Enantioselective addition of nitromethane to α-keto esters catalyzed by copper(II)-iminopyridine complexes

Article abstract of DOI:10.1039/b716446g

The copper complex of a chiral iminopyridine easily prepared from (R)-(-)-fenchone and picolylamine catalyzes the enantioselective Henry (nitroaldol) reaction between nitromethane and α-keto esters. Good yields and modest to good enantioselectivities are obtained for a wide range of α-keto esters, bearing aromatic, alkyl or alkenyl groups attached to the ketone carbonyl group. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b716446g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantioselective addition of nitromethane to a-keto esters catalyzed by
copper(II)–iminopyridine complexes
Gonzalo Blay,* Victor Herna´ndez-Olmos and Jose´ R. Pedro*
Received 25th October 2007, Accepted 23rd November 2007
First published as an Advance Article on the web 12th December 2007
DOI: 10.1039/b716446g
The copper complex of a chiral iminopyridine easily prepared from (R)-(−)-fenchone and picolylamine
catalyzes the enantioselective Henry (nitroaldol) reaction between nitromethane and a-keto esters.
Good yields and modest to good enantioselectivities are obtained for a wide range of a-keto esters,
bearing aromatic, alkyl or alkenyl groups attached to the ketone carbonyl group.
the reaction promoted by Et2Zn with some a-keto esters bearing
Introduction
aliphatic substituents. Low ee is obtained, however, with ethyl
The Henry or nitroaldol reaction represents an important proce-
phenyloxoacetate. The copper complexes of these ligands afford
products with reversed enantioselectivity.10 Recently, Deng et al.
dure for C–C bond formation, providing easy access to nitroalka-
nols by coupling of readily available nitroalkanes and carbonyl
have reported a highly enantioselective nitroaldol reaction of a-
compounds.1 Because of the chemical versatility of the nitro group,
the b-nitroalkanols obtained can be further transformed into
valuable polyfunctional molecular frameworks, such as 1,2-amino
alcohols, hydroxy acids, etc.2 Due to its significance in organic
synthesis, considerable effort has been dedicated to the develop-
ment of the catalytic enantioselective version of this reaction.3
As a consequence, a substantial advance has been achieved for
the enantioselective nitroaldol reaction with aldehydes, for which
several metal-catalyzed4 or organocatalytic5 procedures have been
developed.
In contrast, the development of the nitroaldol reaction with
ketones has met with limited success. In fact a catalytic enantios-
elective procedure for the nitroaldol reaction with simple ketones
still has to be developed, although Shibasaki has described a
resolution of racemic nitroalkanols proceeding from ketones.6 a-
Ketoesters, withanintermediatereactivitybetweensimpleketones
and aldehydes, are more prone to react with nitroalkanes to give
the corresponding b-nitro-a-hydroxy esters with the formation of
a quaternary stereogenic center.7 However, to date, only three
catalytic systems have been identified to afford synthetically
useful enantioselectivity for the addition of nitromethane to a-
keto esters. The first example, reported by Jørgensen, relied
on the combined use of the C2-symmetric Cu–bis(oxazoline)
(BOX) complex and triethylamine.8 The system afforded good
yields and enantioselectivities with a-keto esters bearing aliphatic
substituents, or aromatic rings with electron-withdrawing groups,
and more modest results with keto esters bearing aromatic rings
with electron-releasing groups. The same authors have reported a
related aza-Henry reaction employing tertiary nitro compounds
as nucleophiles and a-imino esters as electrophiles.9 Xu et al. have
developed a series of C2-symmetric tridentate bis(oxazoline) and
bis(thiazoline) ligands which catalyze the enantioselective Henry
reaction with a-keto esters in the presence of Zn(II) or Cu(II)
Lewis acids. Enantiomeric excesses up to 84% are obtained in
keto esters catalyzed by derivatized Cinchona alkaloids.11 The
reaction proceeds with good yields and enantioselectivities with
a range of aromatic and aliphatic a-keto esters. The b-nitro-a-
hydroxy esters that result from these reactions can be used as build-
ing blocks for the preparation of b-lactams, aziridines and other
synthetic intermediates for the preparation of natural products
and biologically active molecules.11 Despite the relative success
attained with some of these catalytic systems, some drawbacks are
still to be solved such as improved enantioselectivities, substrate
scope, reaction conditions or catalyst preparation. Therefore
there is still room for the development of new catalytic systems
that catalyze the Henry reaction with this particular kind of
substrates. As a part of our current research, we have developed
a new group of C1-symmetric N,N-ligands with iminopyridine
structures which are easily prepared in a modular way from readily
available monoterpene ketones and pyridylalkylamines (Fig. 1).12
Although the presence of C2-symmetry in the catalyst is considered
advantageous since it reduces the number of possible transition
states,13 recent examples have shown the potential of C1-symmetric
catalysts which, in some cases, can be more efficient than related
C2-systems.14
We have shown that some of these ligands in combination
with copper(II) acetate catalyze the Henry reaction between ni-
tromethane and aldehydes with high yields and good enantiomeric
excesses.12 In particular ligands 1 and 5 in combination with
Cu(OAc)2 and diisopropylethylamine (DIPEA) afforded the best
results in EtOH or CHCl3, respectively, yielding products with
reversed enantioselectivity (Scheme 1). In this article, we describe
the development of a new enantioselective Henry reaction between
nitromethane and a-keto esters by using this kind of ligands.
Results and discussion
Synthesis of ligand 8
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica, Universitat de
Vale`ncia, Dr. Moliner 50, E-46100-Burjassot, Vale`ncia, Spain. E-mail:
gonzalo.blay@uv.es, jose.r.pedro@uv.es; Fax: +34 963544328; Tel: +34
963544336
Ligand 8 was prepared in a similar way to ligands 1–7,12 by
condensation of commercially available (R)-(−)-fenchone and
picolylamine in the presence of a catalytic amount of BF3·Et2O
468 | Org. Biomol. Chem., 2008, 6, 468–476
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Scheme 2 Synthesis of ligand 8.
Optimization of the reaction conditions
We first focused on the addition of nitromethane to ethyl pheny-
loxoacetate (Scheme 3, R = Et). The reaction was first attempted
under the conditions previously developed for the addition of
nitromethane to aldehydes, using the complexes 1–Cu(OAc)2 and
5–Cu(OAc)2.12 However, in both cases the expected nitroalkanol
was obtained in racemic form. This result caused us to change
the initial reaction conditions drastically. Thus, following reaction
conditions similar to those described by Jørgensen, the reaction
with ethyl phenyloxoacetate was carried out using Cu(OTf)2 as
Lewis acid in nitromethane as solvent and in the presence of Et3N
(20 mol%). We were very pleased to observe that ligand 1 catalyzed
the reaction under these conditions giving the expected product
with 80% conversion and 54% ee in a short reaction time (Table 1,
entry 1). A screening of the different ligands was carried out under
these conditions (Table 1). Iminopyridine 8, derived from (R)-
(−)-fenchone, was the most efficient ligand in terms of conversion
and enantioselectivity giving the expected product in full conver-
sion and 70% ee (entry 8). Ligands 5 and 7 which bear an acidic
function required a larger amount of base for the reaction and
afforded the expected product with no or low enantioselectivity,
respectively (entries 5, 7). It should also be noticed that ligands
6 and 7 yielded products with the opposite stereochemistry to
those obtained with ligands 1–4 and 8. The use of Zn(OTf)2 or
Mg(OTf)2 instead of Cu(OTf)2 gave the nitroalkanol products in
racemic form.
