Diastereoselective Aldol Reactions of Furaldehyde
FULL PAPER
(1ЈR,4R,5R)-7: Acetic anhydride (0.1 mL, 1.1 mmol) was added to
a well-stirred solution of 6b (95 mg, 0.14 mmol) in pyridine (5 mL).
The mixture was heated to reflux for 2 h. When TLC showed con-
sumption of all starting material, the reaction was quenched by
adding 3 HCl (20 mL). Extraction with CH2Cl2 (10 mL ϫ 3),
extracted with CH2Cl2 (10 mL ϫ 3), dried with MgSO4, and fil-
tered to give a crude mixture. Purification by flash column chroma-
tography on silica gel (50 g, 15% EtOAc in hexane) afforded the
inseparable diastereomeric mixture of 10a and 10b (80 mg, 68%) as
1
a white foam with 56% de (R). H NMR (CDCl3, major diastere-
washing with saturated NaHCO3, drying with MgSO4, filtration omer 10b): δ ϭ 1.28 (t, J ϭ 6.9 Hz, 3 H), 2.37Ϫ2.44 (m, 1 H),
and evaporation of the solvent under reduced pressure gave the
crude reaction mixture. Purification by flash column chromato-
graphy on silica gel (50 g, 5% EtOAc in hexane) afforded the de-
sired compound 7 (83 mg, 82%) as a white solid. M.p. 164Ϫ165
2.55Ϫ2.67 (m, 1 H), 3.00 (s, 6 H), 3.08 (d, J ϭ 5.7 Hz, 1 H),
4.09Ϫ4.21 (m, 2 H), 4.90Ϫ4.97 (m, 1 H), 5.45 (s, 2 H), 6.17 (d, J ϭ
1.5 Hz, 1 H), 7.16Ϫ7.38 (m, 21 H) ppm; (minor diastereomer 10a):
δ ϭ 1.21 (t, J ϭ 7.2 Hz, 3 H), 2.37Ϫ2.44 (m, 1 H), 2.55Ϫ2.67 (m,
1 H), 2.95 (d, J ϭ 7.2 Hz, 1 H), 3.01 (s, 6 H), 4.09Ϫ4.21 (m, 2 H),
1
°C. [α]2D0 ϭ Ϫ49 (c ϭ 1.40, CHCl3). H NMR (CDCl3): δ ϭ 0.56
(s, 3 H), 1.02 (s, 3 H), 1.08 (t, J ϭ 7.2 Hz, 3 H), 1.91 (s, 3 H), 3.04 4.90Ϫ4.97 (m, 1 H), 5.48 (s, 2 H), 6.17 (d, J ϭ 1.5 Hz, 1 H),
(s, 6 H), 3.92Ϫ4.00 (m, 1 H), 4.14Ϫ4.25 (m, 1 H), 5.46 (s, 2 H),
7.16Ϫ7.38 (m, 21 H) ppm. 13C NMR (CDCl3): δ ϭ 14.1, 14.2, 40.2,
5.90 (s, 1 H), 6.23 (d, J ϭ 1.8 Hz, 1 H), 7.17Ϫ7.22 (m, 7 H), 41.0, 44.9, 51.9, 60.5, 64.1, 64.6, 78.1, 83.4, 114.0, 127.4, 127.6,
7.26Ϫ7.43 (m, 14 H) ppm. 13C NMR (CDCl3): δ ϭ 14.1, 19.5, 20.6, 127.9, 128.4, 129.5, 140.9, 141.0, 141.0, 163.3, 171.4 ppm. MS:
23.3, 29.7, 46.8, 51.8, 60.4, 72.9, 77.8, 83.3, 114.2, 127.2, 127.3,
m/z (%) ϭ 669 (100) [M ϩ Na]ϩ. C39H39BO8 (646.53): calcd. C
127.4, 127.8, 128.5, 129.7, 141.0, 141.5, 141.7, 157.0, 168.6, 72.45, H 6.08; found C 72.46, H 5.94.
