Highly enantioselective synthesis of syn-aldols of cyclohexanones via chiral primary amine catalyzed asymmetric transfer aldol reactions in ionic liquid

Article abstract of DOI:10.1039/c0ob00682c

Chiral primary-tertiary diamine/TfOH was found to catalyze kinetic resolution of racemic syn-aldols of cyclohexanones in ionic liquid effectively, affording the chiral syn-aldols with up to 99:1 syn/anti and 99% ee.

Full text of DOI:10.1039/c0ob00682c

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PAPER
Highly enantioselective synthesis of syn-aldols of cyclohexanones via chiral
primary amine catalyzed asymmetric transfer aldol reactions in ionic liquid†
Pengxin Zhou,a Sanzhong Luo*b and Jin-Pei Cheng*a,b
Received 6th September 2010, Accepted 23rd November 2010
DOI: 10.1039/c0ob00682c
Chiral primary-tertiary diamine/TfOH was found to catalyze kinetic resolution of racemic syn-aldols
of cyclohexanones in ionic liquid effectively, affording the chiral syn-aldols with up to 99 : 1 syn/anti
and 99% ee.
Introduction
Asymmetric direct aldol reaction, a milestone in the evolution
of aldol chemistry, is undoubtedly one of the most versatile C–
C bond-forming reactions in constructing chiral molecules with
promising reaction (atom, step and redox) economies.1 Accord-
ingly, the search for asymmetric aldol catalysts with exquisite
control of chemo-, regio-, diastereo- and enantio-selectivity has
been and continues to be a research focus in this field.2
Recently, chiral amines, exemplified by chiral pyrrolidines, have
appeared as a prominent type of asymmetric direct aldol catalysts
that enable effective catalysis with ketone and aldehyde donors
via enamine intermediates (Scheme 1).3 Specifically, secondary
amine catalysts have been very successful for both cyclic and
acyclic aldol donors and these reactions normally give excellent
anti-diastereoselectivity and enantioselectivity, presumably via E-
enamines (Scheme 1, I and III). However, syn-selective aldol
reaction remains a challenging subject with the typical secondary
aminocatalysis. This challenge has now been partially addressed
with the identification of chiral primary amine catalysts.4b In par-
ticular, syn-selective aldol reactions of acyclic ketone and aldehyde
donors have been realized via chiral primary aminocatalysis.4 The
Scheme 1
success of primary aminocatalysts in these cases can be ascribed
to their tendency to form thermodynamically stable Z-enamines
(Scheme 1, II).2,4b Notwithstanding these significant advances, syn-
selective direct aldol reactions of cyclic ketone donors have not
been achieved so far. This constitutes an elusive and fundamental
target in asymmetric aminocatalysis both synthetically and mecha-
nistically as cyclic ketone donors (n < 8) are constrained to forming
E-enamines due to the inherent ring strains with both primary
and secondary amines (Scheme 1, III), which consequently leads
to anti-diastereoselectivity as indeed observed experimentally in
numerous previous studies.3 In addition, other currently developed
asymmetric direct aldol strategies also gave predominantly anti-
selectivity for this class of substrates and examples with syn-
selectivity were rare with only modest enantioselectivity.5
Recently, we established that simple chiral primary–tertiary
vicinal diamines such as 1 act as effective catalysts for a series
of syn-selective aldol reactions of acyclic donors such as linear
aliphatic ketones,6a a-hydroxyketones,6b dihydroxyacetone,6c pyru-
vic acetals,6d acetoacetals6e and aliphatic aldehydes.6f Furthermore,
the same chiral primary amines have also been found to be
unprecedented asymmetric catalysts for retro-aldol reactions,
enabling enantioselective synthesis of aldol products that are
usually difficult to obtain through the forward process.7 It is
thus hypothesized that a facile enantioselective synthesis of syn-
aldols of cyclic ketones would be achieved by utilizing 1 catalyzed
aDepartment of Chemistry and State Key Laboratory of Elemental-Organic
Chemistry, Nankai University, Tianjin, 300071, China
bBeijing National Laboratory for Molecule Sciences (BNLMS), CAS
Key Laboratory for Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing, 100190, China. E-mail:
luosz@iccas.ac.cn; Fax: +86-10-62554449; Tel: +86-10-62554446
† Electronic supplementary information (ESI) available: 1H NMR,
13C NMR and HPLC spectrum of syn aldol products. See DOI:
10.1039/c0ob00682c
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Table 1 Optimization of the resolution process
2a reacts much faster than 2b and satisfactory enantioenrichment
could be attained for 2a at >60% conversion (Table 1, entry
1). In contrast, the retro-reaction of 2b is very sluggish even in
the presence of acetone, wherein the in situ generated aldehyde
would be consumed via a forward aldol reaction (i.e. transfer
aldol reaction) (Table 1, entries 2 and 3). In this case, good
enantioselectivity (94% ee) could be obtained by increasing
the reaction temperature to 50 ◦C, albeit with a reduction of
diastereoselectivity (from 99 : 1 to 89 : 11) (Table 1, entry 4).
