Chiral bis(amino alcohol)oxalamides as ligands for asymmetric catalysis. Ti(IV) catalyzed enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2005.01.039

Several chiral bis(aminoalcohol)oxalamides with C₂-symmetry have been prepared and used as ligands for the enantioselective addition of diethylzinc to aromatic and aliphatic aldehydes. The reaction proceeds in the presence of titanium isopropoxide to give the corresponding (S)-alcohols with ee up to 78%. In the absence of Ti(IV), the alcohols with the opposite configuration are obtained.

Full text of DOI:10.1016/j.tetasy.2005.01.039

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1207–1213
Chiral bis(amino alcohol)oxalamides as ligands
for asymmetric catalysis. Ti(IV) catalyzed enantioselective
addition of diethylzinc to aldehydes
*
´ ´ ´
Gonzalo Blay, Isabel Fernandez, Alıcia Marco-Aleixandre and Jose R. Pedro
´ ` `
Departament de Quımica Organica, Universitat de Valencia, Dr. Moliner 50, E-46100-Burjassot, Spain
Received 20 December 2004; accepted 25 January 2005
Abstract—Several chiral bis(aminoalcohol)oxalamides with C2-symmetry have been prepared and used as ligands for the enantio-
selective addition of diethylzinc to aromatic and aliphatic aldehydes. The reaction proceeds in the presence of titanium isopropoxide
to give the corresponding (S)-alcohols with ee up to 78%. In the absence of Ti(IV), the alcohols with the opposite configuration are
obtained.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Herein we report the synthesis of several chiral bis-
(amino alcohol) oxalamides from amino alcohols derived
from natural amino acids (Fig. 1). These ligands may
behave as tetradentate ligands able to coordinate to a
metal center through the hydroxyl and amido groups.
Some of these oxalamides and their analogues have been
The design and synthesis of new molecules able to act as
chiral ligands in catalytic asymmetric reactions is one of
the most important goals in modern organic chemistry.1
For practical applications it is convenient that these
ligands can be prepared through simple synthetic path-
ways from easily accessible starting materials and in
both enantiomeric forms. Special attention has been
aimed toward the synthesis of C2-symmetric molecules
since this kind of symmetry is generally considered
advantageous because it reduces the number of possible
transition states in enantioselective reactions.2 Examples
of widely used C2 ligands include diols,3 such as TADD-
OLs4 and BINOLs,5 diamines and bis-sulfonamides,6
bis-oxazolines,7 etc. However, the preparation of enan-
tiopure compounds of this class is not a trivial task
and requires carefully controlled synthetic strategies,
and in some cases racemate separation.
Me
Ph
R
O
O
NH
NH
Me
OH
O
O
NH
OH
OH
OH
Ph
NH
R
4
1 R = Ph
2 R = PhCH2
3 R = Me2CHCH2
Ph
Ph
R
Ph
NH
Ph
Ph
Diacids such as oxalic or malonic acid derivatives are
good scaffolds for the construction of C2-symmetric
multidentate ligands. Their carboxyl groups can be
reacted with multiple compounds from the chiral pool
providing easy access to multifunctional C2 chiral
ligands with high modularity.8
O
O
O
O
OH
NH
OH
OH
Ph
Ph
NH
R
OH
Ph
Ph
NH
Ph
7
5 R = Ph
6 R = Me2CH
*
Corresponding author. Tel.: +34 963544329; fax: +34 963544328;
e-mail: jose.r.pedro@uv.es
Figure 1.
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.039

1208
G. Blay et al. / Tetrahedron: Asymmetry 16 (2005) 1207–1213
previously prepared and their gelation properties toward
various organic solvents described.9 However, no exam-
ples of their use as ligands for the asymmetric catalysis
have been reported so far to the best of our knowledge.
As a part of our current research on stereoselective reac-
tions10 we decided to investigate the efficiency of these
compounds as ligands in asymmetric catalysis. The addi-
tion of diethylzinc to aldehydes, a typical catalytic asym-
metric benchmark reaction was chosen for this purpose.
This particular carbon–carbon bond formation reaction
has been carried out in an enantioselective manner
under the asymmetric induction of many different
ligands.11 In many cases the reaction involves the
participation of zinc complexes with these ligands, but
the use of titanium-based catalysts tends to be more effi-
cient and selective.12 Furthermore, the titanium-mediate
addition of diethylzinc to aldehydes has previously been
performed using tetradentate ligands.8,13
R
CO2Me
R
O
O
NH
Et3N
THF
LiBH4
1-3
(COCl) +
ClH3N
CO2Me
2
NH
CO2Me
R
8 R = Ph
9 R = PhCH2
10 R = Me2CHCH2
Me
Ph
OH
∆
(CO2Me)2 +
4
Toluene
H2N
Ph
Ph
R
Et3N
THF
5-6
(COCl)2 +
H2N
OH
Ph
Ph
Ph
CO2H
CO2H
COCl
COCl
(COCl)2
DMF-DM
H2N
OH
7
2. Results and discussion
Et3N-THF
Scheme 1. Synthesis of ligands 1–7.
