Absolute configuration determination and convenient asymmetric synthesis of cis-3-(9-anthryl)cyclohexanol with proline as a catalyst

Article abstract of DOI:10.1002/chir.22079

cis-(3R)-(9-anthryl) derivative of cyclohexanol was conveniently obtained in enantiomerically pure form from 2-cyclohexenone using asymmetric Michael addition of anthrone catalyzed by l-proline in a key step. The absolute configuration of the addition product was unequivocally determined by means of electronic circular dichroism measurements combined with calculation of the circular dichroism spectrum by using a density functional theory method. Copyright

Full text of DOI:10.1002/chir.22079

CHIRALITY (2012)
Absolute Configuration Determination and Convenient Asymmetric
Synthesis of cis-3-(9-Anthryl)cyclohexanol with Proline as a Catalyst
*
JĘDRZEJ WYSOCKI, MARCIN KWIT, AND JACEK GAWRONSKI
Department of Chemistry, Adam Mickiewicz University, Poznan, Poland
ABSTRACT
cis-(3R)-(9-anthryl) derivative of cyclohexanol was conveniently obtained in
enantiomerically pure form from 2-cyclohexenone using asymmetric Michael addition of
anthrone catalyzed by L-proline in a key step. The absolute configuration of the addition product
was unequivocally determined by means of electronic circular dichroism measurements com-
bined with calculation of the circular dichroism spectrum by using a density functional theory
method. Chirality 00:000–000, 2012. © 2012 Wiley Periodicals, Inc.
KEY WORDS: asymmetric catalysis; proline; conjugate addition; circular dichroism; DFT
calculations
chromatography (HPLC) analyses were carried out on a Chiralpak-IA
INTRODUCTION
column by using mobile phase and flow rate as indicated. UV and circular
dichroism (CD) spectra were recorded with a Jasco J-810 spectropolari-
meter. Melting points were determined on a Büchi Melting Point B-545
apparatus and are uncorrected. All reagents were used as purchased from
commercial suppliers. All solvents were provided by a local supplier
and were purified by conventional methods prior to use. Commercial
diphenyl-L-prolinol and its O-TMS derivative were used as received.
Methyl L-prolinate was obtained as hydrochloride salt from which the free
base was extracted with CH2Cl2–saturated NaHCO3 solution prior to use.
Enantiomerically pure 3-substituted cyclohexanones and
cyclohexanols are of considerable interest as model mole-
cules for stereochemical studies. Compounds of this type
are accessible most directly by conjugate addition of an
appropriate nucleophile to 2-cyclohexenone (1). With a chiral
catalyst, nonracemic addition product 3 can be obtained
(Scheme 1).
Examples of such additions range from asymmetrically cat-
alyzed additions of organometallic reagents1–4 to additions
of thiols5,6 or 1,2,4-triazole;7 the last two are catalyzed by
Cinchona alkaloid derivatives. Anthrone (2) is an atypical
nucleophile because its reactive deprotonated form is of
tautomeric type, forming 9-anthranolate ion. This ion can
react not only as a nucleophile but also as a diene in Diels–
Alder addition with reactive dienophiles. Indeed, asymmetric
[4 + 2] cycloadditions of 2 to N-substituted maleimides
catalyzed by chiral Brönsted bases have been reported.8–10
However, with a,b-unsaturated esters, ketones and nitro com-
pounds conjugate addition of 2 is the preferred mode of
reaction.11,12 Asymmetric additions of 2 to a,b-unsaturated
aldehydes catalyzed by a derivative of prolinol13 and to
enones using a thiourea derivative of 9-amino-9-deoxyepiqui-
nine as a catalyst14 have been recently disclosed.
