Lipase mediated enantiomer and diastereomer separation of 2,2′-[1,2- and 1,3-phenylenebis(oxy)]dicyclohexanols

Article abstract of DOI:10.1016/j.tetasy.2006.08.015

Separation of diastereomeric and enantiomeric mixtures of 2,2′-[1,2- and 1,3-phenylenebis(oxy)]dicyclohexanols rac-3a and meso-3a, and rac-3b and meso-3b-resulting from the reactions of pyrocatechol 1a and resorcinol 1b with cyclohexene oxide 2-were perfo

Full text of DOI:10.1016/j.tetasy.2006.08.015

Tetrahedron: Asymmetry 17 (2006) 2377–2385
Lipase mediated enantiomer and diastereomer separation of
2,20-[1,2- and 1,3-phenylenebis(oxy)]dicyclohexanols
*
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´
´
´
´
Eniko R. Toke, Pal Kolonits, Lajos Novak and Laszlo Poppe
Institute for Organic Chemistry and Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences,
Budapest University of Technology and Economics, H-1111 Budapest, Szt. Gelle´rt te´r 4, Hungary
Received 7 August 2006; accepted 21 August 2006
Available online 26 September 2006
Abstract—Separation of diastereomeric and enantiomeric mixtures of 2,20-[1,2- and 1,3-phenylenebis(oxy)]dicyclohexanols rac-3a and
meso-3a, and rac-3b and meso-3b—resulting from the reactions of pyrocatechol 1a and resorcinol 1b with cyclohexene oxide 2—were
performed using acetylation catalyzed by the highly stereoselective Candida antarctica lipase B (Novozym 435). The absolute configura-
tions of the resulting diols (S,S,S,S)-3a,b, monoacetates (R,R,S,S)-4a,b and diacetates (R,R,R,R)-5a,b were assigned on the basis of
the steric analogy to the acetylation of racemic trans-2-phenoxycyclohexanol rac-6 with the same enzyme resulting in the known acetate
(ꢀ)-(R,R)-7.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Although the enantioselective preparation of the 2-mono-
substituted trans-cyclohexanol derivatives is well studied
and the synthesis of the stereoisomeric mixtures of 2,20-
[1,2- or 1,3-phenylenebis(oxy)]dicyclohexanols is easy
(Scheme 1), there are no examples describing the prepara-
tion of the pure diastereomers and enantiomers of diols
3a and 3b. These optically active compounds are potential
chiral auxiliaries and can also serve as chiral building
blocks in the synthesis of optically active crown ethers.
Using such chiral units as precursors for highly substituted
crown ether extractants will make crown ether molecules
more rigid limiting their conformational flexibility and
can thus affect their extraction or complexation proper-
ties.6,7 For example, meso-2,20-[1,2-phenylenebis(oxy)]dicy-
clohexanol meso-3a was structurally characterized and is a
potential precursor for highly substituted crown ethers.8 In
addition, a diastereomeric and enantiomeric mixture of
racemic and meso-diols can be separated into pure stereo-
isomers by the aid of a highly selective enzyme. For exam-
ple, acetylation of a diastereomeric mixture of racemic and
meso-2,6-bis (1-hydroxyethyl)pyridine with vinyl acetate
and immobilized Candida antarctica lipase B (Novozym
435) resulted in a mixture of enantiopure (S,S)-diol,
(R,S)-monoacetate and (R,R)-diacetate.9 It can also be as-
sumed that a highly selective enzyme retains its strict steric
preference towards one of the local arrangements [either
(1S,2S) or (1R,2R)] of the 2-trans-substituted cyclohexa-
nols. In acetylation reactions with such an enzyme, the
In organic and bioorganic chemistry, demand is increasing
for convenient methods resulting in enantiomerically pure
compounds. For the synthesis of various optically active
molecules, asymmetric chemical reactions using chiral
auxiliaries, among other methods, can be applied. The
cyclohexanol-based chiral auxiliaries such as (+)- or (ꢀ)-
menthol,1 (ꢀ)-8-phenylmenthol,2 (+)- or (ꢀ)-trans-2-phen-
ylcyclohexanol3 are useful in asymmetric transformations.
Since the structurally related trans-2-aryloxycyclohexan-1-
ol derivatives have also gained some interest as chiral aux-
iliaries in organic synthesis, various methods have been
developed for their synthesis in enantiomerically pure
form. For example, pig liver acetone powder (PLAP) was
applied for the enantiomer selective hydrolysis of racemic
trans-1-acetoxy-2-aryloxycyclohexanes to produce (ꢀ)-
(R,R)-trans-2-aryloxycyclohexan-1-ols in high enantio-
meric purities.4 Hydrolysis of the corresponding racemic
acetates can also be performed using other crude enzymes
such as goat, chicken and bovine liver acetone powders
resulting in the corresponding optically active 2-aryloxy-
cyclohexan-1-ols.5
*
Corresponding author. Tel.: +36 1 463 2229; fax: +36 1 463 3297; e-mail:
poppe@mail.bme.hu
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.08.015

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E. R. Toke et al. / Tetrahedron: Asymmetry 17 (2006) 2377–2385
2378
R
S
S
R
OH
OH
OH
OH
OH
OH
R
S
S
OH
OH
O
O
O
K2CO3
EtOH
R
+
O
R
+
R
+
R
O
O
O
R
S
R
1a,b
2
R
S
meso-3a,b
rac-3a,b
OH
OH
OH
OH
OH
=
R
OH
1b
1a
Scheme 1. Synthesis of diastereomeric and enantiomeric mixtures of 2,20-[1,2- and 1,3-phenylenebis(oxy)]dicyclohexanols rac-3a and meso-3a and rac-3b
and meso-3b.
racemates rac-3a,b should split into the intact diol (slowly
reacting enantiomer) and diacetate (forming from the fast
reacting diol enantiomer), whereas acetylation of the
meso-diastereomers meso-3a,b should lead to a pure mono-
acetate enantiomer. Therefore, enzymatic acetylation of the
stereoisomeric mixtures of 2,20-[1,2- or 1,3-phenylene-
bis(oxy)]dicyclohexanols 3a and 3b with a highly selective
enzyme was expected to result in mixtures of enantiopure
diol, monoacetate and diacetate. Herein, we have synthe-
sized from cyclohexene-oxide 2 and pyrocatechol 1a or
resorcinol 1b the stereoisomeric mixtures of two aromatic
bis-cyclohexanols 3a and 3b and developed efficient enzy-
matic methods for separation of their stereoisomers (dia-
stereomers and enantiomers).
TLC using chemically prepared monoacetates 4a and 4b
and diacetates 5a and 5b as standards. Among the enzymes
tested, only Novozym 435 converted the racemic rac-3a
into its diacetate 5a with a conversion of about 50%, and
the meso-form meso-3a almost totally into monoacetate
4a (Scheme 2). In the case of the stereoisomeric mixture
rac-3b and meso-3b, enzymatic acetylation with Novozym
435 also led to diol 3b, monoacetate 4b and diacetate 5b
in the expected 1:2:1 ratio (Scheme 3). On the basis of
the small scale test results, preparative scale separations
of the stereomers of the two target diols 3a and b were per-
formed using only Novozym 435 as a catalyst.