2.1. Preparation of chiral bis(amino alcohol) oxalamide
ligands
The ligands were prepared according to the synthetic
routes outlined in Scheme 1. Oxalamides 1–3 which have
primary hydroxyl groups, were prepared in two steps
involving condensation of the amino acid methyl ester
with oxalyl chloride in the presence of triethylamine fol-
lowed by reduction of the ester group with lithium boro-
hydride–methanol.14 Oxalamide 4 was prepared by
direct condensation of methyl oxalate and L-norephe-
drine in boiling toluene.15 Oxalamides 5 and 6 bearing
tertiary hydroxyl groups were obtained by condensation
of the corresponding 2-substituted-2-amino-1,1-diphen-
ylethanols16 and oxalyl chloride. 2,2-Dimethylmalon-
amide 7 was obtained in a similar way.
the presence of 0.2 equiv of ligand, 3 equiv of diethylzinc
(1 M solution in hexanes) and 1.4 equiv of titanium iso-
propoxide (Table 1). The reaction proceeded with fair to
good yields and with ees ranging from 12% to 39 % with
ligands 1–3, which bear primary hydroxyl groups
(entries 1–3). The best ee was obtained with the phenyl-
substituted ligand 1 (R = Ph). The oxalamide 4 derived
from L-norephedrine gave an unexpected low yield and
ee, which may be due to mismatching in the asymmetric
induction caused by the two stereogenic centers in the
molecule. Better results were obtained with oxalamides
5 and 6, which have a tertiary hydroxyl group. This
increase in yield and ee is in agreement with the observa-
tions made by Seebach with titanium TADDOLates,
which show that the bulkiness of the ligand increases
the ligand exchange rate and facilitates the catalytic
alkyl additions.17 Again the phenyl substituted ligand
5 (R = Ph) gave the best result. The effect of the distance
between the coordinating groups was studied with the
2.2. Asymmetric addition of diethylzinc to aldehydes
Benzaldehyde was used as test substrate for the reaction.
In a preliminary survey for all the prepared ligands, the
reaction was conducted at 0 ꢁC in methylene chloride in
Table 1. Addition of diethylzinc to benzaldehyde in the presence of ligands 1–7
Entry
Ligand
Conditions
Yielda (%)
Eeb (%)
Config.c
1
1
2
3
4
5
6
7
5
5
5
5
5
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h
Ti(OPri)4 (1.4 equiv), Et2 Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), ꢀ30 ꢁC, 24 h
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), rt, 24 h
Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h
8039
83
(
S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
S)-(ꢀ)
(S)-(ꢀ)
S)-(ꢀ)
(R)-(+)
R)-(+)
(R)-(+)
2
12
16
4
3
62
25
4
5
81
79
58
49
6
7
29
57
0(
43
8
9
8051
92
(
10
11
12
61
Et2Zn (1 M in hexanes, 3 equiv), ꢀ30 ꢁC, 46 h
3024
84
(
Et2Zn (1 M in hexanes, 3 equiv), rt, 24 h
56
a Isolated yields.
b Determined by GLC using a b-dex-225 column.
c Assigned by comparison of the specific rotation sign with those reported in the literature.

G. Blay et al. / Tetrahedron: Asymmetry 16 (2005) 1207–1213
1209
dimethylmalonic acid derivative ligand 7. With this
ligand, the reaction proceeded with low yield giving a
racemic mixture of the addition product. This result is
contradictory to previous reports using the titanium sys-
tem with other tetradentate ligands, where a 1,3-separa-
tion of the coordinating groups improved yields and
ees.8 Having established that the oxalamide derivative
of 2-amino-1,1,2-triphenylethanol was the most appro-
priate of the tested systems, we next studied the influ-
ence of the temperature with ligand 5. Changing the
temperature to ꢀ30 ꢁC (entry 8) decreased the reaction
yield and gave lower ee, while at room temperature,
the reaction proceeded with good yield but with an ee
somewhat lower than at 0 ꢁC. The presence of a maxi-
mum in the plot ee versus T has been reported in many
systems for the addition of dialkylzinc to aldehydes.13e,18
This temperature effect is attributed to the existence of
several competing reaction mechanisms involving
monomeric and dimeric zinc species as active catalysts.19
In our case, this could be due to a shift in the coordina-
tion mode of the ligand from tetracoordinating to trico-
ordinating. When the reaction was performed with
ligand 5 in the absence of titanium isopropoxide at
0 ꢁC, we obtained similar yields and ees to those
obtained with titanium isopropoxide. However, the
resulting alcohol presented the inverted configuration
at the stereogenic carbon. This shift in the enantioselec-
tivity of the reaction may be due to the participation of
dinuclear metal complexes, bearing titanium and zinc
atoms, as active catalysts. These results parallel those
by Seebach20 who found a reversal of selectivity in the
addition of diethylzinc to aldehydes catalyzed by tita-
nium TADDOLates depending on the ratio of diethyl-
zinc and titanium isopropoxide, although in our case
this reversal takes place in the total absence of titanium
alkoxide.