Computational Methods
Starting geometries of dienes 3 and 6 with assumed absolute con-
figurations were obtained by conformational search with the use of a
CONFLEX software and preoptimization of all conformers at the
B3LYP/6-31G(d) level. This allowed identification of the minimum
energy structures, which were further reoptimized in acetonitrile or
methanol solutions, using the polarizable continuum model (integral
equation formalism polarizable continuum model (IEFPCM))15 with the
use of the newly developed M06-2X16 hybrid functionals, in conjunction
with 6-311++G(2d,2p) basis set. The structures thus obtained were the
real minimum energy conformers (no imaginary frequencies have been
found). The total and free energy values were used to obtain the
Boltzmann population of conformers at 298.15 K. For density functional
theory (DFT) calculations, only the results for conformers that differ from
the most stable one by less than 2 kcal molꢀ1 were taken into account,
following a generally accepted protocol.17
The calculations of optical rotations were carried out for all stable
conformers of 3 at [a]D wavelength (589 nm), in the solvent, using the
B3LYP/6-311++G(2d,2p) method. London orbitals (which ensure the
origin independency of the results) have been used.18
For all investigated compounds, electronic circular dichroism (ECD)
spectra were measured in acetonitrile solution and calculated at the
IEFPCM/TDDFT/6-311++G(2d,2p) level for all stable geometries
optimized at the IEFPCM/M06-2X/6-311++G(2d,2p) level, according to
the procedure previously described.19 We employed five different
hybrid functionals to calculate ECD spectra: M06-2X,20 PBE0,21 B2LYP,22
LC-wPBE,23 and CAM-B3LYP.24
We anticipated that addition of 2 to 1 could be achieved in
enantioselective fashion to give product 3 as a key intermediate
for the synthesis of the title compound 5. As a catalyst of the
addition L-proline or its derivatives could be used on the basis
of literature data discussed previously. Further steps of syn-
thesis are shown in Scheme 2 and include diastereoselective
reduction of the carbonyl groups to give diol 4 and selective
dehydration to produce anthracene substituted product 5.
EXPERIMENTAL SECTION
1H nuclear magnetic resonance (NMR) and 13C NMR spectra were
recorded with Bruker Avance II 400 and Varian Oxford 300 spectro-
meters. Chemical shift values are given in parts per million (ppm) relative
to tetramethylsilane (TMS). Column chromatography was performed
using Fluka 60 (70–230 mesh) silica gel, and thin layer chromatography
was carried out with Fluka silica gel precoated plates. Fourier transform
infrared spectroscopy spectra were recorded with a Bruker IFS 66v/S
spectrometer. High-resolution mass spectrometry (HR-MS) spectra were
obtained with a Bruker 320 MS spectrometer. High-performance liquid
Contract grant sponsor: National Centre of Science (Poland), program OPUS 2.
*Correspondence to: Jacek Gawronski, Department of Chemistry, Adam
Mickiewicz University, 60780 Poznan, Poland.
E-mail: gawronsk@amu.edu.pl
Received for publication 12 April 2012; Accepted 11 May 2012
DOI: 10.1002/chir.22079
Published online in Wiley Online Library
(wileyonlinelibrary.com).
© 2012 Wiley Periodicals, Inc.

WYSOCKI ET AL.
TABLE 2. Results of solvent screening with Cat1 as a catalysta
Entry
Solvent
Yield of 3 (%)
Ee (%)
1
2
3
4
5
6
7
8
CH2Cl2
PhMe
THF
32
7
9
17
3
16
43
73
46
9
82
39
47
55
50
52
86
0
Et2O
EtOAc
Me2CO
MeCN
DMF
DMSO
MeOH
Scheme 1. Nucleophilic additions to 2-cyclohexenone.
9
10
0
0
Entry in bold shows optimum result.
aFor experimental details, see Table 1.
TABLE 3. Results of catalyst amount screeninga
Entry
Ratio of 2:1
Cat1 (mol%)
Yield of 3 (%)
Eeb (%)
Scheme 2. Route to cis-3-(9-anthryl)cyclohexanol.
1
2
3
4
5
6
1:1.2
1:1.2
1:1.2
1:2
1:2
1:2
5
10
20
5
10
20
19
39
36
62
76
69
85
86
86
85
87
87
Rotatory strengths were calculated using both length and velocity
representations. In the present study, the differences between the length
and velocity calculated values of rotatory strengths were quite small, and
for this reason, only the velocity representations were further used. The
ECD spectra were simulated by overlapping Gaussian functions25 for
each transition, according to the procedure previously described.26
All calculations were performed with the use of CAChe-WS Pro, Gaussian
09, and Turbomole 6.0 packages.27–29
Entry in bold shows optimum result.
aConditions: 1 = 0.3 mmol, MeCN (1 ml), 66 h, room temperture.
bDetermined by chiral high-performance liquid chromatography after purification.
residue was dissolved in CH2Cl2 and filtered through a short silica gel
column to separate the substrates from the products. The colorless oily
mixture of 3 and traces of 10,100-dihydrobianthrone as a side product was
triturated dropwise with diethyl ether to afford 3 as a white solid (1219 mg,
yield 70%, [a]2D5 =ꢀ5.7ꢂ (c= 0.71, methanol), ee 80%, mp 107–109 ꢂC).