After considerable screening, it is interesting to observe that the
reaction could be significantly accelerated when conducted in an
imidazolium ionic liquid, [BMIM]BF4 (Table 1, entry 5 vs. entry
2). The examination with other ionic liquids such as [BMIM]PF6
gave similar results (Table 1, entry 7). The beneficial effect of an
ionic liquid may be ascribed to its polar and ionic features that
are generally favorable for reactions with charged transition states
or intermediates.9a,9b Combining the use of ionic liquids and the
transfer aldol protocol, we finally reached optimal resolution of
both 2a and 2b at 50 ◦C (Table 1, entries 6–8◦). Under the optimized
conditions (in acetone–[BMIM]BF4 at 50 C), kinetic resolution
factors of 21 and 32 were obtained for 2a and 2b, respectively. The
acetone aldol products obtained from the transfer aldol processes
are of low enantioselectivity (<20% ee) likely due to the high
temperature.
We next examined the generality of the present protocol and
the results are summarized in Table 2. The chiral primary amine 1
catalyzed transfer aldol reactions work smoothly with a range of
racemic syn-aldols derived from cyclohexanone and aromatic alde-
hydes bearing either electron-donating or electron-withdrawing
groups (Table 1, entries 1–13). The enantioenriched syn-aldols
could be obtained with maintained diastereoselectivity (>97 : 3
syn/anti) and excellent enantioselectivity (83–99% ee) except in
the case of 2-morpholinyl benzaldehyde (Table 1, entry 14).
Decreasing diastereo- and enantiostereoselectivity were observed
in this reaction, most likely due to the general base catalysis arisen
from the morpholine moiety. The transfer aldol reaction also
worked well with syn aldol derived from (E)-cinnamaldehyde to
afford optically pure product in 40% isolated yield, 99 : 1 syn/anti
and 98% ee (Table 2, entry 14). Racemic aldols derived from other
substituted cyclohexanones have also been examined in the current
reactions. Again, significant kinetic resolutions were achieved in
these cases to afford enantioenriched products with 88–99% ee
for the syn-diastereomers (Table 2, entries 16–18). In these cases,
erosion of diastereoselectivity was observed. To the best of our
knowledge, most of syn-aldols presented in Table 2 are firstly
obtained as enantiomerically pure products.
Entrya
Conditions
Time (h) Yield (%)b drc
ee (%)d
1
2
3
4
5
6
7
8
rac-2a DCM, rt
rac-2b DCM, rt
rac-2b Acetone, rt
rac-2b Acetone, 50 ◦
rac-2b IL, rt
24
36
36
36
36
33
86
70
45
36
55
57
55
60
98 : 2 98
95 : 5 18
95 : 5 27
89 : 11 94
80 : 20 59
97 : 3 96
95 : 5 95
98 : 2 78
98
C
rac-2b Acetone–IL,e 50 ◦C 36
rac-2b Acetone–IL,f 50 ◦C 36
rac-2a Acetone–IL,e 50 ◦C 24
36
a Unless otherwise stated, all reactions were carried out on 0.1 mmol
scale at 0.25 M in solvent using 20 mol% catalyst 1. b Isolated yield.
c The syn/anti ratios were analyzed by 1H NMR of the crude product.
d Determined by chiral HPLC. e IL: [BMIM]BF4. f IL: [BMIM]PF6.
retro-aldol reactions of racemic syn-aldols (Scheme 2). Our pre-
liminary studies indicated that such a process was indeed possible
(Table 1) and highly enantioenriched syn-aldols of cyclohexanone
could be obtained via kinetic resolution of the racemic syn-
aldols. However, the initial retro-aldol protocol suffered from
the lower activity, unsatisfactory s factors and decreased syn-
diastereoselectivity (Table 1, entries 1 and 2). Herein, we present
a new and improved protocol for the synthesis of syn-aldols of
cyclohexanones by the use of asymmetric transfer aldol in ionic
liquids.
