Synthesis of planar chiral [2.2]paracyclophane Schiff bases for the enantioselective Henry reaction

Article abstract of DOI:10.1016/j.tetasy.2012.06.005

A series of diastereomerically pure Schiff base ligands based on [2.2]paracyclophane backbones were synthesized and separated. The new planar chiral [2.2]paracyclophane Schiff bases were used as ligands in Cu-catalyzed asymmetric Henry reactions with high

Full text of DOI:10.1016/j.tetasy.2012.06.005

Tetrahedron: Asymmetry 23 (2012) 809–817
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of planar chiral [2.2]paracyclophane Schiff bases
for the enantioselective Henry reaction
⇑
Fuyan He, Yudao Ma , Lei Zhao, Wenzeng Duan, Jianqiang Chen, Zhongxi Zhao
Department of Chemistry, Shandong University, Shanda South Road No. 27, Jinan 250100, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 January 2012
Accepted 8 June 2012
A series of diastereomerically pure Schiff base ligands based on [2.2]paracyclophane backbones were syn-
thesized and separated. The new planar chiral [2.2]paracyclophane Schiff bases were used as ligands in
Cu-catalyzed asymmetric Henry reactions with high yields and enantioselectivities.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The Henry reaction,1 which is an important procedure for C–C
bond formation, can be catalyzed by Lewis acids or bases. The
products of this reaction, a coupling of readily available nitroalk-
anes and carbonyl compounds, can be transformed into valuable
building blocks.2 Due to its importance in organic synthesis,
considerable effort has been focused on the development of cata-
lytic enantioselective variants of this reaction.3 As efficient cata-
lysts and weak Lewis acids, chiral Cu(II) complexes have been
employed in asymmetric Henry reactions for obtaining high
enantioselectivity.4
Planar chirality plays an important role in asymmetric catalysis,
such as ferrocenyl ligands and [2.2]paracyclophane derivatives.5
[2.2]Paracyclophane only requires one substituent to afford planar
chiral compounds, and such a versatile backbone structure opens
up the possibility of designing different types of chiral ligands.
Examples of [2.2]paracyclophane-based ligands include diphos-
phanes,6 oxazoline–phosphanes,7 imidazoliums,8 oxazoline-alco-
hols,9 and imine ligands.10
R
R
N
N
HO
OH
OH
HO
1a R=H (Rp,S)
1b R=Br (Sp,S)
1b' R=Br (Rp,S)
1d' R=F (Rp,S)
1e' R=I (Rp,S)
1c R=3-methoxyphenyl (Rp,S)
1d R=F (Sp,S)
1f' R=MeO (Rp,S)
1e R=I (Sp,S)
1f R=MeO (Sp,S)
1g R=2,3-dimethoxyphenyl (Rp,S)
Figure 1. The structure of the ligands.
2. Results and discussion
2.1. Resolution of 1b and 1b0
Recently we have reported that several new planar chiral Schiff
bases 1a, 1b, and 1c (Fig. 1) could be used as ligands in Cu-cata-
lyzed asymmetric Henry reactions under mild conditions with
good yields and enantioselectivities.11 Our preliminary results
showed that a 13-substituted functional group on the [2.2]paracy-
clophane scaffold has a significant influence on the enantioselec-
tivity. However, the scope of the substituent was still somewhat
limited. Herein we report the synthesis of several novel planar
and central chiral Schiff base ligands 1d–g based on [2.2]paracyclo-
phane backbones and the substituent effects on the enantioselec-
tivity in Cu-catalyzed asymmetric Henry reactions (Fig. 1).
In our previous procedure,11 compounds 1b and 1b0 were
prepared separately from enantiopure materials 2. The products
have very different retention factors on silica gel plates; the reten-
tion factors for 1b and 1b0 were 0.3 and 0.5 (CH2Cl2/ethyl ace-
tate = 10/1), respectively. The difference in the polarity of the
diastereoisomers suggests they might be separated by chromatog-
raphy on silica gel. Thus, starting from racemic 2, as shown in
Scheme 1, 13-bromo-4-hydroxyl-5-acetyl[2.2]paracyclophane
and (S)-tert-leucinol were converted into a mixture of 1b and 1b0.
Fortunately, the resolution of the two species was achieved easily
by column chromatography on silica gel. Their structures were
confirmed by comparing the NMR data from the literature,11 in
⇑
Corresponding author. Tel.: +86 531 88361869; fax: +86 531 88565211.
E-mail address: ydma@sdu.edu.cn (Y. Ma).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.005

810
F. He et al. / Tetrahedron: Asymmetry 23 (2012) 809–817
Br
N
OH
HO
TiCl4/CH2Cl2
acetyl chloride
(Sp,S)-1b (48%)
(S)-tert-leucinol
toluene, reflux
Br
Br
rt
Br
0ºC
separated by column chromatography
O
OH
OH
NH2
( )-2
( )-3
( )-10a
Br
N
HO
OH
(Rp,S)-1b' (48%)
Scheme 1. Resolution of 1b and 1b0.
Figure 2. ORTEP diagram of the molecular structure of 1b. Ellipsoids are drawn at the 50% probability level. The solvent molecules have been omitted.
which 1b and 1b0 synthesized from enantiopure materials. The re-
sults of an X-ray diffractional study of 1b is presented in Figure 2.
The chirality of 1b and 1b0 was also reflected by their optical
properties. The CD spectra of them are shown in Figure 3. CD spec-
trum of 1b0 is dominated by strong negative dichroisms, and CD
spectrum of 1b is opposite in sign, but hemiidentic in magnitude,
which reveals that 1b and 1b0 are diastereoisomers.
2.2. Design and synthesis of novel Schiff-base ligands
The key intermediates of our strategy are phenols with diverse
substituents on the 13-position of the [2.2]paracyclophane. Our
synthetic routes to intermediates 5, 8, 9 are described in Scheme 2.
Starting from ( )-2, which was synthesized by a literature pro-
cedure,12 the diazonium fluoroborate was prepared with isoamyl
Figure 3. CD spectra of 1b and 1b0 in CH2Cl2.

F. He et al. / Tetrahedron: Asymmetry 23 (2012) 809–817
811
1. n-BuLi/ THF, -78ºC
1. HBF4/ isoamyl nitrite
-5ºC
2. B(OBu)3, rt
F
F
NH2
Br
3. H2O2/ NaOH, rt
4. H+ , rt
2. toluene, 60-80ºC
(35%)
Br
OH
(88%)
( )-2
( )-4
( )-5
1. n-BuLi/ THF, -78ºC
BBr3/ CH2Cl2
2. I2
rt
Br
I
I
rt
-78ºC
(77%)
(87%)
OMe
OH
OMe
( )-6
( )-7
( )-8
1. n-BuLi/ THF, -78ºC
2. B(OBu)3, rt
OMe
OH
Br
3. H2O2/ NaOH, rt
4. H+ , rt
OMe
(80%)
( )-6
( )-9
Scheme 2. Synthesis of phenols.
R
TiCl4/ClCH2CH2Cl
acetyl chloride
80ºC
N
OH
OMe
HO
1d R = F (Sp,S) (45%)
1e R = I (Sp,S) (46%)
O
1f R = OMe (Sp,S) (44%)
1g R = 2,3-dimethoxyphenyl (Rp,S)
OH
(S)-tert-leucinol
rac
(80%)
R
10d (79%)
toluene, reflux
separated by column chromatography
OH
TiCl4/CH2Cl2
rac
acetyl chloride
R
5 R=F
8 R=I
rt
0ºC
R
9 R=OMe
O
OH
N
rac
HO
10b R=F (98%)
10c R=I (72%)
OH
1d' R = F (Rp,S) (47%)
1e' R = I (Rp,S) (47%)
1f' R = OMe (Rp,S) (45%)
Scheme 3. Synthesis of ligands.

