Chemoenzymatic syntheses of novel ligands derived from trans-cyclohexane-1, 2-diamine: Application in the enantioselective addition of diethylzinc to aromatic aldehydes

Article abstract of DOI:10.1016/j.tetasy.2006.01.003

Enantiopure (1R,2R)-cyclohexane-1,2-diamine derivatives, easily prepared from the corresponding (±)-trans-2-dialkylaminocyclohexanols through a chemoenzymatic route, have been employed as ligands in the enantioselective addition of diethylzinc to aromatic aldehydes. Of all the ligands tested, C ₂-symmetric bisaminoamides derived from pyridine-2,6-dicarboxylic acid proved to be the most efficient.

Full text of DOI:10.1016/j.tetasy.2006.01.003

Tetrahedron: Asymmetry 17 (2006) 449–454
Chemoenzymatic syntheses of novel ligands derived from
trans-cyclohexane-1,2-diamine: application in the
enantioselective addition of diethylzinc to aromatic aldehydes
*
*
´
´
Javier Gonzalez-Sabın, Vicente Gotor and Francisca Rebolledo
Departamento de Quı´mica Orga´nica e Inorga´nica, Universidad de Oviedo, 33071 Oviedo, Spain
Received 16 December 2005; accepted 3 January 2006
Available online 2 February 2006
Abstract—Enantiopure (1R,2R)-cyclohexane-1,2-diamine derivatives, easily prepared from the corresponding ( )-trans-2-dialkyl-
aminocyclohexanols through a chemoenzymatic route, have been employed as ligands in the enantioselective addition of diethylzinc
to aromatic aldehydes. Of all the ligands tested, C2-symmetric bisaminoamides derived from pyridine-2,6-dicarboxylic acid proved
to be the most efficient.
ꢀ 2006 Published by Elsevier Ltd.
OH
1. Introduction
NR1R2
The development of novel and efficient catalysts for
enantioselective reactions is one of the most challenging
goals in modern organic chemistry.1 In this sense, opti-
cally active cyclohexane-1,2-diamine derivatives are
specially attractive, as can be deduced from their wide
range of applicability.2 Thus, some C2-symmetric
ligands, such as bisulfonamides and tetraza derivatives
have been used to catalyze the addition of organozinc
reagents to carbonyl compounds. However, their use
was mainly limited to those ligands easily prepared from
commercially available optically active trans-cyclohex-
ane-1,2-diamine.3 This can be due to the preparation
of optically active nonsymmetric ligands from this
diamine being a more complex task, involving addi-
tional steps of protection, which often takes place with
low yields.4
rac-1
NH2
NR1R2
O
O
O
R3
NH
NR1R2
N
(1R,2R)-2
NH
HN
R1 R1
N
R2
N
R2
O
O
R4
NH
NR1R2
Scheme 1.
In a very recent publication,5 we described a highly effi-
cient chemoenzymatic preparation of a variety of opti-
cally active N,N-disubstituted trans-cyclohexane-1,2-
diamines 2 (Scheme 1) from the corresponding ( )-
trans-2-dialkylaminocyclohexanols 1. The easy accessi-
bility of these diamine encouraged us to prepare some
derivatives, such as carbamates and amides, some of
which had C2-symmetry (Scheme 1), and investigate
their application as chiral ligands in the addition of
diethylzinc to benzaldehyde. This class of ligands, which
has been scarcely investigated in this reaction,6 mimics
the very successful chiral b-amino alcohol-based
ligands7 because the alcohol, amide and carbamate pro-
tons have similar pKa values.8 Moreover, the transfor-
mation of the primary amino group into different
functions as well as the presence of different substituents
in the tertiary amino group could modulate the ligand
activity.
*
Corresponding authors. Tel./fax: +34 985 103448; e-mail addresses:
VGS@fq.uniovi.es; FRV@fq.uniovi.es
0957-4166/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2006.01.003

450
J. Gonza´lez-Sabı´n et al. / Tetrahedron: Asymmetry 17 (2006) 449–454
2. Results and discussion
meric excesses were obtained. The best ligand proved to
be the Boc-derivative of 2a (Table 1, entry 3). It is note-
worthy that the enantiomeric excesses achieved with the
carbamates of 2a and the Cbz-derivative of 2b (entries 2,
3 and 5) are very similar to those obtained with their
analogous b-amino alcohols (1R,2R)-1.9 This means
that diamines can be used as alternative compounds to
the b-amino alcohols, when they bear an NH group of
similar acidity to the OH group of the alcohols.
All ligands described herein were obtained from the cor-
responding enantiopure diamines (1R,2R)-2a–d (Fig. 1),
which were prepared by enzymatic resolution of rac-
trans-2a–d according to Ref. 5.
