Organocatalytic transformation of 1,3-diketones into optically active cyclohexanones

Article abstract of DOI:10.1016/j.tetasy.2005.02.005

The domino Michael-aldol reaction of 1,3-diketones with MVK in the presence of L-proline furnished highly substituted cyclohexanones in a regio- and stereocontrolled manner. When the reaction was performed in NMP, high yields (up to 93%) and enantioselectivities up to 80% were observed.

Full text of DOI:10.1016/j.tetasy.2005.02.005

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1377–1383
Organocatalytic transformation of 1,3-diketones into
optically active cyclohexanones
Dorota Gryko*
Institute of Organic Chemistry of the Polish Academy of Science, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 29 December 2004; accepted 8 February 2005
Abstract—The domino Michael-aldol reaction of 1,3-diketones with MVK in the presence of L-proline furnished highly substituted
cyclohexanones in a regio- and stereocontrolled manner. When the reaction was performed in NMP, high yields (up to 93%) and
enantioselectivities up to 80% were observed.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
solvent for such types of process led to the subsequent
elimination after the aldol reaction as recently reported.4
While this paper was in preparation, the related subject
was described by Jørgensen et al.2e,f They demonstrated
that the addition of a,b-unsaturated ketones to b-keto-
esters in the presence of an imidazolidine catalyst–
phenylalanine derivatives, gave highly substituted cyclo-
hexanones containing 3–4 stereogenic centers in a dia-
stereo- and enantioselective manner. The same authors
widely studied the reactions of a,b-unsaturated enones
with malonates and 4-hydroxycumarins.11
The usual procedure for the synthesis of organic com-
pounds is the stepwise formation of the individual bonds
in a target molecule. However, it would be much more
efficient if several bonds could be formed in one
sequence without isolating the intermediates. This type
of transformation called a domino reaction.1 Among
them the domino Michael-aldol reaction is one of the
simplest methods for the preparation of highly substi-
tuted cyclohexane derivatives in a diastereo- and enan-
tioselective manner.2 This transformation is related to
the proline catalyzed Robinson annulation studied by
the Parrish and Wiechert groups3 and further investi-
gated by Bui and Barbas.4 As it was subsequently
discovered, proline itself can be an effective
organocatalyst of many other asymmetric transform-
ations, such as the aldol,5 Mannich,5a,b,6 Michael5a,b,7
reactions, the direct electrophilic a-amination,8 amin-
oxylation,9 and several others.5a,f
2. Results and discussion
The reaction of 1,3-bisphenyl-propane-1,3-dione 1 with
methyl vinyl ketone (MVK) in DMSO catalyzed by
L-proline has been chosen as a model system for the
optimization studies (Scheme 1).
The results of the initial screening experiments showed
that only L-proline, among catalysts studied [trans-4-hy-
droxy-L-proline, (R)-(ꢀ)-thiazolidine-4-carboxylic acid,
MacMillan catalyst], gave the cyclic product. It was
found that the use of less polar solvents than DMSO
gave very poor yields of the desired cyclohexanone
derivative 3a (Table 1, entries 2–5). The reactions in
CH2Cl2, CH3CN, or dioxane, even, when performed at
high pressure (10.5 kbar) only gave traces of 3a. Using
EtOH as a solvent, Michael adduct 2a was obtained in
50% yield, accompanied by only traces of 3a (Table 1,
entry 7). It should be pointed out that EtOH was the
solvent of choice for the domino Michael-aldol re-
action catalyzed by imidazolidine-type catalyst giving
The objective herein was to develop an efficient, enantio-
selective protocol for the synthesis of 3-hydroxycyclo-
hexanones via a domino Michael-aldol reaction of
acyclic 1,3-diketones with simple a,b-unsaturated
ketones. We envisioned that both steps can be catalyzed
by L-proline or an analogous catalyst. Until very re-
cently, it was known that chiral amines could catalyze
only the first step of such Michael-aldol tandem
sequence.10 On the other hand, the use of DMSO as a
*
Tel.: +48 22 3432129; fax: +48 22 6326681; e-mail: dgryko@
icho.edu.pl
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.02.005

1378
D. Gryko / Tetrahedron: Asymmetry 16 (2005) 1377–1383
Table 2. The enantioselective domino Michael-aldol reaction of 1,3-
diketones 1a–i with MVK in the presence of L-proline in NMP
O
O
O
+
R1
R2
O
Entry
1
Recovery of
1 (%)
Yielda of
2 (%)
Yielda of
3 (%)
Eeb of 3
1a-i
L
-proline
NMP
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
11
39
12
8
14
39
7
63
39
58
43
53
63
67
47
80
67
50
O
O
82
85
7
HO
R1
R1
+
2
52
35
0
47
52
R2
O
16
0
O
R2
R2
1g
1h
1i
81
57 +4
93
2a-i
3a-i
21
0
26
0
R1
a Isolated yield after column chromatography.
b Enantiomeric excesses were determined by chiral HPLC analysis in
comparison with racemic material.
a
b
c
MeO
Cl
MeO
Cl
pounds were synthesized using the Claisen condensation
described by Franek.12 This procedure was selected due
to its simplicity and robustness (purification did not
require column chromatography since the product was
isolated as the sodium enolate salt). The use of other
methods lead to an unseparable mixture of products.
