A temperature study on a stereoselective organocatalyzed aldol reaction in water

Article abstract of DOI:10.1016/j.tet.2008.09.059

We report the first temperature study on the stereoselectivity of the 'in-water' aldol reaction between nicotinaldehyde (3-pyridinecarbaldehyde) and cyclohexanone catalyzed by morpholine and trans-4-tert-butyldimethylsilyloxy-l-proline. Eyring plots of diastereomeric ratio anti/syn gave a constant diastereoselectivity with respect to reaction temperature using morpholine as catalyst. With O(TBS)-l-proline we observed a non-linear behaviour of the Eyring plot with the presence of an inversion temperature (T_inv), which disclosed dynamic solvation effects in water.

Full text of DOI:10.1016/j.tet.2008.09.059

Tetrahedron 64 (2008) 11205–11208
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A temperature study on a stereoselective organocatalyzed aldol reaction in water
*
Enrico Emer, Paola Galletti, Daria Giacomini
Department of Chemistry ‘G.Ciamician’, University of Bologna, Via Selmi 2, 40126 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 June 2008
Received in revised form 3 September 2008
Accepted 18 September 2008
Available online 27 September 2008
We report the first temperature study on the stereoselectivity of the ‘in-water’ aldol reaction between
nicotinaldehyde (3-pyridinecarbaldehyde) and cyclohexanone catalyzed by morpholine and trans-4-tert-
butyldimethylsilyloxy-
diastereoselectivity with respect to reaction temperature using morpholine as catalyst. With O(TBS)-
-proline we observed a non-linear behaviour of the Eyring plot with the presence of an inversion
temperature (Tinv), which disclosed dynamic solvation effects in water.
Ó 2008 Elsevier Ltd. All rights reserved.
L-proline. Eyring plots of diastereomeric ratio anti/syn gave a constant
L
1. Introduction
by morpholine or trans-4-tert-butyldimethylsilyloxy-L-proline
(O(TBS)-proline). The reaction was studied upon temperature var-
iation from 2 to 80 ꢀC and an Eyring plot of ln(anti/syn) versus 1/T
revealed the presence of an inversion temperature (Tinv).
Organocatalysis has been receiving much attention by the
chemical community,1 especially aqueous-phase organocatalysis, in
light of the development of environmental friendly chemical pro-
cesses and to study an analogue of enzyme catalysis. Water was
demonstrated to be a suitable solvent for organocatalyzed cross-
aldol reactions,2 but it gives heterogeneous reaction mixtures with
theneedofsurfactantagents.3 Inrecentyears, wehavebeeninvolved
in studying the effect of solvent and temperature on diastereofacial
2. Results and discussion
Taking into account the ‘in-water’ and ‘on-water’ debate in
organocatalysis,7 we initially spent efforts to design a truly ‘in-
water’ condition with all species soluble and forming a homoge-
neous phase with the aqueous solvent. In these conditions effective
solvation effects could be revealed.
We chose 3-pyridinecarbaldehyde and cyclohexanone as part-
ners in a stoichiometric amount, thus avoiding an excess of the
ketone, which could act as the reaction solvent.
selectivity in nucleophilic addition to a
-chiral aldehydes4 and im-
ines.5 Concerning the aldol reaction, we found that solute–solvent
interactions are able to affect the stereochemical outcome of an aldol
reactioneven in the case of hydrocarbon solventsinwhich only weak
and non-specific interactions are involved.6
OH
O
OH
O
O
O
CHO
cat. 10%
H2O
+
+
+
N
N
N
N
N
1b
syn
1a
2
TBSO
anti
O
or
cat:
N
COOH
N
H
H
We report here our results on the temperature dependence of
diastereo- and enantio-selectivity of an ‘in-water’ cross-aldol re-
action between nicotinaldehyde and cyclohexanone catalyzed
We initially screened some secondary amines at 10 mol % as
catalysts (piperidine, pyrrolidine, morpholine, proline and O(TBS)-
proline). Careful examination of water-solubility, reaction time and
conversion led us to focus our study on two catalysts: one achiral,
morpholine, and one chiral, O(TBS)-proline.
Reactions proceeded smoothly to give anti (1a) and syn (1b)
aldols. The anti and syn configurations were determined by NMR
* Corresponding author. Tel.: þ39 051 209 9528; fax: þ39 051 209 9456.
