Enzymatic resolution of racemic secondary cyclic allylic alcohols

Article abstract of DOI:10.1016/j.tetasy.2010.02.031

The resolutions of five racemic cyclic alcohols: 6,6-dimethylcyclohex-2-en-1-ol (±)-5, 4,4-dimethylcyclohex-2-en-1-ol (±)-7, 5,5-dimethylcyclohex-2-en-1-ol (±)-11 and isomeric trans-(±)-13 and cis-piperitols (±)-14 are presented. They were resolved by enzymatic esterification with vinyl esters or by enzymatic hydrolysis of their racemic esters in phosphate buffer. The following lipases were used as biocatalysts: Novozyme 435 (Candida antarctica), Amano PS (Burkholderia cepacia) and lipase from Candida cylindracea. All isomers of alcohols were obtained with at least 96% ee.

Full text of DOI:10.1016/j.tetasy.2010.02.031

Tetrahedron: Asymmetry 21 (2010) 670–678
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enzymatic resolution of racemic secondary cyclic allylic alcohols
a
a
a
b
´
´
Katarzyna Winska , Aleksandra Grudniewska , Anna Chojnacka , Agata Białonska ,
a,
*
´
Czesław Wawrzenczyk
a Department of Chemistry, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland
b Faculty of Chemistry, University of Wrocław, F. Joliot-Curie 14, 50-383 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The resolutions of five racemic cyclic alcohols: 6,6-dimethylcyclohex-2-en-1-ol ( )-5, 4,4-dimethylcyclo-
hex-2-en-1-ol ( )-7, 5,5-dimethylcyclohex-2-en-1-ol ( )-11 and isomeric trans-( )-13 and cis-piperitols
( )-14 are presented. They were resolved by enzymatic esterification with vinyl esters or by enzymatic
hydrolysis of their racemic esters in phosphate buffer. The following lipases were used as biocatalysts:
Novozyme 435 (Candida antarctica), Amano PS (Burkholderia cepacia) and lipase from Candida cylindracea.
All isomers of alcohols were obtained with at least 96% ee.
Received 2 February 2010
Accepted 31 March 2010
Available online 11 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The modern approach to the studies on chiral bioactive com-
pounds imposes the synthesis and bioassay of all possible stereoiso-
mers. Two general synthetic strategies are used: the first one is the
stereocontrolled synthesis of target compounds from enantiomeri-
cally pure substrates and the second one is the resolution of racemic
products. In many of our syntheses we have applied the first strategy
starting from enantiomerically allylic alcohols,1–7 which were
usually obtained from natural, enantiomerically ketones5–7 or
hydrocarbons.3,4 Taking the advantage that the configuration of
stereogenic centres of allylic alcohols are stereospecifically trans-
Racemic dimethylcyclohexenols 5, 7 and 11 and isomeric (cis and
trans) piperitols 13 and 14 are known compounds. They were usu-
ally obtained by reduction of respective a,b-unsaturated dimethyl-
cyclohexenones or racemic piperitone with lithium aluminium
hydride. The synthesis of ( )-11 from dimedone 8 via 5,5-dimethyl-
cyclohex-2-en-1-one 10 has been previously described.17 Dimethyl-
cyclohexenols ( )-5 and ( )-7 were obtained in a three-step
synthesis from 4,4-dimethylcyclohexan-1,3-dione 1 (Scheme 1),
similar to that described for 11.
Thus diketone 1, like dimedone 8, was converted into the
mixture of known18 ethoxyketones 2 (22%) and 3 (78%) (Scheme 1)
which were separated by column chromatography and trans-
formed by reduction (LiAlH4) and hydrolysis (10% aqueous
H2SO4) to respective ketones 4 and 6. The application of 0.25 mol
of LiAlH4 per one mol of ketone in the reduction of 4 and 6 allowed
us to obtain allylic alcohols ( )-5 and ( )-7 in good yields (95–99%)
as the only products.
Racemic piperitone ( )-12 was obtained by thermal isomeriza-
tion of natural piperitone isolated from Mentha longifolia L. which
contained 70% of (ꢀ)-(R)-piperitone and 30% of (+)-(S)-piperitone.
Reduction of racemic piperitone ( )-12 with LiAlH4 afforded
(according to GC) mixture of racemic trans ( )-13 (65%) and cis
( )-14 (35%) piperitols (Scheme 2), which were separated by col-
umn chromatography.
formed in the Claisen rearrangement to the forming c,d-unsaturated
esters, we could obtain the latter in pure or enantiomerically
enriched form. In the next step they were converted into optically
active lactones with antifeedant2,4,8 or odoriferous properties.5
In the case when the racemic allylic alcohols were the starting
compounds, their enzymatic resolution was the first step of our
strategy. Therefore we have been looking for efficient catalysts
and reaction systems. Several such methods for the separation of
racemic allylic alcohols by their catalytic esterification9–13 or
hydrolysis of their racemic esters9,13,14 are known in the literature.
Both chemical15,16 and biological9–14 catalysts were applied for
these purposes.
Recently we have described the resolution of racemic acyclic
allylic alcohols by enzymatic esterification with vinyl esters cata-
lyzed by some lipases.12 Herein the results of separation of the
racemic secondary cyclic allylic alcohols in chemo-enzymatic
esterification and hydrolysis processes are reported.
2.1. Resolution of racemic 6,6-dimethylcyclohex-2-en-1-ol ( )-5
In the literature only the (+)-(S)-enantiomer of 6,6-dimethylcy-
clohex-2-en-1-ol (+)-(S)-5 is known. It was obtained with 94%
enantiomeric excess as the product of catalytic enantioselective
* Corresponding author. Tel.: +48 71 320 52 57.
E-mail address: czeslaw.wawrzenczyk@up.wroc.pl (C. Wawrzen´ czyk).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.02.031

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K. Winska et al. / Tetrahedron: Asymmetry 21 (2010) 670–678
C2H5O
O
OH
O
ii
iii
4
( )-5
2
O
O
i
+
O
OH
OH
O
O
OC2H5
iii
iii
ii
ii
1
3
6
( )-7
O
O
OC2H5
O
i
9
8
10
( )-11
Scheme 1. Reagents and conditions: (i) EtOH, p-toluenesulfonic acid, benzene, reflux; (ii) (1) LiAlH4, Et2O, rt; (2) 10% aqueous H2SO4; (iii) LiAlH4, Et2O, rt.
biocatalyst. After 3 hours almost pure (+)-(S)-5 (98% ee) was iso-
lated as the unreacted alcohol from the product mixture containing
79% of isomeric alcohols and 21% of acetates.
+
The absolute configurations of the isomeric alcohols were as-
cribed by comparison of the GC retention times of enantiomers
with application of CP-Chirasil-DEX CB (25 m ꢁ 25 mm ꢁ 0.25
O
OH
OH
l
m): GC (95 °C, isotherm): tR (ꢀ)-(R)-5 16.56 min, tR (+)-(S)-5
( )-12
( )-13
( )-14
17.53 min with these referred in the literature for the same col-
umn16: GC (100 °C, isotherm): tR (ꢀ)-(R)-5 11.64 min, tR (+)-(S)-5
12.17 min.
Scheme 2. Reduction of ( )-12 with LiAlH4.
rearrangement of epoxide of racemic 5 with the application of
Li-salt of (1S,3R,4R)-3-(pirrolidyl)-methyl-2-azabicyclo[2.2.1]hept-
anol as chiral catalyst.16
2.2. Resolution of racemic 4,4-dimethylcyclohex-2-en-1-ol ( )-7
The (ꢀ)-(S)-enantiomer of 7 was obtained earlier19 in three-step
synthesis from 4,4-dimethylcyclohex-2-en-1-one 6. However, its
enantiomeric excess did not exceed 50%.
