PAPER
Wuweizisu C Stereoisomers
3387
served as an internal reference. X-ray diffractograms were recorded
on a Rigaku Raxis-IV.
The de value was determined by chiral HPLC [Dikma Chiralcel
OD-RH (4.6 mm × 15 cm); MeOH–H O, 87:13; flow rate = 0.5 mL/
2
min; l = 254 nm; t = 9.17 min].
R
(
4S)-2-(6-Bromo-7-methoxy-1,3-benzodioxol-5-yl)-4-isopropyl-
4
6
1
,5-dihydro-1,3-oxazole [(S)-11]
-Bromo-7-methoxy-1,3-benzodioxol-5-ylcarboxylic acid (8;
9.86 g, 72 mmol) was added to SOCl (145 mL), and the resulting
(+)-(4R,4R¢,M )-2,2¢-(4,4¢-Dimethoxy-5,5¢-bi-1,3-benzodioxole-
ax
6,6¢-diyl)bis(4-isopropyl-4,5-dihydro-1,3-oxazole) [(+)-12]
By following the procedure described above, (R)-11 (12.28 g) was
converted into (+)-12; yield: 5.81 g (62%; >99% de); mp 116–118
2
mixture was refluxed for 3 h then cooled to r.t. The bulk of SOCl2
was removed under reduced pressure. The solid residue was dis-
solved in dry CH Cl (240 mL) and the soln was added dropwise to
soln of L-valinol (8.55 g, 83 mmol) and Et N (23.04 mL, 0.17 mol)
in dry CH Cl (280 mL) in an ice bath. The mixture was stirred
overnight, washed successively with 2 M HCl (200 mL) and sat. aq
NaCl (200 mL), and then dried (Na SO ) and filtered to afford the
soln of amide (S)-10 in CH Cl . To this was added a soln of SOCl
2
0
°C; [a]D +78.45 (c 0.80, CHCl3).
2
2
1
H NMR (300 MHz, CDCl ): d = 7.12 (s, 5-H and 5¢-H, 2 H), 6.00
3
3
(
s, 2 × OCH O, 4 H), 4.07 (m, 4¢¢-H and 4¢¢¢-H, 2 H), 3.80 (s,
2
2
2
2
2
2
× CH O, 6 H), 3.73 (m, 5¢¢-H and 5¢¢¢-H , 4 H), 1.59 (m, 2 × CH,
3
2
2
H), 0.85 (d, J = 6.8 Hz, 2 × CH , 6 H), 0.76 (d, J = 6.8 Hz,
3
2
4
× CH , 6 H).
3
2
2
2
1
3
C NMR (75 MHz, CDCl ): d = 163.1, 148.1, 141.4, 138.7, 125.3,
22.4, 104.2, 101.4, 72.7, 70.2, 59.7, 32.9, 19.0, 18.4.
(
20 mL) in dry CH Cl (120 mL) at –5 °C. The soln was stirred
3
2
2
1
overnight at r.t. and then adjusted to pH 8.0 with sat. aq Na CO .
The separated organic layer was dried (Na SO ), filtered, and con-
centrated under reduced pressure to afford a yellow oil that was add-
ed to a soln of NaOH (11.51 g, 0.29 mol) in MeOH (300 mL) and
H O (300 mL). The mixture was refluxed for 5 h, cooled to r.t., and
the MeOH was evaporated under reduced pressure. The residue was
extracted with CH Cl (3 × 150 mL) and then dried (Na SO ), fil-
2
3
+
2
4
HRMS-ESI: m/z [M + H] calcd for C H N O : 525.2237; found:
2
8
33
2
8
5
25.2232.
The de value was determined by chiral HPLC [Dikma Chiralcel
2
OD-RH (4.6 mm × 15 cm); MeOH–H O 87:13; flow rate = 0.5 mL/
2
min; l = 254 nm; t = 8.16 min].
