Four hydroxyls are better than two. the use of a chiral lithium salt of 3,3′-bis-methanol-2,2′-binaphthol as a multifunctional catalyst of enantioselective Michael addition reactions

Article abstract of DOI:10.1016/j.tetasy.2010.12.003

The catalytic performance of the Li salt of (S)- or (R)-3,3′-bis[bis- (phenyl)hydroxymethyl]-2,2′-dihydroxy-dinaphthalene-1,1′ (BIMBOL) in asymmetric Michael additions of malonic acid derivatives and toluedine has been studied. Nitrostyrene and cyclohex-2

Full text of DOI:10.1016/j.tetasy.2010.12.003

Tetrahedron: Asymmetry 22 (2011) 167–172
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Tetrahedron: Asymmetry
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Four hydroxyls are better than two. The use of a chiral lithium salt
of 3,30-bis-methanol-2,20-binaphthol as a multifunctional catalyst
of enantioselective Michael addition reactions
Yuri N. Belokon a, , Zalina T. Gugkaeva a, Victor I. Maleev a, Margarita A. Moskalenko a, Alan T. Tsaloev a,
⇑
Victor N. Khrustalev a, Karine V. Hakobyan b
a Institute of Russian Academy of Sciences, A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov 28, 119991 Moscow, Russia
b Yerevan State University, Department of Pharmaceutical Chemistry, A. Manoogian st. 1, 0025 Yerevan, Armenia
a r t i c l e i n f o
a b s t r a c t
The catalytic performance of the Li salt of (S)- or (R)-3,30-bis[bis-(phenyl)hydroxymethyl]-2,20-dihy-
droxy-dinaphthalene-1,10 (BIMBOL) in asymmetric Michael additions of malonic acid derivatives and tol-
uedine has been studied. Nitrostyrene and cyclohex-2-enone were chosen as Michael acceptors. Efficient
asymmetric C–C and C–N bond formations with ee’s of up to 95% at room temperature were observed. A
transition state model of the malonic ester addition to cyclohex-2-enone has been proposed based on the
molecular structure of the acetone solvate of BIMBOL. The impact of the catalyst self-association on its
performance is also discussed.
Article history:
Received 23 November 2010
Accepted 3 December 2010
Available online 12 January 2011
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Previously, some of us developed a highly efficient approach for
the asymmetric synthesis of aminoacids via phase transfer
Asymmetric catalysts, which combine both acidic and basic
sites, are attracting ever growing interest in the chemical commu-
nity because of their greater effectiveness when compared to con-
ventional catalysts that contain only either acidic or basic sites.
Such multifunctional catalysts can exhibit both Lewis acidity and
Brønsted basicity (heterobimetallic complexes),1 and contain both
Brønsted acidic and Brønsted basic sites (pure organic catalysts).2
Another emerging simple multifunctional catalytic system is exem-
plified by chiral lithium binaphtholate salts.3c The catalysts contain
a Lewis acidic site, and Brønsted basic, and Brønsted acidic sites
within the confines of the same chiral molecules. The asymmetric
reduction of ketones with trialkoxysilanes3a and trimethylsilylcya-
nation of aldehydes3b have successfully been catalyzed by the mono
lithium salt of (S)-BINOL as reported by Kagan et al. The approach
was further extended by Nakajima to Mukaiyama-type aldol reac-
tions of trimethoxysilyl enol ethers.3c,3d An unexpected beneficial
effect of water as an additive on stereoselectivity was observed in
the reactions.3d The catalytic effects of the lithium binolate were be-
lieved to originate from the formation of chiral hypervalent silicon
intermediates.3a–d Ishihara broadened the use of lithium binolates
to direct Mannich-type reaction of keto-esters and aldimines.3e He
also was the first to recognize the bifunctional (Lewis acidic and
Brønsted basic) nature of the catalyst.3e
alkylation4a,b and Michael reaction4b,c of glycine Ni(II) complexes
catalyzed by (S)- or (R)-2-amino-20-hydroxy-1,10-binaphthol (no-
bin).4a–c Alkalie metal nobinates were assumed to be the active cat-
alytic species in the reactions, serving as a base to ionize the CH
acid.4b The conjugated acids of the nobinates were believed to be
responsible for the asymmetric induction with the hydrogen bond
solvating the glycine carbanion and simultaneously coordinating
the alkalie metal cation in the transition state of alkylation.4b We
reasoned that further modification of the system by introducing
additional hydrogen bond donor groups into the chiral binaphthole
scaffold would further improve the performance of the chiral phe-
nolate catalysts. In addition to greater stabilization of the charged
intermediates, the longer hydrogen bond arrays would be expected
to facilitate the mutual rigid fixation of the reagents in the transi-
tion state of the bimolecular reactions of the electrophiles and the
conjugated bases of the CH-acids. Finally, the classical condensa-
tion reactions of the CH-acids, such as Michael, aldol, Mannich
and so forth, are all formally C–C bond forming reactions, accom-
panied by hydrogen (proton) migration from the CH acid to the
electrophile. The creation of a chain of intramolecular hydrogen
bonded hydroxyl groups could be expected to facilitate the proton
transfer, accompanying the C–C bond formation, as Figure 1
illustrated. Some analogy can be found in the fast proton transport
along one-dimensional water chains confined in carbon
nanotubes.5
⇑
Corresponding author.