Scheme 2
Besides the beneficial effect on reaction rate, the use of ionic
liquid as reaction medium adds further practical merit by facili-
tating a recyclable and reusable catalytic system as widely practised
in the field of ionic liquids.9 Bearing in mind that the catalyst 1
is itself a protonated salt, the potential of a reusable 1 in ionic
liquids has also been explored in our study. After the indicated
reaction time, the product is easily separated by extraction with
ether and the remaining ionic liquid containing 1 could be directly
used for the next run after drying briefly under vacuum. To
our delight, the thus-recycled catalyst 1 could be reused 10
times without much loss of stereoselectivity (Chart 1) and over
>50% conversions were consistently obtained in the subsequent
reuses.
Results and discussion
We started first to develop a convenient synthesis of racemic syn-
aldols of cyclohexanones. The reactions between cyclohexanones
and aromatic aldehydes occurred rapidly to afford the racemic
aldols in the presence of NaOH. Fortunately, the syn- and anti-
aldols of cyclohexanones generally demonstrate large differences
in solubility. Pure diastereoisomers can be easily obtained via
recrystallization, thus providing a practical access to the racemic
syn-aldols.
Racemic syn-aldols 2a and 2b (syn/anti>99 : 1), bearing
electron-donating MeO- and electron-withdrawing NO2-, respec-
tively, were chosen as the representative substrates. As expected,
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Table 2 Substrate scope
Entrya
1
Product
T (h)
Yield (%)b
syn : antic
ee (%)d
se
24
36
45
40
98 : 2
78
98
—
21
2
36
45
97 : 3
96
32
3
4
36
36
42
41
99 : 1
99 : 1
98
98
26
23
5
36
24
42
99 : 1
99
30
22
(55)f
(68)f
6
7
8
36
36
36
42
49
40
97 : 3
99 : 1
99 : 1
94
83
97
18
23
18
9
36
36
48
41
99 : 1
99 : 1
91
98
36
23
10
11
12
13
14
36
24
32
99 : 1
99 : 1
98 : 2
50 : 50
95
9
12
(42)f
(87)f
36
36
24
48
40
49
89
30
21
15
98
77/80
15
16
24
36
39
99 : 1
98
89
19
5
28c
87 : 13
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Table 2 (Contd.)
Entrya
17
Product
T (h)
36
Yield (%)b
30c
syn : antic
ee (%)d
99
se
58 : 42
11
18
36
40c
93 : 7
89
11
a Unless otherwise noted, all reactions were carried out at 0.1 mmol scale in 0.2 mL acetone and 0.4 mL [BMIM]BF4 using 20 mol% catalyst at 50 ◦C.
b Isolated yield. c Determined by 1H NMR. d Determined by chiral HPLC. e Calculated according to the equation developed by Kagan and Fiaud.8
f Conducted in CH2Cl2 at 0.25 M at rt.
(ESI) mass spectrometer. Optical rotations were measured using a
1 mL cell with a 1 dm path length on a Perkin–Elmer 341 digital
polarimeter and are reported as follows: [a]2D0 (c in g per 100 mL of
solvent). All reactions under standard conditions were monitored
by thin-layer chromatography (TLC) on gel F254 plates. Silica
gel (200–300 mesh) was used for column chromatography, and the
distillation range of petroleum was 60–90 ◦C. Enantiomeric excess
was analyzed using ChiralPak columns on HPLC.
General procedure for the kinetic resolution of racemic aldols
To a stirred solution of the catalyst 1 (0.02 mmol, 6.4 mg) in
[BMIM]BF4 (0.4 mL) and acetone (0.2 mL) were added 0.1 mmol
racemic aldol substrates. Then the reaction mixture was reacted at
50 ◦C for the given time. After cooling to room temperature, the
reaction solution was extracted with diethyl ether (2 mL ¥3). The
combined organic layers were concentrated and purified by flash
chromatography to give the pure syn-aldol product. The catalyst
Chart 1 Catalyst 1 recovery and reuse in [BMIM]BF4.
remained in the [BMIM]BF4 could be directly reused in the next
Conclusions
run after evaporating the volatile solvent. Compounds 2a,11 2b,12
2c,12 2d,11 2f,12d 2h,12d 2i,12e 2m,13 2o,14 2p15 and 2q15 are known
In summary, we have developed an effective chiral primary amine
catalyzed transfer aldol reaction for the synthesis of optically
pure syn-aldols between cyclohexanones and aromatic aldehydes,10
which remains difficult to obtain with other methods. The catalysis
of primary amine 1 has been shown to work favorably in ionic
liquids, thus facilitating a recyclable and reusable catalytic system.