Different aldehydes were tested (Table 2) as substrates
for the enantioselective addition of diethylzinc using
the best ligand 5 under the conditions described in Table
1, entry 5. Some of them were also tested in the absence
of titanium isopropoxide under the conditions of Table
1, entry 10. The first remark is that, with the only excep-
tion of benzaldehyde, the presence of titanium isoprop-
oxide increases both the yield and enantioselectivity of
the reaction. A second remark is that, as in the case of
benzaldehyde, in all cases opposite enantiomers were
obtained depending on the presence or absence of
Ti(IV).
The influence of different para-substituted benzalde-
hyde derivatives on the enantioselectivity of the reac-
tion was also studied in order to establish whether
there was any correlation between the Hammet con-
stants21 and the enantiomeric ratio of the secondary
alcohol (Fig. 2). We found little effect with substituents
with poor capability to delocalize electrons by meso-
meric effect. Thus, slightly (p-chloro, entry 5 and p-bro-
mo, entry 7) and strong (p-trifluoromethyl, entry 9)
electron-withdrawing groups by inductive effect gave
similar ees to unsubstituted benzaldehyde (entry 1).
However, substituents with strong electron delocaliz-
ing capabilities by mesomeric effects, either electron-
releasing (p-methoxy, entry 3) or electron-withdrawing
(p-nitro, entry 11 and p-cyano, entry 13) gave lower
ees in any case. Similar plots of ee versus the Hammet
constant have been reported very recently for the addi-
tion of diethylzinc to ortho-substituted benzaldehydes
Table 2. Addition of diethylzinc to aldehydes in the presence of ligand 5
Entry Aldehyde
Conditions
Yielda (%) Eeb (%) Config.c
1
Benzaldehyde
Benzaldehyde
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 81
Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 92
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 6036
Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 26
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 74
Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 21
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 41
Et2Zn (1 M in hexanes, 3 equiv), 0C, 24 h 54
58
61
(S)-(ꢀ)
(R)-(+)
S)-(ꢀ)
2
3
p-Methoxybenzaldehyde
p-Methoxybenzaldehyde
p-Chlorobenzaldehyde
p-Chlorobenzaldehyde
p-Bromobenzaldehyde
p-Bromobenzaldehyde
(
4
38
60(
30(
58
50
56
20(
46
5
(R)-(+)
S)-(ꢀ)
5
6
R)-(+)
(S)-(ꢀ)
( R)-(+)
(S)-(ꢀ)
R)-(+)
(S)-(ꢀ)
(R)-(+)
S)-(ꢀ)
7
8
9
p-Trifluoromethylbenzaldehyde Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 89
p-Trifluoromethylbenzaldehyde Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 36
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 54
Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 12
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 77
Et2Zn (1 M in hexanes, 3 equiv), 0C, 24 h
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 19
10
11
12
13
14
15
16
17
18
19
p-Nitrobenzaldehyde
p-Nitrobenzaldehyde
p-Cyanobenzaldehyde
p-Cyanobenzaldehyde
o-Methylbenzaldehyde
o-Methylbenzaldehyde
Decanal
50(
53
31
6
( R)-(+)
(S)-(ꢀ)
R)-(+)
(S)-(+)
R)-(ꢀ)
(S)-(+)
(S)-(ꢀ)
(S)-(+)
(S)-(ꢀ)
Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h
10(10
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 82
66
(
Decanal
Dihydrocinnamaldehyde
Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h
5041
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 79
74
78
i
20Cyclohexanecarboxyaldehyde
Ti(OPr
)
4
(1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 85
d
21
22
Cyclopentanecarboxyaldehyde
2-Butylhexanal
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), 0 ꢁC, 24 h 8067
35
Ti(OPri)4 (1.4 equiv), Et2Zn (1 M in hexanes, 3 equiv), rt, 24 h
42e
a Isolated yields.
b Determined by GLC using a b-dex-225 column.
c Assigned by comparison of the specific rotation signs with those reported in the literature.
d Determined by 1H and 19F NMR analysis of its Mosher ester.
e Determined by HPLC, chiralcel ODH, hexane:i-PrOH 99:1, 0.5 mL/min, tr (major) 25.9 min, tr (minor) 28.4 min.