Fig. 1 Structures of ligands 1–8.
Scheme 1 Henry reaction with aldehydes catalyzed with ligands 1 and 5.
Scheme 3 Addition of nitromethane to phenyloxoacetate esters.
with azeotropic removal of toluene–water (Scheme 2). Ligand
8 was obtained preferentially with the Z-geometry at the C–N
double bond as was confirmed by the observation of NOE between
the methylene group of the pyridylmethyl moiety (d 4.75) and the
two methyl groups at C3 of the fenchone framework (d 1.24 and
1.19) in NOE and NOESY experiments carried out in DMSO-d6
solution (Fig. 2)
Table 1 Copper(II)-catalyzed enantioselective addition of nitromethane
to ethyl phenyloxoacetate (R = Et) according to scheme 3. Ligand
screeninga
Entry
L
Time/h
Yieldb (%)
Eeb(%)
Config.c
1
2
3
4
5
6
7
8
1
3
24
4
80
46
91
98
97
29
78
97
54
29
48
50
0
22
13
70
R
R
R
R
—
S
2
3
4
3
5d
6
24
24
20
3
7e
8
S
R
a Cu(OTf)2 (20 mol%), L (20 mol%), Et3N (20 mol%), keto ester
(0.25 mmol) in 1 mL CH3NO2, rt. b Conversion and ee determined by
HPLC using a Chiralcel OD-H column. c Configuration assigned by
comparison of the optical rotation sign with literature data (ref. 8).
d 40 mol% Et3N was used. e 30 mol% Et3N was used.
Fig. 2 Some representative NOEs in compound 8.
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Table 2 Copper(II)-catalyzed enantioselective addition of nitromethane
to ethyl phenyloxoacetate (R = Et) according to Scheme 3. Effect of the
basea
Table 4 Copper(II)-catalyzed enantioselective addition of nitromethane
to phenyloxoacetate esters according to Scheme 3. Effect of the ester
group Ra
Entry Base
T/◦C Time/h Yieldb (%) Eeb (%)
Entry
R
T/◦C
Time/h
Yield (%)b
Ee (%)b
1
2
3
4
5
6
7
8
9
Et3N
Bu3N
rt
rt
rt
50
3
3
3
24
5
3.5
20
23
51
3
97
91
90
87
95
95
54
77
50
96
70
70
62
53
68
66
44
62
57
16
1
2
3
4
5
6
7
8
Et
Me
i-Pr
t-Bu
CCl3CH2
PhCH2
Et
rt
rt
rt
rt
rt
rt
3
3.5
4
97
96
95
84
90
90
94c
80c
70
70
62
69
64
59
78
81
DIPEA
Proton sponge
Dicyclohexylamine rt
4
3.5
3.5
24
46
i-Pr2NH
K2CO3
Cs2CO3
Et3Nc
rt
50
rt
rt
rt
0
Et
−20
a Cu(OTf)2 (20 mol%), 8 (20 mol%), Et3N (20 mol%), keto ester
(0.25 mmol) in 1 mL CH3NO2. b Conversion and ee determined by HPLC
using a Chiralcel OD–H column. c Yield of isolated product.
10
Et3Nd
a Cu(OTf)2 (20 mol%), 8 (20 mol%), base (20 mol%), keto ester (0.25 mmol)
in 1 mL CH3NO2, rt. b Conversion and ee determined by HPLC using a
Chiralcel OD–H column; (R)-configuration. c 10 mol% Et3N was used.
d 40 mol% Et3N was used.
Also substrate generality was studied with a number of ethyl
keto esters having different substituents on the ketone carbonyl
group (Scheme 4). The results are gathered in Table 5. Unlike
the catalytic system formed by tridentate bis-oxazolines and
diethylzinc,10 which failed with aromatic keto esters, good yields
and enantiomeric excesses were obtained with our catalyst with
a number of aromatic (entries 1–11) and aliphatic (entries 12–
16) keto esters. Yields above 80% and enantiomeric excesses
between 71–81% were obtained for most of the aromatic keto
esters. The presence of the electron-releasing methoxy group of
ethyl (p-methoxyphenyl)oxoacetate (11e) caused a decrease in the
ee of the Henry product (entry 5). A similar effect was observed
with 2-oxo-2-(2-thienyl)acetate (11k), which is substituted with an
electron-rich thiophene heterocycle. The low yield and ee obtained
with compound 11i is most probably due to the bulkiness of
the two trifluoromethyl groups (entry 9). With alkyl-substituted
keto esters (entries 12–16) we obtained similar results with either
linear (entries 12–14) or branched groups (entries 15–16), which
afforded the expected products with good yields and enantiomeric
excesses in the range of 80%. These results are similar to those
reported by Xu with alkyl-substituted a-keto esters,10 although the
enantioselectivities are lower than those reported with the Cu(II)–
BOX system,8 with the exception of compound 11n (entry 14),
for which the Cu(II)–BOX catalyst afforded the expected product
with 77% ee but only 47% yield. Finally, the more challenging b,c-
unsaturated a-keto esters were screened as substrates for the Henry
reaction (entries 17, 18). With these substrates the 1,4-addition
reaction to the double bond can compete with the 1,2-addition
to the carbonyl group. Furthermore, low enantioselectivities with
these substrates are obtained with the Cu(II)–BOX system.8 Under
our reaction conditions, the reaction took place with excellent
chemoselectivity and yields giving the 1,2-addition products 12q
and 12r, exclusively, with good enantiomeric excesses in both cases
(entries 17, 18).
The effect of different bases was tested next (Table 2). A
number of primary, secondary and tertiary amines, as well as
some inorganic bases, were tested. All of them led to reduced
enantioselectivities compared to Et3N, with the exception of Bu3N
which gave similar results (entry 2). The chiral Lewis acid :
Brønsted base ratio was crucial to the outcome of the reaction. A
lower concentration of Brønsted base relative to Lewis acid led to
a significant drop in enantioselectivity and yield (entry 9), whereas
a higher concentration of Brønsted base gave a high yield of the
Henry product with low ee (entry 10), in a similar way to that which
has previously been described with the Cu(II)–BOX catalyst.8
The anion of the copper salt was also important to the outcome
of the reaction (Table 3). Thus, from all the copper salts tested,
only Cu(ClO4)2 was able to induce some enantioselectivity in the
reaction although the product was obtained in lower ee than with
Cu(OTf)2. On the other hand, the use of CuCl2 or Cu(OAc)2·H2O
gave racemic products (entries 3–4).
Substrate scope
The influence of the ester group in the substrate was tested
next (Table 4). A number of phenyloxoacetate esters were used
as substrates. The best results in terms of conversion and
enantioselectivity were obtained with ethyl (entry 1) and methyl
(entry 2) esters, which gave almost identical results. A further
improvement of the enantioselectivity with the ethyl ester was
obtained by lowering the temperature. Thus, the reaction with
◦
ethyl phenyloxoacetate could be carried out at −20 C to attain
the expected product in 80% yield and 81% ee (entry 8).