Catalyst 1 in the ionic liquid [BMIM]BF4 could be reused at least
9 times with only a little loss of activity and stereoselectivity.
compounds.
Characterization data
syn-Aldol 2a11. 98% ee; [a]D20 = -105.6 (c = 1.0, CHCl3); IR
(KBr, cm-1): 3437, 2948, 1694, 1513, 1248, 1023, 832, 534; H
1
NMR (300 MHz, CDCl3) d 7.22 (d, J = 8.4 Hz, 2H), 6.87 (d, J =
8.7 Hz, 2H), 5.32 (t, J = 2.7 Hz, 1H), 3.80 (s, 1H), 2.99 (d, J =
3.3 Hz, 1H), 2.60 –2.53 (m, 1H), 2.46–2.34 (m, 2H), 2.11–2.04 (m,
1H), 1.88 –1.44 (m, 5H); 13C NMR (75 MHz, CDCl3) d 214.9,
158.6, 133.6, 126.9, 113.6, 70.4, 57.3, 55.3, 42.7, 28.0, 26.2, 24.9.
The ee value was determined by Chiral HPLC. [Daicel Chiralpak
AS-H column, l = 254 nm, 2-propanol : n-hexane = 1: 9, flow rate =
0.8 mL min-1]: tR = 18.26 min (minor), tR = 21.35 min (major).
Experimental section
General
Commercial reagents were used as received, unless otherwise
stated. 1H and 13C NMR were recorded on either a Bruker-DPX
300 or AV-400 spectrometer. Chemical shifts are reported in ppm
from tetramethylsilane with the solvent resonance as the internal
standard. The following abbreviations were used to designate
chemical shift multiplicities: s = singlet, d = doublet, t = triplet,
m = multiplet. All first-order splitting patterns were assigned on
the basis of the appearance of the multiplet. Splitting patterns
that could not be easily interpreted are designated as multiplet
(m) or broad (br). Mass spectra were obtained using a fast atom
bombardment (FAB) spectrometer or electron spray ionization
syn-Aldol 2b12. 96% ee; [a]D20 = -81.2 (c = 0.5, CH3OH); IR
(KBr, cm-1): 3512, 2936, 2864, 1689, 1515, 1339, 854, 571, 538; 1H
NMR (300 MHz, CDCl3) d 8.21 (d, J = 8.7 Hz, 2H), 7.50 (d, J =
8.7 Hz, 2H), 5.49 (s, 1H), 3.16 (d, J = 3.3 Hz, 1H), 2.68–2.60 (m,
1H), 2.49–2.39 (m, 2H), 2.15–2.09 (m, 1H), 1.89–1.76 (m, 1H),
1.73–1.50 (m, 4H); 13C NMR (75 MHz, CDCl3) d 214.0, 149.0,
147.1, 126.6, 147.1, 126.6, 123.5, 70.1, 56.8, 42.6, 27.9, 25.9, 24.8.
The ee value was determined by Chiral HPLC. [Daicel Chiralpak
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AD-H column, l = 254 nm, 2-propanol : n-hexane = 1: 4, flow
rate = 0.5 mL min-1]: tR = 23.01 min (minor), tR = 24.45 min
(major).
222.1059. The ee value was determined by Chiral HPLC. [Daicel
Chiralpak AS-H column, l = 254 nm, 2-propanol : n-hexane = 1:
9, flow rate = 0.8 mL min-1]: tR = 10.84 min (major), tR = 13.60 min
(minor).
syn-Aldol 2c12. 98% ee; [a]D20 = -73.4 (c = 0.5, CHCl3); IR (KBr,
cm-1): 3545, 2943, 2862, 1444, 1312, 1059, 700, 532. H NMR
syn-Aldol 2h12d 97% ee; [a]D20 = -76.0 (c = 0.5, CHCl3); IR (KBr,
.
1
(300 MHz, CDCl3): d 7.35–7.21 (m, 5H), 5.38 (1 H, t, J = 2.7
Hz), 3.02 (d, J = 3.3 Hz, 1H), 2.61–2.55 (m, 1H), 2.44 –2.34 (m,
cm-1): 3537, 3470, 2928, 2875, 1711, 1459, 1115, 996, 823, 664; 1H
NMR (300 MHz, CDCl3) d 7.29–7.22 (m, 4H), 5.35 (t, J = 5.4,
2.7 Hz, 1H), 3.06 (d, J = 3.3 Hz, 1H), 2.59–2.31 (m, 3H), 2.12–2.06
(m, 1H), 1.88–1.82 (m, 1H), 1.74–1.45(m, 4H);13C NMR (75 MHz,
CDCl3) d 214.5, 140.0, 132.7, 128.3, 127.2, 70.1, 57.0, 42.6, 27.9,
26.0, 24.8. The ee value was determined by Chiral HPLC. [Daicel
Chiralpak AD-H column, l = 254 nm, 2-propanol : n-hexane = 1:
4, flow rate = 0.5 mL min-1]: tR = 11.89 min (minor), tR = 13.06 min
(major).