E-mail address: yubel@ineos.ac.ru (Y.N. Belokon).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.12.003

168
Y. N. Belokon et al. / Tetrahedron: Asymmetry 22 (2011) 167–172
R3
Ph
Ph
O
R3
Ph
Ph
O
R
R2
M O-Q(OH)n
OH
OH
R
X
+
HX
R2
M = Li, Na, K, Rb, Cs
R1
OH
OH
R1
OMOM
OMOM
H
OH
OH
R3
OH
OH
Ph
O
R2
X
H
Ph
Ph
Ph
1
2
R1
(R)-BIMBOL
M
R
O
R'
R'
H
O
Ph
H
Ph
O
Ph
Ph
O
H
OH
O
OH
OH
Ph
Ph
=
M O-Q(OH)n
R'
OH
OH
O
R'
Figure 1. Schematic presentation of a Michael reaction of a CH-acid (XH) catalyzed
by polyalcoholate (polyphenolate) species with the nucleophile/electrophile
proton migration facilitated by the multifunctional catalyst.
OH
Ph
a
Ph
(R)-TADDOL
(S)-BIMBOL
We have chosen Li, Na, and K salts of (S)- or (R)-3,30-bis[bis-
(phenyl)hydroxymethyl]-2,20-dihydroxy-dinaphthalene-1,10 (BIM-
BOL)6 as a logical next generation catalyst of the Li-binolate family
to study their performance in a model reaction of asymmetric
Michael addition of malonic ester and other nucleophiles to
cyclohex-2-enone (Scheme 1) and nitrostyrene. The choice of
cyclohex-2-enone was based upon the prevalence of substituted
cyclohexane motifs in pharmaceutical compounds.7 Michael addi-
tion of malonates to nitrostyrene was recently documented as an
efficient approach to antidepressants (R)-rolipram and (3S,4R)-
paroxetine.8
The comparison of BIMBOL, BINOL, and TADDOL derived cata-
lysts indicated that the proof of principle experiments was success-
ful and that the multifunctional catalyst derived from BIMBOL was
much more efficient than the analogs, containing shorter hydrogen
bond arrays.
Chart 1.
Table 1
Asymmetric Michael additions catalyzed by compounds 1, 2, (R)-TADDOL,
(R)-BIMBOL, (S)-BIMBOL with lithium phenolate as a cocatalysta
Entry
Catalyst
Yield (%)
eeb (%)
1
2
3
4
5
1
2
16
14
30
99
99
30 (R)
60 (R)
40 (R)
85 (R)
85 (S)
(R)-TADDOL
(R)-BIMBOL
(S)-BIMBOL
a
Reaction conditions: cyclohex-2-enone (0.258 mmol), diethyl malonate
(0.335 mmol), catalyst (5 mol %), LiOPh (5 mol %), CH2Cl2 (1 mL), under Ar, 48 h, rt.
b
Enantiomeric excess was determined by chiral HPLC analysis using Chiralpak
AS-H columns.
detected, as Figure 2 illustrated. Evidently, the nature of the cata-
lytic species remains the same during the condensation with no
catalyst deterioration taking place in the process.
