Asymmetric CONJUGATE ADDITION of MALONATE ESTERS to α,β- UNSATURATED N-sulfonyl imines: An expeditious route to chiral δ-aminoesters and piperidones

Article abstract of DOI:10.1002/chem.201302687

The asymmetric conjugate addition of malonate esters to α,β-unsaturated N-sulfonyl imines is catalyzed by PyBOX/La(OTf) ₃ complexes in the presence of 4A? MS. The reaction gives the corresponding E enamines bearing a stereogenic center at the allylic position with good yields and enantiomeric ratios up to 97:3. This reaction provides a synthetic entry to chiral δ-aminoesters and piperidones. Copyright

Full text of DOI:10.1002/chem.201302687

FULL PAPER
DOI: 10.1002/chem.201302687
Asymmetric Conjugate Addition of Malonate Esters to a,b-Unsaturated N-
Sulfonyl Imines: An Expeditious Route to Chiral d-Aminoesters and
Piperidones
Miguel Espinosa, Gonzalo Blay,* Luz Cardona, and Josꢀ R. Pedro*[a]
Abstract: The asymmetric conjugate addition of malonate esters to a,b-unsaturat-
ed N-sulfonyl imines is catalyzed by PyBOX/La
(OTf)3 complexes in the presence
Keywords: amino acids · asymmet-
ric catalysis · carbanions · conjugate
addition · imino compounds
of 4 ꢁ MS. The reaction gives the corresponding E enamines bearing a stereogenic
center at the allylic position with good yields and enantiomeric ratios up to 97:3.
This reaction provides a synthetic entry to chiral d-aminoesters and piperidones.
Introduction
dependent on the nucleophile and reaction conditions, often
1,2-addition is preferred,[7] or double nucleophilic addition
products are obtained.[8] On the other hand, only a much re-
duced number of examples regarding the enantioselective
1,4-nucleophilic addition of carbon nucleophiles to unsatu-
rated imines have been reported.[9] In 2005, Ellmanꢀs group
reported the asymmetric conjugate addition of organocup-
rates to chiral N-tert-butylsulfinylimines with good yields
and diastereomeric ratios (d.r.) of up to 93:7.[10] The first ex-
ample of catalytic enantioselective conjugate addition was
reported by Tomiokaꢀs group in 2005. These authors carried
out the addition of diethylzinc to N-sulfonyl aldimines bear-
ing a bulky group on the azomethinic nitrogen atom in the
presence of a phosphine/CuI complex to give the corre-
sponding 1,4-alkylation products with ee values in the 75–
91% range. The group of Carretero reported the conjugate
addition of diethylzinc to unsaturated N-sulfonyl ketimines
by using a CuI/phosphorimidite complex, obtaining the alky-
lated products with moderate enantioselectivity (ee=70–
80%).[11] Later, Palacios described the CuI-catalyzed conju-
gate addition of diethylzinc to a reduced number of N-aryl
imines derived from a-ketoesters, by using a different phos-
phorimidite ligand with enantiomeric excesses in the 76–
88% range.[12] Besides these examples, a conjugate addition
of malonate esters or related 1,3-dicarbonyl compounds to
unsaturated imines in an enantioselective fashion has not
been reported so far, to the best of our knowledge
(Scheme 1).[13] In this paper, we describe the first example
of asymmetric conjugate addition of methyl malonate to un-
saturated N-tosyl imines as an efficient procedure to access
chiral d-amino acid derivatives.