R
S
OAc
OAc
OH
OH
R
S
O
O
Novozym 435
vinyl acetate
2. Results and discussion
rac-3a
+
O
O
The two target diols 2,20-[1,2-phenylenebis(oxy)]dicyclo-
hexanol 3a and 2,20-[1,3-phenylenebis(oxy)]dicyclohexanol
3b were prepared by the ring opening reaction of cyclohex-
ene oxide 2 with the proper phenolic diols 1a or 1b10
(Scheme 1). As previously described,8 the meso- and race-
mic forms of 2,20-[1,2-phenylenebis(oxy)]dicyclohexanol
(meso-3a and rac-3a) were separable by silica gel chroma-
tography. On the other hand, the reaction of cyclohexene
oxide 2 with 1b resulted in a virtually inseparable mixture
of racemic and meso-forms of 2,20-[1,3-phenylene-
bis(oxy)]dicyclohexanols rac-3b and meso-3b. In our previ-
ous study on the enzymatic acetylation of the
diastereomeric mixture (racemic and meso-isomers in a
1:1 ratio) of 2,6-bis(1-hydroxyethyl)pyridine resulting in a
mixture of pure (S,S)-diol, (R,S)-monoacetate and (R,R)-
diacetate in a ratio of 1:2:1,9 the first task was to find a
highly selective enzyme. In order to choose the most selec-
tive enzyme for acetylation of the bis-cyclohexanol sub-
strates 3a and 3b, three series of test reactions were
performed using (i) rac-3a, (ii) meso-3a and (iii) rac-3b
and meso-3b in vinyl acetate in the presence of nine com-
mercially available lipases and a crude esterase prepared
in our laboratory (porcine liver acetone powder, PLAP).
The progress of the enzymatic reactions was checked by
R
S
R
S
(S,S,S,S)-3a
(R,R,R,R)-5a
cat. NaOMe
MeOH
R
R
OAc
OH
R
R
O
O
Novozym 435
vinyl acetate
meso-3a
O
O
S
R
OH
OH
S
R
(R,R,S,S)-4a
(R,R,R,R)-3a
Scheme 2. Novozym 435-catalyzed acetylation of the separated 2,20-[1,2-
phenylenebis-(oxy)]dicyclohexanol diastereomers rac-3a and meso-3a.
For deducing the absolute configuration of the stereoiso-
mers of 2,20-[1,2- or 1,3-phenylenebis(oxy)]dicyclohexanols
3a and 3b, the enzymatic acylation of their monocyclohex-
ene oxide ring opening analogue trans-2-phenoxycyclohex-
anol rac-6 has been used as a model. It can be assumed that

}
E. R. Toke et al. / Tetrahedron: Asymmetry 17 (2006) 2377–2385
2379
S
S
O
O
S
S
OH
OH
(S,S,S,S)-3b
+
rac-3b
cat. NaOMe
MeOH
Novozym 435
vinyl acetate
+
S
R
S
R
O
O
O
O
O
meso-3b
R
R
S
S
OAc
OH
OH
OH
meso-3b
(R,R,S,S)-4b
+
cat. NaOMe
MeOH
R
R
R
R
O
O
O
R
R
R
R
OAc
OH
OAc
OH
(R,R,R,R)-3b
(R,R,R,R)-5b
Scheme 3. Novozym 435-catalyzed acetylation of the diastereomeric and enantiomeric mixture of 2,20-[1,3-phenylenebis(oxy)]dicyclohexanols rac-3b and
meso-3b.
the highly selective C. antarctica lipase B (Novozym 435)
retains its strict steric preference towards one of the local
arrangements [either (1S,2S) or (1R,2R)] of the 2-trans-
aryloxy-substituted cyclohexanol moiety in the acetylation
of rac-6 and also in the acetylation of the 2,20-[1,2- or 1,3-
phenylenebis(oxy)]dicyclohexanol stereoisomers 3a and 3b
as only one of such units of diols 3a or 3b can fit into the
active site at once. As the absolute configuration of (ꢀ)-
trans-2-phenoxycyclohexan-l-ol (ꢀ)-6 was assigned as
(1R,2R)-6 by copper catalyzed monophenylation of (ꢀ)-
(1R,2R)-cyclohexanediol,4 we performed the Novozym
435-catalyzed acetylation of rac-6 to provide enantiomeri-
cally pure (+)-(1S,2S)-6 and (ꢀ)-(1R,2R)-7 (Scheme 4). It
should be noted that the degree of enantiomer selectivity
(E)11 we could achieve in the Novozym 435-catalyzed acet-
ylation (E > 500) was superior to that found in PLAP-cat-
alyzed hydrolysis of rac-7 (E ꢁ 232).4 This experimentally
observed strong preference of Novozym 435 towards the
acetylation of the (1R,2R)-6 enantiomer was also in full
agreement with preliminary enantiomer selectivity calcula-
tions within the active site of this enzyme.12 Based on these
data, we assigned (+)-(1R,2R,10S,20S) absolute configura-
tion to the optically active monoacetates 4a and 4b result-
ing from the enantiotope selective acetylation of meso-3a
and meso-3b diastereomers and (ꢀ)-(1R,2R,10R,20R) abso-
lute configuration to diacetates 5a and 5b forming from the
faster reacting (1R,2R,10R,20R)-enantiomer of rac-3a and
rac-3b.
performed by this enzyme proving the (1R,2R)-stereopre-
ference of the C. antarctica lipase B in hydrolysis as well.
This strict (1R,2R)-stereopreference was observed in enan-
tiotope selective (i.e., asymmetric) acetylation of the meso-
diastereomer meso-3a, leading to exclusive formation of
enantiopure (R,R,S,S)-4a (Scheme 2 and Table 1).
Separation of the stereomeric mixture of rac-3b and meso-
3b was realized in one step by enzymatic acetylation with
vinyl acetate using Novozym 435 lipase as a catalyst
(Scheme 3). The reaction resulted in the formation of enan-
tiopure products such as unreacted diol (S,S,S,S)-3b and
diacetate (R,R,R,R)-5b from rac-3b, and (R,R,S,S)-4b
forming from meso-3b (Table 1). This reaction proved the
strict (1R,2R)-stereopreference of C. antarctica lipase B to-
wards the stereoisomers of 2,20-[1,3-phenylenebis(oxy)]-
dicyclohexanols rac-3b and meso-3b as well. The further
stereoisomers of 3b, meso-3b and (R,R,R,R)-3b, were
prepared in pure form by the chemical hydrolysis of the
corresponding monoacetate (R,R,S,S)-4b and diacetate
(R,R,R,R)-5b.
3. Conclusion
A simple synthesis of the stereoisomeric mixtures of 2,20-
[1,2- or 1,3-phenylenebis(oxy)]-dicyclohexanols 3a and 3b
was developed to provide compounds, which in their stereo-
isomerically pure form, are potential chiral auxiliaries and
can also serve as chiral building blocks in the synthesis of
optically active crown ethers.
