A mechanistic study of the Lewis acid-Br?nsted base-Br?nsted acid catalysed asymmetric Michael addition of diethyl malonate to cyclohexenone

Article abstract of DOI:10.1039/c6cy01697a

The Michael addition of diethyl malonate (Michael Donor, MD) to cyclohexenone (Michael Acceptor, MA) catalysed by the mono-lithium salt of (S)- or (R)-BIMBOL in dichloromethane is shown to exhibit biomimetic behavior. A combination of kinetics, spectrosco

Full text of DOI:10.1039/c6cy01697a

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V. Kondratenko, M. Ezernitskaya, K. Lyssenko, A. S. Peregudov, V. Khrustalev, V. I. Maleev, M. Margarita
Moskalenko, M. North, A. Tsaloev, Z. Gugkaeva and Y. N. Belokon, Catal. Sci. Technol., 2016, DOI:
1
0.1039/C6CY01697A.
Volume 6 Number 1 7 January 2016 Pages 1–308
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ISSN 2044-4753
PAPER
Qingzhu Zhang et al.
Catalytic mechanism of C–F bond cleavage: insights from QM/MM
analysis of fluoroacetate dehalogenase
rsc.li/catalysis

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A mechanistic study of the Lewis acid-Brønsted base-Brønsted
acid catalysed asymmetric Michael addition of diethyl malonate
to cyclohexenone
Received 00th January 20xx,
Accepted 00th January 20xx
a,b
a,c
a
a
DOI: 10.1039/x0xx00000x
Yuri Samoilichenko, Veronica Kondratenko, Mariam Ezernitskaya, Konstantin Lyssenko,
a
a,d
a
a
Alexander Peregudov, , Victor Khrustalev, Victor Maleev, Margarita Moskalenko, Michael
www.rsc.org/
e
f
a
a*
North, Alan Tsaloev, Zalina T. Gugkaeva, and Yuri Belokon
The Michael addition of diethyl malonate (Michael Donor, MD) to cyclohexenone (Michael Acceptor, MA) catalysed by the
mono-lithium salt of (S)- or (R)-BIMBOL in dichloromethane is shown to exhibit biomimetic behavior. A combination of
kinetics, spectroscopic studies, synthesis of catalyst analogues, inhibition studies and DFT calculations are used to show
that the catalyst activates both components of the reaction and uses a chain of proton transfers to facilitate the
deprotonation of diethyl malonate. The initial reaction rate was first order relative to both MA and MD and 0.5 order
relative to the catalyst, indicating that an equilibrium exists between monomeric and dimeric forms of the catalyst, with
1
the dimer predominanting, but only the monomeric form being catalytically active. This was supported by DOSY H NMR
experiments. The importance of the Lewis acidic lithium cation in the catalytic step was established by complete inhibition
of the reaction by lithium complexing agents. The importance of the number of OH-groups and their relative
intramolecular orientation and acidities in the polyol catalyst was shown by studying the relative catalytic activities of
catalyst analogues. DFT calculations allowed the relative energies and structures of the likely intermediates on the
reaction coordinate to be calculated and indicated that the ionisation of MD was facilitated due to the Lewis acidity of the
-1
lithium cation and hydrogen bond formation between deprotonated MD (MD ) and the OH groups of the BIMBOL moiety.
facilitates both simultaneous activation of both reaction
components; and intramolecular proton transfer to lower the
Introduction
4
energy of transition states between reaction intermediates. In
Asymmetric catalysis using synthetic catalysts has
advanced enormously over the last 25 years. Metal catalysed
1
reactions are well established and asymmetric organocatalysis
this paper we show that a chiral synthetic catalyst containing
both metal-based and non-metal based catalytic groups
facilitates both intramolecular proton transfer and reactant
activation in a biomimetic way.
2
,3
has blossomed over the last 15 years, with chiral Brønsted
acid and hydrogen bond donor catalysis being amongst the
3
most recent developments. Despite these impressive
The introduction of basic groups into catalysts, alongside
hydrogen bonding functions, results in highly efficient
bifunctional chiral catalysts capable of simultaneous activation
of both nucleophilic and electrophilic components of
advances, synthetic catalysts still struggle to match the levels
of activity and asymmetric induction achieved with enzymes.
This is due to the presence of multiple, exquisitely orientated,
functional groups within the active site of enzymes which
3
,5
heterolytic reactions. The most popular catalytic motif of
5
this type is represented by amine-thiourea organocatalysts.
Recently, the combined use of metal-based and
organocatalysts has been shown to catalyse tandem
6
processes. As a result of these discoveries the established
mechanisms of asymmetric catalysts have been re-evaluated
and some well accepted cases of Lewis acid catalysis have
7
been shown to originate from hidden Brønsted acid catalysis
8
occurring via Lewis acid activated Brønsted acid catalysis.
Another emerging multifunctional catalytic system for
asymmetric C-C and C-H bond formation is exemplified by
9
chiral alkali binaphtholate salts. These catalysts contain a
Lewis acidic site, Brønsted basic and Brønsted acidic sites. The
corresponding alkali metal salts of TADDOLs and bis-TADDOLs
were also efficient in promoting asymmetric carbon–carbon
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1
different relative activities. The self-association of lithium
1
1
2
derivatives is a well-known phenomenon as is the self-
3
i,j,k
association of derivatives of thiourea,
1
catalytically active
3
10c
silanediols and bis-TADDOLs. This self-association can be
an impeding factor for the catalytic activity of amine-
i,j
thioureas or a favourable one for electrostatically enhanced
3
3
k
13
10c
thioureas, silanediols and bis-TADDOLs. Therefore, we
have carried out a combined experimental and computational
study of the Michael addition of diethyl malonate to
cyclohexanone catalysed by lithium salts of BIMBOL and
related compounds and show that the reaction exhibits the
positive catalytic features associated with enzymatic catalysis.
Results and Discussion
Synthesis of (R)- and (S)-BIMBOL was achieved as reported
1
4
earlier. The syntheses of (R)-H
CF -BIMBOL were achieved from (R)- or (S)-BINOL (S59 ). H
BIMBOL should have lower acidity (greater pK value) than
BIMBOL, whereas (CF -BIMBOL should be more acidic (lower
pK value).
