Enantioselective addition of diethylzinc to aldehydes catalyzed by monosubstituted [2.2]paracyclophane-based N,O-ligands: remarkable cooperative effects of planar and central chiralities

Article abstract of DOI:10.1016/j.tetasy.2006.10.040

Diastereomeric monosubstituted [2.2]paracyclophane-based N,O-ligands, which unite the planar and central chiral elements, were optimized for the enantioselective diethylzinc addition to aldehydes. (S)-1-{(S_p)-[2.2]Paracyclophan-4-yl}methyl-2-pyrrolidine-α,α-diphenylmethanol (S_p,S)-3 catalyzed the addition to give (R)-1-phenyl-1-propanol in a high yield and with a good enantioselectivity (91% ee).

Full text of DOI:10.1016/j.tetasy.2006.10.040

Tetrahedron: Asymmetry 17 (2006) 2847–2856
Enantioselective addition of diethylzinc to aldehydes catalyzed by
monosubstituted [2.2]paracyclophane-based N,O-ligands:
remarkable cooperative effects of planar and central chiralities
Shigeo Sugiyama,* Yoshinori Aoki and Keitaro Ishii*
Department of Medicinal Chemistry, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo 204-8588, Japan
Received 24 May 2006; revised 23 October 2006; accepted 24 October 2006
Abstract—Diastereomeric monosubstituted [2.2]paracyclophane-based N,O-ligands, which unite the planar and central chiral elements,
were optimized for the enantioselective diethylzinc addition to aldehydes. (S)-1-{(Sp)-[2.2]Paracyclophan-4-yl}methyl-2-pyrrolidine-a,a-
diphenylmethanol (Sp,S)-3 catalyzed the addition to give (R)-1-phenyl-1-propanol in a high yield and with a good enantioselectivity (91%
ee).
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
et al. used 4,5-disubstituted [2.2]paracyclophane-based
N,O-ketimine ligands9–12 for asymmetric diethylzinc addi-
tions to aldehydes with moderate to high enantioselectivi-
ties. The ketimine ligands and their analogues also
catalyze alkenylzinc13 and alkynylzinc14 addition to
aldehydes, alkylzinc additions to imines,15 and conjugate
addition to a,b-unsaturated aldehydes and ketones16 with
excellent enantioselectivities. All of the [2.2]paracyclo-
phane-based N,O-ligands are disubstituted derivatives;
however, monosubstituted [2.2]paracyclophane-based
N,O-ligands for the diethylzinc addition have not been
reported.
The asymmetric catalysis of organic reactions to provide
enantiomerically enriched compounds has become one of
the most powerful tools in modern synthetic organic chem-
istry. In particular, the enantioselective diethylzinc addi-
tion to benzaldehyde has been well studied as a carbon–
carbon bond-forming reaction.1,2 Many chiral ligands,
which possess central, axial, and planar chiralities, have
been developed, and excellent enantioselectivities have
been achieved in recent decades. A large number of publi-
cations regarding the enantioselective diethylzinc addi-
tion1,2 have been reported the use of [2.2]paracyclophane-
based ligands for catalytic asymmetric processes over the
last few years.3,4 Some chiral N,O-ligands containing
[2.2]paracyclophanes as chiral elements catalyze the enan-
tioselective addition of diethylzinc to benzaldehyde. The
first report of a [2.2]paracyclophane-based N,O-ligand for
the enantioselective addition was reported in 2001 by
Hou et al.,5,6 who synthesized 4,13-disubstituted [2.2]para-
cyclophane derivatives, providing a 93% ee of 1-phenyl-1-
propanol from diethylzinc and benzaldehyde. Ruzziconi
et al. evaluated the quinolinophenylcarbinol as a catalyst
in the enantioselective addition,7 and, recently, they have
reported improved carbinol catalysts, which have both
planar and central chiralities.8 Bra¨se et al. and Rozenberg
On the other hand, N-substituted prolinol derivatives have
been well-studied as N,O-ligands for diethylzinc addition
to aldehydes17–27 and diphenylzinc addition to 4-chloro-
benzaldehyde28 with a low to excellent enantiomeric excess.
The achiral N-substituents are methyl,17–23,28 ethyl,22,23
2,2-dimethylpropyl,21 benzyl,22–25 mesitylmethyl,28 and 9-
anthrylmethyl,28 while the chiral ones are 1-(ferrocen-
yl)ethyl26 and 1-(2-phenyl-2-tosylamido)ethyl groups.27
Some planar chiral monosubstituted [2.2]paracyclophanes have been
employed by Soai et al. in asymmetric autocatalytic diisopropylzinc
additions to 2-(tert-butylethynylpyrimidine)-5-carbaldehyde to give an
optically active pyrimidyl alkanol;35,36 however, this reaction proceeds
through a completely different process from the diethylzinc addition to
aldehydes with N,O-ligands.1,2
*
Corresponding authors: Tel./fax: +81 42 495 8783; e-mail addresses:
sugiyama@my-pharm.ac.jp; ishiikei@my-pharm.ac.jp
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.10.040

2848
S. Sugiyama et al. / Tetrahedron: Asymmetry 17 (2006) 2847–2856
HN
HO
R
R
N
N
N
7; R = H
8; R = Me
9; R = Ph
Ph
Ph
COX
R
R
R
R
a
HO
Sp)-4
HO
)-1; R = H
)-2; R = Me
)-3; R = Ph
OH
(
(
RSp)-5, X = OH
RSp)-6, X = Cl
b
(Sp
(Sp
(Sp
,
,
,
S
S
S
(
(
(
Rp
Rp
Rp
,S
,S
,S
)-1; R = H
)-2; R = Me
)-3; R = Ph
(
+
Figure 1. Monosubstituted [2.2]paracyclophane-based N,O-ligands.
N
N
R
R
R
R
O
HO
O
OH
Herein we report the efficacy of chiral monosubstituted
[2.2]paracyclophane-based N,O-ligands 1–4 (Fig. 1) for
the enantioselective diethylzinc addition to aldehydes.
Ligands 1–3 are constructed with either (Sp)- or (Rp)-
[2.2]paracyclophane and (S)-prolinol derivatives, and
ligand (Sp)-4 is based on a chiral monosubstituted [2.2]-
paracyclophane without a stereogenic center. [2.2]Paracyclo-
phanes 1–3 bearing chiral substituents would be expected
to control the enantioselectivity of the addition because of
the interplay between the planar chirality of the [2.2]para-
cyclophane and the central chirality of the substituents.
(
(
(
Sp
Sp
Sp
,
,
,
S
S
S
)-10; R = H
)-11; R = Me
)-12; R = Ph
(Rp
(Rp
(Rp
,
,
,
S)-10; R = H
S)-11; R = Me
S)-12; R = Ph
Scheme 1. Reagents and conditions: (a) SOCl2, reflux; (b) Et3N, DMAP,
CH2Cl2, 0 ꢁC to room temp.
The reduction of amides (Sp,S)-10–12 and (Rp,S)-10–12
with lithium aluminum hydride in refluxing THF gave
the desired amino alcohols (Sp,S)-1–3 and (Rp,S)-1–3
(Table 1). In some of these reactions, (Sp)- and (Rp)-4-
hydroxymethyl[2.2]paracyclophanes (Sp)-13 and (Rp)-13
were obtained as byproducts.§
2. Results and discussion
As an easy route into [2.2]paracyclophane-based catalysts,
ligands 1–3 were synthesized from racemic (RSp)-[2.2]para-
cyclophane-4-carboxylic acid (RSp)-5.29,30 After the con-
version of (RSp)-5 into [2.2]paracyclophane-4-carbonyl
chloride (RSp)-6 by thionyl chloride, (RSp)-6 was reacted
with (S)-prolinol derivatives (S)-7–9 to afford the diastereo-
meric mixtures of amides (Sp,S)-10–12 and (Rp,S)-10–12 in
good yields (Scheme 1). All of the amides could be readily
separated by simple silica gel column chromatography
thereby allowing the resolution of the planar chirality.