812
F. He et al. / Tetrahedron: Asymmetry 23 (2012) 809–817
nitrite in 40% HBF4 at ꢀ5 °C.13 After filtration, the residue was
added into toluene with stirring. By incubating the suspension
between 60 and 80 °C, the corresponding compound ( )-4 was
obtained, which was readily converted into the ( )-4-fluoro-13-
hydroxy[2.2]paracyclophane 5.14 Lithiation of ( )-615 with n-BuLi
followed by adding I2 in THF gave the corresponding iodide ( )-7.
Treating 7 with BBr3 in CH2Cl2 afforded the ( )-13-hydroxy-4-
iodo[2.2]paracyclophane 8. Compound ( )-6 was transformed into
( )-13-hydroxy-4-methoxy[2.2]paracyclophane 9 by the same pro-
cedure as for compound 5.
Compounds ( )-10b, ( )-10c, and ( )-10d were prepared by
ortho-selective Friedel–Crafts acylation of phenols. Compounds
( )-5 and ( )-8 could be acylated in CH2Cl2 at 0 °C to give the cor-
responding products.16 However in the case of ( )-9 disappointing
results were obtained under the same reaction conditions. Fortu-
nately, when the reaction was carried out at 80 °C in ClCH2CH2Cl,
the desired product ( )-10d was obtained in good yield17
(Scheme 3).
Finally, from the above racemic trisubstituted [2.2]paracyclo-
phane building blocks, several chiral Schiff-base ligands (Sp,S)-1d,
(Rp,S)-1d0, (Sp,S)-1e, (Rp,S)-1e0, (Sp,S)-1f, and (Rp,S)-1f0 were synthe-
sized by condensation with (S)-tert-leucinol and then separated by
chromatography on silica gel. The absolute configurations of the
diastereoisomers were confirmed by comparison of their CD spec-
tra with 1b and 1b0 (Fig. 4). Compound (Sp,S)-1g can be readily pre-
pared from (Sp,S)-1e by a Suzuki–Miyaura coupling reaction in
dioxane with KF as the base.
2.3. Optimization of the catalytic conditions
We began by optimizing the reaction conditions using 1b as the
ligand; a number of parameters were varied using nitromethane
and 4-nitrobenzaldehyde as model substrates. The reaction condi-
tions were evaluated with a particular emphasis on solvent effects.
As reported in the literature,11,18 protic alcoholic solvents were
superior to aprotic solvents since they might coordinate the copper
to help and enhance the enantioselectivity. The above hypothesis
was confirmed when the alcoholic solvent A was removed com-
pletely by the non-coordinating solvent B (Table 1, entries 4 and
0
Figure 4. CD spectra of 1b–f and 1b0–f in CH2Cl2.
Table 1
Asymmetric Henry reaction catalyzed by a Cu-1b complexa
OH
CHO
10 mol% 1b, 10mol% Cu(OTf)2
18mol% t-BuOK,solvent A
NO2
*
O2N
solvent B/ CH3NO2
25ºC, 48 h
O2N
11a
Entry
Solvent A
Solvent B
Yieldh (%)
Ee (%) (Config)i
1
2
3
EtOH
DCM
DCM
DCM
ClCH2CH2Cl
CHCl3
ClCH2CH2Cl
Toluene
i-PrOH
t-BuOH
t-AmOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
71
75
76
70
70
75
74
76
80
70
99
99
90
95
67
90 (R)
90 (R)
86 (R)
60 (R)
66 (R)
90 (R)
90 (R)
88 (R)
90 (R)
84 (R)
0
i-PrOH
t-BuOH
EtOH
4b
5b
6
EtOH
i-PrOH
i-PrOH
i-PrOH
t-BuOH
t-AmOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
7
8
9
10
11c
12d
13e
14f
15g
0
12 (R)
64 (R)
90 (R)
a
Ligand 1b (0.01 mmol), the base and Cu(OTf)2 were added consecutively to 0.5 mL of solvent A and stirred overnight at 25 °C. Next, solvent A was removed under reduced
pressure. The reaction was carried out using 0.1 mmol of 4-nitrobenzaldehyde in 0.5 mL of solvent B and 0.3 mL of CH3NO2 at 25 °C for 48 h. If solvent A and B were identical
solvents, it was unnecessary to remove solvent A or to add solvent B.
b
Solvent A was removed completely.
c
Cu(OAc)2ꢁH2O was used instead of Cu(OTf)2.
d
Triethylamine was added.
e
NaOAc was added.
The reaction was run at 40 °C.
The reaction was run at 10 °C.
Isolated yield.
f
g
h
i
Enantiomeric excesses were determined by chiral HPLC analysis (Chiralpak IA column).

F. He et al. / Tetrahedron: Asymmetry 23 (2012) 809–817
813
Table 2
Screening of ligandsa
OH
*
CHO
NO2
10 mol% Cu complex
t-BuOH/ CH3NO2
25ºC, 48 h
O2N
O2N
11a
Entries
Ligands
Yieldb (%)
Ee (%) (Config)c
1
2
3
4
5
6
7
8
1a
1b
1b0
1c
1d
1d0
1e
1e0
1f
1f0
1g
68
80
32
78
76
30
85
40
75
35
78
64 (R)
90 (R)
54 (S)
86 (R)
74 (R)
26 (S)
92 (R)
56 (S)
74 (R)
24 (S)
87 (R)
9
10
11
a
The complex was formed in 0.5 mL of t-BuOH and the reaction was carried out using 0.1 mmol of 4-nitrobenzaldehyde and 0.3 mL
of CH3NO2 at 25 °C for 48 h.
b
Isolated yield.
c
Enantiomeric excesses were determined by chiral HPLC analysis (Chiralpak IA column).
5). However, if solvent A was not removed completely, the results
when using different solvents B were almost the same (Table 1,
entries 1–3, 6–7). So, it is sensible to use alcohols as the only
solvent for the whole reaction to make the operation convenient.
Next, different alcoholic solvents were screened; it turned out that
tert-butyl alcohol was the optimal solvent (Table 1, entries 8–10).
In addition to Cu(OTf)2, Cu(OAc)2ꢁH2O was also tested under these
conditions. Although the reaction proceeded completely in 1 h
with good yield, the product was a racemic mixture (Table 1, entry
11). The concurrent activation of the aldehyde and nitromethane in
the Henry reaction, combining the use of discrete Lewis acids and
Brønsted bases has some precedent in the literature.19 However,
the use of different bases as additives in our reaction system gave
poor ee values (Table 1, entries 12 and 13). Additionally, reaction
temperature has a great influence on the reaction rates, yields
and ee values. When the reaction was carried out at 40 °C, the rate
of the reaction was enhanced with decreased selectivity (Table 1,
entry 14). When the reaction was carried out at 10 °C, the ee value
was enhanced, but with a corresponding lower yield (Table 1, entry
15). As a result, room temperature was the optimized temperature
for our reaction system.
Using the optimized reaction conditions, we next screened the
ligands 1a–g to evaluate their catalytic performance and the sub-
stituent effects of diverse substituents at the 13-position of the
[2.2]paracyclophane (Table 2). As can be seen from Table 2, ligands
(Sp,S)-1b, (Sp,S)-1d, (Sp,S)-1e, and (Sp,S)-1f showed the positive
cooperative effect of planar and central chirality; however, their
diastereoisomers (Rp,S)-1b0, (Rp,S)-1d0, (Rp,S)-1e0, and (Rp,S)-1f0
were mismatched. Furthermore, it can be concluded that the
(Sp,S)-configured Schiff-base ligands are more selective than their
counterparts. It was clear that the iodide (Sp,S)-1e was the best li-
gand in terms of stereoselectivity under the present reaction con-
ditions. Meanwhile, the enantioselectivity increased from 64% to
92% as the size of the 13-position substituent was increased fol-
lowing the sequence H < F = MeO < Br < I. However, when the
hydrogen atom at the 13-position was replaced by a 3-methoxy-
phenyl or 2,3-dimethoxyphenyl, the enantioselectivities slightly
decreased. These results suggested that the steric properties of
the substituent at the 13-position of the [2.2]paracyclophane had
a significant influence on the reaction enantioselectivity and it is
very sensitive toward modifications.