Conjugate addition reactions have played a crucial role in
organic synthesis. The research on this transformation has
been boosted by the wide diversity of compounds that can
serve as nucleophiles and electrophiles to generate a varied
array of products.[1] Such reactions often result in the gener-
ation of a new stereocenter, and consequently a considerable
effort has been devoted to the development of asymmetric
catalytic versions of 1,4-addition reactions. Unsaturated car-
bonyl compounds,[2] nitroalkenes,[3] and less frequently unsa-
turated sulfones[4] have been used as electrophilic partners
in asymmetric conjugate additions of easily enolizable nucle-
ophiles, such as 1,3-dicarbonyl and related compounds. In
this context, a,b-unsaturated imines (1-azabutenes), readily
prepared through condensation of N-substituted amines
with the parent unsaturated ketones, have emerged as an in-
teresting family of compounds with important applications
in the synthesis of nitrogen-containing molecules. Thus, nu-
merous applications of 1-azabutenes as heterodienes in
asymmetric cycloaddition reactions have been reported in
the literature.[5]
In contrast to carbonyl substrates and nitroalkenes, the
asymmetric conjugate addition to a,b-unsaturated imines
has been scarcely explored probably due to the lower elec-
trophilicity of these substrates. Furthermore, a,b-unsaturat-
ed imines are ambidented electrophiles that can either un-
dergo 1,2- or 1,4-nucleophilic addition processes.[6] However,
generally, the control of the regioselectivity is difficult and
[a] M. Espinosa, Prof. Dr. G. Blay, Prof. Dr. L. Cardona,
Prof. Dr. J. R. Pedro
Department de Quꢂmica Orgꢃnica-Facultat de Quꢂmica
Universitat de Valꢄncia
C/Dr. Moliner 50, 46100 Burjassot, Valꢄncia (Spain)
Fax : (+34)963544328
Results and Discussion
In this investigation we have used N-tosyl imines 2 as elec-
trophiles since the reactivity of imines toward nucleophilic
attack is significantly increased by the presence of strong
electron-withdrawing groups on the azomethinic nitrogen
E-mail: jose.r.pedro@uv.es
gonzalo.blay@uv.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302687.
Chem. Eur. J. 2013, 19, 14861 – 14866
ꢅ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
14861

conditions. YbIII, ScIII, and InIII triflates in combination with
PyBOX-1 were also tested (entries 3–5) although we did not
observe any advance of the reaction. We also tested differ-
ent PyBOX ligands with LaACTHNUTRGNE(NUG OTf)3 (entries 6–10), although
none of them provided better results than PyBOX-1. The
use of toluene, hexane, or THF was prevented due to the
low solubility of the imine in these solvents. Finally, the
enantioselectivity of the reaction could be increased up to
96:4 e.r. by carrying out the reaction at 08C, although with
a loss of yield (entry 11). The effect of the substituent R at-
tached to the carbonyl group of the nucleophile was also
tested. First we tested the use of other malonate esters. Di-
ethyl malonate (1, R=OEt) performed similarly to dimethyl
malonate providing the expected addition product (3, R=
OEt, R1 =R2 =Ph) with 73% yield and 91.5:8.5 e.r.
(entry 12). However, increasing the bulk of the alkoxy
group as in diisopropyl malonate (1, R=OiPr) produced
a serious decrease on the reaction rate and the conjugate
addition product was obtained in only 16% yield after
120 h. On the other hand, 2,4-pentanedione (1, R=Me) re-
acted slowly with imine 2a to give the corresponding prod-
uct (3, R=Me, R1 =R2 =Ph) in 59% yield, but with low dia-
stereo- and enantioselectivity (entry 14). Finally, malononi-
trile did not react under the optimized conditions.
Next, we studied the scope of the addition of dimethyl
malonate (1, R=OMe) to different imines 2 under the opti-
mized conditions (Table 2). The reaction can be carried out
with imines bearing an aromatic ring attached to the b-
carbon atom substituted with either electron-donating or
-withdrawing substituents (Table 2, entries 1–8), to give the
expected products with good diastereoselectivities (from
71:29 to 97:3) favoring the E diastereomer and high enantio-
meric ratios (from 84.4:15.5 to 96:4). R1 can be also a hetero-
cyclic furanyl ring (entries 9, 10). When R1 was a phenyl
group substituted with electron-withdrawing groups, good
yields of the addition products could be obtained after 24 h.