Table 1. Reduction of amides 10–12
(
Sp
or
Rp
,
S
)-1−3
(
(
Sp
,
S
)-10−12
or
)-10−12
LiAlH4
+
THF
reflux
(
,S)-1−3
Rp
,
S
OH
(Sp)- or (Rp)-13
Entry
Substrate
Product (yield, %)
1
2
3
4
5
6
(Sp,S)-10
(Rp,S)-10
(Sp,S)-11
(Rp,S)-11
(Sp,S)-12
(Rp,S)-12
(Sp,S)-1 (91)
(Rp,S)-1 (95)
(Sp,S)-2 (64)
(Rp,S)-2 (82)
(Sp,S)-3 (64)
(Rp,S)-3 (83)
(Sp)-13 (>5)
(Rp)-13 (>5)
(Sp)-13 (35)
(Rp)-13 (12)
(Sp)-13 (36)
(Rp)-13 (4)
In order to determine the stereochemistry, amides (Sp,S)-10
and (Rp,S)-10 were hydrolyzed under acidic conditions
(sulfuric acid/water/dioxane = 1:1:1, 100 ꢁC, 15 h) to
afford (Sp)-5 and (Rp)-5, respectively. The absolute configu-
rations of (Sp)-5 and (Rp)-5 were determined by the
comparison of their reported specific rotations.29 Acids
(Sp)-5 and (Rp)-5 were converted to the corresponding
methyl ester with (trimethylsilyl)diazomethane,31 and their
enantiomeric excesses were >98% ee, as measured by
HPLC using Chiralcel OD. Next, we attempted to hydro-
lyze amides (Sp,S)-11 and (Sp,S)-12; however, they were
stable against the acidic conditions.à To determine the ste-
reochemistry, (Sp,S)-11 and (Sp,S)-12 were synthesized
from acid chloride (Sp)-6, which was obtained from (Sp)-
5 using thionyl chloride. The absolute stereochemistries
of (Sp,S)-11, (Rp,S)-11, (Sp,S)-12, and (Rp,S)-12 were
determined by the comparison of their diastereomeric
1H NMR spectra with those of (Sp,S)-11 and (Sp,S)-12
obtained from (Sp)-6.
Amino alcohol (Sp)-4 was also synthesized as follows:
2-methylamino-1,1-diphenylethanol 1632,33 was obtained
from N-methoxycarbonylglycine ethyl ester 1434 by the
treatment of excess phenylmagnesium bromide, following
the reduction with lithium aluminum hydride. Acid chlo-
ride (Sp)-6 was reacted with amino alcohol 16 to give amide
(Sp)-17. The reduction of (Sp)-17 with lithium aluminum
hydride in refluxing THF gave amino alcohol (Sp)-4
(Scheme 2).
To investigate the catalytic properties of these N,O-ligands,
the asymmetric addition of diethylzinc to benzaldehyde
was carried out in toluene/hexane. All experiments were
à Some [2.2]paracyclophane-based ketimines are also stable against acidic
hydrolysis.37
§ Alcohol 13 has been obtained with reduction of a sulfamide derived from
[2.2]paracyclophane-4-carboxylic acid.31

S. Sugiyama et al. / Tetrahedron: Asymmetry 17 (2006) 2847–2856
2849
(R)- and (S)-1-phenyl-1-propanols were synthesized with
identical rates.
O
a
b
Ph
Ph
OH
MeO
N
H
14
CO2Et
RHN
Next, we investigated the collaborative effects of the planar
and central chiralities on the efficiency for the asymmetric
diethyzinc addition to benzaldehyde. Ligand (Sp)-4, which
has only (Sp)-planar chirality, provided the (S)-product
with a 41% ee and a quantitative yield (entry 7). This
enantioselectivity is due to the steric effect of the planar
chirality. The effects of the stereogenic centers of ligands
(Sp,S)-3 and (Rp,S)-3 could be estimated from the enantio-
selectivities of the reported values [(S)-1-phenyl-1-propa-
nol, 40% ee] of (S)-1-benzyl-2-pyrrolidine-a,a-diphenyl-
methanol (S)-18 (Fig. 2). The combination of the (Sp)-
planar and (S)-central chiralities increased these moderate
enantioselectivities (41% and 40% ee) to 91% ee [matched
pair; (Sp,S)-3]; however, the combination of the (Rp)-
planar and (S)-central chiralities decreased their effects
[mismatched pair; (Rp,S)-3].
15, R = CO2Me
16, R = Me
b
c
(Sp)-4
N
Ph
Ph
O
HO
Sp)-17
(
Scheme 2. Reagents and conditions: (a) PhMgBr (excess), THF, 0 ꢁC,
30 min; (b) LiAlH4, THF, reflux; (c) (Sp)-6, Et3N, DMAP, CH2Cl2.
carried out at 0 ꢁC for 2 h and then allowed to warm to
room temperature for 16 h using a 5% molar amount of
the ligands and 2 equiv of a 1 mol/L diethylzinc solution
in hexane. The results on the catalyst efficiencies and the
enantiomeric excess of the resulting 1-phenyl-1-propanol
are presented in Table 2. Although the catalyst efficiencies
of ligands (Sp,S)-1, (Rp,S)-1, and (Sp,S)-2, and (Rp,S)-2
were insufficient (entries 1–4), those of ligands (Sp,S)-3
and (Rp,S)-3, possessing a,a-diphenylmethanol moieties,
were excellent, and the yields of the products using
(Sp,S)-3 and (Rp,S)-3 were quantitative (entries 5 and 6).
Surprisingly, the two enantiomeric excesses (91% ee and
1% ee) are completely different in spite of the high yields
(>99%). In general, monosubstituted [2.2]paracyclophane-
based ligands could adopt a large number of conforma-
tions.3 Therefore, a potential explanation for the pheno-
mena of the reaction using (Rp,S)-3 (high yield and no
selectivity) is that more than two active conformations of
the catalyst exist in the reaction mixture and, as a result,
N
R
Ph
HO
Ph
18, R = Bn
19, R = Et
20, R = Me
Figure 2. Ligands with stereogenic centers.
The addition of diethylzinc to benzaldehyde using (S)-1-
ethyl-
and
(S)-1-methyl-2-pyrrolidine-a,a-diphenyl-
methanols 1922,23 and 20,17,20–23 respectively, has also been
reported. For these ligands, the bulkiness of the N-
substituents is in the order benzyl > ethyl > methyl, and
the enantioselectivities22,23 decrease with methyl (93%
ee) > ethyl (87% ee) > benzyl (40% ee). In our study, a
good enantioselectivity was observed using ligand (Sp,S)-
3, even though it possessed a (Sp)-([2.2]paracyclophan-4-
yl)methyl group, which is clearly bulkier than the benzyl
group. Thus, the (Sp)-[2.2]paracyclophane moiety in the
N,O-ligand (Sp,S)-3 would form an effective chiral space
with the (S)-pyrrolidine-a,a-diphenylmethanol moiety
during the reaction.
Table 2. Addition of diethylzinc to benzaldehyde
ligand (5 mol%)
OH
PhCHO
Et2Zn (2.2 equiv)
hexane/toluene (1.1/1)
Ph
*
Entry
Ligand (5 mol %)
Product
ee (%)b
Yielda (%)
Abs. Config.c
Chiral ligand (Sp,S)-3 was then examined for the asym-
metric addition of a series of various aldehydes under the
identical conditions to those of Table 2. The results are
summarized in Table 3. The yields were high to moderate
except p-chlorobenzaldehyde, 2-naphthaldehyde, and
trans-cinnamaldehyde (entries 5, 9, and 11). In spite of
the long reaction times (100 h), the yields were low to
moderate (entries 6, 10, and 12). All the aldehydes gave
the 1-aryl-1-propanols in high to moderate enantiomeric
excesses except p-methoxybenzaldehyde (entry 1).– The
yields and enantiomeric excesses of 1-aryl-1-propanols
1
2
3
4
5
6
7
8
(Sp,S)-1
(Rp,S)-1
(Sp,S)-2
(Rp,S)-2
(Sp,S)-3
(Rp,S)-3
(Sp)-4
20
5
54
1
8
36
91
1
41
40e
R
R
R
R
S
6
40
>99
>99
99
R
S
(S)-18d
89
S
a The yields were calibrated with the internal standard (Ph3CH) by 1H
NMR integration.
b HPLC analysis (Chiralcel OD).
c The absolute configurations were determined by the comparison of the
known elution order from a chiral OD column. See Experimental
section.
