A new class of chiral pyrrolidine for asymmetric Michael addition reactions. New mechanism via simple 4+2 type attack of the enamine on the trans-nitrostyrene

Article abstract of DOI:10.1016/j.tet.2006.10.083

A new chiral organocatalyst is described in this paper. A new mechanism for the overall Michael condensation of ketones with nitroolefins using our catalyst is suggested based on molecular modelling studies.

Full text of DOI:10.1016/j.tet.2006.10.083

Tetrahedron 63 (2007) 740–747
A new class of chiral pyrrolidine for asymmetric Michael addition
reactions. New mechanism via simple 4D2 type attack of the
enamine on the trans-nitrostyrene
a
a
a
a
a
David Diez,a, M. Jose Gil, Rosalina F. Moro, Isidro S. Marcos, P. Garcıa, P. Basabe,
*
ꢀ
Narciso M. Garrido,a Howard B. Broughtonb, and J. G. Urones
*
a
aDepartamento de Quꢀımica Orgaꢀnica, Facultad de Ciencias Quꢀımicas, Universidad de Salamanca,
Plaza de los Caꢀıdos 1-5, 37008 Salamanca, Spain
bLilly S.A., Avda de la Industria 30, 28108 Madrid, Spain
Received 25 September 2006; revised 24 October 2006; accepted 29 October 2006
Available online 15 November 2006
Abstract—A new chiral organocatalyst is described in this paper. A new mechanism for the overall Michael condensation of ketones with
nitroolefins using our catalyst is suggested based on molecular modelling studies.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
have been designed as potential new catalysts for these types
of reaction.12 In the last few years there has been enormous
interest in Michael addition using an organic catalyst.13
Some molecules derived from proline, which have been
used as catalysts to promote addition to nitrostyrenes, can
be seen in Figure 1. Apart from proline, 1, Ley’s analogues
2–414 have been used in the addition of cyclohexanone to
trans-b-nitrostyrene; these replace the carboxylic acid of
the proline by a tetrazole or an acyl sulfonamide. Similarly,
some diamines have been found to work as catalysts, such
as the one described by Barbas, 5,15 or that of Alexakis,
6,16 which have been used in the same reaction. Recently,
Wang has used catalyst 7,17 not only in this reaction but
also in other reactions such as a-sulfenylations,18 a-selenyl-
ations19 and other reactions.20 Recently, catalysts 8 and 9
Numerous new methodologies in asymmetric synthesis have
been developed by chemists over the last few years.1 Re-
cently, there has been enormous interest in the use of small
organic molecules as catalysts instead of using asymmetric
catalysts containing metals. Enantioselective organocataly-
sis using a chiral organic molecule is emerging as a powerful
tool.2 An enantioselective organocatalytic system that has
been studied extensively3 is based on proline, and has been
found to accelerate a range of transformations such as aldol
reactions,4 Robinson annelations,5 Mannich reactions,6
conjugate additions,7 a-aminations,8 a-aminooxylations,9
a-alkylations10 and other reactions.11 In order to improve
the catalysts’ profile many diamines and proline analogues
N
O
COOH
N
H
N
H
N
N
H
N
N
H
C10H21
C10H21
H
N
HN
N
N
NHSO2Ph
N
HN
1
2
3
4
5
N
TBSO
Ph
N
H
N
H
N
H
N
Ph
N
COOH
H
N
H
NHSO2CF3
OH
N
6
7
8
9
10
Figure 1. Organocatalysts used in the Michael addition of cyclohexanone to trans-b-nitrostyrene.
Keywords: Organocatalysis; Proline; Pyrrolidines; Michael addition; Transition state; DFT; Cycloaddition 4+2.
* Corresponding authors. Fax: +34 923 294574 (D.D.); tel.: +34 91 6233337; fax: +34 91 6633411 (H.B.B.); e-mail addresses: ddm@usal.es;
broughton_howard@lilly.com
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.083

D. Diez et al. / Tetrahedron 63 (2007) 740–747
741
have been used by Hayashi et al.21 in the Michael addition of
cyclohexanone to trans-b-nitrostyrene, and Kotsuki et al.
have developed catalyst 10.22
transition state corresponding to the desired bond formation
had been found. As in Wang’s work, a water molecule was
included in the calculation, though we were concerned that
the presence of this water molecule would place a significant
cost on the ternary transition state that was not fully taken
into account in the relative energy calculations (particularly
since the third molecule in the transition-state model was not
the solvent). In the gas phase, the transition states showed
that the B3LYP/6-31G* transition-state energies of the si
and re attacks were as shown in Table 1.
2. Results and discussion
These results prompted us to communicate our observations
in this area. As can be seen, all the above catalysts are either
monosubstituted in the pyrrolidine ring or disubstituted with
a single protected hydroxyl group substituent. It is known
that a subtle change in the functionalization of the core struc-
ture can improve the activity of the catalyst, so we decided to
synthesize a catalyst with two hydroxyl groups at positions
3 and 4 of the pyrrolidine ring protected via a cyclic protect-
ing group. The synthesis of catalyst 14 was achieved as
shown in Scheme 1.
While the energy difference is in the correct direction,
favouring re attack, it is perhaps rather smaller than that
might be desired.
The transition-state complexes were, therefore, subjected to
transition-state geometry optimization calculations with
vibrational frequency calculation using a Jaguar model for
solvation (in chloroform, dielectric constant 4.806, density
1.489 g/mL) to test the hypothesis that the energy difference
would be more marked in the presence of solvent. This
method was unable to locate a true saddle point, even
when input conformations were obtained by stepwise varia-
tion of the length of the newly forming bond from 1.95 to
Epoxide 11 has been previously obtained by us in a simple
way from easily available starting materials.23 Our catalyst,
14, was obtained in good yield using the reactions shown in
Scheme 1.
