Experimental and theoretical studies on Mannich-type reactions of chiral non-racemic N-(benzyloxyethyl) nitrones

Article abstract of DOI:10.1016/j.tetasy.2010.12.004

The nucleophilic addition of both silyl ketene acetals and lithium enolates derived from methyl acetate to chiral non-racemic N-(benzyloxyethyl)nitrones has been studied both experimentally and theoretically. Aromatic nitrones showed lower reactivity that

Full text of DOI:10.1016/j.tetasy.2010.12.004

Tetrahedron: Asymmetry 21 (2010) 2934–2943
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Experimental and theoretical studies on Mannich-type reactions of chiral
non-racemic N-(benzyloxyethyl) nitrones
⇑
Alba Diez-Martinez, Tomas Tejero, Pedro Merino
Laboratorio de Sintesis Asimetrica, Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza, CSIC, E-50009 Zaragoza, Aragon, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The nucleophilic addition of both silyl ketene acetals and lithium enolates derived from methyl acetate to
chiral non-racemic N-(benzyloxyethyl)nitrones has been studied both experimentally and theoretically.
Aromatic nitrones showed lower reactivity that aliphatic nitrones and the addition of the silyl ketene ace-
tal led to lower selectivities than the addition of the corresponding lithium enolate. Whereas low selec-
tivity was obtained for the addition of the silyl ketene acetal, only one diastereomer could be detected in
all cases for the addition of lithium enolate to aliphatic nitrones. The synthetic utility of the two chiral
auxiliaries employed lies in the preparation of enantiomeric compounds. DFT theoretical calculations
confirmed the stepwise mechanism for the addition of silyl ketene acetals to nitrones and are in good
agreement with the observed experimental results.
Received 26 October 2010
Accepted 6 December 2010
Available online 11 January 2011
Dedicated to the memory of Professor Rafael
Suau
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
acetal17 have also been described including two reports in which
the chiral groups are employed as chiral auxiliaries.18 A Man-
Direct Mannich-type reactions between enolizable carbonyl
derivatives and a variety of C@N systems, such as imines, iminium
ions, hydrazones and nitrones are widely recognized as an effective
step in the synthesis of nitrogen-containing compounds of biolog-
ical interest.1 This reaction has been used for preparing enantiome-
rically pure aminoacids,2 nucleoside analogues,2 carbohydrates3
and alkaloids4 among other compounds of interest.5 Hence, the
development of methods providing high stereo- and enantioselec-
tivity is essential for this purpose. Over the past years a great num-
ber of direct Mannich-type reactions with imines as substrates
have been reported.6
nich-type ring-closure has been recently described for rationaliz-
ing the formation of 4-aminocyclohexanols from cyclopropylalkyl
nitrones.19 In past years, we also reported the stereocontrolled
nucleophilic addition of lithium and sodium enolates20 and silyl
ketene acetals21 to chiral non-racemic nitrones as a part of a strat-
egy directed towards the synthesis of nucleoside analogues.22 The
nucleophilic addition of silyl ketene acetals was also used by us as
a key step in the synthesis of sphingosines.23 All of these reactions,
however, employed chiral starting materials and a more general
approach needs more versatile substrates. Since catalytic
approaches seem to fail with these compounds, the use of chiral
auxiliaries emerges as a convenient possibility for obtaining highly
enantiopure compounds.24 The use of chiral auxiliaries incorporated
into nitrones has been illustrated in the cycloaddition25 and nucleo-
philic addition26 reactions. In most cases the chiral auxiliary also
participates in the reaction not only by providing a stereoselective
and biased system but also by enhancing the reactivity, by mainly
participating in coordination processes. In this context, the use of
functionalized groups that can contribute to increase both reactivity
and selectivity represents a very attractive approach.
We have reported very recently the synthesis of N-(benzyl-oxy-
ethyl) nitrones,27 bearing coordinating groups at the nitrone nitro-
gen, suitable towards being eliminated if necessary, and in this
paper we describe a full study of the nucleophilic addition of both
silyl ketene acetals and lithium enolates to such nitrones. It is note-
worthy that apart from our communication more than 10 years
ago there are no previous reports on the nucleophilic addition of
lithium enolates to nitrones. A theoretical rationalization of the ob-
served results will also be provided (see Scheme 1).
Several approaches based on the use of chiral substrates,7 chiral
auxiliaries8 and catalytic methods,9 including organocatalytic
ones,10 have been developed. However, in these reactions, nitrones
have been scarcely used in comparison with imines. There are few
examples in the literature in which nitrones are used as the start-
ing materials in direct Mannich reactions. It has been described
that the reaction of silyl ketene acetals with nitrones is catalysed
by lanthanide triflates,11 trimethylsilyl triflate12 and, more re-
cently, NO cations.13 Only two reports (one of them from our
laboratory) have communicated on chiral-Lewis acid catalysed
reactions showing moderate enantio-selectivities.14 Low enanti-
oselectivities, even with a high amount of catalyst, were obtained
in the only organo-catalytic reported reaction.15 Reactions with
chiral non-racemic nitrones16 and an optically active silyl ketene
⇑
Corresponding author. Tel./fax: +34 976 762075.
E-mail address: pmerino@unizar.es (P. Merino).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.12.004

A. Diez-Martinez et al. / Tetrahedron: Asymmetry 21 (2010) 2934–2943
2935
N#
NH2
O
The reaction proceeded smoothly to give mixtures of the cor-
responding diastereomers. With boron trifluoride etherate as a
Lewis acid (entry 4) no reaction was observed. In most cases
only moderate-to-low selectivities were observed with lower
values for aromatic nitrones 1a,b (entries 1–9) and 2a,b (entries
10–17). In addition, these nitrones showed lower chemical
yields. Better results were obtained with aliphatic nitrones 1c,d
(entries 18–21) and 2c,d (entries 22–25) when zinc(II) triflate
and copper(II) triflate were used as Lewis acids. Indeed, for nit-
rone 1c only one isomer was detected by NMR when the reac-
tion was carried out in the presence of zinc(II) triflate (entry
18). In general, better results were obtained by using zinc(II) tri-
flate as a promoter.
We also tested the reaction under catalytic conditions. Unfor-
tunately, no reaction was observed with aromatic nitrones 1a,b
and 2a,b after 18 h. Some reactivity was observed at higher tem-
peratures (from À20 °C to 0 °C) but only 1:1 mixtures of isomers
were obtained and substantial amounts of starting material were
recovered. With aliphatic nitrones (entries 26–29) the reaction
time increased and the selectivity of the reaction decreased sub-
stantially. It appears that aromatic nitrones lead to lower reac-
tivities and selectivities than aliphatic nitrones and in any case
(either aliphatic or aromatic) no synthetically useful results can
be obtained under the more desirable catalytic conditions.
In most cases inseparable mixtures were obtained and no fur-
ther efforts were made since low selectivities were obtained. The
stereochemical assignment of the obtained compounds was only
achieved for the only diastereomer obtained from nitrone 1c (entry
18) by chemical correlation as indicated below.
OM
R2
R1
R1
R2
R1 = aryl, alkyl
2 = alkyl, aryl, OR
N
# = NR, N+R2, NNR2, N+(O-)R
M = SiR3, Li, Na
R
Scheme 1. The direct Mannich reaction.
2. Results and discussion
2.1. Experimental studies
We first studied the reaction between nitrones 1a–d and 2a–d
and silyl ketene acetal28 3 (Scheme 2). The potential of several Le-
wis acids as catalysts was evaluated (Table 1).
TBSO
R
OBn
N
R
N
O
CO2Me
OBn
OBn
*
OTBS
OMe
1a-d
4
3
Ph
Ph
TBSO
R
OBn
N
R
N
O
CO2Me
*
2a-d
5
Scheme 2. The direct Mannich reaction between nitrones and silyl ketene acetal 3
Due to the limitations mentioned above we turned our atten-
tion to the nucleophilic addition of lithium enolates. Again, aro-
matic nitrones showed lower reactivity than aliphatic ones.
Indeed, with aromatic nitrones no reaction was observed at
À78 °C29 and at higher temperatures only decomposition products
were obtained, probably as a consequence of the instability of the
lithium enolate formed in situ. Thus, for our study we decided to
use aliphatic nitrones 1c–i and 2c–i (Scheme 3, Table 2).
(see Table 1 for details).