– Although a lot of excellent ligands has been developed for the
enatioselective addition of diethylzinc to benzaldehyde to give 1-
phenyl-1-propanol in a high enantiomeric excess, some ligands give 1-
aryl-1-propanols, for example, 1-(p-methoxyphenyl)-1-propanol, from
arylaldehydes in low enantiomeric excesses exceptionally.46–53
d (S)-1-Benzyl-2-pyrrolidine-a,a-diphenylmethanol (Fig. 2).
e Using 5 mol % of (S)-18 in hexane/toluene.22,23 Various reaction condi-
tions using (S)-18 have been examined.22–25

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S. Sugiyama et al. / Tetrahedron: Asymmetry 17 (2006) 2847–2856
Table 3. Addition of diethylzinc to various aldehydes using (Sp,S)-3
Sp )-3 (5 mol%)
(Rp,S)-3 containing central chiral 2-pyrrolidine-a,a-di-
phenylmethanol moieties has led to the development of a
new family of ligands for the enantioselective addition of
diethylzinc to benzaldehyde. Ligand (Sp,S)-3 showed the
best results (91% ee); however, a product with a low enan-
tiomeric excess was obtained by using ligand (Rp,S)-3. The
reaction using planar chiral ligand (Sp)-4 gave the product
in a 41% ee, and the reported enantiomeric excess using
central chiral ligand (S)-18 is 40% ee.22,23 Therefore, ligand
(Sp,S)-3 has shown remarkable cooperative effects of the
planar and central chiralities.
(
,S
OH
RCHO
Et2Zn (2.2 equiv)
hexane/toluene (1.1/1)
R
Entry
Aldehyde
Time (h)
Yielda (%)
eeb,c (%)
1
2
3
4
5
p-MeOC6H4CHO
m-MeOC6H4CHO
o-MeOC6H4CHO
p-BrC6H4CHO
16
16
16
16
16
58
88
93
54
6
4
86
57
80
d
p-ClC6H4CHO
—
6
7
8
9
10
11
12
p-ClC6H4CHO
o-BrC6H4CHO
100
16
16
16
100
16
63
49
52
13
43
<5
33
74
61
71
65
62
—
73
1-Naphthaldehyde
2-Naphthaldehyde
2-Naphthylaldehyde
PhCH@CHCHOe
PhCH@CHCHO
4. Experimental
Melting points were measured with a Yanaco MP-3 appa-
ratus and are uncorrected. Optical rotations were deter-
mined on a JASCO DIP-140 polarimeter. IR spectra
were recorded on a Hitachi 215 spectrophotometer.
NMR spectra were obtained with JEOL JNM-GSX400
(1H NMR: 400 MHz and 13C NMR: 100 MHz), and JEOL
JNM-AL300 (1H NMR: 300 MHz) spectrometers using
tetramethylsilane as an internal standard. MS and high-res-
olution MS (HR-MS) were taken on a JEOL JMS-DX302
spectrometer. Column chromatography was performed
with Merck silica gel 60 (230–400 mesh). Analytical TLC
was performed on plates pre-coated with 0.25 mm layer
of silica gel 60 F254 (Merck).
100
a The yields were calibrated with the internal standard (Ph3CH) by 1H
NMR integration.
b HPLC analysis (Chiralcel OD).
c The all absolute configurations were determined as (S) by comparison of
the known elution order from a Chiralcel OD column. See Experimental
section.
d Not determined.
e trans-Cinnamaldehyde.
from aldehydes using ligand (Sp,S)-3 (Table 3) were lower
than those of 1-phenyl-1-propanol from benzaldehyde
(Table 2, entry 5).
4.1. Synthesis of amides 10–12 (Scheme 1)
N,O-Ligands (Sp,S)-1–3 and (Rp,S)-1–3 were synthesized
easily from racemic (RSp)-5. It has been pointed out that
the progress of the application of [2.2]paracyclophanes in
asymmetric catalysis is currently governed by the ease (or
lack thereof) with which enantiomerically pure [2.2]para-
cyclophanes are synthesized.3 For example, the synthesis
of enantiomerically pure [2.2]paracyclophane-4-carboxylic
acid 5 is dominated by classical resolution procedures, an
approach that can be tedious and low yielding.29,38–40 In
fact, to synthesize the planar chiral ligand (Sp)-4, we
needed enantiopure (Sp)-5. For the synthesis of N,O-
ligands (Sp,S)-1–3 and (Rp,S)-1–3, however, we did not
need optically pure [2.2]paracyclophane-4-carboxylic acid
5 because diastereomeric mixtures of amides (Sp,S)-10–12
and (Rp,S)-10–12 were successfully separated with silica
gel column chromatography. Thus, the stereogenic centers
of the N,O-ligands were not only the active site of catalysts
but also the origins of the separation.k
4.1.1. (S)-2-Hydroxymethyl-1-{(Sp)-[2.2]paracyclophane-4-
carbonyl}pyrrolidine (Sp,S)-10 and (S)-2-hydroxymethyl-1-
{(Rp)-[2.2]paracyclophane-4-carbonyl}pyrrolidine (Rp,S)-10.
A solution of (S)-prolinol 7 (88.2 mg, 0.87 mmol), triethyl-
amine (120 mg, 1.19 mmol), and DMAP (1.9 mg,
0.016 mmol) in dichloromethane (1.0 mL) was added drop-
wise to a solution of (RSp)-6, which had been converted
from (RSp)-529 (200 mg, 0.79 mmol) by thionyl chloride
just before use, in dichloromethane (1.0 mL) at 0 ꢁC. After
being stirred for 12 h while being allowed to warm to room
temperature, the reaction mixture was poured into satu-
rated aqueous ammonium chloride solution and extracted
with dichloromethane. The organic extracts were com-
bined, dried over magnesium sulfate, filtered, and concen-
trated in vacuo. The residue was chromatographed on
silica gel (hexane/ethyl acetate; 1:1) to give (Sp,S)-10
[113 mg, 43% from (RSp)-5] and (Rp,S)-10 [120 mg, 45%
from (RSp)-5].
Compound (Sp,S)-10: Colorless solid, mp 125–126 ꢁC.
24
½aꢀD ¼ þ3:3 (c 0.7, CHCl3). IR (CHCl3): 3000, 2950,
3. Conclusions
1610, 1450, 1210 cmꢁ1. FABMS (glycerol) m/z 336
[(M+1)+]. HRMS (FAB) (glycerol) Calcd for C22H26NO2
(M+1): 336.1953. Found: 336.1964. 1H NMR (CDCl3,
300 MHz) d: 1.52–1.75 (3H, m, NHCHCHH,
NHCH2CH2), 2.06–2.14 (1H, m, NHCHCHH), 2.90–3.21
(10H, m, ArCH2CH2, NHCH2), 3.73–3.85 (2H, m,
–CHCH2OH), 4.39 (1H, ddd, J = 15.4, 7.7, 2.9 Hz,
–NCHCH2), 5.40 (1H, br s, OH), 6.42–6.58 (6H, m, Ar),
6.98 (1H, dd, J = 7.9, 1.5 Hz, Ar). 13C NMR (CDCl3,
100 MHz) d: 24.6 (CH2), 28.6 (CH2), 33.9 (ArCH2), 35.3
In conclusion, the synthesis of planar chiral monosubsti-
tuted [2.2]paracyclophane-based N,O-ligands (Sp,S)-3 and
k Some diastereomixtures of disubstituted [2.2]paracyclophanes5,6,9,10,37,42–44
and monosubstituted [2.2]paracyclophanes41,45 have been separated by
silica gel column chromatography. Very recently, enantiomerically pure
4-substituted [2.2]paracyclophane derivatives (e.g., carboxylic acid 5)
were synthesized from one of the monosubstituted [2.2]paracyclophane
by sulfoxide–metal exchange.45

S. Sugiyama et al. / Tetrahedron: Asymmetry 17 (2006) 2847–2856
2851
(ArCH2), 35.4 (ArCH2), 35.5 (ArCH2), 49.7 (NCH2), 61.1
(NCH), 68.0 (CH2OH), 130.3 (Ar, CH), 131.6 (Ar, CH),
132.3 (Ar, CH), 132.5 (Ar, CH), 132.9 (Ar, CH), 134.4
(Ar, CH), 134.7 (Ar, CH), 134.9 (Ar, C), 137.1 (Ar, C),
138.9 (Ar, C), 139.0 (Ar, C), 139.8 (Ar, C), 171.9 (C@O).