2H), 2.09–2.04 (m, 1H), 1.85–1.75 (m, 1H), 1.73–1.51 (m, 4H); 13
C
NMR (75 MHz, CDCl3) d 214.8, 141.5, 128.2, 127.0, 125.8, 70.6,
57.2, 42.7, 28.0, 26.0, 24.9. The ee value was determined by Chiral
HPLC. [Daicel Chiralpak AS-H column, l = 254 nm, 2-propanol :
n-hexane = 1: 4, flow rate = 0.5 mL min-1]: tR = 14.12 min (major),
tR = 15.97 min (minor).
syn-Aldol 2d11. 96% ee; [a]D20 = -58.8 (c = 0.5, CHCl3); IR
(KBr, cm-1): 3532, 2948, 2830, 1440, 1115, 947, 673, 542; 1H NMR
(300 MHz, CDCl3) d 7.20–7.13 (m, 4H), 5.35 (s, 1H), 2.99 (s, 1H),
2.61–2.54 (m, 1H), 2.44–2.41 (m, 2H), 2.34 (s, 3H), 2.10–2.04 (m,
1H), 1.87–1.53 (m, 5H); 13C NMR (75 MHz, CDCl3) d 214.9,
138.5, 136.5, 128.8, 125.7, 70.6, 57.3, 42.7, 28.0, 26.1, 24.9, 21.1.
The ee value was determined by Chiral HPLC. [Daicel Chiralpak
AD-H column, l = 254 nm, 2-propanol: n-hexane = 1: 9, flow rate =
1.0 mL min-1]: tR = 14.12 min (major), tR = 15.97 min (minor). The
ee value was determined by Chiral HPLC. [Daicel Chiralpak AD-
H column, l = 254 nm, 2-propanol : n-hexane = 1: 9, flow rate =
1.0 mL min-1]: tR = 8.30 min (minor), tR = 8.80 min (major).
syn-Aldol 2i12e
.
91% ee; [a]2D0 = -76.7 (c = 0.5, CHCl3); IR (KBr,
cm-1): 3484, 2941, 2848, 1697, 1498, 1062, 982, 823; H NMR
(300 MHz, CDCl3) d 7.51–7.26 (m, 3H), 5.28 (dd, J = 8.1, 3.9 Hz,
1H), 4.04 (d, J = 4.2 Hz, 1H), 2.64–2.60 (m, 1H), 2.49–2.12 (m,
2H), 2.10–2.07 (m, 1H), 1.85–1.81 (m, 1H), 1.71–1.55 (m, 4H);
13C NMR (75 MHz, CDCl3) d 215.1, 137.8, 133.8, 133.5, 129.3,
128.9, 127.6, 70.1, 57.5, 42.7, 30.4, 27.8, 24.9. The ee value was
determined by Chiral HPLC. [Daicel Chiralpak AD-H column,
l = 254 nm, 2-propanol : n-hexane = 1: 9, flow rate = 1.0 mL min-1]:
tR = 8.18 min (minor), tR = 9.33 min (major).
1
syn-Aldol 2j. 93% ee; [a]D20 = -81.2 (c = 0.5, CHCl3); IR (KBr,
cm-1): 3497, 2954, 2862, 1711, 1128, 995, 823; 1H NMR (300 MHz,
CDCl3) 7.83–7.80 (m, 4H), 7.50–7.43 (m, 2H), 7.38–7.34 (m, 1H),
5.57 (s, 1H), 3.16 (d, J = 3.3 Hz, 1H), 2.73–2.68 (m, 1H), 2.51–
2.34 (m, 2H), 2.11–2.06 (m, 1H), 1.84–1.62 (m, 4H), 1.54–1.45
(m, 1H);13C NMR (75 MHz, CDCl3) d 214.9, 138.9, 133.3, 132.5,
128.0, 127.8, 127.6, 126.1, 125.7, 124.5, 123.9, 70.7, 57.1, 42.7,
28.0, 26.1, 24.9. HRMS for C17H18O2: Calcd. 254.1307; Found:
254.1310. The ee value was determined by Chiral HPLC. [Daicel
Chiralpak AD-H column, l = 254 nm, 2-propanol : n-hexane = 1:
9, flow rate = 1.0 mL min-1]: tR = 10.97 min (minor), tR = 11.80 min
(major).