In order to explore the substrate scope, different types of alde-
hydes were used as substrates by using 1e as the ligand for the Cu-
catalyzed asymmetric Henry reaction. The results are presented in
Table 3. We found that the electronic properties of the substituents
at the aromatic ring had a great effect on the reaction rate and
enantioselectivity. The substrates with an electron-withdrawing
substituent afforded faster reactions leading to higher enantiose-
lectivity. However, substrates with halogenic substituents had
lower reaction rates and enantioselectivities (Table 3, entries 1–8).
The benzaldehyde and other aromatic aldehydes without a sub-
stituent reacted smoothly with nitromethane under the optimized
conditions, giving the nitroaldol adducts in moderate yields and
enantioselectivities (Table 3, entries 9–12). However, aromatic
Table 3
Asymmetric Henry reaction of various aldehydes catalyzed by Cu-1e complexa
OH
10 mol% Cu-1e complex
R
CHO
NO2
R
*
11
t-BuOH/ CH3NO2
25ºC
Entries
R
Product
Time (h)
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
8
4-NO2Ph
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
48
48
48
48
48
96
72
96
72
85
87
80
80
85
50
65
60
63
60
35
34
Trace
Trace
92 (R)
96 (R)
84 (R)
94 (R)
88 (—)
72 (R)
76 (R)
80 (R)
80 (R)
58 (R)
66 (R)
46 (R)
—
2-NO2Ph
3-NO2Ph
4-COOMePh
4-CHOPh
4-BrPh
2,4-Cl2Ph
2-ClPh
1-Naphthyl
2-Naphthyl
Ph
9
10
11
12
13
14
72
120
120
120
120
2-Furfuryl
PhCH2
2-CH3OPh
—
a
The complex was formed in 0.5 mL of t-BuOH and the reaction was carried out
using 0.1 mmol of aldehyde and 0.3 mL of CH3NO2 at 25 °C.
b
Isolated yield.
c
Enantiomeric excesses were determined by chiral HPLC analysis (Chiralpak IA
column).

814
F. He et al. / Tetrahedron: Asymmetry 23 (2012) 809–817
aldehydes with electron-donating groups provided very little reac-
tivity and stereoselectivity (Table 3, entries 13 and 14).
2.80–3.11 (m, 3H), 3.46–3.58 (m, 1H), 3.61–3.71 (m, 3H), 4.04–
4.17 (m, 2H), 6.22–6.25 (d, J = 7.5 Hz, 1H), 6.42–6.54 (m, 3H),
6.86–6.87 (d, J = 1.5 Hz, 1H), 16.00 (s, 1H); 13C NMR (75 MHz,
CDCl3, rt) d 20.5, 27.2, 29.8, 33.5, 33.8, 34.4, 37.7, 63.5, 69.3,
122.0, 122.1, 125.8, 129.1, 131.0, 133.8, 134.4, 135.3, 138.7,
139.5, 140.5, 163.9, 171.8, HRMS: calcd for (M+H)+ C24H31BrNO2:
444.1538, found: 444.1549.
3. Conclusion
In conclusion, several novel planar chiral Schiff-base ligands
based on the [2.2]paracyclophane scaffold were synthesized and
the diastereoisomers were separated successfully. All configura-
tions of the diastereomeric Schiff-base ligands based on [2.2]para-
cyclophane were established by solving the X-ray structure or by
using CD spectra. These new planar chiral [2.2]paracyclophane
Schiff bases were used as ligands in the Cu-catalyzed asymmetric
Henry reaction. The substituent on the 13-position of the
[2.2]paracyclophane had a strong influence on the catalytic perfor-
mance. The best results were obtained with the iodide (Sp,S)-1e,
which was bigger than the other heteroatoms. However, using a
bulkier group such as 3-methoxyphenyl or 2,3-dimethoxyphenyl
at the 13-position of the [2.2]paracyclophane did not cause any
further improvement. Further modification of these ligands as well
as applications in asymmetric catalysis is in progress.
4.3. Synthesis of phenols 5, 8, 9
4.3.1. 4-Bromo-13-fluoro-[2.2]paracyclophane 4
Compound ( )-2 (1.0 g, 3.3 mmol) was added to a stirred solu-
tion of 40% HBF4 (1.5 mL) in ethanol (2.5 mL). The mixture was
purged with nitrogen and then heated to 80 °C, under nitrogen
bubbling, until a clear solution was obtained. After 10 min, the
solution was cooled to ꢀ5 °C, and then isoamyl nitrite was added
dropwise. The temperature was kept at ꢀ5 °C, and stirring was
continued for another 1 h. Diethyl ether (4.0 mL) was added in
one portion, and then the resulting precipitate was filtered, washed
with diethyl ether (2.0 mL), and finally dried under vacuum to ob-
tain 1.18 g of diazonium fluoroborate, which was used without
purification. A solution of diazonium fluoroborate (1.18 g) in tolu-
ene (30 mL) was gently heated to 60–80 °C until nitrogen no longer
evolved. The solvent was evaporated at reduced pressure and the
residue was purified by chromatography on silica gel (petroleum
ether as the eluent). Recrystallization of the product from ethanol
gave ( )-4 (0.35 g, 35%): mp 168–170 °C; 1H NMR (300 MHz, CDCl3,
rt) d 2.74–2.84 (m, 1H), 2.89–3,14 (m, 5H), 3.55–3.71 (m, 2H),
6.12–6.17 (dd, J = 11.4 Hz, 1.5 Hz, 1H), 6.39–6.54 (m, 4H), 6.76 (d,
4. Experimental section
4.1. General methods
Aldehydes were obtained from commercial sources and were
distilled or filtered through a plug of silica gel prior to use. Other
commercially available reagents were used without further purifi-
cation. The solvents were purified by standard techniques. The
reactions were magnetically stirred and monitored by thin layer
chromatography (TLC). Purification of the reaction products was
carried out by chromatography on silica gel (200–400 mesh). Melt-
ing points were recorded on a melting point apparatus and are
uncorrected. Optical rotations were taken on a polarimeter with
a wavelength of 589 nm. 1H and 13C spectra were recorded in CDCl3
on a Bruker AVANCE-300 spectrometer at 298 K. Chemical shifts
are reported in parts per million (ppm) downfield from tetrameth-
ylsilane (TMS) with reference to the internal solvent for 1H NMR
and 13C NMR spectra. Mass spectra were recorded on an Agilent
100 ABIAPI14000 spectrometer. The concentration ‘c’ had units of
g/100 mL (or 10 mg/mL). CD spectra were collected on a JASCO
J-810 Circular Dichroism Spectrometer. Enantiomeric excess was
determined using HPLC on a Chiralpak IA chiral column.
J = 1.8 Hz, 1H); 13C NMR (75 MHz, CDCl3, rt)
d 27.4 (d,
J = 2.25 Hz), 34.2, 34.3, 34.4 (d, J = 1.5 Hz), 120.2 (d, J = 23.25 Hz),
123.4, 124.7 (d, J = 17.25 Hz), 131.6, 134.7, 134.8 (d, J = 7.5 Hz),
135.8, 140.4, 141.7 (d, J = 6.75 Hz), 166.2 (d, J = 246.75 Hz); HRMS:
calcd for (M+H)+ C16H15BrF: 305.0341, found: cannot be ionized by
ESI.
