Chiral monometallic lanthanide(III) salt complexes are arrayed acid-base networks for enantioselective catalysis: A direct, nitroaldol (Henry) reaction

Article abstract of DOI:10.1016/j.tetasy.2005.11.014

Shelf stable, but kinetically labile, highly symmetric, 3:1 complexes of 3,3′-bis-diethylaminomethyl-2,2′-dihydroxy-1,1′-dinaphthalene 1 ('binolam') with lanthanide(III) triflates are easily available compounds possessing an extended array of acid and bas

Full text of DOI:10.1016/j.tetasy.2005.11.014

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 99–106
Chiral monometallic lanthanide(III) salt complexes are
arrayed acid–base networks for enantioselective catalysis:
a direct, nitroaldol (Henry) reaction
*
´
´
´
´
Jose M. Saa, Fernando Tur, Jose Gonzalez and Manuel Vega
Departament de Quı´mica, Universitat de les Illes Balears, 07122 Palma de Mallorca, Spain
Received 17 October 2005; accepted 14 November 2005
Available online 5 December 2005
Abstract—Shelf stable, but kinetically labile, highly symmetric, 3:1 complexes of 3,30-bis-diethylaminomethyl-2,20-dihydroxy-1,10-
dinaphthalene 1 (ꢀbinolamꢁ) with lanthanide(III) triflates are easily available compounds possessing an extended array of acid
and base sites. The enantiopure lanthanum derivative is especially suited to catalyze the direct nitroaldol (Henry) reaction enantio-
selectively. Added non-aqueous base accelerates the reaction.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
(LH-LH = binol derivative; binol = bis-2,20-dihydroxy-
1,10-dinaphthalene) are the triple conjugate acids of
the hitherto missing monometallic complexes of type B
(i.e., Ln = lanthanide, M = H), of which the hetero-
bimetallic congeners are the well-known Shibasakiꢁs
catalysts (Ln = lanthanide, M = alkali metal).2 Provided
we could remove XH from type C complexes with non-
aqueous base, we expected the resulting B system
(M = H) to be worth the analysis for enantioselective
catalysis.
Danishefsky was the first to assess the potential of chiral
lanthanide(III) salts of type A [Ln(L-L)3] to act as chiral
Lewis acids (LA) (Fig. 1) in asymmetric catalysis.1 More
recently, Shibasaki et al. demonstrated the usefulness of
bimetallic lanthanoate complexes of type B [Ln-
(L-L)3M3] to work as Lewis acid–Lewis base (LALB)
bifunctional catalysts.2 Ionic complexes of type C
[Ln(LH-LH)3X3] have not been discovered yet for enan-
tioselective catalysis, although Kobayashi,3 Marko,
4
´
Aspinall,5 Jacobsen,6 and Evans7 pioneered the explora-
tion of 1:1 or 2:15 chiral complexes of lanthanide(III)
salts as Lewis acid (LA) catalysts. Type C complexes
2. Results and discussion
We set out to study a project aimed at finding chiral,
thermodynamically stable, as well as highly symmetric
and well-defined (for eventual easy fine tuning), com-
plexes of lanthanide(III) salts (LnX3) capable of operat-
ing in conventional as well as, if appropriately designed,
non-conventional solvents.
*
X
*
M
L
*
LH
Ln
L
L
Ln
L
LH
LH
L
L
L
*
X
*
Ln
M
*
LH
LH
*
L
L
L
L
HL
L
X
We herein report on the straightforward formation of
thermodynamically, shelf stable, though nevertheless
kinetically labile, highly symmetric, type C complexes
M
*
*
A
B
C
Ln = lanthanide
L-L = acac-
Ln = lanthanide(III)
L-L = binolate2-
M = alkali metal(I)
Ln = lanthanide(III), Sc(III)
LH-LH = binol derivative
3,30-bis-diethylaminomethyl-2,20-dihydroxy-1,10-
-
X = CF3SO3
of
dinaphthalene 1 (ꢀbinolamꢁ) with lanthanide(III) triflates,8
which are armed with an array of acid and base sites
(Lewis acid–Bro¨nsted acid–Lewis base: LABALB)
ideally suited to catalyze the direct nitroaldol (Henry)
reaction9 between nitromethane and aldehydes in an
Figure 1. General structures for lanthanide 3:1 complexes.
*
Corresponding author. Tel.: +34 971 17 32 62; fax: +34 971 17 34
26; e-mail: jmsaa@uib.es
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.11.014

100
J. M. Saa´ et al. / Tetrahedron: Asymmetry 17 (2006) 99–106
X
Y
*
H
HY
N
L
Y
L
H
H
YH
YH
L
L
L
O
O
*
*
Ln
L
X
*
H
L
L
H
N
H
Y
*
HY
Y
X
2Ln Ln = lanthanide; LH-LH = binolam
(S)-1 binolam
X = CF3SO3- ; Y = NEt2
Figure 2. Type C lanthanide complexes of bifunctional ꢀbinolamꢁ (S)-1.
enantioselective manner,10 either in the absence or pres-
ence of externally added amines, which accelerate the
reaction.11,12
Type C complexes 2Ln (Fig. 2) were obtained in quanti-
tative yield by simply mixing the enantiomerically pure,
bifunctional ligand (S)-1 (ꢀbinolamꢁ, 3 equiv) with
1 equiv of the dried lanthanide(III) triflate (Ln = La,
Pr, Nd, Sm, Eu, Gd, Yb, as well as Sc), in dry aceto-
nitrile at room temperature, followed by evaporation
to dryness. Titration experiments revealed a strong ten-
dency of ꢀbinolamꢁ 1 to form stable 3:1 complexes.13,14
Moreover, complexation of racemic (RS)-1 with the tri-
flates above, gave rise to the formation of a pair of enan-
tiomers only, eventually recognized to be the D,R,R,R
and D,S,S,S pair. No other diastereomeric species were
noticed in the NMR spectra of the complexes resulting
from racemic (RS)-1. All these compounds are shelf
stable solids that can be conveniently stored for months
without any special precaution.
