(
1H, dd, J ) 4.77, 7.98 Hz), 1.35 (1H, t, J ) 5.14 Hz), 1.28 (3H,
organic layer was washed sequentially with 1 N HCl solution,
saturated NaHCO solution, and brine. The solution was dried over
anhydrous magnesium sulfate. After evaporation of the solvent, the
residue was purified by silica gel column chromatography using
13
t, J ) 7.13 Hz); C NMR (100 MHz, CDCl
6
1
3
) δ 170.5, 166.7, 67.0,
2.0, 29.3, 27.9, 20.7, 14.1; HRMS (EI) calcd for C
70.0579, found 170.0571.
1R,5S)-[3.1.0]Bicyclic Lactone (1). (1R,5S)-Isomer was syn-
3
H
8 10
O
4
(
10% ethyl acetate/hexane to afford 2 (520 mg, 79.1%) as a colorless
1
thesized from (S)-epichlorohydrin in an identical yield and enan-
tiomeric purity (59%, >99% ee) and had a retention time of 16.88
oil: H NMR (400 MHz, CDCl
3
) δ 4.39 (1H, t, J ) 8.53 Hz), 3.86
(1H, t, J ) 8.74 Hz), 2.60 (2H, m), 2.13 (1H, m), 1.55 (1H, m),
2
0
13
min in a chiral GC analysis: [R]
D
) +166.39 (c 1.22, EtOH),
1.34 (2H, t, J ) 6.95 Hz), 0.89 (6H, t, J ) 6.21 Hz); C NMR
25
16
25
[R]
D
) +134.81 (c 1.00, CH
Cl
2 2
) (lit. [R]
D
) +145.48 (c 1.22,
(100 MHz, CDCl
HRMS (EI) calcd for C
3
) δ 177.2, 73.5, 42.2, 34.8, 33.8, 26.3, 22.6, 22.4;
EtOH) for >97% ee).
8 14 2
H O 142.0994, found 142.0990.
Representative Nucleophilic Cyclopropane Ring-Opening
With the (S)-â-isobutyl γ-butyrolactone in hand, 3 and 4 were
synthesized by straightforward manner as described in the Sup-
porting Information.
(S)-3-Aminomethyl-5-methylhexanoic Acid (Pregabalin) (5).
To a stirred solution of 4 (748 mg, 3.51 mmol) in THF/MeOH/
Reaction (Table 2). (4R)-Ethyl 4-Benzyl-2-oxotetrahydrofuran-
3
mmol) in anhydrous THF (3.5 mL) and Me S (1.0 mL) was added
phenylmagnesium bromide in THF (1.0 M, 3.53 mL, 3.53 mmol)
2
-carboxylate. To a stirred solution of CuBr-Me S (362 mg, 1.76
2
at -40 °C. The solution was stirred for 20 min, with warming to
H O (6/3/1, 30 mL) was added lithium hydroxide monohydrate (736
mg, 17.5 mmol). The reaction mixture was refluxed for 15 min.
2
-20 °C. (1S,5R)-Bicyclic lactone (200 mg, 1.18 mmol) in THF
(3 mL) was added slowly over 1 h to the reaction mixture via
After the reaction was complete, the organic solvents were removed
under reduced pressure. The aqueous layer was acidified with 6 N
HCl and then extracted with methylene chloride (×3). The
combined organic layer was dried over anhydrous sodium sulfate
and then concentrated under reduced pressure. The residue was
purified by silica gel column chromatography using 5% methanol/
methylene chloride to afford (S)-3-azidomethyl-5-methylhexanoic
acid (590.4 mg, 90.9%) as a colorless oil: 1H NMR (400 MHz,
cannula. After 1.5 h of stirring at room temperature, the reaction
mixture was quenched with saturated ammonium chloride solution.
The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (×2). The combined organic layer was
4
washed with 17% aqueous NH OH solution and brine and then
was dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography using 10% ethyl acetate/hexane to afford
CDCl ) δ 11.24 (1H, br), 3.39 (1H, dd, J ) 12.24, 4.92 Hz), 3.29
3
(
4R)-ethyl 4-benzyl-2-oxotetrahydrofuran-3-carboxylate (224.3 mg,
(1H, dd, J ) 12.24, 6.28 Hz), 2.36 (2H, m), 2.15 (1H, m), 1.60
1
7
7.6%) as a colorless oil: H NMR of the major isomer (400 MHz,
CDCl ) δ 7.29 (2H, t, J ) 7.26 Hz), 7.22 (1H, t, J ) 8.11 Hz),
.13 (2H, d, J ) 8.33 Hz), 4.40 (1H, t, J ) 8.05 Hz), 4.08 (2H,
m), 3.97 (1H, t, J ) 8.57 Hz), 3.28 (2H, m), 2.80 (2H, d, J ) 6.38
(1H, m), 1.24 (1H, m), 1.18 (1H, m), 0.89 (6H, dd, J ) 6.58, 2.20
Hz); 13C NMR (100 MHz, CDCl ) δ1 79.1, 54.8, 41.1, 36.7, 33.0,
3
3
7
25.1, 22.6, 22; HRMS (EI) calcd for C H N O 185.1164, found
8
15
3
2
185.1167.