The structure of (R)-BIMBOL (Figure 2 top) has previously
8
-BIMBOL, (S)-BIFOL and (R)-
†
(
3
)
8
8
-
a
3 8
)
a
1
1
been determined by X-ray crystallography and shown to have
two pairs of OH groups each involved in two pairs of
intramolecular hydrogen bonds: naphthol-OH···OH-alcohol and
vice-versa and with both pairs of OH groups situated over the
same face of the naphthyl moieties of BIMBOL (endo-type
1
1
‡
orientation). X-ray analysis of BIFOL also showed that each
pair of OH groups was involved in intramolecular hydrogen
bond formation; but the triphenylmethanol groups were
positioned on different faces of the naphthyl planes (exo-type
orientation, Figure 2 bottom). This raises the question as to
whether rotation around the C3-C17 (or C11-C26) bond is
hindered to such an extent as to make the exo-isomer
observed in the solid state also the atropoisomer present in
solution or whether the exo/endo transition is relatively facile
in solution. Literature data on the rotation barriers for a series
1
5
of closely related 2-methyl-1-naphthyl-fluorenes indicated
that the energy of rotation around a naphthyl-fluorene bond is
>
26 kcal/mol. Our calculation of the barrier to rotation in
†
BIFOL from DFT data (S34 ) gave a value of 16.6 kcal/mol.
1
The H NMR spectra of BIMBOL and BIFOL in CD
Figure 1: Mono-lithium-salts of chiral polyols: TADDOL, bis-TADDOL, BINOL and
BIMBOL and the BINOL derivatives used in this work.
2
Cl
2
†
between 30 °C and −60 °C differed drastically (S55-S56 ). While
all the resonances of BIFOL (especially those of the OH groups)
became narrower as the temperature was lowered, all the
resonances of BIMBOL became broader and those of OH
1
0
bond forming reactions. The combination of both BINOL and
TADDOL motifs in the same molecule to form BIMBOL lithium
salt (Figure 1) improved the catalytic performance of the
system, compared to the corresponding salts of either BINOL
or TADDOL in the benchmark reaction of the Michael addition
1
3
groups separated into several sets. Similarly, the C NMR
spectra of BIFOL and BIMBOL recorded at 30 °C and −40 °C
†
13
1
1
differed immensely (S57-S58 ). At 30 °C, the C NMR spectrum
of BIFOL displayed broad signals for the ipso-carbon atoms
bonded to the OH groups (157.7 and 91.7 ppm) and those
connecting two binaphthyl moieties (122.7 ppm), whereas the
of diethyl malonate (MD) to cyclohexanone (MA). The
BIMBOL catalyst system has the potential to be trifunctional
with the metal ion serving as a Lewis acid whilst the
naphtholate ion and hydroxyls are Brønsted base and Brønsted
acids respectively.
1
3
analogous C resonances of BIMBOL (156.5, 88.3 and 119.7
ppm, respectively) at the same temperature were narrow. In
contrast, at −40 °C, all the BIFOL resonances connected with C-
OH moieties and those of the C1 and C9 atoms became narrow
The enantioselectivity and chemical yields of the BIMBOL
catalysed reaction displayed concentration dependences,
indicating that the catalyst self-associates to give species with
2
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Figure 3: IR monitoring of the
[
ν
(CO) region under the reaction conditions:
=[MD]
o
, 25 C.
BIMBOL]=[PhOLi]=0.0057 M, [MA
]
o
o
=0.11 M, CH
Cl
2 2
in this manner was catalytically identical to one produced by
1
the reaction of BIMBOL with BuLi.
1
The reaction could be easily monitored by IR spectroscopy,
following the disappearance of the cyclohexenone absorptions
-1
-1
at 1671 cm (ε = 409) and 1685 сm or the appearance of the
-1
carbonyl group of the adduct (MP) which absorbs at 1712 сm .
Figure 3 illustrates the progression of the changes of the IR
spectra of the reaction mixture under the experimental
-1
conditions given in Scheme 1. An isobestic point at 1695 cm
was observed in the infrared spectra indicating that no side
reactions occur during the Michael addition. To allow a
quantitative analysis of the kinetic results, curve fitting of the
1
1
Figure 2: The structures of (R)-BIMBOL (top) and (S)-BIFOL (bottom) showing
the different disposition (endo and exo) of the hydrogen bond coupled OH
groups in the crystals of the compounds.
observed spectra in the
experimental section for details) and the rate of formation of
MP exactly matched the rate of disappearance of MA
ν(CO) region was undertaken (see
and no change in the number of other resonances took place.
However, for BIMBOL at −40 °C, all the resonances became
broader and most of them split into multiple signals (S55-
.
Previously we observed that the reaction took almost 48
11
hours to go to completion. However, the kinetic data
†
S58 ). Thus, it appears that BIFOL exists in solution at ambient
obtained from the infrared spectra and displayed in Figure 4
indicate that the reaction occurs in two kinetically distinct
stages (Figure 4, data points a). On the timescale shown in
Figure 4, the changes in reactant concentrations are
sufficiently small that the data can be fitted to pseudo-zero
order kinetics. The rapid, initial section of the reaction
produced almost 20% of MP within 40 minutes. Then, the
Michael addition was significantly slowed down. This effect
temperature as an interconverting endo-exo-atropoisomer,
probably with the isomer depicted in Figure 2 as the major
form. Decreasing the temperature slows the OH group proton
exchange in BIFOL and as a result, the NMR resonances
become progressively narrower and their resolution improves.
In contrast, a decrease in temperature in case of BIMBOL
caused, in addition to slowing the proton exchange, slow
3
2
rotation around the sp -sp bonds (C17-C3 or/and C11-C30)
eventually producing a mixture of several atropoisomeric
conformers, existing in a slowly established equilibrium at
temperatures below −20 °C.
1
a
V = -0.00076
2
R
= 0.98
0.95
0
.9
.85
.8
Vb = -0.00094
The benchmark Michael addition of diethyl malonate (MD
)
2
R
= 0.97
0
to cyclohexenone (MA) was conducted as shown in Scheme 1.
V1 = -0.0043
R2 = 0.99
0
The lithium salt of BIMBOL could be prepared by the reaction
of lithium phenoxide with BIMBOL as the pK
a
of BINOL in
17
0.75
0.7
1
DMSO is approximately 13 whereas that of phenol is 18. In
6
V
2
= -0.0014
2
R
= 1
addition, it was shown previously that the catalyst generated
O
0.65
O
5% (R)-BIMBOL,
0.6
CO
2
Et
0
20
40 t, min 60
80
100
120
5
% PhOLi
+
o
CO Et
Figure 4: Reaction profile versus time plot for the conversion of cyclohexenone
MA) and malonic ester (MD) into MP catalysed by a catalyst prepared in situ
2
5 C, CH Cl
2
CO Et
2
2
(
from BIMBOL and PhOLi in CH
2
o
under Ar at 25 C: [BIMBOL]
2
0.11 M, in CH
Cl
Cl
2
=
[PhOLi]
-
=
1
0.0057
CO Et
M, [MA
]
o
=
[
MD
]
o
=
2
2
; reaction rates (V) are given in min . a) no
MA
MD
2
additives b) 10% (relative to MA) of MP were added. c) half an equivalent of MP
(
R)-MP
was added.