Figure 3. DFT-optimized structure for m2La.
characterized by an arrayed La–O–H–N acid–base net-
work having average distances La–O = 2.548, O–
˚
H = 1.817, H–N = 1.049 A, angles La–O–H = 127.8ꢁ
and dihedrals La–O–N–H = ꢀ125.3ꢁ.
In solution these compounds are kinetically labile as
demonstrated by both the exchange (slow on the
NMR time scale) observed by H NMR of a solution
Initial exploration of complexes 2Ln as catalysts for
the direct, enantioselective nitroaldol condensation
between nitromethane and hydrocinnamaldehyde, led
us to select binolam-derived lanthanum complex 2La
as the most interesting candidate for development.
Working with a polar solvent (CaH2-dried acetonitrile
was the best choice) and lowering the temperature
down to ꢀ40 ꢁC, led to a sound increase in enantiose-
lectivity. At ꢀ40 ꢁC, the lower limit for the catalyst
load was fixed at 5 mol %. During isolation of the nit-
roaldol products 3a–i, the valuable enantiomerically
pure ꢀbinolamꢁ 1 could be recovered unaltered by
acid–base extraction, as previously reported.16 In strik-
ing contrast with expectations for a dissociative pro-
cess, we found that the presence of excess ꢀbinolamꢁ 1
(up to 3 equiv) actually accelerated the direct nitroaldol
condensation.19 Indeed, our best results were found
when carrying out the reaction in the presence of
external strong bases (1 equiv with respect to catalyst)
such as 1,1,3,3-tetramethylguanidine (TMG), 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU), 2,8,9-trimethyl-2,5,8,
9-tetraaza-1-phosphabicyclo[3,3,3]undecane (Verkadeꢁs
base), or 1,8-bis(dimethylamino)naphthalene (proton
spongeꢂ), the last being the best choice. This surprising
behavior is, however, not without precedent.10a,10d The
payoff for working under these conditions is that care
has to be taken to avoid water entering the reaction
mixture as it immediately hydrolyzes the catalyst, thus
stopping the reaction early.
1
of 2La, to which labeled ligand 1-d4 (deuterium instead
of hydrogen at the benzylic carbons of 1) was added,
also by means of an EXSY NMR experiment.15 Unfor-
tunately, in solution, the addition of water caused
hydrolysis (easier for those lanthanides having large,
expansible coordination numbers). All compounds ap-
pear to be isostructural, D3-symmetric, 6-coordinate
3:1 complexes according to their spectroscopic proper-
ties (1H, 13C, 45Sc NMR, FAB-MS, ESI-MS). More-
over, variable temperature (ꢀ40 to +60 ꢁC) NMR
studies in CD3CN showed them to be unique species
in this temperature range (no change was observed,
besides some freezing of the N-CH2–CH3 moiety at
low temperature, and minute hydrolysis occurring at
high temperature).
The DFT-optimized geometry for m2La (a somewhat
simplified model of 2La in which ꢀbinolamꢁ 1 was substi-
tuted by ꢀbiphelamꢁ16) obtained by computation using
B3LYP/6-31G* for non-metal atoms, and the Stuttgart
group pseudopotential (MWB) for the lanthanide
atom,17 attest to the chiral-at-metal18 nature of these
species, thus supporting the fact that complexation of
racemic ꢀbinolamꢁ 1 leads to the formation of the
D,R,R,R and D,S,S,S pair of enantiomers, only
(Fig. 3). In addition, it shows its symmetric structure

J. M. Saa´ et al. / Tetrahedron: Asymmetry 17 (2006) 99–106
Table 1. Enantioselective nitroaldol condensationsa
101
.
[(∆,S,S,S)-binolam]3 La(OTf)3 (5 mol %)
OH
O
Amine (5 mol %)
NO2
(R)-3
+
CH3NO2
CH3CN, -40 oC, 24-96 h
R
R
H
Entry
R
Product
Yield (%)b DBU/
proton spongeꢂ
ee (%)c DBU/
proton spongeꢂ
1
2
3
4
5
6
7
8
9
Ph(CH2)2
c-C6H11
t-Bu
i-Pr
Ph
p-NO2C6H4
p-CNC6H4
p-FC6H4
3a
3b
3c
3d
3e
3f
91/90
63/71
91/91
95/95
88/96
98/73
79/75
62/65
56/98
87/91
80/99
92/83
90/90
65/80
31/28
64/76
75/58
72/72d
3g
3h
3i
(E)-PhCH@CH
a 1 equiv of aldehyde (0.53 mmol) and 10 equiv of nitromethane were used.
b Isolated yields.
c Determined by HPLC (Daicel Chiralpak AD or Chiralcel OD columns); absolute configuration assigned on the basis of literature data.
d Absolute configuration not determined.
In exploring the scope of the reaction of nitromethane
with aldehydes, we found that the reaction works well
for aliphatic, aromatic, and a,b-unsaturated aldehydes,
as illustrated in Table 1. We attributed the poor results
obtained for p-nitro-benzaldehyde due to its ability to
coordinate to the lanthanum core, thereby blocking fur-
ther action at the core nucleus, thus facilitating external
racemic condensation. This result also suggests that
nitromethane likely coordinates to lanthanum prior to
deprotonation (actually, no deprotonation was observed
on mixing nitromethane and proton spongeꢂ in CD3CN).
