E. Arceo et al. / Tetrahedron: Asymmetry 14 (2003) 1617–1621
1619
in a predictable stereochemistry. In this way starting
with the enantiomer of chiral auxiliary 1 and employing
ethanal in the aldol reaction step, (S)-3-hydroxybu-
tanoic acid would be obtained which is another valuable
chiral building block for the synthesis of pheromones
and other natural products.
mixture was stirred at rt for 1.5 h and then saturated
aqueous NaHCO3 solution (150 mL) was added. After
extracting with ethyl acetate (3×75 mL), the combined
organic layers were dried with MgSO4 and the solvent
removed under reduced pressure to give a syrup that was
purified by flash chromatography (hexane–ethyl acetate,
10:1) affording 3.41 g (96% yield) of product as a white
solid: mp 46–49°C; [h]2D5 −14.0 (c 1, CH2Cl2). Data for
1
3. Experimental
3.1. General
major isomer: IR w 3400 (OH), 1699 (CꢀO) cm−1; H
NMR: l 3.93 (m, 1H), 3.06 (s, 1H), 2.95 (dd, J=10, 16
Hz, 1H), 2.84 (s, 1H), 2.49 (dd, J=2.6, 15.8 Hz, 1H),
2.27 (m, 1H), 1.85–1.16 (m, 8H), 1.12 (s, 3H), 0.98 (s,
3H), 0.96 (t, J=7.3 Hz, 3H), 0.84 (s, 3H); 13C NMR: l
214.0, 87.7, 70.4, 52.1, 50.8, 45.6, 45.0, 41.3, 30.3, 29.9,
26.3, 20.9, 20.6, 11.1, 9.9. Anal. calcd for C15H26O3: C,
70.81; H, 10.32. Found: C, 70.79; H, 10.39.
Solvents were dried by distillation from drying agents as
follows:
THF,
Et2O
(Na–benzophenone);
dichloromethane (P2O5); MeOH (Mg). Separations by
flash chromatography were performed on 230–400 mesh
silica gel. Melting points were recorded on a microscopic
apparatus. Microscale distillations were performed in a
3.4. (1S)-2-endo-[(3R)-tert-Butyldiphenylsilyloxypent-
anoyl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol 3b
1
bulb-to-bulb Kugelro¨hr oven Bu¨chi B-580. H and 13C
NMR spectra were obtained in CDCl3 solutions on a
Varian Gemini 200. Elemental analyses were performed
in a Perkin–Elmer 240C Analyzer. Infrared spectra were
recorded on a Nicolet–Avatar 360 FT-IR. Optical rota-
tions were measured in a JASCO-DIP-370 polarimeter.
High-performance liquid chromatography (HPLC)
analyses were carried out on a Waters chromatograph
equipped with a diode-array UV detector. Mass spectra
were recorded on a API Agilent-SL ion trap using the
APCI technique.
Imidazole (2.34 g, 34.5 mmol) and tert-butyldiphenylsi-
lyl chloride (5.43 mL, 20.7 mmol) were added to a stirred
solution of 3a (3.51 g, 13.8 mmol) in anhydrous DMF
(41 mL). The mixture was stirred overnight at rt and
then poured into ice-water and extracted with Et2O
(3×50 mL). The organic phase was washed with brine,
NaHCO3, dried (MgSO4) and the solvent removed. The
crude product was purified by column chromatography
(hexane–ethyl acetate, 50:1) to give a colorless syrup (6.4
g, 94%): [h]2D5 −5.0 (c 1, CH2Cl2). Data for major isomer:
IR w 3444 (OH), 1702 (CꢀO) cm−1; 1H NMR: l 7.70–7.66
(m, 4H), 7.40–7.34 (m, 6H), 4.27–4.10 (m, 1H), 3.28 (s,
1H), 3.16 (dd, J=8.4, 14.6 Hz, 1H), 2.32 (dd, J=4.8,
14.6 Hz, 1H), 2.11 (m, 1H), 1.83–1.17 (m, 8H), 1.12 (s,
3H), 0.99 (s, 9H), 0.95 (s, 3H), 0.83 (s, 3H), 0.65 (t,
J=7.3 Hz, 3H); 13C NMR: l 211.98, 135.86, 135.74,
134.12, 133.03, 129.71, 129.51, 127.56, 127.41, 87.74,
73.06, 52.18, 50.78, 45.49, 41.31, 30.29, 27.00, 26.38,
20.90, 20.51, 19.38, 11.16, 9.39; MS: m/z=475 (MH−
H2O)+.