1.70 (3H, m, NHCHCHH, NHCH2CH2), 2.11–2.13 (1H,
m, NHCHCHH), 2.79–3.41 (10H, m, ArCH2CH2,
NHCH2), 4.31 (1H, t, J = 10.5 Hz, NCHCH2), 6.31 (1H,
d, J = 10.5 Hz, Ar) 6.42–6.58 (5H, m, Ar), 7.07 (1H, d,
J = 10.5 Hz, Ar). 13C NMR (CDCl3, 100 MHz) d: 23.4
(CH3), 24.9 (CH2), 27.7 (CH3), 28.9 (CH2), 34.0 (Ar–
CH2), 35.0 (Ar–CH2), 35.1 (Ar–CH2), 35.3 (Ar–CH2),
51.2 (NCH2), 67.5 (NCH), 73.8 (C–OH), 130.8 (Ar, CH),
131.6 (Ar, CH), 131.9 (Ar, CH), 132.2 (Ar, CH), 132.4
(Ar, CH), 132.5 (Ar, C), 134.5 (Ar, CH), 135.3 (Ar, CH),
137.9 (Ar, C), 138.7 (Ar, C), 139.4 (Ar, C), 139.5 (Ar, C),
172.7 (C@O).
Compound (Rp,S)-10: Colorless solid, mp 201–202 ꢁC.
24
½aꢀD ¼ ꢁ119 (c 0.8, CHCl3). IR (CHCl3): 3000, 2925,
1610, 1420, 1210 cmꢁ1. FABMS (glycerol) m/z 336
[(M+1)+]. HRMS (FAB) (glycerol) Calcd for C22H26NO2
(M+1): 336.1953. Found: 336.1964. 1H NMR (CDCl3,
300 MHz) d: 1.51–1.73 (3H, m, NHCHCHH,
NHCH2CH2), 2.04–2.19 (1H, m, NHCHCHH), 2.85–3.31
(10H, m, ArCH2CH2, –NHCH2), 3.68–3.83 (2H, m,
CHCH2OH), 4.38 (1H, ddd, J = 15.4, 7.7, 2.8 Hz,
NCHCH2), 5.40 (1H, br d, J = 6.2 Hz, OH), 6.4 (1H, dd,
J = 7.9, 1.7 Hz, Ar), 6.42 (1H, d, J = 7.7 Hz, Ar), 6.50–
6.56 (4H, m, Ar), 7.04 (1H, dd, J = 8.1, 1.7 Hz, Ar). 13C
NMR (CDCl3, 100 MHz) d: 24.6 (CH2), 28.6 (CH2), 33.9
(ArCH2), 35.1 (ArCH2), 35.2 (ArCH2), 35.4 (ArCH2),
50.0 (NCH2), 61.1 (NCH), 67.6 (CH2OH), 130.7 (Ar,
CH), 131.6 (Ar, CH), 132.2 (Ar, CH), 132.2 (Ar, CH),
132.7 (Ar, CH), 133.2 (Ar, C), 134.4 (Ar, CH), 135.1 (Ar,
CH), 137.2 (Ar, C), 138.9 (Ar, C), 139.3 (Ar, C), 139.7
(Ar, C), 172.0 (C@O).
4.1.3. (S)-2-(1,1-Diphenyl-1-hydroxy)methyl-1-{(Sp)-[2.2]-
paracyclophane-4-carbonyl}pyrrolidine (Sp,S)-12 and (S)-2-
(1,1-diphenyl-1-hydroxy)methyl-1-{(Rp)-[2.2]paracyclophane-
4-carbonyl}pyrrolidine (Rp,S)-12. According to the proce-
dure described above using (S)-a,a-diphenyl-2-pyrolidine-
methanol (9) (221 mg, 0.87 mmol), we synthesized (Sp,S)-
12 [181 mg, 47% from (RSp)-5] and (Rp,S)-12 [181 mg,
47% from (RSp)-5]. Hexane/ethyl acetate (10:1) was used
for the silica gel column chromatography.
Compound (Sp,S)-12: Colorless solid, mp 181–182 ꢁC.
25
½aꢀD ¼ ꢁ7:1 (c 1.0, CHCl3). IR (CHCl3): 3250, 3000,
2925, 1600, 1425, 1390, 1180 cmꢁ1. FABMS (magic bullet)
4.1.2.
(S)-2-(1-Hydroxy-1-methyl)ethyl-1-{(Sp)-[2.2]para-
m/z 488 [(M+1)+]. HRMS (FAB) (magic bullet) Calcd for
1
cyclophane-4-carbonyl}pyrrolidine (Sp,S)-11 and (S)-2-(1-
hydroxy-1-methyl)ethyl-1-{(Rp)-[2.2]paracyclophane-4-car-
bonyl}pyrrolidine (Rp,S)-11. According to the procedure
described above using (S)-1-methyl-1-(pyrrolidin-4-yl)etha-
nol 8 (113 mg, 0.87 mmol), which was synthesized from
(S)-proline in three steps,54 (Sp,S)-11 [129 mg, 45% from
(RSp)-5] and (Rp,S)-11 [130 mg, 45% from (RSp)-5] were
obtained. Hexane/ethyl acetate (2:1) was used for silica
gel column chromatography.
C34H34NO2 (M+1): 488.2589. Found: 488.2590. H NMR
(CDCl3, 400 MHz) d: 1.26–1.34 (2H, m), 1.89–1.94 (2H,
m), 2.25–2.30 (1H, m), 2.60–2.73 (3H, m), 2.87–3.10 (6H,
m) 5.14 (1H, t, J = 8.3 Hz, NCHCH2), 6.29 (1H, d,
J = 7.8 Hz, Ar), 6.42–6.50 (4H, m, Ar), 6.60 (1H, s, Ar),
6.70 (1H, d, J = 7.8 Hz, Ar), 7.19–7.54 (10H, m, Ar),
7.72 (2H, d, J = 7.6 Hz, Ar). 13C NMR (CDCl3,
100 MHz) d: 23.9 (CH2), 30.7 (CH2), 33.2 (Ar–CH2), 35.2
(Ar–CH2), 35.3 (Ar–CH2), 35.6 (Ar–CH2), 50.5 (NCH2),
69.3 (NCH), 81.2 (C–OH), 126.9 (Ar, CH), 127.0 (Ar,
CH), 127.3 (Ar, CH · 2), 127.46 (Ar, CH · 2), 127.52
(Ar, CH · 2), 127.61 (Ar, CH · 2), 130.64 (Ar, CH),
131.2 (Ar, CH), 132.1 (Ar, CH), 132.2 (Ar, CH), 133.0
(Ar, CH), 134.2 (Ar, CH), 134.4 (Ar, CH), 135.2 (Ar, C),
137.6 (Ar, C), 138.7 (Ar, C), 138.8 (Ar, C), 139.4 (Ar, C),
143.4 (Ar, C), 145.6 (Ar, C), 172.4 (C@O).
Compound (Sp,S)-11: Colorless solid, mp 86–87 ꢁC.
23
½aꢀD ¼ ꢁ22:0 (c 1.2, CHCl3). IR (CHCl3): 3300, 2900,
1600, 1430, 1380, 1170 cmꢁ1. FABMS (glycerol) m/z 364
[(M+1)+]. HRMS (FAB) (glycerol) Calcd for C24H30NO2
(M+1): 364.2276. Found: 364.2270. 1H NMR (CDCl3,
300 MHz) d: 1.28 (6H, s, CMe2), 1.41–1.75 (3H, m,
NHCHCHH,
NHCH2CH2),
2.08–2.17
(1H,
m,
NHCHCHH), 2.91–3.31 (10H, m, ArCH2CH2, NHCH2),
4.30 (1H, t, J = 8.1 Hz, NCHCH2), 6.44–6.58 (5H, m,
Ar), 6.63 (1H, d, J = 1.8 Hz, Ar), 6.94 (1H, dd, J = 7.9,
1.7 Hz, Ar). 13C NMR (CDCl3, 100 MHz) d: 23.8 (Me),
24.6 (CH2), 28.0 (Me), 28.8 (CH2), 34.1 (Ar–CH2), 35.2
(Ar–CH2), 35.3 (Ar–CH2), 35.3 (Ar–CH2), 50.6 (N–CH2),
67.8 (NCH), 73.8 (C–OH), 130.8 (Ar, CH), 131.5 (Ar,
CH), 132.1 (Ar, CH), 132.4 (Ar, CH), 132.7 (Ar, CH),
134.3 (Ar, CH), 134.5 (Ar, CH), 135.2 (Ar, C), 137.3 (Ar,
C), 138.6 (Ar, C), 138.9 (Ar, C), 139.8 (Ar, C), 172.5
(C@O).
Compound (Rp,S)-12: Colorless solid, mp 199–200 ꢁC.