However, when R1 was an aromatic ring substituted with an
electron-donating group, or an electron-rich heterocycle (en-
tries 8–10), the reaction required longer times and the corre-
sponding products were obtained with slightly lower yields.
Finally, the reaction allowed imines with R1 as an aliphatic
group. Imine 2i (R1 =Me) reacted with dimethyl malonate
to give the expected product with almost quantitative yield,
good diastereoselectivity, and 87.5:12.5 e.r. for the major
diastereomer (entry 11). However, imine 2j bearing a bulky
tert-butyl group did not react under similar conditions
(entry 12). The R2 group attached to the imine was also
amenable to variation (entries 13–18). Aromatic rings bear-
ing either electron-donating or -withdrawing groups were
permitted without much influence on the enantioselectivity
of the reaction. The study with unsaturated imines 2 in
which R2 is aliphatic (Me) was not possible because of enoli-
zation of the N-sulfonyl imine during the preparation of the
starting materials.
Scheme 1. Conjugate addition of 1,3-dicarbonyl compounds to unsaturat-
ed N-sulfonyl imines and catalysts used in this study.
atom. For the optimization of the reaction conditions, we
studied the addition of dimethyl malonate (1, R=OMe) to
N-tosyl imine 2a (R1 =R2 =Ph) by using complexes of triva-
lent metals and PyBOX ligands (Scheme 1, Table 1).[14]
Table 1. Enantioselective addition of 1,3-dicarbonyl compounds 1 to un-
saturated imine 2a (R1 =R2 =Ph) according to Scheme 1.[a]
Entry
M
Ligand
R
T
t [h] Yield [%][b] e.r.[c]
[e]
1[d]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
La
La
PyBOX-1 MeO
PyBOX-1 MeO
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
48
24
48
48
48
24
106
16
42
24
64
48
120
170
48
–
81
–
–
–
65
25
60
59
86
63
73
16
69
–
–
93:7
–
–
–
46:54
56:44
47:53
56:44
78:22
96:4
91.5:8.5
–
[e]
[e]
[e]
Yb PyBOX-1 MeO
Sc
In
PyBOX-1 MeO
PyBOX-1 MeO
PyBOX-2 MeO
PyBOX-3 MeO
PyBOX-4 MeO
PyBOX-5 MeO
PyBOX-6 MeO
PyBOX-1 MeO 08C
PyBOX-1 EtO
PyBOX-1 iPrO
La
La
La
La
La
La
La
La
La
La
RT
RT
RT
RT
PyBOX-1 Me
68:32
–
[f]
[e]
PyBOX-1
–
[a] Reaction conditions:
1
(0.3 mmol), 2a (0.12 mmol), ligand
(0.012 mmol), M(OTf)3 (0.012 mmol), 4 ꢁ MS (20 mg), CH2Cl2 (0.8 mL).
ACHTUNGTRENNUNG
[b] Yield of isolated product. [c] Only for the major (E)-diastereomer.
Determined by HPLC analysis with chiral stationary phases. [d] Reaction
carried out without MS. [e] No reaction observed after 48 h. [f] Malono-
nitrile was used as the nucleophile.
