Enzymatic resolution of stereoisomers of 2-iodocyclohexanol

Article abstract of DOI:10.1007/s11172-012-0305-1

All four optically active stereoisomers of 2-iodocyclohexanol were synthesized. Their enantiomeric purity was determined upon derivatization with Mosher's acid, absolute configuration have been established by chemical correlation.

Full text of DOI:10.1007/s11172-012-0305-1

Russian Chemical Bulletin, International Edition, Vol. 61, No. 11, pp. 2175—2177, November, 2012
2175
Enzymatic resolution of stereoisomers of 2ꢀiodocyclohexanol
O. O. Kolodiazhna, A. O. Kolodiazhna, and O. I. Kolodiazhnyi
Institute of Bioorganic Chemistry and Petrol Chemistry, National Academy of Sciences,
1
ul. Murmanskaya, 02094 Kyiv, Ukraine
Fax: +380 (44) 573 2554. Eꢀmail: olegkol321@rambler.ru
All four optically active stereoisomers of 2ꢀiodocyclohexanol were synthesized. Their
enantiomeric purity was determined upon derivatization with Mosher´s acid, absolute configuꢀ
ration have been established by chemical correlation.
Key words: stereoisomers of 2ꢀiodocyclohexanol, kinetic separation, cyclohexꢀ2ꢀenꢀ1ꢀol,
chirality, lipase from Burkholderia cepacia.
Vicinal 2ꢀsubstituted cycloalkanes find application in
hexanol (1R,2S)/(1S,2R)ꢀ1, which was purified by recrysꢀ
tallization from hexane.
synthesis of various biologically active compounds, e.g.,
1
—4
precursors of prostaglandins and leukotrienes . In the
present work, the access to all possible enantiomerically
pure stereoisomers of one compound of this type, namely,
Enzymatic transesterification with vinyl acetate in the
presence of lipase from Burkholderia cepacia (BCL), which
was immobilized on diatomite, turned an effective tool in
separating two individual enantiomers from racemic cisꢀ1.
The process was interrupted at 50% conversion of the startꢀ
ing racemic alcohol, the conversion rate being monitored
by NMR. As a result, nonꢀracemic alcohol (+)ꢀ(1S,2R)ꢀ1
and acetate (–)ꢀ(1R,2S)ꢀ3 with 98—99% enantiomeric
excess (enantioselectivity factor Е > 100) were obtained.
Hydrolysis of acetate (–)ꢀ(1R,2S)ꢀ3 in phosphate buffer
at рН 7.2 in the presence of BCL gave corresponding optiꢀ
cally active alcohol (–)ꢀ(1R,2S)ꢀ1. Additional lowꢀtemꢀ
perature (–20 С) recrystallization of these alcohols from
hexane gave compounds (+)ꢀ(1S,2R)ꢀ1 and (–)ꢀ(1R,2S)ꢀ1
(
1S,2S)ꢀ, (1R,2R)ꢀ, (1S,2R)ꢀ, and (1R,2S)ꢀ2ꢀiodocycloꢀ
hexanols, is described. transꢀ(1S,2S)ꢀ2ꢀIodocyclohexanol
5
was reported earlier , whereas racemic (1R*,2S*)ꢀ2ꢀiodoꢀ
cyclohexanol was not resolved. Our approach involves cyꢀ
clohexene oxide as a starting compound, which upon
treatment with lithium iodide was converted to racemic
transꢀ2ꢀiodocyclohexanol (1), which comprised (1S,2S)ꢀ
and (1R,2R)ꢀenantiomers (Scheme 1). Resulting racemic
6
transꢀ1 was oxidized according to Swern to afford 2ꢀiodoꢀ
cyclohexanone (2). Ketone 2 was reduced with sodium
borohydride in methanol to obtain racemic cisꢀ2ꢀiodoꢀ
Scheme 1
Reagents and conditions: i. (COCl) , Me SO, Et N, CH Cl ; ii. NaBH , MeOH; iii. AcOCH=CH , lipase from Burkholderia cepacia,
2
2
3
2
2
4
2
conversion 50%; iv. H O, phosphate buffer, lipase from Burkholderia cepacia.
2
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2158—2160, November, 2012.