Table 3 Copper(II)-catalyzed enantioselective addition of nitromethane
to ethyl phenyloxoacetate (R = Et) according to Scheme 3. Effect of the
copper(II) salta
Entry
Copper(II) salt
Time/h
Yieldb (%)
Eeb (%)
1
2
3
4
Cu(OTf)2
Cu(ClO4)2
CuCl2
Cu(OAc)2·H2O
3
3
4
3
97
95
90
99
70
35
0
0
a CuX2 (20 mol%), 8 (20 mol%), Et3N (20 mol%), keto ester (0.25 mmol)
in 1 mL CH3NO2, rt. b Conversion and ee determined by HPLC using a
Chiralcel OD–H column; (R)-configuration.
Scheme 4 Addition of nitromethane to ethyl a-keto esters. Substrate
scope.
470 | Org. Biomol. Chem., 2008, 6, 468–476
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Table 5 Copper(II)-catalyzed enantioselective addition of nitromethane to a-keto esters according to Scheme 4a
Entry
11 (R)
T/◦C
Time/h
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph-
a
b
c
d
e
f
g
h
i
j
k
l
m
n
−20
0
−20
−20
rt
−20
−20
−20
−20
−20
rt
−20
−20
−20
46
28
22
16
25
22
28
46
70
94
3
80
86
80
93
73
92
91
90
73
83
75
99
85
81
81
74
76
74
48
71
63
76
52
75
56
78
78
82
4-Me-C6H4-
4-Cl-C6H4-
4-Br-C6H4-
4-MeO-C6H4-
4-NO2–C6H4-
4-CN-C6H4-
3,5-F2–C6H3-
3,5-(CF3)2–C6H3-
2-Naphthyl-
2-Thienyl-
CH3-
CH3(CH2)9-
4
23
40
15
16
(CH3)2CH-
o
p
−20
−20
4
4
99
94
80
78
17
18
q
r
−20
−20
22
24
94
86
73
80
a Cu(OTf)2 (20 mol%), 8 (20 mol%), Et3N (20 mol%), 11 (0.25 mmol) in 1 mL CH3NO2. b Yields refer to isolated product 12 after column chromatography.
c Ee determined by chiral HPLC. (R)-configuration assigned by comparison of the optical rotation signs and HPLC retention times with data reported
in the literature for known compounds, and by analogy for all new compounds.
Mechanistic and stereochemical considerations
the Lewis acid is in excess with respect to the base, then the low
concentration of free amine brings about a slow reaction with low
conversion and poor enantioselectivity.
On the other hand, coordination of the keto ester to the metal
complex 8–CuX2 requires a shift of the X groups (the copper salt
counter ion) by the dicarbonyl substrate, and this is only effective
if X is a poorly coordinating anion such as triflate or, to a lesser
extent, perchlorate, while more coordinating anions such as acetate
or chloride lead to non-selective catalysts.
The reaction catalyzed by the 8–Cu(OTf)2 complex yields
the Henry products with the R configuration at the stere-
ogenic center. Based on previously reported steric and electronic
considerations,4c we propose two transition state models that
account for the observed stereochemistry, which may be both
operative (Fig. 3). The active species simultaneously binds the two
reaction partners to the metal center. In the first model8 (a) the
keto functionality of the a-keto ester is coordinated to one of the
more Lewis acidic equatorial positions, away from the fenchone
skeleton, for maximum electrophilic activation and minimization
The results obtained in the catalytic Henry reaction with different
amounts of base (Table 2, entries 1, 9 and 10) and with different
copper salts (Table 3) can be rationalized (Scheme 5) in terms
very similar to those described by Jørgensen for the Cu(II)–BOX
catalyzed reaction. The enantioselective catalytic pathway requires
the coordination of the a-keto ester to the copper atom of the
8–Cu complex and the presence of a deprotonated molecule of
nitromethane (a nitronate). A competitive equilibrium between tri-
ethylamine and the initial 8–CuX2 with an inactive 8–CuX(Et3N)
is established. The Henry reaction requires the presence in the
solution of enough base to deprotonate the nitromethane. If the
base is in excess with respect to the Lewis acid, the equilibrium
is shifted toward the inactive complex, hence trapping the chiral
Lewis acid. The remaining base induces a non-enantioselective
pathway between the nitronate and uncoordinated keto ester. If
Fig. 3 Proposed transition states for the addition of nitromethane to
a-keto esters catalyzed by 8–Cu(II).
Scheme 5 Mechanistic pathways for the enantioselective Henry reaction.
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of steric interactions. The ester carbonyl group would coordinate
to the copper ion from the upper apical position in order to
minimize steric interactions of the OR group with the C1- or the
axial C3n-methyl groups of the monoterpene. Thus the nitronate
would bind to the vacant equatorial position facing the Re face
of the ketone carbonyl group. In the second model (b) the a-keto
ester would coordinate to the copper atom by the two equatorial
positions of the complex plane.10 The nitronate would occupy
the upper, less hindered, apical position from which it would be
transferred to the Re face of the ketone carbonyl group. In this
model (b), both the electrophile and nucleophile would reach the
maximum activation, although it is probable that coordination of
the keto ester in this way would be hampered by steric interactions
with the pyridine ring and the 1-Me group of the fenchone.
from commercial sources, keto esters 11d, 11i–j, and 11m–p were
prepared by addition of Grignard reagents to ethyl oxalate,17 keto
esters 11q–r were prepared by Wittig reaction.18
Synthesis of ligand 8
A solution of (R)-(−)-fenchone (9, 5.0 g, 32.2 mmol), picolylamine
(10, 3.53 mL, 33.8 mmol) and BF3·Et2O (0.18 mL) in toluene
(75 mL) in a round bottomed flask provided with a Dean–Stark
system was refluxed for 7 d under nitrogen. The reaction mixture
was diluted with EtOAc (50 mL), washed with saturated aqueous
NaHCO3 (15 mL) and dried over MgSO4. Solvent removal
was followed by column chromatography eluting with hexane–
dichloromethane to give 3.22 g (64%) of unreacted fenchone and
1.64 g (21%) of ligand 8: [a]D25 −70.9 (c 0.38 in CHCl3); m/z (EI) 242
(M+, 62%), 241 (100), 93 (65); 242.1780 (M+), C16H22N2 requires
242.1783; dH (300 MHz, CDCl3) 8.50 (1H, d, J 5.4), 7.67 (1H,
t, J 7.5, pyr-H), 7.52 (1H, d, J 7.5, pyr-H), 7.13 (1H, d, J 5.4,
pyr-H), 4.93 (1H, d, J 16.8, CH2-N), 4.86 (1H, d, J 16.8, CH2-
N), 1.87–1.39 (7H, m), 1.29 (3H, s, Me), 1.28 (3H, s, Me), 1.22
(3H, s, Me); dC (300 MHz, CDCl3) 186.5 (s), 161.3 (s), 148.7 (d),
136.5 (d), 121.4 (d), 121.1 (d), 55.8 (t), 52.9 (s), 49.8 (d), 44.4 (s),
42.2 (t), 33.9 (t), 25.2 (t), 24.2 (q), 23.6 (q), 17.7 (q); dH (400 MHz,
DMSO-d6) 8.48 (1H, ddd, J 4.8, 2.0, 0.8, pyr-H), 7.76 (1H, td, J
8.0, 2.0, pyr-H), 7.41 (1H, d, J 8.0, pyr-H), 7.24 (1H, ddd, J 8.0,
4.8, 0.8, pyr-H), 4.75 (2H, AB system, CH2-N), 1.85 (1H, m, 4-H),
1.74 (1H, tt, J 12.0, 2.5, 5n-H), 1.68 (1H, dq, J 10.0, 2.5, 7s-H),
1.58 (1H, m, 5x-H), 1.52 (1H, td, J 12.0, 3.2, 6x-H), 1.38 (1H, dd,
J 10.0, 1.6, 7a-H), 1.31 (1H, m, 6n-H), 1.24 (3H, s, 3n-Me), 1.90
(3H, s, 3x-Me), 1.15 (3H, s, 1-Me); dc (300 MHz, DMSO-d6) 184.5
(s), 160.7 (s), 148.5 (d), 136.5 (d), 121.6 (d), 121.1 (d), 55.4 (t),
52.4 (q), 49.1 (d), 43.7 (s), 41.5 (t), 33.4 (t), 24.8 (t), 23.9 (q),
23.3 (q), 17.7 (q).