Scheme 1: The addition of diethyl malonate (MD) to cyclohexanone (MA) using
(
R)-BIMBOL to give (R)-MP.
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Table 1: The impact of the ratio of (S)-BIMBOL/PhOLi on the reaction kinetics and
ln[BIMBOL-PhOLi]
-4.5
a
enantiomeric excess of the resulting MP. .
-4.4
-
5.5
-5
-4
-3.5
b
-1
b
-4.6
run (S)-BIMBOL, mol% PhOLi, mol% V, min
ee of (S)-MP,
-
-
-
-
3
c.
1
2
3
4
5
5
5
10
2.5
5
4.3 x 10
3.0 x 10
2.8 x 10
4.6 x 10
85-90 (86)
-4.8
3
4
4
86
-5
5
78-86
83-86
-5.2
-5.4
-5.6
10
y = 0.51x - 2.73
R² = 0.99
o
o o 2 2
a) The reaction was conducted under Ar at 25 C, [MA] =[MD] =0.11 M in CH Cl .
b) The initial rate and enantiomeric excess of MP (the estimated range of three
experiments) at 90% conversion. c) The enantiomeric excess of MP at 15%
conversion (the estimated range of three experiments).
-
5.8
-6
[
M A ]
x
y
n
1
Figure 5: Plot of ln(V) versus ln[Cat] for the addition of diethyl malonate (MD) to
cyclohexenone MA): )-BIMBOL/PhOLi 1:1; MA =[MD =0.11 M, solvent
CH Cl
V = -
= k ⋅[ M A ] ⋅[ M D ] ⋅[B IM B O L / Li]
(
(S
[
]
o
]
o
dt ⋅[ M A ]
o
2
2
.
was assumed to be due to catalyst inhibition by the reaction approaching that of the di-Li salt. However, the ratio of (S)-
product and this was supported by the addition of 10–50% of BIMBOL to lithium phenoxide had almost no influence on the
MP relative to MA to the reaction mixture. A twofold excess of enantiomeric excess of the resulting MP (Table 1, runs 1-4)
MP relative to the catalyst was sufficient to generate a new which supported the theory that the catalytically active species
catalytic species, having lower catalytic efficiency (Figure 4, had the same composition in the reaction mixture whatever
data points b). A tenfold excess of MP in the reaction mixture the ratio of the catalytic components.
had almost no additional negative effect on the reaction
kinetics (Figure 4, data points c).
To determine the order with respect to the catalyst
concentration, reactions were carried out in duplicate at four
In order to test if some non-linear effects were present in different catalyst concentrations. The average initial zero order
-1
the system, 10 mol% of MP with 90% enantiomeric purity was rate constants (V, min ) were used to construct a plot of lnV
added to the reaction mixture at the beginning of the reaction against ln([BIMBOL/Li]). The resulting plot is shown in Figure 5
and the enantiomeric purity of the resulting MP was checked and the best fit line through the data points has a slope of
at 10% and 98% of conversion. In each case the ee of MP was 0.51±0.16, suggesting that the reaction had a 0.5 order
found to lie in the ee interval of 85-90%. In addition, 10 mol% dependence on the catalyst concentration (n in equation 1).
of racemic MP was added to the reaction mixture and the final This indicates that the catalytically active species is monomeric
enantiomeric purity of the product was found to be 82% which and exists in a rapid equilibrium with a catalytically inert
corresponded to that of a mixture of 10% of a racemic additive dimeric species, and that the position of equilibrium is strongly
and 90% of enantiomerically enriched MP with ee of 85-90%. shifted towards the dimer (Scheme 2).
Thus, no influence of the ee of MP on the asymmetric concentration of the monomeric component in the reaction
performance of the catalyst was detected.
mixture was supported by the absence of any observable
A very low
To determine the order with respect to substrates MA and additional signals for either the malonic ester or
MD, reactions were carried out at three concentrations of cyclohexenone protons in their separate 1:1 mixtures with
each substrate whilst keeping the other component BIMBOL/Li in deuterated dichloromethane soluꢀons (S37†). In
concentration constant. The initial zero order rates (up to 15% contrast, the more acidic ethyl nitropropanoate had its
conversion) of the reactions were determined and the spectrum significantly changed under the same conditions
coefficients X and Y in equation 1 were found to be 0.87 and (S37†). The earlier observaꢀon of positive non-linear effects in
0
.76 respectively. Thus, there was some deviation from the the reaction, with racemic (S)- and (R)-BIMBOL forming an
1
1
expected second order behaviour, probably, reflecting inert precipitate, provides further indirect evidence for the
competition of the substrate present in excess with the other dimer being catalytically inactive.
substrate for the active sites of the catalyst.
In order to investigate the relative importance of Brønsted
To address the issue of the real composition of the and Lewis acid centres within the catalyst, lithium complexing
catalytically active species, reactions were carried out at agents were added to the reaction mixture and the results are
various ratios of (S)-BIMBOL to lithium phenoxide. The summarised in Table 2. The addition of two equivalents of
malonate carbanion formation should be the key stage of the TMEDA relative to the catalyst completely inhibited the
addition sequence and the amount of basic groups is expected reaction (run 2). The same effect was observed on the addition
to be the most important feature of the catalyst. Since the of just one equivalent of benzo-15-crown-5 (run 3). The
number of basic groups in the case of di-Li salts is twice that of addition of three equivalents of THF or morpholine also
mono-Li-salts one could expect doubling the reaction rate. negatively influenced the yield of the product (runs 4 and 5)
However, the catalytic performance of both was almost the same although to a lesser extent. On the other hand, three
(Table 1, runs 1 and 2), this indicates that the presence of free equivalents of 1,2-dimethoxyethane (DME) improved the yield
hydroxyl groups in the mono-Li salt is an important boost of the of the product (run 6 and 7) whereas the addition of 20
catalytic performance of BIMBOL increasing its activity to
4
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equivalents of DME resulted in complete inhibition of the
reaction.
According to DOSY data, summarised in Table 3, the
formation of mono lithium salts of BIMBOL led to a reduction
of its diffusion coefficient (D) relative to that of BIMBOL from
-
9
-9
2 -1
0
.88x10 to 0.61x10 m s (entries 1 and 2). The formation of
a dimer of the Li-salt is a reasonable explanation of these
results. The addition of benzo-15-crown-5 to BIMBOL / Li in a
1
:1 ratio led to an increase of D in the case of the BIMBOL / Li
-9
salt (entry 3, D=0.82x10 ) and decreased D for the crown
2
ether (entries 3 and 4, D =0.990x10 m s and 1.32x10 m s
-9
-1
-9
2 -1
respectively). This can be explained by the establishment of a
rapid equilibrium between species including significant
amounts of monomeric BIMBOL-Li-benzo-15-crown-5. The
effect of DME on the BIMBOL-Li was different. The addition of
three equivalents of DME had almost no influence on the D of
the lithium salt (runs 2 and 5), but the diffusion coefficient of
DME itself somewhat decreased (run 5 and 6). This suggests
that the interactions of DME were mostly with the lithium
monomer present in small amounts in the solution (Scheme 5).