syn-Aldol 2e. 99% ee; [a]D20 = -97.8 (c = 0.5, CHCl3); IR (KBr,
1
cm-1): 3443, 2950, 2867, 1704, 1449, 1125, 835, 674; H NMR
(300 MHz, CDCl3) d 7.36 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.1 Hz,
2H), 5.36 (t, J = 2.7 Hz, 1H), 2.96 (d, J = 2.1 Hz, 1H), 2.61– 2.56
(m, 1H), 2.44–2.35 (m, 2H), 2.10–2.05 (m, 1H), 1.87–1.54 (m, 5H),
1.31 (s, 9H); 13C NMR (75 MHz, CDCl3) d 214.9, 149.8, 138.5,
125.5, 125.1, 70.5, 57.2, 42.7, 34.5, 31.4, 28.0, 26.1, 24.9. HRMS
for C17H24O2Na: Calcd. 283.1674; Found: 283.1665 [M + Na].
The ee value was determined by Chiral HPLC. The ee value was
determined by Chiral HPLC. [Daicel Chiralpak AD-H column,
l = 254 nm, 2-propanol : n-hexane = 1 : 4, flow rate = 0.5 mL min-1]:
tR = 10.47 min (minor), tR = 11.60 min (major).
syn-Aldol 2k. 95% ee; [a]D20 = -134.4 (c = 0.5, CHCl3); IR (KBr,
cm-1): 3507, 2937, 2857, 1690, 1617, 1503, 1036, 822, 518. 1H NMR
(300 MHz, CDCl3) d 7.33 (d, J = 8.4 Hz, 1H), 6.51–6.42 (m, 2H),
5.54 (t, J = 3.0 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.06 (d, J =
3.3 Hz, 1H), 2.74–2.68 (m, 1H), 2.41–2.35 (m, 2H), 2.09–2.04 (m,
1H), 1.86–1.52 (m, 4H); 13C NMR (75 MHz, CDCl3) d 215.5,
159.8, 156.4, 128.0, 122.0, 103.8, 98.2, 65.9, 55.3, 55.2, 54.6, 42.7,
28.1, 26.5, 24.9; HRMS for C15H20O4Na: Calcd. 287.1159; Found:
287.1256 [M + Na]. The ee value was determined by Chiral HPLC.
[Daicel Chiralpak AD-H column, l = 254 nm, 2-propanol : n-
hexane = 1 : 4, flow rate = 0.5 mL min-1]: tR = 17.54 min (minor),
tR = 19.01 min (major).
syn-Aldol 2f12d
.
94% ee; [a]2D0 = -41.3 (c = 0.5, CHCl3); IR
1
(KBr, cm-1): 3437, 2954, 2867, 1690, 1538, 1134, 1067, 695; H
NMR (300 MHz, CDCl3) d 8.16 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H),
7.64 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 5.45 (s, 1H), 3.25
(s, 1H), 2.67–2.61 (m, 1H), 2.43– 2.37 (m, 2H), 2.11–2.06 (m, 1H),
2.06–1.82 (m, 1H), 1.75–1.49 (m, 4H); 13C NMR (75 MHz, CDCl3)
d 212.5, 146.8, 142.2, 130.5, 127.6, 120.5, 119.4, 68.4, 55.2, 41.1,
25.3, 24.4, 23.2. The ee value was determined by Chiral HPLC.
[Daicel Chiralpak AD-H column, l = 254 nm, 2-propanol : n-
hexane = 1: 9, flow rate = 1.0 mL min-1]: tR = 15.44 min (minor),
tR = 16.34 min (major).