The racemate of 3 was prepared with the same procedure using
194.2 mg (1.0 mmol) of 2, 193.6 ml (2.0 mmol) of 1, 13.9 mg (0.1 mmol)
of pyridinium acetate as catalyst, and 4 ml of CH2Cl2 as solvent. Yield
of rac-3 220.7 mg (76%), mp 135–136 ꢂC.
General Procedure for Addition of 2 to 1
Analytical procedure: 2, 1, and the catalyst in appropriate amounts
(Tables 1–3) were dissolved in a solvent (1 ml) in a 4-ml reaction vial.
The mixture was stirred in the darkness for 66 h, then quenched with
1 M HCl solution, extracted with CH2Cl2 (3 ꢁ 10 ml), dried over MgSO4,
the solution filtered and evaporated. The product (3), a white solid, was
isolated by centrifugal chromatography (eluent: hexane/EtOAc, 9:1);
1H NMR (400 MHz, CDCl3): d 0.99–1.16 (m, 1H), 1.34–1.54 (m, 1H),
1.70–1.75 (m, 1H), 1.83–2.08 (m, 3H), 2.16–2.35 (m, 3H), 4.22
(d, J = 3.1 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.49 (m, 3H), 7.61
(d, J = 7.3 Hz, 2H), 8.28 (m, 2H); 13C NMR (100 MHz, CDCl3): d 24.8,
27.5, 40.9, 45.3, 48.4, 48.6, 127.1, 127.2, 127.4, 127.6, 128.5, 128.7, 132.5,
132.6, 133.3, 133.4, 141.7, 142.3, 185.1, 210.5; HR-MS: m/z calcd
Diastereoselective Reduction of Michael Adduct 3 with
NaBH4 to 4
Michael adduct 3 (20.0 mg, 67.9 mmol, 80% ee) was dissolved in MeOH
(1.5 ml) and cooled to 0 ꢂC in an ice bath. Then, NaBH4 (10.3 mg,
271.6 mmol, 4 eq) was added. The reaction mixture was stirred for 1 h at
room temperature, followed by quenching with water. The mixture was
transferred to a separatory funnel and extracted with CH2Cl2 (3 ꢁ 10 ml).
The combined organic extracts were dried over MgSO4, filtered, and evap-
orated. Purification by column chromatography (eluent: hexane/EtOAc,
4:1) furnished 16.0 mg (79%) of a mixture of diastereomers of 4 (dr 12:1).
for
C
20H18NaO2 ([M + Na]+): 313.1204, found: 313.1238, calcd for
C40H36NaO4 ([2M + Na]+): 603.2511, found: 603.2510.
Large-scale procedure: 2 (1165.4 mg, 6.0 mmol), 1 (1.16 ml, 12.0 mmol),
and Cat1 (69.1mg, 0.6 mmol) were dissolved in MeCN (20ml) and stirred
in dark for 66h, then quenched with 1 M HCl solution, extracted with
CH2Cl2 (3ꢁ 30 ml), dried over MgSO4, filtered, and evaporated. The
Diastereoselective Reduction of Michael Adduct 3 with
LiAlH4 to 4
TABLE 1. Results of screening catalyst efficiencya
The reaction was carried out under argon atmosphere. Michael adduct
3 (20.0 mg, 67.9 mmol, 80% ee) was dissolved in dry tetrahydrofuran
(THF) (1.5 ml) and the solution cooled to ꢀ78 ꢂC (2-propanol-dry ice
bath). The solution was added dropwise to a suspension of LiAlH4 cooled
to ꢀ78 ꢂC (10.3 mg, 271.6 mmol, 4 eq) in dry THF (2 ml). The reaction
mixture was stirred 1 h at room temperature, followed by quenching with
ethyl acetate. The mixture was filtered through celite using ethyl acetate
and evaporated. The residue was dissolved in CH2Cl2 (10 ml), transferred
to a separatory funnel, and washed with brine (10 ml). The organic layer
was dried over MgSO4, filtered, and evaporated to afford crude product in
quantitive yield. Purification (silica gel column, eluent: hexane/EtOAc,
4:1) furnished 4 (19.9 mg, 98%) as a mixture of diastereoisomers (dr 12:1;
equatorial : axial hydroxy group).