NR1R2
NH2
O
Once the utility of these diamines derivatives to catalyze
the addition of diethylzinc to benzaldehyde was demon-
strated, our following objective was to modify the struc-
ture of the ligand to get more enantioselective catalysts.
These modifications were made by taking into account
the following observations: (1) ligands can bind zinc in
a tri- and tetradentate manner.10 (2) In some cases higher
enantioselectivities can be obtained with ligands bearing
multiple stereocentres.11 (3) Pyridine-based ligands are
very efficient catalysts, especially those with a C2 sym-
metry.7c Thus, starting from diamine (1R,2R)-2a, we
prepared three derivatives, the pyridine-2-carboxamide
(1R,2R)-6a and the C2-symmetric benzene-1,3- and
pyridine-2,6-dicarboxamides 7a and 8a, respectively.
The syntheses of the C2-symmetric ligands 7a and 8a
were easily accomplished in quantitative yields by treat-
ment of the diamine with 0.5 equiv of benzene-1,3-dicar-
bonyl dichloride and pyridine-2,6-dicarbonyl dichloride,
respectively.
NR1R2
(1R,2R)-2a-d
N
N
N
a
N
c
d
b
Figure 1. Chemoenzymatically prepared diamines (1R,2R)-2a–d.
In a recent paper,9 we studied the efficiency of enantio-
pure 2-dialkylaminocyclohexanols (1R,2R)-1 (Scheme 1)
to catalyze the enantioselective addition of diethylzinc to
benzaldehyde. In all cases 1-phenylpropan-1-ol was
obtained with very good yields but with moderate enan-
tiomeric excesses, these being dependent of the substitu-
ent on the amino group. Based on these results, we
started choosing diamines (1R,2R)-2a,b, because they
are structurally analogous to the b-amino alcohols that
yielded the most interesting results in the ethylation of
benzaldehyde.
Table 1. Enantioselective addition of Et2Zn to benzaldehyde in the
presence of ligands (1R,2R)-3–5a
Results obtained in the reactions with these new ligands
are shown in Table 2. As can be seen (Table 2, entries 1–
4) the C2-symmetric compounds 7a and 8a were more
efficient catalysts than the corresponding derivatives 3a
and 6a lacking symmetry. After the same reaction time,
the yields of 1-phenylpropan-1-ol obtained in the reac-
tions with 7a and 8a were higher that those obtained
with 3a and 6a. Moreover, a notable increase of enantio-
selectivity was observed with the C2-symmetric ligands,
especially in the case of the bisaminoamide 8a contain-
ing the pyridine unit in its structure. In addition,
another interesting feature of our comparison is the
reversal in enantioselectivity observed depending on
the presence of a benzene or a pyridine moiety. A similar
finding was previously reported by Williams et al.12 in
the addition of diethylzinc to aldehydes in the presence
of C2-symmetric b-amino alcohols containing analogous
benzene and pyridine units. However, in that case, the
enantioselectivities were similar with both ligands, in
contrast to the strong differences observed with our pair
of ligands 7a and 8a.
OH
O
Et2Zn, 6 mol% ligand
toluene-hexane
Ph
(R) and (S)
Yieldb eec Major
Ph
H
Entry
Ligand
(%) (%) enantiomer
1
2
3a (R = Bz) 51
10
54
R
R
NHR
N
4a (R = Cbz) 92
5a (R = Boc) 85
3b (R = Bz) 80
4b (R = Cbz) 93
3
4
5
57
3
R
S
O
NHR
N
25
R
6
5b (R = Boc) 86
7
S
a Reactions were carried out at 20 ꢁC for 16 h.
b Determined by 1H NMR.
c Determined by chiral HPLC analysis (Chiralcel OD column).
After seeing the results obtained with ligand 8a, we
decided to modify its structure in order to improve the
efficiency of the catalytic process. Thus, we prepared
other C2-symmetric ligands 7b–d and 8b–d (Table 2)
from the optically active diamines (1R,2R)-2b–d (see
Fig. 1). In addition, another focus has been in verifying
if the reversal of enantioselectivity shown above also
happens with these bisaminoamides.
