Asymmetric Transformation of 1,3-Cycloalkanediols
HCl (aq), and the methanol was concentrated in vacuo. The resulting
water phases were saturated with NaCl (s) and extracted with EtOAc
(4 × 250 mL). The combined organic phases were dried over
NaSO4 and concentrated in vacuo, and the residue was purified by
flash chromatography (CH2Cl2 to EtOAc/acetone 3:1), affording
the cis-diol (1.29 g, 91%) as white crystals.10
p-Chlorophenyl butyrate (4c): isolated as pale yellow oil; yield
0.873 g (88%); H NMR (CDCl3) δ 7.33 (dm, J ) 8.8, 2H), 7.03
(dm, J ) 8.8, 2H), 2.53 (t, J ) 7.4, 2H), 1.78 (app. hextet, J )
7.4, 2H), 1.04 (t, J ) 7.4, 3H); 13C NMR (CDCl3) δ 171.9, 149.2,
131.0, 129.4, 122.9, 36.1, 18.4, 13.6.
1
p-Chlorophenyl hexanoate (4d): isolated as pale yellow oil;
yield 0.655 g (58%); 1H NMR (CDCl3) δ 7.33 (dm, J ) 8.9, 2H),
7.02 (dm, J ) 8.9, 2H), 2.54 (t, J ) 7.4, 2H), 1.82-1.69 (m, 2H),
1.46-1.30 (m, 4H), 0.98-0.86 (m, 3H); 13C NMR (CDCl3) δ
172.0, 149.2, 131.0, 129.4, 122.9, 34.3, 31.2, 24.5, 22.3, 13.9.
Gereral Procedure for Preparation of Diesters of 1,3-
Cyclohexandiol. To a solution of the cis- or trans-diol 1 (69 mg,
0.6 mmol) and DMAP (1.4 mg, 0.01 mmol) in dichloromethane (1
mL) was added the desired acid chloride (3.0 mmol) dropwise at
0 °C. The reaction was stirred at room temperature overnight. The
solution was evaporated and purified by flash chromatography
(pentane/CH2Cl2). The yields of the diester were >90%.
cis-Diacetate cis-3a:16 1H NMR (CDCl3) δ 4.80-4.68 (m, 2H),
2.29-2.19 (m, 1H), 2.02 (s, 6H), 2.00-1.79 (m, 3H), 1.52-1.18
(m, 4H); 13C NMR (CDCl3) δ 170.2, 70.5, 37.1, 30.7, 21.2, 20.1.
General Procedure for Preparation of Racemic cis-3-Acetoxy-
1-cyclohexanol (cis-2a). To a solution of the cis-diol 1 (58 mg,
0.5 mmol) in THF (5.5 mL) and pyridine (79 mg, 1.0 mmol) at 0
°C was added acetyl chloride (41 mg, 0.525 mmol) dropwise over
10 min. The reaction was stirred at 0 °C for 2 h and at room
temperature for an additional 2 h. The solvent was concentrated in
vacuo, and 1 M HCl (5.5 mL) and CH2Cl2 (10 mL) were added.
The phases were separated, and the aqueous layer was collected
and extracted with CH2Cl2 (5 × 20 mL). The combined organic
phases were washed with saturated aq Na2CO3 (10 mL), water (10
mL) and brine (10 mL) and dried over MgSO4. The solvent was
General Procedure for Desymmetrization of cis-1 Using
Enzymatic Acylation (Table 1). In a typical experiment, p-ClC6H4-
OAc 4a (51 mg, 0.30 mmol) in toluene (1 mL) was degassed with
argon for 1 min and added to a Schlenk tube containing cis-1 (23.2
mg, 0.2 mmol) and CALB (6 mg). The mixture was stirred at room
temperature and monitored by TLC. The mixture was filtered
through a silica pad to remove the enzyme, and the silica pad was
washed with Et2O (3 × 3 mL). The filtrate was collected, the solvent
was concentrated in vacuo, and the residue was analyzed by GC
1
and H NMR.
(1S,3R)-3-Acetoxy-1-cyclohexanol ((R,S)-2a) was prepared ac-
cording to the procedure for the desymmetrization of cis-1, starting
from p-ClC6H4OAc 4a (510 mg, 3.0 mmol), cis-1a (232 mg, 2.0
mmol), and CALB (120 mg) in toluene (6 mL). After filtration,
the silica pad was washed with Et2O (3 × 30 mL), the combined
solvent was concentrated in vacuo, and the residue was purified
by flash chromatography (pentane/EtOAc 1:4 to EtOAc). (R,S)-2a
(263 mg, 83%) was obtained as a colorless oil (>99% ee): 1H
NMR (CDCl3) δ 4.79-4.68 (m, 1H), 3.75-3.66 (m, 1H), 2.27-
2.16 (m, 1H), 2.04 (s, 3H), 1.92-1.72 (m, 3H), 1.44-1.18 (m,
4H); 13C NMR (CDCl3) δ 170.6, 71.2, 68.7, 40.8, 34.5, 30.9, 21.6,
20.1.
General Procedure for Racemization of Monoesters (R,S)-
2a and (R,S)-2b. In a typical experiment, the monoester (0.2 mmol)
and CALB (12 mg) in toluene (1 mL) was stirred in a Schlenk
tube under argon atmosphere at 70 °C. The racemization was
monitored by GC. After standard workup, the mixture was filtered
through a silica pad to remove the enzyme, the silica pad was
washed with acetone (2 mL), and the filtrate was analyzed by GC.