Conclusion
We have described a new catalytic enantioselective Henry reaction
with a-keto esters, using a copper(II)–iminopyridine complex in
combination with triethylamine. The ligands are easily prepared in
a one-step procedure from economical monoterpene ketones and
pyridylalkylamines, their modular design allows structural variety
and they can be prepared in both enantiomeric forms starting from
the appropriate ketone enantiomer. The Henry reaction works
with a wide range of substrates including, aromatic, aliphatic
and b,c-unsaturated a-keto esters. The corresponding products
are obtained with high yields and modest to good enantiomeric
excesses. Compared with the two previously described metal-based
procedures, our catalytic system shows broader scope than the
combination of Zn with tridentate bis-oxazolines, which is limited
to aliphatic keto esters, and it gives higher enantioselectivities with
unsaturated keto esters than the Cu(II)–BOX system. The results
reported here show the usefulness of this kind of iminopyridines,
recently introduced by us, as ligands for metal-catalyzed enantios-
elective reactions.
Synthesis of 2ꢀ,2ꢀ,2ꢀ-trichloroethyl 2-oxo-2-phenylacetate
Oxalyl chloride (0.43 mL, 5.0 mmol) was added to a solution
of phenylglyoxylic acid (0.5 g, 3.33 mmol) and DMF (1 drop) in
dichloromethane (10 mL) at 0 ◦C. The reaction mixture was stirred
at rt for 4 h and concentrated under reduced pressure. The resulting
oil was dissolved in dichloromethane (10 mL), a catalytic amount
of 4-DMAP was added and a solution of trichloroethanol (323 lL,
3.33 mmol) and Et3N (1.33 mL) in dichloromethane (10 mL)
was added dropwise. After 24 h, the reaction mixture was diluted
with dichloromethane (10 mL), washed with water (2 × 10 mL),
10% aqueous NaOH (10 mL) and brine (10 mL), and dried over
MgSO4. Removal of the solvent under reduced pressure followed
by column chromatography eluting with hexane–dichloromethane
(2 : 8) gave 623 mg (67%) of the title compound: m/z (EI) 280 (M+,
0.1%), 105 (100), 77 (43); 279.9470 (M+), C10H7Cl3O3 requires
279.9461; dH (300 MHz, CDCl3) 8.07–8.04 (2H, m, Ph), 7.70 (1H,
tt, J 6.6, 1.2, Ph), 7.57–7.52 (2H, m, Ph), 5.03 (2H, s, CCl3–CH2–
O); dC (75.5 MHz, CDCl3) 184.6 (s), 161.9 (s), 135.4 (d), 132.0 (s),
130.1 (d), 129.0 (d), 93.9 (d), 74.5 (t).
Experimental
General
Commercial reagents were used as purchased. Glassware was
oven-dried overnight at 120 ◦C. 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. Specific optical rotations were recorded on a
Perkin-Elmer 241 polarimeter using sodium light (D line 589 nm).
NMR spectra were recorded on Bruker Advance spectrometers in
the deuterated solvents as stated, using residual non-deuterated
solvent as internal standard and CFCl3 as internal standard
for 19F NMR. J values are given in Hz. The carbon type was
determined by DEPT experiments. Mass spectra were recorded
on a Fisons Instruments VG Autospec GC 8000 series. Mass
spectra (EI) were run at 70 eV. Mass spectra (FAB) were carried
out at 30 kV in a MNBA matrix. Chiral HPLC analyses were
performed in a Hitachi Elite Lachrom instrument equipped with
a Hitachi UV diode-array L-4500 detector using chiral stationary
columns from Daicel. Retention times are given in min. tert-Butyl15
and benzyl phenyloxoacetate16 were prepared according to the
literature. Keto esters 11a–c, 11e–h, 11k–l and 11n–o were obtained
General procedure for the enantioselective nitroaldol reaction
Copper(II) triflate (18.0 mg, 0.05 mmol) contained in a Schlenk
tube was dried under vacuum for 30 min. After this time, the
tube was filled in with nitrogen and a solution of ligand 8
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(13.0 mg, 0.05 mmol) in nitromethane (1 mL) was added. After 1 h,
triethylamine (7 lL, 0.05 mmol) was added (the solution changed
from blue to dark green). The reaction mixture was introduced in a
bath at the reaction temperature and the keto ester 11 (0. 25 mmol)
was added. Stirring was continued until the reaction was complete
(TLC). The b-nitro-a-hydroxy esters 12 were obtained by column
chromatography. Yields and ee are shown in Tables 4 and 5.
CH2Cl2, ee 64%); m/z (EI) 341 (M+, 0.2%), 166 (75), 123 (66),
105 (100), 91 (46), 77 (60); 340.9639 (M+), C11H10Cl3NO5 requires
340.9625; dH (300 MHz, CDCl3) 7.68–7.65 (2H, m, Ph), 7.43–7.10
(3H, m, Ph), 5.38 (1H, d, J 14.4, CH2NO2), 4.97 (1H, d, J 12.0,
CCl3CH2O), 4.80 (1H, d, J 12.0, CCl3CH2O), 4.75 (1H, d, J 14.4,
CH2NO2), 4.20 (1H, br s, OH); dC (75 MHz, CDCl3) 170.4 (s),
135.2 (s), 129.6 (d), 129.1 (d), 125.4 (d), 93.7 (s), 80.6 (t), 76.2 (s),
75.9 (q).
(−)-Methyl 2-hydroxy-3-nitro-2-phenylpropanoate (Table 4,
entry 2)
(−)-Benzyl 2-hydroxy-3-nitro-2-phenylpropanoate (Table 4,
entry 6)
Purified by column chromatography eluting with hexane–EtOAc
(92 : 8). Enantiomeric excess (70%) determined by HPLC (Chiral-
cel OD-H), hexane–i-PrOH 90 : 10, 1 mL min−1, major enantiomer
(−) tR 15.9, minor enantiomer (+) tR 13.1; [a]2D5 −15.6 (c 0.54 in
CH2Cl2, ee 70%); m/z (EI) 225 (M+, 0.7%), 166 (25), 105 (100), 77
(28); 225.0639 (M+), C10H11NO5 requires 225.0637; dH (300 MHz,
CDCl3) 7.61–7.58 (2H, m, Ph), 7.41–7.26 (3H, m, Ph), 5.26 (1H,
d, J 14.1, CH2NO2), 4.69 (1H, d, J 14.1, CH2NO2), 4.29 (1H, br s,
OH), 3.90 (3H, s, MeO); dC (75 MHz, CDCl3) 172.2 (s), 136.2 (s),
129.1 (d), 128.9 (d), 125.2 (d), 80.7 (t), 76.1 (s), 54.0 (q).