The high enantioselectivity of Novozym 435 was confirmed
by preparative scale acetylation of rac-3a yielding virtually
enantiopure diol (S,S,S,S)-3a and diacetate (R,R,R,R)-5a
(Scheme 2 and Table 1). The hydrolysis of (R,R,R,R)-5a
resulting in enantiopure (R,R,R,R)-3a (ee >99.5%) was also
C. antarctica lipase B (Novozym 435) has been found as a
highly stereoselective enzyme for the acetylation of these
Novozym 435
S
+
R
vinyl acetate
O
O
O
R
S
OAc
OH
OH
rac-6
(+)-(S,S)-6
(-)-(R,R)-7
Scheme 4. Novozym 435-catalyzed acetylation of racemic trans-2-phenoxycyclohexanol rac-6.

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E. R. Toke et al. / Tetrahedron: Asymmetry 17 (2006) 2377–2385
2380
Table 1. Specific rotations and enantiomeric composition of stereoisomers 3–5a,b, 6 and 7
25
Compound
Yield (%)
½aꢂD
ee (%)
c 1, CHCl3
c 1, acetone
c 1, EtOH
(S,S,S,S)-3a
(R,R,R,R)-3a
(S,S,S,S)-3b
(R,R,R,R)-3b
(R,R,S,S)-4a
(R,R,S,S)-4b
(R,R,R,R)-5a
(R,R,R,R)-5b
(S,S)-6
21
75
32
75
52
43
16
34
44
38
84
+125.5
ꢀ130.6
+92.4
ꢀ93.3
+51.2
+34.5
ꢀ8.6
+85.5
ꢀ89.0
+78.3
ꢀ79.3
+21.4
+18.8
ꢀ30.9
ꢀ8.8
+65.8
ꢀ68.5
+92.3
96a
>99b
>98a
>99b
>98a
>98a
>99c
>99c
>99f
>99f
>99f
ꢀ92.9
+28.1
+25.7
ꢀ6.8
ꢀ3.1
Not soluble
+69.5d
ꢀ10.0
ꢀ74.9e
+90.8
ꢀ5.2
+43.9
ꢀ15.2
ꢀ54.1
(R,R)-7
(R,R)-6
ꢀ82.9
a Ee was determined by 500 MHz 1H NMR using Pr shift reagent, see Section 4.16.
b Ee was determined by specific rotation compared to the (S,S,S,S)-3a or (S,S,S,S)-3b.
c Ee was deduced from hydrolysis to alcohols (R,R,R,R)-3a or (R,R,R,R)-3b.
25
½aꢂD ¼ þ72:7 (c 1, MeOH); lit.:4 = +66.1 (c 1.26, MeOH).
d
25
½aꢂD ¼ ꢀ80:9 (c 1, MeOH); lit.:4 = ꢀ79.1 (c 0.86, MeOH).
e
f Ee was determined by GC on Hydrodex-b-6-TBDM column, see Section 4.1.3.
diols to provide an easy method for the separation of the
stereoisomeric forms of 3a or 3b as enantiopure diols
(S,S,S,S)-3a or 3b, monoacetates (R,R,S,S)-4a or 4b and
diacetates (R,R,R,R)-5a or 5b.
125 MHz for 13C; TMS; ppm on d scale) in CDCl3 if not sta-
ted otherwise. The 1H and 13C NMR signals were assigned
on the basis of APT, HMQC, HMBC and COSY experi-
ments. GC analyses for the enantiomer separation of 6
and 7 were carried out on HP 5890 instrument equipped
with FID detector using H2 as carrier gas (injector:
250 ꢁC, detector: 250 ꢁC, head pressure: 12 psi, 1:80 split ra-
tio) on Hydrodex-b-6-TBDM (25 m · 0.25 mm · 0.25 lm
film, Macherey & Nagel, No.: 21519/11) column. IR spectra
were taken on a Specord 2000 spectrometer and the wave
numbers are reported in cmꢀ1. Optical rotations were deter-
mined on a Perkin Elmer 241 polarimeter. TLC was carried
out on Kieselgel 60 F254 (Merck) sheets. Spots were visual-
ized by treatment with 5% ethanolic phosphomolybdic acid
solution and heating of the dried plates.
The Novozym 345-catalyzed acetylation of the racemic
trans-2-phenoxycyclohexanol rac-6 with the same enzyme
resulting in the known acetate (ꢀ)-(R,R)-7 proved to not
only be a useful analogy to assign (+)-(1R,2R,10S,20S)
absolute configuration to monoacetates 4a and 4b and
(ꢀ)-(1R,2R,10R,20R) absolute configuration to diacetates
5a and 5b but also its enantiomer selectivity (E > 500)
exceeded that found in PLAP-catalyzed hydrolysis of the
corresponding racemic acetate rac-7.
4.2. 2,20-[1,2-Phenylenebis(oxy)]dicyclohexanol rac-3a and
meso-3a
4. Experimental
4.1. Materials and methods
Cyclohexene oxide 2 (2.94 g, 30 mmol) was added to a mix-
ture of pyrocatechol 1a (1.1 g, 10 mmol) and potassium
carbonate (4.14 g, 30 mmol) in ethanol (50 mL) and the
resulting mixture was stirred at reflux for 15 h. The reac-
tion mixture was filtered and washed with ethanol
(2 · 20 mL). The combined filtrates were concentrated
under reduced pressure to a volume of 15 mL and diluted
with dichloromethane (50 mL). The resulting solution
was washed with 5% HCl (30 mL) and brine (2 · 20 mL),
dried over sodium sulfate and concentrated under reduced
pressure. The residue was subjected to column chromato-
graphy (silica gel/hexane–acetone 10:1 to 10:2) to give
rac-3a (0.820 g, 18%) and meso-3a (0.880 g, 19.5%) as white
powders.
4.1.1. Reagents and solvents. Vinyl acetate, acetic anhyd-
ride, cyclohexene oxide, pyrocatechol, resorcinol, sodium
methoxide and triethylamine were purchased from Aldrich.
All solvents were of analytical grade or freshly distilled.
Praseodymium D-3-heptafluorobutyrylcamphorate was ob-
tained from Alfa Aesar (Karlsruhe, Germany). Racemic
trans-2-phenoxycyclohexanol rac-6 and trans-2-phenoxy-
cyclohexyl acetate rac-7 are known compounds.4
4.1.2. Biocatalysts. Lipase AK, lipase AY and lipase PS
were obtained from Amano Europe. Lipozyme IM 20,
Lipozyme TL IM and Novozym 435 were products of
Novozymes, Denmark. Lipase from Pseudomonas fluores-
cens was purchased from Fluka. PPL was obtained from
Sigma. Pig liver acetone powder (PLAP) was prepared in
our laboratory.