Table 1
Reaction between nitrones 1 and 2, and 3a
Entry
Nitrone
R
Lewis acidb
Yieldc (%)
drd
65:35
61:39
62:38
—
1
2
1a
1a
1a
1a
1b
1b
1b
1b
1b
2a
2a
2a
2b
2b
2b
2b
2b
1c
1c
1d
1d
2c
2c
2d
2d
1c
1d
2c
2d
Ph
Ph
Ph
Ph
Zn(OTf)2
TMSOTf
LiClO4
BF3ÁOEt2
Zn(OTf)2
Cu(OTf)2
Ti(OiPr)4
ZrCl4
58
49
69
—
3
4e
5
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
Ph
Ph
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
iPr
iPr
tBu
tBu
iPr
54
68
52
65
64
52
56
55
40
45
58
64
60
81
82
72
70
80
71
74
69
84
71
78
73
80:20
63:37
75:25
60:40
61:39
60:40
55:45
62:38
70:30
73:27
74:26
67:32
74:26
>98:2
63:37
80:20
78:22
75:25
75:25
70:30
70:30
88:12
72:28
70:30
64:36
6
7f
BnO
8
9
N
O
Yb(OTf)3
Zn(OTf)2
TMSOTf
Cu(OTf)2
Zn(OTf)2
Cu(OTf)2
Ti(OiPr)4
ZrCl4
Yb(OTf)3
Zn(OTf)2
Cu(OTf)2
Zn(OTf)2
Cu(OTf)2
Zn(OTf)2
Cu(OTf)2
Zn(OTf)2
Cu(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
R
R
N
O
10
11
12
13
14
15f
16
17
18
19
20
21
22
23
24
25
26f,g
27f,g
28f,g
29f,g
R
R
O
OBn
OBn
OLi
OMe
1c-h
7a-e
6
Ph
Ph
BnO
N
O
N
O
O
2c-h
8a-e
Scheme 3. Nucleophilic addition of the lithium enolate derived from methyl
acetate to nitrones 1c–h and 2c–h (see Table 2 for details).
iPr
tBu
tBu
iPr
tBu
iPr
The reaction between lithium enolate, generated in situ from
methyl acetate and LDA, and nitrones took place smoothly at
À78 °C in 30 min and only one isomer was observed in all cases.
Only nitrones 1d and 2d were unreactive quite probably because
of the bulkiness of the tert-butyl group. The final product obtained
was the corresponding 5-isoxazolidinones 7 and 8 as a conse-
quence of an intramolecular attack of the intermediate hydroxya-
mino anion on the incipient carbonyl moiety.
tBu
a
The reaction was carried out in CH2Cl2 at À50 °C for 16 h unless otherwise
indicated.
b
1.0 equiv was used unless otherwise indicated.
c
d
e
f
Isolated yield of the mixture of diastereoisomers.
Calculated from the NMR of the crude mixture.
The reaction was carried out for 48 h.
The reaction was carried out for 24 h.
10 mol % of Lewis acid was used.
The isopropyl derivative 7a was also obtained from the only
isomer obtained from nitrone 1c (Table 1, entry 18) through
g

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A. Diez-Martinez et al. / Tetrahedron: Asymmetry 21 (2010) 2934–2943
Table 2
2.2. Theoretical studies
Nucleophilic addition of the lithium enolate derived from methyl acetate to nitrones
1c–h and 2c–ha
All calculations were performed with the GAUSSIAN 09 package.33
The hybrid density functional theory B3LYP34 with the 6-31G⁄ ba-
sis set35 was employed. This method has been successfully used in
theoretical investigations of reactions involving nitrones.36 To
evaluate the inclusion of diffuse functions and solvent effects,
when necessary, single point B3LYP/6-31+G⁄ calculations using
the conductor polarized continuum model (CPCM)37 were carried
out on the gas-phase optimized structures. Geometry optimiza-
tions and vibrational analyses were performed without any con-
straint and all transition structures were characterized by
analysis of the normal mode corresponding to its unique imaginary
frequency. Regarding the computational costs, model systems
maintaining the fundamental features of the real reaction system
have been used. Chiral auxiliary corresponding to nitrones 2 has
been modelled. The methyl group was used to replace side-chains.
ZnCl2 and Me2O were used to replace Zn(OTf)2 and Et2O in actual
reactions.
The mechanism of the reaction between silyl ketene acetals and
nitrones in the presence of Lewis acids has been previously studied
in our group.38 Herein we aimed at gaining a better understanding
of the reaction mechanism, especially for the stereochemical
course of the reaction when chiral substrates are used and two
reaction channels corresponding to Re and Si attacks are possible.
Thus, the present theoretical study is expected to be useful for
the design of new chiral auxiliaries that could lead to high
selectivities.
Entry
Nitrone
R
Product
Yieldb (%)
drc
1
2
3
4
5
6
7
8
9
1c
1e
1f
1g
1h
2c
2e
2f
iPr
iBu
nBu
Cyclopentyl
BnOCH2
iPr
iBu
nBu
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
85
77
83
82
82
89
80
68
85
81
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
2g
2h
Cyclopentyl
BnOCH2
10
a
The reaction was carried out in THF at À78 °C for 30 min. The lithium enolate
was generated in situ from methyl acetate and LDA at À78 °C for 5 min.
b
Isolated yield of the mixture of diastereoisomers.
c
Calculated from the NMR of the crude mixture.
sequential desilylation and cyclization (Scheme 4), thus confirming
the same stereochemical trend for the addition of both silyl ketene
acetal 3 and lithium enolate 6.
TBSO
OBn
°
1) HF-Py, 0 C
N
7a
CO2Me
2) NaOMe, MeOH
4 (R = iPr)
According to our previous study38 there are three possible ini-
tial transition states for the attack of the silyl ketene acetal to
the Lewis acid-coordinated nitrone.39 This makes a total of 12 tran-
sition structures to be calculated since two different approaches
are also possible for the planar silyl ketene acetal. However, from
these two approaches, one of them can be eliminated for present-
ing significant unfavourable steric interactions as a consequence of
the preferred conformation of the silyl ketene acetal.38
Scheme 4. Cyclization of b-hydroxyamino derivatives.
The synthetic utility of the methodology was illustrated with
compound 7a as an example, which was transformed, in a one-
pot procedure, into N-Boc-b-aminoacid 9 after hydrogenation, re-
moval of the chiral auxiliary and N-protection (Scheme 5).30 In
addition, the complementarity of the two chiral auxiliaries studied
was exemplified with 8a, which upon hydrogenation in the pres-
ence of Boc2O yielded enantiomeric ent-9. As expected, the physi-
cal and spectroscopic properties of 9 and ent-9 were identical
except for the sign of the specific rotation.
We located the remaining 6 transition structures corresponding
to the three alternate approaches by Re (a series) and Si (b series)
faces (Fig. 1). The reaction mechanism obtained is showed in
TMSO
H
OMe
Me
H
H
H
H
H
Me
Me
1) H2, Pd(OH)2-C
2) Pb(OAc)4
OTMS
MeO
Me
H
H
Me
H
O
7a
8a
CO2H
NHBoc
N
O
Me
N
O
Me
TS3a
3.60
N
O
OMe
O
O
TMSO
3) Boc2O, DMAP
ZnCl2
ZnCl2
ZnCl2
9 (ee >95%)
Me
Me
TS1a
0.00
TS2a
H2, Pd(OH)2-C
Boc2O, DMAP
4.15
CO2H
NHBoc
TMSO
H
OMe
H
N
H
ent-9 (ee>95%)
H
Me
H
H
Me
OTMS
Me
H
Scheme 5. Synthesis of N-Boc-b-aminoacids.
MeO
H
Me
H
Me
Me
N
O
N
OMe
O
O
O
TMSO
The absolute configuration of the newly formed stereogenic
centre was established unambiguously as (S) for 7a and (R) for
8a by comparison of the specific rotation value of derivatives 9
and ent-9 with that of the literature31 for ent-9 (see Section 4).
The enantiomeric purity for 9 and ent-9 was determined to be
>95% in both cases. The configuration of the only products obtained
from nitrones 7b–e and 8b–e is also expected to be (S) and (R),32
respectively, based on the assumption of a uniform reaction mech-
anism operating during the nucleophilic addition of the lithium
enolate.
ZnCl2
ZnCl2
ZnCl2
O
Me
O
Me
Me
TS2b
TS3b
TS1b
2.39
4.72
0.11
Figure 1. Initial approaches leading to the corresponding transition structures of
silyl ketene acetal to nitrone. The a and b series correspond to Re and Si attacks,
respectively. Relative energies are given in kcal/mol and correspond to values
corrected by solvation energies in CH2Cl2 solution by using CPCM-B3LYP/6-31+G⁄//
B3LYP-6-31G⁄ level.

A. Diez-Martinez et al. / Tetrahedron: Asymmetry 21 (2010) 2934–2943
2937
Table 3
Scheme 6. Total and relative energies for the various species along
Calculated (CPCM-B3LYP/6-31+G⁄//B3LYP/6-31G⁄, solvent = CH2Cl2) free (
D
G, Har-
the predicted Re and Si channels in the model system are listed in
Table 3 and the energy diagrams along the predicted reaction
mechanism are depicted in Figure 2.
trees) and relative energies (DDG, kcal molÀ1) of the starting reagents (coordinated
nitrone SC1 and silyl ketene acetal SK), transition structures, intermediates and
products (see Scheme 5)a
Re channel
Si channel
D
G
DDGb
D
G
DDGb
Me
SC1
SK
À3141.202473
À676.923525
À3818.080999
À3818.074380
À3818.075269
À3818.087474
À3818.081110
À3818.090817
À3818.073687
À3818.124730
—
—
SC1
SK
À3141.202473
À676.923525
À3818.080829
À3818.077194
À3818.073478
À3818.083012
À3818.081064
À3818.092516
À3818.070780
À3818.123176
—
—
OTMS
OMe
N
O
ZnCl2
Me
MeO
TS1a
TS2a
TS3a
IN1a
TS4a
IN2a
TS5a
P1a
28.28
32.43
31.88
24.22
28.21
22.12
32.87
0.84
TS1b
TS2b
TS3b
IN1b
TS4b
IN2b
TS5b
P1b
28.39
30.67
33.00
27.02
28.86
21.05
34.69
1.81
SK
SC1
Re channel
[TS1a]
Si channel
[TS1b]
a
a and b series refers to Re and Si channels, respectively.
