Synthesis of a Polymer-Supported Oxazolidine Aldehyde
The oil was purified by flash column chromatography on silica
gel (20% EtOAc/hexane, Rf ) 0.51) to yield the product as a
1:1 mixture of diastereomers. Yield 2.22 g (90% as a clear oil).
13C NMR (100 MHz, CDCl3): δ 200.4, 199.3, 174.0, 173.9,
153.6, 152.4, 152.2, 137.0, 136.6, 130.6, 129.6, 129.4, 129.3,
128.7, 97.4, 97.2, 96.5, 82.9, 82.6, 82.5, 67.5, 67.4, 67.3, 65.9,
65.4, 65.2, 65.1, 64.8, 64.5, 34.6, 33.8, 33.7, 32.7, 30.2, 30.0,
(m, 2 H), 4.06 (dd, 1 H, J ) 9.4, 3.7 Hz), 3.97 (dd, 1 H, J ) 9.3,
4.9 Hz), 2.35-2.15 (m, 8 H), 1.54 (s, 3 H), 1.48 (s, 3 H), 1.46
(s, 9 H), 1.45 (s, 9 H) [at room temperature 12.0 (br, 1 H)
disappears upon heating or with a D2O shake]. IR (cm-1):
3409, 2978, 1709, 1393, 1167, 1088. HRMS: [M + Na]+ calcd
for C13H21NO6Na 310.1267, found 310.1255.
Mosh er Ester 15. To a solution of oxazolidine alcohol 11
(180 mg, 0.47 mmol), DCC (113 mg, 0.55 mmol), and DMAP
(13.8 mg, 0.10 mmol) in anhydrous CH2Cl2 (2 mL) was added
a solution of (+)-(R)-MTPA (121 mg, 0.52 mmol) in anhydrous
CH2Cl2 (0.65 mL). The mixture was stirred at room temper-
ature for 18 h. The resulting white suspension was filtered
and the filtrate concentrated in vacuo to give a clear oil to
which diethyl ether (4 mL) was added. The resulting suspen-
sion was filtered and the filtrate concentrated in vacuo to give
a clear oil. The oil was purified by flash column chromatog-
raphy on silica gel (15% EtOAc/hexane, Rf ) 0.48) to give the
product as a 1:1 mixture of diastereomers. Yield 153 mg (55%
as a clear oil). 13C NMR (100 MHz, CDCl3): δ 172.8, 172.7,
165.9, 165.8, 151.9, 151.6, 151.3, 151.1, 135.8, 131.8, 131.7,
129.5, 128.3, 128.1, 128.0, 127.3, 127.0, 126.7, 124.5, 121.6,
118.7, 95.2, 95.1, 94.8, 84.9, 84.6, 84.3, 84.1, 81.0, 80.9, 80.6,
66.0, 65.4, 65.0, 64.5, 64.2, 64.0, 63.5, 55.2, 54.9, 54.7, 54.6,
33.4, 32.6, 32.3, 30.7, 29.2, 29.0, 28.6, 28.0, 24.4, 23.6, 22.6,
1
29.8, 29.3, 25.6, 25.0, 24.7, 23.2. H NMR (400 MHz, DMSO,
140 °C): δ 9.57 (d, 1 H, J ) 1.9 Hz), 9.54 (d, 1 H, J ) 2.3 Hz),
7.35 (m, 10 H), 5.12 (s, 2 H), 5.11 (s, 2 H), 4.36 (m, 2 H), 4.11
(m, 2 H), 4.03 (dd, 1 H, J ) 9.4, 3.6 Hz), 3.96 (dd, 1 H, J ) 9.3,
4.9 Hz), 2.44-2.19 (m, 8 H), 1.53 (s, 3 H), 1.48 (s, 3 H), 1.45
(s, 9 H), 1.44 (s, 9 H). IR (cm-1): 2977, 2934, 1736, 1707, 1455,
1390, 1256, 1167, 1084. HRMS: [M + Na]+ calcd for C20H27
-
NO6Na 400.1736, found 400.1754. Anal. Calcd for C20H27NO6:
C, 63.66; H, 7.16; N, 3.71. Found: C, 63.32; H, 7.21; N, 3.81.