066ꢀ5285/12/6111ꢀ2175 © 2012 Springer Science+Business Media, Inc.
1

2
176
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012
Kolodiazhna et al.
with de and ee 99%. This result was confirmed by their
Experimental
7
,8
standard derivatization with Mosher´s (R)ꢀacid chlorꢀ
ide. In the 1 F NMR spectrum of derivatized enantiomer
9
1H, 19F, and 13С NMR spectra were registered on a Bruker
1
(
1R,2S)ꢀ1 only one signal at F –72.21 was observed,
170 Avance spectrometer operating at frequences of 500.07 ( H)
19
13
whereas the spectrum of similar racemic esters cisꢀ1 conꢀ
376.29 ( F) and 125.74 ( С) МHz in CDCl3, using hexamethꢀ
1
13
yldisiloxane ( H and C) or fluorobenzene as internal standards
19F). Thin layer chromatography was performed on silica gel
coated aluminium plates (the thickness of the silica gel layer is
.25 mm), visualization was performed by staining with anisalꢀ
tained two signals at  –72.21 and –72.25. Accordingly,
F
(
in the spectrum of the derivative of (1S,2R)ꢀ1, a single
1
signal at F –71.25 was observed. In the Н NMR specꢀ
0
trum of the Mosher´s derivative of alcohol (1R,2S)ꢀ1,
a single signal of the methoxy group was observed at
H 3.60, whereas the spectrum of the racemate contained
two signals at H 3.60 and 3.57.
Similarly to racemate cisꢀ1, acylation of racemic
transꢀcyclohexanol 1 with vinyl acetate in the presence
of BCL under kinetically controlled conditions (50%
conversion of the starting alcohol) gave alcohol
dehyde. Column chromatography was performed on silica gel
Merck 60. Hexane, toluene, chloroform and dichloromethane
were distilled over Р О before use. Lipase from Burkholderia
4
10
cepacia on diatomite was available from the Amano Pharmaceuꢀ
tical company (Japan), Mosher´s (R)ꢀacid chloride ((S)ꢀ(+)ꢀꢀ
methoxyꢀꢀ(trifluoromethyl)phenylacetyl chloride), oxalyl chloꢀ
ride, and dimethylsulfoxide were purchased from SigmaAldrich.
Racemic transꢀ2ꢀiodocyclohexanol 1 was obtained by reaction of
cyclohexene oxide with lithium iodide9
ꢀIodocyclohexanone (2). A solution of dimethylsulfoxide
3.6 mL, 50 mmol) in dichloromethane (10 mL) was added dropꢀ
wise at stirring to cooled to –70 С solution of oxalyl chloride
2 mL, 2.9 g, 23 mmol) in dichloromethane (40 mL). To the
,10
.
(
–)ꢀ(1S,2S)ꢀ1 and acetate (+)ꢀ(1R,2R)ꢀ3, which were
2
separated by column chromatography. Hydrolysis of
acetate (+)ꢀ(1R,2R)ꢀ3 in phosphate buffer at constant
рН 7.2 resulted in second stereoisomer of transꢀcycloꢀ
hexanol (+)ꢀ(1R,2R)ꢀ1. Enantiomeric purity of alcohol
(
(
reaction mixture, racꢀtransꢀ2ꢀiodocyclohexanol (4.5 g, 20 mmol)
(
+)ꢀ(1R,2R)ꢀ1 (ее > 98%) was assessed by NMR analyꢀ
was added. After stirring for 30 min at –60 С, triethylamine
1
(15 mL) was added, and temperature was allowed to reach 20 С
sis of its Mosher´s derivarive. To this, the Н NMR
spectrum of derivatized enantiomer (+)ꢀ(1R,2R)ꢀ1
contained a single signal of the methoxy group at  3.59.