13
Hz), 1.20 (3H, t, J ) 7.17 Hz); C NMR of the major isomer (100
MHz, CDCl ) δ 171.8, 167.2, 137.0, 128.78, 128.76, 127.0, 71.3,
2.1, 52.00, 4165, 37.8, 13.9; HRMS (EI) calcd for C14
48.1049, found 248.1048.
Synthesis of Pregabalin (Scheme 2). (S)-4-Isobutyldihydro-
A solution of (S)-3-azidomethyl-5-methylhexanoic acid (569.7
mg, 3.08 mmol) and 10% Pd/C (90 mg) in MeOH (30 mL) was
stirred for 3 h under hydrogen balloon. After completion of the
reaction, the reaction mixture was filtered through Celite. The filtrate
was concentrated under reduced pressure to afford 3-aminomethyl-
5-methylhexanoic acid (pregabalin) (5) (485 mg, 99.0%) as a white
solid: mp ) 182-183 °C; [R]20 ) +6.0 (c 0.54, H O); H NMR
3
6
2
16 4
H O
furan-2-one (2). To a stirred suspension of CuI (0.63 g, 3.31 mmol)
in anhydrous THF (20 mL) at -45 °C was added isopropylmag-
nesium chloride in THF (2.0 M, 8.23 mL, 16.46 mmol) dropwise.
The organocuprate formation was typically complete within 1 h.
1
D
2
(400 MHz, CD OD) δ 2.95 (1H, dd, J ) 12.84, 3.54 Hz), 2.82
3
(1H, dd, J ) 12.82, 7.94 Hz), 2.44 (1H, dd, J ) 15.73, 3.37 Hz),
(
(
1R,5S)-Bicyclic lactone 1 (1.12 g, 6.58 mmol) in anhydrous THF
20 mL) was added to the solution via cannula at -45 °C. The
2.25 (1H, dd, J ) 15.70, 8.76 Hz), 2.06 (1H, m), 1.69 (1H, m),
1.23 (2H, m), 0.92 (6H, t, J ) 6.42 Hz); 13C NMR (100 MHz,
resulting solution was stirred for 30 min with warming to -15 °C,
which was quenched with saturated ammonium chloride solution,
then stirred overnight with diethyl ether at room temperature. The
ethereal layer was separated, and the aqueous layer was extracted
with ethyl acetate (×2). The combined organic layers were dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography using 10% ethyl acetate/hexane to afford an 8:1 diaster-
eomeric mixture of lactones (1.34 g, 95% yield): 1H NMR of the
CD OD) δ 180.6, 45.9, 43.4, 43.1, 33.2, 26.2, 23.2, 22.6; HRMS
3
(EI) calcd for C H NO 159.1259, found 159.1259.
8
17
2
Acknowledgment. This work was supported by the Korea
Research Foundation Grant funded by the Korean Government
(MOEHRD, Basic Research Promotion Fund) (KRF-2005-205-
C00043). We thank Dr. Seong Jin Kim (RStech) for the kind
donation of chiral epichlorohydrins. We also thank Prof. Sam
Gellman (University of WisconsinsMadison) for helpful com-
ments on the draft of the manuscript.
crude product (400 MHz, CDCl
Hz), 4.23 (2H, q, J ) 7.11 Hz), 3.85 (1H, t, J ) 8.68 Hz), 3.18
1H, d, J ) 9.39 Hz), 3.03 (1H, m), 1.53 (1H, m), 1.42 (1H, m),
.38 (1H, m), 1.31 (3H, t, J ) 8.96 Hz), 0.90 (6H, t, J ) 6.62 Hz);
3
) δ 4.49 (1H, dd, J ) 8.80, 7.82
(
1
Supporting Information Available: General experimental
procedures, experimental details for the synthesis of compounds
1
3
C NMR of the crude product (100 MHz, CDCl
2.2, 62.1, 52.9, 41.7, 38.3, 26.0, 22.6, 22.4, 14.1; HRMS (EI) calcd
214.1205, found 214.1208.
The diastereomeric mixture of lactones (991 mg, 4.63 mmol)
and LiCl (392 mg, 9.25 mmol) in DMSO/H O (50 mL/1 mL) was
heated for 18 h at 140 °C. After the reaction was complete, water
50 mL) was added to the solution at room temperature. The
solution was extracted with ethyl acetate (×3), and the combined
3
) δ 172.1, 167.8,
1
in entries 1-6 of Table 2, and 3, 4 in Scheme 2, copies of H and
7
13
C NMR spectra of compounds in Table 2 and Scheme 2, chiral
18 4
for C11H O
GC analysis data of (1R,5S)- and (1S,5R)-bicyclic lactones and the
trifluoroacetyl derivative of 4, and CIF files for (1S,5R)-bicyclic
lactone and â-phthalimidylmethyl γ-butyrolactone. This material
is available free of charge via the Internet at http://pubs.acs.org.
2
(
JO0709605
J. Org. Chem, Vol. 72, No. 19, 2007 7393