Entry
Catalyst
Yield of 3 (%)
Eeb (%)
1
2
3
4
5
Cat1
Cat2
Cat3
Cat4
Cat5
32
39
0
0
15
82
0
ꢀ
ꢀ
5
Entry in bold shows optimum result.
aConditions: 2:1 = 0.35:0.30 mmol, catalyst 20 mol%, CH2Cl2 (1ml), 66h, room
temperture.
bDetermined by chiral high-performance liquid chromatography analysis
after purification.
Chirality DOI 10.1002/chir

SYNTHESIS AND ABSOLUTE CONFIGURATION OF CIS-3-(9-ANTHRYL)CYCLOHEXANOL
Large-scale procedure was similar to that previously described, using 3
reactions of 2 to a,b-unsaturated aldehydes as acceptors
were reported to give excellent results under optimized
conditions.13
It is of importance to note that the aforementioned addition
reactions were heterogeneous because of poor solubility of 2
in the reaction medium. Except in CH2Cl2, both yield and
enantioselectivity of the reaction in solvents of low polarity
were low (Table 2, entries 2–6).
Dimethyl sulfoxide is often used as a solvent when
L-proline is used as a catalyst. In the experiment carried out,
only racemic 3 was formed in moderate yield. The same
applies to other polar solvents, DMF and MeOH (entries
8–10, Table 2).
(200 mg, ee 80%) dissolved in THF (15 ml) and LiAlH4 (103 mg) in THF
(20 ml). The product (201 mg) was a mixture of diastereoisomers. Crystal-
lization afforded enantiomer 4, mp 127–130 ꢂC (ee >99%, HPLC); 1H
NMR (400 MHz, CDCl3): d 0.80–1.10 (m, 3H), 1.35 (bs, 1H), 1.43–1.52
(m, 2H), 1.65–1.74 (m, 1H), 1.77–1.88 (m, 2H), 2.15 (d, J = 10.6 Hz, 1H),
3.29–3.44 (m, 1H), 3.72 (d, J = 7.5 Hz, 1H), 5.67 (d, J = 10.5 Hz, 1H),
7.22–7.36 (m, 6H), 7.79 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 23.7, 30.0, 35.3, 40.6, 42.8, 52.8, 67.8, 70.8, 124.3, 126.6, 126.8, 128.7,
137.0, 140.3; HR-MS: m/z calcd for C20H22NaO2 ([M + Na]+): 317.1517,
found: 317.1474.
Dehydration of 4 to 5 with DowexW 50W
DowexW 50 W (30 mg) was added to a solution of 4 (20 mg, 67.9 mmol,
ee > 99%) cooled to 0 ꢂC in CH2Cl2 (1.5 ml), and the mixture was stirred
for 3 days at room temperature. After filtration, the crude product was
purified by column chromatography (eluent: hexane/EtOAc, 15:1) to
afford 5 as a yellowish solid (15.8 mg, 84%), mp 121–123 ꢂC; 1H NMR
(400 MHz, CDCl3): d 1.59–1.77 (m, 2H), 1.82–1.94 (m, 1H), 2.01–2.13
(m, 1H), 2.16–2.31 (m, 2H), 2.39–2.50 (m, 1H), 2.53 (q, J = 12.8 Hz, 1H),
3.87–4.03 (m, 1H), 4.18 (tt, J = 12.8, 3.4 Hz, 1H), 7.39–7.53 (m, 4H), 8.00
(d, J = 8.9 Hz, 2H), 8.35 (s, 1H), 8.60 (bs, 1H); 13C NMR (100 MHz,
The use of MeCN (entry 7, Table 2) increased both the
yield and enantiomeric excess of 3 compared with those
obtained with CH2Cl2 as a solvent. Therefore, MeCN was
chosen as a solvent for further reactions. There was still a
problem of unsatisfactory yield of the reaction. Therefore,
the effect of ratio of the two reactants, 2 and 1, on the yield
of the reaction was examined next. Increase of the ratio of
2:1 from 1:1 to 1:5 resulted in gradual increase of the yield
of 3 from 35% to 80%, whereas ee of the product remained
essentially unchanged (86–87%). Further increase of the
excess of 1 had no effect on the yield of 3. Because of
practical reasons (product separation), the 1:2 ratio of
2:1 was chosen, as a compromise between the optimum
conditions and the cost/operational simplicity.