The rationale behind our choice of the isopropylidene
protected system was based on the observation that the cata-
lysts shown in Figure 1 showed variability in the reaction of
cyclohexanone with trans-b-nitrostyrene, low yields being
obtained in many cases. Recently, the reaction of cyclohexa-
none and trans-b-nitrostyrene has been reported with Wang’s
˚
˚
2.25 A (in 0.02 A steps), and the energy maximum on that
coordinate was used as the starting point for any one of the
transition-state search algorithms available in Jaguar. Invari-
ably, transition states for other processes were found. It may
be that our catalyst prefers a mechanism different from that
suggested by Wang for 7 that the nature of the substrate (cy-
clohexanone in our case, rather than an acyclic ketone as in
Wang’s work) affects the mechanistic preference, or it may
be that the use of chloroform as solvent changes the pre-
ferred transition state, as such a nonpolar solvent would
not favour the development of separation of charges required
by simple Michael attack of the enamine on the nitroolefin. It
is also possible that the differences in the Gaussian solvent
model used by Wang and that used in Jaguar may account
for the difference. In subsequent studies, we also compared
6-31G* with larger basis sets, but found no significant qual-
itative difference in our findings (only the results for the larg-
est basis set tried are reported below).
i
catalyst in PrOH.24 Therefore, we decided to increase the
solubility of the catalyst in nonpolar solvents by adding
more functionality to the pyrrolidine ring, while maintaining
the acidity of the sulfonamide and additionally rigidifying
somewhat the core of the catalyst. In order to see what differ-
ences and possible advantages our catalyst 14 might have, we
decided to do a comparative molecular modelling study with
Wang’s catalyst, 7.
Two approaches were used. In the first, Wang’s published
transition states24 for a ketone–enamine formed with 7 and
pentan-3-one in the reaction with nitrostyrene from the si
or re face, were imported into Sybyl v. 7.1 (Tripos, Inc.,
St. Louis, MO), modified to provide the equivalent com-
plexes with our catalyst 14 as the cyclohexanone enamine
derivatives, and subjected to constrained optimization using
Jaguar v. 6.5 (Schrodinger LLC, New York, NY) (B3LYP/
631G* DFT) with the distance between the atoms of the
newly forming bond maintained constant. The resulting
structures were then subjected to a standard transition-state
optimization without constraints, and then Hessian matrix
and vibrational modes were examined (only one negative
vibrational frequency with absolute value >20 cmꢀ1 corre-
sponds to a stretch of the new bond) to confirm that a true
Table 1. Computed energies of Wang-type transition-state complexes for
the reaction of 14 with nitrostyrene and cyclohexanone
Stereochemistry of attack
si
re
SCF energy (hartrees)
Zero point energy (kcal/mol)
Gibbs free energy Gtot298
(hartrees)
ꢀ2284.00900
348.1
ꢀ2283.5224
ꢀ2284.01296
347.8
ꢀ2283.5269
Free energy relative to
minimum (kcal/mol)
2.8
0
O
O
O
O
O
O
O
O
b
c
a
O
TsO
N
N
H
N
Bn
13
Bn
12
NBnSO2CF3
NHSO2CF3
SO2Ph
NHBn
11
14
Scheme 1. Synthesis of catalyst 14. Reagents and conditions: (a) (1) BnNH2, MeOH, reflux; (2) NaBH4, MeOH, 0 ꢁC, 65%; (b) Tf2O, Et3N, CH2Cl2, 0 ꢁC, 60%;
(c) H2, Pd(OH)2/C, MeOH, rt, 90%.

742
D. Diez et al. / Tetrahedron 63 (2007) 740–747
Given the uncertainty in predictions that arose from the
above models and our concern over the ternary transition
state proposed by Wang, we sought to find other possible
transition states that might obviate this requirement and
give us results that were always consistent with the experi-
mentally observed products.
where applicable searching was constrained to the lowest
bond-stretch mode) and modelling the effect of solvent,
greater accuracy in the SCF and/or using Hessian refinement
on the first three low-frequency modes, no suitable transition
states were identified. This is presumably why the water
molecule was found to be necessary in the Wang transi-
tion-state models. However, geometry optimization starting
from structures obtained from the above bond-length scan-
ning study on the ‘product’ side of the local maximum
gave rise directly, in most cases, to an unexpected interme-
diate, of the type shown in Figure 3.
We studied the process for the addition of the enamine
derived from 14 and cyclohexanone to nitrostyrene, consid-
ering all eight possible approaches and generating initial
geometries with force field methods to optimize all but the
length of the newly forming bond, which was constrained
to 2 A (Fig. 2).
It is known25 that such cyclic intermediates can be isolated
where the nitroolefin is a-substituted, but not otherwise, in
which case the ‘Michael adduct’ is the main observed prod-
uct. This could be either because the mechanism is indeed
simple Michael addition (particularly in more polar media),
or because the cycloadduct breaks down rapidly where there
is no a substituent. Such intermediates have been proposed
previously26 in cases where there is a high level of stereocon-
trol in the addition of a nitroolefin to an enamine, and also in
cases where they could not be isolated but were presumed to
break down subsequently under the reaction conditions to
give the observed products. In our case, these intermediates
could be additionally stabilized by the presence of a possible
hydrogen bond between the nitro group and the sulfonamide,
and this would be expected if anything to increase the prob-
ability that they participate in the reaction process. We,
therefore, felt that it would be valuable to demonstrate
that, at least, the presence of this hypothetical intermediate
at a critical point on the reaction path would be consistent
with observations, even if we could not prove this to be
the case unequivocally. Thus, we attempted to find similar
structures derived from each possible approach of the
reactants to see whether the experimental stereochemical
outcome of the reaction was consistent with such transition-
state-like intermediates.
˚
Thus, each putative global minimum energy conformation
found was subjected to geometry optimization, using Jaguar
(version 6.5) with B3LYP/6-31G** DFT, by scanning the
bond length of the newly formed bond between 2.20 and
˚
˚
1.45 A in 0.05 A steps. By this means all but one of the pos-
sible approaches (the approach from the lower face—the
face opposite the sulfonamide—giving rise to the R,R prod-
uct) were found to show an apparent local maximum with the
˚
bond length of the newly formed bond around 2.00 A, as ex-
pected. The bottom-face approach to give the R,R product
showed just a monotonic increase in energy as the distance
between the putative reacting centres was reduced.