1210
G. Blay et al. / Tetrahedron: Asymmetry 16 (2005) 1207–1213
catalyzed by Ti(IV) complexes with C2-symmetric
bipyridyldiol ligands.22
4. Experimental section
4.1. General
65
60
55
50
45
40
35
30
Commercial reagents were used as purchased. Dichloro-
˚
methane was distilled from CaH2 and stored over 4 A
molecular sieves. All asymmetric reactions were carried
out in dry glassware under an argon atmosphere. Reac-
tions were monitored by TLC analysis using Merck Sil-
ica Gel 60F-254 thin layer plates. Flash column
chromatography was performed on Merck silica gel
60, 0.040–0.063 mm. Optical rotations were measured
using sodium light (D line 589 nm). IR were recorded
as liquid films in NaCl for oils and as KBr discs for
1
1
solids. H NMR were run at 299.95 MHz for H and
at 50.3 MHz for 13C NMR, and referenced to the sol-
vent as the internal standard. The carbon type was
determined by DEPT experiments. MS(EI) were run at
70eV.
1
-0.4
-0.2
0
0.2
0.4
0.6
0.8
σ
Figure 2. Correlation of substituent constants (rp) and the enantio-
meric excesses of the alkylation of para-substituted benzaldehydes in
the presence of Ti(IV)-5 complex.
4.2. N,N0-Bis[(1S)-2-hydroxy-1-phenylethyl]ethane-
diamide 1
The steric effect in the proximities of the aldehyde car-
bonyl group was studied with o-methylbenzaldehyde.
In this case, low yield and ee were obtained probably
due to the steric congestion caused by the four phenyl
groups in the proximities of the coordinating hydroxyl
groups of the ligand.
A solution of oxalyl chloride (0.79 mL, 9.3 mmol) in
THF (0.5 mL) was added dropwise to a solution of
(S)-phenylglycine methyl ester hydrochloride (3.72 g,
18.5 mmol) and triethylamine (5.2 mL, 37 mmol) in
THF (250mL) at 0 ꢁC. After 3 h, the reaction mixture
was filtered and most of the solvent evaporated under
reduced pressure. The resulting solid was filtered and
washed with a small portion of diethyl ether to give
The reaction was also tested with aliphatic aldehydes
(entries 17–22). In general, we observed that aliphatic
aldehydes reacted more efficiently providing the corre-
sponding alcohols with better yields and ees than the
aromatic ones. In these cases ee increased until a
certain level with the steric hindrance in the proximities
of the aldehyde carbonyl group. A 78% ee was
obtained in the case of cyclohexanecarboxyaldehyde
(entry 20) and 74% in the case of dihydrocinnamalde-
hyde (entry 19). However when the steric hindrance
was too high, a drop in the ee (42%) was observed
(entry 22).
4.18 g (98%) of compound 8: Mp 180 ꢁC;
25
½aŠ ¼ þ226:5 (c 0.83, CHCl3); IR m 3293, 1747, 1660,
D
1511 cmꢀ1; MS(EI) 384 (M+, 1), 352 (2), 325 (100);
HRMS 384.1320C 20H20N2O6 required 384.1321; 1H
NMR (CDCl3) d 8.22 (2H, d, J = 7.6 Hz), 7.32 (10H,
s), 5.49 (2H, d, J = 7.6 Hz), 3.73 (6H, s); 13C NMR
(CDCl3) d 170.0 (s), 158.4 (s), 135.3 (s), 129.0 (d),
128.9 (d), 127.3 (d), 56.7 (d), 53.0(q).
A solution of compound 8 (3.9 g, 10mmol) in dry THF
(170mL) was treated with methanol (1.1 mL,
3. Conclusion
26.5 mmol)
and
lithium
borohydride
(0.57 g,
26.5 mmol). After 3 h, the reaction mixture was
quenched with 2 mL of concd. HCl and anhydrous
MgSO4 then added. The mixture was filtered and con-
centrated under reduced pressure and the resulting solid
In summary, we have reported the first example of the
application of tetradentate bis(hydroxy amino)oxala-
mides as ligands in asymmetric catalysis. These ligands
are readily prepared in good yields in short synthetic
sequences and allow high modularity by simply chang-
ing the amino alcohol moiety. These ligands are able
to catalyze the asymmetric addition of diethylzinc to
aromatic and aliphatic aldehydes in the presence of tita-
nium isopropoxide. In general, the best results of the
addition products are obtained with aliphatic aldehydes.