Referred to starting materials (SC + SK = À3818.126068 Hartree).
b
TMSO
Me
OMe
Me
TMSO
Me
OMe
Me
TS5b
N
N
O
O
O
TS4b
TS5a
ZnCl2
ZnCl2
O
TS1b
TS1a
TS4a
IN1b
IN1a
Me
IN1a
Me
IN1b
IN2a
IN2b
[TS4a]rot
[TS4b]rot
P1b
P1a
Re channel
Si channel
MeO
MeO
Me
Me
TMSO
TMSO
N
N
SC1 + SK
Me
Me
O
O
ZnCl2
ZnCl2
Figure 2. Energy diagram (CPCM-B3LYP/6-31+G⁄//B3LYP/6-31G⁄, solvent = CH2Cl2)
for the nucleophilic addition of silyl ketene acetal to nitrone (Scheme 5, Table 1). a
and b series refers to Re and Si channels, respectively.
O
Me
IN2a
O
Me
IN2b
rectly from the starting materials through transition states TS2a
and TS2b, respectively. However, this pathway was discarded be-
cause TS2a and TS2b are 4.15 and 2.28 kcal/mol higher in energy
than TS1a and TS1b, respectively. Transition structures TS3a and
TS3b led to a polar concerted mechanism furnishing stable ortho-
esters that could be transformed into the final products through
unfavoured high-energy transition states. Indeed, we have not
observed the formation of an orthoester in this reaction; according
to the calculations such a product should be isolable. The pathway
corresponding to a concerted mechanism was discarded because
both transition structures TS3a and TS3b and the corresponding
transition structures leading to O-silylhydroxylamines are the
highest in energy.41
For both Re and Si channels, the rate-determining step is pre-
dicted to be silyl transfer from the silyl ketene acetal fragment to
the hydroxyamino moiety (Fig. 2). Both the difference of free ener-
gies between TS5a and TS5b of 1.82 kcal molÀ1 and that between
TS1a and TS1b of 0.11 kcal molÀ1 is in good agreement with the
low selectivity observed for this reaction in favour of Re channel.
From the above data the following conclusions can be derived:
(i) the silyl migration produced in the last stage of the reaction is
the rate-determining step in both channels and (ii) remarkably,
there is a low difference in energy between Re and Si channels
due to the minimal steric influence exerted by the chiral portion
in the rate-determining step (Fig. 3, TS5a and TS5b). In conse-
quence, the future development of chiral auxiliaries to be used in
these processes should take into consideration favouring silyl
migration by one channel in order to achieve high values of
stereoselectivity.
[TS5a]
[TS5b]
Me Me
Me Me
OMe
O
OMe
O
N
N
MeO
OTMS
MeO
OTMS
ZnCl2
ZnCl2
P1a
P1b
Scheme 6. Reaction mechanism for the reaction of a silyl ketene acetal with a
nitrone, catalysed by ZnCl2.
As we demonstrated in our previous study38 it is crucial to con-
sider solvent effects in this reaction since completely different (and
opposite) results are obtained in the gas-phase calculations. Be-
cause of it, and with the aim of modelling close-to-real systems,
we only discuss results corrected by solvation effects. The analysis
of the activation free energies for those TSs revealed that for both
Re and Si approaches, the antiperiplanar approach of the silyl ke-
tene acetal, corresponding to TS1a and TS1b, respectively, is fa-
voured. This is in agreement with the formation of zwitterionic
intermediates IN1a and IN1b. A further bond rotation at these
intermediates through the corresponding transition structures
TS4a and TS4b converts them into the more stable intermediates
IN2a and IN2b.40 Finally, a silyl migration on these intermediates,
favoured by the presence of the Lewis acid, through transition
states TS5a and TS5b, furnishes the corresponding O-silylhydroxyl-
amines. The intermediates IN2a and IN2b can also be formed di-

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A. Diez-Martinez et al. / Tetrahedron: Asymmetry 21 (2010) 2934–2943
R1
N
s
s
O Li
MeO
R2
s
MeO
O
LE
NI
R1
N
O
R2
MeO
s
Li
O
OMe
SC2
Re channel
[TS6a]
Si channel
[TS6b]
R2
R2
R1
R1
N
N
MeO
s
MeO
O
O
O
O
OMe
OMe
Li
Li
s
s = Me2O
R1 = iPr, Ph
R2 = Me, iPr
P2a
P2b
R2
N
R2
R1
R1
N
O
s
O
s
O
O
Li
Li
Me
P3b
O
O
Me
P3a
Scheme 7. Nucleophilic addition of a lithium enolate to nitrones.
Figure 3. Transition states located for the addition of silyl ketene acetal and nitrone
(see Scheme 5). Distances of forming bonds are given in Å. Some hydrogens have
been omitted for clarity.
The reaction mechanism of the nucleophilic addition of the lith-
ium enolate to the nitrone is illustrated in Scheme 7. For this reac-
tion solvent has been modelled as discrete molecules of dimethyl
ether and they have been used for saturating the coordination
sphere of the lithium atom. In addition to the simplest nitrone
(R1 = R2 = Me) we have also studied nitrones with isopropyl and
phenyl groups at the chiral auxiliary (R1 = iPr, Ph) in order to eval-
uate steric and electronic factors of these substituents. Similarly,
C-(isopropyl) nitrone (R2 = iPr) has also been studied.42
The first step of the reaction is the formation of complex SC2 be-
tween nitrone and lithium enolate. The formation of a starting
complex between the nucleophilic organometallic reagent and
the nitrone is a characteristic of nucleophilic additions of organo-
metallic reagents to nitrones; such a complexation activates the
nitrone as an electrophile.43 This complex is formed without an en-
ergy barrier and it is exothermic by 7.87 kcal molÀ1. The complex
evolves through diastereomeric Re and Si channels to give products
P2a and P2b, which cyclize spontaneously, as illustrated in
Scheme 6, to afford the final isoxazolidinones P3a and P3b. The
corresponding transition structures TS6a and TS6b are given in
Figure 4. Total and relative energies for the various species along
the predicted Re and Si channels in the model system are listed
Figure 4. Transition states located for the addition of a lithium enolate to nitrone
NI (R = Me) (see Scheme 6). Distance of forming bonds are given in Å. Some
hydrogens have been omitted for clarity
in Table 4 and the energy diagrams along the predicted reaction
mechanism are depicted in Figure 5.
The analysis of the activation free energies for TS6a and TS6b
revealed that the first one, corresponding to Re approach is fa-
voured by 4.49 kcal molÀ1. This result is in full agreement with
the experimental observations in which only one isomer is de-
tected by NMR spectroscopy.
In this reaction the rate-determining step corresponds to that in
which the new C–C bond is formed (Fig. 5) and it is evident that the

A. Diez-Martinez et al. / Tetrahedron: Asymmetry 21 (2010) 2934–2943
2939
Table 4
position of the spots was detected with 254 nm UV light or by
spraying with 5% ethanolic phospho-molybdic acid. Preparative
centrifugally accelerated radial thin-layer chromatography (radial
chromatography) was performed with a ChromatotronÒ Model
7924 T (Harrison Research, Palo Alto, CA, USA) and with solvents
that were distilled prior to use; the rotors (1 or 2 mm layer thick-
ness) were coated with silica gel Merck grade type 7749, TLC grade,
with binder and fluorescence indicator (Aldrich 34,644-6) and the
eluting solvents were delivered by the pump at a flow-rate of 0.5–
1.5 mL minÀ1. Column chromatography was carried out in a Buchi
Calculated (B3LYP/6-31G⁄) free
(DG, Hartrees) and relative energies (DDG,
kcal molÀ1) of the reagents, starting complex, transition structures and products
(see Scheme 6; R1 = R2 = Me)a
Re channel
Si channel
D
G
DDGb
D
G
DDGb
LE
NI
SC2
TS6a
P2a
À740.209847
À441.424979
À871.707155
À871.703151
À871.720987
—
—
LE
NI
SC2
TS6b
P1b
À740.209847
À441.424979
À871.707155
À871.695999
À871.705732
—
—
À7.87
7.00
À6.97
À7.87
2.51
À16.6
800 MPLC system using silica gel SDS 5–60 lm. Melting points
a
were uncorrected. 1H and 13C NMR spectra were recorded on a Bru-
ker 400 instrument in CDCl3 unless otherwise indicated. Chemical
shifts are reported in ppm (d) relative to CHCl3 (d = 7.26) in CDCl3.
Optical rotations were taken at 25 °C on a Jasco polarimeter. Ele-
mental analysis was performed on a Perkin Elmer 240B microana-
lyzer. Nitrones 1 and 2 were prepared as described.27 Ketene silyl
acetal 3 was also prepared as described.28
a and b series refers to Re and Si channels, respectively.