Attempts were made to locate a transition state using the
quadratic synchronous transit method available in Jaguar,
using the same basis set as before and choosing the local en-
ergy maximum encountered in the earlier study as a model
for the transition state and points on the bond-length scan
either side of this maximum as models for the ‘reactant’
and ‘product’. However, despite extensive attempts to find
a good transition state with just one negative vibrational fre-
quency, including the use of alternate transition-state search
routines (the ‘standard’ method and the linear synchronous
transit method implemented in Jaguar were both tried, and
Each starting structure was obtained by minimal adjustment
in Maestro (v. 7.5.106; Schrodinger LLC, New York, NY) of
the structures previously obtained by DFT minimization of
the product-side bond scan study structures to the topology
of the structures in Figure 3, followed by appropriate molec-
ular mechanics conformational exploration and geometry
pre-optimization. All the low-lying structures were then re-
optimized with the B3LYP/6-31G** DFT using accurate
SCF criteria and a solvent model for CHCl3 (dielectric
4.806, density 1.489 g/mL). Further structures were gener-
ated in which alternate ring-flip conformations were studied,
and, given the possible anomeric effect at the carbon bearing
both nitrogen and oxygen substituents, both the axial-oxy-
gen and axial-nitrogen ring-flips were tried.
NO2
Ph
NO
2 N
Ph
N
F3CO2S
F3CO2S NH
NH
O
O
O
O
Anti–enamine, lower face, phenyl- Syn-enamine, upper face,
endo attack phenyl-exo attack
Figure 2. Two representative approaches of the eight possibilities consid-
ered for the attack of nitrostyrene on the cyclohexanone-derived enamine
(syn or anti enamine rotamer, upper or lower face attack, phenyl endo
or exo).
Ph
Ph
H
H
R
S
R
S
N+
N+
O
-O
HN
-O
HN
O
N
N
SO CF
2
SO CF
2 3
3
O
O
O
O
Figure 3. Left panel, S,R potential intermediate; right panel, R,S potential intermediate.

D. Diez et al. / Tetrahedron 63 (2007) 740–747
743
Table 4. Solvent effect on the asymmetric Michael addition of cyclohexa-
none to trans-b-nitrostyrene
While in principle the Diels–Alder type process giving rise
to this intermediate could (especially if not fully concerted25
and partially reversible, as has been proposed previously27)
give rise to any of the possible four diastereoisomeric prod-
ucts (ignoring the stereocentre at the hemiaminal centre,
which would be lost, e.g., on in situ hydrolysis or on
workup), the most likely transition-state-like intermediates
based on accessible reactant conformations and the energies
observed for the intermediates were those shown in Figure 3,
giving rise to the R,S or S,R stereochemistry in the final prod-
uct. These more promising candidates were subjected to a
DFT geometry optimization study at the B3LYP/6-311G**+
level. The lower energy associated with the S,R intermediate
(left panel, Fig. 3) is consistent with the observed preference
for the S,R product (Tables 2 and 3). Neither putative inter-
mediate showed any negative vibrational frequencies after
optimization in either the gas phase or solvated model, con-
firming that these were intermediates and not transition-state
structures.
Ph
O
O
NO2
NO2
Catalyst 14, (15%)
+
RT, solvent
15
Ph
Entrya
Solvent
Yield (%)b
dr (%)c
ee (%)d
1
2
3
4
5
6
DMSO
iPrOH
CH2Cl2
CHCl3
CH3CN
THF
41
24
10
96
5
>95
>95
>95
94
>95
>95
82
84
80
90
18
0
5
a
For experimental conditions see Section 3.
Yield of the isolated product.
b
c
d
Determined by 1H NMR spectroscopic analysis.
Determined by chiral high-performance liquid chromatography (HPLC)
analysis (Chiralpak OD-H).
a remarkable selectivity for this solvent being observed,
while the yields in more polar solvents such as DMSO or
iPrOH are moderate and in less polar solvents such as THF
are very low. Chloroform is the solvent of choice as it gives
the best yield with very good diastereo- and enantioselectiv-
ity (Table 4, entry 4); this contrasts sharply with Wang’s
If this intermediate is used to serve as a model for the tran-
sition state, the energy difference would be sufficient to ac-
count for the significant preference for the S,R product. It is
also worth noting that the energetic favourability of the S,R
intermediate was found consistently at every level of calcu-
lation tried, from molecular mechanics with MMFF94s to
small basis set DFT, through the calculations described in
detail here, with or without solvent model. The formation
of a cyclic intermediate might also help to explain why the
diastereoisomeric ratios were so good.
i
catalyst where the yields and ees in PrOH are superior to
those in CHCl3, and may support the idea of a change of
mechanism.
With the optimal conditions in hand, we probed the scope of
the reaction with a variety of nitroolefins and ketones in the
presence of 15% of catalyst 14, using chloroform as solvent
at room temperature (20 ꢁC) obtaining yields that vary from
no reaction to high yields showing in all cases good dia-
stereo- and enantioselectivity (Table 5).
As can be seen, the axial-oxygen double-boat arrangements
were those that have the lowest energy and were the most
consistent with possible reaction mechanisms, arising via
simple 4+2 type attack of the enamine on the trans-nitrostyr-
ene in a concerted or near-concerted way, consistent with the
nonpolar media that gave the best experimental results (see
below). The boat has been identified as an important transi-
tion-state geometry of Diels–Alder reactions.28
In conclusion, a new type of catalyst can be added to the va-
riety of organocatalysts for asymmetric ‘Michael addition’
to nitroolefins, demonstrating a highly competitive profile
in terms of convenience, stereoselectivity and yield. In this
case the availability of extra functionality opens the way
for further functionalization in order to increase the effi-
ciency and selectivity in this kind of reaction. A detailed mo-
lecular modelling study, which led to the proposal of a new
mechanism, via simple 4+2 type attack of the enamine on the
trans-nitrostyrene, is included. Further studies, in order to
extend the scope of this catalyst are in progress.