Purified by column chromatography eluting with hexane–EtOAc
(92 : 8). Enantiomeric excess (59%) determined by HPLC (Chiral-
cel OD-H), hexane–i-PrOH 90 : 10, 1 mL min−1, major enantiomer
(−) tR 20.5, minor enantiomer (+) tR 15.3; [a]2D5 −26.5 (c 0.91 in
CH2Cl2, ee 59%); m/z (EI) 302 (M+ + 1, 0.2%), 166 (54), 123 (31),
105 (100), 91 (97), 77 (15); 302.1031 (M+ + 1), C16H16NO5 requires
302.1028; dH (300 MHz, CDCl3) 7.58–7.55 (2H, m, Ph), 7.39–7.33
(6H, m, Ph), 7.31–7.25 (2H, m, Ph), 5.29 (2H, s, PhCH2), 5.25 (1H,
d, J 14.1, CH2NO2), 4.67 (1H, d, J 14.1, CH2NO2), 4.25 (1H, br s,
OH); dC (75 MHz, CDCl3) 171.6 (s), 136.2 (s), 134.2 (s), 129.2 (d),
128.9 (d), 128.8 (d), 128.7 (d), 128.5 (d), 125.2 (d), 80.7 (t), 76.1
(s), 69.2 (t).
(−)-Isopropyl 2-hydroxy-3-nitro-2-phenylpropanoate (Table 4,
entry 3)
Purified by column chromatography eluting with hexane–EtOAc
(92 : 8). Enantiomeric excess (62%) determined by HPLC (Chiral-
pak AD-H), hexane-i-PrOH 95 : 5, 1 mL min−1, major enantiomer
(−) tR 17.2, minor enantiomer (+) tR 15.5; [a]2D5 −2.3 (c 1.07 in
CH2Cl2, ee 62%); m/z (EI) 253 (M+, 0.1%), 166 (15), 105 (100), 77
(26); 253.0945 (M+), C12H15NO5 requires 253.0950; dH (300 MHz,
CDCl3) 7.63–7.60 (2H, m, Ph), 7.44–7.37 (3H, m, Ph), 5.24 (1H,
d, J 13.8, CH2NO2), 5.19 (1H, m, J 6.3, OCHMe2), 4.67 (1H, d, J
13.8, CH2NO2), 4.24 (1H, br s, OH), 1.35 (3H, d, J 6.3, OCHMe2),
1.29 (3H, d, J 6.3, OCHMe2); dC (75 MHz, CDCl3) 171.1 (s), 136.6
(s), 129.0 (d), 128.8 (d), 125.2 (d), 80.7 (t), 75.9 (s), 71.9 (d), 21.5 (q),
21.4 (q).
(R)-(−)-Ethyl 2-hydroxy-3-nitro-2-phenylpropanoate (12a)8,11
Purified by column chromatography eluting with hexane–EtOAc
(92 : 8). Enantiomeric excess (81%) determined by HPLC (Chiral-
cel OD-H), hexane–i-PrOH 90 : 10, 1 mL min−1, major enantiomer
(R) tR 12.9, minor enantiomer (S) tR 10.2; [a]2D5 −15.7 (c 1.06 in
CH2Cl2, ee 81%); dH (300 MHz, CDCl3) 7.62–7.59 (2H, m), 7.44–
7.35 (3H, m, Ph), 5.26 (1H, d, J 14.1, CH2NO2), 4.68 (1H, d, J
14.1, CH2NO2), 4.46–4.29 (2H, CH3CH2O), 4.24 (1H, br s, OH),
1.34 (3H, t, J 7.2, CH3CH2O); dC (75 MHz, CDCl3) 171.7 (s),
136.4 (s), 129.1 (d), 128.9 (d), 125.2 (d), 80.8 (t), 76.0 (s), 63.6 (t),
13.9 (q).
(+)-tert-Butyl 2-hydroxy-3-nitro-2-phenylpropanoate (Table 4,
(R)-(−)-Ethyl 2-hydroxy-3-nitro-2-p-tolylpropanoate (12b)
entry 4)
Purified by column chromatography eluting with hexane–EtOAc
(92 : 8). Enantiomeric excess (74%) determined by HPLC (Chiral-
cel OD-H), hexane–i-PrOH 90 : 10, 1 mL min−1, major enantiomer
(R) tR 13.0, minor enantiomer (S) tR 9.3; [a]2D5 −16.6 (c 1.06
in CH2Cl2, ee 74%); m/z (EI) 253 (M+, 0.6%), 119 (100), 91
(28); 253.0954 (M+), C12H15NO5 requires 253.0950; dH (300 MHz,
CDCl3) 7.50–7.46 (2H, m, Ar), 7.21 (2H, d, J 8.1, Ar), 5.24 (1H, d,
J 14.1, CH2NO2), 4.66 (1H, d, J 14.1, CH2NO2), 4.48–4.27 (2H,
m, CH3CH2O), 4.20 (1H, br s, OH), 2.35 (3H, s, Me-Ar), 1.33 (3H,
t, J 7.2, CH3CH2O); dC 75 MHz, CDCl3) 171.8 (s), 139.1 (s), 133.5
(s), 129.5 (d), 125.1 (d), 80.8 (t), 75.9 (s), 63.5 (t), 21.0 (q) 13.9 (q).
Purified by column chromatography eluting with hexane–EtOAc
(92 : 8). Enantiomeric excess (69%) determined by HPLC (Chiral-
cel OD-H), hexane–i-PrOH 90 : 10, 1 mL min−1, major enantiomer
(+) tR 8.9, minor enantiomer (−) tR 7.4; [a]2D5 +4.9 (c 0.59 in
CH2Cl2, ee 69%); m/z (EI) 267 (M+, 0.1%), 166 (31), 120 (36),
105 (100), 77 (23), 57 (72); 267.1113 (M+), C13H17NO5 requires
267.1107; dH (300 MHz, CDCl3) 7.55–7.51 (2H, m, Ph), 7.36–7.28
(3H, m, Ph), 5.13 (1H, d, J 14.1, CH2NO2), 4.58 (1H, d, J 14.1,
CH2NO2), 4.17 (1H, br s, OH), 1.44 (9H, s, Me3C); dC (75 MHz,
CDCl3) 170.5 (s), 137.0 (s), 129.9 (d), 128.9 (d), 125.2 (d), 85.0 (s),
80.8 (t), 75.9 (s), 27.7 (q).