Even though we have not yet carried out a detailed
kinetic analysis of the reaction, some mechanistic clues
Figure 4. DFT-optimized structure for m4La.
are worth noting: (i) we have found no significant
˚
NLE, thus suggesting the involvement of monomeric
complexes, only;20 (ii) working in the presence of excess
ꢀbinolamꢁ 1 (up to 3 equiv), under the otherwise standard
reaction conditions (i.e., no other external base added),
we found an increase in rate, as expected for an associa-
tive process, likely an acid–base reaction (see part v
below); (iii) working in the presence of external strong
bases led to a significant increase in rate and enantio-
selectivity; (iv) reaction of the species resulting from
mixing La(OTf)3, enantiomerically pure, commercial
(S)-binol [instead of ꢀbinolamꢁ (S)-1] and TMG in either
1:1:2 or 1:3:6 ratios led to the nitroaldol product 3a in
0%, and 7% ee, thus suggesting that our lanthanum cat-
alyst is likely providing its arrayed acid–base network
for binding, activation of the reagents, and eventually
catalyzing the direct nitroaldol condensation; (v) ESI-
MS analysis of some 2Ln complexes, including that of
Sc, in the presence of either proton spongeꢂ, or ꢀbino-
lamꢁ 1, show that precatalysts 2Ln actually lose three
TfOH units (the parent ion shows-up at m/z =
[Mꢀ3TfOH+H+]), thereby giving rise to 4Ln (Ln = La,
Sm, Sc), that is, the Shibasakiꢁs type B species hav-
ing M = H (Fig. 1); the DFT-optimized (B3LYP/
6-31G* and MWB) structure of model m4La (Fig. 4)
shows that this species is in fact a 6-coordinate lantha-
num triaryloxide derivative (La–O1–3 = 2.300, 2.305,
(2.592, 2.688, 2.780 A), the hydroxyl oxygen atoms
being hydrogen-bonded to the nearby nitrogen atoms
˚
(O4–HN = 1.029, O4H–N = 1.647 A, with angle O4–
˚
H–N = 150ꢁ; O5–HN = 1.025, O5H–N = 1.485 A, with
angle
O5–H–N = 153ꢁ;
O6–HN = 1.008,
O6H–
21
˚
N = 1.788 A, with angle O6–H–N = 149.6ꢁ); these
data compared to that of the precursor m2La illustrate
the existence of an active acid–base network system,
which presumably facilitates the catalytic action; (vi)
moreover, careful solution NMR studies upon 2Sc and
2La showed that titration with 1 equiv of proton
spongeꢂ leads to the full 2Sc or partial 2La removal
of one hydrogen atom. Further addition of base does
not change this situation (excess base is in slow equili-
brium). As expected, this mixture has been proved to
catalyze the condensation of added nitromethane and
aldehyde.
On the basis of these grounds, we propose the following
rationale for the mechanistic cycle of the direct nitro-
aldol coupling: monodeprotonation of precatalyst 2La
so as to produce locally, that is, at least at one single
point, the corresponding monometallic type B complex
(M = H) having an array of acid and base sites
(La–O–H–N) for binding of both nitromethane and
aldehyde, followed by deprotonation, coupling, and
eventual recycling of the catalyst.22
˚
2.320 A) having three extra HO4–6–La bonding contacts

102
J. M. Saa´ et al. / Tetrahedron: Asymmetry 17 (2006) 99–106
3. Conclusions
as external reference calibrated at 0 ppm. Low-resolu-
tion mass spectra by use of electronic impact ionization
(EI+) were obtained on a (GC–MS) Shimadzu QP-5000.
Low- and high-resolution mass spectra by use of electro-
spray ionization (ESI+) were obtained on a Micromass
Autospect 3000 spectrometer. Low- and high-resolution
mass spectra by use of fast atom bombardment ioniza-
tion (FAB+) were obtained on a Kratos MS80-RFA
spectrometer using p-nitrobenzyl alcohol (NBA) as
matrix, unless otherwise indicated.
In conclusion, the straightforward access to shelf stable,
chiral-at-metal, ionic complexes of lanthanide(III) tri-
flates (scandium included) of type C, is secured by using
binaphthol derivatives having dialkylaminomethyl arms
at C-3 and C-30 as ligands. The lanthanum triflate com-
plex 2La is, at the moment, our best catalyst for the nit-
roaldol reaction between nitromethane and aldehydes of
all kinds, in an enantioselective manner, either in the
absence (slow reaction) or presence of externally added
bases (fast reaction), proton spongeꢂ, or DBU, being
our best choices. The evidence provided (ESI-MS,
NMR and DFT calculations) suggests the intermediacy
of a monometallic type B complex (i.e., Ln = lantha-
nide, M = H). We expect that these complexes might
be of further use for enantioselective catalysis.
4.1.1. (S)-3,30-Bis(diethylaminomethyl)-2,20-dihydroxy-
1,10-dinaphthalene [(S)-binolam] (S)-1. Obtained, as
reported by Katsuki,24 by reduction of the precursory
amide with LiAlH4. A pale yellow solid. (53.6% yield).