R
2
2
2
4
tered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (EtOAc–PE, 1:5) to give (S)-11
as an orange oil; yield: 18.33 g (74%).
(
–)-(P )-N,N¢-Bis[(2S)-2-acetamido-3-methylbutyl] 4,4¢-Di-
ax
methoxy-5,5¢-bi-1,3-benzodioxole-6,6¢-dicarboxylate [(–)-13]
A soln of (–)-12 (5.12 g, 9.76 mmol) in THF (500 mL) was treated
with powdered Na SO (51.40 g, 0.36 mol), H O (11.6 mL, 0.64
mol), and F CCO H (15.5 mL, 0.20 mol). The suspension was
stirred at r.t. overnight, dried (Na SO ), filtered, and concentrated
2 4
under reduced pressure (bath temperature <30 °C) to give a color-
less oil that was dissolved in dry CH Cl (350 mL) and treated se-
quentially with Ac O (25 mL, 0.26 mol) and pyridine (25 mL, 0.31
1
H NMR (300 MHz, CDCl ): d = 6.88 (s, 6¢-H, 1 H), 6.00 (s,
3
2
4
2
OCH O, 2 H), 4.43 (m, 4-H, 1 H), 4.13 (m, 5-H , 2 H), 4.00 (s,
2
2
3 2
CH O, 3 H), 1.86 (m, CH, 1 H), 1.03 (d, J = 6.7 Hz, CH , 3 H), 0.96
3
3
(
d, J = 6.7 Hz, CH , 3 H).
3
MS (ESI): m/z = 341.8 [M + H]+.
2
2
2
mol). The mixture was stirred at r.t. for 2 days then washed succes-
(
4S)-2-(6-Bromo-7-methoxy-1,3-benzodioxol-5-yl)-4-isopropyl-
,5-dihydro-1,3-oxazole [(R)-11]
sively with 2 M aq HCl (2 × 200 mL) and sat. aq NaHCO (100
4
3
mL). The separated organic layer was dried (Na SO ), filtered, and
By following the procedure described above, 8 (17.02 g) was treat-
2
4
concentrated under reduced pressure to afford (–)-13 as a colorless
solid that used for next step without further purification; yield: 5.96
ed with D-valinol and converted into (R)-11; yield: 14.42 g (68%).
1
H NMR (300 MHz, CDCl ): d = 6.88 (s, 6¢-H, 1 H), 6.01 (s,
20
3
g (95%; > 99% de); mp 189–191 °C; [a]D –73.3 (c 0.54, CHCl3).
OCH O, 2 H), 4.41 (m, 4-H, 1 H), 4.13 (m, 5-H , 2 H), 4.01 (s,
2
2
1
H NMR (300 MHz, CDCl ): d = 7.22 (s, 5-H and 5¢-H, 2 H), 6.09
CH O, 3 H), 1.87 (m, CH, 1 H), 1.03 (d, J = 6.8 Hz, CH , 3 H), 0.97
(
MS (ESI): m/z = 343.5 [M + H]+.
3
3
3
(
s, 2 × OCH O, 4 H), 5.58 (d, J = 9.2 Hz, 2 × NH, 2 H), 4.03 (m, 3¢¢-
d, J = 6.8 Hz, CH , 3 H).
2
3
H and 3¢¢¢-H , 4 H), 3.79 (s, 2 × CH O, 6 H), 1.96 (s, 2 × COCH ,
6
and 2 × CH , 12 H).
1
2
2
3
3
H) 1.28 (m, 4¢¢-H and 4¢¢¢-H, 2 H), 0.84 (d, J = 6.8 Hz, 2 × CH
3
3
(
–)-(4S,4S¢,P )-2,2¢-(4,4¢-dimethoxy-5,5¢-bi-1,3-benzodioxole-
ax
,6¢-diyl)bis(4-isopropyl-4,5-dihydro-1,3-oxazole) [(–)-12]
3
C NMR (75 MHz, CDCl ): d = 169.9, 166.8, 148.6, 141.0, 140.4,
6
3
1
26.0, 124.1, 104.8, 102.1, 65.3, 59.8, 53.2, 28.8, 23.1, 19.2, 18.8.