First, enantiopure diamines (1R,2R)-2a,b were con-
verted into their benzamides 3a and 3b, and benzyl
and tert-butyl carbamates derivatives 4 and 5, respec-
tively, by conventional methods. These compounds were
initially checked as ligands in the diethylzinc addition to
benzaldehyde. Reactions were carried out at 20 ꢁC using
6 mol % of ligand, diethylzinc (2.0 equiv) and a mixture
of toluene-hexane as solvent. As shown in Table 1, 1-
phenylpropan-1-ol was obtained with moderate to high
yield in most cases, but only moderate values of enantio-
The analysis of the results summarized in Table 2 (en-
tries 5–10) reveals for the new ligands the same tendency

J. Gonza´lez-Sab´ın et al. / Tetrahedron: Asymmetry 17 (2006) 449–454
451
Table 2. Enantioselective addition of Et2Zn to benzaldehyde in the presence of ligands (1R,2R)-3a,6a, 7a–d and 8a–da
O
O
O
O
O
O
O
O
O
X
X
X
X
X
NH
N
NH
HN
NH
HN
NH
NH
HN
HN
N
N
N
N
N
N
N
N
O
O
O
3a: X = CH
6a: X = N
7c: X = CH
8c: X = N
7a: X = CH
8a: X = N
7b: X = CH
8b: X = N
7d: X = CH
8d: X = N
OH
O
Et2Zn, 6 mol% ligand
toluene-hexane
Ph
(R) and (S)
Ph
H
Entry
Ligand
Yieldb (%)
eec (%)
Major enantiomer
1
2
3
4
5
6
7
8
9
10
3a
6a
7a
8a
7b
8b
7c
8c
7d
8d
51
65
94
95
90
95
86
92
90
85
10
7
R
S
R
S
R
S
R
S
R
S
21
75
31
68
11
53
32
42
a Reactions were carried out at 20 ꢁC for 16 h.
b Determined by 1H NMR.
c Determined by chiral HPLC analysis (Chiralcel OD column).
Table 3. Addition of diethylzinc to aromatic aldehydes using ligand
as for 7a and 8a. Thus, the major isomer obtained with
all the ligands containing pyridine had an opposite abso-
lute configuration to that observed with the ligands con-
taining a benzene group, and with all pairs of ligands,
higher enantioselectivities were achieved with the pyri-
dine ligands. Anyway, compound 8a was still the most
efficient ligand, and a drastic influence of the selected
diamine was observed over the asymmetric induction.
8aa
OH
O
Et2Zn, 8a (6 mol%)
toluene-hexane
Yieldb (%)
Ar
Ar
H
Entry
Ar
eec (%)
Config.
1
Ph
Ph
Ph
Ph
Ph
95
75
88
81
80
85
88
75
75
15
0
52
32
46
64
60
S
S
—
S
S
S
S
S
2d
3e
4f
5g
6
Further efforts to optimize the reaction with the ligand
8a were carried out (Table 3). First, the alkylation of
benzaldehyde with diethylzinc was performed after pre-
vious formation of the complex with titanium isoprop-
oxide (entry 2). However, the new catalytic system
resulted in a poor enantioselectivity of the alcohol pro-
duced, in contrast to previous reports in which an excess
of the Ti reagent led to excellent enantioselectivities.13
Similar results were achieved by employing the complex
formed with nickel acetate,14 racemic 1-phenylpropan-1-
ol being obtained in this case (entry 3). Next, the loading
of the catalyst was increased to 20 mol %, but a slight
decrease in the enantioselectivity was noticed (entry 4).
Lastly, by changing the temperature to ꢀ50 ꢁC, the reac-
tion rate was lower, resulting in a decrease of both the
conversion and the enantioselectivity (entry 5). With
the best conditions for benzaldehyde, the use of ligand
8a was extended to the asymmetric ethylation of other
aromatic aldehydes (Table 3, entries 6–8). The yields
for the substituted benzaldehydes and naphthaldehyde
were high, although the enantiomeric excesses continued
being moderate. In all cases the configuration of the
p-MeO–C6H4
p-Cl–C6H4
2-Naphthyl
7
8
a Reactions were carried out at 20 ꢁC except that of entry 5.
b Determined by 1H NMR.
c Determined by chiral HPLC analysis (Chiralcel OD column).
d Using Ti(OPri)4 (1 equiv). The catalyst was preformed prior to
aldehyde addition.
e Using the complex formed with the metal salt Ni(OAc)2.
f Ligand 8a (20 mol %).
g Reaction was carried out at ꢀ50 ꢁC.
alcohol produced was S, established after the compari-
son of the elution order in HPLC analysis.13a
3. Conclusion
In conclusion, we have carried out the chemoenzymatic
synthesis of a new class of C2-symmetric bisaminoamide

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J. Gonza´lez-Sabı´n et al. / Tetrahedron: Asymmetry 17 (2006) 449–454
ligands derived from N,N-disubstituted trans-cyclohex-
ane-1,2-diamine with promising applications in asym-
metric catalysis. Thus, we have demonstrated the
utility of these bisaminoamides catalyzing the enantio-
selective addition of diethylzinc to aldehydes, finding
an interesting reversal of the asymmetric induction, with
only a slight modification of the ligand structure.