25
Mp: 139–140 ꢁC. ½aꢁ589 ¼ ꢀ140:8 (c 0.5, CHCl3). 1H
NMR (300 MHz, CDCl3) d: 11.9 (br s, 2H), 7.77 (d,
J = 7.9 Hz, 2H), 7.63 (s, 2H), 7.28–7.18 (m, 6H), 4.19
(d, J = 13.7 Hz, 2H), 3.93 (d, J = 13.7 Hz, 2H), 2.80–
2.60 (m, 8H), 1.10 (t, J = 7.2 Hz, 12H) ppm. 13C
NMR (75.5 MHz, CDCl3) d: 154.7, 134.3, 128.8,
128.2, 128.1, 126.3, 125.6, 125.4, 123.3, 117.1, 58.2,
46.9, 11.7 ppm. IR (KBr) m: 2973, 2825, 2680, 1625,
1430, 1250, 880, 750 cmꢀ1. MS (EI+) m/z (%): 456
[M]+ (79), 427 (66), 385 (86), 354 (100), 312 (84). HRMS
(EI+): Exact mass calcd for C30H36O2N2 [M]+:
456.277679, found: 456.277010. Elemental analysis calcd
for C30H36O2N2: C, 78.91; H, 7.95; N, 6.13. Found: C,
79.09; H, 7.92; N, 5.81. The enantiomeric purity of 1
(>96% ee) was determined by HPLC with a Daicel Chir-
alpak AD column (using a 90:10 hexane/isopropanol
solvent mixture, at a flow rate of 1 mL/min, and UV
detection at k = 254 nm), the major enantiomer having
tr = 5.7 min, whereas the minor one showed
tr = 6.6 min. The absolute configuration of the major
enantiomer was assigned on the basis of literature
data.24
4. Experimental
4.1. General
Commercial (Sigma–Aldrich Co.) scandium(III) and
lanthanide(III) triflates of the highest quality available
were dried under vacuum for 96 h at 220 ꢁC in a Buchi
¨
Glass Oven B-580 and stored in a desiccator. Prior to
use in the nitroaldol reaction, they were dried under vac-
uum for an extra 2 h at 220 ꢁC. Aldehydes, obtained
from commercial sources, were distilled prior to use,
except for 4-nitrobenzaldehyde and 4-cyanobenzalde-
hyde, which were used as received. Nitromethane was
used as received. Commercial grade solvents were boiled
with the appropriate drying agent23 and eventually dis-
tilled prior to use. Analytical thin layer chromatography
was performed on Macherey-Nagel Polygram Sil G/
UV254 plates, whose visualization was accomplished
under UV light or under iodine vapors. Purification of
reaction products was carried out by flash chromatogra-
phy using Merck silica gel 60 (70–230 mesh). Melting
4.1.2. (RS)-3,30-Bis(diethylaminodideuteromethyl)-2,20-
dihydroxy-1,10-dinaphthalene [(RS)-binolam-d4] 1-d4.
Obtained, as above, by reduction of the precursor amide
with LiAlD4. A pale yellow solid. (60% yield). Mp: 139–
points were measured on a Buchi Dr. Tottoli apparatus
¨
and are uncorrected. Optical rotations were measured
on a Perkin Elmer 341 LC polarimeter provided with
1
140 ꢁC. H NMR (300 MHz, CDCl3) d: 11.9 (br s, 2H),
T ðꢂCÞ
a sodium lamp and are reported as follows: ½aꢁk
7.77 (d, J = 6.9 Hz, 2H), 7.62 (s, 2H), 7.27–7.18 (m, 6H),
2.77–2.61 (m, 8H), 1.09 (t, J = 7.2 Hz, 12H) ppm. 13C
NMR (75.5 MHz, CDCl3) d: 154.7, 134.3, 128.8,
128.2, 128.1, 126.3, 125.6, 125.4, 123.3, 117.1, 46.9,
11.7 ppm. MS (EI+) m/z (%): 460 [M]+ (74), 431 (50),
389 (100), 358 (70), 316 (83). HRMS (EI+) Exact mass
calcd for C30H32D4N2O2 [M]+: 460.302786, found:
460.302841.
(c = g/100 mL, solvent). Infrared spectra were recorded
on a FT-IR Bruker IFS 66 spectrometer and are
reported in wavenumbers (cmꢀ1). Enantiomeric excesses
were determined by HPLC analysis using a Waters
600E chromatograph provided with Daicel Chiralpak
AD or Chiralcel OD columns (see products for further
1
details). H NMR spectra were recorded on a Bruker
AMX-300 (300 MHz) spectrometer and are reported in
parts per million using solvent as internal standard
(CDCl3 at 7.26 ppm). Data are reported as s = singlet,
d = doublet, dd = double doublet, t = triplet, q = quar-
tet, m = multiplet, b = broad; coupling constant(s) in
Hertz, integration. Proton-decoupled 13C NMR spectra
were recorded on a Bruker AMX-300 (75.5 MHz) spec-
trometer and are reported in parts per million using sol-
vent as an internal standard (CDCl3 at 77.16 ppm).
Proton-decoupled 45Sc NMR were recorded on a Bruker
AMX-300 (73 MHz) spectrometer and are reported in
parts per million using a solution of ScCl3 1 M in D2O
4.2. P1. General procedure for the preparation of
scandium(III) and lanthanide(III) salt complexes 2Ln
Dried scandium(III) or lanthanide(III) triflates (0.085
mmol, 1 equiv) and (S)-binolam (S)-1 (0.255 mmol,
3 equiv) were put in a flame-dried 5 mL round-bottomed
flask containing a stirring bar. Freshly distilled (CaH2)
acetonitrile (1.5 mL) was added and the mixture stirred
under an argon atmosphere for 1 h. Then, the solvent
was removed under reduced pressure, thereby affording
complexes 2Ln in quantitative yield.

J. M. Saa´ et al. / Tetrahedron: Asymmetry 17 (2006) 99–106
103
4.2.1. [(D,S,S,S)-Binolam]3ÆSc(OTf)3 2Sc. Complex
C92H108F6N6O12S2Nd [MꢀTfOH+H]+: 1808.644818,
2Sc was prepared according to the general procedure
found: 1808.632528.