When the reaction was carried out in the presence of the
LaACHTUNGTRENNUNG(OTf)3/PyBOX-1 in dichloromethane we did not observe
any advance of the reaction after 24 h. However, after addi-
tion of 4 ꢁ molecular sieves (MS)[15] the reaction proceeded
smoothly to give compound 3a (R=OMe, R1 =R2 =Ph) as
an approximately 9:1 mixture of diastereomers with a 93:7
enantiomeric ratio (e.r.) for the major E diastereomer
(Table 1, entry 1). The geometry of the double bond was as-
signed as E for the major diastereomer and Z for the minor
one by NOESY experiments.[16] These results contrast with
those reported for the CuI-catalyzed addition of diethylzinc
to related unsaturated imines, which gave the Z isomers as
the major products.[11] On the other hand, no cyclization to
the corresponding lactam was observed under the reaction
The absolute stereochemistry of compound 3a was estab-
lished by chemical correlation with compound 4 of known
stereochemistry. A sample of compound (E)-3a (e.r.=91:9)
14862
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Chem. Eur. J. 2013, 19, 14861 – 14866

An Expeditious Route to Chiral d-Aminoesters and Piperidones
FULL PAPER
Table 2. Enantioselective addition of dimethyl malonate to unsaturated imines catalyzed by La
PyBOX-1.[a]
ACHTUNGERTN(NUNG OTf)3/
to avoid the steric interaction
of the R2 and tosyl groups with
the phenyl group of the ligand,
thus leading to the conjugate
addition product 3 with the R
configuration at the stereogen-
ic center and the E geometry
at the double bond.
R1
R2
t [h]
3
Yield [%][b]
d.r. (E/Z)
e.r. (E/Z)[c,d]
Enamines 3 can be used as
starting materials for the syn-
thesis of optically active nitro-
genated compounds, such as d-
aminoesters and piperidones
(Scheme 3). Thus, hydrogena-
tion of (E)-3a over Pd/C gave
a 95% yield of a 75:25 mixture
of two diastereomeric d-amino-
diesters 5 and 6, favoring the
(R,S)-diastereomer 5. Both
diastereomers 5 and 6 could be
separated after column chro-
matography and subjected to
chemical transformations sepa-
rately. Decarboxylation of
either 5 or 6 upon treatment
with tetraethylammonium hy-
droxide[20] in DMSO gave the
monoesters 7 and 8 in 70 and
Entry
2
1
a
a
b
b
c
d
e
f
g
h
i
j
k
l
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
24
64
24
64
24
24
24
72
45
45
24
64
24
24
24
24
24
24
a
a
b
b
c
d
e
f
g
h
i
j
k
l
81
63
88
66
93
99
97
80
78
66
98
89:11
95:5
90:10
97:3
93:7/nd
96:4/nd
93:7/nd
95:5/nd
93:7/nd
92.5:7.5/nd
95:5/nd
84.5:15.5/nd
97:3/76:24
92.5:7.5/80:20
87.5:12.5/77:23
–
93:7/77.5:22.5
90:10/73:27
91:9/74.5:25.5
90:10/71:29
91:9/64:36
92:8/74:26
2[e]
3
4-FC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-MeOC6H4
2-furanyl
3-furanyl
Me
tBu
Ph
Ph
Ph
4[e]
5
6
7
8
88:12
77:23
87:13
71:29
79:21
84:16
88:12
–
88:12
84:16
80:20
71:29
76:24
82:18
9
10
11
12
13
14
15
16
17
18
[f]
–
4-FC6H4
4-ClC6H4
4-NO2C6H4
4-MeOC6H4
2-FC6H4
3-NO2C6H4
67
80
84
86
84
99
m
n
o
p
m
n
o
p
Ph
Ph
Ph
[a] Reaction conditions: 1 (0.3 mmol), 2 (0.12 mmol), PyBOX-1 (0.012 mmol), LaACTHNUTRGNEUNG(OTf)3 (0.012 mmol), 4 ꢁ MS
(20 mg), CH2Cl2 (0.8 mL), RT. [b] Yield of isolated product. [c] Determined by HPLC analysis with chiral sta-
tionary phases. [d] nd=not determined. [e] Reaction carried out at 08C. [f] No reaction was observed after
64 h.
was hydrolyzed upon treatment with HCl in THF at 408C to
give ketone 4 in quantitative yield without loss of optical
purity (Scheme 2). By comparison of the optical rotation
Figure 1. Proposed stereochemical model for the LaACTHNURGTNEUNG(OTf)3/PyBOX-1-cat-
alyzed enantioselective conjugate addition of methyl malonate to a,b-un-
saturated N-sulfonyl imines 2.