The method of enzymatic resolution of ( )-7 elaborated herein
is shown in Scheme 4.
In our method of resolution of ( )-5 the enzymatic esterification
was applied. The esterification of ( )-5 with vinyl acetate in the
presence of lipase from Candida cylindracea was the first step in
our approach (Scheme 3). After one day of the reaction the product
mixture contained 51% of isomeric acetates (99% of (ꢀ)-(R)-15 and
1% of (+)-(S)-15) and 49% of unreacted alcohols (+)-(S)-5 (75%) and
of (ꢀ)-(R)-5 (25%). The reaction mixture was separated by column
chromatography and the enantiomer (ꢀ)-(R)-5 was obtained by
chemical hydrolysis of acetate (ꢀ)-(R)-15 with methanolic NaOH.
The mixture of unreacted alcohols was subjected to the next ester-
ification under the same conditions and with the same lipase as
The esterification of ( )-7 with vinyl acetate catalyzed by lipase
Amano PS in hexane after four days gave a mixture of 41% of unre-
acted alcohol (+)-(R)-7 (80%) and (ꢀ)-(S)-7 (20%) and 59% of iso-
meric acetates of (+)-(R)-16 (27%) and of (ꢀ)-(S)-16 (73%).
Unreacted alcohols were separated by column chromatography
and subjected to the next esterification in the same conditions
which afforded, after six days of reaction, a mixture of unreacted
alcohols (36%) and acetates (64%). Chiral GC showed that alcohol
fraction consisted of (+)-(R)-7 (99%) and (ꢀ)-(S)-7 (1%). (+)-(R)-7
OH
OH
OAc
(98% ee) is characterized by ½a D28
¼ þ113:2 (c 0.71, CHCl3).
ꢂ
i
(ꢀ)-(S)-7 was obtained in the three-step procedure from the
mixture of isomeric acetates isolated after first esterification. Thus,
in the first step, this mixture was hydrolyzed in phosphate buffer
(pH 7) in the presence of lipase Amano PS. After five days, the
mixture containing 78% of isomeric alcohols: (ꢀ)-(S)-7 (84%) and
(+)-(R)-7 (16%) and 22% of isomeric acetates was obtained. After
purification the mixture of alcohols was subjected to the next
esterification, but this time with lipase from C. cylindracea as bio-
catalyst. After five days the product mixture consisted of 62% of
enantiomeric acetates (ꢀ)-(S)-16 (98%) and (+)-(R)-16 (2%) and
38% of unreacted alcohols. The chemical hydrolysis (NaOH in
methanol) of acetates was the last step of procedure leading to
enantiomerically enriched (ꢀ)-(S)-7 (96% ee). Its specific rotation
+
( )-5
(+)-(S)-5
ee 50%
(−)-(R)-15
ee 98%
i
ii
OAc
OH
OH
+
(−)-(R)-15
ee 84%
(+)-(S)-5
ee 98%
(−)-(R)-5
ee 98%
was ½a 2D8
¼ ꢀ111:8 (c 0.62, CHCl3). The value found in the litera-
ꢂ
ture19 was much lower: ½a 2D8
¼ ꢀ10:8 (c 1.90, CHCl3) but it was
ꢂ
Scheme 3. Reagents: (i) Lipase from Candida cylindracea, vinyl acetate; (ii) NaOH,
MeOH.
measured for a sample with 25% ee.

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K. Winska et al. / Tetrahedron: Asymmetry 21 (2010) 670–678
OH
OAc
OH
i
+
(−)-(S)-16
ee 46%
(+)-(R)-7
ee 60%
( )-7
i
ii
OH
OH
OAc
OAc
+
+
(+)-(R)-7
ee 98%
(+)-(R)-16
ee 44%
(−)-(S)-7
ee 68%
(+)-(R)-16
ee 40%
iii
OAc
OH
OH
iv
+
(−)-(S)-7
ee 96%
(−)-(S)-7
ee 42%
(−)-(S)-16
ee 96%
Scheme 4. Reagents: (i) Lipase Amano PS, vinyl acetate, hexane; (ii) Lipase Amano PS, phosphate buffer; (iii) Lipase from Candida cylindracea, vinyl acetate, hexane; (iv)
NaOH, MeOH.
The separation of ( )-7 was more complicated and less effective
than the resolution of ( )-5. Practical yields are relatively low: 14%
for (+)-(R)-7 and 17% for isomer (ꢀ)-(S)-7. In our opinion the rea-
son is the almost symmetrical structure of this alcohol.
of unreacted alcohol (86%) containing (+)-(R)-11 (57%) and (ꢀ)-(S)-
11 (43%) and the mixture of acetates (14%) containing (ꢀ)-(S)-17
(94%) and (+)-(R)-17 (6%) (Scheme 5).
The mixture of unreacted alcohols was subjected to successive
esterification using the same biocatalyst. After six days in the prod-
uct mixture 86% of unreacted alcohol (+)-(R)-11 (70%) and (ꢀ)-(S)-
11 (30%) and 14% of acetates (ꢀ)-(S)-17 (91%) and (+)-(R)-17 (9%)
were observed.
2.3. Resolution of racemic 5,5-dimethylcyclohex-2-en-1-ol
( )-11
The resolution of ( )-11 was more complicated than the previ-
ous alcohols (Scheme 5). The first esterification of ( )-11 with the
application of lipase Amano PS, after 12 days, afforded the mixture
The isolated mixture of enantiomeric alcohols was esterified
under the same conditions a third time. After six days, the reaction
mixture contained 55% of unreacted alcohols (+)-(R)-11 (99%) and
OH
i
OH
OAc
+
( )-11
(+)-(R)-11
ee 14%
(−)-(S)-17
ee 88%
i
OH
OAc
+
ii
i
(+)-(R)-11
ee 40%
(−)-(S)-17
ee 82%
OAc
OH
OAc
OH
+
+
(−)-(S)-17
ee 44%
(−)-(S)-11
ee 98%
(−)-(S)-17
ee 70%
(+)-(R)-11
ee 98%
Scheme 5. Reagents: (i) Lipase Amano PS, vinyl acetate, hexane; (ii) Lipase Amano PS, phosphate buffer.

´
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K. Winska et al. / Tetrahedron: Asymmetry 21 (2010) 670–678
(ꢀ)-(S)-11 (1%) and 45% of isomeric acetates (ꢀ)-(S)-17 isomer
(72%) and (+)-(R)-17 (28%). The specific rotation of (+)-(R)-11
(+)-(3R,4R)-13 (98% ee) and (ꢀ)-trans-piperityl propionate (ꢀ)-
(3S,4S)-21 (98% ee). In the case of reaction of ( )-cis-piperitol
( )-14 the (ꢀ)-(3S,4R) enantiomer of alcohol 14 was also the faster
reacting isomer and after seven days the product mixture contained
about 50% of (+)-cis-piperitol ((+)-(3S,4R)-14, 99% ee) and (ꢀ)-cis-
piperityl propionate (ꢀ)-(3S,4R)-22 (97% ee). The hydrolysis of
propionates (ꢀ)-(3S,4S)-21 and (ꢀ)-(3S,4R)-22 afforded respective
(ꢀ)-isomers of trans-(ꢀ)-(3S,4S)-13 and cis-piperitols (ꢀ)-(3S,4R)-
14 with 98% and 97% enantiomeric excesses, respectively.
The configurations of products obtained were ascribed by com-
parison of their specific rotation values with those reported in the
literature.11
(98% ee) is ½a 2D8
¼ þ59:1 (c 0.59, CHCl3).