These data show that the lithium cation constituted the
core of the catalytic system and its coordination with strong
external complexing agents led to the complete loss of the
catalytic activity. However, some weakly coordinating agents
such as DME could increase the catalytic activity in terms of
both yield and enantioselectivity which might indicate a
Scheme 2: Illustration of a possible inactive dimer / active monomer equilibrium to
rationalise the 0.5 order kinetics relative to the (S)-BIMBOL / Li concentration.
Table 2: The influence of coordinating additives on the catalytic performance of beneficial influence of the additive by thwarting the inhibiting
(
S)-BIMBOL / Li.
effects of the product MP on the reaction kinetics and/or
shifting the equilibrium of Scheme 5 towards the monomer
components.
a
b
run
Additive
mol% relative to MA)
Time, Yield of (S)-MP, % (ee%)
h
(
1
2
3
4
5
6
7
8
-
48
24
55 (85-90)
0
In order to investigate the relative importance of the
BIMBOLate hydroxyl groups in the catalysis, the relative
activities of the mono-lithium salts of BIMBOL, BINOL, H8-
BIMBOL, BIFOL, and (CF ) -BIMBOL were studied in the model
TMEDA (10%)
Benzo-15-crown-5 (5%) 24
0
THF (15%)
24
24
24
48
24
22 (n.d.)
10 (n.d.)
60 (85-90)
98 (85-90)
0
3
8
Morpholine (15%)
DME (15%)
reaction (Scheme 1) under identical conditions and the results
are shown in Figure 6 where the initial consumptions of MA
are plotted versus time. As can be seen from Figure 6, BINOL
was much less active than BIMBOL. The superior activity of the
later was not a consequence of the greater acidity of its
DME (15%)
DME (100%)
The reaction was conducted under Ar at 25 °C in CH
2
Cl
2
,
[(S)-
BIMBOL]=[PhOLi]=0.0124 M, [MA] =[MD] =0.248 M. a) The yield was estimated phenolic hydroxyl groups, relative to those of BINOL, as the
o
o
1
by Н NMR. b) The enantiomeric excess of the product was determined by chiral
more acidic (CF
relative to BIMBOL.
BIMBOL-Li had a different type of reactivity with an
3 8
) -BIMBOL also displayed a diminished activity
HPLC analysis of MP.
a
H
8
Table 3: DOSY experiments .
induction period observed at the beginning of the reaction,
followed by a lower reaction rate than that of BIMBOL-Li. The
induction period may reflect slow dissociation of the dimeric
lithium salt, initiated by the substrates. Such processes were
shown to become rate limiting in some reactions of lithium
9
2 -1
run Compound
Log D
-9.083
-9.21
D x10 m s
0.808
1
2
3
BIMBOL
BIMBOL + PhOLi
0.61
BIMBOL / Li + benzo-15-crown-5 BIMBOL -9.0855 0.821
(1:1 relative to Li)
Crown -9.0042
-8.88
0.990
1.32
1
2b
8
derivatives. (R)-H -BIMBOL led to MP of (R)-configuration,
4
5
benzo-15-crown-5
BIMBOL / Li / DME
as also observed for (R)-BIMBOL (see Table 1), though with a
diminished enantiomeric excess of 25% after 1.5 h and 26%
after 27 h. In addition, at longer time intervals, the rate of the
-9.18 (BIMBOL)
-8.63 (DME)
-8.52
0.64
2.34
3.07
(3:1 relative to Li)
6
DME
o
H
8
BIMBOL-Li promoted reaction became faster than that of
a) DOSY experiments were carried out at 20 C in CD
2
Cl
2
, [Polyol]=[PhOLi]=0.03
the BIMBOL-Li catalysed one. It took only 24 h for H -BIMBOL-
8
M. The reaction conditions were the same as those given in the footnote to Table
2
.
Li to bring the reaction to 80% completion, whereas BIMBOL-Li
furnished only 55% of MP within that time interval. The
8
difference in behaviour of BIMBOL and H BIMBOL can be due
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Thus, the presence of four interconnected OH groups with
endo-orientation inside the same chiral molecule is a
prerequisite for the efficient performance of the catalyst
family. The variation in their acidities, mutual orientation and
the rate of the conformational rearrangements could be
decisive factors in determining the catalyst activity of the
system. Finally, the presence of a Lewis acidic lithium counter-
cation is a prerequisite for efficient BIMBOL-Li catalysis.
1
00
(
S)-BIFOL
(R)-BINOL
9
9
8
8
5
0
5
0
(
R)-(CF ) BIMBOL
3 8
(
R)-H BIMBOL
8
In order to shed light on the details of the reaction
mechanism, DFT calculations were performed on the system.
1
8
For analysis of the intramolecular interactions QTAIM theory
(
S)-BIMBOL
was used as that gives an opportunity to locate all the bonding
interactions by a critical point search as well as to estimate the
0
20
40 t, min 60
80
100
1
9
energy of the interactions by means of Espinosa correlation.
Figure 6: Relative activities of the mono-lithium salts of (S)-BIMBOL, (R)-BINOL, (R)-
Firstly, optimisation for two overall uncharged complexes Li1
and Li2 were carried out. The first complex Li1 contained the
anion of BIMBOL, one lithium cation and a neutral malonic
H
8
BIMBOL, (S)-BIFOL, and (R)-(CF
3
)
8
BIMBOL in the model Michael addition reaction in
o
CH
2
Cl
2
at 25 C: [tetraol]=[PhOLi]=0.0057 M, [MA] [MD] =0.11 M.
o
o
to the variation in their acidity and in the torsion angles of ester (Figure 7, top) whereas Li2 contained a neutral BIMBOL,
their naphthyl moieties. The acidities of BINOL and H BINOL in one lithium cation and a malonic ester anion (Figure 7,
DMSO are 13.2 and 17.9 respectively and the minimum bottom). In both complexes, the lithium cation is
energy torsion angle is greater in case of H -BINOL than for tetracoodinated by two oxygen atoms of BIMBOL and two
BINOL. The same trend could be expected to be retained in oxygen atoms of the carbonyl groups of malonic ester. At the
BIMBOL, and H -BIMBOL with the torsional angle in the latter same time in Li1 the lithium cation is coordinated by oxygen
8
1
7
8
8
being greater by approximately six degrees, making the OH atoms of the same naphthalene fragment (O(1) and O(2))
groups of the naphthyl moieties closer to each other whereas in Li2 it forms bonds with both fragments (O(1) and
(
according to MM2 calculations). These two factors combined O(3) atoms). As expected, in the Li1 complex, the Li-O distance
could produce the observed effects. One of the reasons for the with deprotonated O(2) atom is the shortest (1.852 Å), while
greater activity of H BIMBOL-Li at the later stages of the the corresponding bonds with OH groups vary in the range of
8
reaction could be the less likely formation of the non- 1.892-1.917 Å. In contrast, the Li-O bonds with carboxy groups
productive complex with MP because of the combined of malonic ester are shorter in the case of Li2. The additional
acidity/steric properties of H -BIMBOL-Li.
