1412
J. D. Hall et al. / Bioorg. Med. Chem. 13 (2005) 1409–1413
(40mL) was added. After refluxing for 24h the reaction
was quenched by pouring it into 500mL of 5% NaH-
CO3. The layers were separated and the aqueous phase
was extracted three times with CH2Cl2. The combined
organic layers were washed with brine, dried over
Na2SO4, and then concentrated under reduced pressure.
The crude oil was purified by flash chromatography (5–
25% EtOAc/hexanes) to afford oxazoline 7 as a light yel-
low oil in 72% yield (10.0g, 45.5mmol). 1H NMR
(CDCl3): d 7.21 (s, 2H), 4.40 (m, 1H), 4.12 (m, 2H),
3.91 (s, 6H), 3.88 (s, 3H), 1.89 (m, 1H), 1.03 (d,
J = 6.83Hz, 3H), 0.93 (d, J = 6.83Hz, 3H). 13C NMR
(CDCl3): d 163.0, 152.9, 140.5, 123.1, 105.3, 72.6,
70.0, 60.9, 56.2, 32.7, 19.0, 17.9. IR (oil) 1653,
H2O. The separated aqueous layer was extracted three
times with EtOAc. The combined organic layers were
washed with 1M NaOH, brine, dried over Na2SO4,
and then concentrated under reduced pressure. The
crude oil was purified using flash chromatography (35–
70% EtOAc/hexanes) afforded alcohol 11 in 94% yield
1
(0.533g). Mp 163–168°C. H NMR (CDCl3): d 7.00 (s,
2H), 6.28 (br d, J = 8.2Hz, 1H), 3.91 (s, 6H), 3.88 (s,
3H), 3.82 (m, 2H), 2.59 (br s, 1H), 2.02 (m, 1H), 1.04
(d, J = 5.7Hz, 3H), 1.02 (d, J = 5.8Hz, 3H). 13C NMR
(CDCl3): d 168.1, 153.1, 141.0, 130.0, 104.4, 63.7, 60.9,
57.6, 56.3, 29.2, 19.6, 19.1. IR (solid) 3291, 1630,
20
D
20
365
20
436
1128cmꢀ1
.
½aꢁ ꢀ0.266, ½aꢁ ꢀ0.884, ½aꢁ ꢀ0.516,
20
633
½aꢁ ꢀ0.228 (c 1.0, CH2Cl2). Anal. Calcd for
20
20
1587, 1505, 1128cmꢀ1
.
½aꢁ ꢀ0.404, ½aꢁ ꢀ1.79,
C15H23NO5: C, 60.59; H, 7.80; N, 4.71. Found: C,
60.72; H, 8.12; N, 4.63.
D
365
20
436
20
633
½aꢁ ꢀ0.938, ½aꢁ ꢀ0.334 (c 1.0, CH2Cl2). Anal. Calcd
for C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C,
64.01; H, 7.70; N, 4.94.
4.5. (4S)-4-Isopropyl-2-(3,4,5-trimethoxyphenyl)-2-oxaz-
oline 7 via amide alcohol 11
4.3. Methyl (2S)-2-(3,4,5-trimethoxybenamido)-3-methyl-
butanoate 10
To a solution of alcohol 11 (0.158g, 0.531mmol) in
CH2Cl2 (2.70mL) at 0°C was added Et3N (2.34mL,
1.68mmol) then MsCl (0.0822mL, 1.06mmol) dropwise
then warmed to rt. After 16h the solvent was removed
under reduced pressure. The oily residue was redissolved
in a 4:1 EtOAc/H2O solution. The aqueous layer was ex-
tracted three times with EtOAc and then the combined
organic layers were washed with brine and dried over
Na2SO4. After concentrating the organic layer under re-
duced pressure, the oily residue was purified via flash
chromatography (30–37% EtOAc/hexanes) to afford
oxazoline 7 as an oil in 97% yield (0.143g). Spectral data
matched that of the oxazoline via the imidate ester. See
Section 4.2.