ꢂ
(ꢀ)-(S) Isomer of alcohol 11 was obtained by enzymatic hydro-
lysis, in phosphate buffer, of mixture of acetates 17 isolated from
the first and the second esterification steps with application of li-
pase Amano PS. The six-day process afforded 50% of alcohols with
predominance of isomer (ꢀ)-(S)-11 (99%). Its specific rotation is
½
a 2D8
ꢂ
¼ ꢀ59:8 (c 0.62, CHCl3).
The preparative yields of enantiomeric alcohols are as follows:
35% for isomer (+)-(R)-11 and 14% for isomer (ꢀ)-(S)-11.
The configuration of alcohol (+)-(R)-11 was determined by crys-
tallographic analysis of (+)-2-((R)-50,50-dimethylcyclohex-20-en-10-
yl)ethyl (S)-mandalate 20 (Fig. 1). This compound was obtained by
a three-step synthesis from (+)-(R)-11 without loss of enantiomeric
purity (Scheme 6).
3. Experimental
3.1. General methods
1H NMR spectra were recorded in CDCl3 solution on a Bruker
Avance DRX 300 MHz or Bruker Avance II 600 MHz spectrometer.
Chemical shifts are referenced to the residual solvent signal
(dH = 7.26). IR spectra were recorded on a Thermo-Nicolet IR300
FT-IR spectrometer. Optical rotations were determined on an Auto-
pol IV automatic polarimeter (Rudolph) in chloroform, ethanol or
methanol solutions, and concentrations were denoted in g/
100 mL. Analytical TLC was performed on Fluka Kieselgel 60, F254
plates with mixture of hexane, acetone and diethyl ether in various
ratio. Compounds were detected by spraying the plates with 1%
Ce(SO4)2, 2% H3[P(Mo3O10)4] in 10% H2SO4 or 20% ethanolic
H2SO4, containing 0.1% of anisaldehyde, followed by heating to
120 °C. Preparative column chromatography was performed on sil-
ica gel (Kieselgel 60, 230–400 mesh ASTM, Merck) with a mixture
of hexane, acetone and diethyl ether (in various ratio) as eluent.
Gas chromatography analysis was carried out on an Varian
CP3380 instrument (FID, carrier gas H2) using the capillary col-
Figure 1. One of the two crystallographic unrelated molecules of (+)-(2S,10R)-20
with crystallographic numbering.
umns: Thermo TR-5 (30 m ꢁ 0.32 mm ꢁ 1.0
lm) or CP-Chirasil-
DEX CB column (25 m ꢁ 0.25 mm ꢁ 0.25 m). The enantiomeric
The highly stereospecific Claisen rearrangement (orthoacetic
l
modification20–22) of alcohol (+)-(R)-11 generated
c,d-unsaturated
excess was determined with the following temperature pro-
grammes: for 5 and 15: 95 °C (25 min), 200 (20 °C/min), for 7
and 16: 90 °C (25 min), 200 (20 °C/min), for 11 and 17: 85 °C
(30 min), 130 °C (5°/ min), 200 °C (20°/min), for 12: 60 °C (1 min)
100 °C (2 °C/min) (2 min) 200 °C (20 °C/min) (2 min), for 21 and
22: 90 °C, 98 °C (0.2 °C/min), 200 °C (30 °C/min) (2 min). X-ray data
ester (ꢀ)-(R)-18 which in the next step was reduced to the corre-
sponding (ꢀ)-R alcohol 19. In the last step this alcohol 19 was
esterified with (ꢀ)-(S)-mandelic acid.
2.4. Resolution of racemic trans-( )-13 and cis-piperitols ( )-14
were collected on a Kuma KM4CCD diffractometer (MoK
a radia-
Both enantiomers of trans-13 and cis-piperitols 14 are known
compounds.11,13 In 2003 Serra et al. published11 the conditions
for the enzymatic separation of racemic alcohols ( )-13 and ( )-
14 by their lipase-catalyzed esterification. All isomers were ob-
tained with high (81–99%) enantiomeric excesses. Authors applied
lipases from Pseudomonas cepacia and from Candida rugosa (CRL) as
biocatalysts and vinyl acetate as acyl donor.
tion; k = 0.71073 Å) at 100 K using an Oxford Cryosystem device.
Data reduction and analysis were carried out with the CrysAlice
‘RED’ program.23 The space group was determined using the XPREP
program. Structures were solved by direct methods using the XS
program and refined using all F2 data, as implemented by the XL
program.24 Non-hydrogen atoms were refined with anisotropic
displacement parameters. All H atoms were found in
Dq maps or
placed at calculated positions. Before the last cycle of refinement
all H atoms were fixed and were allowed to ride on their parent
atoms. The Friedel pairs were merged before the final refinement.
The absolute structures were chosen on the basis of the known
absolute configuration of (ꢀ)-(S)-mandelic acid used in the
synthesis.
In the enzymatic resolution of racemic trans-( )-13 and cis-pip-
eritols ( )-14 described here only the lipase from P. cepacia and vi-
nyl propionate as acyl donor was applied in solvent-free system
(Scheme 7).
The reaction carried out for ( )-trans-piperitol ( )-13 at room
temperature afforded mixture of about 50% of (+)-trans-piperitol
OH
R
O
R
R
O
R
HO
OH
S
i
ii
iii
O
O
(+)-(R)-11
(−)-(R)-18
(−)-(R)-19
(+)-(2S,1'R)-20
Scheme 6. Reagents: (i) CH3C(OEt)3, CH3COOH, 138 °C; (ii) LiAlH4, Et2O, rt; (iii) (ꢀ)-(S)-mandelic acid, KHSO4, C6H6, reflux.

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K. Winska et al. / Tetrahedron: Asymmetry 21 (2010) 670–678
O
ii
i
+
OH
O
OH
OH
( )-13
(+)-(3R,4R)-13
ee 98%
(−)-(3S,4S)-21
ee 98%
(−)-(3S,4S)-13
ee 98%
O
ii
i
+
OH
OH
OH
O
(−)-(3S,4R)-22
( )-14
(+)-(3R,4S)-14
(−)-(3S,4R)-14
ee 97%
ee 99%
ee 97%
Scheme 7. Reagents: (i) Lipase Amano PS, vinyl propionate; (ii) KOH, MeOH.
3.2. Chemicals and enzymes
3.3.2. 3-Ethoxy-6,6-dimethylcyclohex-2-en-1-one 3
Yield 77%; n2D0 ¼ 1:4792; 1H NMR (600 MHz, CDCl3) d: 1.09 (s,
6H, (CH3)2C—)), 1.34 (t, J = 7.0 Hz, 3H, –OCH2CH3), 1.78 (t,
J = 6.4 Hz, 2H, CH2-5), 2.40 (t, J = 6.4 Hz, 2H, CH2-4), 3.86 (q,
J = 7.0 Hz, 2H, –OCH2CH3), 5.22 (s, 1H, H-2); IR (film, cmꢀ1): 1660
(s), 1620 (s), 1384 (s), 1196 (s).
4,4-Dimethylcyclohexa-1,3-dione 1, 5,5-dimethylcyclohexa-
1,3-dione 8 and lithium aluminium hydride were purchased from
Aldrich Chemicals, vinyl acetate from Fluka and vinyl propionate
and propionyl chloride from Lancaster Synthesis. The biocatalysts
were purchased from the following sources: NovozymeÒ 435
(immobilized Candida antarctica lipase B) from Sigma Chemicals,
lipase Amano PS (Burkholderia cepacia lipase) from Sigma Aldrich
Chemicals and lipase from C. cylindracea from Fluka BioChemika.
3.3.3. 3-Ethoxy-5,5-dimethylcyclohex-2-en-1-one 9
Yield 98%; mp = 57–58 °C (lit.17 mp = 57–58 °C); 1H NMR
(300 MHz, CDCl3) d: 1.04 (s, 6H, (CH3)2C—), 1.33 (t, J = 7.0 Hz, 3H,
OCH2CH3), 2.18 (s, 2H, CH2-4), 2.24 (s, 2H, CH2-6), 4.13 (q,
J = 7.0 Hz, 2H, OCH2CH3), 5.32 (s, 1H, H-2); IR (KBr, cmꢀ1): 1657
(s), 1608 (s).