8
stabilisation of the Li1 and Li2 salts is also due to O(3)-H···O(4),
S)-BIFOL was even less active than BINOL (Figure 6) and O(4)-H···O(7) and O(3)-H···O(4) hydrogen bonds respectively.
(
even after 48 hours no MP formation was observed under the Furthermore, the number of HO…OH and O(4)-H···C(2)
standard conditions with BIFOL-Li catalyst. Several interactions in Li2 have been established by a critical point
explanations could be put forward to rationalise the lack of search. The latter interactions can be interpreted as the O-
catalytic activity of BIFOL-Li:
H···OH hydrogen bonds and can serve as the channel of proton
. The four OH group are unable to form hydrogen bond transfer from the BIMBOL molecule to the malonic ester anion
1
-
supported trimolecular MA and MD (deprotonated MD
1
)
and, according to the principle of microscopic reversibility, the
complexes with BIFOL in which the Michael acceptor and chain of proton removal from the neutral malonic ester to the
donor are situated in appropriate positions for carbon–carbon ionised BIMBOL. The energy of these C-H···O and O-H···O
1
1
bond formation to take place, as hypothesised previously.
. The observation could be connected to the slow rotation significant difference in charge distribution and intramolecular
interactions are 2.0 and 3.2 kcal/mol respectively. Despite the
2
2
of the hydroxyfluorenyl moieties around the sp –sp bonds interactions in Li1 and Li2 their total energy was almost equal,
3
†
C(17)-C(3) or C(11)-C(26) (S34 ). The release of MP from the with Li2 being just 2.0 kcal/mol lower in energy.
catalytic site of the BIMBOLs and, thus, recovery of the catalyst
Generally, Li1 and Li2 differ mostly in the position of a
should be coupled to the breaking of hydrogen bonds between proton on either BIMBOL or malonic ester moieties within
the carbonyl groups of MP and the OH groups of BIMBOLs. their complexes. In other words, the two structures represent
This might necessarily involve the conformational the limiting extremes of an acid-base equilibrium, involving
rearrangement of the endo- to exo-orientation of the BIMBOL-phenolate/BIMBOL conjugated acid and malonic-
triphenylcarbinol moieties of BIMBOLs. In the case of BIFOL ester/malonate-anion. Taking into account that the acidities of
1
7
18
such conformational rearrangement is too slow (vide supra) BINOL and malonic esters in DMSO are 13.2 and 16.4,
and results in very slow catalyst release and slowing of the respectively; such a small difference in energy between Li1 and
reaction.
Li2 was unexpected. It could be an indication of a greatly
. Another explanation might be based on a slow Li-dimer– increased acidity of the coordinated malonic ester by the
monomer dissociation in the case of BIFOL also linked to the stabilisation of malonate anion in Li2, as compared with the
3
slow conformational rearrangements.
free CH-acid. Such stabilisation may originate from the lithium
cation coordination of the malonate and also from the
6
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Figure 7: Views of Li1 (top) and Li2 (bottom) according to DFT calculations. Some
hydrogen atoms are omitted for clarity. The intramolecular interactions are
shown only for contacts for which the critical points (3,-1) of the electron density
function were located.
O(4)-H···C(2) hydrogen bond, linking the BIMBOL moiety and
malonate.
As the next step, energy calculations on the MA adducts
with both Li1 and Li2
conducted. In contrast to Li1 and Li2, the total energies of
complexes Li1MA Li2MA and Li3MA (Figure 8) differed
(Li1MA, Li2MA and Li3MA) were
,
significantly, with the additional stabilisation of the latter two
adducts by 13.6 and 13.5 kcal/mol respectively. The energies
of interaction of MA with Li1 and Li2 were calculated to be
11.0 and 22.6 kcal/mol in Li1MA and Li2MA respectively. An
alternative conformation of MA with L1 was also considered
†
Figure 8: Views of Li1MA (top), Li2MA (middle) and Li3MA (bottom) according to
(
S17 ). In both complexes, the main force that binds MA is a the results of DFT calculations. Some hydrogen atoms are omitted for clarity.
Intramolecular interactions are shown only for contacts for which critical points
O(1)-H···O(9)=C bond with an energy of 10.4 and 11.6 kcal/mol (3,-1) of electron density function were located.
respectively. In addition to this hydrogen-bond, in Li2MA there
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are a number of additional interactions such as C···C (3.58
and O···C (3.2-3.3 ) between the malonate anion and MA facilitate the design and development of other highly effective
with energy varying in the range of 0.7-1.2 kcal/mol. asymmetric catalysts based on BIMBOL and related polyol
Å
)
allows a better understanding of this Michael addition, but will
Å
The Li3MA structure differed from Li2MA by rotation of catalysts. Work in this direction is continuing in our group.
the MA moiety by 180 degrees around the O(1)H···O(9)=C
bond (Figure 8). Although the energy of this complex was
Experimental
almost equal to that of Li2MA (it is less stable by only 0.12
kcal/mol), the type and number of interatomic interactions
between the cyclohexenone and malonate were different. In
contrast to the C(2)···(C5); O(5)···C(4) and O(6)···C(4)
interactions in Li2MA, the atoms of the C=C bond of MA in
Li3MA interact only with the O(8) atom (O···C 3.68 Å) and with
the C(2) atom of the malonate by one of the MA aliphatic
protons. The distances between C(2) and C(5) are 3.58 Å in
General experimental, crystallographic and computational
details are given in the supporting information.
2
1
(
R)-BIMBOL. Synthesised by the previously reported method
2
5
21
starting from (R)-BINOL. [α]
D
3
+109.8 (c 1.00, CHCl ), lit.
2
0
22
[α]
D
+113.4 (c 1.00, CHCl
3
); Mp. 186–188 °C, (lit. mp. 176–
79 °C); H NMR (300 MHz, CDCl ) δ 7.68–7.65 (m, 2H), 7.40–
.28 (m, 24H), 7.19 (s, 2H), 7.17–7.14 (m, 2H), 6.70 (s, 2Н), 4.79
×2H O×(CH CO.
1
1
7
3
L
i2MA and 4.2-4.28 Å in Li3MA. All other interactions in Li3MA
are similar to those in Li2MA.