2. Results and discussion
At first, (R)- or (S)-BIMBOL (Chart 1) was prepared in a three
step sequence from (R)-BINOL, 1, via an intermediate 2.16 The
model reaction (Scheme 1) was conducted in CH2Cl2 at ambient
temperature. The catalytic Li-salt was prepared from 1, 2, (R)-
TADDOL, (R)- or (S)-BIMBOL by mixing them with 1 equiv of dry
Li-phenolate. The procedure allowed the comparison of TADDOL,
2 and the chiral phenols at the same basicity level.
O
O
CH2Cl2, 5% catalyst,
5% base,
CO2Et
CO2Et
*
CO2Et
CO2Et
r.t., 48 h
Figure 2. The variation of the enantiomeric purity of the Michael adduct with the
progress of the reaction catalyzed by the catalytic system (S)-BIMBOL and LiOPh in
CH2Cl2.
Scheme 1. The model Michael addition reaction.
First, we examined the model reaction in the presence of
5 mol % of 1 and 1 equiv of LiOPh. The reaction was sluggish with
only 16% chemical yield and 30% ee of the Michael adduct after
48 h (Table 1, entry 1). No significant improvement in the catalytic
performance was achieved with 2 and (R)-TADDOL (Table 1, entries
2 and 3).
Both enantiomers of BIMBOL provided much higher reactivity
(Table 1, entries 4 and 5), compared with 1, 2, and TADDOL. The
reaction was complete within 48 hours with a good stereocontrol
(85% ee).
Table 2 summarizes the effects of changing the alkalie metal
cations on the performance of the BIMBOL-phenolate catalytic sys-
tem. Both LiOPh, NaOPh, and KOPh catalyzed the condensation to
some extent without any BIMBOL added (Table 2, entries 1, 5,
and 8) but the addition of BIMBOL completely inhibited the reac-
tion in the cases of NaOPh and KOPh (entries 6 and 9) and greatly
improved the performance in the case of LiOPh (entry 2). Other
strongly basic Li salts, such as BuLi and LiOH, were even better cat-
alytic additives, affording greater enantioselectivity in the reaction
(Table 2, entries 3 and 4). The data show the important role of the
metal Lewis acidity, as its expected increase follows the order
Practically no change in the enantioselectivity of the addition
with the progress of the reaction (Table 1, entries 4 and 5) was

Y. N. Belokon et al. / Tetrahedron: Asymmetry 22 (2011) 167–172
169
Table 2
Table 3
Asymmetric Michael addition catalyzed by (S)-BIMBOL and different basesa
Asymmetric Michael addition catalyzed by compound (S)-BIMBOL with LiOPh as
cocatalyst in different solventsa
Entry
Base
Yield (ee) (%)
Entry
Solvent
Yield (%)
ee (%)
1b
2
3
LiOPh
LiOPh
LiOH
47
99 (85 (S))
65 (85 (S))
99 (88 (S))
35
0
0
43
0
0
0
1
2
3
CH2Cl2
Toluene
Ether
Hexane
Dioxane
CCl4
99
99
99
80
58
63
15
85(S)
87(S)
85(S)
27(S)
4(R)
4
BuLi
5b
6
NaOPh
NaOPh
NaH
KOPh
KOPh
KOtBu
KOH
4
5b
6
7
64(S)
14(S)
8b
9
7
CH3CN
a
Reaction conditions: cyclohex-2-enone (0.258 mmol), diethyl malonate
(0.335 mmol), catalyst (5 mol %), LiOPh (5 mol %), solvent (1 mL), under Ar, 48 h, rt.
10
11
b
Reaction was carried out with catalyst (R)-BIMBOL.
a
Reaction conditions: cyclohex-2-enone (0.258 mmol), diethyl malonate
(0.335 mmol), catalyst (5 mol %), base (5 mol %), CH2Cl2 (1 mL), under Ar, 48 h, rt.
The formation of catalyst aggregates was also supported by the
observation of nonlinear effects10 in the reaction. The plot of the
enantiomeric purity of the product versus the enantiomeric purity
of the catalyst is shown in Figure 4. The chemical yields within a
48 h period were also plotted. The values of the product ee have
deviated from the theoretical linear correlation for the classical
monomeric catalyst case.
b
No (S)-BIMBOL was added.