(1S,3R)-3-(2,2,2-Trideuterioacetoxy)-1-cyclohexanol ((R,S)-2a-
d3). p-ClC6H4OAc-d3 (4a-d3) (582 mg, 3.3 mmol) in toluene (6.8
mL) was degassed with argon for 1 min and added to a Schlenk
tube containing cis-1 (260 mg, 2.2 mmol) and CALB (135 mg).
The mixture was stirred at room temperature, monitored by NMR,
and stirred for 9 h. The mixture was filtered through a silica pad to
remove the enzyme, the enzyme was washed with Et2O (3 × 30
mL), the solvent was concentrated in vacuo, and the residue was
purified by flash chromatography (pentane/EtOAc 1:4 to EtOAc)
affording (R,S)-2a-d3 (153 mg, 43%) as a colorless oil (>99% ee):
1H NMR (CDCl3) δ 4.81-4.69 (m, 1H), 3.76-3.64 (m, 1H), 2.27-
2.18 (m, 1H), 2.04-2.00 (m, 0.3H), 1.94-1.78 (m, 3H), 1.46-
1.20 (m, 4H); 13C NMR (CDCl3) δ 170.4, 70.9, 68.4, 40.6, 34.3,
30.6, 21.1(m) 19.9.
concentrated in vacuo and the residue was purified by flash
,
chromatography (CH2Cl2 to (CH2Cl2/acetone 2:1) affording (rac)-
cis-2a (31 mg, 39%) as a pale yellow oil:17 1H NMR (CDCl3) δ
4.79-4.68 (m, 1H), 3.75-3.66 (m, 1H), 2.27-2.16 (m, 1H), 2.04
(s, 3H), 1.92-1.72 (m, 3H), 1.44-1.18 (m, 4H); 13C NMR (CDCl3)
δ 170.6, 71.2, 68.7, 40.8, 34.5, 30.9, 21.6, 20.1.
General Procedure for DYKAT of cis-1. In a typical experi-
ment, p-chlorophenyl ester 4 (0.6 mmol) in toluene (1 mL) was
degassed with argon for 1 min and added to a Schlenk tube
containing cis-1 (23.2 mg, 0.2 mmol), CALB (6.5 mg), and the
ruthenium catalyst 5 (10.8 mg, 5 mol %). The mixture was stirred
at room temperature for 3 h and then for 69 or 93 h at 70 °C. After
24 h, 2,4-dimethyl-3-pentanol was added as a hydrogen source (0.5
equiv/hydroxyl group). The mixture was filtered through a Celite
pad to remove the enzyme. The solid was washed with acetone (3
× 2 mL), solvent was concentrated in vacuo, and the residue was
1
analyzed by GC and H NMR.
General Procedure for DYKAT of 1. In a typical experiment,
p-ClC6H4OAc 4a (102 mg, 0.6 mmol) in toluene (1 mL) was
degassed with argon for 1 min and added to a Schlenk tube
containing cis/trans-1 (23.2 mg, 0.2 mmol), enzyme (6.5 mg), and
the ruthenium catalyst 5 (10.8 mg, 5 mol %). The mixture was
stirred at 70 °C for 24 h, after which time 2,4-dimethyl-3-pentanol
was added as a hydrogen source (0.5 equiv/hydroxyl group). The
mixture was stirred for additionally 48 h and worked up by filtering
through a Celite pad to remove the enzyme. The solid was washed
with acetone (3 × 2 mL), solvent was concentrated in vacuo, and
General Procedure for 4-Chlorophenyl Acyl Donors (4). In
a typical experiment, the appropriate acid chloride (5.5 mmol) was
added dropwise to a solution of 4-chlorophenol (0.643 g, 5.0 mmol),
Et3N (1.52 g, 15 mmol), and DMAP (12 mg, 0.1 mmol) in CH2Cl2
(10 mL). The reaction mixture was stirred at room temperature
overnight. The solution was washed with 1 M HCl (3 × 8 mL),
and the combined aqueous phases were reextracted with ether (3
× 8 mL). The combined organic phases were washed with saturated
Na2CO3 (aq, 5 mL) and brine (4 mL) and dried over MgSO4. The
solvent was concentrated in vacuo, and the crude mixture was
purified on silica (pentane/EtOAc gradient).
1
the residue was analyzed by GC and H NMR.
General Procedure for DYKAT of 1 or (R,S)-2a. A solution
of KO-t-Bu (0.5 in THF; 48 µL, 12 mol %) was added to a 10 mL
Schlenk tube. The THF was carefully removed under vacuum, and
the flask was filled with argon. CALB (4 mg), Na2CO3 (8 mg, 0.08
mmol), and Ru catalyst 7 (12.8 mg, 5 mol % for each hydroxyl
group) were added. The Schlenk flask was evacuated and filled
with argon. Toluene (1 mL) was added, the mixture was stirred
for 6 min, and cis/trans-cyclohexanediol (23 mg, 0.2 mmol) was
added quickly. After an additional 4 min, isopropenyl acetate (65
p-Chlorophenyl propionate (4b): isolated as colorless oil; yield
1
0.698 g (76%); H NMR (CDCl3) δ 7.34 (dm, J ) 9.1, 2H), 7.03
(dm, J ) 9.1, 2H), 2.59 (q, J ) 7.4, 2H), 1.26 (t, J ) 7.4, 3H); 13
NMR (CDCl3) δ 172.7, 149.2, 131.0, 129.4, 122.9, 27.7, 9.0.
C
(16) Hirata, T.; Izumi, S.; Aoki, M.; Gotoh, S.; Utsumi, R Chirality 1997,
9, 250.
(17) Fleming, I. M.; Henning, R.; Parker, D. C.; Plaut H. E.; Sanderson,
P. E. J. J. Chem. Soc., Perkin Trans. 1 1995, 4, 317.
J. Org. Chem, Vol. 71, No. 17, 2006 6315