(s, 2Н); Found (%): C, 79.2; H, 5.8. C46
H
34
O
4
2
3 2
)
Thus, according to the DFT calculations, the ionisation of
MD occurs by its α-proton being removed by the alcohol
oxygen atom O(4) of BIMBOL-Li facilitated by proton
distribution via the chain of hydrogen bonds inside Li1, leading
Calculated (%): C, 78.9; H, 5.9.
(
R)-H
EtOH (39 ml) and H
autoclave. The reaction was carried out at a pressure of 70
atm. of H and 120 °C for 5 hours. The product was purified by
flash chromatography on SiO (n-hexane/EtOAc 5:1).
Recrystallisation from n-hexane gave (R)-H -BINOL (3.8 g, 76%)
+51.8 (c 2.00, CHCl ); mp.
) δ 7.10 (d, J = 8.3 Hz, 2H),
.85 (d, J = 8.3 Hz, 2H), 4.59 (s, 2H), 2.77 (t, J = 6.2 Hz, 4H),
8
-BINOL. (R)-BINOL (5 g, 17.5 mmol), Pd/C 10% wt (1.5 g),
2
O (1 ml) were charged into a 200 ml steel
to formation of Li2 existing in a facile equilibrium with Li1
.
However, the formation of the reactive intermediates
2
0
+1
BIMBOL -Li -xMA-xMD (Li2MA and Li3MA, Figure 8) occurs
-1
2
by the addition of MA to Li2 and not Li1. Within adducts
Li2MA and Li3MA the electrophilicity of the molecule of MA is
greatly increased by the O(1)-H···O(9) hydrogen bond
formation with the BIMBOL moiety. The mutual disposition of
both MA and MD inside the intermediate complex Li2MA or
Li3MA is ideal for the final carbon-carbon bond formation. The
generation of MP can be easily portrayed as proceeding by the
8
2
5
as a white powder. Measured: [α]
D
3
1
1
49-151 °C; H NMR (400 MHz, CDCl
3
6
2
3
2
.40–2.08 (m, 4H), 1.87–1.64 (m, 8H). Literature data for (S)-
0
2
enantiomer: [α]
D
3
−49.3 (c 1.00, CHCl ), mp. 156–157 °C.
-1
formation of a carbon-carbon bond between C(2) of MD and
C(5) of MA. The negative charge transfer is most likely being
(
R)-MOM-H
mmol) in THF (80 ml) under argon at 0 C was added a solution
of (R)-H -BINOL (3.8 g, 13.3 mmol) in THF (18 ml). The reaction
8
-BINOL. To a suspension of 55% NaH (1.2 g, 34.3
o
2
0
accompanied by a chain of proton transfers from O(1)-H to
O(9) and from O(2)-H to O(1). Thus, there are no significant
changes in the position of atoms and charges in the transition
8
mixture was stirred at this temperature for 1 hour, then
MOMCl (4.0 ml, 46 mmol) was added and the reaction left
state of the carbon-carbon bond formation leading to MP
.
overnight. H
which was then extracted with CH
The organic layer was dried over MgSO
in vacuo and the residue was recrystallised from n-hexane to
give (R)-MOM-H -BINOL (4.66 g, 92%) as a white solid.
2
O (50 ml) was added to the reaction mixture
Cl and washed with brine.
, the solvent removed
It is the (R)-Li3MA intermediate that should lead to the
expected R-configuration of MP (Table 1 and 2) whereas (R)-
Li2MA should give rise to MP with S-configuration. As the
energy of both intermediates are almost equal, it is the
energies of the relative transition states and not the initial
intermediates that determine the stereochemical outcome of
the carbon-carbon bond formation.
2
2
4
8
2
5
1
Measured [α]
CDCl ) δ 7.07 (d, J = 8.5 Hz, 2H), 6.97(d, 2H, J=8.5 Hz), 5.03 (d, J
6.7 Hz, 2H) 4.98 (dd, J =6.7 Hz, 2H), 3.36 (s, 6H), 2.44–2.13 (m,
D
3
+47.8 (c 2.00, CHCl ); H NMR (300 MHz,
3
=
4
2
4
H), 1.89–1.63 (m, 8H). Literature data for (S)-enantiomer
2
D
5
1
−46.6; H NMR corresponded to the lit. data.
26
[α]
Conclusions
The family of tetraols, studied in this work, provide an (R)-MOM-H
8
-BIMBOL. To a solution of (R)-MOM-H -BINOL (1.4
8
interesting catalytic behaviour reminiscent of enzymatic g, 3.6 mmol) in dry distilled THF (55 ml) under argon at −5 °C, a
catalysis. Features such as positioning of two substrates on the 2.5 M hexane solution of nBuLi (5.8 mL 14.6 mmol) was added
same catalytic centre, product inhibition of the catalysis and dropwise with stirring. The reaction mixture was stirred at this
proton transfer through a chain of hydrogen bonds can all be temperature for 3 hours, then benzophenone (2.0 g, 11.0
found in typical enzymatic reactions. In addition, the mmol) was added and the reaction left stirring overnight at
trifunctional catalyst derived from BIMBOL-Li displays a room temperature. The reaction was then neutralised by the
sophisticated behaviour with its capabilities concealed by the addition of 0.1 M aqueous HCl. THF was removed in vacuo, the
intrinsic self-association phenomena. The BIMBOL scaffold residue was extracted with CH
should be a versatile unit for the generation of asymmetric with water and then dried over MgSO
catalysts and the mechanistic work reported herein not only removed in vacuo. The product was recrystallised from MeOH
2
Cl
2
, the organic layer washed
4
. The solvent was
8
| J. Name., 2012, 00, 1-3
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ARTICLE
8
to give white crystals of (R)-MOM-H -BIMBOL (1.2 g, 45%). (dd, J = 20.3, 9.1 Hz, 4H), 7.92–7.82 (m, 4H), 7.69 (dd, J = 14.5,
2
5
1
13
[
α]
MHz, CDCl
.01 (d, J =4.6 Hz, 2H), 3.96 (d, J =4.6 Hz, 2H), 2.97 (s, 6H), 129.66, 129.60, 129.42, 128.82, 128.72, 128.51, 128.42,
D
+11.5 (c 1.00, CHCl
3
); mp. 222–224 °C; H NMR (400 7.2 Hz, 6H), 7.62–7.41 (m, 10H), 4.62 (br s, 2H); C NMR (101
3
) δ 7.47–7.22 (m, 20H), 6.36 (s, 2H), 5.92 (s, 2H), MHz, CDCl
3
) δ 152.26, 149.24, 148.44, 139.75, 139.32, 133.92,
4
1
3
2
.68–2.49 (m, 4H), 2.44–2.19 (m, 4H), 1.79–1.63 (m, 8H);
C
126.88, 126.82, 125.34, 124.94, 124.71, 123.70, 120.37,
) δ 150.51, 147.23, 146.95, 138.61, 120.32, 116.88, 86.38; Found (%): C, 85.3; H, 4.2. Calculated
(%): C, 85.4; H, 4.7.