4.2.1. Racemic (1S*,2S*,10S*,20S*)-2,20-[1,2-phenylenebis-
(oxy)]dicyclohexanol rac-3a. Mp: 102–104 ꢁC (aceto-
nitrile); IR (KBr): 3450, 2962, 1590, 1448, 1418, 1356,
1290, 1226, 1118, 1080, 1018, 914; 1H NMR: 1.28
4.1.3. Analytical methods. NMR spectra were recorded on
a Bruker DRX-500 spectrometer (500 MHz for 1H and
ð2H; m; H5 þ H5 Þ, 1.31 ð4H; m; H4 þ H4 þ H6 þ H6 Þ,
0
0
0

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E. R. Toke et al. / Tetrahedron: Asymmetry 17 (2006) 2377–2385
2381
0
0
0
1.46 ð2H; m; H3 þ H3 Þ, 1.71 ð2H; m; H4 þ H4 Þ, 1.74
ð3H; m; H3 þ H5 þ H6Þ, 1.62 (1H, m, H3), 1.75
0
0
0
0
ð2H; m; H5 þ H5 Þ, 2.08 ð2H; m; H6 þ H6 Þ, 2.20 ð2H; m;
ð3H; m; H4 þ H4 þ H5 Þ, 1.78 (1H, m, H5), 1.94 (3H, s,
0
0
0
0
H3 þ H3 Þ, 3.64 (2H, br s, 2OH), 3.73 ð2H; m; H1 þ H1 Þ,
13
CH3), 2.10 ð2H; m; H6 þ H6 Þ, 2.20 ð2H; m; H3 þ H3 Þ,
0 0
0
3.82 ð2H; br s; H2 þ H2 Þ, 6.96 (2H, m, HAr4 + HAr5),
3.4 (1H, br s, OH), 3.76 ð2H; m; H1 þ H2 Þ, 4.25 (1H, m,
H2), 5.07 (1H, m, H1), 6.91 (1H, t, HAr5), 6.96 (1H, t,
HAr4), 6.99 (1H, d, HAr6), 7.02 (1H, d, HAr3); 13C NMR:
21.11 (CH3), 23.10 (C4 or C5), 23.14 (C4 or C5), 23.85
0
7.01 (2H, m, HAr3 + HAr6); C NMR: 23.85 ðC4 þ C4 Þ,
0
0
0
24.30 ðC5 þ C5 Þ, 30.70 (C3 + C3 ), 32.38 ðC6 þ C6 Þ, 73.69
0
0
ðC1 þ C1 Þ, 82.63 (C2 + C2 ), 119.39 (CAr3 + CAr6), 123.13
(CAr4 + CAr5), 149.51 (CAr1 + CAr2). Anal. Calcd for
C18H26O4: C, 70.56, H, 8.55. Found: C, 70.53; H, 8.56.
0
0
ðC5 Þ, 24.16 ðC4 Þ, 29.77 (C3 or C6), 29.84 (C3 or C6),
0
0
0
30.15 ðC3 Þ, 32.12 ðC6 Þ, 73.43 ðC1 Þ, 74.60 (C1), 79.03
0
(C2), 85.69 ðC2 Þ, 116.63 (CAr3), 118.45 (CAr6), 121.77
(CAr5), 122.36 (CAr4), 148.83 (CAr2), 149.24 (CAr1), 170.70
(COO). Anal. Calcd for C20H28O5: C, 68.94; H, 8.10.
Found: C, 69.00; H, 8.07.
4.2.2. meso-(1S,2S,10R,20R)-2,20-[1,2-Phenylenebis(oxy)]-
dicyclohexanol meso-3a. Mp: 112–115 ꢁC (acetonitrile);
IR (KBr): 3448, 2958, 1588, 1448, 1416, 1360, 1288, 1224,
1
1120, 1080, 1020, 912, 816; H NMR: 1.25 ð2H; m; H5þ
4.5. Racemic (1S*,2S*,10S*,20S*)-2,20-diacetoxy-[1,2-phen-
ylenebis(oxy)]dicyclohexane rac-5a
0
0
0
H5 Þ, 1.33 ð4H; m; H4 þ H4 þ H6 þ H6 Þ, 1.41 ð2H; m;
0
0
0
H3 þ H3 Þ, 1.74 ð4H; m; H4 þ H4 þ H5 þ H5 Þ, 2.10
0
0
ð2H; m; H6 þ H6 Þ,
2.24
ð2H; m; H3 þ H3 Þ,
3.71
Racemic 2,20-[1,2-phenylenebis(oxy)]dicyclohexanol rac-3a
(200 mg, 0.65 mmol), acetic anhydride (133 mg, 1.30
mmol), triethylamine (10 mL) and DMAP (5 mg) were stir-
red at rt for 7 days. The reaction mixture was diluted with
chloroform (20 mL) and washed with water (3 · 15 mL),
5% HCl solution (5 mL), saturated NaHCO3 solution
(5 mL) and brine (5 mL). The organic solution was dried
over sodium sulfate and concentrated under reduced pres-
sure. The residue was purified by column chromatography
(silica gel/hexane–acetone 10:2) to give rac-5a (96 mg, 40%)
as a colourless oil. IR (film): 3480, 2936, 2864, 1736, 1496,
0
0
ð4H; m; H1 þ H1 þ H2 þ H2 Þ, 3.88 (2H, br s, 2OH), 6.95
(2H, m, HAr4 + HAr5), 6.99 (2H, m, HAr3 + HAr6); 13C
0
0
NMR: 24.00 ðC4 þ C4 Þ, 24.15 ðC5 þ C5 Þ, 30.02
0
0
0
ðC3 þ C3 Þ, 32.33 ðC6 þ C6 Þ, 73.41 ðC1 þ C1 Þ, 86.30
0
ðC2 þ C2 Þ, 118.95 (CAr3 + CAr6), 122.74 (CAr4 + CAr5),
149.08 (CAr1 + CAr2). Anal. Calcd for C18H26O4: C,
70.56, H, 8.55. Found: C, 70.57; H, 8.49.
4.3. 2,20-[1,3-Phenylenebis(oxy)]dicyclohexanols rac-3b and
meso-3b
1
1456, 1372, 1244, 1040, 752; H NMR: 1.32 ð2H; m; H4þ
Cyclohexene oxide 2 (6 g, 61 mmol) was added to a mixture
of resorcinol 1b (2.2 g, 20 mmol) and potassium carbonate
(6.94 g, 50 mmol) in ethanol (80 mL); the resulting mixture
was stirred at reflux for 15 h. The reaction mixture was fil-
tered and washed with ethanol (2 · 30 mL). The combined
filtrates were concentrated under reduced pressure to a vol-
ume of 20 mL and diluted with dichloromethane (80 mL).
The resulting solution was washed with 5% HCl (30 mL)
and brine (2 · 20 mL), dried over sodium sulfate and con-
centrated under reduced pressure. The residue was purified
by column chromatography (silica gel/hexane–acetone
10:2) to give a mixture of rac-3b and meso-3b (4.2 g,
45%) as a white powder. Mp: 116–120 ꢁC (hexane–acetone
10:2); IR (KBr): 3456, 2928, 2856, 1592, 1488, 1452, 1264,
1180, 1156, 1072, 1044, 832, 768. Anal. Calcd for
C18H26O4: C, 70.56, H, 8.55. Found: C, 70.52; H, 8.51.