We investigated experimentally, in some detail, the influence
of the solvent in the ‘Michael addition’ of cyclohexanone to
trans-b-nitrostyrene. As can be seen in Table 4, the reaction
yields varied significantly in the solvents tested. It can be
appreciated that chloroform is the solvent of choice,
Table 2. Energies of the putative intermediates in gas phase
Stereochemistry
S,R
R,S
3. Experimental section
3.1. General
SCF energy (hartrees)
Zero point energy (kcal/mol)
Gibbs free energy Gtot298
Free energy relative to minimum
(kcal/mol)
ꢀ2208.1574
331.8
ꢀ2207.6927
ꢀ2208.1435
331.2
ꢀ2207.6816
0
7.0
Unless otherwise stated, all chemicals were purchased,
which have highest purity and commercially available, and
were used without further purification. Melting points are un-
corrected. 1H and 13C NMR spectra were recorded at 200/400
and 50/75 MHz, respectively. The spectra were performed in
CDCl3 and referenced to the residual peak of CHCl3 at 7.26
and 77.0 ppm, for 1H and 13C, respectively. Chemical shifts
are reported in parts per million and coupling constants (J)
are given in hertz. Diethyl ether, THF and benzene were dis-
tilled from sodium, and pyridine and dichloromethane were
distilled under argon from CaH2.
Table 3. Energies of the putative intermediates with solvent model for
CHCl3
Stereochemistry
S,R
R,S
SCF energy (hartrees)
Zero point energy (kcal/mol)
Gibbs free energy Gtot298
Free energy relative to minimum
(kcal/mol)
ꢀ2208.1774
350.1
ꢀ2207.6839
ꢀ2208.1674
350.3
ꢀ2207.6734
0
6.7

744
D. Diez et al. / Tetrahedron 63 (2007) 740–747
Table 5. Catalytic asymmetric Michael addition of ketones to different
trans-b-nitrostyrenes catalyzed by 14
3.2. (2R,3S,4R)-N-Benzyl-2-[(benzylamin(e)methyl]-3,4-
isopropylidenedioxy-pyrrolidine (12)
Ar
O
O
NO2
NO2
Catalyst 14, (15%)
To a solution of epoxysulfone 11 (700 mg, 1.49 mmol) in
15 mL of MeOH was added benzylamine (0.81 mL,
7.44 mmol). The mixture was heated under reflux for 12 h
and then cooled to 0 ꢁC and 56 mg (1.50 mmol) of NaBH4
was added. The reaction mixture was stirred for 30 min at
0 ꢁC. After that the mixture was diluted with 1 mL of water
and extracted with EtOAc. The combined organic layers
were washed with water and brine, and then dried over
Na2SO4. The resulting residue was then purified by chroma-
tography on silica gel (n-hexane/EtOAc, 1/1) to provide di-
amine 12 (341 mg, 65%). [a]2D0 ꢀ106.4 (c 1.10 in CHCl3);
R1
R1
+
RT, CHCl3
R2
R2
Ar
Entrya
Yield (%)b
dr (%)c
ee (%)d
NO2
NO2
O
1
2
46
>95
81
16
1
IR (film) n: 2934, 2793, 1495, 1454, 1379, 1208, 1153; H
OMe
NO2
NMR (400 MHz, CDCl3): d¼7.34–7.25 (m, 10H, Ph), 4.66
O
O
O
3
4
62
>95
25
(dd, J(H,H)¼5.2 Hz, J(H,H)¼6.6 Hz, 1H, CH), 4.56 (dd,
4J(H,H)¼4.4 Hz, 3J(H,H)¼6.6 Hz, 1H, CH), 3.97 (d,
100
17
J(H,H)¼13.6 Hz, 1H, CH2), 3.85 (s, 2H, CH2), 3.20 (d,
0
100
J(H,H)¼13.6 Hz, 1H, CH2), 3.02 (d, 1 J(H,H)¼11.4 Hz,
5
O
1H, CH2), 2.97 (d,0 J(H,H)¼11.0 Hz, 1H, CH2), 2.82 (dd,
4J(H,H)¼4.4 Hz, 1 J(H,H)¼11.4 Hz, 1H, CH2), 2.40 (m,
1H, CH), 2.03 (dd, 4J(H,H)¼4.4 Hz, 5J(H,H)¼11.0 Hz,
1H, CH2), 1.50 (s, 3H, CH3), 1.31 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3): d¼140.6, 138.7, 128.8, 128.6, 128.4,
128.3, 127.1, 111.5, 81.1, 78.3, 67.5, 59.6, 57.5, 54.6, 47.8,
26.5, 25.8; EIMS m/z (%) 352 (M++1, 100), 232 (80), 158
(15), 91 (100); HRMS (EI) m/z calculated for C22H28N2O2:
352.2151 (M+); found: 352.2163.
NO2
NO2
3
4
60
45
>95
>95
82
65
18
S
19
3.3. (2R,3S,4R)-N-Benzyl-2-[(benzyl-trifluoromethane-
sulfonylamino)methyl]-3,4-isopropylidenedioxy-pyrrol-
idine (13)
CF3
NO2
O
5
42
70
>95
>95
94
86
20
To a solution of 341 mg (0.97 mmol) of diamine 12 and TEA
(0.162 mL, 1.16 mmol) in 5 mL of CH2Cl2 at 0 ꢁC was added
dropwise (via syringe) trifluoromethanesulfonic anhydride
(0.174 mL, 1.06 mmol). The resulting solution was stirred
for 5 h at room temperature, then diluted with 20 mL of
CH2Cl2 and washed with HCl (1 M) aqueous solution. The
organic layer was dried over Na2SO4 and concentrated in
vacuo. Flash chromatography (n-hexane/EtOAc, 9/1) af-
forded a colourless oil, 13, in 60% yield (281 mg). [a]D20
ꢀ29.5 (c 0.90 in CHCl3); IR (film) n: 2950, 2654, 1450,
1389, 1310, 1100, 980; 1H NMR (400 MHz, CDCl3):
d¼7.44–7.20 (m, 10H, Ph), 4.67 (d, 4J(H,H)¼10.6 Hz,
1H, CH), 4.58 (dd, 3J(H,H)¼10.6 Hz, 4J(H,H)¼4.6 Hz, 1H,
Br
O
O
6
7
NO2
NO2
21
Ph
65
45
>95
>95
n.d.