4.3.2. 4-Fluoro-13-hydroxy-[2.2]paracyclophane 5
At first, n-BuLi (2.5 M solution in n-hexane, 0.29 mL,
0.721 mmol) was added dropwise to a solution of bromide ( )-3
(0.1 g, 0.328 mmol) in THF (2.0 mL) at ꢀ78 °C to give an orange
solution. After stirring for 1 h, B(OBu)3 (0.195 mL, 0.721 mmol)
was added dropwise. The solution was allowed to warm to room
temperature and stirred for 21 h. An aqueous NaOH solution
(5.0 M, 1.0 mL, 5.0 mmol) followed by an aqueous H2O2 solution
(30% w/v, 1.0 mL, 8.93 mmol) were added and the mixture was
stirred for 1 h. A saturated NH4Cl solution (5.0 mL) was then added
and the mixture was shaken vigorously. The aqueous layer was
separated and extracted twice with DCM (5.0 mL). The combined
organic layer was dried over Na2SO4 and concentrated in vacuo
to give the crude product, which was purified by column chroma-
tography (DCM/petroleum ether = 1/1) to give ( )-5 as a white so-
lid; yield: 0.07 g (88%); mp 192–194 °C; 1H NMR (300 MHz, CDCl3,
rt) d 2.70–2.84 (m, 2H), 2.91–3.05 (m, 4H), 3.45–3.62 (m, 2H), 4.58
(br 1H), 5.86–5.87 (d, J = 1.5 Hz, 1H), 6.18–6.24 (m, 2H), 6.35–6.45
(m, 3H); 13C NMR (75 MHz, CDCl3, rt) d 27.5 (d, J = 2.25 Hz), 30.0,
34.9, 35.0, 120.3, 120.6, 121.8, 125.2125.5, 126.0, 129.1 (d
J = 3.0 Hz), 135.4 (d, J = 5.25 Hz), 141.4, 142.0 (d, J = 7.5 Hz),
154.5, 162.5 (d, J = 243.8 Hz); HRMS: calcd for (M+H)+ C16H16OF:
243.1185, found: 243.1191.
4.2. Resolution of 1b and 1b0
The diastereomeric mixtures of 1b and 1b0 were prepared as our
previous procedure;11 racemic 2 was used in place of enantiopure
materials 2. The diastereoisomers were subjected to column chro-
matography on silica gel (CH2Cl2 to CH2Cl2/ethyl acetate = 9/1).
Analytically pure samples were obtained by additional crystalliza-
tion from acetone/hexane (1/10). Compound 1b (48%), orange so-
lid, mp: 204–206 °C; Rf 0.30 (CH2Cl2/ethyl acetate = 10/1);
½
a 2D0
ꢂ
¼ þ817:8 (c 0.20, CH2Cl2); 1H NMR (300 MHz, CDCl3, rt) d
1.17 (s, 9H), 1.80–2.00 (br, 1H), 2.38 (s, 3H), 2.47–2.67 (m, 2H),
2.84–2.97 (m, 2H), 3.06–3.15 (m, 1H), 3.39–3.48 (m, 1H), 3.64–
3.78 (m, 4H), 3.91–3.97 (m, 1H), 6.14–6.17 (d, J = 7.5 Hz, 1H),
6.45–6.49 (d, J = 7.5 Hz, 1H), 6.52–6.61 (m, 2H), 6.70 (s, 1H),
16.03 (s, 1H); 13C NMR (75 MHz, CDCl3, rt) d 20.5, 27.2, 28.1,
34.2, 34.6, 35.2, 37.9, 63.6, 69.0, 121.0, 122.3, 126.0, 129.4, 131.2,
134.3, 134.5, 136.2, 139.4, 139.5, 140.5, 166.0, 172.1, HRMS: calcd
for (M+H)+ C24H31BrNO2: 444.1538, found: 444.1529; 1b0 (48%),
yellow solid, mp: 216–218 °C; Rf 0.50 (CH2Cl2/ethyl acetate = 10/
4.3.3. 4-Iodo-13-methoxy-[2.2]paracyclophane 7
At first, n-BuLi (2.5 M solution in n-hexane, 0.5 mL, 1.25 mmol)
was added dropwise to a solution of ( )-6 (0.2 g, 0.63 mmol) in THF
(3.0 mL) at ꢀ78 °C to give an orange solution. After stirring for 1 h,
iodine (0.32 g, 1.26 mmol) in THF (2.0 mL) was added dropwise.
1); ½a 2D0
ꢂ
¼ ꢀ15:5 (c 0.20, CH2Cl2); 1H NMR (300 MHz, CDCl3, rt) d
1.04 (s, 9H), 1.70–1.80 (br, 1H), 2.36 (s, 3H), 2.56–2.69 (m, 2H),

F. He et al. / Tetrahedron: Asymmetry 23 (2012) 809–817
815
The solution was allowed to warm to room temperature and stir-
red for 2.5 h. An aqueous Na2S2O3 solution (1.0 M, 1.0 mL,
1.0 mmol) was added and the mixture was stirred for 0.5 h. The
aqueous layer was separated and extracted twice with DCM
(5 mL). The combined organic layer was dried over Na2SO4 and
concentrated in vacuo to give the crude product, which was puri-
fied by column chromatography (DCM/petroleum ether = 1/3) to
give ( )-7 as a white solid; yield: 0.2 g (87%); mp 167–168 °C; 1H
NMR (300 MHz, CDCl3, rt) d 2.66–2.75 (m, 1H), 2.82–2.91 (m,
1H), 2.94–3.13 (m, 4H), 3.38–3.47 (m, 1H), 3.53–3.62 (m, 1H),
3.73 (s, 3H), 5.76–5.77 (d, J = 1.2 Hz, 1H), 6.27–6.30 (dd,
J = 7.5 Hz, J = 1.5 Hz, 1H), 6.33–6.35 (d, J = 7.8 Hz 1H), 6.46–6.50
(m, 2H), 6.92–6.93 (d, J = 2.1 Hz,1H); 13C NMR (75 MHz, CDCl3, rt)
d 29.6, 34.1, 34.6, 37.9, 54.7, 96.8, 114.5, 123.9, 126.2, 132.6,
133.7, 134.0, 139.7, 140.9, 141.0, 142.2, 158.2; HRMS: calcd for
(M+H)+ C17H18OI: 365.0402, found: 365.0394.
NMR (300 MHz, CDCl3, rt) d 2.59 (s, 3H), 2.63–2.83 (m, 3H), 2.96–
3.06 (m, 1H), 3.14–3.22 (m, 1H), 3.55–3.70 (m, 3H), 6.11–6.14 (d,
J = 11.4 Hz, 1H), 6.26–6.29 (d, J = 7.8 Hz, 1H), 6.41–6.50 (m, 2H),
6.57–6.60 (d, J = 7.8 Hz, 1H), 12.82 (s, 1H); 13C NMR (75 MHz,
CDCl3, rt) d 27.6 (d, J = 2.25 Hz), 28.9, 31.0, 35.3 (d, J = 0.75 Hz),
37.6, 120.0 (d, J = 24 Hz), 122.4, 125.9 (d, J = 17.25 Hz), 127.7,
128.4 (d, J = 3 Hz), 129.1, 134.9 (d, J = 5.25 Hz), 139.5, 140.8 (d,
J = 7.5 Hz), 141.8, 162.8, 163.5 (d, J = 246 Hz), 204.1; HRMS: calcd
for (M+H)+ C18H18FO2: 285.1291, found: 285.1285.
4.4.2. 5-Acetyl-4-hydroxy-13-iodo-[2.2]paracyclophane 10c
Treatment of ( )-8 (128 mg, 0.366 mmol) according to the pro-
cedure for the synthesis of ( )-10c gave the title compound as yel-
low solid; yield: 103 mg (72%); mp 194–196 °C; 1H NMR (300 MHz,
CDCl3, rt) d 2.55 (m, 5H), 2.90–3.24 (m, 3H), 3.50–3.73 (m, 3H),
6.31–6.33 (d, J = 7.5 Hz, 1H), 6.39–6.42 (d, J = 7.5 Hz, 1H), 6.56–
6.59 (d, J = 7.5 Hz, 1H), 6.63–6.65 (d, J = 7.5 Hz, 1H), 6.93 (s, 1H),
12.9 (s, 1H); 13C NMR (75 MHz, CDCl3, rt) d 28.8, 30.9, 34.8, 37.4,
38.2, 96.5, 122.0, 127.4, 129.0, 132.2, 133.6, 138.9, 139.0, 141.4,
141.8, 143.1, 163.4, 204.1; HRMS: calcd for (M+H)+ C18H18IO2:
393.0351, found: 393.0348.