With aromatic aldehydes better results are obtained
when the aromatic ring bears substituents with weak
electronic character, while strong electron-donating or
withdrawing groups by a mesomeric effect diminish yield
and ee. These ligands can also catalyze the reaction in
the absence of titanium isopropoxide, although with
lower yield and ee. Under these conditions the resulting
alcohol presented an inverted configuration at the stereo-
genic carbon.
was recrystallized from ethanol to give 1.8 g (54%)
25
of compound 1: Mp 263–265 ꢁC; ½aŠ ¼ þ87:0 (c
D
0.1, MeOH); IR m 3293, 1644, 1521 cmꢀ1; MS(EI)
297 (M+ꢀCH3O, 73), 279 (9), 177 (67), 106 (100);
HRMS 297.1238 C17H17N2O3 required 297.1239; 1H
NMR (DMSO-d6) d 9.00 (2H, d, J = 8.7 Hz), 7.4–7.1
(10H, m), 4.98 (2H, d, J = 5.6 Hz), 4.86 (2H, m), 3.71
(2H, dd, J = 7.7, 11.1 Hz), 3.61 (2H, dd, J = 11.2,
5.3 Hz); 13C NMR (DMSO-d6) d 159.5 (s), 140.0 (s),
127.9 (d), 126.8 (d), 126.7 (d), 63.6 (t), 55.5 (d).
4.3. N,N0-Bis[(1S)-1-benzyl-2-hydroxyethyl]ethane-
diamide 2
Following an analogous procedure to that described for
8, from L-phenylalanine methyl ester hydrochloride (4 g,

G. Blay et al. / Tetrahedron: Asymmetry 16 (2005) 1207–1213
1211
18.5 mmol) were obtained 3.8 g (99%) of compound 9:
1527 cmꢀ1; MS(EI) 338 (M+ꢀH2O, 1), 320(3), 250
25
Mp 194–195 ꢁC; ½aŠ ¼ þ16:2 (c 0.04, MeOH); IR m
(17), 231 (23), 160 (35), 118 (100); HRMS 338.1596
C20H22N2O3 required 338.1630; H NMR (DMSO-d6)
D
3283, 1736, 1660, 1521 cmꢀ1; MS(EI) 412 (M+, 0.5),
353 (10), 178 (12), 162 (100); HRMS 412.1605
C22H24N2O6 required 412.1634; 1H NMR (CDCl3) d
7.65 (2H, d, J = 8.5 Hz), 7.3–7.1 (6 H, m), 7.07 (4H,
dd, J = 7.5, 2.1 Hz), 4.77 (2H, m), 3.67 (6H, s), 3.14
(2H, dd, J = 13.7, 5.7 Hz), 3.07 (2H, dd, J = 13.7,
6.6 Hz); 13C NMR (CDCl3) d 170.6 (s), 158.6 (s),
135.2 (s), 129.1 (d), 128.7 (d), 127.3 (d), 53.6 (d), 52.5
(q), 37.9 (t).
1
d 8.43 (2H, d, J = 9.1 Hz), 7.43–7.31 (10H, m), 5.66
(2H, d, J = 4.5 Hz), 4.74 (2H, t, J = 4.5 Hz), 4.02 (2H,
m), 1.08 (6H, d, J = 6.8 Hz); 13C NMR (DMSO-d6) d
159.1 (s), 143.1 (s), 128.2 (d), 127.3 (d), 126.5 (d), 74.0
(d), 51.2 (d), 14.8 (q).
4.6. N,N0-Bis[(1S)-2-hydroxy-1,2,2-triphenylethyl]
ethanediamide 5
Following an analogous procedure to that described for
1, from compound 9 (3.6 g, 8.9 mmol) were obtained
A solution of oxalyl chloride (0.15 mL, 1.75 mmol) in
THF (1.5 mL) was added dropwise to a solution of
(S)-2-amino-1,1,2-trifenilethanol (1 g, 3.46 mmol) and
triethylamine (0.54 mL, 3.8 mmol) in THF (35 mL) at
0 ꢁC. After 2 h, the reaction mixture was filtered and
most of the solvent evaporated under reduced pressure.