NMR (101 MHz, CDCl
3
1
36.97, 132.70, 131.54, 130.82, 127.94, 127.74, 127.72, for C46
27.10, 97.55, 81.81, 56.88, 29.61, 27.72, 22.90 (2C).
30 4
H O
1
(
R)-MOM-BINOL. The preparation of (R)-MOM-BINOL was
-BIMBOL (1.2 g, carried out by the same method used for (R)-MOM-H -BINOL
6.0 mmol) in THF (24 ml) was added 3N aqueous HCl (4.7 ml) and gave (R)-MOM-BINOL as a white solid in 91% yield.
(
R)-H
8
-BIMBOL. To a solution of (R)-MOM-H
8
8
1
and the reaction heated under reflux for 5 hours. After cooling
to room temperature, the reaction mixture was neutralized (R)-Diethyl-MOM-BICBOL. To a solution of (R)-MOM-BINOL
with 5% aqueous Na CO . Then it was extracted with CH Cl (2.8 g, 7.5 mmol) in dry distilled THF (110 ml) under argon at
dried over MgSO , the solvent was removed in vacuo and the −5 °C, a 2.5 M hexane solution of nBuLi (12.7 ml, 31.8 mmol)
resulting solid purified by silica gel column chromatography was added dropwise with stirring. The reaction mixture was
2
3
2
2
,
4
(
eluent: n-hexane/EtOAc 3:1) to give (R)-H
8
-BIMBOL (0.42 g, stirred at this temperature for 3 hours, then the resulting
+50 (c 0.5, CHCl ); mp. 116 °C suspension was added dropwise to diethyl carbonate (70 ml)
) δ 7.42–7.16 (m, 20H), at 0 °C and left to stir overnight at room temperature. The
.26 (s, 2H), 5.99 (s, 2H), 4.60 (s, 2H), 2.58–2.50 (m, 4H), 2.32– reaction was then neutralised by addition of 0.1 M aqueous
2
5
4
0%) as a white solid. [α]
D
3
1
(decomp.); H NMR (400 MHz, CDCl
3
6
2
1
1
2
1
3
.12 (m, 4H), 1.79–1.61 (m, 8H); C NMR (101 MHz, CDCl
49.59, 146.21, 145.72, 136.98, 130.90, 129.74, 128.89, CH
27.93, 127.88, 127.79, 127.73, 127.31, 121.25, 82.64, 77.33, over MgSO
9.38, 26.95, 22.98, 22.92; Found (%): C, 83.3; H, 6.6. residue was purified by silica gel column chromatography
(%): C, 83.9; H, 6.4. (eluent: petroleum ether/EtOAc 4:1) to give (R)-diethyl-MOM-
3
) δ HCl. THF was removed in vacuo, the residue extracted with
Cl and washed with water. The organic layer was dried
and the solvent was removed in vacuo. The
2
2
4
42 4
Calculated for C46H O
2
D
5
BICBOL (1.2 g, 31%) as a white solid. [α]
+80.9 (c= 1, CHCl
) δ 8.56 (s, 2H), 7.98 (d, J = 8.1 Hz,
-BINOL 2H), 7.48 (t, J = 7.5 Hz, 2H), 7.37 (m, 2H), 7.30 (d, J = 8.5 Hz,
and gave (S)-MOM-BINOL as a white solid, in 90% yield, m.p. 2H), 4.86 (m, 4H), 4.47 (q, J = 7.1 Hz, 4H), 2.50 (s, 6H), 1.46 (t, J
3
);
1
(
S)-MOM-BINOL. The preparation of (S)-MOM-BINOL was
H NMR (400 MHz, CDCl
3
carried out by the same method used for (R)-MOM-H
8
1
26
20
1
01-102 °C. H NMR (400 MHz, CDCl
3
) δ 7.97 (d, J =9.0 Hz, 2H), = 7.1 Hz, 6H). Literature data for (R)-enantiomer [α]
D
28
+87.7
1
7
.90 (d, J =8.0 Hz, 2H), 7.50–7.33 (m, 4H), 7.27–7.23 (m, 2H), (c =0.24, CHCl
3
). H NMR corresponded to the lit data.
7
.18 (d, J = 8.3 Hz, 2H), 5.17 (d, J =6.24 Hz, 2H ), 4.9 (d, J =6.2
2
5
Hz, 2H), 3.19 (s, 6H). Literature data m.p. 102-103 °C.
(R)-MOM-(CF
BICBOL (1.2 g, 2.3 mmol) in THF (22 ml) under an argon
S)-BIFOL. To a solution of (S)-MOM-BINOL (2.0 g, 5.4 mmol) in atmosphere at 0 °C, a 0.5 M THF solution of 3,5-di(trifluoro-
3 8
) -BIMBOL. To a solution of (R)-diethyl-MOM-
(
dry distilled THF (50 ml) under argon at −5 °C, a 2.5 M hexane methyl)phenylmagnesium bromide (25 ml, 12.5 mmol) was
solution of nBuLi (7.5 mL, 18.7 mmol) was added dropwise added, then the reaction was left overnight at room
with stirring. The reaction mixture was stirred at this temperature. The reaction was quenched with saturated
temperature for 3 hours, then 9H-fluoren-9-one (2.4 g, 13.3 aqueous NH
mmol) was added and the reaction left stirring overnight at The organic layer was dried over MgSO
room temperature. The reaction was quenched by the addition removed in vacuo. The residue was purified by silica gel
of saturated aqueous NH Cl. THF was removed in vacuo, the column chromatography (eluent: hexane, then hexane/EtOAc
residue extracted with CH Cl and washed with water. The 5:1) to give (R)-MOM-(CF -BIMBOL (2.6 g, 88%) as a mixture
organic layer was dried over MgSO , the solvent removed in of conformers. Data for the major conformer: H NMR (300
vacuo to give (S)-MOM-BIFOL which was deprotected without MHz, CDCl ) δ 8.82–7.95 (m, 12H), 7.71 (d, J = 8.2 Hz, 2H),
4
Cl, extracted with CH
2
Cl
2
and washed with water.