4.3.4. 13-Hydroxy-4-iodo-[2.2]paracyclophane 8
A solution of BBr3 in dry CH2Cl2 (5.0 mL of a solution containing
1.5 mL BBr3 in 50 mL CH2Cl2) was added to a solution of ( )-7
(0.25 g, 0.69 mmol) in dry CH2Cl2 (3.0 mL) at ꢀ78 °C. After 1 h,
the solution was allowed to warm to room temperature and stirred
for 20 h. Water (5.0 mL) was added and the mixture was stirred for
0.5 h. The aqueous layer was separated and extracted twice with
DCM (5.0 mL). The combined organic layer was dried over Na2SO4
and concentrated in vacuo to give the crude product, which was
purified by column chromatography (DCM/petroleum ether = 1/1)
to give ( )-8 as a white solid; yield: 0.148 g (77%); mp 201–202 °C
(dec); 1H NMR (300 MHz, CDCl3, rt) d 2.73–2.80 (t, J = 10.2 Hz, 1H),
2.89–3.18 (m, 5H), 3.47–3.57 (m, 2H), 4.54 (br, 1H), 5.77 (s, 1H),
6.27–6.29 (d, J = 7.5 Hz, 1H), 6.36–6.39 (d, J = 7.5 Hz, 1H), 6.47–
6.49 (m, 2H), 7.06–7.07(d, J = 1.5 Hz, 1H); 13C NMR (75 MHz, CDCl3,
rt) d 30.3, 34.5, 34.6, 38.2, 97.1, 121.4, 125.0, 125.4, 133.4, 134.3,
135.0, 140.6, 141.5, 141.8, 142.6, 155.7; HRMS: calcd for (M+H)+
C16H16IO: 351.0246, found: 351.0271.
4.4.3. 5-Acetyl-4-hydroxy-13-methoxy[2.2]paracyclophane 10d
At first, TiCl4 (0.9 mmol, 0.9 mL of
a 1.0 M solution in
ClCH2CH2Cl) was added to 2.0 mL of dry ClCH2CH2Cl under nitro-
gen and then heated to 80 °C. Next, a mixture of ( )-9 (120 mg,
0.472 mmol) and acetyl chloride (40 mg, 0.5 mmol) in ClCH2CH2Cl
(2.0 mL) was added dropwise to a solution and the resulting mix-
ture was stirred for 1 h at 80 °C. The reaction was quenched with
ice water and the reaction mixture was stirred for an additional
15 min. The phases were separated and the organic layer was
washed twice with water and brine, and dried over MgSO4. After
removal of the solvent under reduced pressure, the residue was
purified by column chromatography on silica gel (petroleum
ether/CH2Cl2 = 1:1) to yield ( )-10d 110 mg as a yellow solid. Yield:
79%; mp 124–126 °C; 1H NMR (300 MHz, CDCl3, rt) d 2.62 (s, 3H),
2.64–2.75 (m, 3H), 2.93–3.04 (m, 1H), 3.17–3.24 (t, 1H), 3.59–
3.70 (m, 6H), 5.78 (s, 1H), 6.22–6.25 (d, J = 7.5 Hz, 1H), 6.29–6.32
(d, J = 7.8 Hz, 1H), 6.46–6.48 (d, J = 7.8 Hz, 1H), 6.55–6.58 (d,
J = 7.5 Hz, 1H), 12.94 (s, 1H); 13C NMR (75 MHz, CDCl3, rt) d 27.6,
29.9, 31.1, 36.1, 38.1, 54.4, 114.9, 121.8, 124.4, 127.6, 128.2,
129.2, 134.3, 139.8, 140.1, 141.8, 158.0, 162.8, 204.1; HRMS: calcd
for (M+H)+ C19H21O3: 297.1491, found: 297.1487.
4.3.5. 13-Hydroxy-4-methoxy-[2.2]paracyclophane 9
Treatment of bromide ( )-6 (0.45 g, 1.42 mmol) according to
the procedure for the synthesis of ( )-5 gave the title compound
( )-9 as a pale yellow solid; yield: 0.29 g (80%); mp 138–140 °C;
1H NMR (300 MHz, CDCl3, rt) d 2.68–2.88 (m, 2H), 2.94–3.10 (m,
4H), 3.27–3.37 (m, 1H), 3.52–3.61 (m, 1H), 3.75 (s, 3H), 4.60–
4.62 (m, 1H), 5.96–5.99 (m, 2H), 6.16–6.20 (dd, J = 7.8 Hz,
J = 1.8 Hz, 1H), 6.23–6.27 (dd, J = 7.5 Hz, J = 1.5 Hz, 1H), 6.32–6.35
(d, J = 7.8 Hz, 1H), 6.41–6.44 (d, J = 7.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3, rt) d 28.5, 29.8, 35.1, 35.5, 55.4, 116.7, 122.1,
125.1, 125.8, 126.7, 127.0, 134.9, 135.1, 141.3, 141.6, 154.5,
154.8; HRMS: calcd for (M+H)+ C17H19O2: 255.1385, found:
255.1379.
4.5. Synthesis and resolution of Schiff-base ligands
General Method: racemic 10b–d (0.5 mmol) was separately dis-
solved in 5.0 mL of toluene, and the amino alcohol (0.55 mmol)
was added. The reaction solution was refluxed in an apparatus
equipped with a Dean–Stark trap filled with anhydrous MgSO4
for 48 h. After removal of the solvent under reduced pressure,
the residue was purified by column chromatography on silica gel
(CH2Cl2 to CH2Cl2/ethyl acetate = 9/1) to yield the desired ligand.
Analytically pure samples were obtained by additional crystalliza-
tion from acetone/hexane (1/10).
4.4. Synthesis of compounds 10
4.4.1. 5-Acetyl-13-fluoro-4-hydroxy-[2.2]paracyclophane 10b
Compound ( )-5 (77 mg, 0.318 mmol) was added to 1.0 mL of
dry CH2Cl2 under nitrogen and then cooled to 0 °C. Next, TiCl4
(0.6 mmol, 0.6 mL of a 1.0 M solution in CH2Cl2) was added to
the suspension and the resulting mixture was stirred for 10 min
at 0 °C. Acetyl chloride (28 mg, 0.35 mmol) was added at 0 °C with
a syringe, and the solution was stirred for an additional 3 h at room
temperature. The reaction was quenched with ice water and the
reaction mixture was stirred for an additional 15 min. The phases
were separated and the organic layer was washed twice with water
and brine, and dried over MgSO4. After removal of the solvent un-
der reduced pressure, the residue was purified by column chroma-
tography on silica gel (petroleum ether/CH2Cl2 = 1:1) to yield ( )-
10b 89 mg as a yellow solid. Yield: 98%; mp 118–120 °C; 1H
4.5.1. (Sp,S)-5-(1-(1-Hydroxy-3,3-dimethylbutan-2-ylimino)ethyl)-
4-hydroxy-13-fluoro-[2.2]paracyclophane 1d
Orange solid. Yield: 45%; mp: 156–158 °C ½a D20
¼ þ655:0 (c 0.1,
ꢂ
CH2Cl2); 1H NMR (300 MHz, CDCl3, rt) d 2.39 (s, 9H), 2.55 (s, 3H),
2.58–2.64 (m, 1H), 2.70–2.82 (m, 3H), 3.00–3.07 (m, 2H), 3.25–
3.32 (t, J = 10.2 Hz, 1H), 3.57–3.76 (m, 4H), 3.92–3.95 (d,
J = 8.4 Hz, 1H), 6.16–6.20 (m, 2H), 6.43–6.55 (m, 3H), 15.41 (br,
1H); 13C NMR (75 MHz, CDCl3, rt)
d 20.5, 26.5, 26.9 (d,
J = 2.25 Hz), 29.3, 33.6, 34.9, 36.9, 62.6, 68.5, 118.5 (d, J = 24 Hz),
121.7, 125.4, 125.6 (d, J = 3.75 Hz), 128.0 (d, J = 3 Hz), 129.0, 134.0

816
F. He et al. / Tetrahedron: Asymmetry 23 (2012) 809–817
(d, J = 5.25 Hz), 136.4, 140.0, 140.2 (d, J = 6.75 Hz), 162.0 (d,
J = 245 Hz), 164.0, 172.4 (d, J = 4.5 Hz); HRMS: calcd for (M+H)+
C24H31FNO2: 384.2339, found: 384.2332.
