Isomer and enantiomer separation of 2- and 4-alkyl-cyclohexanols by stereoselective complex formation with O,O′-dibenzoyl-(2R,3R)-tartaric acid

Article abstract of DOI:10.1081/SCC-100103991

Stereoisomeric mixtures of 2- and 4-alkyl-cyclohexanols form complex with O,O′-dibenzoyl-(2R,3R)-tartaric acid. The diastereoisomer complex formation can be used for isomer and enatiomer separation as it is trans- and enantioselective in the case of 2-alkyl-cyclohexanols and trans-selective in the case of 4-alkyl-cyclohexanols.

Full text of DOI:10.1081/SCC-100103991

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ISOMER AND ENANTIOMER
SEPARATION OF 2- AND 4-
ALKYL-CYCLOHEXANOLS BY
STEREOSELECTIVE COMPLEX
FORMATION WITH O,O′-
DIBENZOYL- (2R,3R)-TARTARIC
ACID
Csaba Kassai a , József Bálint a , Zoltán Juvancz ,
Elemér Fogassy a & Dávid Kozma b
a Department of Organic Chemical Technology,
Budapest University of Technology and Economics,
Budapest, POB 91, H-1521, Hungary
b Department of Organic Chemical Technology,
Budapest University of Technology and Economics,
Budapest, POB 91, H-1521, Hungary
Published online: 09 Nov 2006.
To cite this article: Csaba Kassai , Jzsef Blint , Zoltn Juvancz , Elemr Fogassy
& Dvid Kozma (2001) ISOMER AND ENANTIOMER SEPARATION OF 2- AND 4-ALKYL-
CYCLOHEXANOLS BY STEREOSELECTIVE COMPLEX FORMATION WITH O,O′-
DIBENZOYL- (2R,3R)-TARTARIC ACID, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 31:11, 1715-1719,
DOI: 10.1081/SCC-100103991
To link to this article: http://dx.doi.org/10.1081/SCC-100103991

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SYNTHETIC COMMUNICATIONS, 31(11), 1715–1719 (2001)
ISOMER AND ENANTIOMER SEPARATION
OF 2- AND 4-ALKYL-CYCLOHEXANOLS BY
STEREOSELECTIVE COMPLEX
FORMATION WITH O,O0-DIBENZOYL-
(2R,3R)-TARTARIC ACID
Csaba Kassai,1 Jozsef Balint,1 Zoltan Juvancz,2
Elemer Fogassy,1 and David Kozma1,
*
1Department of Organic Chemical Technology,
Budapest University of Technology and Economics,
Budapest POB 91, H-1521, Hungary
2VITUKI Plc., H-1095, Budapest, Kvassay J. u. 1,
Hungary
ABSTRACT
Stereoisomeric mixtures of 2- and 4-alkyl-cyclohexanols form
complex with O,O0-dibenzoyl-(2R,3R)-tartaric acid. The dia-
stereoisomer complex formation can be used for isomer and
enatiomer separation as it is trans- and enantioselective in the
case of 2-alkyl-cyclohexanols and trans-selective in the case of
4-alkyl-cyclohexanols.
O,O0-dibenzoyl-tartaric acid (DBTA) is one of the most frequently
applied resolving agents via diastereoisomeric salt formation. Recently
we have found that DBTA can act as a complex forming resolving
* Corresponding author. Fax: (361)-4633648; E-mail: david@oct.bme.hu
1715
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1716
KASSAI ET AL.
agent too.1,2 We needed to prepare trans-isomers of different 2- and
4-alkyl-cyclohexanols for a series of pharmacologically active compounds.
The preparation leads to a mixture of all stereoisomers, from which the cis-
and trans-isomers are usually separated by chromatographic methods or by
crystallisation of the ester derivatives of the corresponding alkyl-cyclo-
hexanol.3–8 We assumed that DBTA can act not only as a resolving agent,
but should be able to separate sterical isomers too, by complex formation.
Preparative scale complex formation experiments were performed by sus-
pending DBTA in the hexaneous solution of the 2- and 4-alkyl-cyclo-
hexanols. The ratio of the stereoisomers in the crystalline diastereoisomeric
complex and in the mother liquor were always different from the initial
composition (Table 1).
On reacting 1–3 cis-trans stereoisomeric mixtures with DBTA we
obtained a mixture from the mother liquor, which contained the cis-isomers
in higher ratio than in the initial mixture. From the diastereoisomeric com-
plex crystal the trans-4-alkyl-cyclohexanols can be obtained in higher ratio.
Table 1. Stereo-
and Enantioselectivity of ths Complex Formation of Alkyl-
Cyclohexanols with DBTA
Alcohol/
DBTA
Molar
Ratio
Alcohol
from
Mother
Liquor
Initial
Alcohol
Composition
Alcohol
from
Complex
No.
1
Compound
2:1
cis-1 33%
trans-1 67%
cis-1 25%
trans-1 75%
cis-1 55%
trans-1 45%
2
3
4
2:1
cis-2 34%
trans-2 66%
cis-2 7%
trans-2 93%
cis-2 73%
trans-2 27%
2:1
4:1
cis-3 9%
trans-3 91%
cis-3 8%
trans-3 92%
cis-3 15%
trans-3 85%
IS,2S-4 30%
IR,2R-4 30%
IS,2R-4 20%
IR,2S-4 20%
IS,2S-4 54% IS,2S-4 23%
IS,2S-4 22% IR,2R-4 32%
IS,2R-4 11%
IR,2S-4 13%
IS,2R-4 23%
IR,2S-4 22%