syn-Aldol 2g. 83% ee; [a]D20 = -41.1 (c = 0.5, CHCl3). IR (KBr,
syn-Aldol 2l. 89% ee; [a]D20 = -73.8 (c = 0.5, CHCl3); IR (KBr,
1
1
cm-1): 3423, 2937, 2873, 1694, 1479, 1452, 759, 517; H NMR
cm-1): 3441, 2941, 2880, 1697, 1486, 1231, 933, 809; H NMR
(300 MHz, CDCl3) d 7.55–7.50 (m, 1H), 7.25–7.20 (m, 1H), 7.18–
7.13 (m, 1H), 7.03 –6.97 (m, 1H), 5.66 (s, 1H), 3.19 (d, J = 3.3 Hz),
2.78–2.62 (m, 1H), 2.46–2.38 (m, 2H), 2.08–2.00 (m, 1H), 1.82–
1.55 (m, 5H);13C NMR (75 MHz, CDCl3) d 214.8, 157.3, 128.4,
128.3, 128.3, 128.2, 124.0, 123.9, 115.0, 114.7, 65.3, 65.3, 55.0, 42.6,
28.0, 26.2, 24.9. HRMS for C13H15FO2: Calcd. 222.1056; found:
(300 MHz, CDCl3) d 6.82 (s, 1H), 6.75 (d, J = 2.1 Hz, 2H), 5.93
(s, 2H), 5.28 (s, 1H), 3.00 (d, J = 2.7 Hz, 1H), 2.56–2.30 (m, 3H),
2.10–2.05 (m, 1H), 1.88–1.61 (m, 5H); 13C NMR (75 MHz, CDCl3)
d 214.8, 147.6, 146.4, 135.5, 118.8, 108.0, 106.6, 100.9, 70.5, 57.3,
42.7, 28.0, 26.2, 24.9. HRMS for C14H16O4Na: Calcd. 271.0946;
Found: 271.0959 [M + Na]. The ee value was determined by Chiral
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HPLC. [Daicel Chiralpak AS-H column, l = 254 nm, 2-propanol :
n-hexane = 1: 4, flow rate = 0.5 mL min-1]: tR = 26.35 min (minor),
tR = 28.63 min (major).
210.9, 148.1, 147.3, 126.7, 123.7, 70.2, 59.2, 45.0, 30.8, 29.5.
After the reaction, the product was isolated as a mixture of
diastereoisomers (syn/anti = 58 : 42). 99% ee for syn isomer; the
ee for the anti isomer was not determined. The ee value was
determined by Chiral HPLC. [Daicel Chiralpak AD-H column,
l = 254 nm, 2-propanol : n-hexane = 1 : 4, flow rate = 1.0 mL min-1]:
tR = 15.13 min (major), tR = 25.26 min (minor).
syn-Aldol 2r. IR (KBr, cm-1): 3408, 2959, 2869, 1693, 1222,
1134, 996, 734, 696. 1H NMR (300 MHz, CDCl3) d 7.34-7.24 (m,
5H), 5.44 (s, 1H), 3.95–3.84 (m, 4H), 2.97–2.71 (m, 2H), 2.48–
2.42 (m, 1H), 2.12–1.97 (m, 3H), 1.71–1.65(m, 1H); 13C NMR
(75 MHz, CDCl3) d 212.7, 141.1, 128.3, 127.0, 125.6, 107.6, 70.1,
64.7, 64.5, 53.2, 38.6, 34.4, 32.9. HRMS for C15H18O4: Calcd.
262.1205; Found: 262.1208. After the reaction, the product was
isolated as a mixture of diastereoisomers (syn/anti = 93 : 7). 89%
ee for syn isomer; the ee value was determined by Chiral HPLC.
[Daicel Chiralpak AD-H column, l = 254 nm, 2-propanol : n-
hexane = 1 : 4, flow rate = 1.0 mL min-1]: tR = 13.02 min (minor),
tR = 14.53 min (major).
syn-Aldol 2m13. 98% ee; [a]D20 = -58.2 (c = 0.5, CHCl3); IR
(KBr, cm-1): 3444, 2922, 2862, 1693, 1093, 986, 844, 689. 1H NMR
(300 MHz, CDCl3) d 7.61–7.56 (m, 4H), 7.46–7.33 (m, 5H), 5.43
(t, J = 2.7 Hz, 1H), 3.03 (d, J = 2.7 Hz, 1H), 2.64–2.2.62 (m,
1H), 2.47–2.38 (m, 2H), 2.09–2.08 (m, 1H), 1.85–1.67 (m, 5H);
13C NMR (75 MHz, CDCl3) d 214.7, 140.9, 140.6, 139.9, 128.7,
127.2, 127.0, 126.9, 126.2, 70.5, 57.2, 42.7, 27.9, 26.1, 24.9. HRMS
for C19H20O2: Calcd. 280.1463; Found: 280.1468. The ee value was
determined by Chiral HPLC. [Daicel Chiralpak OD-H column,
l = 254 nm, 2-propanol : n-hexane = 1 : 4, flow rate = 1.0 mL min-1]:
tR = 7.81 min (minor), tR = 8.65 min (major).