0
0
0
H4 Þ, 1.41 ð4H; m; H5 þ H5 þ H6 þ H6 Þ, 1.57 ð2H; m;
0
0
0
H3 þ H3 Þ, 1.72 ð4H; m; H4 þ H4 þ H5 þ H5 Þ, 1.93 (6H,
0
0
s, 2CH3), 2.07 ð4H; m; H3 þ H3 þ H6 þ H6 Þ, 4.20
0
0
ð2H; m; H2 þ H2 Þ, 4.97 ð1H; m; H1 þ H1 Þ, 6.89 (2H, m,
HAr4 + HAr5), 6.97 (2H, m, HAr3 + HAr6); 13C NMR:
0
0
21.22 (2CH3), 22.96 ðC4 þ C4 þ C5 þ C5 Þ, 29.56 ðC3þ
0
0
0
0
C3 or C6 þ C6 Þ, 29.85 ðC3 þ C3 or C6 þ C6 Þ, 74.62
0
0
ðC1 þ C1 Þ, 78.70 ðC2 þ C2 Þ, 118.38 (CAr3 + CAr6), 122.05
(CAr4 + CAr5), 149.25 (CAr1 + CAr2), 170.36 (2 COO).
Anal. Calcd for C22H30O6: C, 67.67; H, 7.74. Found: C,
67.75; H, 7.71.
4.6. Chemical acetylation of 2,20-[1,3-Phenylene-
bis(oxy)]dicyclohexanols rac-3b and meso-3b
A diastereomeric mixture of rac-3b and meso-3b (200 mg,
0.65 mmol), acetic anhydride (102 mg, 1.00 mmol) and
DMAP (5 mg) were added to triethylamine (10 mL) and
the resulting mixture was stirred at rt for 7 days. The reac-
tion mixture was diluted with chloroform (20 mL) and
washed with water (3 · 15 mL), 5% HCl solution (5 mL),
saturated NaHCO3 solution (5 mL) and brine (5 mL).
The organic solution was dried over sodium sulfate and
concentrated under reduced pressure. The residue was puri-
fied by column chromatography (silica gel/hexane–acetone
10:0.5 to 10:2) to give rac-4b and meso-4b (43 mg, 19%) and
rac-5b and meso-5b (66 mg, 26%) as colourless oils.
4.4. Racemic (1R*,2R*)-2-(2-{[(1S*,2S*)-2-hydroxy-
cyclohexyl]oxy}phenoxy)cyclohexyl acetate rac-4a
meso-2,20-[1,2-Phenylenebis(oxy)]dicyclohexanol meso-3a
(300 mg, 0.65 mmol), acetic anhydride (100 mg, 0.98
mmol), triethylamine (10 mL) and DMAP (5 mg) were stir-
red at rt for 7 days. The reaction mixture was diluted with
chloroform (20 mL) and washed with water (3 · 15 mL),
5% HCl solution (5 mL), saturated NaHCO3 solution
(5 mL) and brine (5 mL). The organic solution was dried
over sodium sulfate and concentrated under reduced pres-
sure. The residue was purified by column chromatography
(silica gel/hexane–acetone 10:1) to yield rac-4a (87 mg,
40%) as a colourless oil. IR (film): 3504, 2936, 2864,
The monoacetates rac-4b and meso-4b and diacetates
rac-5b and meso-5b were prepared as standards for TLC
analyses and therefore no detailed spectral characterization
of the diastereomeric mixtures was performed.
1
1736, 1592, 1496, 1456, 1376, 1256, 1040, 748; H NMR:
0
0
0
1.28 ð1H; m; H5 Þ, 1.34 ð3H; m; H4 þ H4 þ H6 Þ, 1.44

}
E. R. Toke et al. / Tetrahedron: Asymmetry 17 (2006) 2377–2385
2382
4.7. Screening the enzymatic acetylation of racemic and
meso-2,20-[1,2-phenylenebis(oxy)]dicyclohexanols meso-3a
and rac-3a and 2,20-[1,3-phenylenebis(oxy)]dicyclohexanols
rac-3b and meso-3b
resulting mixture was shaken at rt for 7 days. After remov-
ing the enzyme by filtration, vinyl acetate was evaporated
off under reduced pressure and the residue was purified
by column chromatography (silica gel/hexane–acetone
10:0.5) to yield (R,R,S,S)-4a (227 mg, 52%) as a colourless
oil.
Enzymes (20 mg, listed in Section 4.1.2) were added to
solutions of racemic and meso-forms of 2,20-[1,2-phenyl-
enebis(oxy)]dicyclohexanol rac-3a/meso-3a, and to 2,20-
4.10.1. (1R,2R)-2-(2-{[(1S,2S)-2-Hydroxycyclohexyl]oxy}-
[1,3-phenylenebis(oxy)]dicyclohexanol
rac-3b + meso-3b
25
phenoxy)cyclohexyl acetate (R,R,S,S)-4a. ½aꢂD ¼ þ51:2
(20 mg, each diol with each enzyme) in vinyl acetate
(1 mL). The resulting suspensions were shaken at rt/
1000 rpm in a sealed glass vial for 5 days. The progress
of the reactions was checked by TLC (hexane–acetone
10:4) using chemically prepared monoacetate rac-4a,b
and diacetate rac-5a,b standards.
25
25
(c 1.0, CHCl3); ½aꢂD ¼ þ21:4 (c 1.0, acetone); ½aꢂD
¼
þ28:4 (c 1.0, EtOH); IR, 1H and 13C NMR data were indis-
tinguishable from the spectra of rac-4a.
4.11. Novozym 435 catalyzed acetylation of the diastereo-
meric mixture of 2,20-[1,3-phenylenebis(oxy)]dicyclohexanols
rac-3b and meso-3b
4.8. Novozym 435 catalyzed acetylation of racemic 2,20-
[1,2-phenylenebis(oxy)]dicyclohexanol rac-3a
A diastereomeric mixture of rac-3b and meso-3b (350 mg,
1.15 mmol) and Novozym 435 (350 mg) were added to
vinyl acetate (25 mL) and the resulting mixture was shaken
at rt for 10 days. After removing the enzyme by filtration,
vinyl acetate was evaporated off under reduced pressure
and the residue was purified by column chromatography
(silica gel/hexane–acetone 10:0.5 to 10:4) to yield
(S,S,S,S)-3b (102 mg, 30%), (R,R,S,S)-4b (157 mg, 41%)
and (R,R,R,R)-5a (128 mg, 31%) as white powders.
Racemic diol rac-3a (400 mg, 1.52 mmol) and Novozym
435 (400 mg) were added to vinyl acetate (25 mL) and the
resulting mixture was shaken at rt for 9 days. After remov-
ing the enzyme by filtration, vinyl acetate was evaporated
off under reduced pressure and the residue was purified
by column chromatography (silica gel/hexane–acetone
10:0.5 to 10:4) to yield (S,S,S,S)-3a (83 mg, 21%) as a white
powder and (R,R,R,R)-5a (79 mg, 16%) as colourless oil.
