Structurally constrained C1-1,1′-bisisoquinoline-based chiral ligands: geometrical implications on enantioinduction in the addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2010.02.022

New highly constrained chiral C₁-1,1′-bisisoquinoline ligands have been synthesized. X-ray crystallographic analysis of these ligands showed peculiar structural differences between the parent 1′,2′,3′,4′-tetrahydro-1,1′-bisisoquinolin e and its alkyl, acyl and sulfonyl derivatives. The consequences of their geometrical conformations on enantioinduction were examined by employing the enantioselective addition of diethylzinc to aldehydes. Such conformations greatly affected the catalytic efficiency of these ligands.

Full text of DOI:10.1016/j.tetasy.2010.02.022

Tetrahedron: Asymmetry 21 (2010) 429–436
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journal homepage: www.elsevier.com/locate/tetasy
0
Structurally constrained C -1,1 -bisisoquinoline-based chiral ligands:
1
geometrical implications on enantioinduction in the addition of diethylzinc
to aldehydes
Gao Qi, Zaher M. A. Judeh *
School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive, N1.2 B1-14, Singapore 637459, Singapore
a r t i c l e i n f o
a b s t r a c t
0
Article history:
1
New highly constrained chiral C -1,1 -bisisoquinoline ligands have been synthesized. X-ray crystallo-
Received 11 January 2010
Accepted 16 February 2010
Available online 8 April 2010
0
0
0
0
graphic analysis of these ligands showed peculiar structural differences between the parent 1 ,2 ,3 ,4 -tet-
rahydro-1,1 -bisisoquinoline and its alkyl, acyl and sulfonyl derivatives. The consequences of their
geometrical conformations on enantioinduction were examined by employing the enantioselective addi-
0
tion of diethylzinc to aldehydes. Such conformations greatly affected the catalytic efficiency of these
ligands.
Ó 2010 Elsevier Ltd. All rights reserved.
0
1
. Introduction
synthesize new C
1
-1,1 -bisisoquinoline ligands (Fig. 2) with the
intention of using them as probes to examine the effect of geomet-
rical constrains on enantioinduction. The addition of Et Zn to alde-
1
Chiral N,N-ligands have been used successfully in various
2
asymmetric reactions.2 However, the number and backbone vari-
ety of such diamines are rather limited, probably due to difficulties
in their synthesis and resolution. The most well-studied and uti-
hydes was considered as a model reaction. This reaction serves as a
good testing ground for ligand development and optimization. It
has attracted much attention because of its simplicity and utility
for the preparation of chiral secondary alcohols which are key
building blocks in the fine chemical and pharmaceutical indus-
lized chiral C
2
-symmetric diamines include cyclohexane-1,2-dia-
0
mine, 1,2-diphenylethan-1,2-diamine, 2,2 -diaminobinaphthyl
3
0
6
and their derivatives. On the other hand, C
2
-symmetric 1,1 -bis-
tries. Various chiral catalysts based on amino alcohols, diols, thi-
isoquinolines (fully aromatic and partially reduced forms) such
ols, diselenides, disulfides, diamines, BINOLs, oxazaborolidines,
bisoxazolidines and sulfinamides have been used successfully for
the asymmetric addition of dialkylzincs to aldehydes. The pres-
as 1–4 (Fig. 1) with their appealing backbone have recently been
4
6,7
examined as new motifs for various asymmetric reactions. Oxida-
0
tive coupling of b-naphthol-2-carboxylate using 1 gave 1,1 -bis-b-
ent ligand system is an aminopyridine type (Fig. 2) that has hardly
naphthol-2-carboxylate in a maximum of 48% ee.4a Conjugate
addition of diethylzinc to cyclohexenone using 2 gave ethylcyclo-
hexanone in only 10% ee.4b Allylic alkylation of naphthyl substrates
been examined in this important transformation. Therefore, it
8
would also be very attractive to examine the use of this class of li-
gand in the asymmetric addition of Et
2
Zn to various aldehydes.
4
c
0
with EtMgBr using N-heterocyclic carbene 3 gave 35–73% ee.
Herein, we report on the design and synthesis of C
1
-1,1 -bisiso-
0
Allylation of benzaldehyde with allyl(trichloro)silane using N,N -
quinolines 5a–e (Fig. 2) and study the defining structural features
responsible for their efficiency as chiral inducers with the aim of
improving their performance and widening their scope in asym-
metric catalysis. We also rationalize the yields and enantioselectiv-
dioxide 4 gave 34–83% ee.4 A closer look at Figure 1 reveals that
d
ligands 2–4 are C
rings containing the chelating nitrogens are either fully saturated
1 and 2), partially saturated 3 or fully aromatic 4. Such geometri-
2
-symmetric structures and that the heterocyclic
(
2
ities of the products obtained from the additions of Et Zn to
cal differences at the stereogenic centres have great effect on the
enantioinduction.
benzaldehyde based on the ligand’s structural features deduced
from the NMR spectroscopy and X-ray crystallographic analysis.
Over the past few years, we have been interested in the chem-
0
5
istry of 1,1 -bisisoquinolines and, in particular, their application as
ligands for asymmetric catalysis. A careful study aimed at investi-
gating the structural features responsible for their efficiency as chi-
ral inducers is lacking. Therefore, we aimed to design and
2
. Results and discussion
Central to the present ligand’s design is the idea of having het-
erocyclic ring A fully aromatic while ring B is fully saturated, con-
sequently introducing C -symmetry to the framework. This design
1
is anticipated to present diverse structural constraints compared to
those observed in structures 1–4 (Fig. 1). The isoquinoline unit
*
Corresponding author. Fax: +65 67947553.
E-mail address: zaher@ntu.edu.sg (Z.M.A. Judeh).
0
957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.02.022

4
30
G. Qi, Z. M. A. Judeh / Tetrahedron: Asymmetry 21 (2010) 429–436
R
Ph
N
N
NH
NH
N
N
N
N
O
O
Cu
Cl
BF -
4
R
Ph
R = i-Bu, i-Pr, cy
1
2
3
4
0
Figure 1. Chiral 1,1 -bisisoquinolines.
greater rigidity afforded by (+)-5b–e would result in higher enanti-
oinduction. Therefore we prepared N-methyl (+)-5b, nitrophenol
(+)-5c, amide (+)-5d and sulfamide (+)-5e derivatives (Scheme 2)
from (+)-5a. Reaction between (+)-5a and methyl iodide in the
ring A
R
H
3
5
5
a
N
N
b
CH
3
1
1
'
5c CH2C6H4-1-OH-4-NO2
5d COCH3
presence of K
2 3 3
CO in CH CN gave (+)-5b as a light yellow foam in
R
7
6% yield. Similarly, the reaction between (+)-5a and 2-hydroxy-
H
5e SO2C6H4-p-CH3
3
'
4-nitro-benzyl bromide gave (+)-5c as an off-white foam in 91%
yield. Treatment of (+)-5a with acetyl chloride in the presence of
ring B
2 3
K CO in THF proceeded to give (+)-5d as a white foam in 89%
0
Figure 2. Chiral C
1
-symmetric 1,1 -bisisoquinoline ligands 5a–e.
yield. Likewise, the reaction of (+)-5a with p-toluenesulfonyl chlo-
ride gave (+)-5e as a white foam in 99% yield (Scheme 2).