Natural (ꢀ)-(R)-piperitone (ꢀ)-12 from M. longifolia L. ½a D23
¼
ꢂ
ꢀ10:6 (c 1.13, MeOH), (ee = 40%) was a generous gift from Depart-
ment of Bioorganic Chemistry, Wroclaw University of Technology.
Racemic piperitone ( )-12 was obtained by distillation of natural
piperitone according to the following procedure.
3.4. Synthesis of ketones 4, 6 and 10
(ꢀ)-(R)-Piperitone (ꢀ)-12 (ee = 40%) (5.00 g, 32.9 mmol) was
distilled at the normal pressure at 234 °C to give racemic piperito-
ne ( )-12 (3.58 g, 23.3 mmol, yield 71%). The GC analysis on a chiral
column confirmed the racemization of natural piperitone. The two
peaks of two enantiomers in equimolecular ratio on the chromato-
gram were observed.
Ketones 4, 6 and 10 were obtained according to the same gen-
eral procedure, which is given below.
To a cooled suspension of LiAlH4 (0.02 mol) in the anhydrous
diethyl ether (200 mL) the solution of ethoxyketone (0.06 mol) in
diethyl ether (50 mL) was added dropwise. The mixture was stirred
at room temperature 12 h. When the reaction was completed (TLC,
GC) water (50 mL) followed by 10% aqueous H2SO4 (50 mL) was
carefully added. The ethereal layer was separated, washed with
saturated Na2CO3 solution, brine and dried over anhydrous MgSO4.
The crude product was purified by column chromatography (hex-
ane–acetone, 9:1). The yields of reaction, physical and spectral data
of ketones 4, 6 and 10 are given below.
3.3. Synthesis of ethoxyketones 2, 3 and 9
Ethoxyketones 2, 3 and 9 were obtained according to the same
general procedure, which is given below.
The solution of diketone (0.07 mol) in absolute ethanol
(0.23 mol) and p-toluenesulfonic acid (1.74 mmol) in benzene
(100 mL) was refluxed with azeotropic removal of water until dike-
tone reacted completely (6 h). The mixture of two products, eth-
oxyketones 2 and 3 (22% and 78%, respectively, according to GC),
were obtained from 4,4-dimethylcyclohexa-1,3-dione (1), and eth-
oxyketone 9 was obtained from 5,5-dimethylcyclohexa-1,3-dione
8. The crude products were purified by column chromatography
using corresponding solvent systems: hexane–acetone, 5:1 (for
ethoxyketone 9) and hexane–acetone, 15:1 (for separation and
purification of ethoxyketones 2 and 3). The yields of reaction, phys-
ical and spectral data of ethoxyketones 2, 3 and 9 are given below.
3.4.1. 6,6-Dimethylcyclohex-2-en-1-one 4
Yield 99%; n2D0 ¼ 1:4745, (lit.25 n2D1 ¼ 1:4704); 1H NMR
(600 MHz, CDCl3) d: 1.09 (s, 6H, (CH3)2C—)), 1.81 (t, J = 6.1 Hz, 2H,
CH2-5), 2.35 (tdd, J = 6.1, 4.0 and 2.0 Hz, 2H, CH2-4); 5.89 (dt,
J = 10.0 and 2.0 Hz, 1H, H-2), 6.84 (dt, J = 10.0 and 4.0, 1H, H-3);
IR (film, cmꢀ1): 3020 (w), 2923 (s),1693 (s).
3.4.2. 4,4-Dimethylcyclohex-2-en-1-one 6
Yield 99%; n2D0 ¼ 1:4710, (lit.26 n2D0 ¼ 1:4775); 1H NMR
(600 MHz, CDCl3) d: 1.14 (s, 6H, (CH3)2C—), 1.85 (t, J = 6.8 Hz, 2H,
CH2-5), 2.43 (t, J = 6.8 Hz, 2H, CH2-6); 5.81 (d, J = 10.0 Hz, 1H, H-
2), 6.63 (d, J = 10.0, 1H, H-3); IR (film, cmꢀ1): 3020 (w), 1692 (s).
3.3.1. 3-Ethoxy-4,4-dimethylcyclohex-2-en-1-one 2
Yield 21%; n2D0 ¼ 1:4745; 1H NMR (600 MHz, CDCl3) d: 1.18 (s,
6H, (CH3)2C—)), 1.34 (t, J = 7.0 Hz, 3H, –OCH2CH3), 1.80 (t,
J = 6.7 Hz, 2H, CH2-5), 2.37 (t, J = 6.7 Hz, 2H, CH2-6), 3.84 (q,
J = 7.0 Hz, 2H, –OCH2CH3), 5.21 (s, 1H, H-2); IR (film, cmꢀ1): 1668
(s), 1600 (s), 1348 (s), 1200 (s), 1164 (s).
3.4.3. 5,5-Dimethylcyclohex-2-en-1-one 10
Yield 98%; n2D0 ¼ 1:4705, (lit.17 n2D0 ¼ 1:4733); 1H NMR
(300 MHz, CDCl3) d: 1.04 (s, 6H, (CH3)2C—), 2.19 (m, 4H, CH2-4,

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K. Winska et al. / Tetrahedron: Asymmetry 21 (2010) 670–678
CH2-6), 6.01 (dt, J = 10.1 and 2.0 Hz, 1H, H-2), 6.82 (dt, J = 10.1 and
1), 1.73 (m, 1H, one of CH2-5, pseudoequatorial), 1.91–2.02 (m, 2H,
CH2-6), 4.13 (m, 1H, H-3), 5.63 (m, 1H, H-2); IR (film, cmꢀ1): 3368
(b, s), 2955 (s), 1383 (m), 1046 (m), 955 (m).
4.1 Hz, 1H, H-3); IR (film, cmꢀ1): 2972 (m), 1664 (s), 1616 (s).
3.5. Synthesis of racemic alcohols ( )-5, ( )-7, ( )-11, ( )-13 and
( )-14
3.6. Synthesis of racemic esters ( )-15, ( )-16, ( )-17, ( )-21 and
( )-22
All racemic alcohols were obtained according to the following
procedure.
Racemic acetates or propionates were obtained as the reference
compounds for GC analysis according to the following procedure.
To a solution of alcohol (5 mmol) and pyridine (7 mmol) in dry
diethyl ether (10 mL), acyl chloride (acetyl chloride or propionyl
chloride) (6 mmol) was added dropwise. The mixture was stirred
at room temperature for 20 min. After that time, the reaction mix-
ture was diluted with diethyl ether and washed with 0.5 M aque-
ous HCl. The ethereal solution was washed with brine, dried
(MgSO4) and evaporated in vacuo. The crude products were puri-
fied by column chromatography using corresponding solvent
systems: hexane–acetone, 9:1 (for esters ( )-15, ( )-16) and hex-
ane–diethyl ether, 4:1 (for esters ( )-21, ( )-22). The yields of reac-
tion, physical and spectral data of esters obtained are given below.
Ketone (10.0 mmol) in anhydrous diethyl ether (100 mL) was
added dropwise to a cooled suspension of LiAlH4 (2.50 mmol) in
anhydrous diethyl ether (50 mL). The mixture was stirred at room
temperature. When the reduction was completed (TLC, GC), the
reaction was quenched by dropwise addition of water (10 mL) and
0.5 M HCl (20 mL). The ethereal layer was separated, washed with
brine, dried (MgSO4) and the solvent was evaporated in vacuo.