Organocatalysis often requires considerable amount of the
catalyst to achieve good enantioselectivity and yield of the
reaction. Although in the preliminary experiments we used
20 mol% of the catalyst, we then determined the optimum
molar amount of the catalyst. It was found that for the two
ratios of substrates 2:1 (1:1.2 and 1:2), the ee of product 3
did not differ much, the yield depended on the amount of
L-proline used and was the highest with 10 mol% of the
catalyst (in relation to anthrone 2, see Table 3).
As the final step, we checked the effect of temperature on
the yield and ee of the addition product 3. We found that
lowering reaction temperature shows little effect on the ee
of 3, whereas it has an adverse effect on the reaction yield.
Thus, room temperature was found the most suitable for
this reaction.
The highest obtained ee of the addition product 3 (87%)
compares favorably with the ee of the product obtained with
the aid of a much more expensive cinchona alkaloid–thiourea
organocatalyst (78%).14
CDCl3):
d 25.3, 30.6, 35.6, 37.9, 41.1, 71.8, 123.5, 124.6, 125.8,
126.3, 126.9, 129.6, 129.7, 137.0; HR-MS: m/z calcd for C21H24KNaO2
([M + K + Na + MeOH]+): 370.1311, found: 370.0916.
Large-scale procedure was the same as described previously using
170 mg of 4 (577 mmol, ee >99%), 255 mg of DowexW 50W resin, and
13 ml of CH2Cl2 as a solvent. Yield 137.7 mg of 5 (86%).
(1S,3R)-3-(9-Anthryl)cyclohexyl benzoate (6): (1S,3R)-3-(9-Anthryl)
cyclohexanol (5) (20.0 mg, 72.4 mmol) was dissolved in pyridine (1 ml).
Then, benzoyl chloride (25.1 ml) was added, and the reaction mixture
was gently refluxed for 2 h. Saturated NaHCO3 (5 ml) solution was added
dropwise, and the resulted mixture was transferred to a separatory fun-
nel. After extraction of the aqueous phase with CH2Cl2 (3 ꢁ 10 ml), the
combined organic phases were dried over MgSO4, filtered, and evapo-
rated. Crude product was purified by column chromatography (eluent:
hexane/EtOAc, 30:1) furnishing 6 (18.6 mg, 68%) as a colorless solid,
1H NMR (400 MHz, CDCl3): d 1.77–1.89 (m, 2H), 1.96 (m, 1H),
2.07–2.21 (m, 1H), 2.31–2.46 (m, 2H), 2.45–2.63 (m, 1H), 2.77
(q, J = 12.6 Hz, 1H), 4.24–4.39 (m, 1H), 5.24–5.41 (m, 1H) 7.38–7.58 (m,
7H), 8.00 (d, J = 8.3 Hz, 2H), 8.04 (d, J = 8.3 Hz, 2H), 8.35 (s, 1H), 8.39
(bs, 1H) 8.64 (bs, 1H); 13C NMR (100 MHz, CDCl3): d 25.2, 30.6, 32.0,
37.1, 38.0, 74.3, 123.6, 124.4, 126.0, 127.0, 128.3, 129.6, 129.7, 130.7,
132.9, 136.5, 166.0.
RESULTS AND DISCUSSION
Synthesis
L-Proline and its derivatives were screened as catalysts for
enantioselective Michael addition of 2 to 1 (Fig. 1).
Standard reaction carried out in dichloromethane solution at
room temperature (Table 1) was successful with L-proline
(Cat1) as organocatalyst to give 3 in moderate yield and good
ee Methyl L-prolinate (Cat2) gave racemic addition product 3.
Neither hydroxy derivative of L-proline (Cat3) nor diphenyl-L-
prolinol (Cat4) was successful as catalysts.
Having determined the optimum conditions for the synthesis
of 3 (2 eq. of 1, 1 eq. of 2, 0.1 eq. of L-proline, solvent MeCN,
room temperature), we attempted to increase the initial enantio-
meric purity of product 3 by crystallization. Crystallization from
toluene–hexane led, however, to a decrease of ee of 3 in the
crystals, whereas the filtrate contained 3 of higher ee (Fig. 2).