Its F NMR spectrum contained the single signal at
F –71.80 whereas the spectrum of the racemate consisted
of signals at F –71.79 and –71.81. Absolute configuꢀ
ration and optical purity of enantiomer (–)ꢀ(1S,2S)ꢀ1
was confirmed by comparison of its optical rotation anꢀ
gle to the corresponding value of the earlier described
and then the mixture was poured into water (50 mL). The
mixture was extracted with dichloromethane, the organic layer
was dried with sodium sulfate, concentrated, and the residue was
H
1
9
1
distilled in vacuo. Yield 65%, b.p. 110 С (10 Torr). H NMR,

: 1.40 (m, 1 H, CH ); 1.60 (m, 2 H, CH ); 1.90 (m, 1 H, CH );
2 3 2
2.10—2.31 (m, 2 H, CH ); 2.45 (m, 2 H, CH ); 5.21 (m, 1 H, CHI).
2
2
racꢀcisꢀ2ꢀIodocyclohexanol (1R,2S)/(1S,2R)ꢀ1. 2ꢀIodoꢀ
cyclohexanone (2) was reduced with sodium borohydride in
1
methanol, yield 70%, m.p. 52—53 С (from hexane). H NMR,
5
: 1.45 (m, 2 H, CH ); 1.45—1.80 (m, 4 H, CH ); 1.91 (m, 2 H,
compound .
2
3
CH ); 2.27 (m, 1 H, OH); 3.16 (m, 1 H, CHI); 4.71 (s, 1 H, CHOH).
For the more reliable determination of the absolute
configuration, enantiomerically pure 1ꢀacetoxyꢀ2ꢀiodoꢀ
cyclohexane (1R,2S)ꢀ3 was dehydroiodinated to give opꢀ
tically active cyclohexꢀ2ꢀenyl acetate (R)ꢀ4 (Scheme 2).
This acetate was hydrolysed to give optically active cycloꢀ
hexꢀ2ꢀenꢀ1ꢀol (+)ꢀ(R)ꢀ5, whose absolute configuration
was determined by comparison of its rotation angle to that
2
13
С NMR, : 21.93 (s, CH ); 24.48 (s, CH ); 32.23 (s, CH );
2
3
2
3
4.12 (s, CH ); 46.51 (s, CHI), 71.01 (s, CHOH). Found (%):
2
C, 31.38; H, 4.50. C H11IO. Calculated (%): C, 31.88; H, 4.90.
6
(1S,2R)ꢀ2ꢀIodocyclohexanol (1S,2R)ꢀ1. Racemate (1R,2S)/
(1S,2R)ꢀ1 (2.25 g, 10 mmol) was acylated with the excess of
vinyl acetate (4 mL) in the presence of BCL (100 mg) upon
stirring for 16 h at 24 С. The solvent was evaporated and the
residue was subjected to flash chromatography (silica gel, eluꢀ
tion with hexane—chloroform, 1 : 1; then chloroform). The first
fraction contained acetate (1R,2S)ꢀ3 and the second fraction
contained unreacted alcohol (1S,2R)ꢀ1, which was recrystalꢀ
8
of the earlier described compound . Based on this, the
absolute configuration of 2ꢀiodocyclohexanols (1R,2S)ꢀ1
and (1S,2R)ꢀ1 was assessed by the chemical correlaꢀ
tion method.
2
0
lized from hexane. Yield 48%, m.p. 52 С, []
–31.4 (c 1,
D
1
CHCl ). H NMR, : 1.45 (m, 2 H, CH ); 1.60—1.80 (m, 4 H,
3
2
CH ); 1.80—1.91 (m, 2 H, CH ); 2.28 (s, 1 H OH); 3.17 (s, 1 H,
Scheme 2
2
2
13
CHI); 4.72 (s, 1 H, CHOH). С NMR, : 21.93 (s, C H ); 24.48
2
(
s, CH ); 32.23 (s, CH ); 34.12 (s, CH ); 46.51 (s, CHI); 71.01
2
2
2
(
s, CHOH).
(
1R,2S)ꢀ1ꢀAcetoxyꢀ2ꢀiodocyclohexane (1R,2S)ꢀ3. Yield 50%,
b.p. 115 C (10 Torr), []D2 +62.5 (c 3, CHCl ). H NMR,
0
1
3

: 1.40—1.65 (m, 4 H, CH ); 1.85 (m, 1 H, CH ); 2.00—2.10
2
2
(
m, 4 H, CH ); 2.15 (s, 3 H, CH ); 2.45 (m, 1 H, OH); 4.05 (m, 1 H,
2 3
13
CHI); 4.95 (m, 1 H, CHOAc). С NMR, : 21.30 (s, CH );
3
2
2.40 (s, CH ); 23.77 (s, CH ); 29.30 (s, CH ); 34.44 (s, CH );
2 2 2 2
Reagents and conditions: i. DBU, 70 C, 12 h; ii. 1 M NaOH,
MeOH; 20 C, 18 h.