2.80 (m, 1H) 2.85 (hept, 1H, J = 6.5 Hz, N–CH), 3.51
(m, 1H), 7.10 (br s, 1H, NH), 7.30–7.45 (m, 3H, Ph),
7.70–7.80 (m, 2H, Ph); 13C NMR (75.5 MHz): d 20.85
(CH3), 21.53 (CH3), 24.43 (CH2), 25.48 (CH2), 25.63
(CH2), 30.76 (CH3), 32.26 (CH2), 50.94 (CH), 51.48
(CH), 63.82 (CH), 126.65 (CH), 128.21 (CH), 130.85
(CH), 135.13 (C), 167.48 (C@O). MS (ESI+)
m/z (rel. intensity): 275.2 [(M+H)+, 100].
4. Experimental
4.1. General
4.3. General procedure for the synthesis of carbamates
(1R,2R)-4a,b and (1R,2R)-5a,b
All reactions were performed under a nitrogen atmo-
sphere. IR spectra were recorded on an Infrared FT spec-
trophotometer using KBr pellets (for solids) or neat (for
liquids). Chiral HPLC analyses were performed using
Chiralcel OD (Daicel), at 20 ꢁC. 1H, 13C NMR and
DEPT were recorded using AC-200 (1H, 200.13 MHz
and 13C, 50.3 MHz), and AC-300 or DPX-300 (1H,
300.13 MHz and 13C, 75.5 MHz) spectrometers using
CDCl3 as solvent. The chemical shifts are given in delta
(d) values and the coupling constants (J) in hertz (Hz).
EI or ESI+ were used to record mass spectra (MS).
A solution of the corresponding diamine (1R,2R)-2a,b
(0.25 mmol) in dichloromethane (5 mL) was treated with
Cbz–Cl (0.30 mmol) or di-tert-butyl dicarbonate
(0.30 mmol). After 7 h of reaction at room temperature,
the solvent was evaporated and the resulting crude was
purified by flash chromatography (mixtures of hexane–
ethyl acetate). Spectroscopic data and specific rotation
values for benzyl carbamates (1R,2R)-4a,b are in agree-
ment with the published data for (1S,2S)-4a,b.5
4.3.1. tert-Butyl (1R,2R)-N-[2-(morpholin-4-yl)cyclo-
hexyl]carbamate (1R,2R)-5a. Yield: 93%; mp 77–
20
4.1.1. N,N-Disubstituted (1R,2R)-cyclohexane-1,2-di-
amines 2a–d. Enantiopure diamines (1R,2R)-2a–d were
obtained by basic hydrolysis (3 M aq NaOH, reflux,
12 h, 93–95% yield) of their corresponding acetamide
derivatives, which in turn were prepared by enzymatic
resolution according to Ref. 5. Spectroscopic data and
specific rotation values are in agreement with the pub-
lished data for rac-2a–d and (1S,2S)-2a–d, respectively.5
79 ꢁC; ½aꢁD ¼ ꢀ51:6 (c 0.80, CHCl3), >99% ee. IR (neat)
1
3358, 1711 cmꢀ1; H NMR (300 MHz): d 1.04–1.25 (m,
4H), 1.30–1.50 (m, 10H), 1.60–1.90 (m, 4H), 2.13 (dt,
1H, J = 10.8 Hz), 2.30–2.45 (m, 3H), 2.60–2.75 (m,
2H), 3.29 (m, 1H), 3.60–3.75 (m, 4H), 5.03 (br s, 1H,
NH); 13C NMR (75.5 MHz) d 23.16 (CH2), 24.64
(CH2), 25.34 (CH2), 28.41 (CH3), 33.31 (CH2), 48.39
(CH2), 50.71 (CH), 67.49 (CH2), 67.79 (CH), 78.75
(C), 156.15 (C@O). MS (ESI+) m/z (rel. intensity):
285.2 [(M+H)+, 65], 307.1 [(M+Na)+, 40].
4.2. General procedure for the synthesis of benzamides
(1R,2R)-3a,b
4.3.2. tert-Butyl (1R,2R)-N-[2-(N0-isopropyl-N0-methyl-
To a solution of the corresponding diamine (1R,2R)-
2a,b (0.25 mmol) and DMAP (15 mg) in dichlorometh-
ane (5 mL), benzoyl chloride (0.35 mmol) was added.