Such a behavior is not favorable for enantiomer separation
by crystallization and is typical for molecules crystallizing
preferentially as racemic compounds. This is confirmed by
comparison of the melting points of rac-3 (135–136 ꢂC) and
enantiomerically pure 3 (107–109 ꢂC). For substances crystal-
lizing as racemic compounds, the difference of melting points
is typically 25–30 ꢂC.
Hayashi’s catalyst (Cat5) gave product 3 with poor yield
and low ee This seemed surprising because similar addition
Consequently, we decided to reduce first the carbonyl
functions of 3 in diastereoselective manner. The best results
were obtained with LiAlH4 (4 eq.) in THF solution. The reduction
of 3 (ee 80%) proceeded in quantitive yield at the temperature of
Chirality DOI 10.1002/chir
Fig. 1. Catalysts used in asymmetric Michael-type addition of 2 to 1.

WYSOCKI ET AL.
vicinal diaxial proton arrangements, whereas J = 3.4 Hz is typical
for vicinal axial-equatorial proton couplings. This means that
there are two vicinal axial and two vicinal equatorial protons that
are coupled to axial proton Ha, whereas the anthryl group is
equatorial (Fig. 4).
A similar situation is found for proton Hb. The signal at
2.53 ppm is split into a quartet with a coupling constant
J = 12.8 Hz. This is a typical value for both geminal and vicinal
diaxial proton coupling constants. Therefore, the hydroxy
group is equatorial, whereas Hb is axial and coupled to one
geminal and two vicinal axial protons.
Absolute Configuration of the Michael Adduct 3
Whereas the relative configuration of substituents in 5 was
determined by 1H NMR spectroscopy, the absolute configura-
tion at the stereogenic C3 atom was subsequently established
using a method of comparing experimental and calculated
optical rotation data and CD spectra of the Michael adduct 3.
Initially, low energy structures of 3, with assumed R absolute
configuration at the stereogenic center, were calculated using
molecular mechanics method followed by preoptimization
at the B3LYP/6-31G(d) level. This furnished six stable con-
formers, three of which with the equatorial anthrone
substituent and the other three with the axial substituent.
The structures of the conformers were then reoptimized at
the M06-2X/6-311++G(2d,2p) level in conjunction with the
polarizable continuum model simulating acetonitrile or
methanol solution. Conformers with axial anthrone substituent
were found to be of much higher energy (over 3 kcalmolꢀ1),
and their population in the equilibrium was negligible in
comparison with the equatorial ones. The diequatorial con-
formers of 3 are shown in Figure 5, and their relative energies
and values of dihedral angle o = H-C3-C(Ar)-H that characterize
the conformation are collected in Table 4. It is important to note
that the conformers differ with regard to the torsion angle o,
involving two secondary carbon atoms. It can be either gauche
Fig. 2. High-performance liquid chromatography traces showing the
results of crystallization of 3: (a) initial sample of 3, ee 62%; (b) crystals of 3,
ee 56%; (c) filtrate containing 3, ee 83%.
dry ice–2-propanol bath. While diastereomeric ratio of the
products was at the level of 12:1 (cis :trans), further experiments
have shown that just one crystallization from ethyl acetate–n-
hexane furnished 4 as a single stereoisomer, yield 64% (Fig. 3).
Reduction of 3 with NaBH4 in methanol at 0 ꢂC proceeded with
a similar diastereoselectivity (12:1); however, the yield of crude
reduction products was lower (79%).
To finalize the synthesis, 4 was chemoselectively dehydrated
under acidic conditions to form the anthracene substituent in 5.
Out of several acids tried, DowexW 50 W resin provided a
very convenient way to obtain the final product in 84% yield,
although the reaction time was long (3 days). Dehydration with
methanesulfonic acid proceeded considerably faster even at
0 ꢂC; however, the yield of isolated 5 was lower (47%) because
of contamination with side products.
1
Interestingly, the analysis of the H NMR spectrum of 5
showed that both groups, hydroxy and anthryl, were equatorial.