The procedure was suitable also for the preparation of
non-symmetrical diketones 1h and 1i. The reaction of
1,3-diaroylmethanes 1a–d with MVK gave cyclohexa-
nones 3a–d as single diastereoisomers in good yields
and moderate enantioselectivities (Table 2, entries 1–
4). An increase in the electronegativity of the functional
group in the para-position resulted in an increase in the
yield of the cyclic product, reaching 85% for the bromo
substituent (Table 2, entry 4). The reaction proceeded
well also for 1,3-diketones bearing heteroaromatic sub-
stituents: 2-furan, 2-thiophen and 4-pyridine (Table 2,
entries 5–7). The highly reactive diketone 1g gave only
cyclohexanone derivative 3g in 81% yield and 80% ee
as a sole product. We have also tried the reaction of
MVK with nonsymmetrical 1,3-diketones 1h and 1j.
The difference in the reactivity of the carbonyl group
strongly influences the course of the domino Michael-
aldol reaction. In the reaction of 1h with MVK, two reg-
ioisomeric cyclohexanones were obtained in a ratio 15
(3h): 1 (Table 2, entry 8). They were separated on col-
umn chromatography and the location of substituents
unambiguously elucidated using 13C–1H GHSQC and
13C–1H GHMBC NMR techniques. When the p-chloro-
phenyl group was replaced by the more electron with-
drawing 4-pyridine substituent only 3i was isolated in
93% yield (Table 2, entry 9).
d
e
Br
Br
S
S
f
O
O
g
N
N
h
i
Cl
MeO
MeO
N
Scheme 1. The domino Michael-aldol reaction of 1,3-diketones 1a–i
with MVK catalyzed by L-proline.
Table 1. Solvent screening for the domino Michael-aldol reaction of
1a with MVK
Entry
Solvent
Yielda of
2a (%)
Yielda of
3a (%)
Eeb of 3a [%]
1
2
3
4
5
6
7
8
9
DMSO
CH2Cl2
CHCl3
CH3CN
THF
17
56
37
52
24
11
50
44
14
46
6
56
45
—
60
—
46
nd
11
58
0
27
0
MeOH
EtOH
DMF
2
Trace
12
61
NMP
In all cases of the domino Michael-aldol reaction, only a
single diastereoisomer was formed. The reaction pro-
ceeds through the initial formation of the Michael prod-
uct, which epimerizes in the reaction mixture because
the pro-stereogenic or the stereogenic carbon center
bears two ketone substituents. Subsequent intramolecu-
lar aldol reaction catalyzed by L-proline proceeds with
high diastereoselectivity but with moderate enantioselec-
tivity. This is intriguing because Jørgensen and co-work-
ers2e postulated that the diastereoselectivity in the
similar Michael-aldol reaction catalyzed by the imidaz-
olidine derivative is controlled by the stable stereogenic
a Isolated yield after column chromatography.
b Enantiomeric excesses were determined by chiral HPLC analysis in
comparison with racemic material.
cyclohexanone derivatives as described by JørgensenÕs
group.2e,f Furthermore, it was observed that the yield,
as well as the enantiomeric excess, could be improved
by using 1-methyl-2-pyrrolidinone (NMP) as a solvent
(Table 1, entry 9). With the defined optimal conditions,
a series of 1,3-diketones 1b–i was examined in order to
establish the scope of the reaction (Table 2). These com-

D. Gryko / Tetrahedron: Asymmetry 16 (2005) 1377–1383
1379
center formed in the initial Michael reaction. This is not
the case when MVK is used as a starting material since
there is no stable stereogenic center in the Michael ad-
duct 2. On the other hand, Christoffers13 reported that
the reaction of benzylidene acetone with b-ketoesters
catalyzed by inorganic bases gave regioisomeric mixture
of cyclic products.
Furthermore, the reaction of 1,3-bisphenyl-propane-1,3-
dione 1 with MVK in the presence of simple organic
base, pyrrolidine, only gave the Michael adduct (with
low yield). Consequently, contrary to Jørgensen and
co-workers2e,f in the domino Michael-aldol reaction
presented in these papers, the intramolecular aldol reac-
tion is catalyzed by the chiral molecule, L-proline. We
believe that the catalyst: (a) activates the Michael accep-
tor by iminium-ion formation, (b) deprotonates the 1,3-
diketone, and (c) activates the donor by the enamine
formation in the intramolecular aldol reaction. Further-
more, it activates the acceptor by the formation of
the hydrogen bond (through carboxylic group), since the
reaction in the presence of pyrrolidine stopped at the
Michael adduct (Scheme 2).
Figure 1. X-ray structure of 3i. Thermal ellipsoids are at 50%
probability level.
The assignment of the relative stereochemistries of
cyclohexanones is based on X-ray crystallographic stud-
ies (Fig. 1, Supporting Information) of 3i. The OH
group is cis to p-MeOPhCO. The same configuration
was assigned for the remaining adducts 3a–h by compar-
ison of their NMR spectra and by analogy to 3i.
3. Conclusion
In summary, we have developed the L-proline catalyzed
domino Michael-aldol reaction that provides cyclohex-
anone derivatives with new type of substitution pattern
in a highly diastereoselective manner and with good
enantioselectivity. The described method is complemen-
tary to the Jørgensen procedure,2e,f which does not
work for MVK. We have demonstrated that the reaction
is also highly regioselective when the non-symmetrical
1,3-diketones were used. The regioselectivity of this pro-
cess increases with an increase in the difference in reac-
tivity of carbonyl groups. It is believed that the
subsequent intramolecular aldol reaction proceeds
through an enamine mechanism and that the chirality
transfer takes place at this stage. These results are not
only of theoretical significance in that they provide in-
sight into factors influencing the course of the reaction
of 1,3-diketones with MVK, but they may also open
the door to practical applications of new cyclohexanone
derivatives.