26
½aꢀD ¼ ꢁ70:9 (c 1.4, CHCl3). IR (CHCl3): 3240, 2970,
2920, 1610, 1420, 1180 cmꢁ1. FABMS (magic bullet) m/z
488 [(M+1)+]. HRMS (FAB) (magic bullet) Calcd for
C34H34NO2 (M+1): 488.2589. Found: 488.2590. 1H
NMR (CDCl3, 400 MHz) d: 1.37–1.42 (2H, m), 1.84–1.90
(1H, m), 1.98–2.00 (1H, m), 2.63–2.82 (4H, m), 2.91–2.99
(2H, m), 3.08–3.10 (2H, m), 3.31–3.38 (2H, m), 5.20 (1H,
t, J = 8.5 Hz, NCHCH2), 5.66 (1H, s, Ar), 6.09 (1H, d,
J = 7.8 Hz, Ar), 6.45 (1H, d, J = 7.8 Hz, Ar), 6.49 (2H, s,
Ar), 6.91 (1H, d, J = 7.6 Hz, Ar), 7.25–7.34 (3H, m, Ar),
7.45–7.50 (5H, m, Ar), 7.72 (2H, d, J = 6.8 Hz, Ar). 13C
NMR (CDCl3, 100 MHz) d: 24.4 (CH2), 30.8 (CH2), 34.2
(Ar–CH2), 35.1 (Ar–CH2), 35.2 (Ar–CH2), 35.4 (Ar–
CH2), 51.4 (N–CH2), 68.5 (NCH), 82.1 (C–OH), 126.9
(Ar, CH), 127.1 (Ar, CH), 127.4 (Ar, CH), 127.4 (Ar,
CH), 127.5 (Ar, CH), 127.5 (Ar, CH), 127.69 (Ar,
CH · 2), 127.71 (Ar, CH · 2), 131.2 (Ar, CH), 131.6 (Ar,
Compound (Rp,S)-11: Colorless solid, mp 149–150 ꢁC.
24
½aꢀD ¼ ꢁ145 (c 1.3, CHCl3). IR (CHCl3): 3300, 2950,
1610, 1420, 1400, 1180 cmꢁ1. FABMS (glycerol) m/z 364
[(M+1)+]. HRMS (FAB) (glycerol) Calcd for C24H30NO2
(M+1): 364.2276. Found: 364.2269. 1H NMR (CDCl3,
300 MHz) d: 1.21 (3H, s, Me), 1.26 (3H, s, Me), 1.41–

2852
S. Sugiyama et al. / Tetrahedron: Asymmetry 17 (2006) 2847–2856
CH), 131.66 (Ar, CH), 131.73 (Ar, C), 132.2 (Ar, CH),
132.4 (Ar, CH), 134.5 (Ar, CH), 135.3 (Ar, CH), 138.6
(Ar, C), 138.7 (Ar, C), 139.2 (Ar, C), 139.6 (Ar, C), 143.3
(Ar, C), 145.2 (Ar, C), 172.2 (C@O).
4.3.2.
(S)-[1-{(Rp)-[2.2]Paracyclophan-4-yl}methylpyrrol-
idin-2-yl]methanol (Rp,S)-1. According to the synthetic
procedure of (Sp,S)-1 from (Sp,S)-10 described above,
(Rp,S)-1 (45.7 mg, 95%) was obtained from (Rp,S)-10
(50.0 mg, 0.15 mmol) as a colorless solid. Mp 124–125 ꢁC.
24
4.2. Acidic hydrolysis of the amides (Table 1)
½aꢀD ¼ ꢁ93:4 (c 0.5, CHCl3). IR (CHCl3): 2940, 1600,
1120 cmꢁ1. FABMS (glycerol) m/z 322 [(M+1)+]. HRMS
4.2.1. (Sp)-[2.2]Paracyclophane-4-carboxylic acid (Sp)-
5. Amide (Sp,S)-10 (40 mg, 0.12 mmol) was dissolved in
dioxane (60 lL), and 50% w/w aqueous sulfuric acid
(47 mg) was added to this solution. The resulting mixture
was stirred for 14 h at 120 ꢁC (bath temperature). After
cooling to room temperature, the reaction mixture was
alkalinized with 10% aqueous sodium hydroxide and
washed with ethyl acetate. The aqueous layer was acidified
with 10% hydrochloric acid and extracted with dichloro-
methane. The extracts were combined, dried over magne-
sium sulfate, filtered, and concentrated in vacuo. The
residue was chromatographed on silica gel (hexane/ethyl
acetate; 2:1) to afford (Sp)-5 (18.5 mg, 62%) as colorless
(FAB) (glycerol) Calcd for C22H28NO (M+1): 322.2171.
Found: 322.2166. H NMR (CDCl3, 300 MHz) d: 1.62–
1
1.69 (2H, m), 1.73–1.81 (1H, m), 1.84–1.93 (1H, m), 2.26
(1H, dd-like m), 2.73–2.80 (1H, m), 2.81–2.86 (1H, m),
2.91–3.17 (7H, m), 3.37–3.44 (2H, m), 3.51–3.61 (3H, m),
6.33 (1H, s, Ar), 6.39 (1H, dd, J = 8.1, 2.0 Hz, Ar), 6.42–
6.50 (3H, m, Ar), 6.53 (1H, dd, J = 7.8, 2.0 Hz, Ar), 6.62
(1H, dd, J = 7.8, 2.0 Hz, Ar). 13C NMR (CDCl3,
100 MHz) d: 23.7 (CH2), 28.1 (CH2), 33.4 (Ar–CH2), 34.5
(Ar–CH2), 35.1 (Ar–CH2), 35.4 (Ar–CH2), 54.8 (CH2),
56.7 (CH2), 62.1 (CH2), 64.5 (N–CH) 128.4 (Ar, CH),
131.2 (Ar, CH), 131.9 (Ar, CH), 133.1 (Ar, CH), 133.2
(Ar, CH), 134.3 (Ar, CH), 134.6 (Ar, CH), 137.4 (Ar, C),
138.0 (Ar, C), 139.0 (Ar, C), 139.4 (Ar, C), 139.8 (Ar, C).
22
25
crystals. ½aꢀD ¼ þ158 (c 0.7, CHCl3). Ref. 29 ½aꢀD ¼ þ164
1
(c 0.5, CHCl3). H NMR spectrum was in good agreement
with that of (RSp)-5.
4.3.3.
(S)-1-Methyl-1-[1-{(Sp)-[2.2]paracyclophan-4-yl}-
methylpyrrolidin-2-yl]ethanol (Sp,S)-2 and (Sp)-4-hydroxy-
methyl-[2.2]paracyclophane (Sp)-13. According to the syn-
thetic procedure of (Sp,S)-1 from (Sp,S)-10 described
above, (Sp,S)-2 (30.7 mg, 64%) and (Sp)-13 (12.2 mg,
35%) were obtained from (Sp,S)-11 (50.0 mg, 0.14 mmol).
4.2.2. (Rp)-[2.2]Paracyclophane-4-carboxylic acid (Rp)-
5. According to the synthetic procedure for acidic hydro-
lysis of amide (Sp,S)-10 described above, (Rp)-5 (13.9 mg,
34%) was obtained from (Rp,S)-10 (55.3 mg, 0.17 mmol).
19
25
½aꢀD ¼ ꢁ159 (c 0.4, CHCl3). Ref. 29 ½aꢀD ¼ ꢁ159 (c 0.5,
CHCl3).
Compound (Sp,S)-2: Colorless solid, mp 79–80 ꢁC.
27
½aꢀD ¼ þ32:7 (c 0.3, CHCl3). IR (CHCl3): 2950, 1600,
4.3. Reduction of amides 10–12 (Table 1)
1400, 1140 cmꢁ1. FABMS (glycerol) m/z 350 [(M+1)+].
HRMS (FAB) (glycerol) Calcd for C24H32NO (M+1):
1
4.3.1.
(S)-[1-{(Sp)-[2.2]Paracyclophan-4-yl}methylpyrrol-
350.2484. Found: 350.2492. H NMR (CDCl3, 300 MHz)
idin-2-yl]methanol (Sp,S)-1. Lithium aluminum hydride
(32.6 mg, 0.86 mmol) was added to a solution of (Sp,S)-
10 (50.0 mg, 0.15 mmol) in THF (0.48 mL) at 0 ꢁC, and
the resulting mixture refluxed for 2 h. After cooling by
use of an ice bath, water (33 lL) was added carefully,
and 15% aqueous sodium hydroxide (33 lL) and then
water (100 lL) were added to the reaction mixture with
stirring. The mixture was filtered through a pad of Celite.