Scheme 2. Hydrolysis and determination of the absolute stereochemistry
of compound (E)-3a.
sign and chiral HPLC retention times of compound 4 ob-
tained in this way with those described in the literature for
its S enantiomer,[2o] we established the configuration of the
stereogenic center of (E)-3a (Table 2, entry 1) to be R.[17]
For the rest of compounds 3b–p, the stereochemistry was as-
signed upon the assumption of a common stereochemical
mechanism. These results indicate the preference of methyl
malonate to attack from the Si face of the double bond of
the unsaturated imine 2. Taking into account previous stud-
ies on LaIII/PyBOX-catalyzed reactions,[14a,18] we propose the
participation of an octa-coordinated LaIII species with both
the 1,3-dicarbonyl compound and the imine coordinated to
the metal center (Figure 1).[19] In this complex, the unsatu-
rated imine 2, in its s-trans conformation would be oriented
60% yield, respectively. Finally, we carried out the lactami-
zation of compounds 5 and 7 to give the chiral piperidones
9[21] and 10, respectively, by basic treatment with lithium
hexamethyl disilazide (LiHMDS) in toluene.[22]
Conclusion
In summary, we have reported the first enantioselective con-
jugate addition of dimethyl malonate to a,b-unsaturated N-
tosylimines to give the corresponding g-dehydro-d-amino
diesters bearing a stereogenic center at the allylic position,
which is catalyzed by LaIII/PyBOX complexes. The reaction
provides the E-enamine as the major diastereomer with
Chem. Eur. J. 2013, 19, 14861 – 14866
ꢅ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14863

G. Blay, J. R. Pedro et al.
Major E diastereomer: Oil; [a]2D0 =À76.0 (c=1.0 in CHCl3, e.r.=93:7);
1H NMR (300 MHz, CDCl3): d=7.57 (d, JH,H =8.4 Hz, 2H), 7.35–7.18 (m,
6H), 7.16 (d, JH,H =8.4 Hz, 2H), 6.96 (dd, JH,H =8.1, 2.4 Hz, 2H), 6.90
(dd, JH,H =8.1, 1.5 Hz, 2H), 6.05 (s, 1H), 5.95 (d, JH,H =10.8 Hz, 2H), 4.00
(t, JH,H =10.5 Hz, 1H), 3.77 (d, JH,H =10.5 Hz, 1H), 3.67 (s, 3H), 3.40 (s,
3H), 2.41 ppm (s, 3H); 13C NMR (75 MHz, CDCl3) d=168.0 (C), 167.7
(C), 143.7 (C), 141.2 (C), 136.4 (C), 135.8 (C), 135.3 (CH), 129.6 (CH),
129.1 (CH), 128.70 (CH), 128.69 (CH), 128.6 (CH), 127.7 (CH), 127.0
(CH), 117.2 (CH), 58.1 (CH), 52.6 (CH3), 52.4 (CH3), 44.1 (CH),
21.7 ppm (CH3).
Minor Z diastereomer: Oil; [a]D20 =À23.4 (c=0.95 in CHCl3, e.r.=n.d.);
1H NMR (300 MHz, CDCl3): d=7.81 (s, 1H), 7.50 (d, JH,H =8.1 Hz, 2H),
7.36–7.32 (m, 2H), 7.22–7.05 (m, 8H), 6.70–6.69 (m, 2H), 5.45 (dd, JH,H
=
10.8, 0.3 Hz, 2H), 3.89 (t, JH,H =10.5 Hz, 1H), 3.74 (d, JH,H =10.2 Hz,
1H), 3.63 (s, 3H), 3.37 (s, 3H), 2.30 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=169.7 (C), 167.7 (C), 143.4 (C), 138.8 (C), 137.8 (C), 137.3
(C), 136.5 (C), 129.7 (CH), 128.8 (CH), 128.6 (CH), 128.1 (CH), 127.8
(CH), 127.6 (CH), 127.4 (CH), 123.0 (CH), 57.8 (CH), 53.3 (CH3), 52.8
(CH3), 43.3 (CH), 21.6 ppm (CH3); HRMS (ESI): m/z: calcd for
C27H27NNaO6S: 516.1451 [M++Na]; found: 516.1453.
