The Journal of Organic Chemistry
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1H and 13C NMR spectra were identical with those of 13; [α]25
=
with saturated brine (2 mL). The aqueous layer was back-extracted
with DCM (6 × 5 mL), and the combined organic extracts were dried
over Na2SO4 and evaporated in vacuo. For the removal of the urea
byproduct, the residue was dissolved in diethyl ether (5 mL), and the
suspension was stirred vigorously for 10 min at rt. This mixture was
filtered through a pad of Celite on sintered glass filter and washed with
diethyl ether (5 mL). The filtrate was evaporated in vacuo, and the
residue was subjected to flash column chromatography (20% EtOAc in
hexanes) to give amide 32 (164 mg, 97%) as a pale yellow amorphous
D
+9.00 (c 2.80, CHCl3); HRMS (ESI) calcd. for C14H32NO3Si [M +
H]+ 290.2146, found 290.2150
(4R,5S)-5-(Aminomethyl-2,2,4-trimethyl-1,3-dioxolan-4-yl)-
methanol (26). Silyl ether 25 (183 mg, 0.63 mmol) was dissolved in
THF (6 mL), and a 1.0 M solution of TBAF in THF (1.9 mL, 1.9
mmol) was added at rt. After 3 h of vigorous stirring, EtOAc (5 mL)
was added, and the mixture was washed with saturated brine (5 mL).
The organic layer was separated, and the aqueous layer was back-
extracted with EtOAc (6 × 6 mL). The combined organic extracts
were dried over Na2SO4 and evaporated in vacuo. The residue was
purified by flash column chromatography (20% MeOH in DCM) to
give alcohol 26 (102 mg, 92%) as a white amorphous solid. This was
used in the next step without further purification: Rf = 0.11 (17%
solid: Rf = 0.64 (50% EtOAc in hexanes); [α]25 = +9.55 (c 2.78,
D
CHCl3); FTIR (KBr) 3358, 3068, 2980, 2932, 2870, 2857, 1656, 1624,
1509 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 15.5 Hz, 1H,
Ar−CH), 7.32 (d, J = 1.6 Hz, 1H, ArH-2), 7.11 (d, J = 8.4 Hz, 1H,
ArH-5), 7.05 (br d, J = 8.4 Hz, 1H, ArH-6), 6.27 (br s, 1H, NH), 6.22
(d, J = 15.5 Hz, 1H, CO-CH), 5.23 (2 × s, 4H, 2 × O−CH2−O),
3.94 (t, J = 6.8 Hz, 1H, CH−O), 3.75−3.68 (m, 1H, CHH-N), 3.69
(d, J = 10.1 Hz, 1H, CHH-O), 3.62−3.58 (m, 1H, CHH-N), 3.50 (s,
3H, CH3−O), 3.48 (s, 3H, CH3−O), 3.24 (d, J = 10.0 Hz, 1H, CHH-
O), 1.37 (s, 3H, CH3−C−CH3), 1.33 (s, 3H, CH3−C−CH3), 1.31 (s,
3H, C−CH3), 0.92 (s, 9H, C(CH3)3), 0.10 (s, 3H, Si-CH3), 0.09 (s,
3H, Si-CH3) ppm; 13C NMR (125 MHz, CDCl3) δ 165.7, 148.5,
147.3, 140.7, 129.1, 123.2, 118.9, 116.0, 114.8, 107.3, 95.3, 95.0, 81.4,
80.5, 65.2, 56.2, 56.1, 38.6, 28.3, 26.3, 25.8, 22.5, 18.1, −5.64, −5.65
ppm; HRMS (ESI) calcd. for C27H45NNaO8Si [M + Na]+ 562.2807,
found 562.2801.
Coupling with EDC. To a magnetically stirred solution of amine 25
(205 mg, 0.71 mmol) in dry CH2Cl2 (3.5 mL) acid 3431 (380 mg, 1.42
mmol), DMAP (87 mg, 0.71 mmol) and EDC·HCl (339 mg, 1.77
mmol) were added at rt. The reaction mixture was left to stir under an
Ar atmosphere for 24 h at rt. Then, it was washed with saturated brine
(2 mL) and water (2 × 2 mL). The aqueous layer was back-extracted
with CH2Cl2 (6 × 5 mL), and the combined organic extracts were
dried over Na2SO4 and evaporated in vacuo. The residue was
subjected to flash column chromatography (20% EtOAc in hexanes) to
give amide 32 (380 mg, 99%) as a pale yellow solid. The data for 32
matches that reported above (coupling with DCC).