25
P1. An orange solid. Mp: >300 ꢁC. ½aꢁ589 ¼ þ139:2 (c
1
0.12, CH2Cl2). H NMR (300 MHz, CD3CN) d: 9.00
4.2.5. [(D,S,S,S)-Binolam]3ÆSm(OTf)3 2Sm. Complex
(br s, 6H), 7.91 (d, J = 8.1 Hz, 6H), 7.51 (s, 6H), 7.28–
7.23 (m, 6H), 7.09–7.04 (m, 6H), 6.81 (d, J = 8.4 Hz,
6H), 2.81 (d, J = 13.2 Hz, 6H), 2.81–2.38 (m, 24H),
2.48 (d, J = 14.1 Hz, 6H), 1.03 (t, J = 7.1 Hz, 18H),
0.61 (t, J = 7.2 Hz, 18H) ppm. 13C NMR (75.5 MHz,
CD3CN) d: 161.8, 136.6, 130.2, 129.1, 128.2, 126.9,
125.4, 122.9, 120.0, 55.4, 47.4, 46.0, 9.6, 8.0. 45Sc
NMR (73 MHz, CD3CN) d: 103 ppm. MS (FAB+)
m/z (%): 1861 [M+H]+ (2.3 · 10ꢀ3), 1712 [MꢀTfOH+
H]+ (13.1), 1256 (33.2), 799 (58), 457 (80.1), 384 (88.2),
311 (100). HRMS (FAB+) Exact mass calcd for
C92H108F6N6O12S2Sc [MꢀTfOH+H]+: 1711.693001,
found: 1711.691898.
2Sm was prepared according to the general procedure
25
P1. An orange solid. Mp: 254–255 ꢁC. ½aꢁ589 ¼ þ70 (c
1
0.12, CH2Cl2). H NMR (300 MHz, CD3CN) d: 8.24
(d, J = 8.1 Hz, 6H), 8.12 (s, 6H), 7.55–7.43 (m, 6H),
7.28–7.20 (m, 12H), 3.49 (br d, J = 12.6 Hz, 6H), 3.21
(br d, J = 12.9 Hz, 6H), 0.45 (t, J = 7.4 Hz, 18H),
0.015 (t, J = 7.4 Hz, 18H). 13C NMR (75.5 MHz,
CD3CN) d: 167.1, 138.3, 132.1, 129.6, 128.5, 127.8,
126.6, 125.2, 123.2, 122.0, 57.3, 47.9, 46.6, 10.1, 6.5.
MS (ESI+) m/z (%): 1818.6898 [MꢀTfOH+H]+.
4.2.6. [(D,S,S,S)-Binolam]3ÆEu(OTf)3 2Eu. Complex
2Eu was prepared according to the general procedure
25
P1. An orange solid. Mp: 256–257 ꢁC. ½aꢁ589 ¼ þ96:7 (c
1
4.2.2. [(D,S,S,S)-Binolam]3ÆLa(OTf)3 2La. Complex
0.12, CH2Cl2). H NMR (300 MHz, CD3CN) d: 15.75
2La was prepared according to the general procedure
(br s, 6H), 7.24 (br d, J = 7.5 Hz, 6H), 7.07 (br s, 6H),
6.61 (br s, 6H), 5.77 (br s, 6H), 5.69 (br d, J = 8.1 Hz,
6H), 5.09 (br s, 6H), 4.82 (br s, 6H), 2.23 (br s,
J = 8.1 Hz, 6H), 1.80 (br s, 18H), 1.38–1.27 (br m,
6H), 0.82 (br s, 18H), ꢀ0.12 (br s, 6H). 13C NMR
(75.5 MHz, CD3CN) d: 186.3, 139.6, 128.8, 127.8,
127.0, 125.5, 124.7, 122.4, 118.9, 107.3, 55.9, 49.7,
48.3, 11.5, 7.3. MS (ESI+) m/z (%): 1819.6525
[MꢀTfOH+H]+. HRMS (FAB+) Exact mass calcd for
C92H108F6N6O12S2Eu [MꢀOTf]+: 1819.658330, found:
1819.633972.
25
P1. An orange solid. Mp: 258–259 ꢁC. ½aꢁ589 ¼ þ25
(c 0.12, CH2Cl2). 1H NMR (300 MHz, CD3CN) d:
9.1 (br s, 6H), 8.04 (d, J = 8.1 Hz, 6H), 7.80 (s,
6H), 7.29–7.24 (m, 6H), 7.10–7.04 (m, 6H), 6.65
(d, J = 8.4 Hz, 6H), 2.95 (d, J = 13.5 Hz, 6H), 2.90–
2.67 (m, 24H), 2.42 (d, J = 13.2 Hz, 6H), 0.84
(t, J = 7.2 Hz, 18H), 0.24 (t, J = 7.2 Hz, 18H) ppm.
13C NMR (75.5 MHz, CD3CN) d: 158.3, 135.8, 130.3,
128.0, 127.0, 126.3, 124.8, 123.7, 122.0, 118.6, 55.9,
47.6, 45.7, 9.5, 5.4. MS (FAB+) m/z (%): 1806
[MꢀTfOH+H]+, 1350 (32.8), 457 (100), 384 (68.9),
311 (61.1). HRMS (FAB+) Exact mass calcd for
C92H108F6N6O12S2La [MꢀTfOH+H]+: 1805.643442,
found: 1805.648186.