Reduction of ketones 4, 6 and 10 gave corresponding allylic
alcohols ( )-5, ( )-7 and ( )-11. Reduction of racemic piperitone
( )-12 afforded mixture of two products: trans-( )-13 and cis-pip-
eritols ( )-14 (65% and 35%, respectively, according to GC). The
crude products were purified by column chromatography using
corresponding solvent systems: hexane–acetone, 9:1 (for alcohols
( )-5, ( )-7 and ( )-11) and hexane–diethyl ether, 95:5?80:20
(for separation and purification of alcohols ( )-13 and ( )-14).
The yields of reaction, physical and spectral data of allylic alcohols
obtained are given below.
3.6.1. ( )-6,6-Dimethylcyclohex-2-en-1-yl acetate ( )-15
Yield 95%; n2D0 ¼ 1:4526; 1H NMR (600 MHz, CDCl3) d: 0.91 and
0.92 (two s, 6H, (CH3)2C—), 1.41 (dt, J = 13.4 and 6.2 Hz, 1H, one of
CH2-5), 1.49 (dt, J = 13.4 and 6.4 Hz, 1H, one of CH2-5), 1.99–2.12
(m, 2H, CH2-4), 2.06 (s, 3H, –C(O)CH3), 4.98 (m, 1H, H-1), 5.57
(ddt, J = 10.0, 3.6 and 2.2 Hz, 1H, H-2), 5.84 (dtd, J = 10.0, 3.6,
1.2 Hz, 1H, H-3); IR (film, cmꢀ1): 3033 (w), 2924 (s), 1734 (s),
1369 (s), 1241 (s), 1023 (m).
3.5.1. ( )-6,6-Dimethylcyclohex-2-en-1-ol ( )-5
Yield 95%; n2D0 ¼ 1:4695 (lit.27 n2D3 ¼ 1:4758); 1H NMR (600 MHz,
CDCl3) d: 0.91 and 0.95 (two s, 6H, (CH3)2C—), 1.36 (dt, 1H, J = 13.5
and 6.8 Hz, 1H, one of CH2-5), 1.49 (dt, J = 13.5 and 5.9 Hz, 1H, one
of CH2-5), 2.02 (m, 2H, CH2-4), 3.74 (m, 1H, H-1), 5.64 (ddt, J = 10.0,
3.1 and 2.2 Hz, 1H, H-3), 5.75 (dtd, J = 10.0, 3.5 and 1.5 Hz, 1H, H-
2); IR (film, cmꢀ1): 3369 (s, b), 3026 (w), 2919 (s), 1453 (w),
1057 (m), 1020 (m).
3.6.2. ( )-4,4-Dimethylcyclohex-2-en-1-yl acetate ( )-16
Yield 90%; n2D0 ¼ 1:4502; 1H NMR (600 MHz, CDCl3) d: 0.97 and
1.03 (two s, 6H, (CH3)2C—), 1.44 (ddd, J = 13.0, 9.2 and 3.2 Hz, 1H,
one of CH2-6), 1.57 (ddd, J = 13.0, 9.3 and 3.2 Hz, 1H, one of CH2-
6), 1.70 (m, 1H, one of CH2-5), 1.91 (m, 1H, one of CH2-5), 2.04
(s, 3H, –C(O)CH3), 5.19 (m, 1H, H-1), 5.53 (dd, J = 10.0 and 3.4 Hz,
1H, H-3), 5.59 (d, J = 10.0 Hz, 1H, H-2); IR (film, cmꢀ1): 3024 (w),
2957 (s), 1737 (s), 1370 (m), 1242 (s), 1029 (m).
3.5.2. ( )-4,4-Dimethylcyclohex-2-en-1-ol ( )-7
Yield 99%; n2D0 ¼ 1:4638 (lit.27 n2D3 ¼ 1:4694); 1H NMR (600 MHz,
CDCl3) d: 0.96 and 1.01 (two s, 6H, (CH3)2C—), 1.42 (ddd, J = 13.2, 9.7
and 3.2 Hz, 1H, one of CH2-6), 1.50 (s, 1H, OH), 1.55 (ddd, J = 13.2,
8.6 and 3.0 Hz, 1H, one of CH2-6), 1.63 (m, 1H, one of CH2-5), 1.90
(m, 1H, one of CH2-5), 4.13 (m, 1H, H-1), 5.52 (d, J = 10.0 Hz, 1H, H-
3), 5.59 (dd, J = 10.0 and 3.0 Hz, 1H, H-2); IR (film, cmꢀ1): 3376 (s,
b), 3032 (w), 2968 (s).
3.6.3. ( )-5,5-Dimethylcyclohex-2-en-1-yl acetate ( )-17
Yield 78%; n2D0 ¼ 1:4495; 1H NMR (600 MHz, CDCl3) d: 0.96 and
0.99 (two s, 6H, (CH3)2C—)), 1.44 (dd, 1H, J = 12.6 and 8.4 Hz, one
of CH2-6), 1.78–1.82 (m, 2H, one of CH2-4, one of CH2-6), 1.93 (m,
1H, one of CH2-4), 2.04 (s, 3H, –C(O)CH3), 5.34 (m, 1H, H-1), 5.62
(dm, J = 10.1 Hz, 1H, H-2) 5.80 (dm, J = 10.1 Hz, 1H, H-3); IR
(film, cmꢀ1): 3034 (w), 2953 (s), 1734 (s), 1370 (s), 1242 (s),
1023 (s).
3.5.3. ( )-5,5-Dimethylcyclohex-2-en-1-ol ( )-11
Yield 97%; n2D0 ¼ 1:4643, (lit.28 n2D0 ¼ 1:4660); 1H NMR
(600 MHz, CDCl3) d: 0.91 and 0.99 (two s, 6H, (CH3)2C—)), 1.29
(dd, 1H, J = 12.5 and 9.2 Hz, one of CH2-6), 1.42 (s, 1H, OH), 1.73
(dm, J = 17.7 Hz, 1H, one of CH2-4), 1.79 (dd, J = 12.5 and 5.7 Hz,
1H, one of CH2-6), 1.90 (dm, J = 17.7 Hz, 1H, one of CH2-4), 4.24
(m, 1H, H-1), 5.69 (m, 2H, H-2 and H-3); IR (film, cmꢀ1): 3327 (s,
b), 3040 (m), 2968 (s), 1455 (m), 1364 (m), 1037 (s).
3.6.4. ( )-trans-Piperityl propionate ( )-21
Yield 94%; 1H NMR (600 MHz, CDCl3) d: 0.82 and 0.93 (two d,
J = 6.9 Hz, 6H, (CH3)2CH–), 1.12 (t, J = 7.6 Hz, 3H, CH3CH2–), 1.40
(m, 1H, one of CH2-5), 1.48 (m, 1H, H-4), 1.66 (s, 3H, CH3-1),
1.67–1.74 (m, 2H, (CH3)2CH– and one of CH2-5), 1.90–2.00 (m,
2H, CH2-6), 2.30 (q, J = 7.6 Hz, 2H, CH3CH2–), 5.26 (m, 1H, H-3),
5.30 (m, 1H, H-2); IR (film, cmꢀ1): 2960 (m), 1733 (s), 1463 (m),
1369 (m), 1188 (s), 1159 (m), 1010 (m), 910 (m).
3.5.4. ( )-trans-Piperitol ( )-13
Yield 59%; 1H NMR (600 MHz, CDCl3) d: 0.82 and 0.95 (two d,
J = 6.9 Hz, 6H, (CH3)2CH–), 1.20–1.32 (m, 2H, H-4 and one of CH2-
5), 1.66 (s, 3H, CH3-1), 1.70 (m, 1H, one of CH2-5), 1.90–2.02 (m,
3H, CH2-6 and (CH3)2CH–), 4.00 (m, 1H, H-3), 5.37 (m, 1H, H-2);
IR (film, cmꢀ1): 3325 (b, s), 2956 (s), 1435 (m), 1384 (m), 1048
(m), 986 (m), 899 (m).