Li > Na > K. In addition, BuLi, LiOH and LiOPh are all stronger bases
than the conjugated base of BIMBOL (intramolecular hydrogen
bonds making phenol groups of BIMBOL more strongly acidic com-
pared to PhOH, vide infra). The observation hinted at the lithium
salt of BIMBOL being the real catalytic particle in the addition.
In order to determine the optimal catalytic ratio of BIMBOL/
LiOPh, a serious of experiments were conducted with the total con-
centration of the catalyst kept constant but the ratio of the two cat-
alytic components varied. The Job plot9 of the chemical yields and
ee of the product versus the ratio is shown in Figure 3. Evidently,
the most efficient catalytic system contained a 1/1 ratio of BIM-
BOL/LiOPh, which supports the notion of the monolithium salt of
BIMBOL as the best catalytically active species. Another active cat-
alytic species seems to have a 1/2 ratio of the components. There is
a significant minimum in chemical yield (the rate of the addition)
at 1/1.5 ratio. Greater than 1/1 relative amounts of BIMBOL to
LiOPh inhibited the catalytic activity of the system. The observa-
tion can be rationalized by assuming the formation of coordin-
atively saturated bis-BIMBOL/LiOPh species with no or low
catalytic activity. The collected data indicated a complex structure
of the real catalytic species, presumably consisting of different
Li-phenolate associates, each having its own catalytic properties.
Figure 4. The plot of the enantiomeric purity and the chemical yield of the product
versus the enantiomeric purity of BIMBOL: Reaction conditions: cyclohex-2-enone
(0.258 mmol), diethyl malonate (0.335 mmol), catalyst (R)-BIMBOL or (S)-BIMBOL
(5 mol %), LiOPh (5 mol %), CH2Cl2 (1 mL), 72 h, under Ar, rt.
The positive deviations from linearity were not the result of
experimental error points, as each point was the average of 3–5
experimental data. The conversion also strongly depended on the
catalyst ee, indicating increased catalytic activity of enantiomeri-
cally enriched species.
If the monomeric Li salts were the predominant and catalytic
species in the reaction mixture, the rate of the reaction would
not depend on the catalyst ee and the conversion would remain
the same within the ee interval. Formation of some insoluble mate-
rial was observed in the case of racemic and partially enriched cat-
alyst, indicating the possible operation of a ‘reservoir effect’
removing the racemic aggregates from the reaction media.10 The
catalyst aggregation phenomena are well established in some cases
of bifunctional asymmetric catalysis.11a Some literature precedents
for different catalytic activities of several polynuclear aggregates of
Li phenolates exist, as exemplified by ROP of lactides catalyzed
with phenolates.11b
Figure 3. Job’s plot of the effect of the BIMBOL/LiOPh ratio on the catalytic activity
of the mixture. Reaction conditions: cyclohex-2-enone (0.26 mmol), diethyl mal-
onate (0.34 mmol), CH2Cl2 (1 mL), under Ar, 48 h, rt. The total concentration of
BIMBOL [either (R)- or (S)-enantiomer] plus LiOPh was kept constant and equal to
10 mol % (2.6 ꢀ 10ꢁ5 mol). Each point was an average of 5 experiments.
As expected, the solvent affected the catalytic performance
(Table 3) with CH2Cl2, toluene, and ether being the best in the ser-
ies in terms of both chemical yield and enantioselectivity (Table 3,
entries 1–3). On the other hand, donor dipolar solvents such as
MeCN and dioxane inhibited the reaction (Table 3, entries 5 and
7), presumably competing with the substrates for hydrogen bonds
with Brønsted acidic sites and coordinating to the Lewis acidic site.
Hexane and CCl4 were also poor solvents (Table 3, entries 4 and 6),
most likely, because of their low polarity, facilitating the formation
of catalyst aggregates with inferior catalytic activities.
The product chemical yield and ee varied with dilution of the
reaction media. Four times the dilution resulted in an increase of
the chemical yield from 66% to 99% and ee from 68% to 85%
(Table 4, entries 1 and 5, 6). The best enantioselectivity of the reac-
tion was observed at 0.5 mL of the solution with the ee of the prod-
uct equal to 95%, albeit with only 60% chemical yield (Table 4,
entry 2). A further six-fold dilution resulted in a significant loss
of catalytic activity of the catalyst (Table 4, entries 7 and 8). The
data supports the notion of different catalytic aggregate formation
at different concentrations of the catalyst.