94
O
O
22
100
Ph
CH), 4.42 (m, 2H,0 CH2), 3.98 (d, J(H,H)¼13.8 Hz,
NO2
1H, CH2), 3.69 (dd, 3 J(H,H)¼14.9, 3.0 Hz, 1H, CH2), 3.61
8
9
0
00
(d, 3 J(H,H)¼14.9 Hz, 1H, CH2), 3.12 (d, 1 J(H,H)¼13.8 Hz,
1H, CH2), 3.01 (d, 5J(H,H)¼11.4 Hz, 1H, CH2), 2.54 (m, 1H,
CH), 2.03 (dd, 4J(H,H)¼4.6 Hz, 5J(H,H)¼11.4 Hz, 1H,
CH2), 1.45 (s, 3H, CH3), 1.32 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3): d¼138.1, 135.1, 128.6, 128.2, 126.9,
111.4, 79.6, 78.0, 67.5, 59.4, 57.2, 53.4, 45.2, 26.2, 25.5;
HRMS (EI) m/z calculated for C23H28N2O4F3S: 485.1722
(M++1); found: 485.1735.
23
S
O
Ph
NO2
68
65
—
20
84
H
H
24
O
Ph
NO2
10
>95
25
3.4. (2R,3S,4R)-2-(Trifluoromethanesulfonylamino)-
methyl-3,4-isopropylidenedioxy-pyrrolidine (14)
a
For experimental conditions see Section 3.
Yield of the isolated product.
b
c
d
Determined by 1H NMR spectroscopic analysis.
A solution of 281 mg (0.58 mmol) of triflate 13 in 6 mL of
MeOH was hydrogenated in the presence of a catalytic
Determined by chiral high-performance liquid chromatography (HPLC)
analysis (Daicel Chiralpak AD).

D. Diez et al. / Tetrahedron 63 (2007) 740–747
745
amount of 20% Pd(OH)2/C with a H2 balloon at room temper-
ature for 16 h. The catalyst was filtered through a pad of
CeliteÒ and washed with MeOH. The product was purified
by flash chromatography (n-hexane/EtOAc, 1/1) to give
156 mg (90%) of compound 14. [a]2D0 ꢀ15.6 (c 0.80 in
CHCl3); IR (film) n: 2964, 1627, 1453, 1375, 1189, 1068;
1H NMR (400 MHz, CDCl3): d¼4.86 (br s, 1H, NH), 4.73
3.5.4. (2S,10R)-2-[20-Nitro-10-(o-furanyl)-ethyl]-cyclohex-
anone (18). Purified using flash column chromatography
(n-hexane/EtOAc, 9/1) to give the title compound as a white
solid (60%). 1H NMR (200 MHz, CDCl3): d¼7.29–6.17 (m,
CH2), 4.65 (dd, 2 J(H,H)¼12.5, 9.3 Hz, 1H, CH2), 3.98 (m,
1H, CH), 2.67 (m, 1H, CH), 2.50–1.31 (m, 8H, 4CH2).
HPLC: Daicel Chiralpak AD; hexane/iPrOH: 0.45 mL
minꢀ1; 230 nm: tR (major)¼10.3 min; tR (minor)¼12.3 min.
0
0
3H, Ar), 4.70 (dd, 2 J(H,H)¼12.5 Hz, 1 J(H,H)¼9.3 Hz, 1H,
0
3
5
(dd, J(H,H)¼5.4 Hz, J(H,H)¼4.0 Hz, 1H, CH), 4.64 (dd,
4J(H,H)¼5.4 Hz, 3J(H,H)¼4.2 Hz, 1H, CH), 3.67 (dd,
5J(H,H)¼14.2 Hz, 2J(H,H)¼4.0 Hz, 1H, CH2), 3.45 (dd,
0
5J(H,H)¼14.2, 8.0 Hz, 1H, CH2), 3.18 (d, 1 J(H,H)¼
3.5.5. (2S,10R)-2-[20-Nitro-10-(o-thiophenyl)-ethyl]-cyclo-
hexanone (19). Purified using flash column chromatography
(n-hexane/EtOAc, 8/2) to give the title compound as a white
solid (45%). 1H NMR (200 MHz, CDCl3): d¼7.21–6.87 (m,
10
13.6 Hz, 1H, CH2), 3.04 (m, 1H, CH), 2.74 (dd, J(H,H)¼
2
13.6 Hz, J(H,H)¼4.0 Hz, 1H, CH2), 1.47 (s, 3H, CH3),
1.31 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): d¼111.7,
81.4, 81.1, 62.9, 52.3, 43.4, 25.8, 23.8; HRMS (EI) m/z calcu-
lated for C9H16N2O4F3S: 305.0777 (M++1); found:
305.0764.
0
0
3H, Ar), 4.89 (dd, 02 J(H,H)¼12.6 Hz, 1 J(H,H)¼4.8 Hz, 1H,
0
CH2), 4.67 (dd, 2 J(H,H)¼12.6 Hz, 1 J(H,H)¼9.3 Hz, 1H,
CH2), 4.15 (m, 1H, CH), 2.71 (m, 1H, CH), 2.58–1.35 (m,
8H, 4CH2). HPLC: Daicel Chiralpak AD; hexane/iPrOH:
0.45 mL minꢀ1; 230 nm: tR (major)¼14.9 min; tR (minor)¼
13.1 min.
3.5. Typical procedure for Michael addition reaction
To a suspension of catalyst 14 (10 mg, 15%) and 0.438 mL
(4.40 mmol) of cyclohexanone in 3.5 mL of CHCl3 was
added 33 mg (0.22 mmol) of trans-b-nitrostyrene. The re-
sulting mixture was allowed to stir at room temperature for
16 h, whereupon the reaction was quenched with saturated
aqueous ammonium chloride (2 mL) and the aqueous layers
were extracted with ethyl acetate. The combined organic
layers were dried over Na2SO4, filtered and evaporated in va-
cuo and the resulting residue was purified by flash column
chromatography using ethyl acetate/hexane.