To a 50mL round bottom flask was added 3,4,5-tri-
methoxybenzoic acid (8) (0.447g, 2.11mmol) and 9mL
of CH2Cl2. This suspension was stirred at 0°C, and then
EDC (0.809g, 4.22mmol) and HOBt (0.570g,
4.22mmol) were added. In a second 50mL round bot-
tom flask was added L-valine methyl ester hydrochloride
(9) (0.500g, 3.17mmol), 9mL of CH2Cl2 and Et3N
(0.588mL, 4.22mmol). (The solution goes from having
a suspension to clear and then back to having a white
suspension.) After 10min the methyl ester solution was
cannulated into the 3,4,5-trimethoxybenzoic acid solu-
tion. Upon mixing the ice bath was removed and the
reaction was stirred for 24h. Then the CH2Cl2 was evap-
orated under reduced pressure and the residue was dis-
solved in a 4:1 mixture of EtOAc/H2O mixture. The
organic layer was then washed two times with 1M
HCl, one time each with satd NaHCO3, H2O, and brine.
The organic layer was dried over Na2SO4, filtered, and
then concentrated under reduced pressure. The residue
was then purified using flash chromatography (15%
EtOAc/hexanes) to yield 10 as an oil in 91% (0.625g,
4.6. (S,Z)-2-(1-Heptyl-5,6,7-trimethoxyisobenzofuran-
3(1H)-ylideneamino)-3-methylbutan-1-ol 13
To
a stirred solution of oxazoline 7 (0.105mg,
0.376mmol) in THF (2.51mL) at ꢀ78°C was added
sec-BuLi (0.418mL of a 1.08M solution in hexanes,
0.451mmol).
After
6h,
n-octanal
(0.070mL,
0.451mmol) was added dropwise at ꢀ78°C. After
45min at ꢀ78°C the reaction was allowed to warm to
rt overnight. The reaction was quenched with the addi-
tion of NH4Cl and stirred for 15min at rt and then di-
luted with Et2O. The aqueous layer was extracted one
time with Et2O then the combined organic layers were
washed with brine and dried over Na2SO4 and concen-
trated under reduced pressure. The crude oil was puri-
fied by flash chromatography (30% EtOAc/hexanes) to
afford 13 as a 1:1 mixture of diastereomers as an oil in
56% yield (0.086g). Characterization of the top diaster-
eomer will be reported for simplicity. (Based on TLC
80% EtOAc/hexanes the top diastereomer has an
Rf = 0.38 and the bottom diastereomer has an
1
2.03mmol). Mp 132–135°C. H NMR (CDCl3): d 7.03
(s, 2H), 6.58 (br d, J = 8.2Hz, 1H), 4.76 (dd, J = 8.6
and 4.9Hz, 1H), 3.92 (s, 6H), 3.89 (s, 3H), 3.79 (s,
3H), 2.28 (m, 1H), 1.02 (d, J = 7.3Hz, 3H), 0.99 (d,
J = 7.0Hz, 3H). 13C NMR (CDCl3): d 172.8, 166.9,
153.2, 141.1, 129.5, 104.4, 60.9, 57.5, 56.3, 52.2, 31.6,
19.0, 18.0. IR (solid) 3288, 1747, 1630, 1124cmꢀ1
.
20
D
20
20
20
633
½aꢁ +0.218, ½aꢁ365 +0.616, ½aꢁ436 +0.466, ½aꢁ +0.180 (c
1.0, CH2Cl2). Anal. Calcd for C16H23NO6: C, 59.06;
H, 7.13; N, 4.31. Found: C, 59.10; H, 7.27; N, 4.18.
4.4. N-((S)-1-Hydroxy-3-methylbutan-2-yl)-3,4,5-tri-
methoxybenzamide 11
1
Rf = 0.23.) H NMR (CDCl3): d 7.16 (s, 1H), 5.45 (dd,
To a stirred solution of ester 10 (0.626g, 1.92mmol) in
THF (28.6mL) at 0°C was added LiBH4 (1.92mL of a
2M solution in THF, 3.85mmol) dropwise and then
warmed to rt. After 20h the reaction was quenched with
2M HCl and then concentrated under reduced pressure.
The residue was dissolved in a 4:1 mixture of EtOAc/
J = 7.4 and 3.1Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.89
(s, 3H), 3.78–3.70 (m, 3H), 2.49 (br s, 1H), 2.06 (m,
1H), 1.87 (m, 1H), 1.60 (m, 1H), 1.22 (m, 10H), 0.97
(d, J = 6.6Hz, 3H), 0.91 (d, J = 6.8Hz, 3H), 0.88 (t,
J = 7.0Hz, 3H). 13C NMR (CDCl3): d 168.8, 155.1,
147.4, 144.5, 131.7, 125.9, 101.1, 82.3, 64.6, 63.7, 61.0,