Activated Cu powder (15.78 g, 0.25 mol) was added to a soln of bro-
mo derivative (S)-11 (14.84 g, 43.37 mmol) in dry DMF (120 mL),
and the mixture was refluxed for 48 h then cooled to r.t. CH Cl
+
HRMS-ESI: m/z [M + H] calcd for C H N O : 645.2660; found:
3
2
41
2
12
2
2
645.2657.
(300 mL) was added, the mixture was filtered, and the residue was
The de value was determined by chiral HPLC [Dikma Chiralcel
washed with CH Cl . The combined filtrates were washed with 5%
2
2
OD-RH (4.6 mm × 15 cm); MeOH–H O, 95:5; flow rate = 0.5 mL/
2
aq NH3 (4 × 200 mL) and sat. aq brine (200 mL) then dried
Na SO ), filtered, and concentrated under reduced pressure to af-
min; l = 254 nm; t = 4.59 min).
R
(
2
4
ford an oil that was purified by flash chromatography (EtOAc–
(
+)-(M )-N,N¢-Bis[(2R)-2-acetamido-3-methylbutyl] 4,4¢-Di-
ax
PE, 1:5) to give (–)-12 as a colorless solid; yield: 8.22 g (68%;
2
0
methoxy-5,5¢-bi-1,3-benzodioxole-6,6¢-dicarboxylate [(+)-13]
By following the procedure described above, (+)-12 (4.07 g) was
converted into (+)-13; yield: 4.74 g (95%, > 99% de); mp 179–
>
99% de); mp 119–122 °C; [a]D –77.5 (c 0.86, CHCl3).
1
H NMR (300 MHz, CDCl ): d = 7.26 (s, 5-H and 5¢-H, 2 H), 6.01
3
(
s, 2 × OCH O, 4 H), 4.08 (m, 4¢¢-H and 4¢¢¢-H, 2 H), 3.80 (s,
20
2
181 °C; [a]D +71.3 (c 0.97, CHCl3).
2
2
2
× CH O, 6 H), 3.70 (m, 5¢¢-H and 5¢¢¢-H , 4 H), 1.59 (m, 2 × CH,
3
2
2
1
H NMR (300 MHz, CDCl ): d = 7.22 (s, 5-H and 5¢-H, 2 H), 6.08
3
H), 0.86 (d, J = 6.8 Hz, 2 × CH , 6 H), 0.76 (d, J = 6.8 Hz,
3
(
s, 2 × OCH O, 4 H), 5.56 (d, J = 9.3 Hz, 2 × NH, 2 H), 4.07 (m, 3¢¢-
2
× CH , 6 H).
3
H and 3¢¢¢-H , 4 H), 3.79 (s, 2 × CH O, 6 H), 1.96 (s, 2 × COCH ,
2
2
3
3
1
3
C NMR (75 MHz, CDCl ): d = 163.1, 148.1, 141.4, 138.7, 125.2,
22.4, 104.1, 101.4, 72.6, 70.2, 59.7, 32.9, 19.0, 18.3.
3
6 H) 1.26 (m, 4¢¢-H and 4¢¢¢-H, 2 H), 0.86 (d, J = 6.8 Hz, 2 × CH
3
1
and 2 × CH , 12 H).
13
3
+
HRMS-ESI: m/z [M + H] calcd for C H N O : 525.2237; found:
2
8
33
2
8
C NMR (75 MHz, CDCl ): d = 169.9, 166.8, 148.6, 141.1, 140.4,
3
5
25.2230.
1
26.0, 124.2, 104.8, 102.1, 65.3, 59.8, 53.3, 28.8, 23.1, 19.2, 18.8.
Synthesis 2009, No. 20, 3383–3390 © Thieme Stuttgart · New York