-
CO2
CO2H
N+
O
N
H
O
O
R1
R2
O
O
CO2H
O
N
N
+H2O
R1
R1
R2
O
R2
O
O
-
CO2
N+
CO2H
O
4. Experimental
HO
R1
R1
R2
4.1. General experimental
O
R2
All chemicals were used as received unless otherwise
noted. Reagent grade solvents (CH2Cl2, hexanes) were
distilled prior use. All reported 1H NMR spectra
were collected on a Bruker spectrometer at 500 (1H
NMR) and 125 (13C NMR) MHz or a Varian Gemini
spectrometer at 200 (1H NMR) and 50 (13C NMR)
MHz. Chemical shifts are reported as d values relative
to the TMS signal defined at d = 0.00 (1H NMR) or
d = 0.0 (13C NMR). IR spectra were obtained on a
+H2O
O
HO
R1
O
R2
Scheme 2. The domino Michael-aldol reaction catalyzed by L-proline.

1380
D. Gryko / Tetrahedron: Asymmetry 16 (2005) 1377–1383
Perkin–Elmer 1640 FTIR unit. Mass spectra were
obtained on an AMD-604 Intectra instrument using
the EI or on a Mariner PerSeptive Biosystem instrument
using the ESI technique. Chromatography was per-
formed on silica (Kieselgel 60, 200–400 mesh). Melting
points were determined using a Kofler hot-stage appara-
tus and are uncorrected. The following ketones were
obtained according to the literature:12 1a–h.
128.9, 133.6, 135.9, 196.3, 208.6. IR (KBr): 3065, 2946,
1700, 1667, 1596, 1449, 1328, 1292, 1252, 1211, 1200,
1180, 1003, 757, 707, 691, 643, 600 cmꢀ1. ESI-MS: obsd:
317.1152 [M+Na]+; calcd exact mass: 317.1148. Anal.
Calcd for C19H18O3: C, 77.53; H, 6.16. Found: C,
77.44; H, 6.18.
4.3.2. Compound 3a. Column chromatography gave a
white solid (204 mg, 64%). mp 127–128 °C (AcOEt/hex-
anes). 1H NMR (CDCl3, 500 MHz): d = 2.2–2.3 (m,
1H), 2.47 (ddd, J = 25.5 Hz, J = 12.6 Hz, J = 4.9 Hz,
1H), 2.54–2.74 (m, 4H), 4.48 (dd, J = 12.3 Hz,
J = 3.8 Hz, 1H), 4.92 (d, J = 2.8 Hz, 1H), 7.15 (t,
J = 7.3 Hz, 1H), 7.25 (t, J = 7.8 Hz, 2H), 7.45 (m, 4H),
7.58 (t, J = 7.4 Hz, 1H), 7.87 (d, J = 7.5 Hz, 2H). 13C
NMR (CDCl3, 125 MHz): d = 26.439.9, 49.1, 55.1,
78.4, 124.3, 127.3, 128.2, 128.5, 128.9, 134.1, 135.9,
145.4, 205.0, 207.0. IR (KBr): 3360, 3056, 2962, 2934,
1707, 1678, 1448, 1379, 1342, 1298, 1253,1235, 1105,
970, 950, 758, 701 cmꢀ1. ESI-MS: obsd: 317.1164
[M+Na]+; calcd exact mass: 317.1148. Anal. Calcd for
C19H18O3: C, 77.53; H, 6.16. Found: C, 77.47; H, 6.27.
ee = 58% determined by HPLC: Chiracel OD-H, hex-
ane/i-PrOH, 8:2, flow rate: 0.5 mL/min, k = 225 nm;
t1(major) = 20.80, t2(minor) = 22.83.
4.2. Synthesis of 1,3-diketones
A solution of methyl pyridine-4-carboxylate (1.90 mL,
16.3 mmol) and 4-methoxy-acetophenone (2.20 g,
14.8 mmol) in a mixture of THF (3.0 mL) and DMSO
(2.0 mL) was added within 1 h under vigorous magnetic
stirring to a cooling (0–10 °C) suspension of NaH
(0.66 g, 60% suspension in a mineral oil) in a mixture
of THF (2.6 mL) and DMSO (2.5 mL). After the addi-
tion, stirring was continued and the temperature raised
to 20 °C within 30 min. Finally the reaction mixture
was stirred at 30 °C for 50 min. The solvents were then
removed in vacuo (water bath 40 °C). A dark-brown
fluid formed, which was then dissolved in water and
washed three times with Et2O. The aqueous layer was
acidified with 10% AcOH. During the acid addition,
dark brown color was disappearing and at the same time
a yellowish precipitate was forming. The precipitate was
filtered off and washed with water. Analytically pure
compound 1i was obtained and recrystallized from
EtOH (yellow needles, 2.8 g, 75%). mp 132–133 °C
(EtOH). 1H NMR (CDCl3, 500 MHz): d = 3.86 (s,
3H), 6.82 (s, 1H), 6.98 (AA0BB0/2, J = 9.0 Hz, 2H),
7.76 (AA0BB0/2, J = 6.2 Hz, 2H), 7.99 (AA0BB0/2,
J = 9.0 Hz, 2H), 8.78 (AA0BB0/2, J = 6.2 Hz, 2H). 13C
NMR (CDCl3, 125 MHz): d = 55.5, 93.4, 114.1, 120.3,
127.8, 129.7, 142.4, 150.6, 163.7, 179.5, 188.2. IR
(KBr): 3035, 2973, 2844, 1607, 1590, 1543, 1518, 1497,
1312, 1267, 1240, 1190, 1181, 1024, 840, 788, 698, 633,
584 cmꢀ1. ESI-MS: obsd: 256.0974 [M+H]+; calcd exact
mass: 256.0968. Anal. Calcd for C15H13NO3: C, 70.47;
H, 5.10; N, 5.48. Found: C, 70.47; H, 4.99; N, 5.48.