Next, ligand (+)-5a was used in the enantioselective addition of
9
with heterocyclic ring A is flat due to its aromaticity while hetero-
cyclic ring B is expected to have a twist-boat conformation.
bite angle between the two chelating nitrogens of ligands 5a–e can
be controlled by metal ions and substituents at the nitrogen of ring
5
b,c
Et Zn to benzaldehyde 7a to optimize the reaction conditions. Ini-
The
2
tially, the effect of amount of Et
obtained in 72% yield and 63% ee when a combination of 10 mol %
of ligand (+)-5a and 2 mol equiv of Et Zn in dry THF/hexane (1/3, v/
v) was employed (Table 1, entry 1). An increase in the amount of
Et Zn from 2 (Table 1, entry 1) to 3 equiv (Table 1, entry 2) resulted
in an increase in both the yield (to 95%) and the ee (to 73%) of alco-
hol 8a. A further increase in the amount of Et Zn to 5 equiv re-
sulted in an increase in the yield of 8a to 97% and a decrease in
its ee to 64% (Table 1, entry 3). Thus, the optimum amount of Et Zn
2
Zn was examined. Alcohol 8a was
B. Compound rac-5a (Scheme 1) was synthesized under the double
2
Bischler–Napieralski conditions.10 Therefore, the treatment of bis-
oxamide 6 with polyphosphoric acid (PPA) at 190 °C furnished,
-symmetric compound rac-5a in 85% yield.
Resolution of rac-5a was achieved using (S)-(+)-
2
unexpectedly, the C
1
a-methyl benzyl
2
1
0
isocyanate (Scheme 1).
To introduce geometrical variations and examine the effects on
enantioinduction, we carefully prepared chiral ligands (+)-5b–e.
We rationalized that since there are no substituents at or next to
the chelating nitrogens of (+)-5a (i.e., at both nitrogens or at car-
bons 3 and 3 ), the active chiral space at the metal centre is rela-
tively ill-defined especially when considering the free rotation
around the C1–C1 bond. We envisioned that the introduction of
substituents of variable sizes at the nitrogen of ring B should lead
to more rigid and well-defined chiral motifs. We expected that the
2
is established to be 3 equiv. When THF was replaced by toluene or
diethyl ether (Table 1, entries 4 and 5, respectively), 8a was ob-
tained in a lower ee of 59% and 65%, respectively, but in near quan-
titative 99% yields. An increase in the temperature from rt to 50 °C
shortened the reaction time to just 3 h and gave 8a in 99% yield
and 62% ee (Table 1, entry 6). A decrease in the reaction tempera-
ture to 0 °C increased the ee to 80% and decreased the yield to 83%
0
0
(Table 1, entry 7). A further decrease in the temperature to ꢀ40 °C
N
*
NH
HN
HN
O
O
N
i
ii
(-)-5a
8
5%
iii
61%, >99% ee
NH
H
N
6
Rac-5a
*
NH
(
+)-5a
5
4%, >99% ee
Scheme 1. Synthesis and resolution of ligand rac-5a. Reagents and conditions: (i) PPA, 190 °C, 18 h; (ii) (S)-(+)-
BuOH, 110 °C, 3 h, recrystallization from EtOH.
2 2
a-methyl benzyl isocyanate, CH Cl , rt 30 min; (iii) NaOBu, n-

G. Qi, Z. M. A. Judeh / Tetrahedron: Asymmetry 21 (2010) 429–436
431
N
O
S
O
*
N
(
+)-5e
iv 99%
3
N
N
N
N
N
i
iii
O
7
6%
89%
*
*
* NH
3
'
(
+)-5d
(
+)-5a
(
+)-5b
ii 91%
N
OH
*
N
NO2
(
+)-5c
3 2 3 3 2 3
Scheme 2. Synthesis of ligands (+)-5b–e. Reagents and conditions: (i) 1.1 equiv CH I, K CO , CH CN, 50 °C, overnight; (ii) 1.1 equiv 2-hydro-5-nitro-benzylbromide, K CO ,
CH
3
CN, 50 °C, overnight; (iii) 1.1 equiv, CH
3
COCl, K
2
CO
3
, THF, 50 °C, overnight; (iv) 1.1 equiv TsCl, K
2
CO
3
, THF, 50 °C, overnight.
Table 1
2
Enantioselective addition of Et Zn to benzaldehyde 7a
O
OH
*
ligand
H
+
Et2Zn
7
a
8a
Entry
Ligand (mol %)
Et
2
Zn (equiv)
Solvent ratio (1:3; v/v)
Temp (°C)
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
(+)-5a (10)
(+)-5a (10)
(+)-5a (10)
(+)-5a (10)
(+)-5a (10)
(+)-5a (10)
(+)-5a (10)
(+)-5a (10)
(+)-5a (1)
(+)-5a (5)
(+)-5a (15)
(+)-5a (20)
(+)-5a (50)
(+)-5a (100)
(+)-5b (15)
(+)-5c (15)
(+)-5d (15)
(+)-5e (15)
—
2
3
5
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
THF/hexane
THF/hexane
THF/hexane
Toluene/hexane
rt
rt
rt
rt
rt
50
0
20
20
20
20
20
3
30
40
30
30
30
30
30
30
30
30
30
30
30
72
95
97
99
99
99
83
9
28
62
96
57
23
9
63
73
64
59
65
62
80
26
49
72
85
82
89
90
15 (S)
0
2
Et O/hexane
THF/hexane
THF/hexane
THF/hexane
THF/hexane
THF/hexane
THF/hexane
THF/hexane
THF/hexane
THF/hexane
THF/hexane
THF/hexane
THF/hexane
THF/hexane
THF/hexane
ꢀ40
0
1
1
1
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0
26
22
15
13
2
0
0
0
0
0
a
Determined by GC using HP-5 column.
b
11a
Determined by GC using Chiraldex G-TA column. The (R)-configuration was determined by comparing the sign of specific rotation value with the literature value.

4
32
G. Qi, Z. M. A. Judeh / Tetrahedron: Asymmetry 21 (2010) 429–436
led to a dramatic decrease in both the yield (9%) and the ee (26%) of
a (Table 1, entry 8) presumably due to precipitation of the (+)-5a/
Et Zn complex which can be clearly seen in the reaction tube. Fur-
ther reactions were conducted at 0 °C to examine the optimum li-
gand loading. As seen in Table 1, entries 9–14, a general trend of
increase in the ee (up to 90%) with increased loading of (+)-5a
can be observed. Unfortunately, the increase in the ee was accom-
panied by a sharp fall in the yield of 8a (Table 1, entries 11–14).