Hydrogenation of compound (R,E)-3a: A solution of (R,E)-3a (140 mg,
0.29 mmol, e.r.=93:7) in MeOH (12 mL) was stirred under a hydrogen
atmosphere (balloon) in the presence of 5% Pd/C (4 mg) for 4 h. Then,
the reaction mixture was filtered through a short pad of silica gel eluting
with EtOAc. The solvent was removed under reduced pressure to give
134 mg (95%) of compound as an approximately 25:75 mixture of two
diastereomers, which were separated after column chromatography on
silica gel eluting with hexane/EtOAc (90:10 to 60:40). Order of elution:
compound 6 (minor diastereomer) first, compound 5 (major diastereo-
mer) second. Chiral HPLC analysis (Chiralpak IC, hexane/iPrOH 80:20,
1 mLminÀ1): major diastereomer 5, major enantiomer (1R,3S): tr =
55.6 min, minor enantiomer (1S,3R): tr =63.6 min; minor diastereomer 6,
major enantiomer (1R,3R): tr =39.7 min, minor enantiomer (1S,3S)-5: tr =
46.6 min.
Scheme 3. Synthesis of d-aminoesters and lactams from 3a.
good yields and enantioselectivities. The enamino esters are
effective synthons for the preparation of optically active d-
aminoesters bearing two stereogenic centers at the b and d-
positions, and for the preparation of optically active lactams.
Major diastereomer (1R,3S)-5: Oil; [a]2D0 =À3.4 (c=1.0 in CHCl3, e.r.=
93:7); 1H NMR (300 MHz, CDCl3): d=7.34 (d, JH,H =8.4 Hz, 2H), 7.30–
7.27 (m, 3H), 7.24–7.17 (m, 3H), 7.08 (d, JH,H =8.4 Hz, 2H), 3.00–6.97
(m, 2H), 6.84–6.81 (m, 2H), 4.61 (d, JH,H =6.0 Hz, 1H), 3.77–3.70 (m,
1H), 3.72 (s, 3H), 3.59 (d, JH,H =10.5 Hz, 1H), 3.32 (s, 3H), 2.91 (td,
Experimental Section
General methods: Commercial reagents were used as purchased. Di-
chloromethane was freshly distilled from CaH2. Powdered 4 ꢁ MS were
stored in the oven at 1408C and left to reach room temperature in a dissi-
cator prior to use. Reactions were monitored by TLC analysis using
Merck Silica Gel 60 F-254 thin layer plates. Reactions were monitored by
TLC analysis using Merck Silica Gel 60 F-254 thin-layer plates. Flash
column chromatography was performed on Merck silica gel 60, 0.040–
0.063 mm. NMR spectra were recorded in the deuterated solvents as
stated, using residual nondeuterated solvent as an internal standard
J
H,H =11.2 Hz, 1H), 2.45–2.26 (m, 2H), 2.37 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3) d=168.5 (C), 167.9 (C), 143.2 (C), 138.9 (C), 138.7 (C),
137.0 (C), 129.5 (CH), 129.0 (CH), 128.7 (CH), 128.6 (CH), 128.4 (CH),
127.6 (CH), 127.3 (CH), 127.2 (CH), 58.4 (CH), 56.4 (CH), 52.7 (CH3),
52.3 (CH3), 42.3 (CH), 39.7 (CH2), 21.6 ppm (CH3).