4.3.3. Compound 2b. Column chromatography gave a
white solid (210 mg, 59%). mp 96–97 °C (AcOEt/cyclo-
hexane). 1H NMR (CDCl3, 500 MHz): d = 2.12 (s,
3H), 2.31 (dd, J = 13.2 Hz, J = 6.5 Hz, 2H), 2.67 (t,
J = 6.5 Hz, 2H), 3.85 (s, 6H), 5.32 (t, J = 6.8 Hz, 1H),
6.92 (m, 4H), 8.02 (m, 4H). 13C NMR (CDCl3,
125 MHz): d = 23.3, 30.0, 40.9, 54.7, 55.5, 114.1, 129.0,
131.0, 163.8, 194.9, 208.8. IR (KBr) : 3425, 2960, 2937,
2839, 1716, 1652, 1599, 1572, 1512, 1345, 1301, 1254,
1238, 1171, 1117, 1093, 1030, 965, 840, 735, 608, 583,
564 cmꢀ1. ESI-MS: obsd: 354.14592 [M]+; calcd exact
mass: 354.14672. Anal. Calcd for C21H22O5: C, 71.17;
H, 6.26. Found: C, 71.22; H, 6.16.
4.3.4. Compound 3b. Column chromatography gave a
white solid (97 mg, 27%). mp 123–124 °C (AcOEt/cyclo-
hexane). 1H NMR (CDCl3, 500 MHz): d = 2.2–2.25
(m, 1H), 2.44 (ddd, J = 25.3 Hz, J = 12.6 Hz,
J = 5.2 Hz, 1H), 2.5–2.7 (m, 4H), 3.71 (s, 3H), 3.86
(s, 3H), 4.39 (dd, J = 12.3 Hz, J = 3.8 Hz, 1H), 5.09 (s,
1H), 6.76 (AA0BB0/2, J = 8.9 Hz, 2H), 6.92 (AA0BB0/2,
J = 8.9 Hz, 2H), 7.36 (AA0BB0/2, J = 8.8 Hz, 2H), 7.88
(AA0BB0/2, J = 8.9 Hz, 2H). 13C NMR (CDCl3,
125 MHz): d = 26.4, 39.9, 48.5, 55.1, 55.4, 55.5, 78.2,
113.8, 114.1, 125.5, 128.8, 130.6, 137.8, 158.5, 164.4,
203.4, 207.3. IR (KBr): 3425, 2960, 2937, 2839, 1716,
1652, 1599, 1572, 1512, 1345, 1301, 1254, 1238, 1171,
4.3. General procedure for the addition of MVK to
diketones
To a solution of diketone (1.0 mmol) and L-proline
(0.2 mmol) in NMP (2.5 mL), MVK (1.0 mmol, 98 lL)
was added at room temperature. The resulting mixture
was stirred for 72 h and then diluted with an aqueous
solution of NH4F. The resulting solution was extracted
with AcOEt three times. The organic layer was washed
with water and dried over Na2SO4. Column chromato-
graphy (mixture of hexanes/AcOEt) gave three frac-
tions: the recovered substrate, the Michael adduct and
the cyclic derivative in the order of elution.
1117, 1093, 1030, 965, 840, 735, 608, 583, 564 cmꢀ1
.
Anal. Calcd for C21H22O5: C, 71.17; H, 6.26. Found:
C, 71.15; H, 6.09. Ee = 43% determined by HPLC:
Chiracel OD-H, hexane/i-PrOH, 1:1, flow rate: 0.8 mL/
min, k = 285 nm; t1(major) = 8.83, t2(minor) = 11.07.
4.3.1. Compound 2a. Crystallization from AcOEt/hex-
1
anes gave white solid (77 mg, 15%). mp 64–65 °C. H
NMR (CDCl3, 500 MHz): d = 2.12 (s, 3H), 2.32 (dd,
J = 13.1 Hz, J = 6.5 Hz, 2H), 2.69 (t, J = 6.4 Hz, 2H),
5.48 (t, J = 6.7 Hz, 1H), 7.46 (t, J = 7.7 Hz, 4H), 7.57
(t, J = 7.4 Hz, 2H), 8.03 (d, J = 7.6 Hz, 4H). 13C NMR
(CDCl3, 125 MHz), d = 23.2, 30.0, 40.8, 54.8, 128.7,
4.3.5. Compound 2c. Column chromatography gave a
white solid (24 mg, 7%). mp 73–74 °C (AcOEt/pentane).