E-mail address: daria.giacomini@unibo.it (D. Giacomini).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.059

11206
E. Emer et al. / Tetrahedron 64 (2008) 11205–11208
Table 1
Table 2
Aldol reaction in water between 3-pyridinecarbaldehyde and cyclohexanone cata-
lyzed by morpholine 10 mol %
anti and syn % in the aldol reaction between 3-pyridinecarbaldehyde and cyclo-
hexanone catalyzed by morpholine or O(TBS)-proline 10% in water
Entry
Time (h)
T (ꢀC)
1a/1b
1aþ1b
2a (Y%)
Entry
Catalyst
Time
(h)
T
(ꢀC)
1aa (%)
anti
1ba (%)
syn
(Y%)
1
2
3
4
5
6
7
8
9
24
0.5
1
2
3
5.5
7
24
24
30
37
37
37
37
37
37
55
70
60:40
64:36
63:37
60:40
58:42
50:50
50:50
51:49
45:55
57
21
37
57
60
88
89
78
47
d
1
2
3
4
5
6
7
8
Morpholine
16
17
16
6
2
2
2
1
1
1
15 min
5 min
3 min
48
25
22
12
23
21
22
24
18
17
2
4
8
61.9
61.4
61.4
61.3
60.7
61.1
60.5
60.3
59.9
61.3
59.9
60.0
50.8
74.0
73.7
73.4
72.5
72.4
71.8
71.2
70.7
70.9
70.4
68.1
65.4
63.1
61.7
59.8
38.1
38.6
38.6
38.7
39.3
38.9
39.5
39.7
40.1
38.7
40.1
40.0
41.2
26.0
26.3
26.6
27.5
27.6
28.2
28.8
29.3
29.1
29.6
31.9
34.6
36.9
38.3
40.2
d
d
d
14
26
34
37
45
47
55
65
71
81
8
13
18
31
34
40
45
50
51
55
60
65
70
75
80
d
Traces
Traces
21
40
9
10
11
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
a
Compound 2 was obtained from crude reaction mixtures by filtration.
analysis by comparison and in analogy with the known products.8
The anti/syn ratio (1a/1b) within the crude reaction mixture was
determined in each experiment by 1H NMR analysis. To test for the
presence of equilibration phenomena we followed the variation of
the diastereomeric ratio (dr) with reaction time and temperature
(Table 1). A preliminary study at 37 ꢀC with 10 mol % morpholine
revealed that the anti/syn ratio was almost constant within 2 h, but
for reaction times exceeding 3 h a significant reequilibration oc-
curred. For a longer reaction time and for higher temperature
values, a considerable amount of the double eliminated adduct
2 appeared and eroded the diastereomeric ratio. The double con-
densed aldol or a mono-eliminated product was never observed.
Due to the constant diastereomeric ratio after 1 h, we choose to
extend the reaction time only for reactions performed at lower
temperatures. With O(TBS)-proline as catalyst we never observed
eliminated products.
O(TBS)-Proline
21
22
16
22
24
a
The reaction yields in 1aþ1b ranged from 15 to 60% depending on time and
temperature. The average standard deviation on 1a and 1b is 0.8% (see Section 4).
intersecting linear trends produced by two distinct solvation clus-
ters. These solute–solvent clusters are the real reacting species in
solution and they have specific thermodynamic properties and
hence distinct stereoselectivities. The solvent effect on selectivity
reflects its different influence on the two diastereomeric paths
The diastereomeric ratio anti/syn was then determined in
a reaction temperature range of 80 ꢀC with morpholine and O(TBS)-
proline (Table 2). The dr data were analyzed according to the
differential Eyring equation:9
through distinct contributions to DDG
s. This interpretation can be
lnðanti=synÞ [ LDDGs=RT [ LðDDHs=RTÞDðDDSs=RÞ
where DDHs
(1)
extended even in this case. In the O(TBS)-proline-catalyzed re-
action the reactive intermediate, presumably the enamine,10 pres-
ents two solvation regimes, which are temperature dependent, one
for T>Tinv and one for T<Tinv at the inversion temperature there is
an equilibrium between the two.