3.6.5. ( )-cis-Piperityl propionate ( )-22
Yield 95%; 1H NMR (600 MHz, CDCl3) d: 0.86 and 0.92 (two d,
J = 6.7 Hz, 6H, (CH3)2CH–), 1.10 (t, J = 7.6 Hz, 3H, CH3CH2–), 1.14
(m, 1H, H-4), 1.45 (tdd, J = 12.8, 12.1 and 5.8 Hz, 1H, one of CH2-
5, pseudoaxial), 1.54 (septet d, J = 6.7 and 2.3 Hz, 1H, (CH3)2CH–),
1.68 (s, 3H, CH3-1), 1.76 (m, 1H, one of CH2-5, pseudoequatorial),
1.92–2.04 (m, 2H, CH2-6), 2.27 (q, J = 7.6 Hz, 2H, CH3CH2–), 5.20
(m, 1H, H-3), 5.63 (m, 1H, H-2); IR (film, cmꢀ1): 2959 (m), 1731
(s), 1462 (m), 1368 (m), 1327 (m), 1191 (s), 906 (m).
3.5.5. ( )-cis-Piperitol ( )-14
Yield 32%; 1H NMR (600 MHz, CDCl3) d: 0.96 and 1.00 (two d,
J = 6.7 Hz, 6H, (CH3)2CH–), 0.98 (m, 1H, H-4), 1.06 (s, 1H, –OH),
1.33 (tdd, J = 13.0, 11.7 and 5.9 Hz, 1H, one of CH2-5, pseudoaxial),
1.64 (septet d, J = 6.7 and 2.7 Hz, 1H, (CH3)2CH–), 1.69 (s, 3H, CH3-

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K. Winska et al. / Tetrahedron: Asymmetry 21 (2010) 670–678
676
3.7. Lipase-catalyzed resolution of the racemic allylic alcohols
( )-5, ( )-7, ( )-11, ( )-13 and ( )-14
7 and the fraction of esters (0.61 g) consisted of 70% of (+)-(R)-16
and 30% of (ꢀ)-(S)-16.
Alcohols obtained after hydrolysis (1.35 g, 10.7 mmol) were
esterified with vinyl acetate (5.0 mL, 54.2 mmol) with hexane
(2 mL) in the presence of 0.35 g lipase from C. cylindracea. After five
days the product mixture was separated on column chromatogra-
phy (hexane–acetone, 9:1). In this way the mixture of unreacted
alcohols (0.35 g) contained 71% of (ꢀ)-(S)-7 and 29% of (+)-(R)-7
and esters (0.96 g) contained 98% of (ꢀ)-(S)-16 and 2% of (+)-(R)-
16 were obtained. Specific rotation of (ꢀ)-(S)-16 (ee = 96%) was
3.7.1. Resolution of ( )-6,6-dimethylcyclohex-2-en-1-ol ( )-5
The racemic mixture of 6,6-dimethylocyclohex-2-en-1-ol ( )-5
(1.92 g, 15.2 mmol), vinyl acetate (10.0 mL, 108.4 mmol) and
1.9 g lipase from C. cylindracea was vigorously stirred at room tem-
perature. The progress of the esterification process and composi-
tion of product mixture were monitored by GC. After 1 day the
reaction mixture was filtered through Celite and the solvent was
evaporated. The products obtained were separated by column
chromatography (hexane–acetone, 9:1). The alcohol fraction
(0.93 g) contained 75% of (+)-(S)-5 and 25% of (ꢀ)-(R)-5 and frac-
tion of esters (0.97 g) contained 99% of (ꢀ)-(R)-15 and 1% of (+)-
as follows: ½a 2D3
¼ ꢀ155:9 (c 0.97, CHCl3).
ꢂ
The mixture of esters (0.96 g, 5.75 mmola) was added to 1 M
aqueous NaOH (18 mL) with 1.0 mL MeOH and stirred at room
temperature for 1 day. After extraction with methylene chloride,
the organic fraction was dried (MgSO4) and concentrated. This
hydrolysis afforded (ꢀ)-(S)-5,5-dimethylocyclohex-2-en-1-ol (ꢀ)-
(S)-7 (0.70 g) with 96% enantiomeric excess. The optical rotation
(S)-15. Specific rotation of (ꢀ)-(R)-15 (ee = 98%) was
½
a 2D4
ꢂ
¼
ꢀ178:6 (c 0.90, CHCl3). The peaks on chiral GC chromatogram were
ascribed to the corresponding enantiomers of alcohols and esters
taking into consideration the retention times of R and S alcohols re-
ferred in the literature.16
of this alcohol (ꢀ)-(S)-7 was ½a D28
ꢂ
¼ ꢀ111:8 (c 0.62, CHCl3) (lit.19
[a]
D = ꢀ10.8 (c 1.90, CHCl3), ee = 25%).
The esters isolated after previous reaction (0.97 g, 5.76 mmol)
were subjected to the alkaline hydrolysis at room temperature
(18 mL of 1 M aqueous NaOH with 1.0 mL of MeOH solution). Pro-
gress of reaction was monitored by TLC. The organic fraction ob-
tained by extraction of product with methylene chloride was
dried (MgSO4) and concentrated under vacuo. (ꢀ)-(R)-6,6-Dimeth-
ylocyclohex-2-en-1-ol (ꢀ)-(R)-5 (0.68 g) was obtained with 98%
The total practical yield of preparative resolution of ( )-7 calcu-
lated in respect to 4.0 g of starting alcohol is 14% of (+)-(R)-7 and
17% of (ꢀ)-(S)-7.
3.7.3. Resolution of ( )-5,5-dimethylcyclohex-2-en-1-ol ( )-11
To the mixture of ( )-5,5-dimetylocyclohex-2-en-1-ol ( )-11
(8.10 g, 64.2 mmol) and vinyl acetate (10.0 mL, 108.4 mmol) in hex-
ane (2.0 mL), the lipase Amano PS (2.40 g) was added and the mix-
ture was stirred at room temperature. After 12 days of reaction
unreacted alcohol and ester formed were separated by column
chromatography (hexane–acetone, 9:1). The fraction of alcohols
(6.11 g) contained 57% of (+)-(R)-11 and 43% of (ꢀ)-(S)-11. The ester
fraction (1.66 g) contained 6% of (+)-(R)-17 and 94% of (ꢀ)-(S)-17.
The mixture of unreacted alcohols (6.11 g, 48.4 mmola) was
esterified again with vinyl acetate (7.5 mL, 81.3 mmol) in hexane
(2.0 mL) in the presence of lipase Amano PS (0.97 g). After six days
the product mixture, which contained isomeric alcohols (4.87 g):
70% of (+)-(R)-11 and 30% of (ꢀ)-(S)-11 and esters (0.93 g): 91%
of (ꢀ)-(S)-17 and 9% of (+)-(R)-17, was separated by column
chromatography.
enantiomeric excess ½a D29
¼ ꢀ126:9 (c 0.81, CHCl3).
ꢂ
The isomeric alcohols 5 obtained in the first esterification
(0.93 g, 7.37 mmol) were added to the suspension of 0.90 g lipase
from C. cylindracea in vinyl acetate (5.0 mL, 54.2 mmol). After 3 h,
the reaction mixture was filtered through Celite, evaporated and
separated by column chromatography (hexane–acetone, 9:1). The
mixture of isomeric alcohols (0.61 g) contained 99% of (+)-(S)-5
and 1% of (ꢀ)-(R)-5 and mixture of esters (0.22 g) contained 92%
of (ꢀ)-(R)-15 and 8% of (+)-(S)-15. Specific rotation of (+)-(S)-5
(ee = 98%) was ½a 2D9
¼ þ126:8 (c 0.87, CHCl3).