170
Y. N. Belokon et al. / Tetrahedron: Asymmetry 22 (2011) 167–172
Table 4
Ethyl and methyl esters of malonic acid added to cyclohex-2-
enone with ee in the range of 80–95% (Table 5, entries 1–3). Cyan-
ophenylacetic ester also added to cyclohex-2-enone under the
conditions although ee dropped to 43% (Table 5, entry 4). The addi-
tion of toluidine to cyclohex-2-enone was also catalyzed by (S)-
BIMBOL with moderate ee of 40% (Table 5, entry 5). To the best
of our knowledge it was the first case of the asymmetric catalytic
reaction of such a weak nucleophile catalyzed by a purely organic
chiral catalyst. But the addition of ethyl malonate to nitrostyrene
led to the racemic product under the same conditions (Table 5, en-
try 6). Ethyl acetoacetate added to nitrostyrene with 1:1 ratio of
the resulting diastereoisomers but with very high enantioselectiv-
ity of one diastereoisomer (Table 5, entry 7).
The crystal structure of the acetone solvate of (R)-BIMBOL is
shown in Figure 5. The salient feature of the structure is the system
of intramolecular phenolic OH to alcoholic OH (and vice versa)
hydrogen bonds. Simultaneously, both phenolic hydroxyl and
alcoholic groups of BIMBOL participated in hydrogen bonding of
two acetone molecules. The acetone molecules link neighboring
BIMBOL molecules forming uninterrupted chains in the crystal.
The influence of dilution on the performance of (S)-BIMBOLa
Run
Solvent (mL)
Ccat (10ꢁ3 mol/L)
Yield (%)
ee (%)
1
2
0.25
0.5
0.75
0.75
1
1
1.5
2
51.5
25.8
17.2
17.2
12.9
12.9
8.6
66
60
26
27
99
99
41
2
68(S)
95(S)
83(S)
86(R)
85(S)
85(R)
83(S)
n.d.
3
4b
5
6b
7
8
5.85
a
Reaction conditions: cyclohex-2-enone (0.258 mmol), diethyl malonate
(0.335 mmol), catalyst (S)-BIMBOL (5 mol %), LiOPh (5 mol %), CH2Cl2 (varied from
0.25 mL to 2 mL), 48 h under Ar, rt.
b
The experiment was conducted with (R)-BIMBOL.
Table 5
Asymmetric Michael addition catalyzed by compounds (S)-BIMBOL and lithium
phenolates in CH2Cl2
a
Entry
1
Product
Yield (%)
33
dr
—
ee (%) (Conf)
O
80 (S)
CO2Me
CO2Me
O
O
O
2
99
60
—
—
85 (S)
95 (S)
CO2Et
CO2Et
3b
CO2Et
CO2Et
Figure 5. Molecular structure of (R)-BIMBOL. The solvate acetone molecules, one of
which is crystallographically dependent, are depicted. The disordered acetone
solvate molecule is not shown for the sake of clarity. Only the hydrogen atoms of
hydroxy-groups are presented. Dashed lines indicate intermolecular hydrogen
bonds.
4
90
70
1/1.2
43/36 (n.d.)
16–45 (n.d.)
*
CO2Et
CN
*
Ph
O
The following mechanism of the Michael addition can be con-
sidered (Fig. 6). The pKa of phenolic hydroxyls in DMSO equals
17–1812a and that of malonic ester is 16.4.12a Thus, the Li salt of
BIMBOL can easily activate the malonic ester by converting it into
the conjugated carbanion, with BIMBOL itself transformed into a
neutral species. The Li cation is coordinated by both the anion
and the OH groups of BIMBOL (Fig. 6). This coordination should re-
sult in a Lewis acid promoted increase of the Brønsted acidity13 of
the OH groups and, thus, facilitate the hydrogen bond transfer
along the intramolecular chain of the four OH groups, the last of
the chain activating the Michael acceptor.
As a result, the two reagents are rigidly positioned relative to
each other. The formation of the C–C bond is accompanied by the
proton transfers along the BIMBOL intramolecular chain of hydro-
gen bonds (Fig. 1). The forming cyclohexenol was expected to have
a pKa value in the range of 29–3112a and can be assumed to be
much less acidic than the hydrogen bond activated diphenylcarbi-
nol group of BIMBOL. A great increase in the acidity of hydroxyl
groups connected by a chain of intramolecular hydrogen bonds is
a well established phenomenon.12b Thus, there seems to be no
acidity obstacle to the proton transfers.