1H NMR (CDCl3, 500 MHz): d = 2.13 (s, 3H), 2.2–2.3
(m, 2H), 2.70 (t, J = 6.2 Hz, 2H), 5.37 (t, J = 6.8 Hz,

D. Gryko / Tetrahedron: Asymmetry 16 (2005) 1377–1383
1381
1H), 7.44 (m, 4H), 7.97 (m, 4H). 13C NMR (CDCl3,
125 MHz): d = 23.1, 30.1, 40.6, 54.9, 129.3, 130.0,
134.0, 140.4, 195.0, 208.7. IR (KBr): 2928, 2913, 1711,
1693, 1665, 1588, 1401, 1288, 1252, 1209, 1159, 1089,
4.3.9. Compound 2e. Column chromatography gave a
white solid (158 mg, 52%). mp 96–97 °C (AcOEt/pen-
1
tane). H NMR (CDCl3, 500 MHz): d = 2.12 (s, 3H),
2.36 (dd, J = 13.0 Hz, J = 6.6 Hz, 2H), 2.68 (t,
J = 6.4 Hz, 2H), 5.09 (t, J = 7.0 Hz, 1H), 7.12 (dd,
J = 4.9 Hz, J = 3.9 Hz, 2H), 7.67 (dd, J = 5.1 Hz, J =
1.1 Hz, 2H), 7.90 (dd, J = 3.9 Hz, J = 1.1 Hz, 2H). 13C
NMR (CDCl3, 125 MHz): d = 23.7, 30.1, 40.6, 58.1,
128.5, 133.2, 134.9, 143.2, 188.2, 208.3. IR (KBr):
3122, 3087, 2921, 1710, 1668, 1634, 1516, 1412, 1352,
1278, 1240, 1198, 1160, 1063, 958, 855, 744, 732,
612 cmꢀ1. ESI-MS: obsd: 329.0280 [M+Na]+; calcd ex-
act mass: 329.0277. Anal. Calcd for C15H14O3S2: C,
58.80; H, 4.61; S, 20.93. Found: C, 58.84; H, 4.52; S,
20.74.
1003, 979, 923, 843, 825 cmꢀ1
.
ESI-MS: obsd:
363.0544 [M]+; calcd exact mass: 363.0549. Anal. Calcd
for C19H16O3Cl2: C, 62.83; H, 4.44; Cl, 19.52. Found: C,
63.09; H, 4.40; Cl, 19.63.
4.3.6. Compound 3c. Column chromatography gave a
white solid (297 mg, 82%). mp 137–139 °C (AcOEt–pen-
tane). 1H NMR (CDCl3, 500 MHz): d = 2.2–2.3 (m,
1H), 2.45 (ddd, J = 25.7 Hz, J = 12.8 Hz, J = 4.6 Hz,
1H), 2.5–2.7 (m, 4H), 4.37 (dd, J = 12.3 Hz,
J = 3.8 Hz, 1H), 4.86 (br s, 1H), 7.22 (AA0BB0/2,
J = 8.6 Hz, 2H), 7.37 (AA0BB0/2, J = 8.6 Hz, 2H), 7.44
(AA0BB0/2, J = 8.6 Hz, 2H), 7.82 (AA0BB0/2,
J = 8.6 Hz, 2H). 13C NMR (CDCl3, 125 MHz):
d = 26.3, 39.8, 49.0, 54.9, 78.1, 125.8, 128.8, 129.4,
129.6, 133.3, 133.9, 141.1, 143.8, 203.5, 206.2. IR
(KBr): 3353, 2957, 2934, 1712, 1681, 1587, 1490, 1403,
1300, 1231, 1094, 1012, 968, 862, 842, 827, 742, 625,
542 cmꢀ1. EI-MS: obsd: 362.04681 [M]+; calcd exact
mass: 362.04765. Anal. Calcd for C19H16O3Cl2: C,
62.83; H, 4.44; Cl, 19.52. Found: C, 62.88; H, 4.54; Cl,
19.37. Ee = 53% determined by HPLC: Chiracel
OD-H, hexane/i-PrOH, 75:15, flow rate: 1 mL/min,
k = 225 nm; t1(major) = 12.67, t2(minor) = 16.27.
4.3.10. Compound 3e. Column chromatography gave a
white solid (144 mg, 47%). mp 134–136 °C (AcOEt/pen-
1
tane). H NMR (CDCl3, 500 MHz): d = 2.27 (m, 1H),
2.51 (m, 2H), 2.61 (m, 1H), 2.71 (d, J = 14.9 Hz, 1H),
2.83 (dd, J = 14.9 Hz, J = 2.0 Hz, 1H), 4.15 (m, 1H),
5.23 (br s, 1H), 6.84 (dd, J = 5.2 Hz, J = 3.6 Hz, 1H),
6.94 (dd, J = 3.6 Hz, J = 1.1 Hz, 1H), 7.11 (dd,
J = 5.0 Hz, J = 1.1 Hz, 1H), 7.18 (dd, J = 4.9 Hz,
J = 3.9 Hz, 1H), 7.73 (dd, J = 4.9 Hz, J = 1.0 Hz, 1H),
7.84 (dd, J = 3.9 Hz, J = 1.0 Hz, 1H). 13C NMR
(CDCl3, 125 MHz): d = 26.4, 39.7, 52.3, 56.0, 77.3,
122.7, 124.4, 127.0, 128.6, 133.1, 135.7, 143.0, 150.7,
196.8, 205.9. IR (KBr): 3361, 3105, 2953, 1717, 1628,
1513, 1409, 1389, 1300, 1249, 1200, 1096, 1086, 1049,
946, 849, 807, 745, 720, 654, 634, 608 cmꢀ1. ESI-MS:
obsd: 329.0281 [M+Na]+; calcd exact mass: 329.0277.
Anal. Calcd for C15H14O3S2: C, 58.80; H, 4.61; S,
20.93. Found: C, 58.82; H, 4.60; S, 20.78. Ee = 67%
determined by HPLC: Diacel Chiralpak OJ, hexane/i-
PrOH, 1:1, flow rate: 0.5;mL/min, k = 245 nm; t1(min-
or) = 28.41, t2(major) = 31.41.