Minor diastereomer (1R,3R)-6: Oil; [a]2D0 =À2.0 (c=0.6 in CHCl3, e.r.=
1
(CHCl3: d=7.26 for H and 77.16 ppm for 13C). The carbon type was de-
93:7); 1H NMR (300 MHz, CDCl3): d=7.54 (d, JH,H =8.4 Hz, 2H), 7.25–
termined by DEPT experiments. Specific optical rotations were measured
using sodium light (D line 589 nm). Mass spectra (ESI) were recorded on
a mass spectrometer equipped with an electrospray source with a capillary
voltage of 3.3 kV. Chiral HPLC analyses were performed in a chromato-
graph equipped with a UV diode-array detector by using chiral stationary
columns from Daicel. Retention times are given in min.
7.21 (m, 3H), 7.15–7.08 (m, 5H), 6.94–6.87 (m, 4H), 5.45 (d, JH,H
=
6.6 Hz, 1H), 4.08–4.01 (m, 1H), 3.77 (s, 3H), 3.59 (d, JH,H =10.2 Hz, 1H),
3.42 (td, JH,H =10.2, 3.0 Hz, 1H), 3.41 (s, 3H), 2.38 (s, 3H), 2.08–1.92 ppm
(m, 2H); 13C NMR (75 MHz, CDCl3) d=169.3 (C), 168.0 (C), 143.0 (C),
142.0 (C), 139.5 (C), 137.8 (C), 129.5 (CH), 128.8 (CH), 128.5 (CH),
128.4 (CH), 127.7 (CH), 127.4 (CH), 127.3 (CH), 126.1 (CH), 57.7 (CH),
56.1 (CH), 53.0 (CH3), 52.5 (CH3), 43.4 (CH2), 43.3 (CH), 21.6 ppm
(CH3); HRMS (ESI): m/z: calcd for C27H29NNaO6S: 516.1608 [M++Na];
found: 518.1613.
General procedure for the enantioselective conjugate addition of methyl
malonate to a,b-unsaturated N-sulfonylimines 2: Anhydrous LaACTHNUTRGNE(NUG OTf)3
(7.3 mg, 0.0125 mmol) and PyBOX-1 (4.6 mg, 0.012 mmol) were intro-
duced to a Schlenk tube and it was filled with nitrogen. Dry CH2Cl2
(0.4 mL) was added via syringe and the mixture was stirred for 30 min.
Powdered 4 ꢁ MS (20 mg) were then added followed by a solution of
imine 2 (0.12 mmol) dissolved in dry CH2Cl2 (0.4 mL) and dimethyl mal-
onate (35 mL, 0.3 mmol). The mixture was stirred at room temperature
for the indicated time and chromatographed on silica gel eluting with
hexane/EtOAc mixtures to give compounds 3. In general the minor Z
diastereomer eluted first from the column followed by the major E dia-
stereomer.
Decarboxylation of compound (R,S)-5: A 25% solution of tetraethylam-
monium hydroxyde in MeOH (157 mL, 0.23 mmol) was added to a solu-
tion of compound 5 (95.4 mg, 0.19 mmol, e.r.=91:9) in dimethylsulfoxide
(5.2 mL) under nitrogen, and the reaction flask was introduced in a bath
at 808C. Additional tetraethylammonium hydroxyde was added after 6
(157 mL, 0.23 mmol) and 24 h (53 mL, 0.08 mmol). After a total reaction
time of 24 h, the reaction mixture was diluted with EtOAc (60 mL),
washed with water (3ꢆ4 mL), brine (4 mL), and dried over MgSO4. Pu-
rification by column chromatography eluting with hexane/EtOAc gave
9 mg (10%) of lactam 9 (see below), followed by 58.0 mg (70%) of com-
pound 7. Chiral HPLC analysis (Chiralpak IC hexane-iPrOH 80:20,
1 mLminÀ1): major enantiomer: tr =26.5 min, minor enantiomer: tr =
29.1 min. Oil; [a]2D0 =À9.1 (c=1.0 in CHCl3, e.r.=91:9); 1H NMR
Dimethyl
2-[(R,E)-1,3-diphenyl-3-(tosylamino)allyl]malonate
(3a):
Chiral HPLC analysis: (Chiralpakl AD-H, hexane/iPrOH 80:20,
1 mLminÀ1): E diastereomer, major enantiomer (R): tr =13.9 min, minor
enantiomer (S): tr =18.3 min; Z diastereomer unresolved: tr =65.3 min.