6.37–6.44 (m, 2H), 15.85–15.86 (d, J = 2.1 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6, rt) d 21.6, 27.5, 27.6, 31.1, 34.2, 36.0, 39.2,
54.5, 62.7, 69.5, 114.4, 122.0, 124.9, 127.1, 127.3, 128.6, 134.7,
136.1, 141.4, 141.5, 158.4, 164.0, 172.1; HRMS: calcd for (M+H)+
C25H34NO3: 396.2539, found: 396.2542.
4.5.2. (Rp,S)-5-(1-(1-Hydroxy-3,3-dimethylbutan-2-ylimino)ethyl)-
4-hydroxy-13-fluoro-[2.2]paracyclophane 1d0
Yellow solid. Yield: 47%; mp: 164–166 °C ½a D20
ꢂ
¼ ꢀ280 (c 0.1,
4.5.7. (Rp,S)-5-(1-(1-Hydroxy-3,3-dimethylbutan-2-ylimino)ethyl)-
4-hydroxy-13-(2,3-dimethoxyphenyl)-[2.2]paracyclophane 1g
A mixture of 1e (100 mg, 0.20 mmol), 2,3-dimethoxylphenylbo-
ronic acid (55.5 mg, 0.30 mmol), KF (35.2 mg, 0.60 mmol), and Pd-
DPPF (1.6 mg, 2 ꢃ 10ꢀ3 mmol) in 1,4-dioxane (1 mL) was stirred
at 90 °C under nitrogen. After 48 h, the reaction mixture was cooled
to room temperature and 2 mL of water were added. The precipita-
tion was filtered and the filtered solution was extracted with CH2Cl2
(3 ꢃ 2.0 mL). The organic phase was washed twice with water and
brine, and dried over MgSO4. After removal of the solvent under re-
duced pressure, the residue was combined with the precipitation
and purified by chromatography on silica gel (CH2Cl2 to CH2Cl2/
ethyl acetate = 9/1) to yield 1g as an orange solid. Yield: 80%; mp:
CH2Cl2); 1H NMR (300 MHz, DMSO-d6, rt) d 0.97 (s, 9H), 2.30 (s,
3H), 2.55–2.58 (d, J = 8.4 Hz, 1H), 2.59–2.75 (m, 2H), 2.78–2.86
(m, 1H), 2.95–3.03 (m, 1H), 3.34 (s, 1H), 3.37 (s, 1H), 3.40–3.49
(m, 1H), 3.51–3.64 (m, 2H), 3.99–4.03 (m, 1H), 4.81–4.84 (m,
1H), 6.18–6.21 (d, J = 7.5 Hz, 1H), 6.36–6.45 (m, 2H), 6.46–6.49
(d, J = 7.5 Hz, 1H), 6.56–6.60 (d, J = 12 Hz, 1H), 15.84–15.85 (d,
J = 1.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6, rt) d 21.5, 27.5, 27.6,
30.2, 34.0, 34.8, 38.4, 62.9, 69.8, 118.8 (d, J = 24 Hz), 123.1, 125.4,
125.3 (d, J = 17.25 Hz), 126.8, 128.9, 129.0 (d, J = 2.25 Hz),
135.5(d, J = 5.25 Hz), 135.8, 141.3, 142.0 (d, J = 7.5 Hz), 162.2 (d,
J = 243 Hz), 163.5, 172.1; HRMS: calcd for (M+H)+ C24H31FNO2:
384.2339, found: 384.2334.
86–88 °C ½a 2D0
ꢂ
¼ þ434:1 (c 0.1, CH2Cl2); 1H NMR (300 MHz, CDCl3,
4.5.3. (Sp,S)-5-(1-(1-Hydroxy-3,3-dimethylbutan-2-ylimino)ethyl)-
rt) d 1.08 (s, 9H), 1.98 (br, 1H), 2.42 (s, 3H), 2.48–2.61 (m, 2H),
2.86–3.10 (s, 3H), 3.22–3.34 (m, 3H), 3.41–3.48 (m, 1H), 3.59–
3.68 (m, 2H), 3.85 (s, 3H), 3.90 (s, 1H), 6.25–6.27 (d, J = 7.5 Hz,
1H), 6.50 (s, 1H), 6.54–6.56 (d, J = 7.5 Hz, 1H), 6.65–6.73 (m, 2H),
6.87–6.90 (d, J = 8.1 Hz, 1H), 7.06–7.11 (t, 1H), 7.70–7.73 (d,
J = 7.8 Hz, 1H), 15.63 (br, 1H); 13C NMR (75 MHz, CDCl3, rt) d 19.8,
26.6, 27.8, 33.4, 33.5, 35.5, 38.2, 54.5, 59.5, 62.9, 67.9, 110.9,
119.0, 122.7, 123.8, 125.7, 129.7, 130.4, 131.1, 132.6, 133.8, 134.6,
135.8, 136.2, 139.2, 140.8, 145.9, 152.0, 167.2, 171.4; HRMS: calcd
for (M+H)+ C32H40NO4: 502.2957, found: 502.2953.
4-hydroxy-13-iodo-[2.2]paracyclophane 1e
Orange solid. Yield: 46%; mp: 202–204 °C ½a D20
¼ þ756:0 (c 0.1,
ꢂ
CH2Cl2); 1H NMR (300 MHz, CDCl3, rt) d 1.15 (s, 9H), 2.43, (s, 3H),
2.48–2.54 (m, 1H), 2.61–2.69 (t, J = 12.6 Hz, 1H), 2.92–3.13 (m,
4H), 3.34–3.42 (t, J = 13.2 Hz, 1H), 3.53–3.72 (m, 4H), 3.87–3.92
(dd, J = 10.8 Hz, 2.4 Hz, 1H), 6.17–6.21 (m, 1H), 6.50 (s, 1H), 6.52
(s, 1H), 6.62–6.64 (d, J = 6.6 Hz, 1H), 6.89 (d, J = 1.5 Hz, 1H), 15.37
(br, 1H); 13C NMR (75 MHz, CDCl3, rt) d 19.9, 26.8, 27.2, 33.7,
34.5, 37.5, 38.5, 62.7, 68.3, 95.3, 119.8, 125.4, 129.2, 131.3, 132.5,
136.0, 138.7, 140.0, 140.3, 142.8, 166.8, 171.9; HRMS: calcd for
(M+H)+ C24H31INO2: 492.1399, found: 492.1392.
4.6. General procedure for the enantioselective Henry reaction
4.5.4. (Rp,S)-5-(1-(1-Hydroxy-3,3-dimethylbutan-2-ylimino)ethyl)-
Ligand 1e (0.01 mmol), t-BuOK (0.018 mmol, 0.4 M t-BuOH
solution), and Cu(OTf)2 (0.01 mmol, 0.1 M t-BuOH solution) were
added consecutively to 1.0 mL of t-BuOH and stirred overnight at
25 °C. Then 0.3 mL of CH3NO2 were added to the green solution.
The dark green solution was stirred for 20 min and the freshly puri-
fied aldehyde (0.1 mmol) was added. The reaction tube was
charged with nitrogen and sealed. The reaction was performed
for the indicated time and then the solvent was evaporated. The
residue was purified by column chromatography on silica gel
(CH2Cl2) to afford the desired nitroaldol product.
Enantiomeric excess was determined using HPLC on Chiralpak
IA chiral column (flow rate: 0.5 mL/min, k = 254 nm). Absolute
configurations were determined by comparison of the rotation val-
ues with literature values.4f,l Original HPLC and rotation data are
listed below.