175.3 ppm. MS: m/z (%) ϭ 686 (34) [MH Ϫ Et]ϩ, 740 (6) [MH ϩ
(1ЈS,4R,5R)-11a and (1ЈR,4R,5R)-11b: Table 4, Entry 2. This reac-
Na]ϩ. C43H45BO9 (716.62): calcd. C 72.07, H 6.33; found C 72.14,
H 6.57. Crystallization of 7 from 5% EtOAc in hexane at room
temperature gave colorless crystals, which were sufficient for X-ray
crystallographic analysis.
tion was carried out with 2 (200 mg, 0.36 mmol), enolate 9b (0.5 m
in DME, 2.9 mL, 1.45 mmol) and anhydrous DME (20 mL) ac-
cording to the procedure described above for the preparation of
compounds 10. Purification by flash column chromatography on
silica gel (80 g, 15% EtOAc in hexane) afforded the diastereomeric
mixture of 11a and 11b (175 mg, 72%) with 23% de (R). The dias-
tereomeric mixture of 11a and 11b was isolated as a white foam. 1H
NMR (CDCl3, major diastereomer 11b): δ ϭ 1.45 (d, J ϭ 3.3 Hz, 1
H), 1.48 (s, 9 H), 2.28Ϫ2.34 (m, 1 H), 2.47Ϫ2.55 (m, 1 H), 3.01 (s,
6 H), 4.86Ϫ4.93 (m, 1 H), 5.45 (s, 2 H), 6.17 (d, J ϭ 1.5 Hz, 1 H),
7.16Ϫ7.38 (m, 21 H) ppm; (minor diastereomer 11a): δ ϭ 1.41 (s,
9 H), 1.45 (d, J ϭ 3.3 Hz, 1 H), 2.28Ϫ2.34 (m, 1 H), 2.47Ϫ2.55
(m, 1 H), 3.02 (s, 6 H), 4.86Ϫ4.93 (m, 1 H), 5.49 (s, 2 H), 6.17 (d,
J ϭ 1.5 Hz, 1 H), 7.16Ϫ7.38 (m, 21 H) ppm. 13C NMR (CDCl3):
δ ϭ 28.0, 28.1, 41.2, 42.3, 51.9, 64.2, 64.8, 78.1, 80.6, 80.8, 83.4,
113.9, 114.1, 127.4, 127.4, 127.6, 127.7, 127.8, 127.9, 127.9, 128.2,
128.4, 129.5, 140.7, 140.8, 140.9, 141.1, 163.5, 164.6, 170.1,
170.8 ppm. MS: m/z (%) ϭ 197 (34) [Ph2COMeϩ], 697 (59) [M ϩ
Na]ϩ. C41H43BO8 (674.59): calcd. C 73.00, H 6.42; found C 72.91,
H 6.50.
(1ЈS,4R,5R)-8a and (1ЈR,4R,5R)-8b: Table 3, Entry 1. These com-
pounds were prepared from aldehyde 2 (91 mg, 0.16 mmol), ketene
silyl acetal 3c (149 mg, 0.65 mmol), ZnCl2 (5 mg) and DME
(15 mL) at 0 °C according to the General Procedure 1 described
above. Purification by column chromatography on silica gel (30 g,
10% EtOAc in hexane) afforded compounds 8a and 8b (93 mg) in
80% yield with 46% de (R). Further purification by column chro-
matography on silica gel (30 g, 5% EtOAc in hexane) afforded dia-
stereomerically pure 8a first and then 8b. Compound 8a was isol-
ated as a white solid. 8a: M.p. 172Ϫ173 °C. [α]2D0 ϭ Ϫ71 (c ϭ 1.40,
acetone). 1H NMR (CDCl3): δ ϭ 0.75Ϫ1.08 (m, 3 H), 1.23 (t, J ϭ
7.2 Hz, 3 H), 1.27Ϫ1.32 (m, 3 H), 1.49Ϫ1.52 (m, 2 H), 1.61Ϫ1.66
(m, 1 H), 1.87Ϫ1.91 (m, 1 H), 3.00 (s, 6 H), 3.56 (d, J ϭ 11.1 Hz,
1 H), 4.07Ϫ4.17 (m, 2 H), 4.39 (d, J ϭ 11.1 Hz, 1 H), 5.44 (s, 2
H), 6.17 (d, J ϭ 1.8 Hz, 1 H), 7.14 (d, J ϭ 1.5 Hz, 1 H), 7.18Ϫ7.25
(m, 6 H), 7.28Ϫ7.36 (m, 14 H) ppm. 13C NMR (CDCl3): δ ϭ 14.1,
22.8, 23.2, 25.6, 26.9, 29.1, 30.8, 51.9, 52.4, 60.5, 74.6, 78.3, 83.4,
114.1, 127.4, 127.6, 127.9, 128.4, 129.6, 140.8, 141.1, 162.2,
174.8 ppm. MS: m/z (%) ϭ 197 (100) [Ph2COMeϩ], 697 (Ͻ 1) [M
Ϫ OH]ϩ. Crystallization of 8a from 5% EtOAc in hexane at room
temperature gave colorless crystals, which were sufficient for X-ray
crystallographic analysis. Compound 8b was isolated as a white
foam. 8b: Softening range: 72Ϫ81 °C. [α]2D0 ϭ Ϫ27 (c ϭ 1.20, acet-
(1ЈS,4R,5R)-4a and (1ЈR,4R,5R)-4b: Me3SiCl (0.1 mL, 0.80 mmol)
was added to a well-stirred solution of 10 (70 mg, 0.11 mmol), im-
idazole (29 mg, 0.43 mmol) in THF (10 mL) at room temp. The
reaction mixture turned milky immediately. The mixture was stirred
for a further 3 h. Saturated NaHCO3 solution (20 mL) was added
to quench the reaction. Extraction with CH2Cl2 (10 mL ϫ 3), dry-
ing with MgSO4, and filtration gave crude colorless oil. Purification
by flash column chromatography on silica gel (50 g, 5% EtOAc in
hexane) afforded a diastereomeric mixture of 4a and 4b (73 mg,
94%), whose physical and spectrometric data are identical with
those reported previously.