MeOH in CH2Cl2); [α]25 = +1.73 (c 6.50, MeOH); FTIR (KBr)
D
3398, 3312, 3066, 2986, 2937, 2855, 1578, 1458 cm−1; 1H NMR (500
MHz, CD3OD) δ 4.04 (dd, J = 8.2, 3.3 Hz, 1H, CH−O), 3.53 (d, J =
11.2 Hz, 1H, CHH-O), 3.30 (d, J = 11.2 Hz, 1H, CHH-O), 3.20−3.06
(m, 2H, CH2−N), 1.41 (s, 3H, CH3−C−CH3), 1.38 (s, 3H, CH3−C−
CH3), 1.32 (s, 3H, C−CH3) ppm; 13C NMR (125 MHz, CD3OD) δ
109.6, 83.0, 82.4, 65.4, 40.7, 28.8, 27.1, 22.5 ppm; HRMS (ESI) calcd.
for C8H18NO3 [M + H]+ 176.1281, found 176.1280.
4-((E)-3-(((4S,5R)-5-(tert-Butyldimethylsilyloxymethyl)-2,2,5-
trimethyl-1,3-dioxolan-4-yl)methylamino)-3-oxoprop-1-en-1-
yl)-1,2-phenylene diacetate (29). Coupling with BOP. Dry Et3N
(14 μL, 0.1 mmol) was added to a magnetically stirred solution of
amine 25 (28 mg, 0.1 mmol) in dry CH2Cl2 (0.4 mL) at rt. To this
solution acid 3130 (28 mg, 0.11 mmol) and BOP (64 mg, 0.15 mmol)
were added, and the mixture was left to stir under an Ar atmosphere
for 1 h at rt. An additional amount of dry Et3N (14 μL, 0.1 mmol) was
added, and the mixture was further stirred for 2 h at rt. Then, it was
evaporated to dryness, and the residue was purified by flash column
chromatography (25% EtOAc in hexanes) to give amide 29 (27 mg,
52%) as a pale yellow oil: Rf = 0.12 (30% EtOAc in hexanes); [α]25
=
D
+4.31 (c 1.08, CHCl3); FTIR (neat) 3364, 3077, 2985, 2940, 2871,
1
2854, 1759, 1650, 1614, 1516 cm−1; H NMR (300 MHz, CDCl3) δ
7.57 (d, J = 15.5 Hz, 1H, Ar−CH), 7.34 (dd, J = 8.3, 1.9 Hz, 1H,
ArH-6), 7.30 (d, J = 1.9 Hz, 1H, ArH-2), 7.19 (d, J = 8.3 Hz, 1H, ArH-
5), 6.28 (d, J = 15.5 Hz, 1H, CO-CH), 6.18 (br t, J = 6.0 Hz, 1H,
NH), 3.72−3.65 (m, 2H, CH2−N), 3.71 (d, J = 9.9 Hz, 1H, CHH-O),
3.28 (d, J = 9.9 Hz, 1H, CHH-O), 2.29 (s, 3H, CH3−CO), 2.28 (s,
3H, CH3−CO), 1.39 (s, 3H, CH3−C−CH3), 1.35 (s, 3H, CH3−C−
CH3), 1.32 (s, 3H, C−CH3), 0.94 (s, 9H, C(CH3)3), 0.12 (s, 3H, Si-
CH3) 0.11 (s, 3H, Si-CH3) ppm; 13C NMR (75 MHz, CDCl3) δ
167.90, 167.88, 165.2, 143.0, 142.4, 139.4, 137.8, 125.9, 123.8, 122.4,
121.8, 107.5, 81.5, 80.9, 65.4, 38.9, 28.4, 26.5, 25.9, 22.6, 20.6, 20.5,
18.2, −5.55, −5.58 ppm; HRMS (ESI) calcd. for C27H41NNaO8Si [M
+ Na]+ 558.2494, found 558.2499.
Coupling with DCC. To a magnetically stirred solution of amine 25
(87 mg, 0.3 mmol) in dry CH2Cl2 (1.5 mL), acid 3130 (160 mg, 0.6
mmol), DMAP (37 mg, 0.3 mmol) and DCC (155 mg, 0.75 mmol)
were added at rt. The reaction mixture was left to stir under an Ar
atmosphere for 24 h at rt. Then, it was washed with saturated brine (2
mL). The aqueous layer was back-extracted with DCM (6 × 5 mL),
and the combined organic extracts were dried over Na2SO4 and
evaporated in vacuo. For the removal of the urea byproduct, the
residue was dissolved in diethyl ether (3 mL), and the suspension was
stirred vigorously for 10 min at rt. This mixture was filtered through a
pad of Celite on sintered glass filter and washed with diethyl ether (3
mL). The filtrate was evaporated in vacuo, and the residue was
subjected to flash column chromatography (25% EtOAc in hexanes) to
give amide 29 (68 mg, 43%) as a pale yellow oil. The data for 29
matches that reported above (coupling with EDC).