3.5.6. (2S,10R)-2-[20-Nitro-10-(o-trifluoromethylphenyl)-
ethyl]-cyclohexanone (20). Purified using flash column
chromatography (n-hexane/EtOAc, 6/4) to give the title com-
pound as a white solid (42%). 1H NMR (200 MHz, CDCl3):
0
d¼7.70–7.39 (m, 4H, Ph), 4.98 (dd, 2 J(H,H)¼12.5 Hz,
0
0
1 J(H,H)¼4.5 Hz, 1H, CH2), 4.76 (dd, 2 J(H,H)¼12.5,
9.9 Hz, 1H, CH2), 4.03 (m, 1H, CH), 2.70 (m, 1H, CH),
2.50–1.26 (m, 8H, 4CH2). HPLC: Daicel Chiralpak AD; hex-
ane/iPrOH: 0.45 mL minꢀ1; 230 nm: tR (minor)¼6.8 min;
tR (major)¼9.7 min.
Compounds 15,29 16,14a 17,22 18,14a 19,22 20,14a 21,30 22,14a
23,7a 2431 and 2532 are known.
3.5.7. (2S,10R)-2-[20-Nitro-10-(p-bromophenyl)-20-nitro-
ethyl]-cyclohexanone (21). Purified using flash column
chromatography (n-hexane/EtOAc, 7/3) to give the title com-
3.5.1. (2S,10R)-2-[10-Phenyl-20-nitro-ethyl]-cyclohexan-
one (15). Purified using flash column chromatography
(n-hexane/EtOAc, 9/1) to give the title compound as a white
solid (96%); 1H NMR (200 MHz, CDCl3): d¼7.34–7.16 (m,
pound as a yellow solid (70%). 1H NMR (200 MHz, CDCl3):
0
d¼7.62–7.03 (m, 4H, Ph), 4.95 (dd, 2 J(H,H)¼4.6 Hz,
0
0
1 J(H,H)¼12.4 Hz, 1H, CH2), 4.58 (dd, 2 J(H,H)¼10.0,
12.4 Hz, 1H, CH2), 3.75 (m, 1H, CH), 2.44 (m, 1H, CH),
2.04–1.13 (m, 8H, 4CH2). HPLC: Daicel Chiralpak AD; hex-
ane/iPrOH: 0.45 mL minꢀ1; 230 nm: tR (minor)¼13.0 min;
tR (major)¼20.1 min.
0
0
5H, Ph), 4.93 (dd, 2 J(H,H)¼12.5 Hz, 1 J(H,H)¼4.5 Hz, 1H,
0
CH2), 4.60 (dd, 2 J(H,H)¼12.5, 9.9 Hz, 1H, CH2), 3.76 (m,
1H, CH), 2.69 (m, 1H, CH), 2.50–1.52 (m, 8H, 4CH2).
HPLC: Daicel Chiralpak AD; hexane/iPrOH: 0.45 mL
minꢀ1; 230 nm: tR (minor)¼10.8 min; tR (major)¼13.1 min.
3.5.8. (2S,10R)-2-[10-Phenyl-20-nitro-ethyl]-tetrahydro-
pyran-4-one (22). Purified using flash column chromato-
graphy (n-hexane/EtOAc, 7/3) to give the title compound
3.5.2. (2S,10R)-2-[20-Nitro-10-(o-nitro-phenyl)-ethyl]-cy-
clohexanone (16). Purified using column chromatography
(n-hexane/EtOAc, 7/3) to give the title compound as a yellow
solid (46%); 1H NMR (200 MHz, CDCl3): d¼8.12–7.50 (m,
as a yellow solid (65%). 1H NMR (200 MHz, CDCl3):
0
d¼7.37–7.16 (m, 5H, Ph), 4.95 (dd, 1 J(H,H)¼4.4 Hz,
0
0
0
0
4H, Ph), 4.99 (dd, 2 J(H,H)¼13.1 Hz, 1 J(H,H)¼4.4 Hz, 1H,
2 J(H,H)¼12.8 Hz, 1H, CH2), 4.64 (dd, 2 J(H,H)¼12.8,
9.8 Hz, 1H, CH2), 4.20 (m, 1H, CH), 3.78–3.65 (m, 1H,
CH), 3.26–2.4 (m, 6H, 3CH2). HPLC: Daicel Chiralpak
AD; hexane/iPrOH: 0.45 mL minꢀ1; 230 nm: tR (minor)¼
not determined; tR (major)¼not determined.
0
CH2), 4.71 (dd, 2 J(H,H)¼13.1, 10.2 Hz, 1H, CH2), 3.92 (m,
1H, CH), 2.74 (m, 1H, CH), 2.46–1.24 (m, 8H, 4CH2O).
HPLC: Daicel Chiralpak AD; hexane/iPrOH: 0.45 mL
minꢀ1; 230 nm: tR (major)¼82.0 min; tR (minor)¼99.0 min.
3.5.3. (2S,10R)-2-[10-(o-Methoxyphenyl)-20-nitroethyl]-
cyclohexanone (17). Purified using flash column chromato-
graphy (n-hexane/EtOAc, 6/4) (62%). H NMR (200 MHz,
3.5.9. (2S,10R)-2-[10-Phenyl-20-nitro-ethyl]-tetrahydro-
thiopyran-4-one (23). Purified using flash column chroma-
tography (n-hexane/EtOAc, 7/3) to give the title compound
1
0
CDCl3): d¼7.25–6.84 (m, 4H, Ph), 4.83 (dd, 2 J(H,H)¼
as a yellow solid (45%). 1H NMR (200 MHz, CDCl3):
0
0
12.6 Hz, 1 J(H,H)¼4.5 Hz, 1H, CH2), 3.95 (m, 1H, CH2),
3.84 (s, 3H, CH3), 3.00 (m, 1H, CH), 2.44 (m, 1H, CH),
2.00–1.17 (m, 8H, 4CH2). HPLC: Daicel Chiralpak AD; hex-
ane/iPrOH: 0.45 mL minꢀ1; 230 nm: tR (major)¼21.8 min;
tR (minor)¼24.1 min.
d¼7.37–7.14 (m, 5H, Ph), 4.72 (dd, 2 J(H,H)¼12.5 Hz,
0
0
1 J(H,H)¼4.5 Hz, 1H, CH2), 4.60 (dd, 2 J(H,H)¼12.5,
0
10.0 Hz, 1H, CH2), 3.99 (ddd, 2J(H,H)¼15.4 Hz, 2 J(H,H)¼
10.6, 4.8 Hz, 1H, CH), 3.09–3.01 (m, 1H, CH), 3.0–2.9 (m,
2H, CH2), 2.85–2.75 (m, 2H, CH2), 2.55–2.40 (m, 2H,

746
D. Diez et al. / Tetrahedron 63 (2007) 740–747
CH2). HPLC: Daicel Chiralpak AD; hexane/iPrOH:
0.45 mL minꢀ1; 230 nm: tR (major)¼7.9 min; tR (minor)¼
14.8 min.