(2R/S,4R)-2-(2-Ca r b oxyet h yl)-4-h yd r oxym et h yl-2-m e-
th yloxa zolid in e-3-ca r boxylic Acid ter t-Bu tyl Ester , 5. To
a round-bottomed flask containing 10% Pd-C (23.3 mg, ap-
proximately 10% w/w) under argon was added anhydrous
methanol (1 mL) followed by a solution of benzyl ester 11 (102
mg, 0.26 mmol) in methanol (1 mL). The flask was purged
twice with hydrogen, then stirred vigorously under 1 atm of
hydrogen (balloon) at room temperature. After 4 h, when all
of the starting material had been consumed as judged by TLC,
the mixture was filtered through a short pad of Celite and the
filtrate concentrated in vacuo to give the crude product as a
clear oil (70 mg) in a 1:1 mixture of diastereomers. An
analytical sample was obtained after purification by flash
column chromatography on silica gel (25% hexane/EtOAc, Rf
) 0.29). 13C NMR (100 MHz, DMSO): δ 175.2, 152.4, 152.2,
152.1, 95.2, 95.1, 80.4, 80.0, 79.9, 66.4, 66.2, 65.7, 65.4, 61.8,
61.6, 60.9, 59.4, 59.1, 59.0, 58.7, 34.4, 33.8, 33.3, 31.8, 29.9,
29.4, 29.0, 28.9, 26.6, 24.9, 23.8, 22.2, 20.6. 1H NMR (400 MHz,
DMSO, 140 °C): δ 3.94 (m, 4 H), 3.86 (m, 2 H), 3.66 (m, 2 H),
3.41 (dd, 1 H, J ) 10.7, 8.1 Hz), 3.35 (dd, 1 H, J ) 10.2, 8.5
Hz), 2.30-2.11 (m, 8 H), 1.46 (s, 21 H), 1.43 (s, 3 H) [at room
temperature 11.7 (br, 1 H) and 4.87 (br, 1 H) disappear upon
heating or with a D2O shake]. IR (cm-1): 3196, 2978, 2676,
1694, 1393, 1255, 1167, 1086. HRMS: [M + Na]+ calcd for
1
21.3. H NMR (400 MHz, DMSO, 140 °C): δ 7.46 (m, 10 H),
7.35 (m, 10 H), 5.11 (m, 4 H), 4.55 (m, 2 H), 4.40 (dd, 1 H, J )
10.9, 6.9 Hz), 4.24 (dd, 1 H, J ) 10.6, 8.0 Hz), 4.09, (m, 2 H),
3.96 (m, 2 H), 3.71 (m, 2 H), 3.50 (s, 6 H), 2.42-2.19 (m, 8 H),
1.46 (s, 18 H), 1.43 (s, 3 H), 1.39 (s, 3 H). 19F NMR (400 MHz,
CDCl3, with reference to CDF3): δ -71.75, -71.95. IR (cm-1):
2978, 2934, 1752, 1696, 1454, 1384, 1257, 1168, 1021. HRMS:
[M + Na]+ calcd for C30H36NO8F3Na 618.2291, found 618.2277.
Anal. Calcd for C30H36NO8F3: C, 60.49; H, 6.10; N, 2.35.
Found: C, 60.23; H, 6.11; N, 2.42.
Mosh er Ester 17. 17 was prepared in an identical manner
to 15 with ent-11. ent-11 was prepared from ent-9 in an
identical manner to 11. Yield 55% as a clear oil in a 1:1 mixture
of diastereomers. 13C NMR (100 MHz, CDCl3): δ 172.9, 172.8,
166.1, 166.0, 152.1, 151.8, 151.4, 151.2, 135.9, 132.0, 129.6,
128.4, 128.2, 127.2, 124.6, 121.7, 118.9, 95.3, 95.2, 94.9, 85.0,
84.7, 84.4, 84.2, 81.3, 81.1, 80.7, 66.2, 65.7, 65.4, 65.3, 65.0,
64.8, 64.5, 64.4, 64.0, 55.3, 55.1, 55.0, 33.6, 32.7, 32.2, 30.7,
29.4, 29.3, 28.7, 28.2, 24.6, 23.7, 22.7, 21.4. 1H NMR (400 MHz,
DMSO, 140 °C): δ 7.47 (m, 10 H), 7.35 (m, 10 H), 5.12 (m, 4
H), 4.55 (m, 2 H), 4.40 (dd, 1 H, J ) 10.9, 6.9 Hz), 4.25 (dd, 1
H, J ) 10.6, 8.1 Hz), 4.10 (m, 2 H), 3.98 (m, 2 H), 3.70 (m, 2
H), 3.50 (m, 6 H), 2.40-2.18 (m, 8 H), 1.45 (s, 18 H), 1.43 (s,
3 H), 1.39 (s, 3 H). 19F NMR (400 MHz, CDCl3, with reference
to CDF3): δ -71.82. IR (cm-1): 2932, 1746, 1695, 1454, 1384,
C
13H23NO6Na 312.1423, found 312.1424.