¼
D
Hsantiꢁ
D
Hssyn and DDSs
¼
D
Ssantiꢁ
D
Ss
.
syn
The temperature dependence of dr values is illustrated in Fig-
ure 1, where the natural logarithm of anti/syn is plotted against the
reciprocal temperature. The catalyst has a significant influence on
the temperature profile of diastereoselectivity. This accounts for an
effective and determining presence of the catalyst within the
stereoselective step.10 Data were then analyzed by least squares
fitting to Eq. 1 to obtain linear correlations. For each data set we
applied a residual statistical analysis to evaluate the number of
linear trends. At all temperature values and with both catalysts
there was a predominance of the anti isomer and O(TBS)-proline
was found to be a better catalyst than morpholine in terms of
diastereoselectivity.
To understand the nature of the present temperature effect it is
necessary to consider the activation parameters in more detail. In
the case of morpholine, DDH S
s and DD s have very low values, the
two diastereomeric reaction paths are so little differentiated by
activation enthalpy (ꢁ0.2 kcal/mol) that low diastereomeric ratios
T (°C)
85
60
40
20
5
1.2
1
With O(TBS)-proline the Eyring plot showed a non-linear be-
haviour with two linear trends and the presence of an inversion
temperature (Tinv),11 with morpholine the dr remained constant at
all temperatures.
46
Tinv = 53 °C
0.8
0.6
0.4
0.2
0
38
30
With morpholine as catalyst there is only one temperature do-
main with its activation parameters (DDHs and DD s), whereas
S
20
10
with O(TBS)-proline the presence of a Tinv in the Eyring plot de-
termines the existence of two temperature domains characterized
by two sets of activation parameters one for T>Tinv and one for
T<Tinv. Activation parameters were calculated according to Eq. 1
and reported in Table 3.
0.0026
0.0028
0.003
0.0032
1/T (K-1)
0.0034
0.0036
0.0038
In previous papers, we demonstrated that the presence of a Tinv
in temperature-dependent studies of enantio- and diaster-
eoselectivity depends on dynamic solvation effects.12 In our in-
terpretation, an Eyring plot featuring a Tinv is the result of two
Figure 1. Eyring plots of the diastereomeric ratios anti/syn in the aldol reaction be-
tween 3-pyridinecarbaldehyde and cyclohexanone catalyzed by morpholine (A) or
O(TBS)-proline (-).

E. Emer et al. / Tetrahedron 64 (2008) 11205–11208
11207
Table 3
which prevented the possibility of a data analysis via the Eyring
Eq. 1. It is known that organocatalyzed aldol reactions in water as
reaction solvent give poor results in terms of enantioselectivity
except for the use of a low amount of water.2 Our result strengthens
the hypothesis that a better enantioselectivity in organocatalyzed
aldol reaction could be achieved in an ‘on-water’ condition with the
reaction taking place at the interfacial hydrophobic region.14
Differential activation parameters
catalyst
DDHs
(kcal/mol)
DDSs
(cal/mol K)
Morpholine
O(TBS)-proline
ꢁ0.20ꢃ0.04
0.1ꢃ0.1
Tinv¼53 ꢀ
T>Tinv
T<Tinv
C
ꢁ4.3ꢃ0.2
ꢁ11.5ꢃ0.6
ꢁ0.4ꢃ0.1
ꢁ0.71ꢃ0.03
3. Conclusions
are obtained, moreover a low differential activation entropy di-
minished the effect of temperature. With O(TBS)-proline we have
to consider the two T domains: for T>Tinv the activation enthalpy
favours the anti isomer (a negative DDHs derives from
In conclusion, we have reported the first temperature study on an
aldol reaction catalyzed by morpholine or O(TBS)-proline with the
reactants, nicotinaldehydeand cyclohexanone, solubilized inwateras
the true reaction solvent. Treatment of data according to Eyring
equationallowedustocalculatethedifferentialactivationparameters
D
Hs
>D
Hsanti), whereas the negative value of activation entropy
syn
favours the syn one because a greater loss in activation entropy for
the anti isomer occurred (a negative DDSs derives from
DDHs and DD s. With morpholine we had a constant diaster-
S
j
D
Ssantij>j
D
Sssynj).11a This counteracting action of the two activa-
eoselectivity with temperature. With silyloxyproline we observed
a non-linear behaviour with the presence of an inversion tempera-
ture, which disclosed the presence of dynamic solvation effects in
water. Discussions on water-based organocatalysis contribute once
moretoabetterunderstandingoftheroleofwaterontheseprocesses.
tion parameters does not allow great dr values even if there is
a considerable temperature effect for T>Tinv essentially due to the
enthalpy factor.