The filtrate was concentrated in vacuo, and the residue
purified with silica gel column chromatograpy (hexane/
d: 1.15 (3H, s, Me), 1.24 (3H, s, Me), 1.57–1.70 (3H, m),
1.77–1.83 (1H, m), 2.37 (1H, dd, J = 9.2, 7.2 Hz), 2.68–
2.74 (2H, m), 2.81–2.89 (1H, m), 2.93–3.16 (6H, m), 3.34
(1H, d, J = 13.7 Hz, –NCHHC), 3.54 (1H, t-like m), 4.10
(1H, d, J = 13.4 Hz, –NCHHC), 6.27 (1H, s, Ar),
6.36 (1H, dd, J = 7.8, 1.7 Hz, Ar), 6.42–6.54 (4H, m, Ar),
6.60 (1H, dd, J = 7.8, 1.7 Hz, Ar). 13C NMR (CDCl3,
100 MHz) d: 25.0 (CH2), 25.2 (Me), 27.9 (CH2), 28.8
(Me), 33.7 (Ar–CH2), 34.4 (Ar–CH2), 35.2 (Ar–CH2),
35.4 (Ar–CH2), 55.4 (NCH2CH2), 62.8 (CCH2N), 72.9
(C–OH), 73.6 (NCH), 128.8 (Ar, CH), 131.5 (Ar, CH),
131.9 (Ar, CH), 133.0 (Ar, CH), 133.1 (Ar, CH), 134.8
(Ar, CH), 134.9 (Ar, CH), 138.3 (Ar, C), 139.2 (Ar, C),
139.3 (Ar, C), 138.4 (Ar, C).
ethyl acetate, 4:1) to afford (Sp,S)-1 (43.6 mg, 91%) as a
28
colorless solid. Mp 157–158 ꢁC. ½aꢀD ¼ þ27:6 (c 0.6,
CHCl3). IR (CHCl3): 2950, 1600, 1120 cmꢁ1. FABMS
(glycerol) m/z 322 [(M+1)+]. HRMS (FAB) (glycerol)
Calcd for C22H28NO (M+1): 322.2171. Found: 322.2169.
1H NMR (CDCl3, 300 MHz) d: 1.57–1.63 (2H, m), 1.74–
1.89 (1H, m), 2.16 (1H, dd-like m), 2.62–2.66 (1H, m),
2.69–2.73 (1H, m), 2.82–2.88 (1H, m), 2.93–3.18 (7H, m),
3.44–3.50 (2H, m), 3.73 (1H, dd, J = 10.7, 3.4 Hz), 3.96
(1H, d, J = 12.5 Hz), 6.23 (1H, s, Ar), 6.38 (1H, dd,
J = 7.8, 1.7 Hz, Ar), 6.44–6.53 (4H, m, Ar), 6.58 (1H, dd,
J = 7.8, 1.7 Hz, Ar). 13C NMR (CDCl3, 100 MHz) d:
23.4 (CH2), 27.5 (CH2), 33.3 (Ar–CH2), 34.4 (Ar–CH2),
34.9 (Ar–CH2), 35.2 (Ar–CH2), 54.4 (CH2), 58.0 (CH2),
61.9 (CH2), 64.3 (N–CH) 128.8 (Ar, CH), 131.6 (Ar,
CH), 131.8 (Ar, CH), 132.8 (Ar, CH), 133.0 (Ar, CH),
134.7 (Ar, CH), 135.2 (Ar, CH), 137.3 (Ar, C), 138.2 (Ar,
C), 139.1 (Ar, C), 139.1 (Ar, C), 139.2 (Ar, C).
28
Compound (Sp)-13: Colorless solid, mp 111–112 ꢁC. ½aꢀD
¼
20
þ67:6 (c 0.9, CHCl3). Ref. 55 ½aꢀD ¼ þ68 (c 0.43, CHCl3).
IR (CHCl3): 2920, 1600 cmꢁ1. EIMS m/z 238 (M+, 64%),
134 (61), 119 (46), 105 (100), 104 (88), 91 (36). HRMS
1
(EI) Calcd for C17H18O: 238.1358. Found: 238.1361. H
NMR (CDCl3, 300 MHz) d: 2.81–2.91 (1H, m), 2.96–3.19
(6H, m), 3.40 (1H, ddd, J = 13.2, 10.1, 2.4 Hz), 4.38 (1H,
d, J = 12.9 Hz, OCHH), 4.71 (1H, d, J = 12.7 Hz, m,
OCHH), 6.37–6.40 (2H, m, Ar), 6.45–6.55 (4H, m, Ar),
6.60 (1H, dd, J = 7.9, 1.7 Hz, Ar). 13C NMR (CDCl3,
100 MHz) d: 32.9 (CH2), 34.5 (CH2), 35.2 (CH2), 35.4
(CH2), 64.6 (CH2OH), 128.9 (Ar, CH), 131.97 (Ar, CH),
132.01 (Ar, CH), 132.2 (Ar, CH), 133.1 (Ar, CH), 133.2

S. Sugiyama et al. / Tetrahedron: Asymmetry 17 (2006) 2847–2856
2853
(Ar, CH), 134.8 (Ar, CH), 137.3 (Ar, C), 139.1 (Ar, C),
139.1 (Ar, C), 139.4 (Ar, C), 139.6 (Ar, C). Enantiomeric
excess was measured as >99% ee (Sp-enantiomer) by HPLC
analysis (column; Chiralcel OD, eluent, hexane/i-PrOH,
4:1, flow rate; 0.5 mL/min, UV detector; 254 nm) [tR(Sp-
enantiomer) = 21.0 min, tR(Rp-enantiomer) = 28.0 min].
(Ar, C), 138.7 (Ar, C), 139.0 (Ar, C · 2), 139.4 (Ar, C),
147.1 (Ar, C), 148.5 (Ar, C).
4.3.6. (S)-1-{(Rp)-[2.2]Paracyclophan-4-yl}methyl-2-pyrrol-
idine-a,a-diphenylmethanol (Rp,S)-3 and (Rp)-13. Accord-
ing to the synthetic procedure of (Sp,S)-1 from (Sp,S)-10
described above, (Rp,S)-3 (473 mg, 83%) and (Rp)-13
(12.1 mg, 4%) were obtained from (Rp,S)-12 (585 mg,
1.2 mmol).
4.3.4.
(S)-1-Methyl-1-[1-{(Rp)-[2.2]paracyclophan-4-yl}-
methyl-2-pyrrolidin-2-yl]ethanol (Rp,S)-2 and (Rp)-13.
According to the synthetic procedure of (Sp,S)-1 from
(Sp,S)-10 described above, (Rp,S)-2 (39.6 mg, 82%) and
(Rp)-13 (4.2 mg, 12%) were obtained from (Rp,S)-11
(50.0 mg, 0.14 mmol).
Compound (Rp,S)-3: Colorless solid, mp 154–155 ꢁC.
25
½aꢀD ¼ ꢁ59:8 (c 0.4, CHCl3). IR (CHCl3): 2920, 2850,
1600, 1450, 1120 cmꢁ1. FABMS (magic bullet) m/z 474
[(M+1)+]. HRMS (FAB) (magic bullet) Calcd for
C34H36NO2 (M+1): 474.2797. Found: 474.2787. 1H
NMR (CDCl3, 400 MHz) d: 1.50–1.56 (2H, m), 1.64–1.70
(1H, m), 1.82–1.90 (1H, m), 2.18 (1H, q, J = 8.1 Hz),
2.43–2.50 (1H, m), 2.63–2.77 (2H, m), 2.90–3.21 (8H, m),
4.08 (1H, dd, J = 9.0, 5.6 Hz, NCHCH2), 5.62 (1H, dd,
J = 7.8, 1.7 Hz, Ar), 5.96 (1H, dd, J = 7.8, 2.0 Hz, Ar),
6.09 (1H, s, OH), 6.29–6.37 (3H, m, Ar), 6.42 (1H, dd,
J = 7.8, 1.7 Hz, Ar), 7.15 (1H, t, J = 7.3 Hz, Ar), 7.23–
7.32 (4H, m, Ar), 7.44–7.48 (2H, m, Ar), 7.61 (2H, dd,
J = 8.3, 1.2 Hz, Ar), 7.92 (2H, dd, J = 8.8, 1.2 Hz, Ar).