Referred to starting materials (LE + NI-2ÁMe2O = À871.694618 Hartree).
b
TS6b
TS6a
NI + LE
4.1. Addition of silyl ketene acetal 3 to nitrones. General
procedure
P2b
SC2
A 50-mL round bottomed flask was charged, under an argon
atmosphere, with 3 Å activated molecular sieves (200 mg), the cor-
responding nitrone (2.0 mmol) and anhydrous dichloromethane
(15 mL). The resulting mixture was cooled to 0 °C and then a solu-
tion of the corresponding Lewis acid (see Table 1) in anhydrous
dichloromethane (5 mL) was added dropwise. After 10 min of stir-
ring the mixture is cooled down to À50 °C and a solution of silyl
ketene acetal 3 (0.565 g, 3 mmol) in dichloromethane (5 mL) was
added slowly over 10 min. After 16 h of stirring at À50 °C the reac-
tion mixture was quenched with water, warmed to rt and treated
with aq saturated NaHCO3 (10 mL). The organic phase was sepa-
rated and the aqueous one extracted with EtOAc (2 Â 15 mL). The
combined organic extracts were filtered through a pad of Celite,
washed with brine (40 ml), dried over anhydrous MgSO4 and con-
centrated under reduced pressure. The crude product was purified
by radial chromatography (hexane/EtOAc, 95:5) to yield the pure
products.
Re channel
Si channel
P2a
Figure 5. Energy diagram (B3LYP/6-31G⁄) for the nucleophilic addition of lithium
enolate to nitrone (Scheme 6, Table 2). a and b series refers to Re and Si channels,
respectively.
chiral auxiliary exerts enough influence to differentiate both Re
and Si approaches, contrary to that accounted for the addition of
the silyl ketene acetal.
3. Conclusions
In conclusion, we have studied in detail the Mannich-type reac-
tions of both silyl ketene acetal and lithium enolates, derived from
methyl acetate, with N-(benzyloxyethyl) nitrones. The addition of
silyl ketene acetal showed low selectivity and under catalytic con-
ditions only aliphatic nitrones are reactive enough to allow the
reaction to go to completion. On the other hand, the addition of
lithium enolate afforded only one isomer showing high values of
stereoselectivity. A limitation to the generalization of this method-
ology may also result from the lack of reactivity of aromatic nitro-
nes. The stereoselectivity observed is well-explained in qualitative
terms by means of computational methods, which correctly predict
both the obtention of mixtures on the addition of silyl ketene ace-
tals and a high selectivity on the addition of lithium enolates.
Moreover, those computational studies confirm that the reaction
of a silyl ketene acetal with a nitrone follows a stepwise mecha-
nism in which the silyl transfer from the enolate to the hydroxya-
mino function is the rate-determining step of the reaction. This
situation is probably responsible for the low selectivity observed
in that reaction. In the case of the addition of lithium enolates
the computational study is in agreement with previous studies,
which predicted the formation of a starting complex between the
organometallic reagent and the nitrone. Application of the illus-
trated methodology in the preparation of enantiomerically pure
synthetic intermediates will be the subject of further research in
our laboratory.
4.2. (S)-Methyl 3-(((S)-1-(benzyloxy)-3-methylbutan-2-yl)((tert-
butyldimethylsilyl)oxy)amino)-4-methylpentanoate 4 (R = iPr)
(0.732 g, 81%), oil; [
a
]D = À103 (c 1.12, CHCl3); dH (400 MHz,
CDCl3) 0.15 (s, 3H), 0.18 (s, 1H), 0.88 (d, 3H, J = 6.8 Hz), 0.90 (s,
9H), 0.98 (d, 3H, J = 6.8 Hz), 1.05 (d, 3H, J = 6.7 Hz), 1.07 (d, 3H,
J = 6.7 Hz), 1.78 (dcc, 1H, J = 8.3, 6.8, 6.8 Hz), 1.93 (dq, 1H, J = 8.1,
6.7 Hz), 2.30 (dd, 1H, J = 16.9, 7.3 Hz), 2.72 (dt, 1H, J = 8.1, 4.1 Hz),
3.00 (dd, 1H, J = 16.9, 3.5 Hz), 3.26 (ddd, 1H, J = 8.3, 7.3, 3.5 Hz),
3.56 (s, 3H), 3.63 (dd, 1H, J = 10.0, 4.1 Hz), 3.78 (dd, 1H, J = 10.0,
4.0 Hz), 4.42 (d, 1H, J = 11.9 Hz), 4.48 (d, 1H, J = 11.9 Hz), 7.21–
7.37 (m, 5H); dC (100 MHz, CDCl3) À3.8, À3.7, 18.7, 19.3, 21.4,
21.5, 26.3, 29.4, 29.6, 31.7, 33.1, 50.8, 66.6, 67.3, 71.4, 72.7,
127.4, 127.7, 129.2, 138.5, 173.8. HRMS: m/z [M+Na]+ calcd for
C
C
25H45NNaO4Si: 474.3016; found: 474.3020. Anal. Calcd for
25H45NO4Si (451.71): C, 66.47; H, 10.04; N, 3.10. Found: C,
66.50; H, 10.11; N, 3.02.
4.3. Addition of lithium enolate 6 to nitrones. General
procedure
4. Experimental
To a cooled (À78 °C) solution of freshly distilled lithium diiso-
propylamine (0.202 g, 2.0 mmol) in THF (10 mL) was added a
1.6 M hexane solution of nBuLi (0.13 mL, 2.0 mmol) under an argon
atmosphere, and the mixture was stirred for 10 min. The resulting
mixture was treated with a solution of the corresponding nitrone
The reaction flasks and other glass equipments were heated in
an oven at 130 °C overnight and assembled in a stream of Ar. All
reactions were monitored by TLC on Silica Gel 60 F254; the

2940
A. Diez-Martinez et al. / Tetrahedron: Asymmetry 21 (2010) 2934–2943
(1.0 mmol) in THF (5 mL) and stirring was maintained at À78 °C for
30 min. The reaction mixture was quenched with water and ex-
tracted with EtOAc (2 Â 10 mL). The combined organic extracts
were washed with brine (20 ml), dried over anhydrous MgSO4
and concentrated under reduced pressure. The crude product was
purified by radial chromatography (hexane/EtOAc, 90:10) to yield
the pure products.
1028, 907, 864, 731, 699. dH (400 MHz, CDCl3) 0.97 (d, 3H,
J = 6.8 Hz), 1.00 (d, 3H, J = 6.8 Hz), 1.22–1.26 (m, 2H), 1.58–1.65
(m, 5H), 1.78–1.83 (m, 2H), 2.03–2.07 (m, 1H), 2.45 (dd, 1H,
J = 17.4, 7.7 Hz), 2.78 (dd, 1H, J = 17.4, 8.5 Hz), 2.84 (ddd, 1H,
J = 7.6, 6.7, 3.5 Hz), 3.57 (dd, 1H, J = 10.4, 3.5 Hz), 3.74–3.80 (m,
1H,), 3.81 (dd, 1H, J = 10.4, 7.7 Hz), 4.44 (d, 1H, J = 11.6 Hz), 4.50
(d, 1H, J = 11.6 Hz), 7.28–7.35 (m, 5H); dC (100 MHz, CDCl3) 19.7,
20.1, 25.0, 25.4, 28.0, 29.8, 30.5, 34,2, 43, 6, 66.8, 67.9, 70.7, 73.4,
127.7, 127.7, 128.4, 137.6, 175.8. HRMS: m/z [M+Na]+ calcd for
4.4. (S)-2-((S)-1-(Benzyloxy)-3-methylbutan-2-yl)-3-
isopropylisoxazolidin-5-one 7a
C
C
20H29NNaO3: 354.2045; found: 354.2043. Anal. Calcd for
20H29NO3 (331.45): C, 72.47; H, 8.82; N, 4.23. Found: C, 72.60;
(0.260 g, 85%), oil; [
a
]D = À97 (c 1.00, CHCl3); IR (nujol)
m :
cmÀ1
H, 8.68; N, 4.35.
2960, 2873, 1775, 1467, 1454, 1365, 1212 1101, 737, 698. dH
(400 MHz, CDCl3) 0.91 (d, 6H, J = 7.0), 0.93 (d, 3H, J = 7.0 Hz), 0.99
(d, 3H, J = 6.8 Hz), 1.03 (d, 3H, J = 6.8 Hz), 1.83–1.87 (m, 2H), 2.49
(dd, 1H, J = 17.4, 8.2 Hz), 2.69 (dd, 1H, J = 17.4, 8.7 Hz), 2.81 (ddd,
1H, J = 7.5, 7.3, 3.5 Hz), 3.60 (dd, 1H, J = 10.4, 3.5 Hz), 3.73 (ddd,
1H, J = 8.5, 8.4, 4.9 Hz), 3.85 (dd, 1H, J = 10.4, 7.5 Hz), 4.46 (d, 1H,
J = 11.6 Hz), 4.52 (d, 1H, J = 11.6 Hz), 7.29–7.38 (m, 5H); dC
(100 MHz, CDCl3) 16.7, 18.9, 19.8, 20.3, 30.5, 30.6, 31.8, 67.9,
68.0, 70.7, 73.5, 127.8, 127.8, 128.5, 137,7, 176.0. HRMS: m/z
[M+Na]+ calcd for C18H27NNaO3: 328.1889; found: 328.1883. Anal.
Calcd for C18H27NO3 (305.20): C, 70.79; H, 8.91; N, 4.59. Found: C,
70.73; H, 9.05; N, 4.43.