One of the crucial arguments for the aldol reaction in water with
secondary amines as catalysts is that the reaction could proceed by
an enamine mechanism or by a base-catalyzed mechanism. In our
case, the nicotinaldehyde, which possesses the pyridine moiety,
could act itself as a catalyst. By mixing nicotinaldehyde and cyclo-
hexanone in water without a catalyst, the pH is 5.9 and the reaction
does not proceed in 24 h reaction time (Table 4, entry 1), thus ex-
cluding the hypothesis of autocatalysis by the aldehyde. In buffered
aqueous solution at pH 4.8 and 10.8 (the same pH values of the
organocatalyzed reaction with O(TBS)-proline and morpholine,
respectively) in the absence of an amine, the aldol reaction takes
place only at pH 10.8 but with a low diastereomeric ratio (cf. entries
2 and 3). In the morpholine catalyzed reaction the pH results at 10.8
and the conversion % and dr are quite similar to entry 3, thus
suggesting general base catalysis.13 With morpholine in buffered
solution at lower pHs the conversion is lower and the dr is only
slightly higher. In the proline-catalyzed reaction the pH is 4.8, the
reaction is slow but with an enhanced diastereomeric ratio (entry
8), whereas with buffered solutions at pH 6 and 4 (entries 9 and 10)
the dr decreases and at low pH the conversion is very low. The
temperature profile in Eyring plots and the pH profile indicate that
in unbuffered aqueous solution morpholine generates a basic pH
and the reaction has a general base catalysis by hydroxide ion,
whereas O(TBS)-proline proceeds by an enamine mechanism sub-
jected to temperature-dependent solvation effects.
4. Experimental section
4.1. General
TLC: Merck 60 F254. Column chromatography: Merck silica gel
200–300 mesh. FT-IR: Nicolet 205 measured as films or Nujol mull
between NaCl plates and reported in cmꢁ1. 1H and 13C NMR spectra
were obtained on a Varian INOVA 300 with a 5 mm probe. All
chemical shifts have been quoted relative to deuterated solvent
signals, d in parts per million, J in hertz. The anti and syn ratios were
determined by 1H NMR analysis of the crude and 64–128 scans were
collected for each experiment. After establishment of an equal T1
relaxation time, the resonance signals at 5.42 ppm (syn isomer) and
4.84 ppm (anti isomer) of the protons CH–OH were manually in-
tegrated. A standard deviation of 0.8% on the integrals was calcu-
lated.15 In the O(TBS)-proline-catalyzed reactions, the enantiomeric
ratio was determined by HPLC on a chiral stationary phase: Chiracel
OJ 25ꢂ0.46 isocratic elution 90:10 hexane–isopropanol, 0.5 ml/min.
To set and maintain temperature in the range of ꢃ1 ꢀC, a Techne
TE-10D Tempunit and Fison Haake K15 were used. trans-4-tert-
Butyldimethylsilyloxy-L-proline was prepared according to Ref. 2.
HPLC-MS: Agilent Technology HP1100, column ZOBRAX-Eclipse
XDB-C8 Agilent Technologies coupled with Agilent Technologies
MSD1100 single-quadrupole mass spectrometer, full-scan mode
from m/z 50 to 2600, scan time 0.1 s in positive ion mode, ESI spray
voltage 4500 V, nitrogen gas 35 psgi, drying gas flow 11.5 ml/min,
fragmentor voltage 20 V. The compounds were eluted with CH3CN/
H2O, gradient: from 30% to 80% of CH3CN in 8 min, then 80% of
CH3CN for 15 min.