36.04 (s, CHI); 72.95 (s, CHOH); 170.16 (s, C=O). Found (%):
C, 35.68; H, 4.71. C H IO . Calculated (%): C, 35.84; H, 4.89.
8
13
2

Stereoisomers of 2ꢀiodocyclohexanol
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2177
(
1R,2S)ꢀ2ꢀIodocyclohexanol (1R,2S)ꢀ1. Acetate (1R,2S)ꢀ3
10 mmol) was hydrolyzed in the presence of BCL (100 mg) in
.05 М phosphate buffer (15 mL, 6.8 g of KH PO in 1 L of
then concentrated and the residue was distilled under reꢀ
2
0
(
0
duced pressure. Yield 50%, m.p. 60 С (10 Torr); []
+180
D
1
(с 3, CHCl ) (cf. Ref. 11). H NMR, : 2.02 (s, 3 H, CH );
2
4
3
3
distilled water), рН 7.2, the progress of the reaction was moniꢀ
tored by TLC, and the pH was maintained at 7.2 by addition of
2.29—1.63 (m, 6 H, CH ); 5.73—5.67 (m, 1 H, OH); 5.99—5.92
(m, 1 H, CH=); 5.28—5.23 (m, 1 H, CH=).
2
2
0
1
М NaOH. Yield 60%, m.p. 50 С (from hexane), []
+31.14
(1R)ꢀCyclohexꢀ2ꢀenꢀ1ꢀol (R)ꢀ5. To a solution of acetate
(R)ꢀ4 (0.57 g, 4.0 mmol) in methanol (1 mL), 1 М NaOH (8 mL)
was added. The mixture was stirred at 20 С for 18 h, and the
product was extracted with dichloromethane. The extract was
dried, the solvent was removed and the residue was distilled
under reduced pressure. Yield 0.35 g (85%), colorless oil, b.p.
D
1
(
c 1, CHCl ). H NMR, : 1.46 (m, 2 H, CH ); 1.60—1.80
3
2
(
3
m, 4 H, CH ); 1.80—1.90 (m, 2 H, CH ); 2.27 (m, 1 H, OH);
2 2
.16 (m, 1 H, CHI); 4.72 (s, 1 H, CHOH). С NMR, : 21.93
13
(
(
s, CH ); 24.48 (s, CH ); 32.23 (s, CH ); 34.12 (s, CH ); 46.51
s, CHI); 71.01 (s, CHOH). Found (%): C, 31.77; H, 4.65.
2 2 2 2
96—97 С (75 Torr); []D20 +123.5 (c 2, CHCl ). H NMR,
1
C H11IO. Calculated (%): C, 31.88; H, 4.90.
6
3
(
1S,2S)ꢀ2ꢀIodocyclohexanol (1S,2S)ꢀ1 was obtained simiꢀ
: 2.11—1.39 (m, 7 H); 4.29—4.03 (m, 1 H, CHOH); 5.97—5.58
larly to (1S,2R)ꢀ1 by enzymatic acylation of the racemic transꢀ1.
Yield 49%, m.p. 46 С (from hexane), []
cf. Refs. 5, 11: []D +33.1 (c 2.4, CHCl )). H NMR, : 1.25—1.49
m, 3 H, CH); 1.60 (m, 1 H, CH); 1.85 (m, 1 H, CH); 2.05—2.20
m, 2 H, CH ); 2.35 (s, 1 H, CH); 2.50 (d, 1 H, OH, J = 5.0 Hz);
.65 (м, 1 H, CHI); 4.10 (m, 1 H, CHOH). С NMR, : 24.50
s, CH ); 24.60 (s, CH ); 34.01 (s, CH ); 34.20 (s, CH ); 38.60
(m, 2 H, CH=).9
2
0
+34 (с 5, CHCl3)
D
1
20
This work was financially supported by Russian Founꢀ
dation for Basic Research and the State Fund for Fundaꢀ
mental Research of Ukraine (joint research project
F40.3/034).