4.11.1. (1S,2S,10S,20S)-2,20-[1,3-Phenylenebis(oxy)]dicyclo-
hexanol (S,S,S,S)-3b. Mp 126–128 ꢁC (hexane–acetone
4.8.1. (1S,2S,10S,20S)-2,20-[1,2-Phenylenebis(oxy)]dicyclo-
25
hexanol (S,S,S,S)-3a. Mp: 108–110 ꢁC; ½aꢂD ¼ þ125:5 (c
25
25
25
25
10:2); ½aꢂD ¼ þ92:4 (c 1.0, CHCl3); ½aꢂD ¼ þ78:3 (c 1.0,
1.0, CHCl3); ½aꢂD ¼ þ85:5 (c 1.0, acetone); ½aꢂD ¼ þ65:8
25
(c 1.0, EtOH); IR, H and 13C NMR data were indistin-
1
acetone); ½aꢂD ¼ þ92:3 (c 1.0, EtOH); IR (KBr): 3432,
1
2944, 2864, 1592, 1488, 1456, 1264, 1160, 1040, 776; H
guishable from the spectra of rac-3a.
0
0
0
NMR: 1.33 ð6H; m; H3 þ H3 þ H4 þ H4 þ H5 þ H5 Þ,
0
0
1.41 ð2H; m; H6 þ H6 Þ, 1.77 ð4H; m; H4 þ H4 þ H5 þ
4.8.2.
1,2-Phenylenebis[oxy(1R,2R)cyclohexane-2,1-diyl]
25
0
0
0
H5 Þ, 2.12 ð2H; m; H6 þ H6 Þ, 2.18 ð2H; m; H3 þ H3 Þ,
diacetate (R,R,R,R)-5a. ½aꢂD ¼ ꢀ8:6 (c 1.0, CHCl3);
25
25
0
2.52 (2H, br s, 2OH), 3.72 ð2H; m; H1 þ H1 Þ, 4.00
½aꢂD ¼ ꢀ30:9 (c 1.0, acetone); ½aꢂD ¼ ꢀ6:8 (c 1.0, EtOH);
1
IR, H and 13C NMR data were indistinguishable from
0
ð2H; m; H2 þ H2 Þ, 6.57 (1H, s, HAr2), 6.58 (2H, d,
J ꢁ 7.5 Hz, HAr4,6), 7.17 (1H, t, J ꢁ 7.5 Hz, HAr5); 13C
the spectra of rac-5a.
0
0
0
NMR: 23.88 ðC4 þ C4 or C5 þ C5 Þ, 23.98 ðC4 þ C4 or
0
0
0
4.9. (1R,2R,10R,20R)-2,20-[1,2-Phenylenebis(oxy)]dicyclo-
hexanol (R,R,R,R)-3a
C5 þ C5 Þ, 29.22 ðC6 þ C6 Þ, 32.05 ðC3 þ C3 Þ, 73.40
0
0
ðC1 þ C1 Þ, 82.19 ðC2 þ C2 Þ, 101.96 (CAr2), 108.87
(CAr4 + CAr6), 129.99 (CAr5), 159.16 (CAr1 + CAr3). Anal.
Calcd for C18H26O4: C, 70.56, H, 8.55. Found: C, 70.58;
H, 8.52.
A solution of diacetate (R,R,R,R)-5a (40 mg, 1.21 mmol)
and sodium methoxide (4 mg) in methanol (2 mL) was stir-
red at rt for 48 h. The resulting mixture was diluted with
dichloromethane (20 mL) and washed with 5% HCl
(25 mL) and satd Na2CO3 solution (2 · 5 mL) and dried
over K2CO3. After concentrating under reduced pressure,
the residue was purified by column chromatography (silica
gel/hexane–acetone 10:4) to yield (R,R,R,R)-3a (25 mg,
75%) as a white powder. Mp: 107–110 ꢁC (acetonitrile);
4.11.2. (1R,2R)-2-(3-{[(1S,2S)-2-Hydroxycyclohexyl]oxy}-
phenoxy)cyclohexyl acetate (R,R,S,S)-4b. Mp 56–58 ꢁC
25
25
(hexane); ½aꢂD ¼ þ34:5 (c 1.0, CHCl3); ½aꢂD ¼ þ18:8 (c
25
1.0, acetone); ½aꢂD ¼ þ25:7 (c 1.0, EtOH); IR (film):
3488, 2928, 2864, 1720, 1600, 1492, 1376, 1256, 1144,
1
0
1064, 1040, 844, 768; H NMR: 1.30 ð1H; m; H6 Þ, 1.33
25
25
½aꢂD ¼ ꢀ130:6 (c 1.0, CHCl3); ½aꢂD ¼ ꢀ89:0 (c 1.0, acet-
0
0
0
ð2H; m; H4 þ H5 Þ, 1.38 ð3H; m; H4 þ H5 þ H3 Þ, 1.42
25
1
one); ½aꢂD ¼ ꢀ68:5 (c 1.0, EtOH); IR, H and 13C NMR
data were indistinguishable from the spectra of rac-3a.
(1H, m, H3 or H6), 1.53 (1H, m, H3 or H6), 1.72 (2H, m,
0
0
H4 + H5), 1.75 ð2H; m; H4 þ H5 Þ, 1.96 (3H, s, CH3),
0
2.04 (1H, m, H3 or H6), 2.09 (2H, m, ðH3 or H6Þ þ H3 Þ,
4.10. Novozym 435 catalyzed acetylation of meso-2,20-
[1,2-phenylenebis(oxy)]dicyclohexanol meso-3a
2.16 ð1H; m; H6 Þ, 2.3 (1H, br s, OH), 3.70 ð1H; m; H2 Þ,
0
0
0
3.98 ð1H; m; H1 Þ, 4.20 (1H, m, H2), 4.96 (1H, m, H1),
6.53 (2H, m, HAr4 + HAr6), 6.55 (1H, m, HAr2), 7.14 (1H,
meso-Diol meso-3a (400 mg, 1.52 mmol) and Novozym 435
m, HAr5); 13C NMR: 21.17 (CH3), 22.90 (C4 or C5), 23.00
0
0
0
0
(400 mg) were added to vinyl acetate (25 mL) and the
(C4 or C5), 23.84 ðC4 or C5 Þ, 23.92 ðC4 or C5 Þ, 29.19

}
E. R. Toke et al. / Tetrahedron: Asymmetry 17 (2006) 2377–2385
2383
0
0
0
ðC6 Þ, 29.59 (2C: C3 and C6), 31.99 ðC3 Þ, 73.31 ðC2 Þ, 73.93
(CAr2), 108.88 (CAr4 + CAr6), 129.98 (CAr5
(CAr1 + CAr3). Anal. Calcd for C18H26O4: C, 70.56, H,
8.55. Found: C, 70.61; H, 8.48.
)
