtOAc/hexane 1:3; tR 17.1 min): [R]D +109°, [R]546 +132°
(EtOAc, c 4.6 g L-1); 1H NMR δ 7.50-7.12 (m), 7.07-6.80 (m),
6.72 (d, J ) 8.5 Hz), 6.67, 6.52 (ABq, J ) 8.5 Hz), 6.60 (s),
6.30 (s), 6.21 (s), 6.18 (s), 6.09 (s), 6.00 (s), 5.51 (s), 5.33 (d, J
) 11 Hz), 5.21 (d, J ) 12 Hz), 5.17-5.07 (m), 5.04 (s), 4.91
(presumably one line of a partially concealed d), 4.87 (s), 4.81
(s), 4.69 (d, J ) 5 Hz), 4.63, 4.49 (ABq, J ) 11.5 Hz), 4.04 (d,
J ) 8 Hz), 3.87 (s), 3.83 (s), 3.81 (s), 3.75 (s), 3.73 (s), 3.64 (s),
3-O-(ter t-Bu t yld im et h ylsilyl)-5,7,3′,4′-t et r a -O-(m et h -
a n esu lfon yl)ep ica tech in (13). A solution of 188 mg (246
µmol) of 11 in 4 mL of EtOAc was hydrogenated at 1 bar over
34 mg of 20% Pd(OH)2/C for 1 h. Filtration over cotton,
evaporation, and drying in vacuo gave 109 mg of 12 as a
colorless foam which was pure except for solvent residues: 1H
NMR (CDCl3/CD3OD 9:1, TMS) δ 8.69 (br s, 1 H), 8.63 (s, 1
H), 8.10 (br s, 1 H), 7.67 (br s, 1 H), 6.93 (d, 1 H, J ) 1.5 Hz),
6.80, 6.76 (ABq, 2 H, J ) 8 Hz, B part d with J ) 1.5 Hz),
5.98, 5.94 (ABq, 2 H, J ) 2 Hz), 4.88 (s, 1 H), 4.20 (narrow m,
1 H), 2.82, 2.69 (ABq, 2 H, J ) 16 Hz, both parts d with J )
4.5 and 4 Hz, respectively), 0.77 (s, 9 H), -0.15 (s, 3 H), -0.20
(s, 3 H). The crude intermediate 12 was dissolved in 1 mL of
anhydrous pyridine, and a solution of 0.15 mL (2.0 mmol) of
MeSO2Cl in 0.5 mL of anhydrous pyridine was added dropwise
with ice cooling and exclusion of moisture in 4 min. After
standing at 0 °C for 71 h, 0.2 mL of water was added, and the
mixture was allowed to stand for 10 min. Twenty milliliters
of CH2Cl2 and 40 mL of 0.5 M aqueous H3PO4 were added,
the phases were separated, and the aqueous phase was
extracted with 10 mL of CH2Cl2. The combined organic phases
were washed with 30 mL of water and 15 mL of saturated
aqueous NaHCO3, dried over MgSO4, and evaporated. CC of
the residue (SiO2, EtOAc/hexane 3:2), evaporation, and drying
in vacuo gave 163.5 mg (93%) of 13 as a colorless film: [R]D
1
-9.3°, [R]546 -12.2° (EtOAc, c 6.6 g L-1); H NMR δ 7.53 (s, 1
H), 7.51, 7.46 (ABq, 2 H, J ) 8.5 Hz, B part d with J ) 1.5
Hz), 6.92 (s, 2 H), 5.09 (s, 1 H), 4.29 (br s, 1 H), 3.253 (s, 3 H),
3.246 (s, 3 H), 3.238 (s, 3 H), 3.19 (s, 3 H), 3.10, 2.97 (ABq, 2
H, J ) 17 Hz, both parts d with J ) 3.5 and 3 Hz, respectively),
0.68 (s, 9 H), -0.10 (s, 3 H), -0.39 (s, 3 H); 13C NMR (CDCl3,
TMS) δ 155.73, 148.20, 147.74, 140.85, 140.56, 139.27, 126.54,
123.91, 122.57, 113.75, 109.35, 108.97, 78.49, 66.00, 38.62,
38.46, 38.33, 37.60, 29.56, 25.51, 17.83, -5.11, -5.55. Anal.
Calcd for C25H36O14S4Si: C, 41.89; H, 5.06. Found: C, 42.15;
H, 4.90.
3-O-(ter t-Bu tyld im eth ylsilyl)-5,7,3′,4′-tetr a -O-(tr iflu o-
r om eth a n esu lfon yl)ep ica tech in (14). A solution of 67.6 mg
(88.4 µmol) of 11 in 2 mL of EtOAc was hydrogenated at 1 bar
over 20 mg of 20% Pd(OH)2/C for 40 min. Filtration over cotton,
evaporation, and drying in vacuo gave a residue of crude 12
which was dissolved in 0.5 mL of anhydrous DMF. After
cooling to -45 °C and addition of 73 µL (0.49 mmol, 5.5 equiv)
of DBU, a solution of 189 mg (0.53 mmol, 6 equiv) of N,N-bis-