(2R/S,4S)-2-(2-Ca r b oxy-et h yl)-4-for m yl-2-m et h yl-oxa -
zolid in e-3-ca r boxylic Acid ter t-Bu tyl Ester , 4. Hyd r o-
gen olysis: To a round-bottomed flask containing 10% Pd-C
(200 mg, approximately 10% w/w) under argon was added
anhydrous methanol (1 mL) followed by a solution of benzyl
ester 12 (1.904 g, 5.0 mmol) in methanol (4 mL). The flask
was purged twice with hydrogen, then stirred vigorously under
1 atm of hydrogen (balloon) at room temperature. After 4 h,
all of the starting material had been consumed as judged by
TLC. The mixture was filtered through a short pad of Celite
and the filtrate concentrated in vacuo to give the crude product
as a clear oil (1.353 g) in a 1:1 mixture of diastereomers. An
analytical sample was obtained after purification by flash
column chromatography on silica gel (33% EtOAc/hexane, Rf
) 0.24). Oxid a tion : To a solution of oxalyl chloride (18.6 µL,
0.22 mmol) in anhydrous CH2Cl2 (1 mL) at -78 °C was added
dropwise DMSO (22.0 µL, 0.31 mmol). The mixture was stirred
for 5 min at -78 °C and a solution of oxazolidine alcohol 5
(44.7 mg, 0.16 mmol) in anhydrous CH2Cl2 (1 mL) at -78 °C
was added by cannulation. The solution was stirred for 30 min
at -78 °C and Et3N (87 µL, 0.62 mmol) was added. After being
allowed to warm to room temperature (∼15 min) the mixture
was poured into water and the organic layer was separated
and washed with 10% citric acid solution and brine, dried with
Na2SO4, and concentrated in vacuo to yield a yellow oil. The
oil was purified as before. Yield 45.7 mg (100% as a clear oil).
13C NMR (100 MHz, CDCl3): δ 199.2, 198.2, 179.1, 152.6,
152.3, 151.4, 151.1, 96.2, 96.0, 95.4, 82.0, 81.6, 64.8, 64.2, 63.9,
63.7, 63.4, 33.3, 32.6, 32.4, 31.5, 28.9, 28.6, 28.2, 24.5, 23.6,
23.2, 22.1. 1H NMR (400 MHz, DMSO, 140 °C): δ 9.58 (d, 1
H, J ) 1.9 Hz), 9.54 (d, 1 H, J ) 2.3 Hz), 4.35 (m, 2 H), 4.13
1257, 1165, 1084, 1022. HRMS: [M + Na]+ calcd for C30H36
NO8F3Na 618.2291, found 618.2298. Anal. Calcd for C30H36
-
-
NO8F3: C, 60.49; H, 6.10; N, 2.35. Found: C, 60.52; H, 6.20;
N, 2.49.
Oxa zolid in e Ald eh yd e 3. F r om 4: to amino-methylated
Merrifield resin (0.75 mmol g-1, 200 mg, 0.15 mmol) preswollen
in CH2Cl2 was added a solution of crude oxazolidine acid 4
(130 mg, 0.45 mmol), HOBt (72 mg, 0.47 mmol), and DIC (72
µL, 0.46 mmol) in anhydrous CH2Cl2/DMF (1:1, mL). The
mixture was shaken for 18 h at room temperature. The resin
was drained, washed with CH2Cl2 (3×), MeOH (3×), DMF
(3×), MeOH (3×), and CH2Cl2 (3×), and then dried in vacuo.
F r om 14: To alcohol 14 (0.64 mmol g-1, 200 mg, 0.13 mmol)
preswollen in CH2Cl2 was added Et3N (110 µL, 0.79 mmol) in
CH2Cl2 (2.5 mL) followed by a solution of Py‚SO3 (125 mg, 0.79
mmol) in DMSO (3 mL). The resin was stirred for 12 h at room
temperature. The resin was drained, washed with 10% citric
acid solution/THF (1:1, 3×), THF (3×), MeOH (3×), and CH2-
Cl2 (3×), and then dried in vacuo. 13C gel-phase NMR (100
MHz, CDCl3): δ 198.8, 198.5, 171.8, 95.8, 95.2, 82.0, 81.3, 64.9,
64.3, 63.8, 63.5, 34.0, 33.4, 32.2, 31.0, 28.3, 28.0, 24.6, 23.6,
23.3, 22.3. IR (cm-1, CH2Cl2 gel): 3437, 1790, 1673.
J . Org. Chem, Vol. 67, No. 19, 2002 6651