159.13
0
(C1), 77.25 (C2), 82.06 ðC1 Þ, 104.83 (CAr2), 108.75 (CAr6),
108.92 (CAr4), 129.84 (CAr5), 159.07 (CAr3), 159.52 (CAr1),
170.51 (COO). Anal. Calcd for C20H28O5: C, 68.94; H,
8.10. Found: C, 68.77; H, 8.13.
4.14. Racemic (1R*,2R*)-2-(3-{[(1S*,2S*)-2-hydroxy-
cyclohexyl]oxy}phenoxy)cyclohexyl acetate rac-4b
4.11.3. 1,3-Phenylenebis[oxy(1R,2R)cyclohexane-2,1-diyl]
diacetate (R,R,R,R)-5b. Mp 118–120 ꢁC (hexane);
meso-2,20-[1,3-Phenylenebis(oxy)]dicyclohexanol meso-3b
(30 mg, 0.098 mmol), acetic anhydride (24 mg, 0.24 mmol),
triethylamine (1.2 mL) and DMAP (1 mg) were stirred at rt
for 7 days. The reaction mixture was diluted with chloro-
form (10 mL) and washed with water (3 · 5 mL), 5% HCl
solution (3 mL), saturated NaHCO3 solution (3 mL) and
brine (3 mL). The organic solution was dried over sodium
sulfate and concentrated under reduced pressure. The resi-
due was purified by column chromatography (silica gel/
hexane–acetone 10:2) to yield rac-4b (17 mg, 50%) as col-
25
25
½aꢂD ¼ ꢀ3:1 (c 1.0, CHCl3); ½aꢂD ¼ ꢀ8:8 (c 1.0, acetone);
IR (film): 2944, 2872, 1736, 1588, 1488, 1368, 1272, 1236,
1
0
1184, 1156, 1048; H NMR: 1.38 ð4H; m; H4 þ H4 þ
0
0
H5 þ H5 Þ, 1.44 ð2H; m; H3 þ H3 Þ, 1.52 ð2H; m; H6 þ
0
0
0
H6 Þ, 1.73 ð4H; m; H4 þ H4 þ H5 þ H5 Þ, 1.95 (6H, s,
0
0
2CH3), 2.10 ð4H; m; H3 þ H3 þ H6 þ H6 Þ, 4.19 ð2H; m;
0
0
H2 þ H2 Þ, 4.96 ð2H; m; H1 þ H1 Þ, 6.51 (1H, m,
HAr2), 6.52 (2H, m, HAr4 + HAr6), 7.12 (1H, m, HAr5);
13C NMR: 21.14 (2CH3), 22.99 ðC4 þ C4 or C5 þ C5 Þ,
0
0
1
ourless oil. H and 13C NMR spectra of rac-4b were iden-
0
0
0
0
23.10 ðC4 þ C4 or C5 þ C5 Þ, 29.66 ðC3 þ C3 þ C6 þ C6 Þ,
0
0
74.04 ðC1 þ C1 Þ, 77.53 ðC2 þ C2 Þ, 104.73 (CAr2), 108.71
(CAr4 + CAr6), 129.67 (CAr5), 159.42 (CAr1 + CAr3), 170.43
(2COO). Anal. Calcd for C22H30O6: C, 67.67; H, 7.74.
Found: C, 67.61; H, 7.77.
tical to the spectra of pure enantiomer (R,R,S,S)-4b.
4.15. Novozym 435 catalyzed acetylation of racemic trans-2-
phenoxycyclohexanol rac-6
4.12. (1R,2R,10R,20R)-2,20-[1,3-Phenylenebis(oxy)]dicyclo-
hexanol (R,R,R,R)-3b
Racemic alcohol rac-6 (500 mg, 2.6 mmol) and Novozym
435 (500 mg) were added to vinyl acetate (25 mL) and the
resulting mixture was shaken at rt for 3 h. After removing
the enzyme by filtration, vinyl acetate was evaporated off
under reduced pressure and the residue was purified by col-
umn chromatography (silica gel/toluene–ethylacetate
10:0.2 to 10:0.4) to yield (S,S)-6 (220 mg, 44%) as a white
powder and (R,R)-7 (230 mg, 38%) as colourless oil.
A solution of (R,R,R,R)-5b (40 mg, 1.21 mmol) and
sodium methoxide (4 mg) in methanol (2 mL) was stirred
at rt for 48 h. The resulting mixture was diluted with di-
chloromethane (20 mL) and washed with 5% HCl (20
mL) and satd Na2CO3 solution (2 · 5 mL) and dried over
K2CO3. After concentrating under reduced pressure, the
residue was purified by column chromatography (silica
gel/hexane–acetone 10:4) to yield (R,R,R,R)-3b (26 mg,
78%) as a white powder. Mp 128–129 ꢁC (hexane–acetone
4.15.1. (+)-(1S,2S)-2-Phenoxycyclohexanol (1S,2S)-6. Mp
25
82–83 ꢁC (hexane), lit.:13 82 ꢁC (hexane); ½aꢂD
¼
25
25
þ90:8 ðc 1; CHCl3Þ; ¼ þ43:9 ðc 1; acetoneÞ; ¼ þ69:5 ðc 1;
EtOHÞ, +72.7 (c 1, MeOH) (ee > 99% by GC), lit.:4 +66.1
10:4); ½aꢂD ¼ ꢀ93:3 (c 1.0, CHCl3); ½aꢂD ¼ ꢀ79:3 (c 1.0,
25
acetone); ½aꢂD ¼ ꢀ92:9 (c 1.0, EtOH); IR, 1H and 13C
1
(c 1.26, MeOH); H NMR: 1.35 (3H, m, H3 + H4 + H5),
NMR data were indistinguishable from the spectra of
1.42 (1H, m, H6), 1.78 (2H, m, H4 + H5), 2.13 (1H, m,
H6), 2.18 (1H, m, H3), 2.56 (1H, s, OH), 3.74 (1H, m,
H1), 4.03 (1H, m, H2), 6.98 (2H, d, J ꢁ 8 Hz, HAr2,6),
6.99 (1H, t, J ꢁ 8 Hz, HAr4), 7.31 (2H, t, J ꢁ 8 Hz,
HAr3,5); 13C NMR: 23.85 (H4 or H5), 23.92 (H4 or H5),
29.14 (H3), 32.00 (H6), 73.34 (H1), 82.13 (H2), 116.34
(HAr12,6), 121.20 (HAr4), 129.48 (HAr3,5), 157.80 (HAr1).
IR, H and 13C NMR data agree well with the published
spectra4 of (1S,2S)-6.
rac-3b.