ꢂ
The total practical yield of preparative resolution, calculated in
respect to 1.92 g of starting ( )-6,6-dimethylcyclohex-2-en-1-ol
(( )-5) is 35% for (ꢀ)-(R)-5 and 32% for (+)-(S)-5.
The alcohols from previous reaction (4.87 g, 38.6 mmol) were
esterified again with vinyl acetate (6.0 mL, 65.1 mmol) in hexane
(2 mL) in the presence of 0.60 g lipase Amano PS. After six days
the reaction was stopped and separated by column chromatogra-
phy to give unreacted alcohols (2.82 g): 99% of (+)-(R)-11 and 1%
of (ꢀ)-(S)-11 and fraction of esters (1.52 g): 72% of (ꢀ)-(S)-17
and 28% of (+)-(R)-17. The enantiomer (+)-(R)-11 was obtained
3.7.2. Resolution of ( )-4,4-dimethylcyclohex-2-en-1-ol ( )-7
Racemic 4,4-dimethylocyclohex-2-en-1-ol ( )-7 (4.00 g, 31.7
mmol) was stirred with the suspension of hexane (2.0 mL), vinyl
acetate (10.0 mL, 108.4 mmol) and lipase Amano PS (2.5 g) at
room temperature. After four days the mixture was worked up
as described above and after column chromatography the mix-
ture of alcohols (1.39 g) containing 80% of (+)-(R)-7 and 20% of
(ꢀ)-(S)-7 was obtained. The fraction of esters (2.68 g) that con-
sisted of isomers 73% of (ꢀ)-(S)-16 and 27% of (+)-(R)-16 was also
isolated.
with 98% enantiomeric excess ½a D28
¼ þ59:1 (c 0.59, CHCl3).
ꢂ
The mixture of esters (2.59 g, 20.5 mmol) obtained from the
first and second enzymatic esterification was added to the suspen-
sion of lipase Amano PS (0.5 g) in phosphate buffer (pH 7.0, 50 mL).
After 6 days, the reaction mixture was worked up and separated by
column chromatography (hexane–acetone, 9:1). The mixture of
alcohols (1.12 g) contained 99% of (ꢀ)-(S)-11 and 1% of (+)-(R)-11
and mixture of esters (1.07 g) contained 85% of (ꢀ)-(S)-17 and
15% of (+)-(R)-17. (ꢀ)-(S)-5,5-Dimethylocyclohex-2-en-1-ol (ꢀ)-
(S)-11 was obtained in this reaction with 98% enantiomeric excess
The fraction of alcohols (1.39 g, 11.0 mmol) was esterified again
with vinyl acetate (5.0 mL, 54.2 mmola) in hexane (2.0 mL) in the
presence of 0.40 g lipase Amano PS. After six days the reaction mix-
ture was worked up as described above and after separation by col-
umn chromatography the fraction of alcohols (0.55 g) contained
99% of (+)-(R)-7 and 1% (ꢀ)-(S)-7 and the fraction of esters
(0.65 g) contained 72% of (+)-(R)-16 and 28% of (ꢀ)-(S)-16.
The enantiomeric excess of enantiomer (+)-(R)-7 was 98%
and its specific rotation value was ½a D28
¼ ꢀ59:8 (c 0.62, CHCl3).
ꢂ
In this way (+)-(R) isomer of 11 was obtained in 35% and (ꢀ)-(S)
isomer of 11 in 14% preparative yield.
½
a 2D8
ꢂ
¼ þ113:2 (c 0.71, CHCl3).
The isomeric mixture of esters (2.59 g, 20.5 mmol) obtained in
the first esterification containing 73% of (ꢀ)-(S)-16 and 27% of
(+)-(R)-16 was hydrolyzed in phosphate buffer at pH 7.0 (30 mL)
in the presence of lipase Amano PS (0.6 g). After five days the reac-
tion mixture was worked up and the products were separated by
column chromatography (hexane–acetone, 9:1). The fraction of
alcohols (1.35 g) consisted of 84% of (ꢀ)-(S)-7 and 16% of (+)-(R)-
3.7.4. Resolution of ( )-trans-piperitol ( )-13
A
mixture of the racemic trans-piperitol ( )-13 (4.23 g,
28.05 mmol), lipase Amano PS (2.00 g) and vinyl propionate
(5 mL) was stirred at room temperature and the formation of the
propionate was monitored by chiral GC. The reaction was stopped
at about 50% of substrate conversion (after 11 days). The mixture of

´
677
K. Winska et al. / Tetrahedron: Asymmetry 21 (2010) 670–678
products was separated by column chromatography (hexane–
diethyl ether, 4:1) to give (ꢀ)-trans-piperityl propionate (ꢀ)-
(3S,4S)-21 with 98% enantiomeric excess (2.75 g, yield 48%,
J = 17.7 Hz, 1H, one of CH2-40), 2.21 and 2.30 (two dd, J = 14.9 and
7.3, 2H, CH2-2), 2.60 (m, 1H, H-10), 4.15 (q, J = 7.1 Hz, 2H,
–OCH2CH3), 5.49 (dm, J = 10.0 Hz, 1H, H-20), 5.63 (dm, J = 10.0 Hz,
1H, H-30); IR (film, cmꢀ1): 3019 (m),1735 (s), 1367 (m), 1269 (s),
1165 (s), 1033 (m).
½
a 2D4
ꢂ
¼ ꢀ128:1 (c 1.53, CHCl3)) and unreacted (+)-trans-piperitol
(+)-(3R,4R)-13 (1.86 g, 44%, ½a D27
ꢂ
¼ þ35:4 (c 1.40, EtOH) [lit.11
½
a 2D0
ꢂ
¼ þ24:0 (c 2.0, EtOH)].
3.9. Synthesis of (ꢀ)-(R)-2-(50,50-dimethylocyclohex-20-en-10-
yl)ethanol (ꢀ)-(R)-19
The enantiomers of racemic trans-piperitols ( )-13 were not sep-
arable on the chiral columns being at our disposal. To determine the
enantiomeric excess value of the remaining alcohol it was necessary
to convert it into the propionate by the chemical esterification
according to the standard procedure. (+)-trans-Piperityl propionate
(+)-(3R,4R)-21 (76.90 mg, yield 94%, ee = 98%) was obtained and
enantiomeric excess of (+)-trans-piperitol (+)-(3R,4R)-13 deter-
mined in this way was 98%. To obtain (ꢀ)-trans-piperitol (ꢀ)-
(3S,4S)-13 the ester (ꢀ)-(3S,4S)-21 was hydrolyzed according to
the following procedure. (ꢀ)-trans-Piperityl propionate ((ꢀ)-
(3S,4S)-21) (2.58 g, 12.30 mmol) was refluxed for 2 h in 2.5% KOH/
MeOH solution (50 mL) and water (1 mL). When the reaction was
completed (GC, TLC), methanol was removed under reduced pres-
sure. The residual solid was diluted with water (30 mL) and ex-
tracted with diethyl ether (3 ꢁ 50 mL). The organic phase was
washed with brine, dried (MgSO4) and evaporated in vacuo. (ꢀ)-
Reduction of ester (ꢀ)-(R)-18 (1.50 g, 7.65 mmol) with LiAlH4
(1.63 g, 4.21 mmol) according to the same procedure which was
applied for synthesis of alcohols ( )-5, ( )-7, ( )-11, ( )-13 and
( )-14 afforded pure alcohol (ꢀ)-(R)-19 (1.00 g, yield 85%). Its
physical and spectral data are given below. ½a D22
¼ ꢀ51:7 (c 0.90,
ꢂ
CHCl3), n2D0 =1.4715 (lit.17 nD20 ¼ 1:4674); 1H NMR (600 MHz, CDCl3)
d: 0.89 and 0.94 (two s, 6H, (CH3)2C—)), 1.03 (dd, J = 12.6 and
12.1 Hz, 1H, one of CH2-60), 1.43 (s, 1H, OH), 1.44 (dd, J = 12.6
and 5.4 Hz, 1H, one of CH2-60), 1.54 (dq, J = 16.8, 7.0 Hz, 1H, one
of CH2-2), 1.62 (dq, J = 16.8, 6.9 Hz, 1H, one of CH2-2), 1.69 and
1.85 (dm, J = 17.5 Hz, 2H, CH2-40), 2.26 (m, 1H, H-10), 3.72 and
3.75 (two dt, J = 10.8, 6.9 Hz, 2H, –CH2OH), 5.53 (m, 1H, H-20),
5.60 (ddt, J = 10.0, 5.4 and 2.4 Hz, 1H, H-30); IR (film, cmꢀ1): 3337
(s, b), 3017 (m), 1456 (m), 1363 (m), 1055 (m).