5c
—
*
N
H
O–
N+
O
O
6
7
99
99
—
0
CO2Et
CO2Et
O–
N+
1/1
99/10 (n.d.)
CO2Et
O
a
Reaction conditions: cyclohex-2-enone (0.258 mmol), catalyst (5 mol %), LiOPh
(5 mol %), solvent (1 mL), under Ar, 48 h, rt.
b
Solvent 0.5 mL
Catalyst (5 mol %)/BuLi (5 mol %).
c
We explored the scope of the reaction with a different set of CH
acids and Michael acceptors (Table 5).
The data summarized in Table 5 hint that the orientation of
Michael acceptor within the transition state of the addition does

Y. N. Belokon et al. / Tetrahedron: Asymmetry 22 (2011) 167–172
171
H
R
R
H2
C
H
O
O
O
H
C
CH2
CH2
H
C
CH2
H2C
R
O
R
O
O
O
C
H
O
H2
H
H
O
O
H
H
O
H
O
O
Li
H
O
Li
H
O
O
O
O
H
H
Unfavorable
Figure 6. Proposed transition state of (S)-BIMBOL catalyzed addition of malonic ester to cyclohex-2-enone.
Favorable
depend on the structure of the nucleophile. Otherwise all the sub-
strates would have produced the corresponding adducts with the
same high enantioselectivity.
The proposed mechanism of the reaction may have some bear-
ing on the positive effect of water and alcohol addition to some
Li-binolate catalyzed reactions. Possibly, the additives create some
additional proton transfer chains to improve performance of the
catalyst.
(solvent: hexane/iPrOH = 98/2, flow rate: 0.8 mL/min). The specific
rotation of (R)-BIMBOL ½a D25
¼ þ112:3 (c 1.00, CHCl3), and that of
ꢂ
(S)-BIMBIL ½a 2D5
ꢂ
¼ ꢁ100:5 (c 1.00, CHCl3). 1H NMR (300 MHz,
CDCl3): d 7.63 (m, 2H), 7.34–7.23 (m, 24H), 7.13 (s, 2H), 7.10 (d,
J = 6 Hz, 2H), 6.57 (s, 2H), 4.67 (s,2H). 13C (70 MHz, CDCl3): d
151.2, 145.4, 145.2, 133.8, 133.2, 130.8, 128.9, 128.4, 128.1,
128.0, 127.8, 127.5, 124.2, 124.1, 114.2, 82.9. Anal. Calcd for
C46H34O4 (R)-BIMBOL: C, 84.90; H, 5.27. Found: C, 84.98; H, 5.35.
4.2. Asymmetric Michael reaction (general procedure)
3. Conclusion
A Schlenk flask was evacuated and filled with argon, whilst
being heated with a heatgun. Then the flask was cooled to room
temperature under a flow of argon. A catalyst (0.013 mmol) and
a base (0.013 mmol) were added to the flask and a cyclohex-2-en-
one (0.025 mL, 0.258 mmol) solution in CH2Cl2 was added. Then
the solution was stirred for 5 min and diethyl malonate (0.05 mL,
0.0536 g, 0.335 mmol) was added. The reaction mixture was stir-
red for 48 h under Ar. The catalyst was removed from the reaction
mixture by column chromatography on silica gel, using hexane/
EtOAc 5:1 as an eluent. The enantiomeric purity of the product
was determined by chiral HPLC.
Evidently, the experiments support the notion of the multifunc-
tional nature of the BIMBOLate Li catalytic system with Lewis
acidic, Brønsted basic and Brønsted acidic sites, acting in concert
in the transition state of the Michael addition. The catalytic system
represents a perspective alternative to the enamine-type catalysis
of the Michael addition reactions.14 The system can be easily mod-
ified with the acidity of its hydroxyl groups increased. The catalyst
aggregate formation could also be controlled by varying the steric
properties of the diphenylcarbinol moieties. Further work to ex-
plore the scope of the catalytic system and its future generations
is ongoing in our laboratory and will be reported in due course.