4.3.7. Compound 2d. Column chromatography gave a
white solid (34 mg, 8%). mp 99–100 °C (MeOH). 1H
NMR (CDCl3, 500 MHz): d = 2.13 (s, 3H), 2.29 (dd,
J = 12.7 Hz, J = 6.4 Hz, 2H), 2.69 (t, J = 6.2 Hz, 2H),
5.36 (t, J = 6.7 Hz, 1H), 7.61 (AA0BB0/2, J = 8.6 Hz,
4H), 7.89 (AA0BB0/2, J = 8.6 Hz, 4H). 13C NMR
(CDCl3, 125 MHz): d = 23.0, 30.1, 40.6, 54.8, 129.1,
130.1, 132.3, 134.4, 195.2, 208.7. IR (KBr) : 2927,
2910, 1710, 1695, 1664, 1583, 1430, 1395, 1287, 1252,
1208, 1159, 1067, 1002, 978, 841, 822, 727, 604 cmꢀ1
.
4.3.11. Compound 2f. Column chromatography gave a
white solid (95 mg, 35%). mp 47–48 °C (Et2O/pentane).
1H NMR (CDCl3, 500 MHz): d = 2.11 (s, 3H), 2.31
(dd, J = 13.8 Hz, J = 6.9 Hz, 2H), 2.60 (t, J = 6.9 Hz,
2H), 4.94 (t, J = 7.0 Hz, 1H), 6.54 (dd, J = 3.6 Hz,
J = 1.7 Hz, 2H), 7.34 (d, J = 3.6 Hz, 2H), 7.57 (d,
J = 1.7 Hz, 2H). 13C NMR (CDCl3, 125 MHz):
d = 22.5, 29.9, 40.6, 56.0, 112.6, 118.7, 147.0, 151.8,
184.1, 207.9. ESI-MS: obsd: 297.0748 [M+Na]+; calcd
exact mass: 297.0748. Anal. Calcd for C15H14O5: C,
65.69; H, 5.14. Found: C, 65.66; H, 5.14.
ESI-MS: obsd: 472.9381 [M+Na]+; calcd exact mass:
472.9358. Anal. Calcd for C19H16O3Br2: C, 50.47; H,
3.57; Br, 35.35. Found: C, 50.48; H, 3.65; Br, 35.40.
4.3.8. Compound 3d. Column chromatography gave a
white solid (297 mg, 82%). mp 148–149 °C (MeOH).
1H NMR (CDCl3, 500 MHz): d = 2.2–2.3 (m, 1H),
2.43 (ddd, J = 25.7 Hz, J = 12.8 Hz, J = 5.0 Hz, 1H),
2.53 (m, 1H), 2.6–2.7 (m, 3H), 4.38 (dd, J = 12.4 Hz,
J = 3.7 Hz, 1H), 4.86 (br s, 1H), 7.32 (AA0BB0/2,
J = 8.6 Hz, 2H), 7.38 (AA0BB0/2, J = 8.6 Hz, 2H), 7.62
(AA0BB0/2, J = 8.6 Hz, 2H), 7.75 (AA0BB0/2,
J = 8.6 Hz, 2H). 13C NMR (CDCl3, 125 MHz):
d = 26.2, 39.7, 48.9, 54.8, 78.1, 121.4, 126.1, 129.6,
129.9, 131.7, 132.4, 134.3, 144.3, 203.7, 206.2. IR
(KBr): 3428, 2958, 1720, 1655, 1580, 1484, 1397, 1305,
1230, 1210, 1091, 1070, 1008, 959, 839, 782, 741, 589,
562 cmꢀ1. ESI-MS: obsd: 472.9384 [M+Na]+; calcd
exact mass: 472.9385. Anal. Calcd for C19H16O3Br2:
C, 50.47; H, 3.57; Br, 35.35. Found: C, 50.49; H,
3.48; Br, 35.44. Ee = 63% determined by HPLC:
Chiracel OD-H, hexane/i-PrOH, 8:2, flow rate: 0.8 mL/
min, k = 225 nm; t1(major) = 11.52 min, t2(minor) =
14.00 min.
4.3.12. Compound 3f. Column chromatography (very
slow) gave a white solid (146 mg, 52%). mp. 143–144
1
(Et2O/pentane) H NMR (CDCl3, 500 MHz): d = 2.16
(m, 1H), 2.42 (ddd, J = 25.4 Hz, J = 12.7 Hz,
J = 4.7 Hz, 1H), 2.52 (d, J = 6.3 Hz, 1H), 2.60–266 (m,
1H), 2.71 (dd, J = 14.9 Hz, J = 2.7 Hz, 1H), 2.83 (d,
J = 14.92 Hz, 1H), 4.41 (dd, J = 12.2 Hz, J = 3.9 Hz,
1H), 4.68 (br s, 1H), 6.22 (dd, J = 3.3 Hz, J = 1.8 Hz,
1H), 6.25 (d, J = 3.2 Hz, 1H), 6.57 (dd, J = 3.6 Hz,
J = 1.7 Hz, 1H), 7.21 (d, J = 1.0 Hz, 1H), 7.28 (d,
J = 3.6 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H). 13C NMR
(CDCl3, 125 MHz): d = 24.9, 39.6, 48.4, 52.1, 75.5,
105.8, 110.5, 112.8, 119.1, 141.7, 147.7, 151.6, 157.1,

1382
D. Gryko / Tetrahedron: Asymmetry 16 (2005) 1377–1383
192.3, 206.4. IR (KBr): 3360, 2963, 2922, 1710, 1673,
1562, 1468, 1400, 1306, 1264, 1150, 1110, 1090, 989,
882, 781, 732, 594 cmꢀ1. ESI-MS: obsd: 297.0736
[M+Na]+; calcd exact mass: 297.0733. Anal. Calcd for
C15H14O5: C, 65.69; H, 5.14. Found: C, 65.60; H, 5.27.