4.8. (S)-2-((S)-1-(Benzyloxy)-3-methylbutan-2-yl)-3-
((benzyloxy)methyl)isoxazolidin-5-one 7g
(0.314 g, 82%), oil; [
a]
D = À69 (c 1.28, CHCl3); IR (nujol)
m :
cmÀ1
3063, 3030, 2960, 2926, 2870, 1778, 1723, 1652, 1496, 1454, 1365,
1206, 1097, 1027, 910, 738, 698. dH (400 MHz, CDCl3) 0.94 (d, 1H),
0.98 (d, 3H, J = 6.8), 1.81 (dqq, 1H, J = 8.2, 6.7, 6.7 Hz), 2.58 (dd, 1H,
J = 17.4, 8.2 Hz), 2.79 (dd, 1H, J = 17.4, 8.7 Hz), 2.96 (ddd, 1H, J = 8.2,
6.2, 3.8 Hz), 3.49 (dd, 1H, J = 9.7, 3.8 Hz), 3.55 (dd, 1H, J = 9.7, 6.2H),
3.59 (dd, 1H, J = 10.3, 3.8 Hz), 3.87 (dd, 1H, J = 10.3, 8.4 Hz), 4.15
(dddd, 1H, J = 8.4, 8.2, 5.7, 3.8 Hz), 4.43 (d, 1H, J = 11.5 Hz), 4.49
(d, 1H, J = 11.5 Hz), 4.50–4.54 (m, 2H), 7.28–7.35 (m, 10H); dC
(100 MHz, CDCl3) 19.5, 20.1, 30.4, 33.3, 63.0, 68.1, 71.1, 71.5,
73.5, 73.5, 127.7, 127.8, 127.9, 128.4, 128.5, 137.7, 137.8, 175.1.
HRMS: m/z [M+Na]+ calcd for C23H29NNaO4: 406.1994; found:
406.1998. Anal. Calcd for C23H29NO4 (383.48): C, 72.04; H, 7.62;
N, 3.65. Found: C, 71.92; H, 7.89; N, 3.47.
4.5. (R)-2-((S)-1-(Benzyloxy)-3-methylbutan-2-yl)-3-
isobutylisoxazolidin-5-one 7d
(0.246 g, 77%), oil; [
a]D = À122 (c 1.08, CHCl3); IR (nujol)
m :
cmÀ1
2958, 2872, 1777, 1495, 1457, 1366, 1213, 1101, 837, 698. dH
(400 MHz, CDCl3) 0.85 (d, 3H, J = 6.5 Hz), 0.92 (d, 3H, J = 6.5 Hz),
0.97 (d, 3H, J = 6.7 Hz), 0.98 (d, 3H, J = 6.7 Hz), 1.35 (ddd, 1H,
J = 13.4, 8.5, 5.8 Hz), 1.49 (ddd, 1H, J = 13.4, 8.5, 4.9 Hz), 1.57–
1.62 (m, 1H), 1.80–1.85 (m, 1H), 2.40 (dd, 1H, J = 16.8, 10.3 Hz),
2.75 (dd, 1H, J = 16.8, 7.3 Hz), 2.84 (ddd, 1H, J = 7.2, 6.9, 3.5 Hz),
3.54 (dd, 1H, J = 10.4, 3.5 Hz), 3.88 (dd, 1H, J = 10.4, 7.2 Hz), 3.91–
3.96 (m, 1H), 4.45 (d, 1H, J = 11.7 Hz), 4.50 (d, 1H, J = 11.7 Hz),
7.27–7.37 (m, 5H); dC (100 MHz, CDCl3) 19.4, 20.2, 22.0, 23.4,
25.6, 30.3, 36.7, 42.2, 61.8, 67.6, 68.5, 73.3, 127.6, 127.7, 128.3,
137.8, 174.8. HRMS: m/z [M+Na]+ calcd for C19H29NNaO3:
342.2045; found: 342.2046. Anal. Calcd for C19H29NO3 (319.44):
C, 71.44; H, 9.15; N, 4.38. Found: C, 71.23; H, 9.27; N, 4.10.
4.9. (R)-2-((R)-2-(Benzyloxy)-1-phenylethyl)-3-
isopropylisoxazolidin-5-one 8a
(0.302 g, 89%), oil; [a]D = +49 (c 1.05, CHCl3); IR (nujol) m :
cmÀ1
3063, 3031, 2960, 2873, 1785, 1722, 1652, 1603, 1495, 1453, 1364,
1177, 1099, 1028, 917, 751, 700. dH (400 MHz, CDCl3) 0.69 (d, 3H,
J = 6.8 Hz), 0.72 (d, 3H, J = 6.8 Hz), 1.50–1.56 (m, 1H), 2.28 (dd, 1H,
J = 17.9, 3.3 Hz), 2.62 (dd, 1H, J = 17.9, 8.9 Hz), 3.19 (ddd, 1H, J = 8.9,
6.5, 3.3 Hz), 3.74 (dd, 1H, J = 9.8, 6.7 Hz), 3.95 (dd, 1H, J = 9.8,
5.4 Hz), 4.07 (dd, 1H, J = 6.7, 5.4 Hz), 4.35 (d, 1H, J = 12.0 Hz), 4.42
(d, 1H, J = 12.0 Hz), 7.07–7.12 (m, 3H), 7.15–7.30 (m, 7H); dC
(100 MHz, CDCl3) 15.7, 16.3, 28.4, 29.4, 64.1, 69.1, 69.4, 71.1,
125.3, 125.4, 126.0, 126.1, 126.3, 126.4, 135.4, 135.6, 174.8. HRMS:
m/z [M+H]+ calcd for C21H26NO3: 340.1913; found: 340.1916. Anal.
Calcd for C21H25NO3 (339.43): C, 74.31; H, 7.42; N, 4.13. Found: C,
74.52; H, 7.62; N, 4.27.
4.6. (R)-2-((S)-1-(Benzyloxy)-3-methylbutan-2-yl)-3-
butylisoxazolidin-5-one 7e
(0.265 g, 83%), oil; [
a]D = À203 (c 1.25, CHCl3); IR (nujol)
m :
cmÀ1
3030, 2958, 2931, 2872, 1780, 1496, 1454, 1365, 1230, 1202, 1102,
1028, 904, 843, 736, 698. dH (400 MHz, CDCl3) 0.89 (t, 3H,
J = 7.0 Hz), 0.97 (d, 1H, J = 6.8 Hz), 0.98 (d, 3H, J = 6.8 Hz), 1.22–
1.36 (m, 4H), 1.37–1.48 (m, 1H), 1.59–1.68 (m, 1H), 1.83 (ddd,
1H, J = 6.8, 6.8, 6.6 Hz), 2.43 (dd, 1H, J = 16.9, 10.3 Hz), 2.73 (dd,
1H, J = 16.9, 7.4 Hz), 2.84 (ddd, 1H, J = 7.4, 6.6, 3.7 Hz), 3.56 (dd,
1H, J = 10.3, 3.7 Hz), 3.87 (dd, 1H, J = 10.3, 7.4 Hz), 4.45 (d, 1H,
J = 11.7 Hz), 4.50 (d, 1H, J = 11.7 Hz), 7.26–7.37 (m, 5H); dC
(100 MHz, CDCl3) 13.9, 20.2, 22.6, 27.9, 30.3, 32.7, 36.3, 63.3,
67.7, 68.7, 73.3, 127.6, 128.4, 137.8, 137.8, 174.8. HRMS: m/z
[M+H]+ calcd for C19H30NO3: 320.2226; found: 320.2224. Anal.
Calcd for C19H29NO3 (319.44): C, 71.44; H, 9.15; N, 4.38. Found:
C, 71.36; H, 9.01; N, 4.11.
4.10. (S)-2-((R)-2-(Benzyloxy)-1-phenylethyl)-3-
isobutylisoxazolidin-5-one 8d
(0.283 g, 80%), oil; [a]D = +45 (c 1.20, CHCl3); IR (nujol) m
cmÀ1: 3030, 2955, 2868, 1787, 1495, 1453, 1366, 1167, 1099,
889, 738, 700. dH (400 MHz, CDCl3) 0.52 (d, 3H, J = 6.5 Hz), 0.73
(d, 3H, J = 6.6 Hz), 1.06–1.14 (m, 1H), 1.39–1.46 (m, 1H), 1.51–
1.58 (m, 1H), 2.26 (dd, 1H, J = 17.5, 4.0 Hz), 2.89 (dd, 1H,
J = 17.5, 8.1 Hz), 3.54–3.60 (m, 1H), 3.84 (dd, 1H, J = 9.7,
6.7 Hz), 4.05 (dd, 1H, J = 9.7, 5.1 Hz), 4.13 (dd, 1H, J = 6.7,
5.1 Hz), 4.44 (d, 1H, J = 12.1 Hz), 4.51 (d, 1H, J = 12.1 Hz), 7.15–
7.19 (m, 2H), 7.24–7.39 (m, 8H); dC (100 MHz, CDCl3) 21.9,
22.4, 24.5, 34.2, 43.6, 59.7, 70.9, 71.7, 73.4, 127.6, 127.6, 128.3,
128.5, 128.6, 128.7, 137.7, 137.8, 176.5. HRMS: m/z [M+Na]+
calcd for: C22H27NNaO3 376.1889; found: 376.1890. Anal. Calcd
for C22H27NO3 (353.45): C, 74.76; H, 7.70; N, 3.96. Found: C,
74.82; H, 7.41; N, 4.21.