4.13. meso-2,20-[1,3-Phenylenebis(oxy)]dicyclohexanol
meso-3b
A
solution of monoacetate (R,R,S,S)-4b (80 mg,
0.232 mmol) and sodium methoxide (6 mg) in methanol
(4 mL) was stirred at rt for 48 h. The resulting mixture
was diluted with dichloromethane (30 mL) and washed
with 5% HCl (30 mL) and satd Na2CO3 solution
(2 · 10 mL) and dried over K2CO3. After concentrating
under reduced pressure, the residue was purified by column
chromatography (silica gel/hexane–acetone 10:4) to yield
meso-3b (50 mg, 72%) as a white semisolid. IR (nujol):
3448, 1586, 1256, 1154, 1036; 1H NMR: 1.30
4.15.2. (ꢀ)-(1R,2R)-2-Phenoxycyclohexyl acetate (1R,2R)-
25
7. ½aꢂD ¼ ꢀ82:9 ðc 1; CHCl3Þ; ¼ ꢀ54:1 ðc 1; acetoneÞ; ¼
ꢀ74:9 ðc 1; EtOHÞ (ee >99% by GC); 1H NMR: 1.38 (1H,
m, H4 or H5), 1.46 (2H, m (H4 or H5) + H6), 1.58 (1H, m,
H3), 1.77 (2H, m, H4 + H5), 1.96 (3H, s, –CH3), 2.08 (1H,
m, H6), 2.16 (1H, m, H3), 4.25 (1H, m, H2), 5.01 (1H, m,
H1), 6.96 (1H, t, J ꢁ 8 Hz, HAr4), 6.98 (2H, d, J ꢁ 8 Hz,
HAr2,6), 7.29 (2H, t, J ꢁ 8 Hz, HAr3,5); 13C NMR: 21.02
(CH3), 22.94 (H4 or H5), 23.03 (H4 or H5), 29.62 (H3 or
H6), 29.67 (H3 or H6), 74.09 (H1), 77.56 (H2), 116.26
(HAr2,6), 120.94 (HAr4), 129.30 (HAr3,5), 158.24 (HAr1),
0
0
0
ð6H; m; H3 þ H3 þ H4 þ H4 þ H5 þ H5 Þ, 1.39 ð2H; m;
0
0
0
H6 þ H6 Þ, 1.74 ð4H; m; H4 þ H4 þ H5 þ H5 Þ, 2.09
0
0
ð2H; m; H6 þ H6 Þ, 2.15 ð2H; m; H3 þ H3 Þ, 2.57 (2H, br
0
0
s, 2OH), 3.70 ð2H; m; H1 þ H1 Þ, 3.98 ð2H; m; H2 þ H2 Þ,
6.54 (2H, br s, HAr4,6), 6.56 (1H, br s, HAr2), 7.15 (1H, t,
J ꢁ 8 Hz, HAr5); 13C NMR: 23.88 ðC4 þ C4 or C5 þ C5 Þ,
0
0
1
170.36 (COO). IR, H and 13C NMR data agree well with
0
0
0
23.95 ðC4 þ C4 or C5 þ C5 Þ, 29.20 ðC6 þ C6 Þ, 30.05
the published spectra4 of (1R,2R)-7.
0
0
0
ðC3 þ C3 Þ, 73.38 ðC1 þ C1 Þ, 82.19 ðC2 þ C2 Þ, 105.09

}
2384
E. R. Toke et al. / Tetrahedron: Asymmetry 17 (2006) 2377–2385
B
A
OH
OH
OH
O
O
O
10 mg
+
95.7 1.3 %ee
-
O
OH
rac-3a
(
S,S,S,S)-3a
+ Pr-shift
0 mg
5 mg
10 mg
20 mg
rac-3a
+ Pr-shift
7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8
7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8
Figure 1.
4.16. Determination of the enantiomeric composition of the
optically active (S,S,S,S)-3a, (S,S,S,S)-3b, (R,R,S,S)-4a and
(R,R,S,S)-4b
4.16.3. Enantiomeric composition of (R,R,S,S)-4a. By
adding a Pr shift reagent to rac-4a (for preparation, see
Section 4.4), the 6.99 ppm (1H, d, HAr6) and 7.02 ppm
(1H, d, HAr3) signals were gradually separated into two
pairs of signals (in 1:1 ratio, each). By adding 20 mg of
Pr shift reagent to the racemic sample, the signal at
6.99 ppm shifted to 5.04 and 5.18 ppm, whereas the signal
at 7.02 ppm shifted to 4.34 and 4.52 ppm. When the opti-
cally active (R,R,S,S)-4a was treated with 20 mg of Pr shift
reagent, signals were detected only at 4.86 and 4.08 ppm,
without observable peaks of the minor enantiomer.
The enantiomeric compositions of the optically active
(S,S,S,S)-3a, (S,S,S,S)-3b, (R,R,S,S)-4a and (R,R,S,S)-4b
1
were determined by H NMR using praseodymium D-3-
heptafluorobutyryl-camphorate shift reagent as indicated in
1
Figure 1. H NMR spectra of the optically active [(S,S,
S,S)-3a,b and (R,R,S,S)-4a,b] or racemic [rac-3a,b and
rac-4a,b] compound (10 mg) in CDCl3 (600 lL) were taken
in the presence of increasing amounts of the shift reagent
(2–25 mg). The ee values determined by praseodymium
shift reagent are listed in Table 1.
4.16.4. Enantiomeric composition of (R,R,S,S)-4b. By
adding a Pr shift reagent to rac-4b (for preparation, see
Section 4.14), the 6.53 ppm (1H, m, HAr2) signal separated
into signals in 1:1 ratio (5 mg of Pr shift reagent: 5.86 and
5.98 ppm; 10 mg of Pr shift reagent: 5.14 and 5.37 ppm).
Adding Pr shift reagent to the sample of optically active
(R,R,S,S)-4b, only a single peak could be observed (5 mg
of Pr shift reagent: 5.09 ppm; 10 mg shift reagent:
4.38 ppm).
4.16.1. Enantiomeric composition of (S,S,S,S)-3a. By add-
ing a Pr shift reagent to the rac-3a sample, the 6.96 ppm
(2H, m, HAr4 + HAr5) and 7.01 ppm (2H, m, HAr3 + HAr6
)
signals were separated into two pairs of signals (in 1:1 ra-
tio, each). By adding 20 mg of Pr shift reagent, the signal
at 6.96 ppm shifted to 5.63 and 5.72 ppm, whereas the sig-
nal at 7.01 ppm shifted to 3.9 and 4.2 ppm. When the opti-
cally active (S,S,S,S)-3a was treated with 20 mg of Pr shift
reagent major signals were detected at 5.75 and 4.02 ppm,
along with minor signals at 5.67 and 4.28 ppm (Fig. 1).
From the ratio of these signals, 95.7% ee was calculated
for (S,S,S,S)-3a.
Acknowledgement
The authors thank the Hungarian Scientific Research Fund
(OTKA T-048854) for financial support.
4.16.2. Enantiomeric composition of (S,S,S,S)-3b. By add-
ing a Pr shift reagent to rac-3b [prepared by mixing
(S,S,S,S)-3b and (R,R,R,R)-3b in 1:1 (w/w) ratio], the
6.57 ppm (1H, s, HAr2) signal separated into signals in 1:1
ratio (5 mg of Pr shift reagent: 6.03 and 5.94 ppm; 10 mg
of Pr shift reagent: 5.82 and 5.73 ppm). Adding a Pr shift
reagent to the sample of optically active (S,S,S,S)-3b, only
a single peak could be observed (5 mg of Pr shift reagent:
6.04 ppm; 10 mg of Pr shift reagent: 5.23 ppm).
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