Ee = 47% determined by HPLC: Diacel Chiralpak OJ,
hexane/i-PrOH, 1:1, flow rate: 0.5 mL/min, k = 285 nm;
t1(minor) = 20.32, t2(major) = 22.16.
4.3.16. Regioisomer of 3h. Column chromatography
(very slow) gave a white solid (33 mg, 4%). mp 124–
126 °C (AcOEt/cyclohexane).1H NMR (CDCl3,
500 MHz): d = 2.1–2.2 (m, 1H), 2.44 (ddd, J =
25.4 Hz, J = 12.8 Hz, J = 4.5 Hz, 1H), 2.54 (dt,
J = 14.0 Hz, J = 6.3 Hz, 1H), 2.60–266 (m, 3H), 3.82
(s, 3H), 4.22 (dd, J = 12.2 Hz, J = 3.7 Hz, 1H), 4.76
(br s, 1H), 6.77 (AA0BB0/2, J = 8.9 Hz, 2H), 7.33
(AA0BB0/2, J = 8.9 Hz, 2H), 7.43 (AA0BB0/2,
J = 8.9 Hz, 2H), 7.81 (AA0BB0/2, J = 8.9 Hz, 2H). 13C
NMR (CDCl3, 125 MHz): d = 26.2, 39.8, 49.3, 55.2,
55.3, 78.1, 113.9, 125.5, 129.3, 129.6, 134.2, 137.4,
140.8, 158.7, 203.9, 209.8. IR (KBr): 3334, 2958, 2931,
1710, 1681, 1612, 1589, 1513, 1400, 1369, 1298, 1257,
1236, 1179, 1096, 1031, 1013, 957, 831, 753, 685,
585 cmꢀ1. ESI-MS: obsd: 381.0883 [M+Na]+; calcd
exact mass: 381.0864. Anal. Calcd for C20H19O4Cl: C,
66.95; H, 5.34. Found: C, 66.81; H, 5.21. Ee = 47%
determined by HPLC: Chiracel OD-H, hexane/i-PrOH,
8:2, flow rate: 0.5 mL/min, k = 225 nm; t1(major) =
19.95 min, t2(minor) = 22.11 min.
4.3.13. Compound 3g. Column chromatography (silica,
CH2Cl2/MeOH) gave a white solid (241 mg, 81%). mp
179–181 °C (MeOH/CH2Cl2). 1H NMR (DMSO-d6,
500 MHz): d = 2.04–2.21 (m, 3H), 2.25–2.4 (m, 3H),
2.7–2.8 (m, 1H), 3.17 (d, J = 14.3 Hz, 1H), 4.73 (dd,
J = 11.8 Hz, J = 3.56 Hz, 1H), 5.47 (s, 1H), 7.45 (m,
2H), 7.60 (m, 2H), 8.35 (m, 2H), 8.66 (m, 2H). 13C
NMR (CDCl3, 125 MHz): d = 24.5, 39.0, 49.9, 53.7,
76.8, 120.1, 120.9, 142.8, 149.3, 150.5, 154.0, 201.8,
207.4. IR (KBr): 3417, 3163, 2972, 2935, 1708, 1694,
1597, 1556, 1411, 1370, 1343, 1300, 1230, 1207, 1110,
1063, 957, 948, 822, 658, 605, 577 cmꢀ1. ESI-MS: obsd:
297.1245 [M+H]+; calcd exact mass: 297.1234. Anal.
Calcd for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45.
Found: C, 68.79; H, 5.36; N, 9.40. Ee = 80% determined
by HPLC: Chiracel ODH, hexane/i-PrOH, 1:1, flow
rate: 0.5 mL/min, k = 225 nm; t1(major) = 14.91,
t2(minor) = 20.40.
4.3.17. Compound 3i. Column chromatography
(CH2Cl2/Et2O then CH2Cl2/MeOH, 5%) gave white
crystals (303 mg, 93%) suitable for X-ray analysis. mp
142–144 °C (CH2Cl2). 1H NMR (CDCl3, 500 MHz):
d = 2.25–2.32 (m, 1H), 2.48 (ddd, J = 25.6 Hz,
J = 12.4 Hz, J = 5.8 Hz, 1H), 2.6–2.7 (m, 4H), 3.88
(s, 3H), 4.40 (dd, J = 12.4 Hz, J = 3.8 Hz, 1H), 5.26
(br s, 1H), 6.93 (AA0BB0/2, J = 8.9 Hz, 2H), 7.43 (d,
J = 6.0 Hz, 2H), 7.88 (AA0BB0/2, J = 8.9 Hz, 2H), 8.51
(d, J = 4.4s Hz, 2H). 13C NMR (CDCl3, 125 MHz):
d = 26.4, 39.9, 48.0, 54.0, 55.6, 77.7, 114.3, 119.8,
128.2, 130.7, 149.5, 155.0, 164.8, 202.5, 205.8. IR
(KBr): 3371, 2961, 2932, 1707, 1668, 1599, 1574, 1411,
1258, 1238, 1173, 1024, 866, 818, 598, 576 cmꢀ1. ESI-
MS: obsd: 326.1370 [M]+; calcd exact mass: 326.1387.