(
(
(
3
(
(
3
2
13
2 2 2 2
s, CHI); 75.81 (s, CHOH).
1R,2R)ꢀ1ꢀAcetoxyꢀ2ꢀiodocyclohexane (1R,2R)ꢀ3 was obꢀ
tained by acylation of racꢀtransꢀ1 similarly to (1R,2S)ꢀ3. Yield
References
(
2
0
5
[
0%, b.p. 115 С (10 Torr), []
–60.0 (c 3, CHCl ) (cf. Ref. 11:
1. S. Busato, O. Tinembart, Z. Zhang, R. Scheffold, Tetraꢀ
hedron, 1990, 46, 3155.
D
3
]D2 –47.1 (c 2.15, CHCl )). H NMR, : 1.40—1.65 (m, 4 H,
0
1
3
CH ); 1.85 (m, 1 H, CH); 2.00—2.10 (m, 4 H, CH ); 2.15 (s, 3 H,
2. T. Sate, Y. Gotoh, M. Watanabe, T. Fujisawa, Chem. Lett.,
1983, 1533.
3. R. Hayes, T. W. Wallace, Tetrahedron Lett., 1990, 31, 3355.
4. J. S. Sabol, R. J. Cregge, Tetrahedon Lett., 1989, 30, 3377.
5. C. Kassai, E. Fogassi, D. Kozma, Synth. Commun.,
2006, 1015.
2
2
CH ); 2.45 (m, 1 H, OH); 4.05 (m, 1 H, CHI); 4.95 (m, 1 H,
3
13
CHOH). С NMR, : 21.23 (s, CH ); 23.56 (s, CH ); 27.06
2
2
(
s, CH ); 31.57 (s, CH ); 31.78 (s, CHI); 37.84 (s, CH ); 77.00
2 2 2
(
s, CHO); 169.60 (s, C=O). Found (%): C, 35.60; H, 4.85.
C H IO . Calculated (%): C, 35.84; H, 4.89.
8
13
2
(1R,2R)ꢀ2ꢀIodocyclohexanol (1R,2R)ꢀ1 was obtained by hyꢀ
6. T. T. Tidwell, Synthesis, 1990, 857.
drolysis of (1R,2R)ꢀ3, yield 48%, m.p. 46 С (from hexane),
7. J. A. Dale, H. S. Mosher, J. Am. Chem. Soc., 1973, 95, 512.
8. D. Parker, Chem. Rev., 1991, 91, 1441.
9. M. Asami, Chem. Lett., 1984, 829.
10. H. Kotsuki, N. Shimanouchi, Tetrahedron Lett., 1996,
37, 1845.
2
0
1
[
]D –34 (c 4, CHCl ). H NMR, : 1.25—1.49 (m, 3 H, CH);
3
1
.60 (m, 1 H, CH); 1.85 (m, 1 H, CH); 2.05—2.20 (m, 2 H,
CH); 2.35 (s, 1 H, CH); 2.50 (d, 1 H, OH, J = 5.0 Hz); 3.65
m, 1 H, CHI); 4.10 (m, 1 H, CHOH). 13С NMR, : 24.51 (s, CH );
(
2
2
7
4.60 (s, CH ); 34.00 (s, CH ); 34.21 (s, CH ); 38.60 (s, CHI);
5.81 (s, CHOH).
11. T. Fukazawa, T. Hashimoto, Tetrahedron: Asymmetry, 1993,
4, 2323.
2
2
2
(1R)ꢀCyclohexꢀ2ꢀenyl acetate (R)ꢀ4. A solution of (+)ꢀ(1R,2S)ꢀ
1
ꢀacetoxyꢀ2ꢀiodocyclohexane (2 g, 7.5 mmol) (1R,2S)ꢀ3 in DBU
(
5 ml) was heated at 70 С for 12 h, diluted with diethyl ether,
Received March 13, 2012;
filtered, washed with diluted hydrochloric acid, NaHCO (aq.),
in revised form October 31, 2012
3