4.2.1. Diethyl 2-(3-oxocyclohexyl)malonate
4. Experimental
Prepared according to general procedure. The product was
obtained in 98% yield, colorless oil. 1H NMR (300 MHz, CDCl3):
d (ppm) 1.19–1.24 (m, 6H), 1.40–1.52 (m, 1H), 1.55–1.70 (m, 1H),
1.88–1.92 (m, 1H), 1.98–2.06 (m, 1H), 2.15–2.26 (m, 2H), 2.31–
2.50 (m, 3H), 3.23 (d, J = 7.8 Hz, 1H), 4.11–4.19 (m, 4H). The enan-
tiomeric excess was determined by HPLC analysis with a Chiralpak
AS-H column (9:1 hexanes/isopropanol, 1 mL/min, 210 nm):
17.51 min, 20.67 min.
1H NMR spectra were recorded on Bruker Avance 300
(300.13 MHz) spectrometers; chemical shifts were measured rela-
tive to the residual protons of the deuterated solvent (CDCl3). Opti-
cal rotations were measured on a Perkin–Elmer 241 polarimeter in
a 5-cm cell temperature-stabilized at 25 °C. Column chromatogra-
phy was performed with the use of Silica Gel Kieselgel 60 (Merck).
Elemental analyses were carried out in the Laboratory of
Microanalysis of the A. N. Nesmeyanov Institute of Organoelement
Compounds of the Russian Academy of Sciences. All solvents were
purified according to standard procedures.
The enantiomeric purity of the synthesized Michael adducts
was determined by chiral HPLC analysis (Chiralpak AS-H chiral sta-
tionary phase, iPrOH/hexane 1–9, 210 nm). The absolute configura-
tion of the major product of the cyclohex-2-enone/malonic ester
condensation was determined by comparison with the reported
value of the specific rotation.15
4.2.2. (3S)-Ethyl-2-acetyl-4-nitro-3-phenylbutyrate
To a stirred solution of catalyst (0.011 g, 0.0167 mmol) and
LiOPh (0.0169 mmol) in dry CH2Cl2 was added trans-b-nirostyrene
(0.05 g, 0.335 mmol) and then acetoacetate (0.043 g, 0.335 mmol)
After being stirred for 48 h, the reaction mixture was concentrated
in vacuo. The residue was purified by column chromatography on
silica gel, using hexane/EtOAc 5:1 as an eluent. Rf = 0.3. The diaste-
reomers could not be separated. Colorless oil; ½a D25
¼ ꢁ28:1 (c 0.57
ꢂ
in CHCl3). 1H NMR (300 MHz, CDCl3): d (ppm) 0.99 (t, J = 6.9 Hz, 1.8
H), 1.27 (t, J = 7.2 Hz, 1.5 H), 2.05 (s, 1.3H), 2.27 (s, 1.6H), 3.89–4.02
(m. 1.6H), 4.07–4.23 (m, 2.5H), 4.71 (d, J = 6 Hz, 1H), 4.80–4.82 (m,
0.8H), 7.16 (d, J = 7.5 Hz, 2H), 7.23–7.28 (m, 3H). The enantiomeric
excess was determined by HPLC analysis with a Chiralcel AD col-
umn (9:1 hexanes/isopropanol, 1 mL/min, 210 nm). Reaction
times: (major enantiomer) 8.68; 14.65 min, (minor enantiomer)
9.86; 23.92 min.
4.1. Preparation (R)-BIMBOL and (S)-BIMBOL
Catalyst (R)-BIMBOL and (S)-BIMBOL was synthesized according
to a reported procedure.16
The product was recrystallized from acetone. The enantiomeric
purity of (R)-BIMBOL was 98% ee, (S)-BIMBOL was 100% ee as
determined by using HPLC-Kromasil KR100-5CHI-DMB column

172
Y. N. Belokon et al. / Tetrahedron: Asymmetry 22 (2011) 167–172
4.2.3. 3-(p-Tolylamino)cyclohexanone
wR2 = 0.159 for all 4889 independent reflections, S = 1.006. All cal-
culations were carried out using the SHELXTL program.18 Crystallo-
graphic data for (R)-BIMBOL have been deposited with the
Cambridge Crystallographic Data Center. CCDC 794881 contains
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from the Director, CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (Fax: +44 1223 336033; e-mail: de-
posit@ccdc.cam.ac.uk or www.ccdc.cam.ac.uk).