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one). H NMR (CDCl3): δ ϭ 0.70Ϫ0.77 (m, 1 H), 1.12Ϫ1.43 (m,
6 H), 1.25 (t, J ϭ 7.2 Hz, 3 H), 1.52Ϫ1.54 (m, 2 H), 2.01Ϫ2.04 (m,
1 H), 3.03 (s, 6 H), 3.52 (d, J ϭ 10.5 Hz, 1 H), 4.12Ϫ4.23 (m, 2
H), 4.55 (d, J ϭ 10.5 Hz, 1 H), 5.45 (s, 2 H), 6.17 (d, J ϭ 1.8 Hz,
1 H), 7.13 (d, J ϭ 1.8 Hz, 1 H), 7.18Ϫ7.20 (m, 5 H), 7.29Ϫ7.40
(m, 15 H) ppm. 13C NMR (CDCl3): δ ϭ 14.0, 22.1, 22.8, 25.9, 26.9,
29.3, 32.7, 50.5, 51.8, 60.7, 72.1, 77.6, 83.3, 113.6, 127.3, 127.6,
127.8, 128.4, 129.6, 140.9, 141.2, 141.3, 161.7, 175.8 ppm. MS:
m/z (%) ϭ 197 (100) [Ph2COMeϩ], 697 (Ͻ 1) [M Ϫ OH]ϩ. Ele-
mental analysis was carried out on a mixture of both diastereomers.
C44H47BO6 (714.65): calcd. C 73.95, H 6.63; found C 73.83, H 6.89.
(1ЈR,4R,5R)-12b: This compound was prepared from a diastereom-
eric mixture of 11 (150 mg, 0.22 mmol), imidazole (60 mg,
0.88 mmol), Me3SiCl (0.2 mL, 1.59 mmol) and THF (20 mL) ac-
cording to the procedure described above for the synthesis of 4.
Purification by flash column chromatography on silica gel (70 g,
5% EtOAc in hexane) afforded the diastereomeric mixture of 12a
and 12b (159 mg, 96%). The major diastereomer 12b (28 mg) was
crystallized from 3% EtOAc in hexane and was isolated as colorless
(1ЈS,4R,5R)-10a and (1ЈR,4R,5R)-10b: Table 4, Entry 1. Freshly
prepared enolate 9a (0.5 m in THF, 1.5 mL, 0.75 mmol) was added crystals. 12b: M.p. 207Ϫ208 °C. [α]2D0 ϭ Ϫ69 (c ϭ 0.55, CHCl3).
to a well-stirred solution of 2 (102 mg, 0.18 mmol) in anhydrous
THF (10 mL) at Ϫ78 °C under N2. The mixture was then stirred 2.7, 14.9 Hz, 1 H), 2.44 (dd, J ϭ 10.5, 14.9 Hz, 1 H), 3.02 (s, 6 H),
for 12 h from Ϫ78 °C to room temp. and the reaction was quenched 5.05 (dd, J ϭ 2.7, 10.6 Hz, 1 H), 5.45 (s, 2 H), 6.09 (d, J ϭ 1.8 Hz,
by addition of saturated NH4Cl (30 mL). The resulting mixture was 1 H), 7.16Ϫ7.21 (m, 7 H), 7.25Ϫ7.40 (m, 14 H) ppm. 13C NMR
1H NMR (CDCl3): δ ϭ Ϫ0.25 (s, 9 H), 1.52 (s, 9 H), 1.82 (dd, J ϭ
Eur. J. Org. Chem. 2003, 82Ϫ91
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