4
and solvent was
4
2
2
3 8
)
1
4
3
further purification. The (S)-MOM-BIFOL was dissolved in 7.50–7.38 (m, 4H), 7.18 (d, J = 8.3 Hz, 2H), 7.05 (s, 2H), 6.45 (s,
dimethoxyethane (100 ml) and 6N aqueous HCl (64 ml) added. 2H), 4.37 (d, J = 5.9 Hz, 2H), 4.01 (d, J = 5.9 Hz, 2H), 3.03 (s,
1
9
13
The reaction was stirred at room temperature for 3 days, then 6H); F NMR (376 MHz, CDCl
neutralised with 5% aqueous Na CO , extracted with CH Cl (101 MHz, CDCl ) δ 153.00 (s), 149.49 (s), 147.05 (s), 137.27 (s),
and dried over Na SO . The solvent was removed in vacuo and 134.20 (s), 132.45–130.91 (m), 131.20 (s), 129.63 (s), 129.21
the product purified by silica gel column chromatography (s), 128.68 (s), 127.94 (s), 127.26 (d, J = 7.1 Hz), 126.43 (s),
eluting with petroleum ether/EtOAc 5:1, then 2:1). The 125.64 (s), 125.17 (s), 124.54 (d, J = 7.2 Hz), 121.51–122.10
resulting material was dried under vacuo over P and (m), 119.12 (d, J = 7.0 Hz), 99.73 (s), 80.01 (s), 57.53 (s); Found
paraffin at the temperature of boiling toluene to give (S)-BIFOL (%): C, 54.1; H, 2.7; F, 35.4. Calculated for C58 24 (%): C,
1.64 g, 47%) as a pale yellow crystalline compound. 54.3; H, 2.7; F, 35.5.
3
) δ 14.94 (s), 14.70 (s); C NMR
2
3
2
2
3
2
4
(
2 5
O
34 6
H O F
(
2
D
5
1
[α]
+52.4 (c 0.21, CHCl
3
); mp. 200 °C (decomp.); H NMR
(400 MHz, CDCl ) δ 9.37 (br s, 2H), 8.07 (d, J = 7.1 Hz, 2H), 7.96
3
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(R)-(CF
3 8 3 8 2
) -BIMBOL. To a solution of (R)-MOM-(CF ) -BIMBOL aliquot was immediately taken to fill a cell (CaF , l = 0.062mm).
(2.6 g, 2.0 mmol) in dioxane (65 ml), 26% aqueous HCl (28 ml) IR spectra were then recorded with intervals of 3-5 minutes.
was added and the reaction heated under reflux at 60 °C for 7
hours. The reaction mixture was quenched with aqueous Methodology for ab-initio calculations. Ab-initio calculations
2
8
Na
washed with water, dried over MgSO
removed in vacuo. The residue was purified by silica gel functional with empirical correction for dispersion interactions
2
CO
3
until it was just slightly acidic, extracted with CH
2
Cl
2
,
were performed using the ORCA software suite within a
2
9
4
and solvent was Density Functional Theory (DFT) framework. The PBE
3
0
column chromatography (hexane then hexane/acetone 1:1) to to the total energy was used for geometry optimisation, and
3
-BIMBOL (1.5 g, 63%) as a beige crystalline solid. PBE0 functional was used for single-point energy evaluation
1
give (R)-(CF
5
3
)
8
2
1
[
α]
D
−96.8 (c 1.00, CHCl
3
); mp. 175 °С; H NMR (400 MHz, in optimised geometry, in combination with a def-4 basis set
3
2
CDCl
3
) δ 7.94 (d, J = 20.3 Hz, 4H), 7.85 (d, J = 8.4 Hz, 8H), 7.76 based on a loosely contracted triple-ζ def2-TZV basis.
(
d, J = 7.2 Hz, 2H), 7.53–7.39 (m, 4H), 7.14–7.07 (m, 4H), 5.60 Numerical approximations implemented in the ORCA suite (a
1
9
(s, 2H), 5.20 (s, 2H); F NMR (376 MHz, CDCl
3
) δ 14.93 (s), dual-grid integration technique in DFT calculation, RI and RI-JK
) δ 149.65 (s), 147.74 (s), approximations) were used to speed up the calculations, as
46.32 (s), 132.81 (s), 132.44 (s), 132.10 (s), 131.77 (s), 131.73 test calculations without these approximations yielded
1
3
1
4.85 (s). C NMR (101 MHz, CDCl
3
1
(s), 131.36 (s), 129.51 (s), 129.35 (s), 128.51 (s), 127.76 (br s), virtually the same energy differences.
1
1
3
27.21 (br s), 125.91 (s), 124.45 (s), 123.19 (s), 122.32 (br s),
21.74 (s), 112.76 (s), 80.89 (s); Found (%): C, 53.9; H, 2.5; F,
Acknowledgements
26 4
7.8. Calculated for C54H O F24 (%): C, 54.3; H, 2.2; F, 38.2.
Authors gratefully thank the financial support from RSF 15-13-
Diethyl (S)-2-(3-oxocyclohexyl)malonate (MP). To a solution
of (S)-BIMBOL (8.1 mg, 0.0124 mmol), PhOLi (1.3 mg, 0.013
mmol) and cyclohexenone (23.8 mg, 0.248 mmol) in anhydrous
0
0039 and RBFR 15-53-05014 grants.
CH
2
Cl
2
(1 ml) under argon at room temperature diethyl Notes and references
malonate (39.7 mg, 0.248 mmol) was added and the reaction
was stirred for 48 hours. Then the reaction was quenched by
adding acetic acid, the mixture was evaporated and diethyl
‡
CCDC and given code CCDC 1409564.
2
Crystallographic data for (S)-BIFOL×H O has been submitted to
1
For reviews see: ‘Comprehensive Asymmetric catalysis,
and Supplements 1 and 2’, E. N. Jacobsen, A. Pfaltz and
H. Yamamoto Eds., Springer, New York, 1999; K.
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(S)-2-(3-oxocyclohexyl)malonate isolated as a colourless oil
(
60.0 mg, 94%) by preparative thin layer chromatography
2
5
eluting with petroleum/EtOAc 5:1. [α]
1
D
3
−2.7 (c 0.5, CHCl );
2
048; ‘Introduction to Frontiers in Transition Metal
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H NM R (400 MHz, CDCl ) δ 4.22 (qd, J = 7.1, 4.1 Hz, 4H), 3.31
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(d, J = 7.9 Hz, 1H), 2.55 (dtd, J = 15.2, 7.8, 3.7 Hz, 1H), 2.44 (t, J
=
=
17.0 Hz, 2H), 2.36–2.20 (m, 2H), 2.14–2.04 (m, 1H), 1.98 (d, J
2
For reviews see: M. Waser ‘Progress in the Chemistry of
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12.7 Hz, 1H), 1.81–1.61 (m, 1H), 1.62–1.45 (m, 1H), 1.29-1,20
(
m, 6H), Found (%): C, 61.4; H, 7.8. Calculated for C13
5
H
20
O
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(%):
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C, 60.9; H, 7.9. [α]
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-2.7 (c 1.00, CHCl ) Enantiomeric analysis:
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D
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3% ee H NMR corresponded to the lit data.
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-
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1
0 | J. Name., 2012, 00, 1-3
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Tarkanyi, P. Kiraly, T. Soos and S. Varga, Chem. Eur. J.,
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