13C NMR (CDCl3, 100 MHz) d: 23.9 (CH2), 29.8 (CH2),
33.7 (Ar–CH2), 34.7 (Ar–CH2), 35.2 (Ar–CH2), 35.4
(Ar–CH2), 55.6 (N–CH2–CH2), 57.3 (CCH2N), 70.6
(NCH), 125.2 (Ar, CH), 125.2 (Ar, CH), 125.8 (Ar,
CH · 2), 126.0 (Ar, CH), 126.6 (Ar, CH), 128.0
(Ar, CH · 2), 128.2 (Ar, CH · 2), 128.5 (Ar, CH), 130.2
(Ar, CH), 131.8 (Ar, CH), 132.5 (Ar, CH), 132.9 (Ar,
CH), 134.0 (Ar, CH), 134.1 (Ar, CH), 137.3 (Ar, C),
138.7 (Ar, C · 2), 139.01 (Ar, C · 2), 139.6 (Ar, C), 146.8
(Ar, C).
Compound (Rp,S)-2: Colorless solid, mp 69–70 ꢁC.
27
½aꢀD ¼ ꢁ85:1 (c 0.8, CHCl3). IR (CHCl3): 2950, 1610,
1360, 1140 cmꢁ1. FABMS (glycerol) m/z 350 [(M+1)+].
HRMS (FAB) (glycerol) Calcd for C24H32NO (M+1):
1
350.2484. Found: 350.2492. H NMR (CDCl3, 300 MHz)
d: 1.20 (3H, s, Me), 1.33 (3H, s, Me), 1.58–1.71 (3H, m),
1.82–1.88 (1H, m), 2.24 (1H, td, J = 10.5, 6.8 Hz), 2.71–
3.14 (9H, m), 3.31 (1H, t-like m), 3.70 (2H, dd, J = 15.9,
14.2 Hz), 6.34 (1H, dd, J = 7.8, 1.7 Hz, Ar), 6.40 (1H, d,
J = 7.8 Hz, Ar), 6.46 (2H, d, J = 7.6 Hz, Ar), 6.54 (2H,
dd, J = 7.8, 2.0 Hz, Ar), 6.65 (1H, dd, J = 7.8, 2.0 Hz,
Ar). 13C NMR (CDCl3, 100 MHz) d: 25.1 (Me), 25.2
(CH2), 27.9 (CH2), 28.6 (Me), 33.4 (Ar–CH2), 34.5 (Ar–
CH2), 35.2 (Ar–CH2), 35.4 (Ar–CH2), 55.4 (NCH2CH2),
60.3 (CCH2N), 72.8 (C–OH), 73.1 (NCH), 128.1 (Ar,
CH), 130.5 (Ar, CH), 131.6 (Ar, CH), 133.0 (Ar, CH),
133.1 (Ar, CH), 133.2 (Ar, CH), 134.3 (Ar, CH), 137.6
(Ar, C), 138.7 (Ar, C), 138.9 (Ar, C), 139.3 (Ar, C), 139.8
(Ar, C).
4.3.5. (S)-1-{(Sp)-[2.2]Paracyclophan-4-yl}methyl-2-pyrrol-
idine-a,a-diphenylmethanol (Sp,S)-3 and (Sp)-13. Accord-
ing to the synthetic procedure of (Sp,S)-1 from (Sp,S)-10
described above, (Sp,S)-3 (362 mg, 64%) and (Sp)-13
(109 mg, 36%) were obtained from (Sp,S)-12 (585 mg,
1.2 mmol).
4.4. Synthesis of amino alcohol (Sp)-4 (Scheme 2)
4.4.1. Ethyl N-(2-hydroxy-2,2-diphenylethyl)carbamate
15. A solution of phenylmagnesium bromide in diethyl
ether (3.0 mol/L, 14.3 mL, 42.8 mmol) was added dropwise
to a solution of N-(ethoxycarbonyl)glycine ethyl ester 1434
(1.72 g, 10.7 mmol) in THF (21 mL) at 0 ꢁC. After being
stirred for 1 h at this temperature, the reaction was
quenched with saturated aqueous ammonium chloride.
The mixture was extracted with diethyl ether. The extracts
were combined, dried over magnesium sulfate, filtered, and
concentrated in vacuo to give 15 (2.02 g, 70%) as a colorless
solid. The solid was recrystallized from tert-butyl methyl
ether, and the crystal was used for the spectrum analysis.
Mp 124–125 ꢁC. IR (KBr): 3390, 1690, 1540, 1450, 1345,
1260, 1180, 1065, 965 cmꢁ1. FABMS (glycerol) m/z 272
[(M+1)+], 254 (MꢁH2O). HRMS (FAB) (glycerol) Calcd
for C16H18NO3 (M+1): 272.1287. Found: 272.1277. Anal.
Calcd for C16H17NO3: C, 70.83; H, 6.32; N, 5.17. Found:
Compound (Sp,S)-3: Colorless solid, mp 204–205 ꢁC.
25
½aꢀD ¼ ꢁ17:9 (c 0.8, CHCl3). IR (CHCl3): 2920, 2850,
1600, 1450, 1100 cmꢁ1. FABMS (magic bullet) m/z 474
[(M+1)+]. HRMS (FAB) (magic bullet) Calcd for
C34H36NO2 (M+1): 474.2797. Found: 474.2787. 1H
NMR (CDCl3, 400 MHz) d: 1.43–1.52 (2H, m), 1.57–1.63
(1H, m), 1.72–1.80 (1H, m), 2.09–2.23 (2H, m), 2.46–2.50
(1H, m), 2.64–2.74 (3H, m), 2.91–3.06 (5H, m), 3.49 (1H,
d, J = 12.0 Hz), 3.94 (1H, dd, J = 9.3, 5.4 Hz, NCHCH2),
5.82 (1H, dd, J = 7.8, 1.7 Hz, Ar), 6.05 (1H, s, OH), 6.15
(1H, dd, J = 7.8, 2.0 Hz, Ar), 6.31–6.35 (2H, m, Ar),
6.39–6.42 (2H, m, Ar), 7.10–7.14 (2H, m, Ar), 7.22–7.28
(3H, m, Ar), 7.42–7.46 (2H, m, Ar), 7.58 (2H, dd,
J = 8.3, 1.2 Hz, Ar), 7.94 (2H, dd, J = 8.5, 1.2 Hz, Ar).
13C NMR (CDCl3, 100 MHz) d: 23.5 (CH2), 29.7 (CH2),
33.1 (Ar–CH2), 33.9 (Ar–CH2), 35.0 (Ar–CH2), 35.4 (Ar–
CH2), 55.6 (NCH2CH2), 61.9 (CCH2N), 70.7 (NCH),
124.9 (Ar, CH · 2), 125.7 (Ar, CH · 2), 125.9 (Ar, CH),
126.5 (Ar, CH), 127.9 (Ar, CH · 2), 128.3 (Ar, CH · 2),
128.5 (Ar, CH), 131.9 (Ar, CH · 2), 132.8 (Ar, CH),
133.0 (Ar, CH), 134.6 (Ar, CH), 135.4 (Ar, CH), 138.2
1
C, 70.91; H, 6.54; N, 4.95. H NMR (CDCl3, 400 MHz)
d: 3.54 (3H, s, MeO), 3.63 (1H, br s, OH), 3.94 (2H, d,
J = 6.0 Hz, CH2), 5.11 (1H, br s, NH), 7.21–7.31 (2H, m,
Ar), 7.28–7.31 (4H, m, Ar), 7.38–7.40 (4H, m, Ar). 13C
NMR (CDCl3, 100 MHz) d: 50.6 (NCH2), 52.8 (Me),
78.1 (HOC), 125.9 (CH · 4, Ar), 127.1 (CH · 2, Ar) 128.2
(CH · 4, Ar), 144.3 (C · 2, Ar), 157.7 (C@O).

2854
S. Sugiyama et al. / Tetrahedron: Asymmetry 17 (2006) 2847–2856
4.4.2. 2-Methylamino-1,1-diphenylethanol 16. A mixture
of 15 (0.92 g, 3.43 mmol) and lithium aluminum hydride
(0.26 g, 6.86 mmol) in THF (8.6 mL) was refluxed for
16 h. After cooling, the reaction mixture was diluted with
diethyl ether (17 mL). Water (0.25 mL), 15% aqueous
sodium hydroxide (0.25 mL), and then water (0.75 mL)
were added. After being stirred for 1 h, the mixture was
filtered through a pad of Celite, and the filtrate was concen-
trated in vacuo to give 16 (0.75 g, 96%) as a colorless solid.