4.7. (S)-2-((S)-1-(Benzyloxy)-3-methylbutan-2-yl)-3-
cyclopentylisoxazolidin-5-one 7f
(0.272 g, 82%), oil; [
3063, 3029, 2950, 2867, 1785, 1494, 1450, 1365, 1232, 1205, 1110,
a
]
D = À89 (c 1.28, CHCl3); IR (nujol)
m :
cmÀ1

A. Diez-Martinez et al. / Tetrahedron: Asymmetry 21 (2010) 2934–2943
2941
4.11. (S)-2-((R)-2-(Benzyloxy)-1-phenylethyl)-3-
butylisoxazolidin-5-one 8e
4.15. (S)-3-((tert-Butoxycarbonyl)amino)-4-methylpentanoic
acid 9
(0.240 g, 68%), oil; [
a
]
D = +50 (c 1.10, CHCl3); IR (nujol)
m
cmÀ1
:
To a solution of 7a (0.153 g, 0.45 mmol) in THF (10 mL) was
added Pd(OH)2 (300 mg); the resulting mixture was stirred under
an H2 atmosphere (3 atm) at room temperature for 6 h. The sus-
pension was then filtered through Celite and concentrated in va-
cuo to give a residue which was taken up into a 2:1 mixture of
CH2Cl2/MeOH (5 mL). The resulting solution was treated with
Pb(OAc)4 (248 mg, 0.45 mmol) at 0 °C and stirred for 5 min at
which time satd aq NaHCO3 was added. The reaction mixture
was evaporated to dryness under reduced pressure without the
temperature exceeding 25 °C and the residue was taken up into
dioxane (10 mL) and treated with Boc2O (0.75 mmol) and a cata-
lytic amount of DMAP at room temperature for 12 h. The reaction
mixture was then evaporated under reduced pressure and the res-
idue was redissolved in satd aq Na2CO3, washed with diethyl
ether, acidified to pH 2 with citric acid and extracted with EtOAc
(2 Â 10 mL). The combined organic extracts were washed with
brine, dried (MgSO4), and evaporated under reduced pressure to
give a residue, which was purified by column radial chromatogra-
phy (hexane/EtOAc, 85:15) to give pure 9 (0.072 g, 62%, >95% ee)
3063, 3030, 2956, 2929, 2860, 1786, 1454, 1363, 1169, 1099, 739,
700. dH (400 MHz, CDCl3) 0.77 (t, 3H, J = 7.1 Hz), 1.05–1.15 (m, 2H),
1.20–1.31 (m, 3H), 1.45–1.32 (m, 1H), 2.30 (dd, 1H, J = 17.5, 4.5),
2.82 (dd, 1H, J = 17.5, 8.1), 3.50 (ddd, 1H, J = 11.4, 7.8, 5.4 Hz),
3.83 (dd, 1H, J = 9.7, 6.7 Hz), 4.05 (dd, 1H, J = 9.7, 5.1 Hz), 4.14
(dd, 1H, J = 6.7, 5.1 Hz), 4.44 (d, 1H, J = 12.1 Hz), 4.51 (d, 1H,
J = 12.1 Hz), 7.16–7.19 (m, 2H), 7.24–7.38 (m, 8H); dC (100 MHz,
CDCl3) 13.8, 22.2, 27.6, 34.0, 61.6, 71.0, 71.7, 73.4, 127.6, 128.3,
128.4, 128.5, 128.7, 137.7, 137.8, 176.4. HRMS: m/z [M+Na]+ calcd
for C22H27NNaO3: 376.1889; found: 376.1885. Anal. Calcd for
C
22H27NO3 (353.45): C, 74.76; H, 7.70; N, 3.96. Found: C, 74.63;
H, 7.91; N, 3.78.
4.12. (R)-2-((R)-2-(Benzyloxy)-1-phenylethyl)-3-
cyclopentylisoxazolidin-5-one 8f
(0.311 g, 85%), oil; [a]D = +43 (c 1.22, CHCl3); IR (nujol) m :
cmÀ1
3062, 3030, 2952, 2867, 1785, 1603, 1495, 1453, 1419, 1363, 1246,
1170, 1098, 1028, 913, 913, 871, 751, 701. dH (400 MHz, CDCl3)
0.78–0.87 (m, 1H), 0.87–0.98 (m, 1H), 1.20–1.37 (m, 4H), 1.38–
1.50 (m, 1H), 1.55–1.66 (m, 1H), 1.72–1.85 (m, 1H), 2.18 (dd,
1H, J = 17.8, 2.4 Hz), 2.67 (dd, 1H, J = 17.8, 8.4 Hz), 3.15 (ddd,
1H, J = 8.6, 8.5, 2.4 Hz), 3.69 (dd, 1H, J = 9.8, 6.8 Hz), 3.90 (dd, 1H,
J = 9.8, 5.2 Hz), 4.01 (dd, 1H, J = 6.8, 5.2 Hz), 4.29 (d, 1H,
J = 12.0 Hz), 4.36 (d, 1H, J = 12.0 Hz), 7.00–7.05 (m, 2H), 7.09–7.27
(m, 8H); dC (100 MHz, CDCl3) 24.6, 24.7, 28.6, 29.7, 32,1, 43.7,
64.7, 71.0, 71.7, 73.3, 127.4, 127.5, 128.2, 128.3, 128.5, 128.6,
137.6, 137.8, 175.8. HRMS: m/z [M+Na]+ calcd for C23H27NNaO3:
388.1889; found: 388.1886. Anal. Calcd for C23H27NO3 (365.47):
C, 75.59; H, 7.45; N, 3.83. Found: C, 75.48; H, 7.38; N, 3.67.
as a white solid; mp 69–71 °C; [a]D = +21 (c 1.01, CHCl3). Lit. for
enantiomer: [
a
]
D = À23.4 (c 1.0, CHCl3).31a
[
[a]
a
]
D = À20.2 (c 1.0,
D = À20.3 (c 1.0,
-beta-
CHCl3).31b
[
a]
D = À23.2 (c 1.0, CHCl3).31c
CHCl3).31d Value observed for an authentic sample (Boc-
D
Leu-OH; Aldrich 80674): [a]D = +22 (c 1.00, CHCl3). IR (nujol) m
cmÀ1: 3302, 2967, 2931, 2875, 1714, 1684, 1365, 1173, 1114,
860. dH (400 MHz, CDCl3) 0.93 (d, 1H, J = 6.7 Hz), 0.94 (d, 3H,
J = 6.8 Hz), 1.42 (s, 9H), 1.73–1.90 (m, 1H), 2.37–2.58 (m, 2H),
3.70–3.78 (m, 1H), 4.87–5.00 (d, 1H, J = 9.3 Hz), 8.76 (m, 1H); dC
(100 MHz, CDCl3) 18.5, 19.3, 28.3, 31.7, 37.1, 52.8, 79.4, 155.7,
176.9. HRMS: m/z [M+Na]+ calcd for C11H21NNaO4: 254.1368;
found: 254.1362. Anal. Calcd for C11H21NO4 (231.29): C, 57.12;
H, 9.15; N, 6.06. Found: C, 57.27; H, 9.23; N, 5.88.
4.13. (R)-2-((R)-2-(Benzyloxy)-1-phenylethyl)-3-
((benzyloxy)methyl)isoxazolidin-5-one 8g
4.16. (R)-3-((tert-Butoxycarbonyl)amino)-4-methylpentanoic
acid ent-9
(0.338 g, 81%), oil; [a]D = +42 (c 1.11, CHCl3); IR (nujol) m :
cmÀ1
3062, 3025, 2963, 2925, 2850, 1788, 1454, 1360, 1165, 1096, 742,
702. dH (400 MHz, CDCl3) 2.49 (dd, 1H, J = 17.8, J = 4.2 Hz), 2.64 (dd,
1H, J = 17.8, 8.6 Hz), 3.27–3.30 (m, 2H), 3.68–3.73 (m, 1H), 3.75 (dd,
1H, J = 9.8, 6.6 Hz), 3.96 (dd, 1H, J = 9.8, 5.2 Hz), 4.14 (dd, 1H, J = 6.6,
5.2 Hz), 4.29–4.50 (m, 4H) ppm 7.16 (m, 15H); dC (100 MHz, CDCl3)
31.1, 60.8, 71.1, 71.3, 71.6, 73.3, 73.4, 127.6, 127.6, 128.3, 128.4,
128.4, 128.7, 137.5, 137.5, 137.8, 175.9. HRMS: m/z [M+Na]+ calcd
for C26H27NNaO4: 440.1838; found: 440.1841. Anal. Calcd for
To a solution of 8a (0.170 g, 0.5 mmol) in THF (10 mL) was
added Pd(OH)2 (300 mg); the resulting mixture was stirred under
an H2 atmosphere (50 atm) at room temperature for 24 h. The sus-
pension was then filtered through Celite and concentrated in vacuo
to give a residue which was taken up into dioxane (10 mL) and
treated with Boc2O (0.75 mmol) and a catalytic amount of DMAP
at room temperature for 12 h. The reaction mixture was then evap-
orated under reduced pressure and the residue was redissolved in
satd aq Na2CO3, washed with diethyl ether, acidified to pH 2 with
citric acid and extracted with EtOAc (2 Â 10 mL). The combined or-
ganic extracts were washed with brine, dried (MgSO4), and evapo-
rated under reduced pressure to give a residue which was purified
by column radial chromatography (hexane/EtOAc, 85:15) to give
pure ent-9 (0.105 g, 91%, >95% ee) as a white solid; mp 68–70 °C;
C26H27NO4 (417.50): C, 74.80; H, 6.52; N, 3.35. Found: C, 74.98;
H, 6.41; N, 3.58.