The best result was obtained when a loading of 15 mol % of (+)-
latter case, apparently, ligands (+)-5c–e were not involved in the cat-
alytic cycle. To examine this view, the reaction was repeated under
the same conditions but without ligands to examine the extent of
reactionconversion (Table1, entry19). Here, 8awas obtainedinonly
2% yield indicating the importance of the ligands in the catalytic cy-
8
2
cle. Further to this, the addition of a solution of Et
2
Zn to a sample of
(+)-5c in CDCl brought no significant chemical shift changes in the
3
1
H NMR spectrum in contrast to considerable shifts observed in the
case of (+)-5a. More evidence for the non-involvementof ligands (+)-
5c–e in the catalytic cycle was sought from the crystal structures of
the ligands. Therefore, we attempted the crystallization of ligands
5a–e to examine the structural arrangements and the extent of con-
strains in these ligands. All attempts to crystallize enantiopure com-
pounds (+)-5b–e from various solvents were unsuccessful.
Gratifyingly, crystallization of (ꢀ)-5a, rac-5d and rac-5e from etha-
5
a was used (Table 1, entry 11) whereby 8a was obtained in 96%
yield and 85% ee. Therefore, further reactions were conducted
using these conditions.
Next, ligands 5b–e were examined under the optimized condi-
tions as shown in Table 1, entry 11. While addition of Et
in the presence of (+)-5b gave 8a in both low yield (26%) and ee
15%) (Table 1, entry 15), surprisingly, the addition of Et Zn in the
2
Zn to 7a
1
2
(
2
nol gave single crystals suitable for X-ray anlysis. Crystallographic
presence of ligands (+)-5c, (+)-5d or (+)-5e gave 8a again in low
yields (22%, 15% and 13%, respectively) and startlingly in racemic
form with no induction whatsoever (Table 1, entries 16–18). In the
analysis of (ꢀ)-5a revealed the following main features: (i) the C1–
0
C1 bridging bond between rings A and B is seen to be in the equato-
rial orientation with respect to the two heterocyclic rings. (ii) The
Figure 3. ORTEP diagram showing the crystal structures of (ꢀ)-5a, rac-5d and rac-5e.

G. Qi, Z. M. A. Judeh / Tetrahedron: Asymmetry 21 (2010) 429–436
433
two isoquinoline ring systems of (ꢀ)-5a are oriented with a small
and (+)-5e which may explain the lack of enantioinduction ob-
served. Moreover, the crowding at the chelating nitrogens of (+)-
5b is expected to be less than that of (+)-5c, (+)-5d and (+)-5e since
a methyl substituent is less bulky than a hydroxy nitrobenzyl, an
acetyl or a tosyl group. This may explain the low enantioselectivity
observed for (+)-5b (Table 1, entry 15). While we cannot rule out
the contributions due to electronic effects on the enantioinduction,
we strongly believe that the fundamental issue here is the lack of
0
0
bias to the syn conformation with a C8a–C1–C1 –C8a dihedral angle
of 62°. (iii) Heterocyclic ring B adopted a twist-boat conformation.
(
iv) The fully aromatic isoquinoline moiety (top portion of the struc-
ture) is projecting towards the main plane of ring B. These arrange-
ments are in stark difference to the geometrical conformations
0
2
observed in the C -symmetric structure 2 (Fig. 1) where the C1–C1
bond is observed to be in the equatorial position and the two iso-
quinoline rings are in the anti orientation.4b This type of arrange-
chelation of Et
2
Zn to the nitrogens that mainly determines the
ment represents a fundamental geometrical preference observed
course of selectivity due to the preferred conformations.
0
in C
1
- and C
2
-1,1 -bisisoquinolines.
To study the scope and limitation of ligand (+)-5a, a number of
aromatic aldehydes having electron-donating (7b–h) and electron-
withdrawing (7i–p) substituents were examined along with 7q and
7r under the optimized conditions reported in Table 1, entry 11. In
general, very good yields and enantioselectivities of the secondary
alcohols 8a–r were obtained (Table 2). The following observations
can be made from Table 2: (i) electron-withdrawing substituents
(Table 2, entries 9–16) gave better yields and enantioselectivities
compared to poor (Table 2, entries 2–5) and strong (Table 2, entries
6–8) electron-donating substituents; (ii) generally, electron-donat-
ing substituents at the ortho-positions gave better enantioselectiv-
ities compared to the same substituents at the para and meta
positions, while substituents at the meta positions gave better re-
sults compared to those at the para positions (see e.g., Table 2, en-
tries 2–4 and entries 6–8); (iii) the substituent effect is more
pronounced at the ortho position due to the steric bulkiness that
these groups exert compared to the same meta or para substitu-
ents. In support of this fact, doubly substituted 2,6-dichlorobenzal-
dehyde gave the highest yield of 99% and highest ee of 87%; (iv) the
A closer look at the crystal structures of rac-5d and rac-5e
(
(
Fig. 3) reveals the following common features in both structures:
0
i) the C1–C1 bridging bond between rings A and B is seen to be in
the axial orientation with respect to the two heterocyclic rings; (ii)
the fully aromatic isoquinoline moiety is projecting with an almost
complete offset with respect to the main plane of the saturated
ring B (lower portion of the structure); (iii) heterocyclic ring B
adapted a twist-boat conformation. Comparing the crystal struc-
tures of (ꢀ)-5a, rac-5d and rac-5e, it can be seen that the two nitro-
gens in rac-5d and rac-5e are not sharing a common space and thus
metal chelation to both of them is less likely. Moreover, the prefer-
ential conformations of rac-5d and rac-5e resulted in severe
crowding at the chelating nitrogens and at the chiral core. Conse-
quently, 8a was formed in low yields and in racemic form. Such
conformations are in stark contrast to that of (ꢀ)-5a where easy
chelation is feasible. Although single X-ray quality crystals could
not be obtained for ligands (+)-5b and (+)-5c, the structural
arrangement of (+)-5c is expected to be similar to those of (+)-5d
Table 2
2
Enantioselective addition of Et Zn to aldehydes catalyzed by (+)-5a
O
H
OH
1
5 mol% (+)-5a
+
3 Et2Zn
X
X
º
THF:hexane (1:3), 0 C, 30 h
8
a-r
7
a-r
Entrya
Aldehyde
Product
Yieldb (%)
eec (%)
1
2
3
O
X = H 7a
X = o-CH
X = m-CH
X = p-CH
X = p-C
X = o-MeO 7f
X = m-MeO 7g
X = p-MeO 7h
X = o-I 7i
X = m-I 7j
X = p-I 7k
X = p-F 7l
X = p-Cl 7m
X = p-Br 7n
X = 2,6-di-Cl 7o
8a
8b
8c
8d
8e
8f
8j
8h
8i
8j
8k
8l
8m
8n
8o
8p
96
51
85
70
3
7b
7c
7d
69
17
38
83
82
51
95
89
59
33
90
52
99
88
65
40
71
74
73
52
73
80
66
61
72
71
87
72
H
3
4
5
6
7
8
9
0
1
2
3
4
5
6
X
3
2
5
H 7e
1
1
1
1
1
1
1
3
X = p-F C 7p
O
1
7
8
7q
8q
8r
73d
81e
O
1
7r
55
68
a
b
c
2
Reaction conditions: 15 mol % (+)-5a, 3.0 equiv Et Zn, THF/hexane (1:3, v/v), 30 h, 0 °C.