syn-Aldol 2n. IR (KBr, cm-1): 3475, 2956, 2858, 1696, 1447,
1111, 932,552;1H NMR (300 MHz, CDCl3) d 7.39–7.15 (m, 4H),
5.68 (t, J = 3.0 Hz, 1H), 4.46 (d, J = 3.9 Hz, 1H), 3.81–3.76
(m, 4H), 3.05–2.98 (m, 2H), 2.85–2.76 (m, 3H), 2.51–2.45 (m,
1H), 2.37–2.33 (m, 1H), 2.04–2.03 (m, 1H), 1.90–1.68 (m, 4H),
1.53–1.49 (m, 1H); 13C NMR (75 MHz, CDCl3) d 213.8, 149.6,
137.5, 127.9, 127.7, 125.6, 122.0, 68.4, 67.5, 56.3, 53.6, 42.5,
27.6, 26.4, 24.8. HRMS for C17H23NO3: Calcd. 289.1678; Found:
289.1682. After reactions, the product was isolated as a mixture
of diastereoisomers (syn/anti = 50 : 50), 77% ee for syn and 80%
ee for anti; the ee value was determined by Chiral HPLC. [Daicel
Chiralpak AD-H column, l = 254 nm, 2-propanol : n-hexane =
1: 9, flow rate = 1.0 mL min-1]: tR = 16.86 min (major), tR = 19.76
min (minor) for syn diastereoisomers; tR = 27.45 min (major), tR =
31.94 min (minor) for anti diastereoisomers.
Acknowledgements
This project was supported by the Natural Science Foundation of
China (NSFC 20702052 and 20972163), the Ministry of Science
and Technology (2009ZX09501-018), and the Chinese academy of
Sciences.
Notes and references
1 For reviews on asymmetric aldol reactions, see: (a) R. Mahrwald,
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syn-Aldol 2o14. 98% ee; [a]D20 = -27.1 (c = 0.5, CHCl3); IR
(KBr, cm-1): 3458, 2936, 2858, 1693, 1118, 969, 743, 696; 1H NMR
(300 MHz, CDCl3) d 7.40–7.23 (m, 5H), 6.63 (dd, J = 16.0, 0.6 Hz,
1H), 6.19 (dd, J = 15.9, 6.0 Hz, 1H), 4.76 (dd, J = 3.0, 1.5 Hz, 1H),
2.97 (d, J = 4.8 Hz, 1H), 2.56–2.43 (m, 3H), 2.13–2.07 (m, 2H),
1.94–.92 (m, 1H), 1.69–1.63 (m, 3H), 1.38–1.58 (m, 1H); 13C NMR
(75 MHz, CDCl3) d 214.3, 136.8, 130.9, 129.0, 128.6, 127.6, 126.4,
70.6, 55.6, 42.6, 27.6, 27.4, 24.9. The ee value was determined by
Chiral HPLC. [Daicel Chiralpak OJ-H column, l = 254 nm, 2-
propanol : n-hexane = 1: 9, flow rate = 0.8 mL min-1]: tR = 16.77
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1
1522, 1091, 707. H NMR (300 MHz, CDCl3) d 8.20 (d, J =
8.4 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 5.52 (s, 1H), 4.25–
4.19 (m, 1H), 3.88–3.66 (m, 3H), 2.98 (d, J = 3.9 Hz, 1H),
2.95–2.88 (m, 1H), 2.76–2.65 (m, 1H), 2.48–2.43 (m, 1H); 13C
NMR (75 MHz, CDCl3) d 208.2, 148.0, 126.3, 123.7, 68.8, 68.3,
67.5, 57.2, 43.1. HRMS for C12H13NO5: Calcd. 251.0794; Found:
251.0790. After the reaction, the product was isolated as a mixture
of diastereoisomers (syn/anti = 87 : 13). 89% ee for syn isomer; the
ee value was determined by Chiral HPLC. [Daicel Chiralpak AD-
H column, l = 254 nm, 2-propanol : n-hexane = 1: 4, flow rate =
1.0 mL min-1]: tR = 13.39 min (minor), tR = 15.11 min (major).
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734, 703. 1H NMR (300 MHz, CDCl3) d 8.22 (d, J = 8.7 Hz, 2H),
7.51 (d, J = 8.7 Hz, 2H), 5.51(1H, s), 3.10–2.81(m, 5H), 2.81–
2.77(m, 2H), 2.53–2.49 (m, 1H); 13C NMR (75 MHz, CDCl3)
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