The signal of Ha at 4.18 ppm was split into a triplet of triplets
(J = 12.8Hz and 3.4Hz). The value J = 12.8Hz is typical for
Fig. 3. High-performance liquid chromatography traces showing changes
of dr and ee of product 4 because of crystallization: (a) rac-4; (b) 4 prior to
crystallization, ee 80%; (c) 4 after one crystallization, ee >99%.
Fig. 4. Coupling pattern of protons Ha and Hb in the 1H nuclear magnetic
resonance spectrum of 5.
Chirality DOI 10.1002/chir

SYNTHESIS AND ABSOLUTE CONFIGURATION OF CIS-3-(9-ANTHRYL)CYCLOHEXANOL
Fig. 5. Structures of individual conformers of (a) (R)-3 and (b) benzoate (1S,3R)-6 calculated at the IEFPCM/M06-2X/6-311++G(2d,2p) level.
TABLE 4. Total energies (in Hartree), relative energies (E, G in kcal molꢀ1), percentage populations, and values of torsion angles v
(in degrees) calculated at the IEFPCM/M06-2X/6-311++G(2d,2p) level for individual conformers of 3 and 6
Conformer
Energy
E
Population
G
Population
oa
3 (conf. 1)
3 (conf. 2)
3 (conf. 3)
6 (conf. 1)
6 (conf. 2)
ꢀ923.3561525
ꢀ923.3560365
ꢀ923.3534997
ꢀ1193.685516
ꢀ1193.685227
0.00
0.07
1.66
0.00
0.18
51
46
3
58
42
0.00
0.19
1.14
0.25
0.00
53
39
8
40
60
63.8
ꢀ65.3
176.9
—
—
ao = H–C3–C(Ar)–H in 3.
(+ or ꢀ) or anti, whereas the cyclohexanone ring remains in a
chair form.
Introduction of the benzoate chromophore to 5 makes the
molecule bichromophoric. The experimental and calculated
ECD spectra of 6 are shown in Figure 6.
The measured optical rotation of 3 was [a]2D5 = ꢀ5.7ꢂ
(c = 0.71, methanol) for a sample of ee 80%. When corrected
to 100% ee, this corresponds to the specific rotation ꢀ7.2ꢂ
and is in good accordance with the value calculated at the
IEFPCM/B3LYP/6-311++G(2d,2p) level for the R enantiomer
(ꢀ9.4ꢂ), using the conformer population calculated at the
IEFPCM/M06-2X/6-311++G(2d,2p) level.
The presence of a negative exciton couplet in the range of
265–215 nm is due to the negative sign of the dihedral angle
between the electric dipole transition moment of the benzoate
chromophore and the electric transition moment along the
longitudinal axis of the anthracene chromophore (Fig. 5b).
Additionaly, there is also a second, positive exciton couplet in
the range 210–185 nm, which refers to the positive sign of
the dihedral angle between the transition moment of the
benzoate, as in the first couplet, and the electric dipole
transition moment polarized along shorter axis of the
anthracene chromophore. These two facts establish the 1S,3R
absolute configuration of the two chiral carbon atoms in
molecule 6 and hence also in target molecule 5.
The predictions based on empirical exciton chirality rule
were further confirmed by calculation of ECD spectrum of 6
with the use of TDDFT methods. In this case, we observed
almost perfect agreement between the calculation and the
experiment. Because the observed Cotton effects of 6 are
generated by electronic transitions within the p-electron
systems, the calculated CD spectrum of 6 is more reliable
than that of 3. All density functionals tested gave consistent
Chirality DOI 10.1002/chir
The five density functionals, which have been tested, i.e.,
M06-2X, PBE0, B2LYP, LC-wPBE, and CAM-B3LYP, differ in
the amount of Hartree-Fock XC and the philosophy of their
construction.30 The best agreement with the experiment was
found when either M06-2X or CAM-B3LYP functional was
employed.31 The G based Boltzmann averaged CD spectra of
(R)-3, calculated at the IEFPCM/M06-2X/6-311++G(2d,2p)
level, as well as the experimentally measured spectrum, are
shown in Figure 6. The match of the signs and magnitudes of
the Cotton effects is barely acceptable, even if the differences
in the wavelengths (energies) of transitions are neglected. It
is worth to note that other functionals gave no better results.
A confirmation of the absolute configuration of target
molecule 5 was obtained from the CD spectrum of its benzoate
derivative 6, using the CD exciton chirality method.32

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