Determined by GC using Chiraldex G-TA column.
Determined by GC using Chiraldex G-TA column. The configuration was determined by comparing the sign of specific rotation values with literature values.
Isolated yields.
11
d
e
Determined by HPLC using a Chiral OD-H column.

4
34
G. Qi, Z. M. A. Judeh / Tetrahedron: Asymmetry 21 (2010) 429–436
ee increases with an increase in electronegativity of the para-halo-
gens (except for entry 12, Table 2). Alkylation of b-naphthaldehyde
J = 5.7 Hz, Ar-H), 7.76 (1H, d, J = 8.1 Hz, Ar-H), 8.42 (1H, d,
13
J = 8.7 Hz, Ar-H), 8.52 (1H, d, J = 5.7 Hz, Ar-H).
C
NMR
0
0
7
q and cyclohexanecarbaldehyde 7r gave 81% and 68% ee, respec-
(75.6 MHz, CDCl
3
) d: 29.8 (C4 ), 44.7 (NCH
3
), 53.5 (C3 ), 75.1
0
tively (Table 2, entries 17 and 18, respectively).
(C1 ), 121.0, 125.9, 126.2, 126.4, 126.5, 126.9, 127.0, 127.3, 128.6,
1
29.7, 133.5, 137.3, 137.6, 141.1, 162.1 (15 ꢁ Ar-C). Mass (ESI)
calcd for C19
H
18
N
2
: 274.15, found 275.13 (M+1).
3
. Conclusion
0
0
0
0
0
0
4.3. Preparation of (+)-N -(2-hydroxy-5-nitro-benzyl)-1 ,2 ,3 ,4 -
1
New highly constrained chiral C -1,1 -bisisoquinoline ligands
0
tetrahydro-1,1 -bisisoquinoline (+)-5c
havebeensynthesized. Theirgeometricalconformationswere found
to greatly affect the catalytic efficiency and extensively influence the
enantioinduction in the addition of Et Zn to benzaldehyde. X-ray
2
crystallographic analysis of (ꢀ)-5a, rac-5d and rac-5e revealed pecu-
liar structural features that were helpful in explaining the chelating
and catalytic efficiencies of these ligands. The equatorial arrange-
2
-Hydroxy-5-nitro-benzylbromide (58 mg, 0.28 mmol) was
added to a mixture of (+)-5a (65 mg, 0.25 mmol) and K CO
69 mg, 0.5 mmol) in CH CN (3 mL). The mixture was heated up
2
3
(
3
to 50 °C and stirred overnight. The reaction mixture was cooled
to room temperature, filtered and the solid was washed with
CH Cl (20 mL). The combined organic phases were evaporated un-
2 2
der vacuum to dryness. The off-white solid residue was purified by
0
ment of the C1–C1 bridging bond joining heterocyclic rings A and
0
B of the C
1
-1,1 -bisisoquinoline ligands seems to be essential for
the high catalytic efficiency. Ligand (+)-5a afforded the desired sec-
ondary alcohols in excellent yield and up to 87% ee. Further studies
using these ligands are currently under investigation in our
laboratory.
column chromatography (EtOAc) to give (+)-5c as an off-white
2
D
5
foam (93.5 mg, 91%). Mp 98–101 °C. ½
a
ꢂ
¼ þ62:5 (c 0.77, CH
2 2
Cl ).
FTIR (Nujol) max: 3058, 2832, 1588, 1491, 1337, 1288, 1091, 829,
m
H
ꢀ1
1
7
1
50 cm
.
NMR (300 MHz, CDCl
3
)
d: 2.73–2.82 (1H, m,
0
0
0
ꢁ H4 ), 2.92 (1H, d, J = Hz, 1 ꢁ H4 ), 3.32–3.43 (2H, m, H3 ), 3.52
4
4
. Experimental
(1H, d, J = 14.4 Hz, NCHH), 3.91 (1H, d, J = 14.1 Hz, NCHH), 5.60
0
(
1H, s, H1 ), 6.61 (1H, d, J = 7.8 Hz, Ar-H), 6.72 (1H, d, J = 9.0 Hz,
.1. General
Ar-H), 6.91 (1H, t, J = 7.5 Hz, Ar-H), 7.11 (1H, t, J = 7.4 Hz, Ar-H),
.19 (1H, d, J = 6.9 Hz, Ar-H), 7.56–7.69 (3H, m, 3 ꢁ Ar-H), 7.83–
7.86 (2H, m, 2 ꢁ Ar-H), 7.97 (1H, dd, J = 9.0 Hz, 2.7 Hz, Ar-H), 8.16
7
All commercial materials were used as received. Analytical thin
1
3
layer chromatography (TLC) was performed using Merck 60 F254
precoated silica gel plate (0.2 mm thickness). Column chromatog-
raphy was performed using Merck Silica Gel 60 (230–400 mesh).
THF, diethyl ether and toluene were obtained from PURE SOLV
PS-400-5-MD system. Melting points were determined on a Bam-
stead Electrothermal 9100 melting point tester. FTIR were recorded
(1H, d, J = 8.4 Hz, Ar-H), 8.54 (1H, d, J = 5.7 Hz, Ar-H). C NMR
0
0
(75.6 MHz, CDCl ) d: 29.0 (C4 ), 48.9 (C3 ), 58.0 (NCH Ph), 69.0
3
2
0
(C1 ), 116.5, 121.5, 122.1, 125.1, 125.2, 125.3, 126.5, 126.9, 127.2,
127.3, 127.91, 127.94, 129.0, 130.4, 133.5, 136.1, 137.3, 140.0,
142.0, 160.2, 163.7 (21 ꢁ Ar-C). Mass (ESI) calcd for C25H21N O :
3
3
411.16, found 412.07 (M+1).
1
on a Perkin–Elmer FTIR system Spectrum BX. H NMR spectra were
recorded at 300 MHz and 13C NMR spectra were recorded at
0
0
0
0
0
0
4.4. Preparation of (+)-N -ethanoyl-1 ,2 ,3 ,4 -tetrahydro-1,1 -
7
5.47 MHz on a Bruker Advanced DPX 300. Routine mass spectra
bisisoquinoline (+)-5d
were recorded on an ABI QSTAR Elite mass spectrometer. X-ray sin-
gle crystal diffraction data were obtained on a Bruker-AXS Smart
Apex CCD single-crystal diffractometer. HPLC was performed on
an Agilent 1100 using Diacel chiralcel OD-H chiral column. GC
was performed on an Agilent 6890 using Chiraldex G-TA,
Acetyl chloride (43.2 mg, 39.1
mixture of (+)-5a (130 mg, 0.5 mmol) and K CO (138 mg,
ll, 0.55 mmol) was added to a
2
3
1.0 mmol) in dry THF (5 mL) under a nitrogen atmosphere. The
reaction mixture was stirred at 50 °C overnight. The solvent was re-
moved under vacuum and the solid formed was re-dissolved in a
mixture of H O (10 mL) and CH Cl (15 mL). The aqueous layer
3
0 m ꢁ 0.25 mm ID chiral column. Optical rotations were mea-
sured using a JASCO P-1020 polarimeter.
2
2
2
was separated and extracted further with CH
combined organic extracts were washed with brine, dried over
2
Cl
2
(3 ꢁ 10 mL). The
0
0
0
0
0
0
4
.2. Preparation of (+)-N -methyl-1 ,2 ,3 ,4 -tetrahydro-1,1 -
bisisoquinoline (+)-5b
MgSO , filtered and evaporated till dryness under vacuum. The
4
white solid residue was purified by column chromatography
(EtOAc/hexane = 1/9) to give (+)-5d as a white foam (134.0 mg,
Iodomethane (78.1 mg, 0.55 mmol) was added to a mixture of
2
D
5
(
+)-5a (130 mg, 0.5 mmol) and K
CH CN (4 mL). The mixture was heated overnight at 50 °C. The sol-
vent was removed under vacuum and the solid formed was re-dis-
solved in a mixture of H O (10 mL) and CH Cl (15 mL). The
aqueous layer was separated and extracted further with CH Cl
2
CO
3
(138 mg, 1.0 mmol) in
89%). Mp 97–99 °C. ½
aꢂ
¼ þ399:4 (c 0.65, CH Cl ). FTIR (Nujol)
2
2
ꢀ1 1
3
m
max
: 3430, 1585, 1333, 1161, 1091, 971, 735, 667 cm
(300 MHz, CDCl ) d: 2.16 (3H, s, CH ), 3.07–3.11 (2H, m, H4 ), 3.81
(1H, m, J = 13.5 Hz, 3.9 Hz, 1 ꢁ H3 ), 4.15–4.25 (1H, m, 1 ꢁ H3 ),
6.88 (1H, d, J = 7.8 Hz, Ar-H), 7.07 (1H, m, J = 7.4 Hz, 1.5 Hz, Ar-H),
7.17 (1H, t, J = 7.2 Hz, Ar-H), 7.22 (1H, apparent d, J = 6.9 Hz, Ar-
.
H NMR
0
3
3
0
0
2
2
2
2
2
(
3 ꢁ 10 mL). The combined organic extracts were washed with
0
brine, dried over MgSO
4
, filtered and evaporated under vacuum till
H), 7.53 (1H, d, J = 5.4 Hz, Ar-H), 7.67 (1H, s, H1 ), 7.69–7.75 (2H,
dryness. The off-white solid was purified by column chromatogra-
m, 2 ꢁ Ar-H), 7.80–7.83 (1H, m, Ar-H), 8.37 (1H, d, J = 5.4 Hz, Ar-
1
3
phy (EtOAc) to give (+)-5b as light yellow foam (104.1 mg, 76%).
H), 8.96 (1H, apparent d, J = 9.3 Hz, Ar-H). C NMR (75.6 MHz,
2
D
5
0
0
0
Mp 89–93 °C. ½
a
ꢂ
¼ þ159:7 (c 1.13, CH
2
Cl
2
). FTIR (Nujol)
m
max
:
3 3
CDCl ) d: 21.8 (COCH ), 29.3 (C4 ), 41.3 (C3 ), 52.9 (C1 ), 120.4,
ꢀ1
1
2
(
3
(
786, 1717, 1621, 1344, 1140, 822, 754, 736 cm
.
H NMR
126.0, 126.2, 126.7, 127.1, 127.3, 127.9, 128.0, 129.0, 130.1, 134.2,
300 MHz, CDCl
3
) d: 2.19 (3H, s, NCH
3
), 2.74 (1H, m, J = 11.7 Hz,
136.1, 136.6, 141.7, 161.2 (15 ꢁ Ar-C), 169.2 (NCOCH ). Mass (ESI)
3
0
0
.6 Hz, 1 ꢁ H4 ), 2.93 (1H, apparent d, J = 16.5 Hz, 1 ꢁ H4 ), 3.25
20 18 2
calcd for C H N O: 302.14, found 303.73 (M+1).
0
1H, ddd, J = 11.3 Hz, 5.7 Hz, 1.8 Hz, 1 ꢁ H3 ), 3.50 (1H, ddd,
0
0
0
0
0
0
0
0
J = 16.2 Hz, 11.7 Hz, 5.7 Hz, 1 ꢁ H3 ), 4.98 (1H, s, H1 ), 6.53 (1H, d,
J = 7.8 Hz, Ar-H), 6.85 (1H, t, J = 7.5 Hz, Ar-H), 7.08 (1H, t,
J = 7.4 Hz, Ar-H), 7.19 (1H, d, J = 7.5 Hz, Ar-H), 7.33 (1H, t,
J = 7.2 Hz, Ar-H), 7.54 (1H, t, J = 7.5 Hz, Ar-H), 7.61 (1H, d,
4.5. (+)-N -Tosyl-1 ,2 ,3 ,4 -tetrahydro-1,1 -bisisoquinoline (+)-5e
p-Toluene sulfonyl chloride (95 mg, 0.55 mmol) was added to a
mixture of (+)-5a (130 mg, 0.5 mmol) and K2CO3 (138 mg,

G. Qi, Z. M. A. Judeh / Tetrahedron: Asymmetry 21 (2010) 429–436
435
1
.0 mmol) in dry THF (5 mL) under a nitrogen atmosphere. The
4.11. (+)-1-(4-Ethylphenyl)-1-propanol 8e (Table 2, entry 5)
reaction mixture was stirred at 50 °C overnight. The reaction mix-
ture was worked as described above to give white solid that was
purified by column chromatography (EtOAc/hexane = 1/9) to give
The ee of 71% was determined by GC. GC (Chiraldex G-TA col-
umn): helium flow rate = 3.0 mL/min, oven = 130 °C, t = 6.50 min
¼ þ21:3 (c 1.22, CHCl ).
1
2
D
5
(
+)-5e as white foam (204.5 mg, 99%). Mp 122–125 °C.
for (+) and t
2
= 6.57 min for (ꢀ). ½
aꢂ
3
25
½
a
1
ꢂ
¼ þ243:5 (c 1.0, CH
2 2
Cl ). FTIR (Nujol) mmax: 2912, 1643,
D
ꢀ1 1
430, 835, 769, 747, 635 cm
.
H NMR (300 MHz, CDCl
3
) d: 2.24
4.12. (1R)-1-(2-Methoxyphenyl)-1-propanol 8f (Table 2, entry 6)
0
(
3H, s, PhCH
3
), 2.89–3.02 (2H, m, H4 ), 3.91 (1H, m, J = 14.4 Hz,
0
0
4
.4 Hz, 1 ꢁ H3 ), 4.11–4.21 (1H, m, 1 ꢁ H3 ), 6.81 (1H, d,
The ee of 74% was determined by GC. GC (Chiraldex G-TA col-
J = 7.8 Hz, Ar-H), 6.88 (2H, apparent d, J = 7.8 Hz, 2 ꢁ Ar-H), 6.99
umn):
helium
flow
rate = 2.0 mL/min,
oven = 110 °C,
0
25
(
1H, m, J = 6.9 Hz, 2.4 Hz, Ar-H), 7.07 (1H, s, H1 ), 7.06–7.13 (2H,
t
1
= 31.22 min for (R) and t
2
= 33.57 min for (S). ½
a
ꢂ
¼ þ19:6 (c
D
1
1a
26
D
m, 2 ꢁ Ar-H), 7.28 (1H, apparent d, J = 8.1 Hz, 2Ar-H), 7.44 (1H, d,
0.85, CHCl
3
) {lit.
½
a
ꢂ
¼ þ23:7 (c 1.40, CHCl
3
) for 95% ee (R)}.
J = 5.4 Hz, Ar-H), 7.68–7.79 (3H, m, 3Ar-H), 8.21 (1H, d, J = 5.7 Hz,
13
Ar-H), 8.80 (1H, apparent d, J = 9.3 Hz, Ar-H). C NMR (75.6 MHz,
4.13. (1R)-1-(3-Methoxyphenyl)-1-propanol 8g (Table 2, entry 7)
0
0
0
3 3
CDCl ) d: 21.3 (PhCH ), 27.8 (C4 ), 40.5 (C3 ), 55.7 (C1 ), 120.3,
1
1
25.3, 126.1, 126.8, 126.9, 127.0, 127.17, 127.19, 128.0, 128.9,
29.2, 130.1, 133.8, 134.9, 136.6, 136.8, 141.8, 142.7, 160.1
The ee of 73% was determined by GC. GC (Chiraldex G-TA col-
umn):
helium
flow
rate = 2.0 mL/min,
= 45.08 min for (S). ½
oven = 110 °C,
25
(
21 ꢁ Ar-C). Mass (ESI) calcd for C25
H
22
N
2
O
2
S: 414.14, found
t
1
= 42.94 min for (R) and t
2
a
ꢂ
¼ þ22:8 (c
D
1
1a
26
D
4
15.20 (M+1).
0.43, CHCl
3
) {lit.
½
aꢂ
¼ þ40:3 (c 1.21, CHCl
3
) for 95% ee (R)}.
4
.6. General procedure for the asymmetric addition of
4.14. (1R)-1-(4-Methoxyphenyl)-1-propanol 8h (Table 2, entry 8)
diethylzinc to aldehydes using (+)-5a
The ee of 52% was determined by GC. GC (Chiraldex G-TA col-
Ligand (+)-5a (39 mg, 0.15 mmol) was dissolved in THF (1 mL)
and diethylzinc (3 mL, 1 M in hexane, 3 mmol) was added drop-
wise whereby an orange-red solution was obtained. The mixture
was cooled down to 0 °C, stirred for 10 min. The aldehyde (1 mmol)
was added via syringe and the reaction mixture was stirred at 0 °C
for a specific time (TLC). The reaction was then quenched with sat-
umn):
helium
flow
rate = 2.0 mL/min,
oven = 110 °C,
25
t
1
= 39.71 min for (R) and t
2
= 40.98 min for (S). ½
a
ꢂ
¼ þ20:3 (c
D
1
1a
26
D
0.76, CHCl
3
) {lit.
½
a
ꢂ
¼ þ38:9 (c 1.23, CHCl
3
) for 96% ee (R)}.
4.15. (+)-1-(2-Iodophenyl)-1-propanol 8i (Table 2, entry 9)
urated NH
4
Cl (5 mL), washed with 1 N HCl (3 ꢁ 5 mL), saturated
The ee of 73% was determined by GC. GC (Chiraldex G-TA col-
Na CO
2
3
(3 ꢁ 5 mL) and dried over MgSO
4
and filtered. The filtrate
umn):
= 21.10 min for (ꢀ) and t
1.71, CHCl ).
helium
flow
rate = 3.0 mL/min,
= 24.12 min for (+). ½
oven = 130 °C,
25
was subjected to GC directly or purified by column chromatogra-
phy and then subjected to HPLC. The ee values were determined
by GC using Chiraldex G-TA column or HPLC using Chiralcel OD-
H column. The absolute configuration of the major enantiomer
was assigned by making a comparison of the specific rotation value
with literature values.
t
1
2
aꢂ
¼ þ17:8 (c
D
3
4.16. (+)-1-(3-Iodophenyl)-1-propanol 8j (Table 2, entry 10)
The ee of 80% was determined by GC. GC (Chiraldex G-TA col-
umn):
= 27.27 min for (+) and t
.70, CHCl ).
helium
flow
rate = 3.0 mL/min,
= 29.26 min for (ꢀ). ½
oven = 130 °C,
25
4
.7. (1R)-1-Phenyl-1-propanol 8a (Table 2, entry 1)
t
1
1
2
aꢂ
¼ þ15:3 (c
D
3
The ee of 85% was determined by GC. GC (Chiraldex G-TA col-
umn) helium flow rate = 2.0 mL/min, oven = 110 °C, t
1
= 8.98 min
3
) {lit.
4.17. (+)-1-(4-Iodophenyl)-1-propanol 8k (Table 2, entry 11)
25
11a
for (R) and t
2
= 9.23 min for (S). ½
a
ꢂ
¼ þ43:8 (c 1.30, CHCl
D
26
½
aꢂ
¼ þ40:3 (c 1.21, CHCl ) for 96% ee (R)}.
3
The ee of 66% was determined by GC. GC (Chiraldex G-TA col-
D
umn):
= 28.16 min for (+) and t
.85, CHCl ).
helium
flow
rate = 3.0 mL/min,
= 29.45 min for (ꢀ). ½
oven = 130 °C,
25
4
.8. (1R)-1-(2-Methylphenyl)-1-propanol 8b (Table 2, entry 2)
t
0
1
2
aꢂ
¼ þ16:8 (c
D
3
The ee of 70% was determined by GC. GC (Chiraldex G-TA col-
umn):
helium
flow
rate = 2.0 mL/min,
oven = 110 °C,
4.18. (1R)-1-(4-Fluorophenyl)-1-propanol 8l (Table 2, entry 12)
25
t
1
= 16.44 min for (R) and t
2
= 18.82 min for (S). ½
a
ꢂ
¼ þ40:5 (c
D
1
1d
18
D
0
.45, CHCl
3
) {lit.
½
aꢂ
¼ ꢀ43:0 (c 0.97, CH
2
Cl
2
) for 78% ee (S)}.
The ee of 61% was determined by GC. GC (Chiraldex G-TA col-
1
umn): helium flow rate = 3.0 mL/min, oven = 130 °C, t = 3.50 min
2
D
5
11e
4
.9. (1R)-1-(3-Methylphenyl)-1-propanol 8c (Table 2, entry 3)
for (R) and t
2
= 3.64 min for (S). ½
a
ꢂ
¼ þ23:5 (c 0.30, CHCl
3
) {lit.
½
a
ꢂ ¼ þ29:7 (c 3.0, CHCl
3
) for 79% ee (R)}.
D
The ee of 65% was determined by GC. GC (Chiraldex G-TA col-
umn):
helium
flow
rate = 2.0 mL/min,
= 14.56 min for (S). ½
¼ þ37:9 (c 1.76, CHCl ) for 95% ee (R)}.
oven = 110 °C,
4.19. (1R)-1-(4-Chlorophenyl)-1-propanol 8m (Table 2, entry 13)
2
5
t
1
= 14.18 min for (R) and t
2
a
ꢂ
¼ þ38:7
D
1
1b
25
D
(
c = 0.68, CHCl
3
) {lit.
½
aꢂ
3
The ee of 72% was determined by GC. GC (Chiraldex G-TA col-
1
umn): helium flow rate = 3.0 mL/min, oven = 130 °C, t = 9.19 min
2
D
5
11a
4
.10. (1R)-1-(4-Methylphenyl)-1-propanol 8d (Table 2, entry 4)
for (R) and t
2
= 9.58 min for (S). ½
aꢂ
¼ þ21:7 (c 2.31, CHCl
3
) {lit.
2
6
½
aꢂ
¼ þ30:6 (c 2.08, CHCl ) for 96% ee (R)}.
3
D
The ee of 40% was determined by GC. GC (Chiraldex G-TA col-
umn):
helium
flow
rate = 2.0 mL/min,
= 13.63 min for (S). ½
¼ ꢀ27:7 (c 1.24, CH Cl ) for 65% ee
oven = 110 °C,
4.20. (1R)-1-(4-Bromophenyl)-1-propanol 8n (Table 2, entry 14)
2
5
t
1
= 13.37 min for (R) and t
2
a
ꢂ
¼ þ18:3
D
1
1d
18
D
(
(
c = 0.21, CHCl
S)}.
3
) {lit.
½
a
ꢂ
2
2
The ee of 71% was determined by GC. GC (Chiraldex G-TA col-
umn):
helium
flow
rate = 3.0 mL/min,
oven = 130 °C,

4
36
G. Qi, Z. M. A. Judeh / Tetrahedron: Asymmetry 21 (2010) 429–436
2
D
5
t
0
1
= 15.14 min for (R) and t
2
= 15.88 min for (S). ½
aꢂ
¼ þ23:4 (c
4. (a) Arai, S.; Takita, S.; Nishida, A. Eur. J. Org. Chem. 2005, 5262–5267; (b) Cavell,
K. J.; Elliott, M. C.; Nielsen, D. J.; Paine, J. S. Dalton Trans. 2006, 4922–4925; (c)
Seo, H.; Hirsch-Weil, D.; Abboud, K. A.; Hong, S. J. Org. Chem. 2008, 73, 1983–
1
1c
20
D
3
.61, CHCl ) {lit.
½
aꢂ
¼ þ26:7 (c 1.50, CHCl ) for 98% ee (R)}.
3
1
986; (d) Hrdina, R.; Dra cˇ ínsk yˆ , M.; Valterová, I.; Hoda cˇ ová, J.; Císaová, I.;
4
1
.21. (ꢀ)-1-(2,6-Dichlorophenyl)-1-propanol 8o (Table 2, entry
Kotora, M. Adv. Synth. Catal. 2008, 350, 1449–1456.
(a) Shen, H. Y.; Ying, L. Y.; Jiang, H. L.; Judeh, Z. M. A. Int. J. Mol. Sci. 2007, 8, 505–
5.
5)
512; (b) Craig, D. C.; Judeh, Z. M. A.; Read, R. Tetrahedron 2003, 59, 461–472; (c)
Busato, S.; Craig, D. C.; Judeh, Z. M. A.; Read, R. Aust. J. Chem. 2002, 55, 733–736;
(d) Judeh, Z. M. A.; Ching, C. B.; Bu, J.; McCluskey, A. Tetrahedron Lett. 2002, 43,
The ee of 87% was determined by GC. GC (Chiraldex G-TA col-
5089–5091.
umn):
= 13.29 min for (+) and t
.82, CHCl ).
helium
flow
rate = 3.0 mL/min,
= 13.74 min for (ꢀ). ½
oven = 130 °C,
25
6. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994;
(b) Soai, K.; Shibata, T.. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999; Vol. 2, pp 911–
t
1
1
2
aꢂ
¼ ꢀ16:4 (c
D
3
9
22.
For comprehensive reviews, see: (a) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–
24; (b) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833–856; (c) Noyori, R.;
7
.
4
.22. (1R)-1-(4-Trifluoromethylphenyl)-1-propanol 8p(Table 2,
entry 16)
8
Kitamura, M. Angew. Chem., Int. Ed. 1991, 30, 49–69; Other literature see: (d)
Mori, M.; Nakai, T. Tetrahedron Lett. 1997, 38, 6233–6236; (e) Zhang, F. Y.; Yip,
C. W.; Cao, R.; Chan, A. S. C. Tetrahedron: Asymmetry 1997, 8, 585–589; (f) Shen,
X.; Guo, H.; Ding, K. L. Tetrahedron: Asymmetry 2000, 11, 4321–4327; (g) Zhang,
F. Y.; Chan, A. S. C. Tetrahedron: Asymmetry 1997, 8, 3651–3655; (h) Huang, Z.;
Lai, H.; Qin, Y. J. Org. Chem. 2007, 72, 1373–1378; (i) Xiao, F. Y.; Takuji, H.;
Guang, Y. Z. Tetrahedron: Asymmetry 2008, 19, 1670–1675; (j) José, E. D.;
Martins, M. W. Tetrahedron: Asymmetry 2008, 19, 1250–1255; (k) Jiang, F. Y.;
Liu, B.; Dong, Z. B.; Li, J. S. J. Organomet. Chem. 2007, 692, 4377–4380; (l)
Manabu, H.; Takashi, M.; Kazuaki, I. J. Org. Chem. 2006, 71, 6474–6484; (m)
Tanaka, T.; Yasuda, Y.; Hayashi, M. J. Org. Chem. 2006, 71, 7091–7093; (n) Liu,
S.; Wolf, C. Org. Lett. 2007, 9, 2965–2968; (o) Blay, G.; Fernández, I.; Olmos, V.
H.; Marco-Aleixandre, A. G.; Pedro, J. R. J. Mol. Catal. A: Chem. 2007, 276, 235–
243; (p) Shi, M.; Sui, W. S. Tetrahedron: Asymmetry 1999, 10, 3319–3325; (q)
Burguete, M. I.; Collado, M.; Escorihuela, J.; Luis, S. V. Angew. Chem., Int. Ed.
The ee of 72% was determined by GC. GC (Chiraldex G-TA col-
umn):
helium
flow
rate = 2.0 mL/min,
oven = 110 °C,
25
D
t
1
= 12.34 min for (R) and t
.30, CHCl
2
= 13.18 min for (S). ½
aꢂ
¼ þ15:8 (c
1
1c
20
D
1
3
) {lit.
½
a
ꢂ
¼ þ18:6 (c 3.40, CHCl
3
) for 98% ee (R)}.
4
.23. (1R)-1-(2-Naphthyl)-1-propanol 8q (Table 2, entry 17)
The ee of 81% was determined by HPLC. HPLC (Chiralcel OD-H
column):
= 14.93 min for (S) and t
.77, CHCl
hexane/IPA = 95/5,
1.0 mL/min,
25 °C,
254 nm,
¼ þ28:6 (c
25
t
1
2
= 17.09 min for (R). ½
aꢂ
D
1
1c
20
D
2
007, 46, 9002–9005; (r) Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. 1991,
30, 1321–1323; (s) Shaohua, G.; Judeh, Z. M. A. Tetrahedron Lett. 2009, 50, 281–
83; (t) Tanaka, T.; Sano, Y.; Hayashi, M. Chem. Asian J. 2008, 3, 1465–1471.
Cheng, Y. Q.; Bian, Z.; Kang, C. Q.; Guo, H. Q.; Gao, L. X. Tetrahedron: Asymmetry
008, 19, 1572–1575.
Xi, H. W.; Judeh, Z. M. A.; Lim, K. H. J. Mol. Struct.: Theochem. 2009, 897, 22–32.
0
3
) {lit.
½
aꢂ
¼ þ35:1 (c 2.40, CHCl
3
) for 92% ee (R)}.
2
8
.
.
4
.24. (1R)-1-Cyclohexylpropanol 8r (Table 2, entry 18)
2
9
The ee of 68% was determined by GC. GC (Chiraldex G-TA col-
10. Gao, Q.; Judeh, Z. M. A. Tetrahedron, in press.
1. (a) Zhang, J. C.; Guo, H. C.; Wang, M. G.; Yin, M. M.; Wang, M. Tetrahedron:
Asymmetry 2007, 18, 734–741; (b) Bisai, A.; Singh, P. K.; Singh, V. K. Tetrahedron.
1
umn): helium flow rate = 1.0 mL/min, oven = Gradient 65–95 °C,
2
D
5
t
1
= 52.50 min for (R) and t
2
= 53.33 min for (S). ½
aꢂ
¼ þ6:6 (c
2007, 63, 598–601; (c) Bulut, A.; Aslan, A.; Izgü, E. C.; Dogan, O. Tetrahedron:
1
1a
26
D
0
3
.65, CHCl ) {lit.
½
aꢂ
¼ þ5:4 (c 0.61, CHCl ) for 93% ee (R)}.
3
Asymmetry 2007, 18, 1013–1016; (d) Lin, R. X.; Chen, C. P. J. Mol. Catal. A: Chem.
2
1
006, 89–98; (e) Vysko cˇ il, Š.; Jaracz, S.; Smr cˇ ina, M.; Ko cˇ ovsky, P. J. Org. Chem.
998, 63, 7727–7737.
Acknowledgement
1
2. X-ray crystallographic data for (ꢀ)-5a: Formula
C
18
H
16
N
2
,
M = 260,
orthorhombic, space group P2(1)2(1)2(1), a = 6.9631(3) Å, b = 8.6098(4) Å,
3
3
We gratefully acknowledge the Nanyang Technological Univer-
sity for financial support (Grant No. RG27/07).
c = 22.6379(10) Å, b = 90°, V = 1357.16(10) Å ,
D
calcd = 1.274 Mg/m , Z = 4.
1.80° < h < 26.45°. The number of reflections was 1630 considered to be
observed of 9107 unique data. Final
R
indices (I > 2
O, M = 302, triclinic, space
group P1, a = 7.4307(4) Å, b = 10.0093(4) Å, c = 11.5391(6) Å, b = 89.319(3)°,
1
r(I)) R = 0.0303,
2 18 2
wR = 0.0943. Compound rac-5d: Formula C20H N
ꢀ
References
3
3
V = 771.31(7) Å , Z = 2, Dcalcd = 1.302 Mg/m , 1.92° < h < 30.00°. The number of
reflections was 4487 considered to be observed of 20076 unique data. Final R
1
2
.
.
Jean-Claude, K. Chem. Rev. 2008, 108, 140–205.
(a) Martins, J. E. D.; Morris, D. J.; Wills, M. Tetrahedron Lett. 2009, 50, 688–692;
indices (I > 2
1 2
r(I)) R = 0.1096, wR = 0.2686. Compound rac-5e: Formula
ꢀ
25 22 2 2
C H N O
S, M = 414, triclinic, space group P1, a = 8.1599(3) Å,
(
b) Bandini, M.; Melucci, M.; Piccinelli, F.; Sinisi, R.; Tommasi, S.; Umani-
3
b = 9.1169(3) Å, c = 14.7016(4) Å, b = 83.359(2)°. V = 1000.55(6) Å , Z = 2,
Ronchi, A. Chem. Commun. 2007, 43, 4519–4521; (c) Wang, S.; Seto, C. T. Org.
Lett. 2006, 8, 3979–3982; (d) Kina, A.; Ueyama, K.; Hayashi, T. Org. Lett. 2005, 7,
3
D
calcd = 1.376 Mg/m , 1.40° < h < 32.88°. The number of reflections was 7416
considered to be observed of 28209 unique data. Final R indices (I > 2 (I))
= 0.0537, wR = 0.1615. CCDC 746424, 746425 and 746426 contain the
r
5
889–5892; (e) Alexakis, A.; Tomassini, A.; Andrey, O.; Bernardinelli, G. Eur. J.
R
1
2
Org. Chem. 2005, 7, 1332–1339.
supplementary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via http://
www.ccdc.cam.ac.uk/data_request/cif.
3
.
(a) Bennani, Y. L.; Hanessian, S. Chem. Rev. 1997, 97, 3161–3195; (b) Anaya de
Parrodi, C.; Juaristi, E. Synlett 2006, 2699–2715; (c) Achard, T. R. J.; Clutterbuck,
L. A.; North, M. Synlett 2005, 1828–1847; (d) Ooi, T.; Ohmatsu, K.; Uraguchi, D.;
Maruoka, K. Tetrahedron Lett. 2004, 45, 4481–4484; (e) Bayardon, J.; Sinou, D.
Synthesis 2005, 3, 425–428.