Mp 58–62 ꢁC. IR (CHCl3): 3400, 2980, 2940, 2840, 1445,
1115 cmꢁ1. EIMS m/z 227 (M+, 1.7%), 183 (26), 105 (58),
77 (36), 44 (100). HRMS (EI) Calcd for C15H17NO:
(25.7 mg, 77%) was obtained from (Sp)-17 (34.3 mg,
0.074 mmol) as a colorless viscous oil. ½aꢀD ¼ þ24:9 (c
26
0.5, CHCl3). IR (film): 3000, 2930, 2850, 1600, 1495,
1453, 1380 cmꢁ1. FABMS (glycerol) m/z 448 [(M+1)+],
221. HRMS (FAB) (glycerol) Calcd for C32H34NO
(M+1): 448.2642. Found: 448.2647. 1H NMR (CDCl3,
400 MHz) d: 2.56–2.63 (1H, m), 2.71–2.79 (1H, m), 2.90–
3.02 (m, 5H), 3.05 (1H, d, J = 12.7 Hz, NCHH), 3.25
(1H, t-like m), 3.34 (2H, s, NCH2), 3.47 (1H, d,
J = 12.7 Hz, NCHH), 6.09–6.20 (3H, m, Ar), 6.37–6.47
(4H, m, Ar), 7.16–7.25 (2H, m, Ar), 7.27–7.38 (4H, m,
Ar), 7.56 (2H, d, J = 16.3 Hz), 7.58 (2H, d, J = 16.6 Hz,
Ar). 13C NMR (CDCl3, 100 MHz) d: 33.4 (CH2), 34.5
(CH2), 35.1 (CH2), 35.4 (CH2), 44.0 (Me), 61.8 (CH2),
67.8 (CH2), 74.4 (C–OH), 125.6 (CH · 2, Ar), 125.7
(CH · 2, Ar), 126.5 (CH · 2, Ar), 128.0 (CH · 2, Ar),
128.1 (CH · 2, Ar), 131.5 (CH, Ar), 131.9 (CH, Ar),
132.9 (CH, Ar), 133.0 (CH, Ar), 134.6 (CH, Ar),
135.2 (CH, Ar), 137.3 (C, Ar), 138.4 (C, Ar), 139.1
(C, Ar), 139.2 (C, Ar), 139.4 (C, Ar), 147.1 (C, Ar), 147.2
(C, Ar).
1
227.1311. Found 227.1308. H NMR (CDCl3, 400 MHz)
d: 2.45 (3H, s, Me), 3.28 (2H, s, CH2), 7.19–7.25 (2H, m,
Ar), 7.29–7.33 (4H, t-like m, Ar), 7.45–7.47 (4H, d-like
m, Ar). 13C NMR (CDCl3, 100 MHz) d: 36.7 (Me), 61.2
(CH2), 76.2 (C–OH), 125.9 (CH · 4, Ar), 126.8 (CH · 2,
Ar), 128.1 (CH · 4, Ar), 145.5 (C · 2, Ar).
4.4.3.
N-(2-Hydroxymethyl-2,2-diphenyl)ethyl-N-methyl-
(Sp)-[2.2]paracyclophane-4-carboxamide (Sp)-17. Thionyl
chloride (50 lL, 0.68 mmol) was added dropwise to a mix-
ture of (S)-4-carboxy[2.2]paracyclophane (Sp)-5 (44 mg, 0.18
mmol) and DMF (10 lL) in benzene (0.6 mL) in an atmo-
sphere of argon at room temperature. After being stirred for
2 h at 70 ꢁC, the reaction mixture was concentrated in vacuo.
4.5. General procedure for the addition of diethylzinc to
benzaldehyde (Table 2)
A solution of diethylzinc in hexane (0.99 mol/L, 0.67 mL)
was added dropwise to a solution of amino alcohol
(Sp,S)-1 (4.8 mg, 0.015 mmol) in toluene (0.6 mL) at 0 ꢁC
in an atmosphere of argon. After being stirred for
30 min, benzaldehyde (31.8 mg, 0.3 mmol) was added.
The mixture was stirred for 2 h at 0 ꢁC and then for 16 h
while being allowed to warm to room temperature. The
reaction was quenched with ice-cooled 5% hydrochloric
acid, and the mixture was extracted with diethyl ether.
The extracts were combined, dried over magnesium, fil-
tered, and triphenylmethane (18.3 mg, 0.075 mmol) was
added as an internal standard. The mixture was concen-
trated in vacuo, and the yield of 1-phenyl-1-propanol was
Amino alcohol 16 (65 mg, 0.29 mmol), DMAP (2.6 mg)
and triethylamine (54 mL, 0.39 mmol) were added to a
solution of the residue in dichloromethane (0.65 mL) with
stirring at 0 ꢁC. The resulting mixture was stirred for 12 h
and allowed to warm to room temperature. The resulting
mixture was poured into saturated aqueous ammonium
chloride solution and extracted with dichloromethane.
The organic extracts were combined, dried over magnesium
sulfate, filtered, and concentrated in vacuo. The residue
was chromatographed on silica gel (hexane/ethyl acetate;
1:1) to give (Sp)-17 as a colorless amorphous foam.
23
1
½aꢀD ¼ þ28:8 (c 0.5, CHCl3). IR (CHCl3): 3370, 3000,
calculated as 20% by H NMR integral value. Enantio-
2930, 1735, 1665, 1610, 1530, 1495, 1455 cmꢁ1. FABMS
(glycerol) m/z 461 [(M+1)+], 444 (MꢁH2O). HRMS
(FAB) (glycerol) Calcd for C32H32NO2 (M+1): 462.2435.
Found: 462.2425. 1H NMR (CDCl3, 400 MHz) d: 2.26
(3H, s, Me), 2.73–2.80 (1H, m), 2.85–3.00 (4H, m), 3.08–
3.20 (3H, m), 4.26 (1H, d, J = 13.9 Hz, NCHH), 4.55
(1H, d, J = 13.9 Hz, NCHH), 6.19 (1H, s, Ar), 6.32–6.39
(3H, m, Ar), 6.47–6.55 (3H, m, Ar), 6.99 (1H, m, Ar),
7.24–7.28 (2H, m, Ar), 7.33 (4H, m, Ar), 7.56 (2H, d,
J = 7.6 Hz, Ar), 7.61 (2H, d, J = 7.3 Hz, Ar). 13C NMR
(CDCl3, 100 MHz) d: 33.6 (CH2), 35.26 (CH2), 35.34
(CH2), 35.4 (CH2), 40.0 (Me), 60.4 (CH2N), 79.1 (C–
OH), 126.2 (CH2 · 2, Ar), 126.3 (CH · 2, Ar), 126.9 (CH,
Ar), 127.0 (CH, Ar), 127.9 (CH · 2, Ar), 128.0 (CH · 2,
Ar), 130.6 (CH, Ar), 131.6 (CH, Ar), 132.2 (CH, Ar),
132.3 (CH, Ar), 132.5 (CH, Ar), 132.8 (CH, Ar), 134.4
(CH, Ar), 134.8 (CH, Ar), 137.7 (C, Ar), 138.9 (C, Ar),
139.1 (C, Ar), 139.7 (C, Ar), 145.3 (C, Ar), 145.8 (C, Ar),
174.5 (C@O).
meric excess was measured as 54% ee [(S)-enantiomer] by
HPLC analysis.
4.6. General conditions for HPLC analysis of the chiral
alcohols
Chiralcel OD column eluted with hexane/2-propanol (97:3,
Method A or 98:2, Method B) at 0.5 mL/min using UV
detector at 254 nm. All the absolute configurations were
determined as (S) by the comparison of the known elution
order from a chiral OD column.56–60
4.6.1. (S)-1-Phenyl-1-propanol. Method B: tR = 20.6 min
and tS = 24.3 min.57–59
4.6.2. (S)-1-(p-Methoxyphenyl)-1-propanol. Method A:
tR = 32.2 min and tS = 38.3 min (4% ee).57–60
4.6.3. (S)-1-(m-Methoxyphenyl)-1-propanol. Method B:
tR = 49.3 min and tS = 51.7 min (86% ee).57,60
4.4.4. 2-{N-Methyl-N-(Sp)-[2.2]paracyclophan-4-ylmethyl}-
amino-1,1-diphenylethanol (Sp)-4. According to the syn-
thetic procedure of (Sp,S)-1 from (Sp,S)-10, (Sp)-4
4.6.4. (S)-1-(o-Methoxyphenyl)-1-propanol. Method A:
tR = 29.6 min and tS = 26.1 min (57% ee).59,60

S. Sugiyama et al. / Tetrahedron: Asymmetry 17 (2006) 2847–2856
2855
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