4.14. Cyclization of compound 4 (R = iPr)
To a cooled (0 °C) solution of 4 (R = iPr) (0.226 g, 0.5 mmol) in
THF (15 mL) was added hydrogen fluoride–pyridine complex
(0.4 g). After 1 h of stirring at 0 °C, the reaction mixture was diluted
with satd aq NaHCO3 (10 mL) and ethyl acetate (10 mL). The organic
layer was separated, and the aqueous layer was extracted with ethyl
acetate. The combined organic extracts were washed with brine,
dried (MgSO4), and evaporated under reduced pressure. The residue
was taken up into methanol (10 mL) and treated with sodium meth-
oxide (32.4 mg, 0.6 mmol) at ambient temperature. After 2 h of stir-
ring, the reaction mixture was diluted with aqueous NH4Cl (20 mL)
and ethyl acetate (20 mL). The organic layer was separated, washed
with brine, dried (MgSO4), and evaporated under reduced pressure
to give a residue, which was purified by column radial chromatogra-
phy (hexane/EtOAc, 90:10) to give pure 7a (0.110 g, 72%).
[
[
a
a
]
]
D = À22 (c 0.95, CHCl3). Lit.: [
a
]
D = À23.4 (c 1.0, CHCl3).28a
D = À20.2 (c 1.0, CHCl3).28b
[
a]
D = À23.2 (c 1.0, CHCl3).28c The
spectroscopic properties were identical to those of 9. HRMS: m/z
[M+Na]+ calcd for C11H21NNaO4: 254.1368; found: 254.1364. Anal.
Calcd for C11H21NO4 (231.29): C, 57.12; H, 9.15; N, 6.06. Found: C,
57.01; H, 9.21; N, 6.17.
Acknowledgements
We thank them for their support of our programs: the
Spanish Ministry of Science and Innovation (Madrid, Spain. Projects
CTQ2007-67532-C02-01 and CTQ2010-19606) and the Government

2942
A. Diez-Martinez et al. / Tetrahedron: Asymmetry 21 (2010) 2934–2943
22. Chiacchio, U.; Corsaro, A.; Romeo, G.; Merino, P. Chem. Rev. 2010, 110, 3337–
3370.
of Aragon (Zaragoza, Spain). A.D.-M. also thanks the Government
of Aragon for a pre-doctoral fellowship. Dr. Ignacio Delso is
acknowledged for helpful discussions and NMR assistance.
23. Merino, P.; Jimenez, P.; Tejero, T. J. Org. Chem. 2006, 71, 4685–4688.
24. For recent reviews illustrating the convenience of using chiral auxiliaries see:
(a) Gnas, Y.; Glorius, F. Synthesis 2006, 1899–1930; (b) Evans, D. A.; Helmchen,
G.; Rüeping, M. In Asymmetric Synthesis: The Essentials; Christmann, M., Ed.;
Wiley-VCH: Weinheim, 2008; pp 3–9. and next chapters.
References
25. (a) Hanselmann, R.; Zhou, J.; Ma, P.; Confalone, P. N. J. Org. Chem. 2003, 68,
8739–8741; (b) Ali, S. A.; Iman, M. Z. N. Tetrahedron 2007, 63, 9134–9145; (c)
Chiacchio, U.; Rescifina, A.; Saita, M. G.; Iannazzo, D.; Romeo, G.; Mates, J. A.;
Tejero, T.; Merino, P. J. Org. Chem. 2005, 70, 8991–9001.
26. (a) Hubregtse, T.; Hanefeld, U.; Arends, I. W. C. E. Eur. J. Org. Chem. 2007, 2413–
2422; (b) Patel, S. K.; Murat, K.; Py, S.; Vallée, Y. Org. Lett. 2003, 5, 4081–4084;
(c) Patel, S. K.; Py, S.; Pandya, S. U.; Chavant, P. Y.; Vallée, Y. Tetrahedron:
Asymmetry 2003, 14, 525–528.
27. Diez-Martinez, A.; Gültekin, Z.; Delso, I.; Tejero, T.; Merino, P. Synthesis 2010,
678–688.
28. Heathcock, C. H.; Davidsen, S. K.; Hug, K.; Flippin, L. A. J. Org. Chem. 2002, 51,
3027–3037.
29. Aromatic aldimines have also showed a considerable lack of reactivity with
lithium enolate 6. See: Saito, S.; Hatanaka, K.; Yamamoto, S. Tetrahedron 2001,
57, 875–887.
30. The chiral auxiliary was eliminated and the nitrogen protected through a one-
pot variation of the method described by Py and Vallée: see Ref.26b. For an
organocatalytic preparation of enantioenriched isoxazolidines and further
conversion into b-amino acids see: (a) Deliana, L.; Zhao, G.-L.; Lin, S.; Dziedzic,
P.; Zgang, Q.; Leijonmarck, H.; Córdova, A. Adv. Synth. Catal. 2010, 352, 2291–
2298; (b) Ibrahem, I.; Rios, R.; Vesely, J.; Zhao, G.-L.; Córdova, A. Chem.
Commun. 2007, 849–851.
1. (a) Ipaktschi, J.; Saidi, M. R. In Science of Synthesis; Georg Thieme Verlag:
Stuttgart, 2008; Vol. 40a, pp 435–478; (b) Bordunov, A. V.; Bradshaw, J. S.;
Pastushok, V. N.; Izatt, R. M. Synlett 1996, 933–948; (c) Abonia, R.; Insuasty, B.;
Quiroga, J.; Nogueras, M.; Meier, H. Mini-Rev. Org. Chem. 2004, 1, 387–402; (d)
Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 2169–2178; (e) Arend, M.;
Wang, X.; Wirth, T. In Organic Synthesis Highlights V; Schmalz, H.-G., Ed.; Wiley-
VCH Verlag: Weinheim, 2003; pp 134–143; (f) Liu, M.; Sibi, M. P. Tetrahedron
2002, 58, 7991–8035; (g) Burk, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221–
3242.
2. b-Aminoacids: (a) Ueno, M.; Kobayashi, S. In Enantioselective Synthesis of
b-Aminoacids; Juaristi, E., Soloshonok, V. A., Eds., 2nd ed.; John Wiley
&
sons: Hoboken, 2005; pp 139–157. Chapter 6; ,b-Diaminoacids: (b)
a
Arrayas, R. G.; Carretero, J. C. Chem. Soc. Rev. 2009, 38, 1940–1948;
Pipecolic acids: (c) Carbonnel, S.; Fayet, C.; Gelas, J.; Troin, Y. Tetrahedron
Lett. 2000, 41, 8293–8296.
3. (a) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Tetrahedron Lett. 1998, 39,
6411–6414; (b) Evans, G. B.; Furneaux, R. H.; Tyler, P. C.; Schramm, V. L. Org.
Lett. 2003, 5, 3639–3640; (b) Merino, P. Curr. Med. Chem. AIA 2002, 1, 389–411;
(c) Merino, P. Curr. Med. Chem. 2006, 13, 539–545.
4. (a) Wang, Y.; Wang, F.; Wang, Y.; Mao, Z.; Chen, R. Adv. Synth. Catal. 2008, 350,
2339–2344; (b) Dziedzic, P.; Ibrahem, I.; Córdova, A. Tetrahedron Lett. 2008, 49,
803–807; (c) Ibrahem, I.; Zou, W.; Xu, Y.; Córdova, A. Tetrahedron Lett. 2005, 46,
3363–3367.
5. (a) Stoye, A.; Quandt, G.; Brunnhofer, B.; Kapatsina, E.; Baron, J.; Fischer, A.;
Weymann, M.; Kunz, H. Angew. Chem., Int. Ed. 2009, 48, 2228–2230; (b) Martin,
S. F. Acc. Chem. Res. 2002, 35, 895–904; (c) Padwa, A.; Bur, S. K.; Danca, D. M.;
Ginn, J. D.; Lynch, S. M. Synlett 2002, 851–862; (d) Chan, Y.; Balle, J.; Kevin, S. J.;
Boyd, P. D. W.; Brimble, M. A.; Barker, D. Tetrahedron 2010, 66, 7179–7191.
6. (a) Galatsis, P. In Name Reactions for Homologations. Part 2; Li, J. J., Ed.; John
Wiley & sons: Hoboken, 2009; pp 635–670; (b) Marques, M. M. B. Angew.
Chem., Int. Ed. 2006, 45, 348–352; (c) Córdova, A. In Handbook of C–H
Transformations; Dyker, G., Ed.; Wiley-VCH: Weinheim, 2005; pp 359–370;
(d) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1045–
1070; (e) Blicke, F. F. Org. React. 1942, 1, 303.
7. (a) Ciblat, S.; Besse, P.; Canet, J.-L.; Troin, Y.; Veschambre, H.; Gelas, J.
Tetrahedron: Asymmetry 1999, 10, 2225–2235; (b) Buckley, B. R.; Page, P. C. B.;
Heaney, H.; Sampler, E. P.; Carley, S.; Crocke, C.; Brimble, M. A. Tetrahedron
2005, 61, 5876–5888; (c) Chen, S.-L.; Ji, S.-J.; Loh, T.-P. Tetrahedron Lett. 2003,
44, 2405–2408.