(R)-(−)-Ethyl 2-(4-chlorophenyl)-2-hydroxy-3-nitropropanoate
(−)-Trichloroethyl 2-hydroxy-3-nitro-2-phenylpropanoate
(12c)8,11
(Table 4, entry 5)
Purified by column chromatography eluting with hexane–EtOAc
(92 : 8). Enantiomeric excess (76%) determined by HPLC (Chiral-
cel OD-H), hexane–i-PrOH 90 : 10, 1 mL min−1, major enantiomer
(R) tR 12.8, minor enantiomer (S) tR 10.5; [a]2D5 −25.4 (c 0.83 in
CH2Cl2, ee 76%); dH (300 MHz, CDCl3) 7.56 (2H, d, J 8.7, Ar),
Purified by column chromatography eluting with hexane–EtOAc
(92 : 8). Enantiomeric excess (64%) determined by HPLC (Chiral-
cel OD-H), hexane–i-PrOH 90 : 10, 1 mL min−1, major enantiomer
(−) tR 17.0, minor enantiomer (+) tR 10.9; [a]2D5 −9.4 (c 0.96 in
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7.40–7.36 (2H, m, Ar), 5.22 (1H, d, J 14.1, CH2NO2), 4.64 (1H, d,
J 14.1, CH2NO2), 4.44–4.31 (2H, m, CH3CH2O), 4.25 (1H, br s,
OH), 1.34 (3H, t, J 7.2, CH3CH2O); dC (75 MHz, CDCl3) 171.3 (s),
135.3 (s), 134.9 (s), 129.1 (d), 126.8 (d), 80.6 (t), 75.7 (s), 63.8 (t),
13.9 (q).
CH3CH2O), 1.34 (3H, t, J 7.2, CH3CH2O); dC (75 MHz, CDCl3)
170.6 (s), 141.3 (s), 132.6 (d), 126.3 (d), 118.0 (s), 113.3 (s), 80.3 (t),
75.8 (s), 64.2 (t), 13.9 (q).
(R)-(−)-Ethyl 2-(3,5-difluorophenyl)-2-hydroxy-3-nitropropanoate
(12h)
(R)-(−)-Ethyl 2-(4-bromophenyl)-2-hydroxy-3-nitropropanoate
Purified by column chromatography eluting with hexane–EtOAc
(92 : 8). Enantiomeric excess (76%) determined by HPLC (Chi-
ralcel OD-H), hexane–i-PrOH 90 : 10, 0.5 mL min−1, major
enantiomer (R) tR 17.9, minor enantiomer (S) tR 16.9; [a]2D5 −11.8
(c 1.01 in CH2Cl2, ee 76%); m/z (EI) 275 (M+, 0.4%), 141 (100),
113 (26); 275.0604 (M+), C11H11F2NO5 requires 275.0605; dH
(300 MHz, CDCl3) 7.23–7.14 (2H, m, Ar), 6.83 (1H, tt, J 8.7, 2.4,
Ar), 5.17 (1H, d, J 14.1, CH2NO2), 4.63 (1H, d, J 14.1, CH2NO2),
4.49–4.31 (2H, m, CH3CH2O), 4.31 (1H, br s, OH), 1.36 (3H, t,
J 7.2, CH3CH2O); dC (75 MHz, CDCl3) 170.7 (C), 163.2 (d, JC-F
249.9, CF), 163.0 (d, JC-F 249.9, CF), 140.2 (t, JC-F 9.0, C), 109.1–
108.7 (m, 2 × CH), 104.7 (t, JC-F 25.5, CH), 80.3 (CH2), 75.5 (C),
64.2 (CH2), 13.9 (CH3); dF (282 MHz, CDCl3) −107.8.
(12d)
Purified by column chromatography eluting with hexane–EtOAc
(92 : 8). Enantiomeric excess (74%) determined by HPLC (Chiral-
cel OD-H), hexane–i-PrOH 90 : 10, 1 mL min−1, major enantiomer
(R) tR 15.5, minor enantiomer (S) tR 11.3; [a]2D5 −16.3 (c 1.02 in
CH2Cl2, ee 74%); m/z (EI) 319 (2.1%), 317 (M+, 2.1%), 246 (21),
244 (21), 185 (98), 183 (100), 157 (16), 155 (18); 316.9896 (M+),
C11H12BrNO5 requires 316.9899; dH (300 MHz, CDCl3) 7.55–7.47
(4H, m, Ar), 5.22 (1H, d, J 14.1, CH2NO2), 4.64 (1H, d, J 14.1,
CH2NO2), 4.45–4.29 (2H, m, CH3CH2O), 4.25 (1H, br s, OH),
1.34 (3H, t, J 7.2, CH3CH2O); dC (75 MHz, CDCl3) 171.2 (s),
135.4 (s), 132.0 (d), 127.1 (d), 123.6 (s), 80.5 (t), 75.7 (s), 63.9 (t),
13.9 (q).
(R)-(−)-Ethyl 2-(3,5-bis(trifluoromethyl)phenyl)-
(R)-(−)-Ethyl 2-hydroxy-2-(4-methoxyphenyl)-3-nitropropanoate
2-hydroxy-3-nitropropanoate (12i)
(12e)8,11
Purified by column chromatography eluting with hexane–diethyl
ether (90 : 10). Enantiomeric excess (52%) determined by HPLC
(Chiralpak AD-H), hexane–i-PrOH 99 : 1, 0.5 mL min−1, major
enantiomer (R) tR 20.6, minor enantiomer (S) tR 16.9; [a]2D5 −6.2
(c 1.11 in CH2Cl2, ee 52%); m/z (EI) 375 (M+, 0.1%), 356 (21),
259 (46), 256 (38), 241 (100), 227 (28), 213 (34); 375.0560 (M+),
C13H11F6NO5 requires 375.0541; dH (300 MHz, CDCl3) 8.15 (2H, s,
Ar), 7.92 (1H, s, Ar), 5.26 (1H, d, J 14.1, CH2NO2), 4.68 (1H, d,
J 14.1, CH2NO2), 4.54–4.36 (2H, m, CH3CH2O), 4.47 (1H, br s,
OH), 1.37 (3H, t, J 7.2, CH3CH2O); dC (75 MHz, CDCl3) 170.3
(C), 139.1 (C), 132.4 (q, JC-F 33.9, C), 126.0 (q, JC-F 3.0, CH),
123.3 (m, JC-F 3.8, CH), 122.9 (q, JC-F 273.3, CF3), 80.4 (CH2),
64.5 (CH2), 13.8 (CH3); dF (282 MHz, CDCl3) −63.4.
Purified by column chromatography eluting with hexane–EtOAc
(92 : 8). Enantiomeric excess (48%) determined by HPLC (Chiral-
cel OD-H), hexane–i-PrOH 90 : 10, 1 mL min−1, major enantiomer
(R) tR 15.7, minor enantiomer (S) tR 14.8; [a]2D5 −10.5 (c 0.83 in
CH2Cl2, ee 48%); dH (300 MHz, CDCl3) 7.51 (2H, d, J 9.0, Ar),
6.91 (2H, d, J 9.0, Ar), 5.22 (1H, d, J 14.1, CH2NO2), 4.65 (1H, d,
J 14.1, CH2NO2), 4.44–4.27 (2H, m, CH3CH2O), 4.21 (1H, br s),
3.81 (3H, s, MeO), 1.33 (3H, t, J 7.2, CH3CH2O); dC (75 MHz,
CDCl3) 171.8 (s), 160.1 (s), 128.3 (s), 126.5 (d), 114.2 (d), 80.8 (t),
75.7 (s), 63.4 (t), 55.3 (q), 13.9 (q).