After 24 h at room temperature, the solvent was evapo-
rated and the resulting crude purified by flash chroma-
tography (mixtures of hexane–ethyl acetate).
amino)cyclohexyl]carbamate
(1R,2R)-5b. Colourless
20
oil; yield: 83%; ½aꢁD ¼ ꢀ112:5 (c 0.70, CHCl3), >99%
ee; IR (neat) 3375, 1716 cmꢀ1; H NMR (300 MHz): d
1
0.94 (d, 3H, J = 6.5 Hz, CH3), 0.97 (d, 3H, J = 6.5 Hz,
CH3), 1.10–1.25 (m, 2H), 1.30–1.45 (m+s, 11H), 1.55–
1.75 (m, 3H), 2.10 (s, 3H, CH3), 2.20–2.30 (m, 1H),
2.35–2.45 (m, 1H) 2.76 (hept, 1H, J = 6.5 Hz, N–CH),
3.11 (m, 1H), 5.20 (br s, 1H, NH); 13C NMR
(75.5 MHz): d 20.45 (CH3), 21.51 (CH3), 24.47 (CH2),
25.54 (CH2), 25.64 (CH2), 28.28 (CH3), 31.09 (CH3),
33.05 (CH2), 50.30 (CH), 51.85 (CH), 63.99 (CH),
78.39 (C), 156.43 (C@O). MS (ESI+) m/z (rel. intensity):
271.2 [(M+H)+, 100].
4.2.1.
(1R,2R)-N-[2-(Morpholin-4-yl)cyclohexyl]benz-
amide (1R,2R)-3a. Yield: 92%; mp 197–199 ꢁC;
20
½aꢁD ¼ ꢀ93:7 (c 0.70, CHCl3), >99% ee; IR (neat)
3288, 1632 cmꢀ1 1H NMR (300 MHz): d 1.05–1.45
;
(m, 4H), 1.65–2.10 (m, 3H), 2.35–2.45 (m, 3H), 2.60–
2.75 (m, 3H), 3.55–3.80 (m, 5H) 6.87 (br s, 1H, NH),
7.40–7.55 (m, 3H, Ph), 7.75–7.80 (m, 2H, Ph); 13C
NMR (75.5 MHz): d 23.12 (CH2), 24.54 (CH2), 25.41
(CH2), 32.65 (CH2), 48.21 (CH2), 50.58 (CH), 67.52
(CH2), 67.57 (CH), 126.70 (CH), 128.45 (CH), 131.12
(CH), 135.13 (C), 167.53 (C@O). MS (ESI+) m/z (rel.
intensity): 289.2 [(M+H)+, 100], 311.2 [(M+Na)+, 25],
327.2 [(M+K)+, 5].
4.4. Synthesis of (1R,2R)-N-[2-(morpholin-4-yl)cyclo-
hexyl]pyridine-2-carboxamide (1R,2R)-6a
The method was the same as for the synthesis of the benz-
amides except that DMAP was not used. Yield: 91%;
20
mp 134–136 ꢁC; ½aꢁD ¼ ꢀ79:2 (c 0.50, CHCl3), >99%
ee; IR (neat) 3379, 1675 cmꢀ1; H NMR (300 MHz): d
1
4.2.2. (1R,2R)-N-[2-(N0-Isopropyl-N0-methylamino)cyclo-
1.10–1.40 (m, 4H), 1.60–1.90 (m, 3H), 2.30–2.50 (m,
4H), 2.55–2.75 (m, 2H), 3.40–3.85 (m, 5H), 7.40 (t,
1H, J = 6.1 Hz), 7.83 (t, 1H, J = 7.2 Hz), 8.17 (d, 1H,
J = 7.7 Hz), 8.39 (br s, 1H, NH), 8.55 (d, 1H, J =
4.3 Hz); 13C NMR (75.5 MHz): d 23.66 (CH2), 24.68
(CH2), 25.32 (CH2), 32.74 (CH2), 48.40 (CH2), 50.08
hexyl]benzamide (1R,2R)-3b. Yield: 90%; mp 101–
20
103 ꢁC; ½aꢁD ¼ ꢀ13:1 (c 0.70, CHCl3), >99% ee; IR
(neat) 3406, 1635 cmꢀ1 1H NMR (300 MHz): d 1.01
;
(d, 6H, J = 6.5 Hz, 2CH3), 1.05–1.40 (m, 4H), 1.60–
1.85 (m, 3H), 2.13 (s, 3H, CH3), 2.54 (m, 1H), 2.70–

J. Gonza´lez-Sab´ın et al. / Tetrahedron: Asymmetry 17 (2006) 449–454
453
(CH), 67.43 (CH2), 67.54 (CH), 121.94 (CH), 125.75
(CH), 137.11 (CH), 147.96 (CH), 150.39 (C), 164.18
(C@O). MS (ESI+) m/z (rel. intensity): 290.1 [(M+H)+,
100], 312.1 [(M+Na)+, 25], 328.1 [(M+K)+, 10].
22.30 (CH2), 23.61 (CH2), 24.33 (CH2), 24.59 (CH2),
32.01 (CH2), 47.13 (CH2), 52.29 (CH), 61.68 (CH),
125.27 (CH), 128.43 (CH), 129.66 (CH), 135.11 (C),
166.77 (C@O). MS (ESI+) m/z (rel. intensity): 467.5
[(M+H)+, 100].