4.2.7. [(D,S,S,S)-Binolam]3ÆGd(OTf)3 2Gd. Complex
2Gd was prepared according to the general procedure
25
P1. An orange solid. Mp: 260–261 ꢁC. ½aꢁ589 ¼ þ125 (c
0.12, CH2Cl2). MS (FAB+) m/z (%): 1825
[MꢀTfOH+H]+ (14.43). HRMS (FAB+) Exact mass
calcd for C92H108F6N6O12S2Gd [MꢀTfOH+H]+:
1824.661198, found: 1824.643657.
4.2.3. [(D,S,S,S)-Binolam]3ÆPr(OTf)3 2Pr. Complex
2Pr was prepared according to the general procedure
25
P1. An orange solid. Mp: 254–255 ꢁC. ½aꢁ589 ¼ þ58:3 (c
1
0.12, CH2Cl2). H NMR (300 MHz, CD3CN) d: 11.45
(br s, 6H), 7.47 (d, J = 7.8 Hz, 6H), 6.98–6.86 (m,
18H), 5.98 (d, J = 8.4 Hz, 6H), 4.80–4.76 (br m, 6H),
4.45–4.43 (br m, 6H), 3.34–3.14 (m, 12H), 1.84 (br d,
J = 12.6 Hz, 6H), 1.39 (t, J = 3.6 Hz, 18H), 0.95 (t,
J = 3.6 Hz, 18H), 0.5 (br d, J = 12.6 Hz, 6H). 13C
NMR (75.5 MHz, CD3CN) d: 139.7, 133.8, 129.4,
129.1, 128.4, 127.9, 126.6, 126.0, 123.5, 117.5, 55.4,
50.3, 47.4, 11.1, 7.6. MS (ESI+) m/z (%): 1807.6498
[MꢀTfOH+H]+. HRMS (FAB+) Exact mass calcd for
C92H108F6N6O12S2Pr [MꢀTfOH+H]+: 1807.644744,
found: 1807.627701.
4.2.8. [(D,S,S,S)-Binolam]3ÆYb(OTf)3 2Yb. Complex
2Yb was prepared according to the general procedure
25
P1. An orange solid. Mp: >300 ꢁC. ½aꢁ589 ¼ þ175:8 (c
1
0.12, CH2Cl2). H NMR (300 MHz, CD3CN) d: 34.1
(br s), 12.55 (br s), 11.8 (br s), 7.38 (br s), 7.02 (br s),
5.82 (br s), 5.30 (br s), 3.36 (br s), 2.91 (br s), 1.36 (br
s), ꢀ0.55 (br s), ꢀ6.30 (br s). 13C NMR (75.5 MHz,
CD3CN) d: 128.5, 124.4, 123.6, 123.3, 122.6, 122.0,
122.0, 121.7, 109.0, 56.1, 51.9, 51.1, 14.9, 10.8. MS
(ESI+) m/z (%): 1838.6671 [MꢀTfOH+H]+.
4.3. P2. General procedure for the catalytic asymmetric
nitroaldol reaction
4.2.4. [(D,S,S,S)-Binolam]3ÆNd(OTf)3 2Nd. Complex
2Nd was prepared according to the general procedure
25
P1. An orange solid. Mp: 258–259 ꢁC. ½aꢁ589 ¼ þ48:8 (c
Complex 2Ln (0.0265 mmol, 5 mol %) was added to a
flame-dried 10 mL Schlenk tube containing a stirring
bar. Freshly distilled (CaH2) acetonitrile (2 mL) was
added. To the stirred mixture a solution of either proton
spongeꢂ (95 lL, 280 mM in dry acetonitrile,
0.0265 mmol, 5 mol %), or DBU (4 lL, 0.0265 mmol,
5 mol %) was added and cooled to ꢀ40 ꢁC. Aldehyde
(0.53 mmol, 1 equiv) and nitromethane (5.3 mmol,
10 equiv) were added and the resulting mixture stirred
at ꢀ40 ꢁC under an argon atmosphere for 24–96 h.
1
0.25, CH2Cl2). H NMR (300 MHz, CD3CN) d: 8.80
(s, 6H), 8.44 (d, J = 7.8 Hz, 6H), 7.71 (d, J = 8.1 Hz,
6H), 7.55–7.43 (m, 12H), 3.49 (br s, 6H), 3.17 (br s,
6H), 2.45 (br m, 6H), 2.22 (br m, 6H), 1.13 (br s, 6H),
0.59 (br s, 6H), 0.14 (br s, 18H), ꢀ0.26 (br s, 18H).
13C NMR (75.5 MHz, CD3CN) d: 142.9, 136.2, 135.6,
131.9, 130.9, 129.1, 128.2, 127.8, 127.4, 124.5, 57.3,
47.5, 46.1, 9.8, 6.3. MS (ESI+) m/z (%): 1808.6449
[MꢀTfOH+H]+. HRMS (FAB+) Exact mass calcd for

104
J. M. Saa´ et al. / Tetrahedron: Asymmetry 17 (2006) 99–106
The reaction was quenched by adding aqueous 5% HCl
solution (10 mL) and the resulting mixture partitioned
with CH2Cl2 (10 mL). The organic phase was washed
with aqueous 5% HCl solution (2 · 10 mL), then dried
over Na2SO4, and filtered. After evaporation of the
solvent, the residue was purified by column chromato-
graphy to afford the nitroaldol product 3a–3i.
solvent mixture, at flow rate 1 mL/min and UV detec-
tion at k = 230 nm); the major enantiomer tr =
10.9 min, minor enantiomer tr = 12.2 min. The absolute
configuration of the major enantiomer was assigned on
the basis of literature data.10e
4.3.4. (R)-3-Methyl-2-nitrobutan-2-ol 3d. Compound
3d10e was prepared according to the general procedure
P2 and purified by column chromatography (15%
EtOAc/hexanes) to give a colorless oil. (95% yield with
Proton spongeꢂ or DBU as additive). 1H NMR
(300 MHz, CDCl3) d: 4.44–4.29 (m, 2H), 4.03–3.99 (m,
1H), 3.22 (br s, 1H), 1.74–1.65 (m, 1H), 0.91 (d,
J = 4.5 Hz, 3H), 0.88 (d, J = 4.5 Hz, 3H). 13C NMR
(75.5 MHz, CDCl3) d: 79.4, 73.4, 31.7, 18.2, 17.3 ppm.