STEREOSELECTIVE COMPLEX FORMATION
1717
The stereoselectivity of the separation increases by increasing the alkyl
groups.
The complex formation is trans selective and enantiospecific for com-
pounds 4 and 5, the complex contains the cis stereoisomer practically in
equal ratio. Similarly to 4-alkyl-cyclohexanols, the larger is the alkyl group
in 2-alkyl-cyclohexanols, the higher is the enantiospecificity. DBTA does not
form diastereoisomeric complex with 2-tert-butyl-cyclohexanol, probably
alkyl groups larger than isopropyl in the 2 position do not fit in the dia-
stereoisomeric crystal structure.
Our results show that DBTA can be used for isomer and enatiomer
separation of 2- and 4-alkyl-cyclohexanols by diastereoisomeric complex
formation. The procedure has very good chances for practical application,
because the DBTA is not expensive and the separation method is simple.
EXPERIMENTAL
A HP 5890/II instrument was used for GC analysis with FID detection
applying 1:100 split ratio. Analysis were made on a 12 m ꢀ 0.100 mm FSOT
column coated with ChirasilDex (permethylated b-cyclodextrin containing
silicone polymer). The achiral separations were confirmed on a 25 m ꢀ
0.25 mm i.d. FSOT column coated with OV-1701, because the achiral
column showed better efficiency. Sample 4 was analysed in acetyl derivative
form, the samples 1–3 and 5 in free form. DBTA monohydrate was pur-
chased from Elso Magyar Vegyi Industria Co., 1 from Fluka, 2, 3, 5 from
Aldrich, 4 was prepared by us.
I.) 5.00 g (43.8 mmol) of 1 was dissolved in 40 ml hexane and DBTA
monohydrate (8.24 g, 21.9 mmol) was suspended in this solution.
The suspension was allowed to stay for 4 days, then the solid
phase was filtered off and dried in air (11.75 g). The mother
liquor was evaporated and the residue (1.28 g) was distilled
in vacuo (72–74ꢀC/15 mm), we got 0.62 g (5.4 mmol) of 1. The
solid phase was dissolved in H2O-Na2CO3 solution (50 ml H2O,
2.64 g Na2CO3), extracted with 4 Â 10 ml of CH2Cl2. The organic
phase was evaporated, the residue (5.90 g) was distilled, we got
3.09 g (27 mmol) of 1.
II.) 2.00 g (15.6 mmol) of 2 was dissolved in 20 ml hexane and DBTA
monohydrate (2.94 g, 7.8 mmol) was suspended in this solution.
The suspension was allowed to stay for 7 days, then the solid
phase was filtered off and dried in air (3.61 g). The mother liquor