4-hydroxy-13-iodo-[2.2]paracyclophane 1e0
Yellow solid. Yield: 47%; mp: 204–206 °C ½a D20
¼ ꢀ431:8 (c 0.1,
ꢂ
CH2Cl2); 1H NMR (300 MHz, CDCl3, rt) d 1.05 (s, 9H), 2.37, (s, 3H),
2.53–2.66 (m, 2H), 2.79–2.89 (m, 1H), 3.02–3.11 (m, 2H), 3.45–
3.73 (m, 4H), 4.14–4.23 (m, 1H), 6.23–6.25 (d, J = 7.5 Hz, 1H),
6.39–6.41 (d, J = 7.8 Hz, 1H) 6.50–6.56 (m, 2H), 7.06 (d, J = 1.5 Hz,
1H), 15.89 (br, 1H); 13C NMR (75 MHz, CDCl3, rt) d 20.9, 27.8,
30.0, 34.0, 34.7, 38.2, 38.6, 63.9, 69.8, 96.5, 122.3, 126.3, 129.6,
132.1, 133.6, 135.7, 139.7, 140.4, 141.1, 143.0, 164.7, 172.3; HRMS:
calcd for (M+H)+ C24H31INO2: 492.1399, found: 492.1396.
4.5.5. (Sp,S)-5-(1-(1-Hydroxy-3,3-dimethylbutan-2-ylimino)ethyl)-
4-hydroxy-13-methoxy-[2.2]paracyclophane 1f
Orange solid. Yield: 44%; mp: 68–70 °C ½a D20
¼ þ964:0 (c 0.1,
ꢂ
CH2Cl2); 1H NMR (300 MHz, DMSO-d6, rt) d 1.08 (s, 9H), 2.31 (s,
3H), 2.53–2.60 (m, 2H), 2.83–3.04 (m, 2H), 3.28–3.48 (m, 5H),
3.55–3.59 (m, 1H), 3.61 (s, 3H), 3.78–3.84 (m, 1H), 4.53–4.57 (m,
1H), 5.75–5.76 (d, J = 1.2 Hz, 1H), 6.01–6.03 (d, J = 7.5 Hz, 1H),
6.32 (s, 1H), 6.35 (s, 1H), 6.52–6.55 (d, J = 7.5 Hz, 1H), 15.18–
15.19 (d, J = 2.7 Hz, 1H); 13C NMR (75 MHz, DMSO-d6, rt) d 20.7,
26.1, 26.7, 30.9, 33.2, 35.7, 37.4, 54.4, 62.1, 68.5, 114.6, 120.6,
124.2, 126.0, 127.0, 127.5, 133.6, 135.8, 139.9, 140.3, 157.5,
164.1, 170.4; HRMS: calcd for (M+H)+ C25H34NO3: 396.2539, found:
396.2544.
4.6.1. (R)-(ꢀ)-1-(4-Nitrophenyl)-2-nitroethanol 11a
Off-white solid, n-hexane/i-PrOH, 4:1, tmajor = 26.1 min, tminor
=
34.4 min; ½a 2D0
¼ ꢀ31:5 (c 0.24, CH2Cl2) 92% ee.
ꢂ
4.6.2. (R)-(+)-1-(2-Nitrophenyl)-2-nitroethanol 11b
Brown solid, n-hexane/i-PrOH, 6:1, tminor = 22.8 min, tmajor
=
=
24.8 min; ½a 2D0
¼ þ225:3 (c 0.25, CH2Cl2) 96% ee.
ꢂ
4.6.3. (R)-(ꢀ)-1-(3-Nitrophenyl)-2-nitroethanol 11c
Off-white solid, n-hexane/i-PrOH, 8:1, tminor = 37.4 min, tmajor
4.5.6. (Rp,S)-5-(1-(1-Hydroxy-3,3-dimethylbutan-2-ylimino)ethyl)-
40.3 min; ½a 2D0
¼ ꢀ30:0 (c 0.25, CH2Cl2) 84% ee.
ꢂ
4-hydroxy-13-methoxy-[2.2]paracyclophane 1f0
Yellow solid. Yield: 45%; mp: 202–204 °C ½a D20
¼ ꢀ613:1 (c 0.1,
ꢂ
CH2Cl2); 1H NMR (300 MHz, DMSO-d6, rt) d 0.95 (s, 9H), 2.32 (s,
3H), 2.45–2.62 (m, 3H), 2.73–2.84 (m, 1H), 2.94–3.00 (m, 1H),
3.35–3.65 (m, 8H), 3.93–3.97 (m, 1H), 4.78–4.80 (m, 1H), 6.05 (s,
1H), 6.09–6.11 (d, J = 7.5 Hz, 1H), 6.25–6.28 (d, J = 7.5 Hz, 1H),
4.6.4. 4-((1R)-1-Hydroxy-2-nitroethyl)benzoic acid methyl ester
11d
White solid, n-hexane/i-PrOH, 10:1, tmajor = 31.2 min, tminor
=
33.5 min; ½a 2D0
¼ ꢀ17:8 (c 0.25, CH2Cl2) 94% ee.
ꢂ

F. He et al. / Tetrahedron: Asymmetry 23 (2012) 809–817
817
2003, 1, 153–156; (d) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H.; Shaw, J. T.;
Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692–12693; (e) Lang, K.; Park, J.;
Hong, S. J. Org. Chem. 2008, 73, 4330–4333; (f) Yang, W.; Liu, H.; Du, D. Org.
Biomol. Chem. 2010, 8, 2956–2960; (g) Cooper, C. J.; Jones, M. D.; Brayshaw, S.
K.; Sonnex, B.; Russell, M. L.; Mahon, M. H.; Allan, D. R. Dalton Trans. 2011, 40,
3677–3682; (h) Colak, M.; Demirel, N. Tetrahedron: Asymmetry 2008, 19, 635–
639; (i) Colak, M.; Aral, T.; Hosgoren, H.; Demirel, N. Tetrahedron: Asymmetry
2007, 18, 1129–1133; (j) Gan, C.; Lai, G.; Zhang, Z.; Wang, Z.; Zhou, M.
Tetrahedron: Asymmetry 2006, 17, 725–728; (k) Lai, G.; Guo, F.; Zheng, Y.; Fang,
Y.; Song, H.; Xu, K.; Wang, S.; Zha, Z.; Wang, Z. Chem. Eur. J. 2011, 17, 1114–
1117; (l) Blay, G.; Domingo, L. R.; Hernandez-Olmos, V.; Pedro, J. R. Chem. Eur. J.
2008, 14, 4725–4730; (m) Jin, W.; Li, X.; Huang, Y.; Wu, F.; Wan, B. Chem. Eur. J.
2010, 16, 8259–8261; (n) Breuning, M.; Hein, D.; Steiner, M.; Gessner, V. H.;
Strohmann, C. Chem. Eur. J. 2009, 15, 12764–12769.
4.6.5. (ꢀ)-1-(4-Formylphenyl)-2-nitroethanol 11e
Yellow oil, n-hexane/EtOH, 6:1, tminor = 36.5 min, tmajor = 39.1 -
min; ½a 2D0
ꢂ
¼ ꢀ190:9 (c 0.15, CH2Cl2) 88% ee; 1H NMR (300 MHz,
CDCl3, rt) d 3.18 (br, 1H), 4.08–4.15 (m, 2H), 5.55–5.59 (m, 1H),
7.60–7.62 (2H), 7.91–7.94 (2H),10.02 (s, 1H).
4.6.6. (R)-(ꢀ)-1-(4-Bromophenyl)-2-nitroethanol 11f
Yellow oil, n-hexane/i-PrOH, 8:1, tmajor = 19.8 min, tminor = 25.3 -
min; ½a 2D0
¼ ꢀ50:3 (c 0.21, CH2Cl2) 72% ee.