MS (EI+) m/z (%): 92, 86, 73, 55. The enantiomeric pur-
ity of 3d (90% ee with either Proton spongeꢂ or DBU as
additive) was determined by HPLC with a Daicel
Chiralcel OD column (using a 95:5 hexane/isopropa-
nol solvent mixture, at flow rate 1 mL/min, and UV
detection at k = 230 nm); the major enantiomer hav-
ing tr = 12.5 min, whereas the minor one showed
tr = 13.5 min. The absolute configuration of the major
enantiomer was assigned on the basis of literature
data.10e
4.3.1. (R)-1-Nitro-4-phenylbutan-2-ol 3a. Compound
3a10e was prepared according to the general procedure
P2 and purified by column chromatography (20%
EtOAc/hexanes) to give a white solid. (90% yield with
Proton spongeꢂ as additive, 91% yield with DBU as
additive). Mp: 102–103 ꢁC. 1H NMR (300 MHz,
CD2Cl2) d: 7.33–7.20 (m, 5H), 4.41–3.38 (m, 2H),
4.34–4.28 (m, 1H), 2.89–2.65 (m, 3H), 1.80 (m, 2H)
ppm. 13C NMR (75.5 MHz, CD2Cl2) d: 141.3, 128.8,
128.7, 126.5, 81.1, 68.3, 35.6, 31.6 ppm. MS (EI+) m/z
(%): 195, 177, 135, 105, 90, 60. The enantiomeric purity
of 3a (91% ee with Proton spongeꢂ as additive, 87% ee
with DBU as additive) was determined by HPLC with
a Daicel Chiralpak AD column (using a 90:10 hexane/
isopropanol solvent mixture, at flow rate of 1 mL/min
and UV detection at k = 254 nm); the major enantiomer
having tr = 13.7 min whereas the minor one showed
tr = 16.6 min. The absolute configuration of the major
enantiomer was assigned on the basis of the literature
data.10e
4.3.5. (R)-2-Nitro-1-phenylethanol 3e. Compound 3e10e
was prepared according to the general procedure P2 and
purified by column chromatography (15% EtOAc/hex-
anes) to give a pale yellow oil. (96% yield with Proton
spongeꢂ as additive, 88% yield with DBU as additive).
1H NMR (300 MHz, CDCl3) d: 7.40–7.32 (m, 5H),
5.42 (dd, J = 6, 3.3 Hz, 1H), 4.62–4.45 (m, 2H), 3.37
(br s, 1H). 13C NMR (75.5 MHz, CDCl3) d: 138.3,
129.0, 128.9, 126.0, 81.3, 71.0. MS (EI+) m/z (%): 167,
149, 134, 120, 105, 77, 51. The enantiomeric purity of
3e (80% ee with Proton spongeꢂ as additive, 65% ee with
DBU as additive) was determined by HPLC with a Dai-
cel Chiralcel OD column (using a 90:10 hexane/isopro-
panol solvent mixture, at flow rate 1 mL/min, and UV
detection at k = 254 nm); the major enantiomer having
tr = 18.1 min, whereas the minor one showed
tr = 22.3 min. The absolute configuration of the major
enantiomer was assigned on the basis of literature
data.10e
4.3.2. (R)-1-Cyclohexyl-2-nitroethanol 3b. Compound
3b10e was prepared according to the general procedure
P2 and purified by column chromatography (15%
EtOAc/hexanes) to give a pale yellow oil. (80% yield
with Proton spongeꢂ as additive, 63% yield with DBU
1
as additive). H NMR (300 MHz, CDCl3) d: 4.55–4.35
(m, 2H), 4.09–4.03 (m, 1H), 2.82 (br s, 1H), 1.82–1.62
(m, 5H), 1.50–1.39 (m, 1H), 1.28–1.01 (m, 5H). 13C
NMR (75.5 MHz, CDCl3) d: 79.5, 73.0, 41.6, 28.9,
28.0, 26.2, 26.0, 25.8 ppm. MS (EI+) m/z (%): 127, 95,
75, 67, 45. The enantiomeric purity of 3b (99% ee
with Proton spongeꢂ as additive, 80% ee with DBU as
additive) was determined by HPLC with a Daicel
Chiralcel OD column (using a 97:3 hexane/isopropanol
solvent mixture, at flow rate 1 mL/min and UV detec-
tion at k = 230 nm); the major enantiomer having
tr = 20.2 min, whereas the minor one showed tr =
21.2 min. The absolute configuration of the major
enantiomer was assigned on the basis of literature
data.10e
4.3.6. (R)-2-Nitro-1-(4-nitrophenyl)ethanol 3f. Com-
pound 3f10g was prepared according to the general
procedure P2 and purified by column chromatography
(10–20% EtOAc/hexanes) to give a yellow solid. (73%
yield with Proton spongeꢂ as additive, 98% yield with
4.3.3. (R)-3,30-Dimethyl-1-nitrobutan-2-ol 3c. Com-
pound 3c10e was prepared according to the general pro-
cedure P2 and purified by column chromatography (5%
EtOAc/hexanes) to give a colorless oil. (91% yield with
Proton spongeꢂ or DBU as additive). 1H NMR
(300 MHz, CDCl3) d: 4.48 (dd, J = 12.6, 2.2 Hz), 4.32
(dd, J = 12.6, 10.2 Hz, 1H), 3.97 (d, J = 9.9 Hz, 1H),
2.94 (br s, 1H), 0.91 (s, 9H). 13C NMR (75.5 MHz,
CDCl3) d: 78.4, 76.3, 34.3, 25.5 ppm. MS (EI+) m/z
(%): 87, 71, 57. The enantiomeric purity of 3c (83% ee
with Proton spongeꢂ as additive, 92% ee with DBU as
additive) was determined by HPLC with a Daicel
Chiralcel OD column (using a 95:5 hexane/isopropanol
1
DBU as additive). Mp: 83–85 ꢁC. H NMR (300 MHz,
CDCl3) d: 8.29–8.24 (m, 2H), 7.65–7.60 (m, 2H), 5.63–
5.58 (m, 1H), 4.65–4.55 (m, 2H), 3.13 (d, J = 3 Hz,
1H). 13C NMR (75.5 MHz, CDCl3) d: 148.0, 145.1,
127.1, 124.3, 80.7, 70.1. MS (EI+) m/z (%): 151, 135,
120, 105, 77, 51. The enantiomeric purity of 3f (28%
ee with Proton spongeꢂ as additive, 31% ee with DBU
as additive) was determined by HPLC with a Daicel
Chiralcel OD column (using a 90:10 hexane/isopropanol
solvent mixture, at flow rate 1 mL/min, and UV detec-
tion at k = 254 nm); the major enantiomer having tr =
34.4 min, whereas the minor one showed tr = 42.5 min.