K. A. Chem. Commun. 2002, 620; (g) Tang, Z.; Hiang, F.;
Yu, L.-T.; Cui, W.; Gong, L.-Z.; Mi, A.-Q.; Jian, Y.-Z.; Wu,
Y.-D. J. Am. Chem. Soc. 2003, 125, 5262.
5. (a) Tajagopal, D.; Narayanan, R.; Swaminathan, S. Tetrahedron
Lett. 2001, 42, 4887; (b) Bui, T.; Barbas, C. F., III. Tetrahedron
Lett. 2000, 41, 6951.
6. (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336; (b) List, B.;
Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc.
3.5.10. (4S)-5-Nitro-4-phenyl-pentan-2-one (24). Purified
using flash column chromatography (n-hexane/EtOAc, 7/3)
to give the title compound as a yellow solid (68%). H
1
NMR (200 MHz, CDCl3): d¼7.34–7.23 (m, 5H, Ph), 4.65
4
5
ꢀ
2002, 124, 827; (c) Cordova, A.; Watanabe, S.; Notz, W.;
Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124,
ꢀ
1866; (d) Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.;
Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842; (e)
(td, J(H,H)¼1.4, 7.0 Hz, 2H, CH2), 4.00 (dd, J(H,H)¼
1.4 Hz, 3J(H,H)¼7.8 Hz, 1H, CH), 2.92 (d, 3J(H,H)¼
6.0 Hz, 2H, CH2), 2.13 (s, 3H, CH3). HPLC: Daicel Chiral-
pak AD; hexane/iPrOH: 0.45 mL minꢀ1
; 230 nm: tR
ꢀ
Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas,
(major)¼10.6 min; tR (minor)¼11.2 min.
C. F., III. Tetrahedron Lett. 2003, 44, 1923; (f) Notz, W.;
Tanaka, F.; Watanabe, S.-I.; Chowdari, N. S.; Turner, J. M.;
Thayumanavan, R.; Barbas, C. F., III. Tetrahedron Lett. 2003,
68, 9624; (g) Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima,
T.; Shoji, M.; Sakai, K. Angew. Chem., Int. Ed. 2003, 42, 3677;
(h) Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem.
Soc. 2003, 125, 11208; (i) Notz, W.; Sakthivel, K.; Bui, T.;
Barbas, C. F., III. Tetrahedron Lett. 2001, 42, 199; (j)
Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F., III. Synlett
2003, 1906; (k) Zhuang, W.; Saaby, S.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2004, 43, 476; (l) Chowdari, N. S.;
Suri, J. T.; Barbas, C. F., III. Org. Lett. 2004, 6, 2507; (m)
3.5.11. (3S,4R)-3-Methyl-5-nitro-4-phenyl-pentan-2-one
(25). Purified using flash column chromatography (n-hex-
ane/EtOAc, 7/3) to give the title compound as a yellow solid
1
(65%). H NMR (200 MHz, CDCl3): d¼7.4–7.2 (m, 5H,
5
Ph), 4.60 (dd, J(H,H)¼4.8, 1.8 Hz, 2H, CH2), 3.72–3.60
(m, 1H, CH), 3.2–2.8 (m, 1H, CH), 2.2 (s, 3H, CH3), 0.95
0
(d, 1 J(H,H)¼7.3 Hz, 3H, CH3). HPLC: Daicel Chiralpak
AD; hexane/iPrOH: 0.45 mL minꢀ1; 230 nm: tR (major)¼
9.4 min; tR (minor)¼7.9 min.
ꢀ
Ibrahem, I.; Cordova, A. Chem. Commun. 2006, 1760.
Acknowledgements
7. (a) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 16,
2423; (b) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975;
(c) Enders, D.; Seki, A. Synlett 2002, 26.
Financial support for this work came from the E.F.S., Span-
ish MEC (CTQ2005-06813/BQU, CTQ2006-08296/BQU)
8. (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656; (b)
Kumaraguruban, N.; Juhl, K.; Zhuang, W.; Bøgevig, A.;
Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254; (c)
Bøgevig, A.; Kumaraguruban, N.; Juhl, K.; Zhuang, W.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790; (d)
Vogt, H.; Vanderheiden, S.; Brase, S. Chem. Commun. 2003,
2448; (e) Suri, J. T.; Steiner, D. D.; Barbas, C. F., III. Org.
Lett. 2005, 7, 3885; (f) Chowdari, N. S.; Barbas, C. F., III.
Org. Lett. 2003, 7, 868; (g) Iwamura, H.; Mathew, S. P.;
Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, 11770.
9. (a) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247; (b)
ꢀ
and Junta de Castilla y Leon (Spain) (SA045A05,
SA007A06). The authors thank also Dr. A. M. Lithgow for
ꢀ
the NMR spectra and Dr. Cesar Raposo for the mass spectra.
M.J.G. and P.G. are grateful for a doctoral fellowship to
ꢀ
Junta de Castilla y Leon and the University of Salamanca,
respectively.
References and notes
1. (a) Comprehensive Asymmetric Catalyst; Jacobsen, E. N.,
Pafltz, A., Yamamoto, H., Eds.; Springer: New York, NY,
1999; Vols. I–III; (b) Noyori, R. Asymmetric Catalysis in
Organic Synthesis; Wiley: New York, NY, 1994; (c) Ojima, I.
Catalytic Asymmetric Synthesis; Wiley-VCH: Weinheim,
1993.
ꢀ
Bøgevig, A.; Sunden, H.; Cordova, A. Angew. Chem., Int. Ed.
2004, 43, 1109; (c) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.;
Shoji, M. Angew. Chem., Int. Ed. 2004, 43, 1112; (d)
ꢀ
Cordova, A.; Sunden, H.; Engqvist, M.; Ibrahem, I.; Casas, J.