trans-Piperitol ((–)-(3S,4S)-13) (1.60 g, yield 85%, ½a D27
¼ ꢀ42:3 (c
ꢂ
1.40, EtOH) [lit.11
½
a 2D0
ꢂ
¼ ꢀ30:4 (c 2.0, EtOH)] was obtained.
3.10. Synthesis of (+)-2-((R)-50,50-dimethylcyclohex-20-en-10-
yl)ethyl (S)-mandalate ((+)-20)
3.7.5. Resolution of ( )-cis-piperitol ( )-14
The lipase-catalyzed esterification of ( )-cis-piperitol ( )-14
(2.15 g, 14.00 mmol) was carried out according to the procedure
described above for isomer trans-( )-13 and after seven days gave
the mixture of (ꢀ)-cis-piperityl propionate (ꢀ)-(3S,4R)-22 with
The mixture of (ꢀ)-(R)-2-(50,50-dimethylocyclohex-20-en-10-
yl)ethanol (0.3 g, 0.002 mol), (ꢀ)-(S)-mandelic acid (0.46 g,
0.003 mol) and KHSO4 (0.41 g, 0.003 mol) in benzene (25 mL)
was refluxed for 2 h. When reaction was completed (TLC) the solu-
tion was diluted with diethyl ether (10 mL), washed with water
and brine and dried over anhydrous MgSO4. The crude product
was purified by column chromatography (hexane–acetone, 5:1).
The pure ester (+)-20 (0.3 g, 51% yield) was obtained. mp = 49 °C
97% enantiomeric excess (1.16 g, yield 40%, ½a D27
¼ ꢀ288:6 (c
ꢂ
1.60, CHCl3)) and unreacted (+)-cis-piperitol (+)-(3R,4S)-14
(0.81 g, 38%, ½a 2D6
ꢂ
¼ þ192:9 (c 2.06, EtOH) [lit.11
½
a 2D0
ꢂ
¼ þ184:0 (c
2.00, EtOH)]; mp = 31–32 °C [lit.11 mp = 32 °C].
It was impossible to evaluate the enantiomeric excess of (+)-cis-
piperitol (+)-(3R,4S)-14 by chromatographic methods with applica-
tion of chiral columns being at our disposal. To determine the
enantiomeric excess value of unreacted alcohol (+)-(3R,4S)-14 it
was converted into the propionate by the chemical esterification
according to standard method. The esterification of (+)-cis-piperitol
(+)-(3R,4S)-14 (60.00 mg, 0.39 mmol) gave (+)-cis-piperityl propio-
nate (+)-(3R,4S)-22 (75.26 mg, yield 92%, ee = 99%). The enantio-
meric excess of (+)-cis-piperitol (+)-(3R,4S)-14 determined in this
way was 99%.
(recrystallization from hexane); ½a D29
ꢂ
¼ þ33:6 (c 0.75, CH3OH); 1H
NMR (600 MHz, CDCl3) d: 0.81 and 0.92 (two s, 6H, (CH3)2C—)),
0.94 (m, 1H, one of CH2-60), 1.32 (dd, J = 12.6 and 5.5 Hz, 1H, one
of CH2-60), 1.54 (m, 1H, one of CH2-2), 1.66 and 1.71 (two m, 2H,
one of CH2-2 and one of CH2-40), 1.82 (m, 1H, one of CH2-40), 2.07
(m, 1H, H-10), 3.50 (s, 1H, –OH), 4.21 and 4.24 (two m, 2H, CH2-
1), 5.19 (s, 1H, –CH(OH)–), 5.42 (dm, J = 10.1 Hz, 1H, H-20), 5.61
(m, 1H, H-30), 7.33–7.46 (m, 5H, –C6H5); IR (film, cmꢀ1): 3448 (s,
br), 3017 (m), 1730 (s), 1456 (m), 1206 (m), 1099 (m), 733 (m),
695 (m); crystal data: C18H24O3, M = 288.37, colourless needle,
crystal dimensions 0.35 ꢁ 0.10 ꢁ 0.07 mm, monoclinic, space
group C2, a = 27.008(3), b = 5.691(2), c = 24.065(3) Å, b = 19.963°,
Treatment of (ꢀ)-cis-piperityl propionate (ꢀ)-(3S,4R)-22 (1.0 g,
4.76 mmola), similar to the hydrolysis of (ꢀ)-trans-piperityl propi-
onate (ꢀ)-(3S,4S)-21), afforded (ꢀ)-cis-piperitol ((–)-(3S,4R)-14)
(0.71 g, yield 97%,
½
a 2D6
ꢂ
¼ ꢀ250:0 (c 1.50, EtOH) [lit.11
V = 3204.6(16) Å3, Z = 8, Dc = 1.195 Mg mꢀ3
0.041, wR = 0.070 (3348 reflections with I > 2 (I)) for 379 variables.
,
T = 100(2) K, R =
½
a 2D0
ꢂ
¼ ꢀ203:0 (c 2.00, EtOH)]; mp = 31–32 °C [lit.11 mp = 32 °C].
r
Crystallographic data (excluding structure factors) for the structure
in this paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication number CCDC
763081. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: +44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk.
3.8. Synthesis of (ꢀ)-(R)-ethyl (50,50-dimethylcyclohex-20-en-10-
yl)acetate (ꢀ)-(R)-18
The mixture of (+)-(R)-11 (1.28 g, 8.31 mmol), triethyl orthoace-
tate (15 mL, 81.3 mmol) and catalytic amount of propionic acid (one
drop) was heated at 138 °C for 7 h under the conditions for distilla-
tive removal of ethyl alcohol. When the reaction was completed (GC,
TLC) the excess of triethyl orthoacetate was distilled off and the
crude product was purified by column chromatography (hexane–
diethyl ether, 20:1). The pure ester (ꢀ)-(R)-18 (1.65 g; yield 84%)
was obtained. Its physical and spectral data are given below.
a2D3 ¼ ꢀ33:5 (c 0.71, CHCl3), nD20 ¼ 1:4540 (lit.17 n2D0 ¼ 1:4578); 1H
NMR (600 MHz, CDCl3) d: 0.91 and 0.94 (two s, 6H, (CH3)2C—)),
1.04 (m, 1H, one of CH2-60), 1.26 (t, J = 7.1 Hz, 3H,
–OCH2CH3), 1.44 (dd, J = 12.6 and 5.4 Hz, 1H, one of CH2-60), 1.70
(ddd, J = 17.7, 4.8 and 1.7 Hz, 1H, one of CH2-40), 1.84 (dm,
Acknowledgement
This work is a part of research supported by Polish Ministry of
Science and Higher Education (Grant No. N N310 146835).
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