8. (a) Wang, Y.; Wang, Y.; Yu, J.; Miao, Z.; Chen, R. Chem. Eur. J. 2009, 15, 9290–
9293; (b) Iza, A.; Vicario, J. L.; Carrillo, L.; Badia, D. Synthesis 2006, 4065–4074;
(c) Gessier, F.; Schaeffer, L.; Kimmerlin, T.; Flogel, O.; Seebach, D. Helv. Chim.
Acta 2005, 88, 2235–2249; (d) Allef, P.; Kunz, H. Tetrahedron: Asymmetry 2000,
11, 375; (e) Knauer, S.; Kunz, H. Tetrahedron: Asymmetry 2005, 16, 529.
9. (a) Córdova, A. Acc. Chem. Res. 2004, 37, 102–112; (b) Kazmaier, U. Angew.
Chem., Int. Ed. 2009, 48, 5790–5792; (c) Córdova, A.; Ríos, R. In Amino Group
Chemistry; Ricci, A., Ed.; Wiley-VCH: Weinheim, 2008; pp 185–205; (d)
Kobayashi, S.; Ueno, M. In Comprehensive Asymmetric Catalysis; Springer:
Berlin, 2004; Vol. 1, pp 143–150.
10. (a) Notz, W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580–591; (b)
Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T.
Chem. Soc. Rev. 2008, 37, 29–41; (c) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007,
5797–5815; (d) Tanaka, F.; Barbas, C. F., III In Enantioselective Organocatalysis:
Reactions and Experimental Procedures; Dalko, P. I., Ed.; Wiley-VCH: Weinheim,
2007; pp 19–55.
31. (R)-ent-9: [
N. M.; Martihoni, B.; Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta 1996,
79, 913–941; [
D = À20.2 (c 1.0, CHCl3): (b) Kantharaju, B. S. P. Ind. J. Chem.,
Sect. B: Org. Chem. Med. Chem. 2005, 44, 2611–2613; [
D = À23.2 (c 1.0, CHCl3):
(c) Vasanthakumar, G. R. Ind. J. Chem., Sect. B: Org. Chem. Med. Chem. 2003, 42,
1691–1695; [
a]D = À23.4 (c 1.0, CHCl3): (a) Seebach, D.; Overhand, M.; Kühnle, F.
a
]
a
]
a D = À20.3 (c 1.0, CHCl3): (d) Babu, V. V. S.; Gopi, H. N. Lett. Pept.
]
Sci. 1999, 6, 173–178.
32. The assigned configurations are based by considering the R group as the second
in priority after the nitrogen atom, which correlates with aminoacids 9 and
ent-9.
33. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.;
Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven,
T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.;
Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas,
Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. GAUSSIAN 09, Revision A.1;
Gaussian, Inc.: Wallingford CT, 2009.
34. (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652; (b) Lee, C.; Yang, W.; Parr, R.
G. Phys. Rev. B 1998, 37, 785–789; (c) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H.
Chem. Phys. Lett. 1989, 157, 200–205.
35. (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54, 724–728; (b)
Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56, 2257–2261; (c)
Hariharan, P. C.; Pople, J. A. Mol. Phys. 1974, 27, 209–214; (d) Gordon, M. S.
Chem. Phys. Lett. 1980, 76, 163–168; (e) Franci, M. M.; Pietro, W. J.; Hehre, W. J.;
Binkley, J. S.; DeFrees, D. J.; Pople, J. A.; Gordon, M. S. J. Chem. Phys. 1982, 77,
3654–3655; (f) Rassolow, V. A.; Pople, J. A.; Ratner, M. A.; Windus, T. L. J. Chem.
Phys. 1998, 109, 1223–1229.
36. For recent and representative references see: (a) Delso, I.; Marca, E.;
Mannucci, V.; Tejero, T.; Goti, A.; Merino, P. Chem. Eur. J. 2010, 16, 9910–
9919; (b) Jasinski, R.; Wasik, K.; Mikulska, M.; Baranski, A. J. Phys. Org. Chem.
2009, 22, 717–725; (c) Wang, F.; Meng, Q.; Wang, J.; Li, M. Struct. Chem. 2009,
20, 129–137; (d) Merino, P.; Tejero, T.; Mannucci, V. Tetrahedron Lett. 2007,
48, 3385; (c) Kazuta, Y.; Abe, H.; Matsuda, A.; Shuto, S. J. Org. Chem. 2004, 69,
9143–9150.
37. Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995–2001.
38. Domingo, L. R.; Arno, M.; Merino, P.; Tejero, T. Eur. J. Org. Chem. 2006, 3464–
3472. There is another report on this reaction (see: Milet, A.; Gimbert, Y.;
Greene, A. E. J. Comput. Chem. 2006, 27, 157–162). However, this report, carried
out with very simple models far from actual reaction systems, did not consider
the presence either Lewis acids or solvent, claiming a concerted mechanism. In
our previous study we demonstrated (both theoretically and experimentally)
that the reaction in the absence of any Lewis acid is not possible, a stepwise
mechanism being much more favourable when a Lewis acid is present and
solvent interactions are considered.
11. Qian, C.; Wang, L. Tetrahedron Lett. 2000, 56, 7193–7197.
12. Degiorgis, F.; Lombardo, M.; Trombini, C. Synthesis 1997, 1243–1245.
13. Yamashita, Y.; Kobayashi, S. Chem. Lett. 2009, 678–679.
14. (a) Murahashi, S.-I.; Imada, Y.; Kawakami, T.; Harada, K.; Yonemushi, Y.;
Tomita, N. J. Am. Chem. Soc. 2002, 124, 2888–2889; (b) Merino, P.; Franco, S.;
Jimenez, P.; Tejero, T.; Chiacchio, M. A. Lett. Org. Chem. 2005, 2, 302–305.
15. Okino, T.; Hoashi, Y.; Takemoto, Y. Tetrahedron Lett. 2003, 44, 2817.
16. (a) Kita, T.; Tamura, O.; Itoh, F.; Kishino, H.; Miki, T.; Kohno, M.; Tamura, Y.
Chem. Pharm. Bull. 1989, 37, 2002–2007; (b) Ohtake, H.; Imada, Y.; Murahashi,
S.-I. Bull. Chem. Soc. Jpn. 1999, 72, 2737–2754; (c) Saha, N.; Desai, V. N.;
Dhavale, D. D. Tetrahedron 2001, 57, 39–46; (d) Kita, Y.; Itoh, F.; Tamura, O.; Ke,
Y. Y.; Tamura, Y. Tetrahedron Lett. 1987, 28, 1431–1434.
17. Ohtake, H.; Imada, Y.; Murahashi, S.-I. J. Org. Chem. 1999, 64, 3790–3791.
18. Chiral auxiliary on nitrones: (a) Jost, S.; Gimbert, Y.; Greene, A. E.; Fotiadu, F. J.
Org. Chem. 1997, 62, 6672–6677; Chiral auxiliary on a silyl ketene acetal: (b)
Kawakami, T.; Ohtake, H.; Arakawa, H.; Okachi, T.; Imada, Y.; Murahashi, S.-I.
Bull. Chem. Soc. Jpn. 2000, 73, 2423–2444.
19. Dias, D. A.; Kerr, M. A. Org. Lett. 2009, 11, 3694–3697.
20. Merino, P.; Franco, S.; Garcés, N.; Merchan, F. L.; Tejero, T. Chem. Commun.
1998, 493–494.
21. (a) Merino, P.; del Alamo, E. M.; Bona, M.; Franco, S.; Merchan, F. L.; Tejero, T.;
Vieceli, O. Tetrahedron Lett. 2000, 41, 9239–9243; (b) Merino, P.; Franco, S.;
Merchan, F. L.; Tejero, T. J. Org. Chem. 2000, 65, 5575–5589.
39. The starting complex between nitrone and ZnCl2 is formed without an energy
barrier and is exothermic in 4.93 kcal molÀ1
.
40. It is also possible to consider rotation along the opposite pathway. However,
this possibility was discarded because it led to the intermediate orthoester
formed through TS3, which is not actually obtained. This route was clearly
energetically unfavoured (see below).

A. Diez-Martinez et al. / Tetrahedron: Asymmetry 21 (2010) 2934–2943
2943
41. We have carried out the full theoretical study in the gas-phase, which is
necessary for introducing solvation correction. These results as well as
additional calculations considering introduction of diffuse functions and
solvation effects for pathways corresponding to higher TSs, including the
concerted pathway, are available from the authors on request. Diez-Martinez,
A. Ph.D. Dissertation, in course.
the rest of possibilities (R1 = iPr, Ph; R2 = Me, iPr) are available from the authors
on request. Diez-Martinez, A. Ph.D. Dissertation, in course.
43. (a) Merino, P.; Mannucci, V.; Tejero, T. Tetrahedron 2005, 61, 3335–3347; (b)
Merino, P.; Tejero, T.; Revuelta, P.; Cicchi, S.; Mannucci, V.; Brandi, A.; Goti, A.
Tetrahedron: Asymmetry 2003, 14, 367–379; (c) Merino, P.; Tejero, T.
Tetrahedron 2001, 57, 8121–8128. See also Ref.33a
.
42. Since similar results are obtained in all cases, in this manuscript only the
simplest study (R1 = R2 = Me) is discussed. Full data regarding calculations with