(E)-3-(3,4-Bis(methoxymethoxy)phenyl]-N-(((4S,5R)-5-hy-
droxymethyl-2,2,5-trimethyl-1,3-dioxolan-4-yl)methyl)-
acrylamide (33). Silyl ether 32 (380 mg, 0.70 mmol) was dissolved in
THF (7 mL), and a mixture of a 1.0 M solution of TBAF in THF (3.6
mL, 3.6 mmol) and glacial AcOH (0.2 mL, 3.6 mmol) was added
under an Ar atmosphere at rt. After 48 h of vigorous stirring at rt,
EtOAc (5 mL) was added, and the mixture was washed with saturated
brine (5 mL). The organic layer was separated, and the aqueous layer
was back extracted with EtOAc (6 × 5 mL). The combined organic
extracts were dried over Na2SO4 and evaporated in vacuo. The residue
was purified by flash column chromatography (80% EtOAc in
hexanes) to give alcohol 33 (276 mg, 92%) as a pale white amorphous
solid: Rf = 0.11 (50% EtOAc in hexanes); [α]25 = −4.94 (c 1.95,
D
CHCl3); FTIR (KBr) 3385, 3300, 3045, 2928, 2870, 2857, 1655, 1604,
1509 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 15.6 Hz, 1H,
Ar−CH), 7.32 (d, J = 1.2 Hz, 1H, ArH-2), 7.11 (d, J = 8.4 Hz, 1H,
ArH-5), 7.08 (dd, J = 8.5, 1.4 Hz, 1H, ArH-6), 6.75 (br t, J = 5.8 Hz,
1H, NH), 6.35 (d, J = 15.6 Hz, 1H, CO−CH), 5.24 (s, 4H, 2 × O−
CH2−O), 4.03 (dd, J = 7.6, 5.2 Hz, 1H, CH−O), 3.83−3.78 (m, 1H,
CHH-N), 3.61 (d, J = 11.0 Hz, CHH-O), 3.61−3.56 (m, 1H, CHH-
N), 3.52 (s, 3H, CH3−O), 3.50 (s, 3H, CH3−O), 3.48 (d, J = 11.2 Hz,
CHH-O), 1.43 (s, 3H, CH3−O−CH3), 1.37 (s, 6H, CH3−O−CH3
and C−CH3) ppm; 13C NMR (125 MHz, CDCl3) δ 166.2, 148.5,
147.1, 140.7, 129.0, 123.1, 118.8, 116.0, 115.0, 107.6, 95.2, 94.9, 81.5,
80.9, 64.7, 56.03, 56.02, 38.3, 28.1, 26.3, 22.0 ppm; HRMS (ESI) calcd.
for C21H31NNaO8 [M + Na]+ 448.1942, found 448.1949.
(3aS,6aS)-5-((E)-3-(3,4-Bis(methoxymethoxy)phenyl)-
acryloyl)-2,2,3a-trimethyldihydro-3aH-[1,3]dioxolo[4,5-c]-
pyrrol-4(5H)-one (35). A solution of alcohol 33 (211 mg, 0.5 mmol)
in acetone (1.2 mL) was added to a 5% aq. NaHCO3 solution (1.2
mL) containing KBr (6 mg, 0.05 mmol), and the resulting slurry was
cooled to 0 °C. TEMPO (108 mg, 0.69 mmol) was then added
followed by 5% aq. NaOCl solution (1.2 mL). The pH was adjusted to
8 by adding solid NaHCO3, and the mixture was stirred for 3 h at 0
(E)-3-(3,4-Bis(methoxymethoxy)phenyl)-N-(((4S,5R)-5-(tert-
butyldimethylsilyloxymethyl)-2,2,5-trimethyl-1,3-dioxolan-4-
yl)methyl)acrylamide (32). Coupling with DCC. To a magnetically
stirred solution of amine 25 (91 mg, 0.31 mmol) in dry CH2Cl2 (1.6
mL), acid 3431 (169 mg, 0.63 mmol), DMAP (38 mg, 0.31 mmol) and
DCC (162 mg, 0.79 mmol) were added at rt. The reaction mixture was
left to stir under an Ar atmosphere for 24 h at rt. Then, it was washed
G
dx.doi.org/10.1021/jo5011735 | J. Org. Chem. XXXX, XXX, XXX−XXX