ꢂ
4.6.7. (R)-(ꢀ)-1-(2,4-Dichlorphenyl)-2-nitroethanol 11g
Yellow oil, n-hexane/i-PrOH, 10:1, tmajor = 18.0 min, tminor
5. (a) Blaser, H.; Schmidt, E. Asymmetric Catalysis on an Industrial Scale; Wiley-
VCH: Weinheim, 2003; (b) Dahmen, S.; Bräse, S. J. Am. Chem. Soc. 2002, 124,
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1269; (d) Wu, X. W.; Zhang, T. Z.; Yuan, K.; Hou, X. L. Tetrahedron: Asymmetry
2004, 15, 2357–2365; (e) Bräse, S.; Höfener, S. Angew. Chem., Int. Ed. 2005, 44,
7879–7881; (f) Whelligan, D. K.; Bolm, C. J. Org. Chem. 2006, 71, 4609–4618; (g)
Rozenberg, V.; Sergeeva, E.; Hopf, H. In Modern Cyclophane Chemistry; Gleiter,
R., Hopf, H., Eds.; Wiley-VCH: Weinheim, Germany, 2004; pp 435–462; (h) Aly,
A.; Brown, A. B. Tetrahedron 2009, 65, 8055–8089; (i) Paradies, J. Synthesis 2011,
23, 3749–3766.
6. (a) Pye, P. J.; Rossen, K.; Reamer, R. A.; Tsou, N. N.; Volante, R. P.; Reider, P. J. J.
Am. Chem. Soc. 1997, 119, 6207–6208; (b) Pye, P. J.; Rossen, K.; Reamer, R. A.;
Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998, 39, 4441–4444; (c) Zanotti-
Gerosa, A.; Malan, C.; Herzberg, D. Org. Lett. 2001, 3, 3687–3690; (d)
Dominguez, B.; Zanotti-Gerosa, A.; Hems, W. Org. Lett. 2004, 6, 1927–1930.
7. (a) Wu, X. W.; Yuan, X. K.; Sun, W.; Zhang, M. J.; Hou, X. L. Tetrahedron:
Asymmetry 2003, 14, 107–112; (b) Whelligan, D. K.; Bolm, C. J. Org. Chem. 2006,
71, 4609–4618; (c) Stemmler, R. T.; Bolm, C. Adv. Synth. Catal. 2007, 349, 1185–
1198.
8. (a) Bolm, C.; Focken, T.; Raabe, G. Tetrahedron: Asymmetry 2003, 14, 1733–
1746; (b) Focken, T.; Rudolph, J.; Bolm, C. Synthesis 2005, 3, 429–436; (c)
Focken, T.; Raabe, G.; Bolm, C. Tetrahedron: Asymmetry 2004, 15, 1693–1706;
(d) Ma, Y. D.; Song, C.; Ma, C. Q.; Sun, Z. J.; Chai, Q.; Andrus, M. B. Angew. Chem.,
Int. Ed. 2003, 42, 5871–5874; (e) Song, C.; Ma, C. Q.; Ma, Y. D.; Feng, W. H.; Ma,
S. T.; Chai, Q.; Andrus, M. B. Tetrahedron Lett. 2005, 46, 3241–3244; (f) Ma, Q. S.;
Ma, Y. D.; Liu, X.; Duan, W. Z.; Qu, B.; Song, C. Tetrahedron: Asymmetry 2010, 21,
292–298; (g) Hong, B.; Ma, Y. D.; Zhao, L.; Duan, W. Z.; He, F. Y.; Song, C.
Tetrahedron: Asymmetry 2011, 22, 1055–1062.
9. (a) Hou, X. L.; Wu, X. W.; Dai, L. X.; Cao, B. X.; Sun, J. Chem. Commun. 2000,
1195–1196; (b) Wu, X. W.; Hou, X. L.; Dai, L. X.; Tao, J.; Cao, B. X.; Sun, J.
Tetrahedron: Asymmetry 2001, 12, 529–553; (c) Wu, X. W.; Zhang, T. Z.; Yuan,
K.; Hou, X. L. Tetrahedron: Asymmetry 2004, 15, 2357–2365.
=
21.7 min; ½a 2D0
¼ ꢀ47:8 (c 0.17, CH2Cl2) 76% ee.
ꢂ
4.6.8. (R)-(ꢀ)-1-(2-Chlorphenyl)-2-nitroethanol 11h
Yellow oil, n-hexane/i-PrOH, 6:1, tminor = 19.3 min, tmajor = 20.6 -
min; ½a 2D0
¼ ꢀ46:8 (c 0.20, CH2Cl2) 80% ee.
ꢂ
4.6.9. (R)-(ꢀ)-1-(1-Naphthyl)-2-nitroethanol 11i
Yellow oil, n-hexane/i-PrOH, 20:1, tminor = 36.3 min, tmajor
=
=
=
37.8 min; ½a 2D0
¼ ꢀ20:5 (c 0.20, CH2Cl2) 80% ee.
ꢂ
4.6.10. (R)-(ꢀ)-1-(2-Naphthyl)-2-nitroethanol 11j
Yellow solid, n-hexane/CH2Cl2, 1:1, tminor = 20.0 min, tmajor
21.9 min; ½a 2D0
¼ ꢀ40:3 (c 0.15, CH2Cl2) 58% ee.
ꢂ
4.6.11. (R)-(ꢀ)-1-Phenyl-2-nitroethanol 11k
Colorless oil, n-hexane/CH2Cl2, 1:1, tminor = 17.9 min, tmajor
19.1 min; ½a 2D0
¼ ꢀ28:8 (c 0.19, CH2Cl2) 66% ee.
ꢂ
4.6.12. (R)-(ꢀ)-1-Furfuryl-2-nitroethanol 11l
Yellow oil, n-hexane/i-PrOH/CHCl3, 8:1:1, tmajor = 17.8 min,
tminor = 19.1 min; ½a D20
¼ ꢀ15:9 (c 0.27, CH2Cl2) 46% ee.
ꢂ
Acknowledgements
10. (a) Bräse, S.; Dahmen, S.; Höfener, S.; Lauterwasser, F.; Kreis, M.; Ziegert, R. E.
Synlett 2004, 2647–2669; (b) Lauterwasser, F.; Nieger, M.; Mansikkamäki, H.;
Nättinen, K.; Bräse, S. Chem. Eur. J. 2005, 11, 4509–4525; (c) Lauterwasser, F.;
Vanderheiden, S.; Bräse, S. Adv. Synth. Catal. 2006, 348, 443–448; (d) Danilova,
T. I.; Rozenberg, V. I.; Sergeeva, E. V.; Starikova, Z. A.; Bräse, S. Tetrahedron:
Asymmetry 2003, 14, 2013–2019; (e) Dahmen, S. Org. Lett. 2004, 13, 2113–
2116; (f) Danilova, T. I.; Rozenberg, V. I.; Starikova, Z. A.; Bräse, S. Tetrahedron:
Asymmetry 2004, 15, 223–229; (g) Sugiyama, S.; Aoki, Y.; Ishii, K. Tetrahedron:
Asymmetry 2006, 17, 2847–2856; (h) Lauterwasser, F.; Gall, J.; Höfener, S.;
Bräse, S. Adv. Synth. Catal. 2006, 348, 2068–2074; (i) Danilova, T. I.; Rozenberg,
V. I.; Vorontsov, E. V.; Starikova, Z. A.; Hopf, H. Tetrahedron: Asymmetry 2003,
14, 1375–1383; (j) Bräse, S.; Höfener, S. Angew. Chem., Int. Ed. 2005, 44, 7879–
7881; (k) Kreis, M.; Nieger, M.; Bräse, S. J. Organomet. Chem. 2006, 691, 2171–
2181; (l) Dahmen, S.; Bräse, S. J. Am. Chem. Soc. 2002, 124, 5940–5941.
11. Xin, D. Y.; Ma, Y. D.; He, F. Y. Tetrahedron: Asymmetry 2010, 21, 333–338.
12. Duan, W. Z.; Ma, Y. D.; Xia, H. Q.; Liu, X.; Ma, Q. S.; Sun, J. J. Org. Chem. 2008, 73,
4330–4333.
Financial support from the National Natural Science Foundation
of China (Grant No. 20671059) and the Department of Science and
Technology of Shandong Province is gratefully acknowledged.
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