We also analyzed the temperature dependence of the enantio-
meric excesses of the syn and anti isomers (Supplementary data). In
the aldol reaction catalyzed by O(TBS)-proline, the T dependence of
eeanti and eesyn is almost null. The enantiomeric ratios ranged from
0.8 to 2.4 (see Supplementary data) with a high level of scattering,
Table 4
4.2. General procedure for the organocatalyzed aldol reaction
Control of pH in the aldol reaction between 3-pyridinecarbaldehyde and
cyclohexanone
In a typical experiment, 5 ml of water (HPLC grade) was placed
in a 20 ml test tube equipped with screw-cap and magnetic bar. The
desired temperature was reached and kept constant by use of
a temperature control apparatus. Freshly distilled cyclohexanone
(1.2 mmol), catalyst (morpholine or O(TBS)-proline) (0.1 mmol)
and 3-pyridinecarbaldehyde (1.0 mmol) were added to the test
tube under constant stirring. After the time indicated in Tables 1
and 2, the reaction mixture was extracted with dichloromethane
(3ꢂ20 ml). The combined organic layers were dried over anhydrous
sodium sulfate. After removal of solvent, the crude was analyzed for
dr determination (1H NMR). The residue was purified by flash-
column chromatography on silica gel (cyclohexane/ethylacetate
Entry
Time (h)
T (ꢀC)
Catalyst 10%
Buffer
(20 mM)
pHa
Y (%)
1a/1b
1
2
3
4
5
6
7
8
9
10
24
1
1
1
1
1
1
12
12
24
45
50
50
50
50
55
50
50
50
50
d
d
5.9
4.8
10.8
10.8
6
7.5
8
4.8
6
d
d
57
47
2
13
14
15
14
4
d
d
Acetate
Carbonate
d
d
d
58:42
57:43
60:40
62:38
60:40
70:30
58:42
53:47
Morpholine
Morpholine
Morpholine
Morpholine
Proline
Proline
Proline
Phosphate
Phosphate
Borate
d
Phosphate
Citrate
4
a
pH was measured in the reaction tube.

11208
E. Emer et al. / Tetrahedron 64 (2008) 11205–11208
Weinheim, 2005; (c) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719–724; (d)
Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. C. Drug Discov. Today 2007,
12, 8–27; (e) Dalko, P. I. Enantioselective Organocatalysis; Wiley-VCH: Weinheim,
2007; (f) Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18,
2249–2293; (g) List, B. Chem. Rev. 2007, 107, 5413–5415; (h) Pellissier, H. Tet-
rahedron 2007, 63, 9267–9331; (i) Blackmond, D. G.; Armstrong, A.; Coombe, V.;
Wells, A. Angew. Chem., Int. Ed. 2007, 46, 3798–3800.
2. For a recent example of organocatalyzed aldol reaction in water, see: Aratake,
S.; Itoh, T.; Oakano, T.; Nagae, N.; Sumiya, T.; Shoji, M.; Hayashi, Y. Chem.dEur. J.
2007, 13, 10246–10256 and references cited therein.
3. (a) Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.; Sumiya, T.; Shoji, M.
Angew. Chem., Int. Ed. 2006, 45, 5527–5529; (b) Huang, J.; Zhang, X.; Arm-
strong, D. W. Angew. Chem., Int. Ed. 2007, 46, 9073–9077; (c) Luo, S.; Xu, H.; Li,
J.; Zhang, L.; Mi, X.; Zhenga, X.; Chenga, J.-P. Tetrahedron 2007, 63, 11307–
11314.
4. (a) Berardi, R.; Cainelli, G.; Galletti, P.; Giacomini, D.; Gualandi, A.; Muccioli, L.;
Zannoni, C. J. Am. Chem. Soc. 2005, 127, 10699–10706; (b) Cainelli, G.; Galletti, P.;
Giacomini, D.; Gualandi, A.; Quintavalla, A. Tetrahedron 2005, 61, 69–75.
5. Cainelli, G.; Giacomini, D.; Galletti, P.; Quintavalla, A. Eur. J. Org. Chem. 2002, 18,
3153–3161.
85:15) to give the mixture of the two aldols 1a anti and 1b syn,
which was analyzed by HPLC for determination of enantiomeric
ratios. The compounds 1a and 1b are known products,8 however
their spectra were never reported.
nmax: 3387, 2937, 2858, 1709 cmꢁ1
.
HPLC/ESI-MS: (tR 2.89 min.): 206.1 [MþH]þ, 228.1 [MþNa]þ,
433.1 [2 MþNa]þ.
Compound 1b (syn): 1H NMR (300 MHz, CDCl3)
d 1.49–2.13 (6H,
m), 2.31–2.52 (2H, m, CH2), 2.58–2.66 (1H, m, CH), 4.13 (1H, br s,
OH), 5.42 (1H, s, CHOH), 7.25–7.31 (1H, m, arom), 7.68–7.71 (1H, m,
arom), 8.48–8.54 (2H, m, arom).