The catalyst (0.0169 g, 0.026 mmol) and BuLi (0.016 mL, 1.6 M)
in dry Et2O was stirred for 30 min. The solution was evaporated
than cyclohex-2-enone (0.05 g, 0.52 mmol) and p-toluidine
(0.056 g, 0.52 mmol) in dry CH2Cl2 were added. After being stirred
for 48 h, the reaction mixture was concentrated in vacuo. The res-
idue was purified by column chromatography on silica gel, using
hexane/EtOAc 5:1 as an eluent. 1H NMR (300 MHz, CDCl3): d
(ppm) 1.70–1.81 (m, 2 H), 2.05–2.11 (m, 2 H), 2.28 (s, 3H), 2.35–
2.50 (m, 4H), 2.84–2.89 (dd, J = 3.6 Hz, J = 10 Hz, 1H), 3.80 (m,
1H), 6.58 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H). The enantio-
meric excess was determined by HPLC analysis with a Chiralpak
AS-H column (9:1 hexanes/isopropanol, 1 mL/min, 254 nm). Reac-
tion times: (major enantiomer) 27.58 min, (minor enantiomer)
23.66 min.
References
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4.2.4. Ethyl (2-cyano-2-(3-oxocyclohexyl)-2-phenylacetate
Prepared according to the general procedure.
A catalyst
(0.0169 g, 0.026 mmol) and LiOPh (0.026 mmol) were added to
the flask and cyclohex-2-enone (0.05 g, 0.252 mmol) solution in
CH2Cl2 was added. Then the solution was stirred for 5 min and
ethyl 2-cyano-2 phenylacetate (0.098 g, 0.52 mmol) was added.
The reaction mixture was stirred for 48 h under an argon atmo-
sphere. The catalyst was removed from the reaction mixture by
column chromatography on silica gel, using hexane/EtOAc 5:1 as
an eluent. Colorless oil; 1H NMR (300 MHz, CDCl3): d (ppm)
1.26–1.31 (m, 3H), 1.48–1.61 (m, 1H), 1.74–1.96 (m, 2H), 2.03–
2.26 (m, 2H), 2.34–2.48 (m, 2H), 2.65–2.61 (m, 1H), 2.86–2.95
(m, 1H), 4.17–4.38 (m, 2H), 7.42–7.49 (m, 3H), 7.58–7.67 (m,
2H). The enantiomeric excess was determined by HPLC analysis
with a Chiralcel OD column (95/5 hexanes/isopropanol, 1 mL/
min, 210 nm). Reaction times: (major enantiomer) 8.68;
14.65 min, (minor enantiomer) 9.86; 23.92 min.
4. (a) Belokon, Y.; Kochetkov, K.; Churkina, T.; Ikonnikov, N.; Larionov, O.;
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The crystal of (R)-BIMBOL (C46H34O4 ꢀ 1.75C3H6O, M = 752.37)
is monoclinic, space group P21, at T = 120 K: a = 15.9754(13) Å,
b = 9.2420(7) Å, c = 16.0119(13) Å, b = 116.745(2)°, V = 2111.2(3)
Å3, Z = 2, dcalcd = 1.184 g/cm3, F(0 0 0) = 796,
l
= 0.076 mmꢁ1. Data
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(k(MoK )-radiation, graphite monochromator,
u
and scan mode,
x
a
hmax = 27o). The structure was solved by direct methods and re-
fined by full-matrix least squares technique on F2 with anisotropic
displacement parameters for non-hydrogen atoms. The indepen-
dent part of the unit cell of (R)-BIMBOL contains two acetone sol-
vate molecules, one of which is disordered over two sites with the
occupancies of 0.50:0.25. The hydrogen atoms of the hydroxy-
groups in (R)-BIMBOL were localized in the difference-Fourier
map and included in the refinement with fixed positional and iso-
tropic displacement parameters (Uiso(H) = 1.5Ueq(O)). The other
hydrogen atoms were placed in calculated positions and refined
within the riding model with fixed isotropic displacement
parameters (Uiso(H) = 1.5Ueq(C) for the CH3-groups and Uiso
(H) = 1.2Ueq(C) for the other groups). The absolute structure of
(S)-BIMBOL cannot be objectively determined, because it includes
no heavy atoms with Z > Si. The final divergence factors were
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R1 = 0.060 for 3912 independent reflections with I > 2r(I) and