J. Am. Chem. Soc. 2004, 126, 8914.
10. Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450.
11. (a) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III.
Synlett 2003, 1910; (b) Chowdari, N. S.; Ramachary, D. B.;
Barbas, C. F., III. Org. Lett. 2003, 5, 1685; (c) Halland, N.;
Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67,
8331; (d) Halland, N.; Brauton, A.; Bachamann, S.; Marigo,
M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790; (e)
List, B. Synlett 2001, 1675.
2. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 113,
3726; (b) List, B. Synlett 2001, 1675; (c) Brown, S. P.;
Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2003, 125, 10808; (d) Pidathala, C.; Hoang, L.;
Vignola, N.; List, B. Angew. Chem., Int. Ed. 2003, 42, 2785;
(e) Asymmetric Organocatalysis: From Biomimetic Concepts
to Applications in Asymmetric Synthesis; Berkessel, A.,
€
Groger, H., Eds.; Wiley-VCH: Weinheim, 2005.
12. (a) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245;
(b) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res.
2004, 37, 580.
13. (a) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem.
2002, 1877; (b) Seayad, J.; List, B. Org. Biomol. Chem. 2005,
3, 719; (c) Zhu, M.-K.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.;
Gong, L.-Z. Tetrahedron: Asymmetry 2006, 17, 491; (d)
Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006,
128, 1454; (e) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc.
3. (a) List, B. Tetrahedron 2000, 58, 5573; (b) List, B. Chem.
Commun. 2006, 819.
4. (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395; (b) List, B.; Pojarliev, P.; Castello, C. Org.
Lett. 2001, 3, 573; (c) Northrup, A. B.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2002, 124, 6798; (d) Northrup, A. B.;
Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew.
Chem., Int. Ed. 2004, 43, 2152; (e) Sakthivel, K.; Notz, W.;
Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123,
5260; (f) Bøgeving, A.; Kumaragurugaran, N.; Jørgensen,
ꢀ
2006, 128, 7170; (f) Mossee, S.; Laars, M.; Kriis, K.;

D. Diez et al. / Tetrahedron 63 (2007) 740–747
747
Kanger, T.; Alexakis, A. Org. Lett. 2006, 8, 2559; (g) Lattanzi,
A. Tetrahedron: Asymmetry 2006, 17, 837; (h) Luo, S.; Mi, X.;
Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Angew. Chem., Int. Ed.
2006, 45, 3093.
20. (a) Wang, W.; Wang, J.; Li, H. Tetrahedron Lett. 2004, 45,
7235; (b) Wang, W.; Wang, J.; Li, H. Tetrahedron Lett. 2004,
45, 7243; (c) Wang, W.; Li, H.; Wang, J. Tetrahedron Lett.
2005, 5077.
14. (a) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold,
J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84; (b) Tori,
H.; Nakadai, M.; Ishikara, K.; Saito, S.; Yamamoto, H.
Angew. Chem., Int. Ed. 2004, 43, 1983; (c) Franckevicius, V.;
Knudsen, K. R.; Ladlow, M.; Longbottom, D. A.; Ley, S. V.
Synlett 2006, 889; (d) Hartikka, A.; Arvidsson, P. I. Eur. J.
Org. Chem. 2005, 4287; (e) Hartikka, A.; Arvidsson, P. I.
Tetrahedron: Asymmetry 2004, 15, 1831; (f) Knudsen, K. R.;
Mitchell, C. E. T.; Ley, S. V. Chem. Commun. 2006, 66.
15. (a) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka,
F.; Barbas, C. F., III. Synthesis 2004, 9, 1509; (b) Mase, N.;
Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Org. Lett.
2004, 6, 2527; (c) Betancor, J. M.; Barbas, C. F., III. Org.
Lett. 2001, 3, 3737.
21. Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem.,
Int. Ed. 2005, 44, 4212.
22. Ishi, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem.
Soc. 2004, 126, 9558.
ꢀ
ꢀ
23. Dıez, D.; Beneitez, M. T.; Marcos, I. S.; Garrido, N. M.;
Basabe, P.; Sanz, F.; Broughton, H. B.; Urones, J. G. Org.
Lett. 2003, 5, 4361.
24. Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W. Chem.—
Eur. J. 2006, 12, 4321.
25. Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137.
€
26. Chinchilla, R.; Backvall, J.-E. Tetrahedron Lett. 1992, 33,
5641.
27. Risaliti, A.; Forchiassin, M.; Valentin, E. Tetrahedron 1968, 24,
1889.
16. (a) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611; (b)
Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5,
2559; (c) Andrey, O.; Vidonne, A.; Alexakis, A. Tetrahedron
Lett. 2003, 44, 7901; (d) Andrey, O.; Alexakis, A.; Romassini,
A.; Bernadinelli, G. Adv. Synth. Catal. 2004, 346, 1147.
17. Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44,
1369.
18. Wang, W.; Li, H.; Wang, J. Tetrahedron Lett. 2004, 45, 8229.
19. (a) Wang, W.; Wang, H.; Li, H. Org. Lett. 2004, 6, 2817; (b)
Wang, J.; Li, H.; Mei, Y.; Lou, B.; Xu, D.; Xie, D.; Guo, H.;
Wang, W. J. Org. Chem. 2005, 70, 5678.
28. (a) Kraka, E.; Wu, A.; Cremer, D. J. Phys. Chem. A 2003, 107,
9008; (b) Isobe, H.; Takano, Y.; Kitagawa, Y.; Kawakami, T.;
Yamanaka, S.; Yamaguchi, K.; Houk, K. N. J. Phys Chem. A
2003, 107, 682.
29. Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay,
T.; Simson, M.; Seebach, D. Synthesis 1993, 1271.
30. Seebach, D.; Lyapkalo, I. M.; Dahinden, R. Helv. Chim. Acta
1999, 11, 1829.
31. Schionato, A.; Paganelli, S.; Botteghi, C.; Chelucci, G. J. Mol.
Catal. 1989, 50, 11.
32. Yamamoto, Y.; Nishii, S. J. Org. Chem. 1988, 53, 3597.