J. M. Saa´ et al. / Tetrahedron: Asymmetry 17 (2006) 99–106
105
The absolute configuration of the major enantiomer was
4.4. Computational details
assigned on the basis of literature data.10g
Ground state geometries of m2La and m4La were fully
optimized using gradient techniques at the DFT
(B3LYP) level of theory, using split-valence d-polarized
6-31G* basis set for H, C, N, and O, and the Sttutgartsꢁs
group effective core potential MWB for lantha-
num(III),17 as implemented in Gaussian 98.25 Stationary
points were fully characterized as minima (all frequen-
cies real) by vibrational analysis. The zero-point vibra-
tional energies (ZPVE) were computed at the same
level and were not scaled.
4.3.7. (R)-4-(1-Hydroxy-2-nitroethyl)benzonitrile 3g.
Compound 3g was prepared according to the general
procedure P2 and purified by column chromatography
(30% EtOAc/hexanes) to give a pale brown solid. (75%
yield with Proton spongeꢂ as additive, 79% yield with
1
DBU as additive). Mp: 80–81 ꢁC H NMR (300 MHz,
CDCl3) d: 7.70 (d, J = 4.8 Hz, 2H), 7.55 (d, J = 6.6 Hz,
2H), 5.56–5.52 (m, 1H) 4.62–4.51 (m, 2H), 3.35 (br s,
1H). 13C NMR (75.5 MHz, CDCl3) d: 143.5, 132.9,
126.9, 118.3, 80.8, 70.3. MS (EI+) m/z (%): 130, 102,
76, 50. The enantiomeric purity of 3g (76% ee with Pro-
ton spongeꢂ as additive, 64% ee with DBU as additive)
was determined by HPLC with a Daicel Chiralcel OD
column (using a 90:10 hexane/isopropanol solvent mix-
ture, at flow rate 1 mL/min, and UV detection at
k = 254 nm); the major enantiomer having tr = 4.0 min,
whereas the minor one showed tr = 9.0 min. The abso-
lute configuration of the major enantiomer was assigned
by analogy and is supported by the consistent order of
elution during chiral stationary phase HPLC.
Acknowledgments
This work is dedicated to Prof. R. Suau (UM, Spain) on
the occasion of his 60th birthday. Financial support by
the DGES of the Spanish Ministerio de Ciencia y Tec-
´
nologıa (CTQ2004-02375/BQU) is gratefully acknowl-
edged. Thanks are due to CESCA and CESGA and
the UIB for their generous allocation of computer time.
´
A. Lledos and G. Druris (UAB) are thanked for their
assistance with computations.
4.3.8. (R)-1-(4-Fluorophenyl)-2-nitroethanol 3h. Com-
pound 3h10g was prepared according to the general
procedure P2 and purified by column chromatography
(20% EtOAc/hexanes) to give a colorless oil. (65% yield
with Proton spongeꢂ as additive, 62% yield with DBU
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1
additive). Mp: 60–61 ꢁC. H NMR (300 MHz, CDCl3)
d: 7.45–7.29 (m, 5H), 6.77 (d, J = 15.9 Hz, 1H), 6.14
(dd, J = 17.2, 6.3 Hz, 1H), 5.06–5.02 (m, 1H), 4.51 (d,
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128.8, 128.7, 128.6, 126.8, 125.2, 80.0, 69.7. MS (EI+)
m/z (%): 131, 103, 77, 51. The enantiomeric purity of
3i (72% ee with either Proton spongeꢂ or DBU as addi-
tive, 72% ee with DBU as additive) was determined by
HPLC with a Daicel Chiralcel OD column (using a
90:10 hexane/isopropanol solvent mixture, at flow rate
1 mL/min, and UV detection at k = 254 nm); the major
enantiomer showed tr = 55.0 min, whereas the minor
one showed tr = 46.9 min. The absolute configuration
of the major enantiomer was not determined.

106
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with the kinetic lability of the complexes, we found that
the NMR spectra of the 3:1 complexes resulting from the