The resulting solid was filtered and washed with a small
25
D
2.2 g (69%) of compound 2: Mp 253 ꢁC; ½aŠ ¼ ꢀ43:7
(c 0.03, MeOH); IR m 3411, 3298, 1655, 1516 cmꢀ1
;
MS(FAB) 357 (M++1, 100), 339 (17), 313 (8); HRMS
357.1834 C20H25N2O4 required 357.1814; 1H NMR
(DMSO-d6) d 8.39 (2H, d, J = 9.2 Hz), 7.3–7.1 (10H,
m), 4.94 (2H, t, J = 5.6 Hz), 4.00 (2H, m), 3.42 (4H,
m), 2.90(2H, dd, J = 13.6, 5.5 Hz), 2.76 (2H, dd,
J = 13.6, 8.5 Hz); 13C NMR (DMSO-d6) d 159.2 (s),
138.5 (s), 128.7 (d), 127.8 (d), 125.7 (d), 61.9 (t), 52.7
(d), 35.8 (t).
portion of diethyl ether to give 1.06 g (97%) of com-
25
pound 5: Mp 286–287 ꢁC; ½aŠ ¼ ꢀ198:5 (c 0.014,
D
THF); IR m 3411, 3344, 1645, 1511 cmꢀ1; MS(EI) 614
(M+ꢀH2O, 2), 596 (19), 432 (21), 256 (100); HRMS
614.2538 C42H34N2O3 required 614.2569; 1H NMR
(DMSO-d6) d 9.35 (2H, d, J = 9.6 Hz), 7.50(4H, d,
J = 7.2 Hz), 7.44 (4H, d, J = 7.4 Hz), 7.4–6.9 (26H, m),
6.63 (2H, s), 5.85 (2H, d, J = 9.6 Hz); 13C NMR
(DMSO-d6) d 159.0(s), 146.6 (s), 144.8 (s), 138.5 (s),
129.3 (d), 128.3 (d), 127.6 (d), 127.2 (d), 127.1 (d),
126.9 (d), 126.5 (d), 126.1 (d), 126.0(d), 79.5 (s), 60.0
(d).
4.4. N,N0-Bis[(1S)-2-hydroxy-1-isobutylethyl]ethane-
diamide 3
Following an analogous procedure to that described for
8, from L-leucine methyl ester hydrochloride (4 g,
22 mmol) were obtained 3.7 g (97%) of compound 10:
25
Mp 119–120 ꢁC; ½aŠ ¼ ꢀ51:9 (c 0.65, MeOH); IR m
D
3344, 1742, 1665, 1516 cmꢀ1; MS(EI) 344 (M+, 0.5),
285 (43), 225 (10), 144 (24), 86 (100); HRMS 344.1939
C16H28N2O6 required 344.1947; 1H NMR (CDCl3) d
7.67 (2H, d, J = 8.8 Hz), 4.56 (2H, m), 3.72 (6H, s),
1.7-1.5 (6H, m), 0.92 (6H, d, J = 6.1 Hz), 0.91 (6H, d,
J = 6.3 Hz); 13C NMR (CDCl3) d 171.9 (s), 159.0(s),
52.5 (q), 51.1 (d), 41.4 (t), 24.7 (d), 22.7 (q), 21.7 (q).
4.7. N,N0-Bis[(1S)-2-hydroxy-1-isopropyl-2,2-triphenyl-
ethyl]ethanediamide 6
Following a similar procedure to that described for the
preparation of 5 from 0.5 g (1.96 mmol) of (S)-2-ami-
no-2-isopropyl-1,1-diphenylethanol
were
obtained
390mg (70%) of compound 6: Mp 266–267 ꢁC;
25
½aŠ ¼ ꢀ71:8 (c 0.04, MeOH); IR m 3426, 3350, 1660,
D
Following an analogous procedure to that described for
1, from compound 10 (3.4 g, 10mmol) were obtained
1516 cmꢀ1; MS(EI) 546 (M+ꢀH2O, 1), 528 (70), 486
(6), 220 (100); HRMS 546.2924 C36H38N2O3 required
25
D
3375, 3283, 1655,
1.2 g (46%) of compound 3: Mp 174–175 ꢁC; ½aŠ
1527 cmꢀ1; MS(EI) 288 (M+, 3), 257 (94), 239 (16), 86
(100); HRMS 288.2044 C14H28N2O4 required
¼
546.2882; 1H NMR (DMSO-d6)
d 8.53 (2H, d,
ꢀ30:2 (c 1.0, MeOH); IR
m
J = 10.4 Hz), 7.48 (4H, d, J = 7.5 Hz), 7.35 (4H, d,
J = 7.5 Hz), 7.28 (4H, t, J = 7.5 Hz), 7.13 (4H, t,
J = 7.5 Hz), 7.04 (2H, t, J = 7.5 Hz), 6.33 (2H, s), 4.80
(2H, dd, J = 10.4, 2.1 Hz), 1.78 (2H, m), 0.86 (6H, d,
J = 6.8 Hz), 0.65 (6H, d, J = 6.8 Hz); 13C NMR
(DMSO-d6) d 159.7 (s), 147.0(s), 146.0(s), 128.0(d),
127.7 (d), 126.2 (d), 126.1 (d), 125.1 (d), 125.0(d), 80.1
(s), 58.9 (d), 28.5 (d), 23.1 (q), 18.1 (q).
