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C. A. Martinez et al. / Tetrahedron: Asymmetry 21 (2010) 2408–2412
layers were dried with sodium sulfate and concentrated in vacuo to
give a mixture of (R)-2 and (S)-5 as a yellow oil (2480 g).
4.6. Synthesis of (S)-5 from a mixture of (R)-6 and (S)-5
The mixture was separated by column chromatography in
1100–1300 g batches on 25 kg of silica gel (MP silitech 32-63,
60A) using a gradient of heptanes and ethyl acetate. The column
can be used 6 times without a loss of activity. The volume and gra-
dient of the elution solvents are as follows: heptanes (40 L), 2%
ethyl acetate in heptanes (20 L), 5% ethyl acetate in heptanes
(40 L), 7% ethyl acetate in heptanes (20 L), 9% ethyl acetate in hep-
tanes (20 L), 100% ethyl acetate in heptanes (10 L),and 0% ethyl
acetate in heptanes (40 L to regenerate the column). Fractions
(10 L/fraction) were collected [compound (S)-5 was eluted in frac-
tions 10–13 and compound (R)-2 was eluted in fractions 15–17]
and evaporated to give a colorless oil [compound (S)-5, 43%,
>99% ee, Rf: 12.95 min.]. The enantiomeric purity of (S)-5 was
determined using a Chiracel OJ-RH (150 ꢂ 4.6 mm) CH3CN/water
(50:50; 0.6 mL/min). The other enantiomer of (S)-5 (structure not
shown) was eluted at 11.55 min.
Potassium acetate (0.027 g, 0.26 mmol) was added to a solution
of a mixture of (R)-6 and (S)-5 (0.48 mmol) in 4 mL of DMF under a
nitrogen atmosphere. The reaction mixture was heated to 100 °C
for 12 h. Water (20 mL) was added to the reaction mixture and
EtOAc (2 ꢂ 20 mL) was added to extract the aqueous solution.
The combined organic layers were dried, filtered, and evaporated
to give an oil (S)-5 (72 mg, 61% yield over two steps) in 97.6% ee.
4.7. Crystallization and X-ray structure determination of (S)-2
Vapor diffusion of hexanes into a diethyl ether solution of (S)-2
yielded X-ray quality crystals in the form of colorless needles. The
single crystal X-ray diffraction studies were carried out on a
Bruker Kappa APEX-II CCD diffractometer equipped with Cu K
a
radiation. A 0.18 ꢂ 0.08 ꢂ 0.05 mm colorless needle was mounted
on a Cryoloop with Paratone oil. Data were collected in a nitrogen
Compound (S)-5: 1H NMR (CDCl3) d ppm 1.66 (d, J = 7.1, 3H), 2.08
(s, 3H), 6.39 (q, J = 6.9, 1H), 7.02 (t, J = 8.5, 1H), 7.26 (dd, J = 9.0, 4.7,
1H); 13C NMR (CDCl3) d ppm 17.8, 20.7, 69.5, 115.9, 116.1, 121.9
(d, J = 19.0), 129.5 (d, J = 7.3), 137.7, 157.4 (d, J = 248.8), 170.2.
gas stream at 100(2) K using u and - scans. Crystal-to-detector
distance was 45 mm and exposure time was 60 s/frame using a
scan width of 1.0°. The data were integrated using the Bruker
11
SAINT software program and scaled using the SADABS software
11
program. Solution by direct methods (SHELXS
)
produced a com-
plete phasing model consistent with the proposed structure. All
nonhydrogen atoms were refined anisotropically by full-matrix
least-squares (SHELXL-97).12 All hydrogen atoms were placed using
a riding model. Their positions were constrained relative to their
parent atom using the appropriate HFIX command in SHELXL-97.
Absolute configuration was established by anomalous dispersion
effects in diffraction measurements on the crystal, giving a value
of 0.04(2).
4.4.2. (1S)-1-(2,6-Dichloro-3-fluorophenyl)ethanol (S)-2
Lithium hydroxide hydrate (307 g, 7.33 mol, 3 equiv) was added
to a solution of (S)-5 (213 g, 2.44 mol) in methanol (10 L) at 0–5 °C
over 45 min. The mixture was stirred for 5 min and concentrated in
vacuo (maintain water bath temperature at 45 °C). The resulting
solid residue was partitioned between TBME (3 L) and sat. NaHCO3
(aq) (2 L). The organic layer was separated and the milky aqueous
layer was extracted again with MTBE (3 ꢂ 0.5 L). The combined or-
ganic layers were dried over Na2SO4 and concentrated to afford
compound (S)-2 as a white solid (98% ee, 479 g, 2.29 mol, 94%
Acknowledgments
yield). ½a 2D0
ꢃ
¼ þ6:9 ꢄ 1:1 (c 0.87, MeOH). 1H NMR (CDCl3) d ppm
The authors thank Dr. Asayuki Kamatani for many helpful dis-
cussions and Jeff Elleraas for performing chiral SFC analyses.
1.65 (d, J = 6.8 Hz, 3H), 2.94 (d, J = 9.9, 1H), 5.58 (dq, J = 10.0, 6.9,
1H), 6.92–7.08 (m, 1H), 7.26 (dd, J = 9.0, 4.9, 1H); 13C NMR (CDCl3)
d ppm 21.3, 68.4, 115.5, 115.8, 121.4 (d, J = 19.0), 129.6 (d, J = 8.1),
140.5, 157.3 (d, J = 248.8); Anal. Calcd for C8H7Cl2FO: C, 45.96; H,
3.38. Found: C, 46.04; H, 3.32.
References
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4.5. Synthesis of (R)-6 from (R)-2
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Methanesulfonyl chloride (0.06 mL, 0.6 mmol) was added to a
solution of a mixture of (R)-2 and (S)-5 (0.48 mmol) in 4 mL of pyr-
idine under a nitrogen atmosphere. The reaction mixture was stir-
red at room temperature for 3 h, and then evaporated to obtain an
oil. Water (20 mL) was added to the mixture and then ethyl acetate
(2 ꢂ 20 mL) was added to extract the aqueous solution. The organic
layers were combined, dried, filtered, and evaporated to give a
mixture of (R)-6 and (S)-5. This mixture was used in the next step
reaction without further purification. Compound (R)-6: 1H NMR
(CDCl3) d ppm 1.85 (d, J = 6.8, 3H), 2.92 (s, 3H), 6.46 (q, J = 7.0,
1H), 7.12 (dd, J = 8.8, 7.8, 1H), 7.34 (dd, J = 8.8, 4.8, 1H); 13C NMR
(CDCl3) d ppm 19.3, 38.4, 75.2, 117.1, 117.3, 122.3 (d, J = 19.8),
129.1 (d, J = 3.7), 135.6, 157.4 (d, J = 256.9).
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