3.2. (1S)-2-endo-[(3R)-Hydroxypentanoyl]-2-trimethylsi-
lyloxy-1,7,7-trimethylbicyclo[2.2.1]heptane 2
To a cooled (−78°C) solution of diisopropylamine (0.84
mL, 6 mmol) in dry THF (15 mL) a 2.5 M solution of
BuLi in THF (2.4 mL, 6 mmol) was added dropwise
under nitrogen. After 30 min of stirring, a solution of
methyl ketone 1 (1.34 g, 5 mmol) in 10 mL of THF was
added keeping the temperature below −70°C during the
addition. The mixture was maintained for 1 h at the
same temperature and then freshly distilled propanal
(0.74 mL, 10 mmol) was added dropwise. After 3 h at
−78°C the reaction mixture was quenched with a satu-
rated solution of NH4Cl (25 mL) and extracted with
CH2Cl2 (2×25 mL). The organic layer was dried
(MgSO4) and the solvent removed in vacuum to afford
the crude aldol 2 as a mixture of diastereomers 97:3.
Purification by flash chromatography (hexane–ethyl ace-
tate, 45:1) gave 1.52 g (93%) of a colorless syrup: [h]D25
−10.0 (c 1, CH2Cl2). Data for major isomer: IR w 3510
(OH), 1698 (CꢀO) cm−1; 1H NMR: l 3.96–3.84 (m, 1H),
3.52 (bs, 1H), 2.74 (dd, J=2.6, 17.9 Hz, 1H), 2.66–2.46
(m, 2H), 1.81–1.06 (m, 8H), 1.04 (s, 3H), 0.98 (s, 3H),
0.96 (t, J=7.3 Hz, 3H), 0.82 (s, 3H), 0.10 (s, 9H); 13C
NMR: l 214.0, 90.7, 68.9, 51.8, 50.9, 45.2, 44.9, 40.3,
30.2, 29.6, 25.8, 20.9, 20.3, 11.4, 9.8, 1.7; MS: m/z=327
(MH)+.
3.5. (R)-3-tert-Butyldiphenylsilyloxypentanoic acid 4
To a cooled solution (0°C) of 3b (5.91 g, 12 mmol) in
acetonitrile (146 mL) a solution of CAN (19.7 g, 36
mmol) in water (72 mL) was added dropwise. After
stirring for 20 min at the same temperature, water was
added (75 mL) and the reaction mixture was extracted
with CH2Cl2 (5×15 mL). Usual workup yielded 6.21 g of
a syrup containing the carboxylic acid 4 and the chiral
auxiliary. Purification by column chromatography (hex-
ane–ethyl acetate, from 25:1 to 1:1) allowed the recovery
of the starting camphor (1.8 g, 98%) along with 4 (3.94
g, 92%) as a white solid. Mp 69–72°C; IR: w 1710 (CꢀO)
cm−1; 1H NMR: l 7.70–7.64 (m, 4H), 7.48–7.33 (m, 6H),
4.13–4.01 (m, 1H), 2.49 (d, J=6.2 Hz, 2H), 1.59–1.45 (m,
2H), 1.04 (s, 9H), 0.76 (t, J=7.3 Hz, 3H); 13C NMR: l
176.85, 135.78, 135.76, 133.74, 133.44, 129.61, 129.63,
127.49, 127.46, 71.34, 40.90, 29.62, 26.94, 19.33, 9.18;
[h]2D5 +4.0 (c 1, CH2Cl2). HPLC: Chiralcel OD-R,
methanol/water 80:20, flow rate 0.5 mL/min, Rt 43.8 min
(determined as methyl ester derivative). Anal. calcd for
C21H28O3Si: C, 70.75; H, 7.91. Found: C, 70.85; H, 8.02.
3.3.(1S)-2-endo-[(3R)-Hydroxypentanoyl]-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-2-ol 3a
Compound 2 (4.55 g, 14 mmol) was dissolved in MeOH
(70 mL) and treated with 48% aq. HF (15 mL). The