14864
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Chem. Eur. J. 2013, 19, 14861 – 14866

An Expeditious Route to Chiral d-Aminoesters and Piperidones
FULL PAPER
(300 MHz, CDCl3): d=7.40 (d, JH,H =8.4 Hz, 2H), 7.35–7.25 (m, 3H),
7.21–7.12 (m, 3H), 7.08 (d, JH,H =8.4 Hz, 2H), 7.05–6.97 (m, 2H), 6.91–
6.82 (m, 2H), 5.09 (d, JH,H =6.6 Hz; NH), 3.88 (ddd, JH,H =10.5, 6.6,
5.4 Hz), 3.52 (s, 3H), 2.73 (m. 1H), 2.52 (m, 2H), 2.37 (s, 3H), 2.35–
2.12 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=172.2 (C), 143.0 (C),
142.2 (C), 139.6 (C), 137.2 (C), 129.4 (CH), 128.76 (CH), 128.75 (CH),
128.0 (CH), 127.8 (CH), 127.2 (CH), 127.1 (CH), 127.0 (CH), 56.4 (CH),
51.5 (CH3), 42.2 (CH2), 41.7 (CH2), 38.7 (CH), 21.6 ppm (CH3); HRMS
(ESI): m/z: calcd for C25H27NNaO4S: 460.1553 [M++Na]; found:
460.1560.
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0.056 mmol) in toluene (1.2 mL) under nitrogen was treated with 1m
LiHMDS in THF (112 mL, 0.112 mmol). The mixture was stirred at 908C
for 18 h. Then, the reaction was quenched with 1m HCl (1 mL), diluted
with water (4 mL), extracted with dichloromethane (3ꢆ30 mL), dried
over MgSO4, and concentrated under reduced pressure to give 19 mg
(73%) of compound 9: Oil; [a]D20 = +2.1 (c=0.8 in CHCl3, e.r.=91:9);
1H NMR (300 MHz, CDCl3): d=7.56 (d, JH,H =8.4 Hz, 2H), 7.40–7.20 (m,
8H), 7.14 (d, JH,H =8.4 Hz, 2H), 7.10–6.98 (m, 2H), 5.90 (dd, JH,H =5.1,
2.4 Hz), 3.72 (d, JH,H =12.0 Hz, 1H), 3.58 (s, 3H), 3.50 (td, JH,H =12.0,
3.0 Hz, 1H), 2.59 (td, JH,H =13.5, 5.4 Hz, 1H), 2.40 (s, 3H), 2.21 ppm (dt,
H,H =13.8, 2.7 Hz), 1H); 13C NMR (75 MHz, CDCl3) d=169.2 (C), 166.8
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(C), 144.3 (C), 140.0 (C), 139.5 (C), 135.9 (C), 129.8 (CH), 128.9 (CH),
128.7 (CH), 128.0 (CH), 127.7 (CH), 126.8 (CH), 59.9 (CH), 58.3 (CH),
52.6 (CH3), 37.8 (CH2), 37.4 (CH), 21.6 ppm (CH3); HRMS (ESI): m/z:
calcd for C26H26NO5S: 464.1526 [M++H]; found: 464.1529.
Acknowledgements
Financial support from the MINECO (Gobierno de EspaÇa) and
FEDER (European Union) (CTQ2009—13083), and from Generalitat
Valenciana (ACOMP2012–212 and ISIC2012/001) is gratefully acknowl-
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4 ꢁ MS work as effective proton scavengers favoring the generation
of metal enolates in high concentrations. For a discussion on the use
Received: July 10, 2013
Published online: September 17, 2013
14866
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Chem. Eur. J. 2013, 19, 14861 – 14866