13C NMR (75 MHz, CDCl3):
d 24.8, 27.7, 30.7, 42.6, 56.8, 68.9,
123.2, 133.8, 136.9, 147.5, 148.4, 214.3.
Compound 1a (anti): 1H NMR (300 MHz, CDCl3)
d 1.49–2.13 (6H,
m), 2.31–2.52 (2H, m, CH2), 2.58–2.66 (1H, m, CH), 3.30 (1H, br s,
OH), 4.84 (1H, d, J¼8.7 Hz, CHOH), 7.25–7.31 (1H, m, arom), 7.68–
7.71 (1H, m, arom), 8.48–8.54 (2H, m, arom).
6. Cainelli, G.; Galletti, P.; Giacomini, D.; Orioli, P. Tetrahedron Lett. 2001, 42, 7383–
7385.
7. For what concerns the ‘in-water/on-water’ debate, see: (a) Brogan, A. P.;
Dickerson, T. J.; Janda, K. D. Angew. Chem., Int. Ed. 2006, 45, 8100–8102 and
references cited therein; (b) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 8103–
8104 and references cited therein.
13C NMR (75 MHz, CDCl3)
d 24.6, 27.7, 30.9, 42.6, 57.1, 72.6, 123.5,
134.5, 136.4, 148.8, 149.3, 215.1.
8. (a) Wang, Y.; Wei, S.; Sun, J. Synlett 2006, 3319–3323; (b) Cheng, C.; Wei, S.; Sun,
J. Synlett 2006, 2419–2422; (c) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org.
Lett. 2006, 8, 4417–4420.
Acknowledgements
9. Eyring, H. J. Chem. Phys. 1935, 3, 107–115.
The authors are very grateful to Prof. Gianfranco Cainelli for
fruitful discussions, suggestions, and his enthusiasm. This work was
supported by MIUR and University of Bologna.
10. (a) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H. Y.; Houk, K. N. Acc.
Chem. Res. 2004, 37, 558–569; (b) Clemente, F.; Houk, K. N. Angew. Chem., Int. Ed.
2004, 43, 5766–5768; (c) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am.
Chem. Soc. 2003, 125, 16–17.
11. (a) Cainelli, G.; Giacomini, D.; Galletti, P. Chem. Commun. 1999, 567–572; (b)
Buschmann, H.; Scharf, H.-D.; Hoffmann, N.; Esser, P. Angew. Chem., Int. Ed. Engl.
1991, 30, 477–515.
12. (a) Cainelli, G.; Galletti, P.; Pieraccini, S.; Quintavalla, A.; Giacomini, D.; Spada,
G. P. Chirality 2004, 16, 50–56; (b) Cainelli, G.; Galletti, P.; Giacomini, D.; Gua-
landi, A.; Quintavalla, A. Helv. Chim. Acta 2003, 86, 3548–3559; (c) Cainelli, G.;
Giacomini, D.; Galletti, P.; Orioli, P. Angew. Chem., Int. Ed. 2000, 39, 523–527; (d)
Cainelli, G.; Giacomini, D.; Galletti, P.; Marini, A. Angew. Chem., Int. Ed. 1996, 35,
2849–2852.
Supplementary data
Supplementary data contains: 1H NMR and 13C NMR spectra of
1a and 1b. HPLC analysis for the determination of enantiomeric
ratios and their temperature dependence. Supplementary data
associated with this article can be found in the online version, at
doi:10.1016/j.tet.2008.09.059.
13. Chimni, S. S.; Mahajan, D. Tetrahedron 2005, 61, 5019–5025; Dickerson, T. J.;
Janda, K. D. J. Am. Chem. Soc. 2002, 124, 3220–3221; Reymond, J.-L.; Chen, Y.
J. Org. Chem. 1995, 60, 6970–6979.
References and notes
14. Zotova, N.; Franzke, A.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2007,
129, 15100–15101.
15. Deubner, R.; Holzgrabe, U. Magn. Reson. Chem. 2002, 40, 762–766.
1. For recent reviews see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43,
5138–5175; (b) Berkssel, A.; Gro¨ger, H. Asymmetric Organocatalysis; Wiley-VCH: