Catalytic asymmetric dialkynylation reaction of α-dinitrone by utilizing tartaric acid ester as a chiral auxiliary

Article abstract of DOI:10.1016/j.tetasy.2008.03.033

The asymmetric addition of alkynylzinc reagents, prepared in situ from dimethylzinc and 1-alkynes, to α-dinitrones derived from glyoxal and N-(4-isopropylbenzyl)hydroxylamine was investigated by utilizing dicyclohexyl (R,R)-tartrate as a chiral auxiliary. The addition reaction of methyl(2-phenylethynyl)zinc afforded the corresponding optically active C₂-symmetric (R,R)-bis(hydroxylamine) derivative with enantioselectivities of 90% and 81% ee by utilizing a stoichiometric and catalytic amount of the tartrate, respectively. Furthermore, the catalytic addition reaction of several alkynylzinc reagents also furnished the corresponding bis(hydroxylamine) with moderate to good enantioselectivities.

Full text of DOI:10.1016/j.tetasy.2008.03.033

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 921–931
Catalytic asymmetric dialkynylation reaction of a-dinitrone
by utilizing tartaric acid ester as a chiral auxiliary
Masakazu Serizawa, Shuhei Fujinami, Yutaka Ukaji* and Katsuhiko Inomata*
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma,
Kanazawa, Ishikawa 920-1192, Japan
Received 8 February 2008; accepted 18 March 2008
Abstract—The asymmetric addition of alkynylzinc reagents, prepared in situ from dimethylzinc and 1-alkynes, to a-dinitrones derived
from glyoxal and N-(4-isopropylbenzyl)hydroxylamine was investigated by utilizing dicyclohexyl (R,R)-tartrate as a chiral auxiliary. The
addition reaction of methyl(2-phenylethynyl)zinc afforded the corresponding optically active C2-symmetric (R,R)-bis(hydroxylamine)
derivative with enantioselectivities of 90% and 81% ee by utilizing a stoichiometric and catalytic amount of the tartrate, respectively.
Furthermore, the catalytic addition reaction of several alkynylzinc reagents also furnished the corresponding bis(hydroxylamine) with
moderate to good enantioselectivities.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
benzyl)hydroxylamine, was examined in toluene at 0 °C,
as shown in Eq. 1, Table 1. In the presence of 0.2 molar
of bis(methylzinc) salt of diisopropyl (R,R)-tartrate 1a,
prepared in situ from 0.2 molar amount of diisopropyl
(R,R)-tartrate and 0.4 molar amount of dimethylzinc, the
a-dinitrone 2a was treated with dimethylzinc, followed by
the addition of phenylacetylene 3A. The corresponding
(S,S)-bis(hydroxylamine) 4Aa was obtained with a low
enantioselectivity of 21% ee as well as a small amount of
meso-isomer 5Aa (entry 1). Conversely, the bis(bromomag-
nesium) salt 1b afforded the opposite (R,R)-enantiomer
with a slightly enhanced enantiomeric excess (entry 2). 2-
Bromomagnesium 3-methylzinc salt 1c realized a higher
enantioselection for (R,R)-4Aa (entry 3). In these reactions,
a-dinitrone 2a was scarcely soluble in toluene, meaning
that the reaction mixture was heterogeneous and 2a was
supplied gradually into the reaction with the progress of
the dialkynylation reaction. Next, the influence of the ester
groups in 2-bromomagnesium 3-methylzinc salt 1 was
investigated (entries 4–9). The use of the esters derived
from primary alcohols afforded product 4Aa with a lower
selectivity (entries 4 and 5). In the case of the t-butyl ester,
the enantioselectivity was also poor (entry 9). The esters de-
rived from secondary alcohols were more effective and the
cyclohexyl ester was the ester of choice to give the highest
selectivity of 70% ee (entry 8).
Optically active 1,2-diamine frameworks, which are con-
tained in the numerous biologically active compounds
and used as chiral auxiliaries, have attracted a great deal
of attention in organic synthesis.1,2 Catalytic asymmetric
C–C bond formation via the nucleophilic addition of a
C-nucleophile to imine functions provides one of the most
important methods for synthesizing optically active
amines.3 The addition of an alkynyl nucleophile has a stra-
tegic advantage to produce more functionalized nitrogen-
containing substances.4 Recently, we have reported on
the enantioselective nucleophilic addition of alkynylzinc re-
agents to acyclic nitrones by utilizing tartaric acid ester as a
chiral auxiliary.5 Herein, we report a catalytic asymmetric
dialkynylation of a-dinitrone, derived from glyoxal, by uti-
lizing tartaric acid ester as a chiral auxiliary to afford the
corresponding optically active C2-symmetric (R,R)-
bis(hydroxylamine) derivatives, which are versatile build-
ing blocks for chiral 1,2-diamino compounds.
2. Results and discussion
First, the addition reaction of an alkynylzinc reagent to an
a-dinitrone 2a, derived from glyoxal and N-(4-isopropyl-
Furthermore, the enantioselectivity was found to be influ-
enced by the substituents on nitrogen of the a-dinitrones
*
Corresponding authors. Tel.: +81 76 264 5700; fax: +81 76 264 5742
(K.I.); e-mail: inomata@cacheibm.s.kanazawa-u.ac.jp
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.033

922
M. Serizawa et al. / Tetrahedron: Asymmetry 19 (2008) 921–931
1) Me2Zn (3.0 eq.)
O
N
Ph
2)
(1.0 eq.)
Ar
2a
Ar
OH
N
M
M
1O
2O
CO2R
CO2R
N
ð1Þ
O
+
Ar
meso-isomer
Ar
3) Ph
H
3A (3.0 eq.)
N
5Aa
Toluene, 0 oC, Time
HO
1a-i (0.2 eq.)
Ph
(Ar = 4-iPrC6H4)
4Aa
Table 1. The effect of metals (M1, M2) and ester groups (R) in catalysts 1
Entry
M1
M2
R
1
Time (h)
Yield of 4Aa (%)
ee of 4Aa (%)
Yield of 5Aa (%)
1
2
3
4
5
MeZn
BrMg
BrMg
BrMg
BrMg
MeZn
BrMg
MeZn
MeZn
MeZn
iPr
iPr
iPr
Et
a
b
c
d
e
18
5
5
5
5
56
70
81
75
67
21a
47
59
12
7
>5
>3
>3
>3
>6
Bn
6
7
BrMg
BrMg
MeZn
MeZn
f
5
5
72
74
30
51
>6
>3
g
8
9
BrMg
BrMg
MeZn
MeZn
h
i
4
5
73
69
70
9
12
tBu
>4
a A major product was the opposite (S,S)-enantiomer.
1) Me2Zn (3.0 eq.)
O
N
Ph
Ar
2)
(1.0 eq.)
Ar
Ar
OH
N
N
O
2a-e
Ph
6b (Ar = Ph)
BrMgO
MeZnO
CO2
CO2
ð2Þ
N
O
+
Ar
meso-isomer +
5Aa-Ae
Ar
3) Ph
H
3A (3.0 eq.)
O
N
N
6c (Ar = 4-ClC6H4)
Ph
Toluene, 0 oC, Time
HO
1h (0.2 eq.)
Ar
Ph
4Aa-Ae
Table 2. The effect of substituents on nitrogens in a-dinitrones 2
Entry
ArCH2
2
Time (h)
4 or 5
Yield of 4 (%)
ee of 4 (%)
Yield of 5 (%)
Yield of 6 (%)
iPr
CH2
CH2
1
a
4
Aa
73
70
12
—
15
2
3
b
c
40
41
Ab
Ac
30
44
24
11
3
CH2
10
<10
Cl
Me
4
5
d
e
18
3
Ad
Ae
54
74
47
37
14
6
—
—
CH2
Me
tBu
CH2

M. Serizawa et al. / Tetrahedron: Asymmetry 19 (2008) 921–931
923
1) Me2Zn (3.0 eq.)
O
N
Ph
Ar
2)
(1.0 eq.)
Ar
Ar
OH
N
N
O
2a
BrMgO
MeZnO
CO2
CO2
Ph
ð3Þ
N
O
+ meso-isomer +
Ar
Ar
3) Ph
H
3A (3.0 eq.)
O
N
N
5Aa
Ph
Solvent, 0 oC, Time
6a (Ar = 4-iPrC6H4)
HO
1h (0.2 eq.)
(Ar = 4-iPrC6H4)
Ph
Ar
4Aa
Table 3. The effect of solvent
Entry
Solvent
Time (h)
Yield of 4Aa (%)
ee of 4Aa (%)
Yield of 5Aa (%)
Yield of 6a (%)
1
2
3
4
5
6
7a
Toluene
CH2Cl2
MeCN
THF
4
1
19
20
3
73
67
18
31
73
75
73
70
57
6
46
83
84
81
12
15
11
3
11
13
12
—
—
<17
31
—
—
—
Et2O
tBuOMe
tBuOMe
3
3
8
3
74
79
14
—
OMe
DME
9
19
58
67
9
13
a 0.20 molar amount of dicyclohexyl (R,R)-tartrate was successively treated with 0.26 molar amount of nBuMgBr and 0.20 molar amount of Me2Zn for the
preparation of 1h instead of using 0.20 molar amount of nBuMgBr.
as shown in Eq. 2, Table 2. When a-dinitrones 2b–d were
used, the alkynylation reactions proceeded slowly to afford
the corresponding bis(hydroxylamine)s 4Ab–Ad in low
chemical yields and with poor enantioselectivities (entries
2–4). On the other hand, the reaction of the 4-t-butylbenzyl
substituted a-dinitrone 2e proceeded smoothly to give a
satisfactory amount of the product 4Ae, however, the
enantioselectivity decreased (entry 5). These results might
be due to the solubility of the a-dinitrones. In the catalytic
asymmetric alkynylation reaction of an alkynylzinc re-
agent, the solubility of a-dinitrones 2 could control the rate
of supplying a-dinitrones into the reaction and the balance
between the reaction rate and the supply rate of a-dinitrone
might be crucial. The nitrones 2b–d are less soluble in tol-
uene and t-butylbenzyl substituted nitrone 2e is rather sol-
uble, so that the amounts of the catalyst 1h and a-
dinitrones in the solution were not balanced in these cases
to realize high enantioselectivity. In the case of less soluble
a-dinitrones 2b and 2c, the alkynylation reaction required a
longer time to consume the a-dinitrone and a part of the
addition product cyclized further to give the corresponding
biisoxazolines 6b and 6c (entries 2 and 3).
vents, a part of the addition product cyclized to give the
corresponding biisoxazoline 6a (entries 3, 4, and 9).
Unfortunately, the enantioselectivities varied depending on
the Grignard reagent used for the preparation of 1h. It was
found that a slight excess amount of nBuMgBr was effective
to realize reproducible high enantioselectivity (entry 7),
probably because a part of bromomagnesium salt in 1h
might be exchanged to the corresponding methylzinc salt
in the presence of an excess amount of methylzinc species
to generate bis(methylzinc) salt 1j (Eq. 4). As mentioned
above, the addition reaction catalyzed by 1j gave (S,S)-
4Aa, which might decrease the enantioselectivity. When a
n
slight excess amount of BuMgBr was used, partially pro-
duced bis(bromomagnesium) salt 1k could react with 1j
to regenerate 1h (Eqs. 5 and 6).
Furthermore, when the asymmetric dialkynylation reaction
was carried out using
a stoichiometric amount of
1h, bis(hydroxylamine) 4Aa was obtained with a higher
enantioselectivity of 90% ee (Eq. 7), which indicated the
formation of an efficient chiral environment from dicyclo-
hexyl tartrate.
The effect of the solvent was also examined and the results
are listed in Eq. 3, Table 3. Dichloromethane afforded the
bis(hydroxylamine) 4Aa with a slightly low enantioselectiv-
ity (entry 2). The strongly coordinative solvents, such as
MeCN or THF, decreased the enantioselectivity (entries 3
and 4). On the other hand, when acyclic ethers were used,
the enantiomeric excesses were further improved (entries 5–
The catalytic asymmetric addition of various alkynes 3B–G
were carried out under the optimized conditions to afford
the corresponding bis(hydroxylamine)s 4Ba–Ga with mod-
erate to good enantioselectivities (Eq. 8, Table 4). In the
cases of 1-hexyne 3F and (trimethylsilyl)acetylene 3G, the
alkynylation reactions proceeded slowly to afford the prod-
ucts 4Fa,Ga in slightly lower chemical yields (entries 6 and
7).
t
8). Especially, BuOMe realized an enhanced enantioselec-
tivity of 84% ee (entry 6). In the case of the high-polar sol-

924
M. Serizawa et al. / Tetrahedron: Asymmetry 19 (2008) 921–931
BrMgO
MeZnO
CO2R
CO2R
MeZnO
MeZnO
CO2R
CO2R
+
MeZnX
+
MgBrX
ð4Þ
1h
1j
HO
HO
CO2R
CO2R
BrMgO
HO
CO2R
CO2R
BrMgO
BrMgO
CO2R
CO2R
+
nBuMgBr
0.26
+
0.20
0.14
0.06 1k
ð5Þ
BrMgO
MeZnO
CO2R
CO2R
BrMgO
BrMgO
CO2R
CO2R
excess Me2Zn
+
0.14 1h
0.06 1k
3. Conclusion
X = Me, C
C Ph or OR
ð6Þ
2 1h
1j + 1k
R = Cyclohexyl
In conclusion, we have developed an enantio- and dia-
stereoselective dialkynylation reaction of an a-dinitrone
by utilizing tartaric acid ester as a chiral auxiliary.
This reaction provides a simple and attractive approach
to optically active C2-symmetric bis(hydroxylamine)
derivatives.
The absolute configuration of the dialkynylation product
4Aa was determined to be (R,R) as follows: The enantiome-
rically enriched 4Aa (60% ee) was treated with (1S,4R)-
camphanic chloride 7 and Et3N to give the corresponding
diastereomeric mixture of esters, 8 and 9, in 60% yield
(Eq. 9). Purification by recrystallization gave diastereomer-
ically pure 8, whose absolute configuration was determined
to be R,R by X-ray crystallographic analysis (Fig. 1).6 The
absolute stereochemistries of the other products were ten-
tatively assigned to be (R,R).
4. Experimental
4.1. General
All the melting points were determined by a micro melting
apparatus (Yanagimoto-Seisakusho) and are uncorrected.
The H NMR spectra were recorded on JEOL Lambda
Although the precise reaction mechanism is still unclear, a
plausible catalytic cycle is shown in Scheme 1. The first
enantioselective alkynylation proceeds via the transition
state A to afford the (R)-configuration as confirmed above.
The remaining nitrone moiety in the mono-adduct subse-
quently coordinates to Lewis acidic magnesium of the cata-
lyst, followed by the transmetallation as depicted in B. The
second enantioselective alkynylation may proceed via the
transition state C, which is similar to the transition state
A of the first alkynylation, to afford the (R,R)-product 10.
1
400 spectrometers. The chemical shifts were determined
in the d-scale relative to tetramethylsilane (d 0) as an inter-
nal standard. The IR spectra were measured by JASCO
FT/IR-230 spectrometer. The MS spectra were recorded
with a JEOL SX-102A mass spectrometer. Optical rota-
tions were recorded on a JASCO DIP-370 spectrometer.
THF and Et2O were freshly distilled from sodium diph-
enylketyl. All other solvents were distilled according to
1) Me2Zn (3.0 eq.)
O
N
Ph
2)
(1.0 eq.)
Ar
Ar
OH
N
2a
BrMgO
MeZnO
CO2
CO2
N
O
ð7Þ
+
Ar
meso-isomer
Ar
3) Ph
H
3A (3.0 eq.)
N
5Aa 9%
tBuOMe, 0 ºC, 2.5 h
HO
4Aa
73%, 90% ee
1h (1.0 eq.)
Ph
(Ar = 4-iPrC6H4)

M. Serizawa et al. / Tetrahedron: Asymmetry 19 (2008) 921–931
925
1) Me2Zn (3.0 eq.)
O
N
R'
2)
(1.0 eq.)
Ar
2a
Ar
OH
N
BrMgO
MeZnO
CO2
CO2
N
ð8Þ
O
+
Ar
meso-isomer
5Aa-Ga
Ar
3) R'
H 3A-G (3.0 eq.)
N
tBuOMe, 0 oC, Time
HO
1h (0.2 eq.)
(Ar = 4-iPrC6H4)
R'
4Aa-Ga
Table 4. The influence of substituent in alkynes 3a
Entry
R0
3
Time (h)
4 or 5
Aa
Yield of 4 (%)
ee of 4 (%)
Yield of 5 (%)
1
2
Ph
A
B
3
73
62
81
76
12
15
n Pen
3
3
3
6
Ba
Ca
Da
Ea
3
4
5
C
D
E
63
64
78
72
59
74
12
5
MeO
CF3
F
10
6
7
nBu
TMS
F
19
24
Fa
Ga
24
57
79
70
10
15
G
a 0.20 molar amount of dicyclohexyl (R,R)-tartrate was treated with 0.26 molar amount of nBuMgBr and 0.2 molar amount of Me2Zn for the preparation
of 1h.
O
O
O
Ph
(2.3 eq.)
Ph
O
O
Cl
7
8
OH
O
N
O
N
(
R
)
(R)
Ar
Ar
Et3N (2.3 eq.)
CH2Cl2, 0 oC, 2 h
Ar
Ar
N
O
ð9Þ
N
O
O
HO
4Aa (60% ee)
(Ar = 4-iPrC6H4)
Ph
Ph
O
+ (
S,S)-isomer 9
60% (Diastereomeric mixture)
the usual manner and stored over drying agents. Flash
column chromatography, thin-layer chromatography
(TLC), and recycling HPLC were performed on Cica-
Merck’s Silica Gel 60 (No. 9385-5B), Merck’s Silica
Gel 60 PF254 (Art. 107749), and JAIGL-SIL (s-043-15),
respectively.
After most of the MeOH was evaporated under reduced
pressure, the mixture was extracted with Et2O. The com-
bined extracts were washed with brine, dried over Na2SO4,
and condensed under reduced pressure to give almost pure
4-isopropylbenzaldehyde oxime (7.33 g, 99%). The crude
oxime was used in the following reaction without further
purification. To a solution of 4-isopropylbenzaldehyde
oxime (7.25 g, 44.4 mmol) in MeOH (35 ml) was added a
solution of NaBH3CN (2.79 g, 44.4 mmol) in MeOH
(30 ml) and two drops of an aqueous methyl orange solu-
tion were added as an indicator. Then a 1 M aqueous
HCl solution was added with stirring until the color turned
red. The mixture was stirred for 2 h at room temperature
by adding a 1 M aqueous HCl solution to maintain the
red color. The mixture was adjusted to pH 10 by adding
a 6 M aqueous KOH solution and the mixture was
extracted with AcOEt. The combined extracts were washed
4.2. Preparation of a-dinitrones
4.2.1. N,N0-(Ethane-1,2-diylidene)bis[(4-isopropylphenyl)-
methanamine oxide] 2a. To a solution of 4-isopropylbenz-
aldehyde (6.72 g, 45.3 mmol) in MeOH (70 ml) was added
a solution of hydroxyammonium chloride (4.73 g, 68.0
mmol) in H2O (25 ml) and the mixture was stirred for
20 min at room temperature. To the mixture was added a
solution of Na2CO3 (3.60 g, 34.0 mmol) in H2O (25 ml)
and the mixture was stirred for 19.5 h at room temperature.

926
M. Serizawa et al. / Tetrahedron: Asymmetry 19 (2008) 921–931
O
Ar =
(R)
O
(R)
(S)
(S)
Ar
O
H
Ph
O
Ph
(R)
(R)
(R)
(R)
H
N
N
O
O
Ar
(S)
(S)
O
(R)
(R)
O
Figure 1. ORTEP diagram of 8.
with brine, dried over Na2SO4, and condensed under re-
duced pressure to give crude N-(4-isopropylbenzyl)hydrox-
ylamine. To a solution of the crude hydroxylamine in THF
(45 ml) was added a mixture of 40% aqueous glyoxal solu-
tion (3.22 g, 22.2 mmol) and THF (25 ml), followed by stir-
ring for 4.5 h at room temperature. The precipitated crude
a-dinitrone 2a was filtered off. The product was purified by
recrystallization from CHCl3/hexane to give pure 2a
(5.38 g, 69%, 2 steps from 4-isopropylbenzaldehyde oxime).
Mp 185–186 °C (decomp., recrystallized from CHCl3/hex-
ane); IR (KBr) 3099, 3054, 2961, 2871, 1525, 1466, 1443,
1421, 1373, 1323, 1307, 1282, 1195, 1151, 1058, 1019,
4H), 7.79 (s, 2H); Calcd for C16H14N2O2Cl2: C, 56.99; H,
4.19; N, 8.31. Found: C, 57.11; H, 4.19; N, 8.31.
4.2.4. N,N0-(Ethane-1,2-diylidene)bis[(3,5-dimethylphenyl)-
methanamine oxide] 2d. Mp 206–207 °C (decomp., recrys-
tallized from CHCl3/AcOEt); IR (KBr) 3098, 3057, 3022,
2955, 2917, 2867, 1606, 1530, 1469, 1369, 1321, 1307,
1280, 1192, 1153, 1038, 996, 925, 914, 891, 849, 740,
679 cmꢀ1 1H NMR (CDCl3) d 2.31 (s, 12H), 4.84 (s,
;
4H), 7.00 (s, 6H), 7.78 (s, 2H); Calcd for C20H24N2O2: C,
74.04; H, 7.46; N, 8.64. Found: C, 74.19; H, 7.45; N, 8.69.
967, 893, 865, 845, 816, 755, 713, 663 cmꢀ1
;
1H NMR
4.2.5. N,N0-(Ethane-1,2-diylidene)bis[(4-t-butylphenyl)meth-
anamine oxide] 2e. Mp 174–175 °C (decomp., recrystal-
lized from AcOEt/hexane); IR (KBr) 3092, 3053, 2961,
2904, 2868, 1529, 1473, 1436, 1417, 1362, 1321, 1269,
1188, 1153, 1109, 1024, 949, 895, 842, 810, 751, 691,
(CDCl3) 1.23 (d, J = 6.83 Hz, 12H), 2.90 (sept,
d
J = 6.83 Hz, 2H), 4.88 (s, 4H), 7.23 (d, J = 8.05 Hz, 4H),
7.31 (d, J = 8.05 Hz, 4H), 7.78 (s, 2H); Calcd for
C22H28N2O2: C, 74.96; H, 8.01; N, 7.95. Found: C, 75.14;
H, 8.06; N, 7.89.
658 cmꢀ1 1H NMR (CDCl3) d 1.30 (s, 18H), 4.89 (s,
;
4H), 7.32 (d, J = 8.29 Hz, 4H), 7.40 (d, J = 8.29 Hz, 4H),
7.79 (s, 2H); Calcd for C24H32N2O2: C, 75.75; H, 8.48;
N, 7.36. Found: C, 75.71; H, 8.51; N, 7.38.
In a similar manner, a-dinitrones 2b–2e were synthesized
using hydroxylamines prepared from the corresponding
aldehydes.
4.3. Catalytic asymmetric dialkynylation reaction
4.2.2.
N,N0-(Ethane-1,2-diylidene)bis(phenylmethanamine
4.3.1. Representative procedure for catalytic asymmetric
dialkynylation of an a-dinitrone (Table 3, entry 7). To a
tBuOMe (1.0 ml) solution of dicyclohexyl (R,R)-tartrate
(32 mg 0.10 mmol) was added butylmagnesium bromide
(0.13 mmol, 0.25 ml of 0.536 M solution in THF) at 0 °C
under an argon atmosphere, and the mixture was stirred
for 10 min. After adding dimethylzinc (1.6 mmol, 1.6 ml
of 1.0 M solution in hexane), the resulting suspension
was stirred for 10 min at 0 °C. To the suspension, solid
a-dinitrone 2a (180 mg, 0.51 mmol) was added and the sus-
pension was stirred for 10 min at 0 °C. To the reaction mix-
oxide) 2b. Mp 205–206 °C (decomp., recrystallized from
DMSO/H2O); IR (KBr) 3100, 3056, 3033, 2984, 2921,
1527, 1495, 1456, 1443, 1375, 1337, 1315, 1291, 1197,
1149, 1028, 964, 925, 887, 863, 831, 756, 699, 670 cmꢀ1
;
1H NMR (CDCl3) d 4.93 (s, 4H), 7.39 (s, 10H), 7.80 (s,
2H); Calcd for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44.
Found: C, 71.50; H, 6.06; N, 10.46.
4.2.3. N,N0-(Ethane-1,2-diylidene)bis[(4-chlorophenyl)meth-
anamine oxide] 2c. Mp 213–214 °C (decomp., recrystal-
lized from DMSO/H2O); IR (KBr) 3101, 3056, 2985,
2923, 2849, 1599, 1577, 1526, 1494, 1443, 1408, 1374,
1330, 1304, 1281, 1197, 1153, 1145, 1097, 1019, 968, 893,
t
ture, a BuOMe (1.0 ml) solution of phenylacetylene 3A
(156 mg, 1.53 mmol) was added and the suspension was
stirred for 3 h at 0 °C. The reaction was quenched by the
addition of a saturated aqueous NaHCO3 solution. After
warming to room temperature, the precipitate containing
869, 847, 808, 737, 682 cmꢀ1; H NMR (CDCl3) d 4.89
1
(s, 4H), 7.34 (d, J = 9.03 Hz, 4H), 7.37 (d, J = 9.03 Hz,

M. Serizawa et al. / Tetrahedron: Asymmetry 19 (2008) 921–931
927
Ar
MeZn
N
R'
O
N
O
Me
Zn
O
OR
Ar
Ar
R'
ZnMe
N
O
O
N
Ar
Mg
Br
O
CO2R
O
R'
ZnMe
10
Ar
Me
Br
O
OR
Zn
O
N
O
Mg
O
R
Ar
O
Me
O
N
O
OR
N
O
O
Zn
O
R'
R'
Zn
Ar
H
N
Ar
N
O
Mg
Me
O
A
Ar
R'
OR
H
O
Br
Zn
Me
O
N
R'
ZnMe
OR
OZnMe
Ar
R'
Me
Zn
R'
O
OR
Me
Zn
O
O
Ar
H
N
O
Mg
O
Zn
R'
O
Mg
Br
OR
H
Me
Ar
O
Br
OR
Zn
Me
O
N
O
N
OZnMe
O
Me
Zn
Ar
O
C
N
(
R)
B
Ar
R'
Scheme 1. A plausible catalytic reaction cycle.
meso-isomer 5Aa was separated by filtration through Celite
to give the filtrate (F) and precipitate (P). The precipitate
(P) was suspended in CHCl3 and the mixture was heated
to dissolve 5Aa. The insoluble inorganic matter was filtered
off through Celite and the filtrate was condensed under re-
duced pressure to give the meso-isomer 5Aa (29 mg, 10%).
The filtrate (F) was extracted with AcOEt and the com-
bined extracts were washed with brine, dried over Na2SO4,
and condensed under reduced pressure. The resulting resi-
due was dissolved in a small amount of Et2O, followed by
the addition of hexane to precipitate the additional meso-
isomer 5Aa, which was separated by filtration (5 mg, 2%).
The filtrate was condensed and the residue was purified
by TLC (SiO2, hexane/AcOEt = 5:1) to give dl-isomer
4Aa (206 mg, 73%). The enantiomeric ratio was determined
by HPLC analysis (Daicel Chiralcel IA, hexane/iPrOH =
30/1, detected at 254 nm) to be 81% ee.
4.3.2. N,N0-[(R,R)-1,6-Diphenylhexa-1,5-diyne-3,4-diyl]bis-
[N-(4-isopropylbenzyl)hydroxylamine] 4Aa. Mp 125–
126 °C (decomp., recrystallized from AcOEt/hexane);
25
½aꢁD ¼ þ14 (c 0.824, EtOH, 81% ee); IR (KBr) 3487,
3218, 3054, 3023, 2960, 2927, 2907, 2869, 2225, 1598,
1513, 1489, 1443, 1363, 1327, 1304, 1100, 1069, 1055,
1
1020, 959, 914, 805, 758, 691 cmꢀ1; H NMR (CDCl3) d
1.24 (d, J = 6.83 Hz, 12H), 2.90 (sept, J = 6.83 Hz, 2H),
3.98 (d, J = 12.69 Hz, 2H), 4.20 (d, J = 12.69 Hz, 2H),
4.25 (s, 2H), 5.48 (br, 2H), 7.20 (d, J = 8.05 Hz, 4H),
7.28–7.33 (m, 6H), 7.34 (d, J = 8.05 Hz, 4H), 7.47–7.55
(m, 4H); Calcd for C38H40N2O2: C, 81.98; H, 7.24; N,
5.03. Found: C, 81.71; H, 7.28; N, 5.02.
4.3.3. N,N0-[(R,R)-1,6-Diphenylhexa-1,5-diyne-3,4-diyl]bis-
[N-(benzyl)hydroxylamine] 4Ab. Mp 114–115 °C (de-
25
comp., recrystallized from AcOEt/hexane); ½aꢁD ¼ þ7 (c
0.73, EtOH, 24% ee). The enantiomeric ratio was deter-
mined by HPLC (Daicel Chiralcel OD–H, hexane/
EtOH = 100:1, detected at 254 nm). IR (KBr) 3420, 3061,
3031, 2905, 2860, 2225, 1598, 1572, 1541, 1490, 1455,
1442, 1302, 1259, 1177, 1157, 1069, 1029, 967, 915, 822,
In a similar way, the asymmetric addition reactions of alky-
nylzinc reagent to the a-dinitrones 2 were carried out to
give the corresponding bis(hydroxylamine)s 4. The physical
and spectral data of 4, 5, and 6 are given in the following.

928
M. Serizawa et al. / Tetrahedron: Asymmetry 19 (2008) 921–931
1
756, 691 cmꢀ1; H NMR (CDCl3) d 4.00 (d, J = 12.82 Hz,
2H), 4.23 (d, J = 12.82 Hz, 2H), 4.25 (s, 2H), 5.22 (s, 2H),
7.26–7.38 (m, 12H), 7.42 (d, J = 6.71 Hz, 4H), 7.47–7.56
(m, 4H); Calcd for C32H28N2O2: C, 81.33; H, 5.97; N,
5.93. Found: C, 81.29; H, 6.02; N, 5.95.
2H), 5.23 (br, 2H), 7.12 (d, J = 8.05 Hz, 4H), 7.19 (d, J =
7.81 Hz, 4H), 7.33 (d, J = 8.05 Hz, 4H), 7.42 (d,
J = 7.81 Hz, 4H); Calcd for C48H60N2O2: C, 82.71; H,
8.68; N, 4.02. Found: C, 82.45; H, 8.78; N, 3.94.
4.3.8. N,N0-[(R,R)-1,6-Bis(4-methoxyphenyl)hexa-1,5-diyne-
3,4-diyl]bis[N-(4-isopropylbenzyl)hydroxylamine] 4Ca. Mp
4.3.4. N,N0-[(R,R)-1,6-Diphenylhexa-1,5-diyne-3,4-diyl]bis-
[N-(4-chlorobenzyl)hydroxylamine] 4Ac. Mp 107–108 °C
125–126 °C (decomp., recrystallized from AcOEt/hexane);
25
25
(decomp., recrystallized from AcOEt/hexane); ½aꢁD ¼ þ5
½aꢁD ¼ þ12 (c 0.788, EtOH, 72% ee). The enantiomeric ra-
(c 0.488, EtOH, 11% ee). The enantiomeric ratio was deter-
mined by HPLC (Daicel Chiralcel OD–H, hexane/
EtOH = 40:1, detected at 254 nm). IR (KBr) 3551, 3290,
3060, 2919, 2861, 2227, 1598, 1491, 1442, 1407, 1363,
1299, 1226, 1090, 1070, 1049, 1016, 967, 915, 851, 833,
tio was determined by HPLC (Daicel Chiralcel IA, hexane/
EtOH = 7:1, detected at 254 nm). IR (KBr) 3435, 3008,
2958, 2932, 2892, 2837, 2225, 1606, 1569, 1509, 1462,
1442, 1418, 1384, 1363, 1334, 1290, 1248, 1171, 1104,
1030, 970, 920, 831, 804, 764, 725 cmꢀ1; 1H NMR (CDCl3)
d 1.24 (d, J = 6.83 Hz, 12H), 2.89 (sept, J = 6.83 Hz, 2H),
3.81 (s, 6H), 3.96 (d, J = 12.69 Hz, 2H), 4.19 (d, J =
12.69 Hz, 2H), 4.22 (s, 2H), 5.46 (br, 2H), 6.83 (d,
J = 9.03 Hz, 4H), 7.19 (d, J = 8.05 Hz, 4H), 7.33 (d,
J = 8.05 Hz, 4H), 7.44 (d, J = 9.03 Hz, 4H); Calcd for
C40H44N2O4: C, 77.89; H, 7.19; N, 4.54. Found: C, 77.77;
H, 7.19; N, 4.61.
801, 757, 724, 690 cmꢀ1 1H NMR (CDCl3) d 3.96 (d,
;
J = 12.93 Hz, 2H), 4.21 (d, J = 12.93 Hz, 2H), 4.24 (s,
2H), 5.32 (br, 2H), 7.28–7.38 (m, 14H), 7.47–7.53 (m,
4H); Calcd for C32H26N2O2Cl2: C, 70.98; H, 4.84; N,
5.18. Found: C, 70.93; H, 4.82; N, 5.16.
4.3.5.
N,N0-[(R,R)-1,6-Diphenylhexa-1,5-diyne-3,4-diyl]-
bis[N-(3,5-dimethylbenzyl)hydroxylamine] 4Ad. Mp 138–
139 °C (decomp., recrystallized from EtOH/hexane);
4.3.9. N,N0-{(R,R)-1,6-Bis[4-(trifluoromethyl)phenyl]hexa-
1,5-diyne-3,4-diyl}bis[N-(4-isopropylbenzyl)hydroxylamine]
4Da. The dl-isomer 4Da and meso-isomer 5Da were sepa-
rated by recycling HPLC on silica gel (hexane/AcOEt =
25
½aꢁD ¼ þ10 (c 0.584, EtOH, 47% ee). The enantiomeric ra-
tio was determined by HPLC (Daicel Chiralcel OD-H, hex-
ane/EtOH = 100:1, detected at 254 nm). IR (KBr) 3465,
3208, 3019, 2915, 2861, 2228, 1607, 1490, 1459, 1442,
1377, 1362, 1326, 1307, 1259, 1159, 1102, 1069, 1041,
6:1). Mp 114–115 °C (decomp., recrystallized from
25
AcOEt/hexane); ½aꢁD ¼ þ9 (c 0.912, EtOH, 59% ee). The
1
981, 915, 853, 815, 756, 690, 668 cmꢀ1; H NMR (CDCl3)
enantiomeric ratio was determined by HPLC (Daicel Chi-
ralcel IA, hexane/iPrOH = 20:1, detected at 254 nm). IR
(KBr) 3296, 3055, 3025, 2962, 2929, 2871, 1615, 1515,
1463, 1420, 1405, 1385, 1363, 1324, 1168, 1129, 1105,
d 2.30 (s, 12H), 3.92 (d, J = 12.69 Hz, 2H), 4.16 (d,
J = 12.69 Hz, 2H), 4.26 (s, 2H), 5.55 (br, 2H), 6.92 (s,
2H), 7.04 (s, 4H), 7.28–7.34 (m, 6H), 7.48–7.54 (m, 4H);
Calcd for C36H36N2O2: C, 81.78; H, 6.86; N, 5.30. Found:
C, 81.66; H, 6.87; N, 5.27.
1
1067, 1017, 971, 843, 810, 732, 715, 659 cmꢀ1; H NMR
(CDCl3) d 1.24 (d, J = 6.83 Hz, 12H), 2.87 (sept, J =
6.83 Hz, 2H), 3.96 (d, J = 12.69 Hz, 2H), 4.19 (d, J =
12.69 Hz, 2H), 4.27 (s, 2H), 5.52 (s, 2H), 7.20 (d, J =
8.05 Hz, 4H), 7.32 (d, J = 8.05 Hz, 4H), 7.58 (d, J =
9.03 Hz, 4H), 7.60 (d, J = 9.03 Hz, 4H); Calcd for
C40H38N2O2F6: C, 69.35; H, 5.53; N, 4.04. Found: C,
69.35; H, 5.60; N, 3.98.
4.3.6.
N,N0-[(R,R)-1,6-Diphenylhexa-1,5-diyne-3,4-diyl]-
bis[N-(4-t-butylbenzyl)hydroxylamine] 4Ae. Mp 107–
25
108 °C (from EtOH/hexane); ½aꢁD ¼ þ5 (c 0.884, EtOH,
37% ee). The enantiomeric ratio was determined by HPLC
(Daicel Chiralcel IA, hexane/iPrOH = 60:1, detected at
254 nm). IR (KBr) 3285, 3057, 3031, 2962, 2903, 2867,
1598, 1509, 1490, 1474, 1459, 1442, 1413, 1395, 1363,
1296, 1269, 1109, 1069, 1048, 1023, 963, 914, 844, 809,
4.3.10. N,N0-[(R,R)-1,6-Bis(2-fluorophenyl)hexa-1,5-diyne-
3,4-diyl]bis[N-(4-isopropylbenzyl)hydroxylamine] 4Ea. Mp
1
756, 690, 669 cmꢀ1; H NMR (CDCl3) d 1.31 (s, 18H),
108–109 °C (decomp., recrystallized from AcOEt/hexane);
25
3.99 (d, J = 12.69 Hz, 2H), 4.21 (d, J = 12.69 Hz, 2H),
4.26 (s, 2H), 5.44 (br, 2H), 7.29–7.34 (m, 6H), 7.35 (s,
8H), 7.49–7.53 (m, 4H); Calcd for C40H44N2O2: C, 82.15;
H, 7.58; N, 4.79. Found: C, 82.36; H, 7.72; N, 4.81.
½aꢁD ¼ þ11 (c 0.948, EtOH, 74% ee). The enantiomeric ra-
tio was determined by HPLC (Daicel Chiralcel IA, hex-
ane/iPrOH = 10:1, detected at 254 nm). IR (KBr) 3241,
3060, 2960, 2927, 2870, 1612, 1574, 1514, 1493, 1448,
1420, 1384, 1363, 1303, 1271, 1255, 1216, 1104, 1055,
4.3.7. N,N0-[(R,R)-1,6-Bis(4-pentylphenyl)hexa-1,5-diyne-
1031, 1021, 967, 944, 854, 827, 808, 758, 667 cmꢀ1 1H
;
3,4-diyl]bis[N-(4-isopropylbenzyl)hydroxylamine]
4Ba.
NMR (CDCl3) d 1.24 (d, J = 6.83 Hz, 12H), 2.89 (sept,
J = 6.83 Hz, 2H), 4.01 (d, J = 12.69 Hz, 2H), 4.24 (d,
J = 12.69 Hz, 2H), 4.31 (s, 2H), 5.43 (br, 2H), 7.04–7.12
(m, 4H), 7.19 (d, J = 8.05 Hz, 4H), 7.27–7.34 (m, 2H),
7.35 (d, J = 8.05 Hz, 4H), 7.46–7.53 (m, 2H); Calcd for
C38H38N2O2F2: C, 77.00; H, 6.46; N, 4.73. Found: C,
77.06; H, 6.60; N, 4.72.
Mp 105–106 °C (decomp., recrystallized from EtOH/hex-
25
ane); ½aꢁD ¼ þ13 (c 0.892, EtOH, 76% ee). The enantio-
meric ratio was determined by HPLC (Daicel Chiralcel
IA, hexane/iPrOH = 15:1, detected at 254 nm). IR (KBr)
3276, 3083, 3026, 2958, 2928, 2857, 2227, 1611, 1509,
1460, 1420, 1382, 1362, 1317, 1182, 1115, 1081, 1055,
1
1020, 965, 834, 816, 715 cmꢀ1; H NMR (CDCl3) d 0.88
(t, J = 6.59 Hz, 6H), 1.24 (d, J = 6.83 Hz, 12H), 1.27–
1.36 (m, 8H), 1.60 (quint, J = 7.56 Hz, 4H), 2.59 (t, J =
7.56 Hz, 4H), 2.89 (sept, J = 6.83 Hz, 2H), 3.96 (d,
J = 12.69 Hz, 2H), 4.20 (d, J = 12.69 Hz, 2H), 4.23 (s,
4.3.11. N,N0-[(R,R)-Tetradeca-5,9-diyne-7,8-diyl]bis[N-(4-
isopropylbenzyl)hydroxylamine] 4Fa. Obtained as an oil;
25
½aꢁD ¼ ꢀ10 (c 0.248, EtOH, 79% ee). The enantiomeric
ratio was determined by HPLC (Daicel Chiralcel IA,

M. Serizawa et al. / Tetrahedron: Asymmetry 19 (2008) 921–931
929
hexane/iPrOH = 50:1, detected at 220 nm). IR (neat) 3230,
3093, 3053, 3012, 2958, 2931, 2871, 2233, 1614, 1567,
1514, 1464, 1421, 1381, 1362, 1328, 1301, 1237, 1142,
Calcd for C32H26N2O2Cl2: C, 70.98; H, 4.84; N, 5.18.
Found: C, 70.79; H, 5.05; N, 5.03.
1103, 1056, 1020, 954, 809, 740, 715 cmꢀ1 1H NMR
;
4.3.16.
N,N0-[(R,S)-1,6-Diphenylhexa-1,5-diyne-3,4-diyl]-
(CDCl3) d 0.93 (t, J = 7.08 Hz, 6H), 1.24 (d, J = 6.83 Hz,
12H), 1.42–1.65 (m, 8H), 2.30 (t, J = 7.08 Hz, 4H), 2.88
(sept, J = 6.83 Hz, 2H), 3.82 (d, J = 12.69 Hz, 2H), 3.87
(s, 2H), 4.07 (d, J = 12.69 Hz, 2H), 5.39 (br, 2H), 7.16 (d,
J = 8.05 Hz, 4H), 7.28 (d, J = 8.05 Hz, 4H); HRMS
(FAB+), Found: m/z 517.37900. Calcd for C34H49N2O2:
(M++H), 517.37941.
bis[N-(3,5-dimethylbenzyl)hydroxylamine] 5Ad. Mp 164–
165 °C (decomp., recrystallized from CHCl3/hexane); IR
(KBr) 3232, 3019, 2914, 2873, 2225, 1606, 1489, 1458,
1442, 1379, 1349, 1299, 1235, 1166, 1088, 1071, 1029,
979, 928, 903, 859, 810, 756, 710, 691, 668 cmꢀ1 1H
;
NMR (CDCl3) d 2.28 (s, 12H), 3.97 (d, J = 12.93 Hz,
2H), 4.22 (d, J = 12.93 Hz, 2H), 4.30 (s, 2H), 5.16 (br,
2H), 6.91 (s, 2H), 7.07 (s, 4H), 7.31–7.37 (m, 6H), 7.51–
7.58 (m, 4H); Calcd for C36H36N2O2: C, 81.78; H, 6.86;
N, 5.30. Found: C, 81.56; H, 6.97; N, 5.24.
4.3.12. N,N0-[(R,R)-1,6-Bis(trimethylsilyl)hexa-1,5-diyne-3,
4-diyl]bis[N-(4-isopropylbenzyl)hydroxylamine] 4Ga. Ob-
25
tained as an oil; ½aꢁD ¼ ꢀ9 (c 0.536, EtOH, 70% ee). The
4.3.17.
N,N0-[(R,S)-1,6-Diphenylhexa-1,5-diyne-3,4-diyl]-
enantiomeric ratio was determined by HPLC (Daicel Chi-
ralcel IA, hexane/iPrOH = 100:1, detected at 220 nm). IR
(neat) 3277, 3012, 2959, 2898, 2870, 2173, 1612, 1514,
1460, 1420, 1384, 1362, 1249, 1056, 1020, 982, 842, 808,
bis[N-(4-t-butylbenzyl)hydroxylamine] 5Ae. Mp 186–
187 °C (decomp., recrystallized from CHCl3/hexane); IR
(KBr) 3268, 3060, 3028, 2962, 2903, 2871, 2223, 1598,
1511, 1489, 1476, 1463, 1442, 1412, 1393, 1364, 1297,
1270, 1110, 1081, 1029, 995, 973, 860, 845, 824, 804, 755,
1
760, 700 cmꢀ1; H NMR (CDCl3) d 0.22 (s, 18H), 1.24
(d, J = 6.83 Hz, 12H), 2.89 (sept, J = 6.83 Hz, 2H), 3.83
(d, J = 12.93 Hz, 2H), 3.96 (s, 2H), 4.09 (d, J = 12.93 Hz,
2H), 5.21 (br, 2H), 7.18 (d, J = 8.05 Hz, 4H), 7.28 (d,
J = 8.05 Hz, 4H); HRMS (FAB+), Found: m/z
549.33305. Calcd for C32H49N2O2Si2: (M++H), 549.33327.
690 cmꢀ1 1H NMR (CDCl3) d 1.31 (s, 18H), 4.01 (d,
;
J = 13.17 Hz, 2H), 4.27 (d, J = 13.17 Hz, 2H), 4.30 (s,
2H), 5.25 (br, 2H), 7.31–7.40 (m, 14H), 7.50–7.56 (m,
4H); Calcd for C40H44N2O2: C, 82.15; H, 7.58; N, 4.79.
Found: C, 82.05; H, 7.84; N, 4.76.
4.3.13.
N,N0-[(R,S)-1,6-Diphenylhexa-1,5-diyne-3,4-diyl]-
4.3.18. N,N0-[(R,S)-1,6-Bis(4-pentylphenyl)hexa-1,5-diyne-
3,4-diyl]bis[N-(4-isopropylbenzyl)hydroxylamine] 5Ba. Mp
157–158 °C (decomp., recrystallized from Et2O/hexane);
IR (KBr) 3243, 3050, 3026, 2958, 2927, 2871, 2857, 1509,
1463, 1418, 1297, 1240, 1184, 1085, 1021, 855, 832, 804,
bis[N-(4-isopropylbenzyl)hydroxylamine] 5Aa. Mp 169–
170 °C (decomp., recrystallized from AcOEt/hexane); IR
(KBr) 3261, 3051, 2965, 2929, 2869, 2217, 1557, 1540,
1508, 1489, 1465, 1442, 1417, 1297, 1239, 1083, 1029,
998, 972, 919, 857, 832, 804, 758, 691 cmꢀ1 1H NMR
;
1
736, 715 cmꢀ1; H NMR (CDCl3) d 0.90 (t, J = 6.83 Hz,
(CDCl3) d 1.24 (d, J = 6.83 Hz, 12H), 2.89 (sept, J =
6.83 Hz, 2H), 4.00 (d, J = 12.93 Hz, 2H), 4.27 (d,
J = 12.93 Hz, 2H), 4.29 (s, 2H), 5.23 (br, 2H), 7.18 (d,
J = 8.05 Hz, 4H), 7.31–7.36 (m, 6H), 7.37 (d, J =
8.05 Hz, 4H), 7.51–7.56 (m, 4H); Calcd for C38H40N2O2:
C, 81.98; H, 7.24; N, 5.03. Found: C, 81.71; H, 7.25; N,
4.94.
6H), 1.24 (d, J = 7.07 Hz, 12H), 1.28–1.40 (m, 8H), 1.62
(quint, J = 7.56 Hz, 4H), 2.61 (t, J = 7.56 Hz, 4H), 2.89
(sept, J = 7.07 Hz, 2H), 3.99 (d, J = 12.93 Hz, 2H), 4.25
(d, J = 12.93 Hz, 2H), 4.26 (s, 2H), 5.24 (br, 2H), 7.15 (d,
J = 8.05 Hz, 4H), 7.18 (d, J = 8.05 Hz, 4H), 7.36 (d,
J = 8.05 Hz, 4H), 7.44 (d, J = 8.05 Hz, 4H); Calcd for
C48H60N2O2: C, 82.71; H, 8.68; N, 4.02. Found: C, 82.53;
H, 8.76; N, 4.01.
4.3.14.
N,N0-[(R,S)-1,6-Diphenylhexa-1,5-diyne-3,4-diyl]-
bis[N-(benzyl)hydroxylamine] 5Ab. Mp 173–174 °C (de-
comp., recrystallized from AcOEt); IR (KBr) 3240, 3084,
3063, 3030, 2934, 2879, 1598, 1492, 1454, 1443, 1344,
1296, 1236, 1215, 1079, 1031, 990, 971, 931, 915, 838,
4.3.19.
N,N0-[(R,S)-1,6-Bis(4-methoxyphenyl)hexa-1,5-
diyne-3,4-diyl]bis[N-(4-isopropylbenzyl)hydroxylamine] 5Ca.
Mp 197–198 °C (decomp., recrystallized from CHCl3/hex-
ane); IR (KBr) 3220, 3008, 2959, 2931, 2872, 2218, 1606,
1509, 1461, 1415, 1290, 1251, 1172, 1104, 1084, 1029,
818, 764, 742, 697 cmꢀ1 1H NMR (CDCl3) d 4.04 (d,
;
J = 13.17 Hz, 2H), 4.30 (d, J = 13.17 Hz, 2H), 4.30 (s,
2H), 5.17 (s, 2H), 7.28–7.37 (m, 12H), 7.43–7.48 (m, 4H),
7.51–7.57 (m, 4H); Calcd for C32H28N2O2: C, 81.33; H,
5.97; N, 5.93. Found: C, 81.23; H, 6.02; N, 5.87.
857, 830, 805, 708 cmꢀ1 1H NMR (CDCl3) d 1.24 (d,
;
J = 7.07 Hz, 12H), 2.89 (sept, J = 7.07 Hz, 2H), 3.83 (s,
6H), 3.99 (d, J = 12.69 Hz, 2H), 4.25 (d, J = 12.69 Hz,
2H), 4.26 (s, 2H), 6.86 (d, J = 8.78 Hz, 4H), 7.18 (d,
J = 8.05 Hz, 4H), 7.36 (d, J = 8.05 Hz, 4H), 7.46 (d,
J = 8.78 Hz, 4H), Signals of the hydroxy proton (OH)
was not observed clearly; Calcd for C40H44N2O4:
C, 77.89; H, 7.19; N, 4.54. Found: C, 77.98; H, 7.29; N,
4.54.
4.3.15.
N,N0-[(R,S)-1,6-Diphenylhexa-1,5-diyne-3,4-diyl]-
bis[N-(4-chlorobenzyl)hydroxylamine] 5Ac. Mp 169–
170 °C (decomp., recrystallized from AcOEt/hexane); IR
(KBr) 3253, 3064, 2876, 2216, 1598, 1541, 1507, 1490,
1465, 1457, 1442, 1405, 1339, 1298, 1236, 1177, 1091,
1029, 1017, 975, 948, 915, 856, 830, 801, 755, 690 cmꢀ1
;
4.3.20. N,N0-{(R,S)-1,6-Bis[4-(trifluoromethyl)phenyl]hexa-
1,5-diyne-3,4-diyl}bis[N-(4-isopropylbenzyl)hydroxylamine]
5Da. Mp 161–162 °C (decomp., recrystallized from
AcOEt/hexane); IR (KBr) 3232, 3055, 3024, 2961, 2928,
1H NMR (CDCl3) d 4.00 (d, J = 13.42 Hz, 2H), 4.25 (d,
J = 13.42 Hz, 2H), 4.26 (s, 2H), 5.86 (br, 2H), 7.29 (d,
J = 8.54 Hz, 4H), 7.33–7.41 (m, 10H), 7.49–7.55 (m, 4H);

930
M. Serizawa et al. / Tetrahedron: Asymmetry 19 (2008) 921–931
2894, 2873, 1614, 1568, 1514, 1462, 1406, 1326, 1300, 1258,
1169, 1131, 1105, 1088, 1068, 1017, 855, 842, 804, 730,
4.3.25. (3R,30R)-2,20-Dibenzyl-5,50-diphenyl-2,20,3,30-tetra-
hydro-3,30-biisoxazole 6b. Mp 113–114 °C (decomp.,
recrystallized from CH2Cl2/hexane); IR (KBr) 3106,
3085, 3061, 3031, 2877, 2839, 1653, 1600, 1577, 1494,
1449, 1360, 1342, 1316, 1278, 1248, 1219, 1043, 1024,
656 cmꢀ1 1H NMR (CDCl3) d 1.24 (d, J = 7.07 Hz,
;
12H), 2.90 (sept, J = 7.07 Hz, 2H), 4.00 (d, J = 12.93 Hz,
2H), 4.23 (d, J = 12.93 Hz, 2H), 4.32 (s, 2H), 5.29 (s,
2H), 7.19 (d, J = 8.05 Hz, 4H), 7.34 (d, J = 8.05 Hz, 4H),
7.60 (d, J = 8.54 Hz, 4H), 7.63 (d, J = 8.54 Hz, 4H); Calcd
for C40H38N2O2F6: C, 69.35; H, 5.53; N, 4.04. Found: C,
69.31; H, 5.55; N, 4.09.
1
916, 889, 757, 726, 691 cmꢀ1; H NMR (CDCl3) d 4.07
(d, J = 13.42 Hz, 2H), 4.19 (s, 2H), 4.24 (d, J = 13.42 Hz,
2H), 5.24 (s, 2H), 7.26–7.40 (m, 12H), 7.41–7.45 (m, 4H),
7.45–7.50 (m, 4H); Calcd for C32H28N2O2: C, 81.33; H,
5.97; N, 5.93. Found: C, 81.05; H, 5.93; N, 5.84.
4.3.21. N,N0-[(R,S)-1,6-Bis(2-fluorophenyl)hexa-1,5-diyne-
3,4-diyl]bis[N-(4-isopropylbenzyl)hydroxylamine] 5Ea. Mp
177–178 °C (decomp., recrystallized from AcOEt/hexane);
IR (KBr) 3249, 3087, 3012, 2960, 2925, 2889, 1612, 1576,
1492, 1467, 1448, 1363, 1300, 1254, 1214, 1103, 1083,
4.3.26. (3R,30R)-2,20-Bis(4-chlorobenzyl)-5,50-diphenyl-2,20,
3,30-tetrahydro-3,30-biisoxazole 6c. Mp 134–135 °C (de-
comp., recrystallized from Et2O/hexane); IR (KBr) 3112,
3084, 3065, 3036, 2925, 2900, 2846, 1659, 1598, 1577,
1491, 1447, 1406, 1331, 1243, 1228, 1089, 1042, 1015,
937, 919, 882, 817, 802, 761, 745, 735, 709, 689,
1057, 1031, 997, 954, 856, 832, 822, 803, 759, 726 cmꢀ1
;
1H NMR (CDCl3) d 1.24 (d, J = 7.07 Hz, 12H), 2.89 (sept,
J = 7.07 Hz, 2H), 4.03 (d, J = 12.93 Hz, 2H), 4.28 (d,
J = 12.93 Hz, 2H), 4.33 (s, 2H), 5.19 (br, 2H), 7.05–7.15
(m, 4H), 7.18 (d, J = 8.05 Hz, 4H), 7.29–7.36 (m, 2H),
7.38 (d, J = 8.05 Hz, 4H), 7.49–7.55 (m, 2H); Calcd for
C38H38N2O2F2: C, 77.00; H, 6.46; N, 4.73. Found: C,
77.21; H, 6.46; N, 4.73.
663 cmꢀ1 1H NMR (CDCl3) d = 4.02 (d, J = 13.42 Hz,
;
2H), 4.14 (s, 2H), 4.20 (d, J = 13.42 Hz, 2H), 5.22 (s,
2H), 7.25–7.37 (m, 14H), 7.43–7.49 (m, 4H); Calcd for
C32H26N2O2Cl2: C, 70.98; H, 4.84; N, 5.18. Found: C,
70.69; H, 4.90; N, 5.01.
4.4. Determination of absolute configuration (Eq. 9)
4.3.22. N,N0-[(R,S)-Tetradeca-5,9-diyne-7,8-diyl]bis[N-(4-
isopropylbenzyl)hydroxylamine] 5Fa. Mp 161–162 °C (de-
comp., recrystallized from AcOEt/hexane); IR (KBr) 3376,
3056, 3012, 2956, 2932, 2867, 2230, 1516, 1462, 1422, 1384,
1362, 1351, 1333, 1300, 1235, 1138, 1096, 1056, 1023, 1002,
To a CH2Cl2 (3 ml) solution of N,N0-[(R,R)-1,6-diphenyl-
hexa-1,5-diyne-3,4-diyl]bis[N-(4-isopropylbenzyl)hydroxyl-
amine] 4Aa (150 mg, 0.27 mmol, 60% ee) was added a
CH2Cl2 (3 ml) solution of Et3N (63 mg, 0.62 mmol) at
0 °C under a nitrogen atmosphere. To the mixture was
added a CH2Cl2 (3 ml) solution of (1S,4R)-camphanic
chloride 7 (134 mg, 0.62 mmol), and the mixture was stir-
red for 2 h at 0 °C. After quenching the reaction by the
addition of water, the mixture was extracted with AcOEt.
The combined extracts were washed with brine, dried over
Na2SO4, and condensed under reduced pressure. The
product was recrystallized from AcOEt/hexane to give a
diastereomeric mixture of 8 and 9 (147 mg, 60%). Diaste-
reomerically pure 8 (89 mg, 36%) was obtained by recrys-
tallizing further twice (first: AcOEt/hexane, second:
toluene/hexane).
956, 885, 852, 836, 813, 778, 737, 715 cmꢀ1 1H NMR
;
(CDCl3) d 0.94 (t, J = 7.08 Hz, 6H), 1.24 (d, J = 7.07 Hz,
12H), 1.41–1.63 (m, 8H), 2.32 (t, J = 6.83 Hz, 4H), 2.89
(sept, J = 7.07 Hz, 2H), 3.83 (d, J = 12.93 Hz, 2H), 3.91
(s, 2H), 4.13 (d, J = 12.93 Hz, 2H), 5.19 (br, 2H), 7.17 (d,
J = 8.05 Hz, 4H), 7.30 (d, J = 8.05 Hz, 4H); Calcd for
C34H48N2O2: C, 79.02; H, 9.36; N, 5.42. Found: C, 79.12;
H, 9.54; N, 5.38.
4.3.23. N,N0-[(R,S)-1,6-Bis(trimethylsilyl)hexa-1,5-diyne-3,
4-diyl]bis[N-(4-isopropylbenzyl)hydroxylamine] 5Ga. Mp
162–163 °C (decomp., recrystallized from AcOEt/hexane);
IR (KBr) 3387, 3012, 2961, 2867, 2175, 1514, 1462, 1420,
1362, 1298, 1243, 1094, 1056, 1016, 996, 846, 811, 762,
4.4.1. N,N0-[(3R,4R)-1,6-Diphenylhexa-1,5-diyne-3,4-diyl]-
bis{N-(4-isopropylbenzyl)-O-[(1S0,4R0)-4,7,7-trimethyl-2-ox-
abicyclo[2.2.1]heptane-3-one-1-carbonyl]hydroxylamine} 8.
696 cmꢀ1 1H NMR (CDCl3) d 0.24 (s, 18H), 1.24 (d,
;
J = 6.83 Hz, 12H), 2.89 (sept, J = 6.83 Hz, 2H), 3.85 (d,
J = 12.93 Hz, 2H), 3.96 (s, 2H), 4.14 (d, J = 12.93 Hz,
2H), 5.08 (br, 2H), 7.17 (d, J = 8.05 Hz, 4H), 7.31 (d,
J = 8.05 Hz, 4H); Calcd for C32H48N2O2Si2: C, 70.02; H,
8.81; N, 5.10. Found: C, 69.82; H, 8.91; N, 5.00.
Mp 148–149 °C (decomp., recrystallized from toluene/hex-
25
ane); ½aꢁD ¼ þ80 (c 0.14, EtOH, 100% ee); IR (KBr) 3053,
3018, 2962, 2934, 2871, 2230, 1781, 1599, 1513, 1490, 1443,
1398, 1381, 1332, 1309, 1254, 1227, 1167, 1103, 1051, 1018,
993, 956, 934, 847, 825, 756, 690 cmꢀ1; 1H NMR (CDCl3) d
0.55 (s, 6H), 0.70 (s, 6H), 0.97 (s, 6H), 1.21 (d, J = 6.83 Hz,
12H), 1.35–1.49 (m, 2H), 1.62–1.78 (m, 4H), 1.95–2.15 (m,
2H), 2.88 (sept, J = 6.83 Hz, 2H), 4.28 (d, J = 13.42 Hz,
2H), 4.46 (br, 2H), 4.86 (s, 2H), 7.17 (d, J = 8.05 Hz,
4H), 7.29–7.38 (m, 6H), 7.42 (d, J = 8.05 Hz, 4H), 7.45–
7.51 (m, 4H); Calcd for C58H64N2O8: C, 75.95; H, 7.03;
N, 3.06. Found: C, 75.92; H, 6.96; N, 3.06. Crystal data
(Fig. 1):6 C58H64N2O8, FW 917.15, monoclinic, P21, a =
4.3.24. (3R,30R)-2,20-Bis(4-isopropylbenzyl)-5,50-diphenyl-
2,20,3,30-tetrahydro-3,30-biisoxazole 6a. Obtained as an
oil; IR (KBr) 3056, 3025, 2959, 2925, 2870, 1652, 1601,
1577, 1514, 1494, 1448, 1420, 1362, 1335, 1280, 1243,
1181, 1097, 1071, 1047, 1022, 1000, 917, 890, 822, 770,
1
724, 691 cmꢀ1; H NMR (CDCl3) d 1.27 (d, J = 6.83 Hz,
12H), 2.92 (sept, J = 6.83 Hz, 2H), 4.01 (d, J = 12.93 Hz,
2H), 4.19 (s, 2H), 4.20 (d, J = 12.93 Hz, 2H), 5.23 (s,
2H), 7.21 (d, J = 8.05 Hz, 4H), 7.29–7.33 (m, 6H), 7.36
(d, J = 8.05 Hz, 4H), 7.40–7.50 (m, 4H); HRMS (FAB+),
Found: m/z 557.31687. Calcd for C38H41N2O2: (M++H),
557.31681.
˚
˚
˚
12.478(3) A, b = 13.085(3) A, c = 15.514(3) A, b =
90.240(6)°, V = 2533.0(9) A , Z = 2. Dcalcd = 1.202 g cmꢀ3
.
3
˚
R = 0.082 (Rw = 0.111) for 8489 reflections with
I > 3.00r(I) and 613 variable parameters.

M. Serizawa et al. / Tetrahedron: Asymmetry 19 (2008) 921–931
931
3708–3715; (i) Ooi, T.; Kameda, M.; Fujii, J.; Maruoka, K.
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Acknowledgements
The present work was financially supported in part by
Grant-in-Aid for Scientific Research on Priority Areas ‘Ad-
vanced Molecular Transformations of Carbon Resources’
from The Ministry of Education, Culture, Sports, Science
and Technology (MEXT) and NOVARTIS Foundation
(Japan) for the Promotion of Science.
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