(R)-(−)-Ethyl 2-hydroxy-3-nitro-2-(4-nitrophenyl)propanoate
(12f)8
(R)-(−)-Ethyl 2-hydroxy-2-(2-naphthyl)-3-nitropropanoate (12j)
Purified by column chromatography eluting with hexane–EtOAc
(85 : 15). Enantiomeric excess (71%) determined by HPLC
(Chiralcel OD-H), hexane–i-PrOH 90 : 10, 1 mL min−1, major
enantiomer (R) tR 26.6, minor enantiomer (S) tR 24.5; [a]2D5 −12.1
(c 1.07 in CH2Cl2, ee 71%); dH (300 MHz, CDCl3) 8.25 (2H, d, J
9.0, Ar), 7.85 (2H, d, J 9.0, Ar), 5.28 (1H, d, J 14.1, CH2NO2),
4.68 (1H, d, J 14.1, CH2NO2), 4.48–4.31 (2H, m, CH3CH2O), 4.42
(1H, br s, OH), 1.35 (3H, t, J 7.2, CH3CH2O); dC (75 MHz, CDCl3)
170.5 (s), 148.3 (s), 143.1 (s), 126.7 (d), 123.9 (d), 80.3 (t), 75.9 (s),
64.3 (t), 13.9 (q).
Purified by column chromatography eluting with hexane–EtOAc
(92 : 8). Enantiomeric excess (75%) determined by HPLC (Chiral-
cel OD-H), hexane–i-PrOH 80 : 20, 1 mL min−1, major enantiomer
(R) tR 34.6, minor enantiomer (S) tR 12.3; [a]2D5 −37.7 (c 1.01 in
CHCl3, ee 75%); dH (300 MHz, CDCl3) 8.13 (d, J 1.5, 1H, Ar),
7.89–7.83 (3H, m, Ar), 7.67 (1H, dd, J 9.0, 2.1, Ar), 7.56–7.51
(2H, m, Ar), 5.40 (1H, d, J 14.1, CH2NO2), 4.77 (1H, d, J 14.1,
CH2NO2), 4.48–4.31 (2H, m, CH3CH2O), 4.39 (1H, br s), 1.36
(3H, t, J 7.2, CH3CH2O); dC (75 MHz, CDCl3) 171.6 (s), 133.6
(s), 133.2 (s), 133.0 (s), 128.8 (d), 128.4 (d), 127.6 (d), 127.0 (d),
126.7 (d), 125.1 (d), 122.3 (d), 80.7 (t), 76.2 (s), 63.7 (t), 14.0 (q).
(R)-(−)-Ethyl 2-(4-cyanophenyl)-2-hydroxy-3-nitropropanoate
(12g)11
(R)-(−)-Ethyl 2-hydroxy-3-nitro-2-(2-thienyl)propanoate (12k)
Purified by column chromatography eluting with hexane–EtOAc
(90 : 10). Enantiomeric excess (63%) determined by HPLC
(Chiralcel OD-H), hexane–i-PrOH 90 : 10, 1 mL min−1, major
enantiomer (R) tR 23.8, minor enantiomer (S) tR 22.3; [a]2D5 −18.2
(c 1.07 in CHCl3, ee 63%); dH (300 MHz, CDCl3) 7.78 (2H, d, J 8.7,
Ar), 7.72–7.69 (2H, m, Ar), 5.24 (1H, d, J 14.1, CH2NO2), 4.65
(1H, d, J 14.1, CH2NO2), 4.65 (1H, br s, OH), 4.47–4.30 (2H, m,
Purified by column chromatography eluting with hexane–EtOAc
(92 : 8). Enantiomeric excess (56%) determined by HPLC (Chiral-
cel OD-H), hexane–i-PrOH 95 : 5, 1 mL min−1, major enantiomer
(R) tR 15.6, minor enantiomer (S) tR 14.8; [a]2D5 −17.0 (c 0.45 in
CH2Cl2, ee 56%); m/z (EI) 245 (M+, 1.3%), 172 (15), 126 (17), 111
(100); 245.0350 (M+), C9H11NO5S requires 245.0358; dH (300 MHz,
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CDCl3) 7.33 (1H, dd, J 4.8, 0.8, Het), 7.14 (1H, dd, J 3.6, 0.8, Het),
7.02 (1H, dd, J 4.8, 3.6, Het), 5.18 (1H, d, J 14.1, CH2NO2), 4.76
(1H, d, J 14.1, CH2NO2), 4.49–4.33 (2H, m, CH3CH2O), 4.46 (1H,
br s, OH), 1.37 (3H, t, J 7.2, CH3CH2O); dC (75 MHz, CDCl3)
170.6 (s), 140.4 (s), 127.5 (d), 126.8 (d), 125.1 (d), 80.6 (t), 74.8 (s),
63.9 (t), 13.9 (q).
3.57 (1H, br s, OH), 1.97 (1H, m, J 6.9, Me2CH), 1.33 (3H, t, J
7.2, CH3CH2O), 0.98 (3H, d, J 6.9, Me2CH), 0.89 (3H, d, J 6.9,
Me2CH); dC (75 MHz, CDCl3) 173.0 (s), 80.1 (t), 77.5 (s), 62.9 (t),
34.0 (d), 16.8 (q), 16.2 (q), 14.0 (q).
(R)-(+)-Ethyl 2-cyclohexyl-2-hydroxy-3-nitropropanoate (12p)
Purified by column chromatography eluting with hexane–EtOAc
(80 :20). Enantiomeric excess (78%) determined by HPLC (Chi-
ralcel OD-H), hexane–i-PrOH 90 : 10, 0.5 mL min−1, major
enantiomer (R) tR 11.6, minor enantiomer (S) tR 12.3; [a]2D5 +17.3
(c 1.05 in CH2Cl2, ee 78%); m/z (EI) 246 (M+ + 1, 7%), 172 (46),
129 (57), 117 (30), 111 (41), 83 (100), 55 (43); 246.1344 (M+ + 1),
C11H19NO5 requires 246.1263; dH (300 MHz, CDCl3) 4.81 (1H, d,
J 13.5, CH2NO2), 4.68 (1H, d, J 13.5, CH2NO2), 4.39–4.28 (2H,
m, CH3CH2O), 3.58 (1H, br s, OH), 1.79–1.59 (5H, m), 1.40–1.01
(6H, m), 1.33 (3H, t, J 7.2, CH3CH2O); dC (75 MHz, CDCl3) 172.9
(s), 79.9 (t), 77.6 (s), 62.9 (t), 43.7 (d), 26.7 (t), 26.2 (t), 26.0 (t),
25.9 (t), 25.8 (t), 14.0 (q).