4.5. Synthesis of bisaminoamides. General procedure
4.5.5. (10R,100R,20R,200R)-N,N0-Bis-[2-(morpholin-4-yl)-
To a solution of diamine (1R,2R)-2a–d (0.26 mmol) in
dichloromethane (5.0 mL), the corresponding acid
dichloride (0.13 mmol) was added under a nitrogen
atmosphere. After stirring to room temperature for
4 h, the solvent was evaporated and the resulting crude
purified by flash chromatography (mixtures of hexane–
ethyl acetate).
cyclohexyl]pyridine-2,6-dicarboxamide 8a. Yield: 93%;
20
mp 110–112 ꢁC; ½aꢁD ¼ ꢀ167:0 (c 0.60, CHCl3), >99%
ee; IR (neat) 3453, 3354, 1663 cmꢀ1
;
1H NMR
(300 MHz): d 1.05–1.45 (m, 8H), 1.65–2.00 (m, 6H),
2.25–2.75 (m, 12H), 3.45–3.85 (m, 10H), 8.01 (t, 1H,
J = 7.8 Hz), 8.21 (d, 2H, NH, J = 5.7 Hz), 8.32 (d, 2H,
J = 8.0 Hz); 13C NMR (75.5 MHz): d 23.44 (CH2),
24.39 (CH2), 25.30 (CH2), 32.82 (CH2), 48.33 (CH2),
50.16 (CH), 67.39 (CH2), 67.64 (CH2), 124.40 (CH),
138.62 (CH), 148.91 (C), 163.48 (C@O). MS (EI+) m/z
(rel. intensity): 499.5 (M+, 32), 469.5 (26), 167.1 (90).
4.5.1. (10R,100R,20R,200R)-N,N0-Bis-[2-(morpholin-4-yl)-
cyclohexyl]benzene-1,5-dicarboxamide 7a. Yield: 95%;
20
mp 85–87 ꢁC; ½aꢁD ¼ ꢀ98:9 (c 0.67, CHCl3), >99% ee;
1
IR (neat) 3462, 3322, 1643 cmꢀ1; H NMR (300 MHz):
d 1.10–1.35 (m, 8H), 1.65–2.05 (m, 6H), 2.35–2.75 (m,
12H), 3.45–3.80 (m, 10H), 7.06 (br s, 2H, NH), 7.49 (t,
1H, J = 7.7 Hz), 7.89 (d, 2H, J = 7.7 Hz), 8.28 (s, 1H);
13C NMR (75.5 MHz): d 23.13 (CH2), 24.51 (CH2),
25.26 (CH2), 32.62 (CH2), 48.17 (CH2), 50.47 (CH),
67.33 (CH2+CH), 125.44 (CH), 128.72 (CH), 129.44
(CH), 135.22 (C), 166.65 (C@O). MS (EI+) m/z (rel.
intensity): 498.5 [M+, 37], 468.5 (33), 167.1 (100).
4.5.6. (10R,100R,20R,200R)-N,N0-Bis-{2-[isopropyl(methyl)-
amino]cyclohexyl}pyridine-2,6-dicarboxamide 8b. Yield:
20
93%; mp 116–118 ꢁC; ½aꢁD ¼ ꢀ183:8 (c 0.93, CHCl3),
1
>99% ee; IR (neat) 3442, 3396, 1666 cmꢀ1; H NMR
(300 MHz): d 0.90–1.50 (m, 20H), 1.60–1.95 (m, 6H),
2.22 (m, 6H), 2.45–2.70 (m, 4H), 2.93 (hept, 2H,
J = 6.3 Hz), 3.79 (m, 2H), 7.97 (t, 1H, J = 7.8 Hz), 8.15
(br s, 2H, NH), 8.31 (d, 2H, J = 7.8 Hz); 13C NMR
(75.5 MHz): d 20.81 (CH3), 21.60 (CH3), 24.68 (CH2),
25.71 (CH2), 26.60 (CH2), 31.14 (CH3), 33.01 (CH2),
51.02 (CH), 51.08 (CH), 51.17 (CH), 64.30 (CH),
124.28 (CH), 138.39 (CH), 149.14 (C), 163.46 (C@O).
MS (EI+) m/z (rel. intensity): 471.5 (M+, 17), 428.5 (100).