Anal. Calcd for C19H20NO4: C, 70.14; H, 5.89; N,
4.31. Found: C, 70.10; H, 5.71; N, 4.22. Ee = 50% deter-
mined by HPLC: Chiracel OD-H, hexane/i-PrOH, 8:2,
flow rate: 1.0 mL/min, k = 260 nm; t1(major) = 18.91
min, t2(minor) = 26.77 min.
4.3.14. Compound 2h. Column chromatography (very
slow) gave a white solid (94 mg, 26%). mp 81–82 °C
(AcOEt/cyclohexane). 1H NMR (CDCl3, 500 MHz):
d = 2.12 (s, 3H), 2.30 (dd, J = 13.0 Hz, J = 6.5 Hz,
2H), 2.68 (t, J = 6.4 Hz, 2H), 3.86 (s, 3H), 5.35 (t,
J = 6.8 Hz, 1H), 6.95 (AA0BB0/2, J = 7.0 Hz, 2H), 7.41
(AA0BB0/2, J = 7.4 Hz, 2H), 7.95 (AA0BB0/2,
J = 7.9 Hz, 2H), 8.03 (AA0BB0/2, J = 8.0 Hz, 2H). 13C
NMR (CDCl3, 125 MHz): d = 23.2, 30.0, 40.7, 54.8,
55.5, 114.2, 128.7, 129.2, 130.0, 131.1, 134.3, 140.0,
164.1, 194.6, 195.2, 208.7. IR (KBr): 2950, 1714, 1691,
1651, 1600, 1571, 1421, 1397, 1351, 1318, 1266, 1206,
1180, 1171, 1032, 1011, 998, 854, 842, 580, 542 cmꢀ1
.
ESI-MS: obsd: 381.0879 [M]+; calcd exact mass:
381.0888. Anal. Calcd for C22H18O4Cl: C, 66.95; H,
5.34; Cl, 9.86. Found: C, 67.20; H, 5.38; Cl, 9.86.
5. Crystallographic data of X-ray structure of 3i
4.3.15. Compound 3h. Column chromatography (very
slow) gave a white solid (203 mg, 57%). mp 117–
118 °C (AcOEt/cyclohexane). 1H NMR (CDCl3,
500 MHz): d = 2.2–2.3 (m, 1H), 2.45 (m, 1H), 2.51–
2.65 (m, 4H), 3.87 (s, 3H), 4.37 (dd, J = 12.4 Hz,
J = 3.7 Hz, 1H), 5.15 (br s, 1H), 6.93 (m, 2H), 7.21 (m,
2H), 7.39 (m, 2H), 7.87 (m, 2H). 13C NMR (CDCl3,
125 MHz): d = 26.5, 39.9, 48.3, 55.0, 55.6, 78.1, 114.2,
125.9, 128.5, 128.6, 129.1, 130.7, 133.1, 144.2, 164.6,
203.0, 206.6. IR (KBr): 3419, 3359, 2956, 2937, 1719,
1644, 1599, 1573, 1422, 1384, 1267, 1237, 1170, 1092,
1014, 840, 602, 566 cmꢀ1. ESI-MS: obsd: 381.0885
[M+Na]+; calcd exact mass: 381.0864. Anal. Calcd
for C20H19O4Cl: C, 66.95; H, 5.34; Cl, 9.88. Found:
C, 66.93; H, 5.50; Cl, 9.63. Ee = 67% determined by
Chiracel OD-H, hexane/i-PrOH, 8:2, flow rate:
1 mL/min, k = 285nm; t1(major) = 10.33 min, t2(minor) =
15.20 min.
Measurement of the crystal structure was performed on
a Kuma KM4CCD j-axis diffractometer with graphite-
monochromated MoKa radiation. The crystal was
positioned at 65 mm from the KM4CCD camera. One
thousand two hundred and four frames were measured
at 1.0° intervals with a counting time of 20 s. The data
were corrected for Lorentz and polarization effects.
None absorption correction was applied. Data reduc-
tion and analysis were carried out with the Kuma
Diffraction (Wrocław) programs.
The structure was solved by direct methods14 and re-
fined using SHELXL.15 The refinement was based on
F2 for all reflections except those with very negative F2
weighted R factors wR and all goodness-of-fit S values
are based on F2. Conventional R factors are based on
F with F set to zero for negative F2. The F 02 > 2sðF 02Þ

D. Gryko / Tetrahedron: Asymmetry 16 (2005) 1377–1383
1383
Chem., Int. Ed. 2004, 43, 5138–5175; (e) List, B. In
Mahrwald, R., Ed.; Modern Aldol Reactions; Wiley-
Interscience: Weinheim, 2004; Vol. 1, pp 161–200; (f)
Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis;
Wiley-Interscience, 2005.
criterion was used only for calculating R factors and is
not relevant to the choice of reflections for the refine-
ment. The R factors based on F2 are about twice as large
as those based on F. All hydrogen atoms were located in
idealized averaged geometrical positions, allowed to ride
at the heavy atoms. Scattering factors were taken from
Tables 6.1.1.4 and 4.2.4.2.16
´
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Acknowledgements
I would like to thank Prof. Janusz Jurczak for helpful
discussions. The X-ray measurements were undertaken
in the Crystallographic Unit of the Physical Chemistry
Lab. at the Chemistry Department of the University of
Warsaw.17
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