1718
KASSAI ET AL.
was evaporated and the residue (0.75 g) was distilled in vacuo
(90ꢀC/15 mm), we got 0.25 g (1.9 mmol) of 2. The solid phase
wad dissolved in H2O-Na2CO3 solution (30 ml H2O, 0.84 g
Na2CO3), extracted with 4 Â 10 ml of CH2Cl2. The organic
phase was evaporated the residue (1.44 g) was distilled, we got
0.95 g (7.4 mmol) of 2.
III.) 4.00 g (25.6 mmol) of 3 was dissolved in 60 ml hexane and DBTA
monohydrate (4.82 g, 12.8 mmol) was suspended in this solution.
The suspension was allowed to stay for 7 days, then the solid
phase was filtered off and dried in air (7.78 g). The mother liquor
was evaporated and the residue (1.22 g) was distilled in vacuo
(106–108ꢀC/15 mm), we got 0.62 g (3.9 mmol) of 3. The solid
phase was dissolved in H2O-Na2CO3 solution (100 ml H2O,
1.36 g Na2CO3), extracted with 3 Â 50 ml of CH2Cl2. The organic
phase was evaporated the residue (3.22 g) was distilled, we got
2.49 g (27 mmol) of 3.
IV.) 100 g (0.891 mol) racemic 2-methyl-cyclohexanone (purchased
from Merck) was dissolved in 200 ml MeOHand NaBH
4
33.72 g (0.891 mol) was added portionwise. The solution was
stirred 20 min and boiled. The MeOHwas evaporated in vacuo.
The suspension was dissolved in a solution of 150 ml water and
2 ml 37% HCl. The solution was extracted with 4 Â 100 ml of
CH2Cl2, the organic phase was evaporated, the residue was dis-
tilled (bp. 188–120ꢀC/760 mm) which yielded 82.2 g (0.718 mol)
2-methyl-cyclohexanol (4) mixture of cis and trans isomers.
8.00 g (70.0 mmol) of 4 was dissolved in 60 ml hexane and
DBTA monohydrate (6.59 g, 17.5 mmol) was suspended in this
solution. The suspension was allowed to stay for 7 days, then the
solid phase was filtered off and dried in air (6.29 g). The mother
liquor was evaporated and the residue was distilled, we got 5.12 g
(44.5 mmol) of 4. The solid phase was dissolved in H2O-Na2CO3
solution (80 ml H2O, 2.00 g Na2CO3), extracted with 4 Â 10 ml of
CH2Cl2. The organic phase was evaporated the residue was dis-
tilled, we got 2.49 g (21.8 mmol) or 4.
V.) 8.00 g (15.6 mmol) of 5 was dissolved in 20 ml hexane and DBTA
monohydrate (1.47 g, 3.9 mmol) was suspended in this solution.
The suspension was allowed to stay for 7 days, then the solid
phase was filtered off and dried in air (0.87 g). The mother liquor
was evaporated and the residue was distilled in vacuo (78–79ꢀC/
15 mm), we got 1.33 g (10.3 mmol) of 5. The solid phase
was dissolved in H2O-Na2CO3 solution (20 ml H2O, 0.41 g

STEREOSELECTIVE COMPLEX FORMATION
1719
Na2CO3), extracted with 3 Â 10 ml of CH2Cl2. The organic phase
was evaporated the residue was distilled, we got 0.43 g
(3.3 mmol) of 5.
ACKNOWLEDGMENTS
The authors are grateful of financial support to OTKA Foundation
(grant numbers: T29251 (E.F.), D32705 (J.B), T31711 (D.K.)), C.K. for the
J. Varga Foundation.
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Accepted in the Netherlands August 21, 2000