4.5.2. (10R,100R,20R,200R)-N,N0-Bis-{2-[isopropyl(methyl)-
amino]cyclohexyl}benzene-1,5-dicarboxamide 7b. Yield:
20
95%; mp 80–82 ꢁC; ½aꢁD ¼ ꢀ111:1 (c 0.50, CHCl3),
>99% ee; IR (neat) 3358, 1642 cmꢀ1
;
1H NMR
(300 MHz): d 0.90–1.55 (m, 20H), 1.65–2.00 (m, 6H),
2.23 (s, 6H), 2.55–2.80 (m, 4H), 2.98 (hept, 2H,
J = 6.3 Hz), 3.70 (m, 2H), 7.49 (t+br s, 1H+2NH,
J = 7.8 Hz), 7.90 (dd, 2H, J = 7.8 and 1.6 Hz), 8.30 (s,
1H); 13C NMR (75.5 MHz): d 20.39 (CH3), 21.31
(CH3), 24.52 (CH2), 25.58 (CH2), 31.13 (CH3), 32.50
(CH2), 51.29 (CH), 51.41 (CH), 64.38 (CH), 125.47
(CH), 128.49 (CH), 129.74 (CH), 135.11 (C), 166.78
(C@O). MS (ESI+) m/z (rel. intensity): 471.5
[(M+H)+, 30].
4.5.7. (10R,100R,20R,200R)-N,N0-Bis-[2-(piperidin-1-yl)cyclo-
hexyl]pyridine-2,6-dicarboxamide 8c. Yield: 90%; mp
20
79–81 ꢁC; ½aꢁD ¼ ꢀ186:9 (c 0.50, CHCl3), >99% ee; IR
1
(neat) 3472, 3349, 1668 cmꢀ1; H NMR (300 MHz): d
1.05–1.60 (m, 20H), 1.65–2.00 (m, 5H), 2.20–2.70 (m,
13H), 3.68 (m, 2H), 8.01 (t, 1H, J = 7.8 Hz), 8.34 (d,
2H, J = 7.8 Hz), 8.57 (d, 2H, NH, J = 3.9 Hz); 13C
NMR (75.5 MHz): d 23.46 (CH2), 24.55 (CH2), 24.79
(CH2), 25.66 (CH2), 27.04 (CH2), 32.67 (CH2), 49.29
(CH2), 51.04 (CH), 67.90 (CH), 124.11 (CH), 138.53
(CH), 149.02 (C), 165.73 (C@O). MS (ESI+) m/z (rel.
intensity): 496.5 [(M+H)+, 100], 518.5 [(M+Na)+, 20].
4.5.3. (10R,100R,20R,200R)-N,N0-Bis-[2-(piperidin-1-yl)cyclo-
hexyl]benzene-1,5-dicarboxamide 7c. Yield: 94%; mp
20
177–179 ꢁC; ½aꢁD ¼ ꢀ130:7 (c 0.50, CHCl3), >99% ee;
IR (neat) 3333, 1644 cmꢀ1
,
1H NMR (300 MHz): d
4.5.8. (10R,100R,20R,200R)-N,N0-Bis-[2-(pyrrolidin-1-yl)-
1.05–2.00 (m, 26H), 2.10–2.75 (m, 12H), 3.66 (m, 2H),
7.28 (br s, 2H, NH), 7.53 (t, 1H, J = 7.8 Hz), 7.94 (d,
2H, J = 7.8 Hz), 8.27 (s, 1H); 13C NMR (75.5 MHz): d
23.01 (CH2), 24.49 (CH2), 24.72 (CH2), 25.51 (CH2),
26.73 (CH2), 32.40 (CH2), 49.11 (CH2), 51.08 (CH),
67.73 (CH), 125.29 (CH), 128.61 (CH), 129.40 (CH),
135.37 (C), 166.92 (C@O). MS (ESI+) m/z (rel. inten-
sity): 495.5 [(M+H)+, 100].
cyclohexyl]pyridine-2,6-dicarboxamide 8d. Yield: 90%;
20
mp 94–96 ꢁC; ½aꢁD ¼ ꢀ117:8 (c 0.50, CHCl3), >99% ee;
IR (neat) 3471, 3339, 1666 cmꢀ1
;
1H NMR
(300 MHz): d 1.00–1.90 (m, 22H), 2.40–2.65 (m, 12H),
3.70–3.90 (m, 2H), 7.98 (t, 1H, J = 7.7 Hz), 8.30 (d+br
s, 2H+2NH, J = 7.7 Hz); 13C NMR (75.5 MHz): d
23.10 (CH2), 23.81 (CH2), 24.09 (CH2), 24.42 (CH2),
31.61 (CH2), 47.60 (CH2), 51.68 (CH), 62.09 (CH),
124.33 (CH), 138.59 (CH), 149.01 (C), 163.28 (C@O).
MS (ESI+) m/z (rel. intensity): 468.5 [(M+H)+, 100].