288.2049; 1H NMR (DMSO-d6)
d 8.35 (2H, d,
J = 9.4 Hz), 4.83 (2H, t, J = 5.6 Hz), 3.94 (2H, m),
3.44 (4H, m), 1.55 (4H, m), 1.40(2H, m), 0.96 (6H, d,
J = 6.4 Hz), 0.95 (6H, d, J = 6.4 Hz); 13C NMR
(DMSO-d6) d 160.1 (s), 63.7 (t), 49.9 (d), 39.9 (t), 24.6
(d), 23.6 (q), 22.2 (q).
4.8. N,N0-Bis[(1S)-1,2,2-triphenyl-2-hydroxyethyl]-2,2-
dimethylpropanodiamide 7
4.5. N,N0-Bis[(1S,2R)-2-hydroxy-1-methyl-2-phenyl-
ethyl]ethanediamide 4
To
a
solution of dimetilmalonic acid (460mg,
A solution of L-(ꢀ)-norephedrine (4 g, 26.5 mmol) and
diethyl oxalate (1.8 mL, 13.25 mmol) in toluene
(25 mL) was refluxed for 2 h. The reaction mixture
was cooled at room temperature and filtered. The
solid was washed with toluene and dried to give
3.46 mmol) in dichloromethane (15 mL) was added oxa-
lyl chloride (0.37 mL, 4.3 mmol) and 2 drops of DMF.
The reaction mixture was stirred for 1 h and then the
solvent was evaporated under reduced pressure. The
resulting acid dichloride was dissolved in dry THF
(1 mL) and injected into a solution of (S)-2-amino-1,1,2-
triphenylethanol (1 g, 3.46 mmol) and triethylamine
3.85 g (82%) of compound 4: Mp 236–237 ꢁC;
25
½aŠ ¼ þ38:5 (c 0.83, DMSO); IR m 3375, 3278, 1655,
D

1212
G. Blay et al. / Tetrahedron: Asymmetry 16 (2005) 1207–1213
120, 117–120; (d) Zhang, F.-Y.; Yip, C.-W.; Cao, R.;
Chan, A. S. C. Tetrahedron: Asymmetry 1997, 8, 585–589;
(e) Kitajima, H.; Aoki, Y.; Katsuki, T. Bull. Chem. Soc.
Jpn. 1997, 70, 207–217.
(0.54 mL, 3.85 mmol) in THF (34 mL) at 0 ꢁC. After
2 h, the reaction mixture was filtered, concentrated
and the resulting solid washed with diethyl ether to
give 1.1 g (98%) of compound 7: Mp 255–256 ꢁC;
25
6. (a) Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka,
M.; Kobayashi, S. Tetrahedron 1992, 48, 5691–5700;
(b) Takahashi, H.; Kawakita, T.; Yoshioka, M.; Koba-
yashi, S.; Ohno, M. Tetahedron Lett. 1989, 30, 7095–7098.
7. (a) Falorni, M.; Collu, C.; Conti, S.; Giacomelli, G.
Tetrahedron: Asymmetry 1996, 7, 293–299; (b) Seebach,
D.; Pichota, A.; Beck, A. K.; Pikerton, A. B.; Litz, T.;
Karjalainen, J.; Gramlich, V. Org. Lett. 1999, 1, 55–58; (c)
Hwang, C.-D.; Uang, B.-J. Tetrahedron: Asymmetry 1998,
9, 3979–3984.
½aŠ ¼ ꢀ175:4 (c 0.02, MeOH); IR m 3421, 3350, 1644,
D
1490cm ꢀ1; MS(EI) 656 (M+ꢀH2O, 2), 638 (34), 473
(23), 256 (100); HRMS 656.3048 C45H40N2O3 required
656.3039; 1H NMR (DMSO-d6)
d 7.98 (2H, d,
J = 8.8 Hz), 7.54 (4H, d, J = 7.5 Hz), 7.34 (4H, t,
J = 7.5 Hz), 7.30–7.05 (14H, m), 7.03 (4H, t,
J = 7.5 Hz), 6.92 (4H, d, J = 7.5 Hz), 6.25 (2H, s), 5.90
(2H, d, J = 8.8 Hz), 0.81 (6H, d, J = 6.8 Hz); 13C
NMR (DMSO-d6) d 171.7 (s), 146.2 (s), 144.8 (s),
138.9 (s), 129.0(d), 127.6 (d), 127.3 (d), 126.6 (d),
126.4 (d), 126.2 (d), 126.1 (d), 125.9 (d), 125.8 (d), 79.9
(s), 59.2 (d), 48.6 (s), 23.4 (q).