(R)-(+)-Ethyl 2-hydroxy-2-methyl-3-nitropropanoate (12l)8,10,11
Purified by column chromatography eluting with hexane–EtOAc
(80 : 20). Enantiomeric excess (78%) determined by HPLC
(Chiralpak AD-H), hexane–i-PrOH 90 : 10, 0.5 mL min−1, major
enantiomer (R) tR 20.6, minor enantiomer (S) tR 19.4; [a]2D5 +15.3
(c 0.54 in CH2Cl2, ee 78%); dH (300 MHz, CDCl3) 4.84 (1H, d, J
13.8, CH2NO2), 4.55 (1H, d, J 13.8, CH2NO2), 4.41–4.25 (2H, m,
CH3CH2O), 3.76 (1H, br s, OH), 1.45 (3H, s, MeCO), 1.34 (3H, t,
J 7.2, CH3CH2O); dC (75 MHz, CDCl3) d 173.4 (s), 80.9 (t), 72.4
(s), 63.1 (t), 23.8 (q), 14.0 (q).
(R)-(+)-Ethyl 2-hydroxy-2-(nitromethyl)dodecanoate (12m)
(R, E)-(−)-Ethyl 2-hydroxy-2-(nitromethyl)pent-3-enoate (12q)8,11
Purified by column chromatography eluting with hexane–EtOAc
(95 : 5). Enantiomeric excess (78%) determined by HPLC (Chi-
ralcel OD-H), hexane–i-PrOH 98 : 2, 0.5 mL min−1, major
enantiomer (R) tR 14.7, minor enantiomer (S) tR 15.8; [a]2D5 +8.4
(c 0.50 in CH2Cl2, ee 78%); m/z (FAB) 304 (M+ + 1, 100%), 289
(12), 154 (95); 304.2112 (M+ + 1), C15H30NO5 requires 304.2124;
dH (300 MHz, CDCl3) 4.81 (1H, d, J 13.5, CH2NO2), 4.55 (1H, d,
J 13.5, CH2NO2), 4.42–4.26 (2H, m, CH3CH2O), 3.70 (1H, br s,
OH), 1.73–1.55 (2H, m), 1.54–1.39 (1H, m), 1.33 (3H, t, J 7.2,
CH3CH2O), 1.24 (14H, m), 1.14–1.03 (1H, m), 0.87 (3H, t, J 6.6,
Me); dC (75 MHz, CDCl3) 172.9 (s), 80.9 (t), 75.2 (s), 63.0 (t),
36.5 (t), 31.8 (t), 29.5 (t), 29.4 (t), 29.3 (t), 29.3 (t), 29.3 (t), 22.6 (t),
22.6 (t), 14.1 (q), 14.1 (q).
Purified by column chromatography eluting with hexane–EtOAc
(90 : 10). Enantiomeric excess (73%) determined by HPLC
(Chiralpak AD-H), hexane–i-PrOH 90 : 10, 0.8 mL min−1, major
enantiomer (R) tR 10.7, minor enantiomer (S) tR 9.8; [a]2D5 −46.7
(c 1.11 in CHCl3, ee 73%); dH (300 MHz, CDCl3) 6.18 (1H,
m, olefinic), 5.44 (1H, d, J 15.3, olefinic), 4.86 (1H, d, J 14.1,
CH2NO2), 4.47 (1H, d, J 14.1, CH2NO2), 4.45–4.25 (2H, m,
CH3CH2O), 3.79 (1H, br s, OH), 1.74 (3H, dt, J 6.6, 1.5, Me-
olefinic), 1.33 (3H, t, J 7.2, CH3CH2O); dC (75 MHz, CDCl3)
171.8 (s), 130.7 (d), 125.7 (d), 79.9 (t), 75.1 (s), 63.2 (t), 17.6 (q),
14.0 (q).
(R, E)-(−)-Ethyl 5-(benzyloxy)-2-hydroxy-2-
(nitromethyl)pent-3-enoate (12r)11
(R)-(+)-Ethyl 2-hydroxy-2-(nitromethyl)-4-phenylbutanoate
(12n)8,10,11
Purified by column chromatography eluting with hexane–EtOAc
(90 : 10). Enantiomeric excess (80%) determined by HPLC
(Chiralpak AD-H), hexane–i-PrOH 90 : 10, 0.8 mL min−1, major
enantiomer (R) tR 20.7, minor enantiomer (S) tR 19.1; [a]2D5 −27.1
(c 1.05 in CHCl3, ee 80%); dH (300 MHz, CDCl3) 7.39–7.30 (5H,
m, Ph), 6.25 (1H, dt, J 15.3, 4.8, olefinic), 5.76 (1H, dt, J 15.3,
1.8, olefinic), 4.89 (1H, d, J 13.8, CH2NO2), 4.53 (2H, s, CH2O),
4.49 (1H, d, J 13.8, CH2NO2), 4.42–4.26 (2H, m, CH3CH2O),
3.89 (1H, br s, OH), 1.34 (3H, t, J 7.2, CH3CH2O); dC (75 MHz,
CDCl3) 171.4 (s), 137.7 (s), 131.6 (d), 128.4 (d), 127.8 (d), 127.7 (d),
125.7 (d), 79.8 (t), 75.1 (s), 72.7 (t), 69.0 (t), 63.4 (t), 13.9 (q).
Purified by column chromatography eluting with hexane–EtOAc
(90 : 10). Enantiomeric excess (82%) determined by HPLC
(Chiralpak AD-H), hexane–i-PrOH 90 : 10, 1 mL min−1, major
enantiomer (R) tR 14.4, minor enantiomer (S) tR 11.7; [a]2D5 +23.8 (c
1.08 in CH2Cl2, ee 82%); dH (300 MHz, CDCl3) 7.32–7.14 (5H, m,
Ph), 4.84 (1H, d, J 13.8, CH2NO2), 4.59 (1H, d, J 13.8, CH2NO2),
4.41–4.24 (2H, m, CH3CH2O), 3.87 (1H, br s, OH), 2.88–2.78
(1H, m, CH2CO), 2.54–2.44 (1H, m, CH2CO), 2.08–1.91 (2H, m,
CH2Ph), 1.34 (3H, t, J 7.2, CH3CH2O); dC (75 MHz, CDCl3)
172.6 (s), 140.2 (s), 128.5 (d), 128.3 (d), 126.3 (d), 80.8 (t), 75.0 (s),
63.2 (t), 38.2 (t), 29.0 (t), 14.0 (q).
Acknowledgements
(R)-(+)-Ethyl 2-hydroxy-3-methyl-2-(nitromethyl)butanoate (12o)
Financial support from the Ministerio de Educacio´n y Ciencia
(CTQ 2006–14199) and the Generalitat Valenciana (GV 05/10)
is gratefully acknowledged. V.H.-O. thanks the Universitat de
Vale`ncia by a pre-doctoral grant (V Segles program).
Purified by column chromatography eluting with hexane–EtOAc
(80 : 20). Enantiomeric excess (80%) determined by HPLC (2 ×
Chiralpak AD-H), hexane–i-PrOH 99 : 1, 1 mL min−1, major
enantiomer (R) tR 104.9, minor enantiomer (S) tR 110.4; [a]2D5 +17.9
(c 0.37 in CH2Cl2, ee 80%); m/z (EI) 206 (M+ + 1, 0.2%), 132 (22),
89 (60), 85 (22), 71 (100); 206.1020 (M+ + 1), C8H15NO5 requires
206.0950; dH (300 MHz, CDCl3) 4.82 (1H, d, J 13.5, CH2NO2),
4.66 (1H, d, J 13.5, CH2NO2), 4.35 (2H, qd, J 7.2, 1.5, CH3CH2O),
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