4.5.4. (10R,100R,20R,200R)-N,N0-Bis-[2-(pyrrolidin-1-yl)-
cyclohexyl]benzene-1,5-dicarboxamide 7d. Yield: 95%;
20
mp 120–122 ꢁC; ½aꢁD ¼ ꢀ84:9 (c 0.50, CHCl3), >99%
4.6. Addition of diethylzinc to aldehydes. General
procedure
ee; IR (neat) 3317, 1643 cmꢀ1; H NMR (300 MHz): d
1
1.05–2.00 (m, 22H), 2.10–2.75 (m, 12H), 3.66 (m, 2H),
7.15 (br s, 2H, NH), 7.45 (t, 1H, J = 7.8 Hz), 7.85 (d,
2H, J = 8.0 Hz), 8.36 (s, 1H); 13C NMR (75.5 MHz): d
To a solution of the optically active ligand (0.10 mmol)
in toluene (1.8 mL), diethylzinc (3.2 mmol, 3.2 mL of a

454
J. Gonza´lez-Sabı´n et al. / Tetrahedron: Asymmetry 17 (2006) 449–454
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, Germany, 1999; Vols. 1–3.
1 M solution in hexane) was slowly added at 0 ꢁC under
a nitrogen atmosphere. The mixture was stirred to room
temperature during 30 min and then aldehyde
(1.6 mmol) was added at 0 ꢁC. The mixture was allowed
to reach room temperature and stirred during 16 h.
After this time, 1 M aq HCl was added and the mixture
was extracted with dichloromethane (3 · 15 mL). Evap-
oration of the organic solvents yielded the correspond-
ing 1-arylpropan-1-ol.
2. For some recent examples of the utility of trans-cyclohex-
ane-1,2-diamine derivatives in asymmetric catalysis, see:
(a) Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005,
127, 8964–8965; (b) Evans, D. A.; Seidel, D. J. Am. Chem.
Soc. 2005, 127, 9958–9959; (c) Aoyama, H.; Tokunaga,
M.; Kiyosu, J.; Iwasawa, T.; Obora, Y.; Tsuji, Y. J. Am.
Chem. Soc. 2005, 127, 10474–10475.
´
3. For a review, see: (a) Hechavarrıa Fonseca, M.; Ko¨nig, B.
´
Adv. Synth. Catal. 2003, 345, 1173–1185; (b) Hechavarrıa
Fonseca, M.; Eibler, E.; Zabel, M.; Ko¨nig, B. Tetrahe-
dron: Asymmetry 2003, 14, 1989–1994, and references cited
therein.
4.7. Chiral HPLC analyses of the 1-arylpropan-1-ols
A Chiralcel OD column was used in all cases. T = 20 ꢁC.
UV detection, k = 210 nm.
4. Kaik, M.; Gawronski, J. Tetrahedron: Asymmetry 2003,
14, 1559–1563, and references cited therein.
´
´
5. Gonzalez-Sabın, J.; Gotor, V.; Rebolledo, F. Chem. Eur.
4.7.1. 1-Phenylpropan-1-ol. Hexane–2-propanol 97:3;
0.8 mL/min. tR = 14.7 (R) and 16.1 (S) min. RS = 1.5.
J. 2004, 10, 5788–5794.
6. Richmond, M. L.; Seto, C. T. J. Org. Chem. 2003, 68,
7505–7508.
4.7.2. 1-(4-Methoxyphenyl)propan-1-ol. Hexane–2-pro-
panol 97:3; 1.0 mL/min. tR = 18.3 (R) and 20.9 (S) min.
RS = 2.6.
7. For some reviews about the use of b-amino alcohols in the
dialkylzinc addition to aldehydes, see: (a) Noyori, R.;
Kitamura, M. Angew. Chem., Int. Ed. 1991, 30, 49–69; (b)
Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833–856; (c) Pu,
L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824.
8. (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463; (b)
Zhang, X.-M.; Bordwell, F. G. J. Org. Chem. 1994, 59,
6456–6458.
4.7.3. 1-(4-Chlorophenyl)propan-1-ol. Hexane–2-pro-
panol 99:1; 0.5 mL/min. tR = 27.0 (S) and 28.8
(R) min. RS = 1.1.
´
´
9. Gonzalez-Sabın, J.; Gotor, V.; Rebolledo, F. Tetrahedron:
4.7.4. 1-(20-Naphthyl)propan-1-ol. Hexane–2-propanol
95:5; 1.0 mL/min. tR = 19.0 (S) and 21.9 (R) min.
RS = 2.3.
Asymmetry 2004, 15, 1335–1341.
10. (a) Corey, E. J.; Yuen, P. W.; Hannon, F. J.; Wierda, D.
A. J. Org. Chem. 1990, 55, 784–786; (b) Dangel, B. D.;
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Acknowledgements
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1269–1279; (b) Cobb, A. J. A.; Marson, C. M. Tetra-
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We thank Novo Nordisk Co. for the generous gift of the
CAL-B. This work has been supported by MEC (Spain;
Project MEC-04-CTQ-04185). J.G.-S. thanks the Span-
ish MEC, for a predoctoral fellowship.
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