8. Pastor, I. M.; Adolfsson, H. Tetrahedron Lett. 2002, 43,
1743–1746.
´
9. (a) Frkanec, L.; Jokic, M.; Makarevic, J.; Wolsperger, K.;
Zinic, M. J. Am. Chem. Soc. 2002, 124, 9716–9717; (b)
´
ˇ
ˇ
ˇ
´
´
´
´
ˇ
´
´
Stefanic, Z.; Kojic-Prodic, B.; Dzolic, Z.; Katalenic, D.;
Zinic, M.; Meden, A. Acta. Cryst 2003, C59, o286–o288;
4.9. General procedure for the enantioselective addition of
diethylzinc to aldehydes
´
ˇ
´
(c) Makarevic, J.; Jokic, M.; Raza, Z.; Stefanic, Z.; Kojic-
Prodic, B.; Zinic, M. Chem. Eur. J. 2003, 9, 5567–5580; (d)
´
´
´
ˇ
´
´
´
Makarevic, J.; Jokic, M.; Peric, B.; Tomisic, V.; Kojic-
Prodic, B.; Zinic, M. Chem. Eur. J. 2001, 7, 3328–
´
´
´
´
To a solution of the corresponding ligand (0.2 mmol) in
dry CH2Cl2 (5 mL) under Ar was added TiðOPriÞ
ˇ
´
´
4
3341.
10. (a) Blay, G.; Fernandez, I.; Formentın, P.; Pedro, J. R.;
(0.42 mL, 1.4 mmol). After 1 h, the reaction mixture
was cooled to 0 ꢁC and a 1 M solution of diethylzinc
in hexane (3 mL, 3 mmol) was added. After 30min,
the aldehyde (1 mmol) was added and stirring continued
at this temperature for 24 h. Then, the reaction mixture
was quenched with 1 M HCl (20mL), filtered and ex-
tracted with ether (3 · 15 mL). The organic layer was
washed with brine, dried over anhydrous MgSO4,
filtered and concentrated under reduced pressure. Flash
chromatography on silica gel eluting with hexane–
diethyl ether mixtures gave the corresponding alcohol.
Yields and ee are included in Tables 1 and 2.
´
Rosello, A. L.; Ruiz, R.; Journaux, Y. Tetrahedron Lett.
´
´
1998, 39, 3327–3330; (b) Blay, G.; Fernandez, I.; Form-
´
entın, P.; Monje, B.; Pedro, J. R.; Ruiz, R. Tetrahedron
´
2001, 57, 1075–1081; (c) Blay, G.; Fernandez, I.; Monje,
´
B.; Pedro, J. R.; Ruiz, R. Tetrahedron Lett. 2002, 43,
´
8463–8466; (d) Blay, G.; Cardona, L.; Fernandez, I.;
Michelena, R.; Pedro, J. R.; Ramırez, T.; Ruiz-Garcıa, R.
´
´
´
Synlett 2003, 2325–2328; (e) Blay, G.; Fernandez, I.;
Monje, B.; Pedro, J. R. Tetrahedron 2004, 60, 165–170; (f)
´
Blay, G.; Fernandez, I.; Monje, B.; Pedro, J. R. Molecules
2004, 9, 365–372; (g) Barroso, S.; Blay, G.; Cardona, L.;
´
´
Fernandez, I.; Garcıa, B.; Pedro, J. R. J. Org. Chem. 2004,
69, 6821–6829; (h) Barroso, S.; Blay, G.; Fernandez, I.;
´
Pedro, J. R. Tetrahedron Lett. 2004, 45, 8583–8586; (i)
´
Blay, G.; Fernandez, I.; Monje, B.; Pedro, J. R. Tetrahe-
dron Lett. 2004, 45, 8039–8042.
Acknowledgements
This work was financially supported by the Spanish
Government (MCYT, project BQU 2001-3017) and in
part by Generalitat Valenciana (AVCYT, groups 03/
168). A.M.-A. thanks the MECCD for a grant (FPU
program).
11. Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824.
12. (a) Duthaler, R. O.; Hafner, A. Chem. Rev. 1992, 92, 807–
832; (b) Lake, F.; Moberg, C. Tetrahedron: Asymmetry
2001, 12, 755–760; (c) Xu, Q.; Wang, H.; Pan, X.; Chan,
A. S. C.; Yang, T. Tetrahedron Lett. 2001, 42, 6171–6173.
13. (a) Qiu, J.; Guo, C.; Zhang, X. J. Org. Chem. 1997, 62,
2665–2668; (b) Zhang, X.; Guo, C. Tetrahedron Lett.
1995, 4947–4950; (c) Guo, C.; Qiu, J.; Zhang, X.;
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