Asymmetric ortho-lithiation of 1,n-dioxa[n]paracyclophane derivatives for the generation of planar chirality

Article abstract of DOI:10.1016/j.tet.2011.12.031

The asymmetric induction of planar chirality in 1,n-dioxa[n]paracyclophane derivatives via asymmetric ortho-lithiation is described. Enantioselective ortho-lithiation of unflippable 1,n-dioxa[n]paracyclophanes (n≤11) using sec-BuLi-(-)-sparteine at -78 °C

Full text of DOI:10.1016/j.tet.2011.12.031

Tetrahedron 68 (2012) 1407e1416
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Asymmetric ortho-lithiation of 1,n-dioxa[n]paracyclophane derivatives for the
generation of planar chirality
,
Kazumasa Kanda a, Risa Hamanaka a, Kohei Endo b, Takanori Shibata a
*
a Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 65-504, 3-4-1, Okubo, Shinjuku, Tokyo 169-8555, Japan
b Waseda Institute for Advanced Study, 1-6-1, Nishiwaseda, Shinjuku, Tokyo 169-8050, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric induction of planar chirality in 1,n-dioxa[n]paracyclophane derivatives via asymmetric
ortho-lithiation is described. Enantioselective ortho-lithiation of unflippable 1,n-dioxa[n]paracyclophanes
(nꢀ11) using sec-BuLi-(ꢁ)-sparteine at ꢁ78 ꢂC and subsequent treatment with electrophiles gave the
corresponding planar-chiral monosubstituted paracyclophanes with excellent ee. Further lithiation of
these compounds and treatment with electrophiles gave planar-chiral paracyclophanes with two dif-
ferent substituents. Dilithiation of unflippable 1,n-dioxa[n]paracyclophanes gave the corresponding C2-
symmetrical disubstituted products with almost perfect ee. In the case of flippable 1,n-dioxa[n]para-
cyclophanes (nꢃ12), a stepwise reaction was required for the highly enantioselective formation of di-
substituted products.
Received 21 November 2011
Received in revised form 12 December 2011
Accepted 12 December 2011
Available online 19 December 2011
Keywords:
Enantioselective
ortho-Lithiation
Planar chirality
Paracyclophane
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
of cyclooctenes sensitized by planar-chiral paracyclophane.4i In
these cases, enantiomerically enriched compounds were generally
Paracyclophane consists of a benzene ring with an ansa chain
connecting the para positions.1a,b,2 Unsubstituted paracyclophanes
are symmetrical and achiral. In contrast, monosubstituted [n]par-
acyclophanes (nꢀ11) have planar chirality, and the enantiomers
can be resolved at rt based on sterically hindered rotation of the
ansa chain around the benzene ring.2aec In the case of [n]para-
cyclophanes with longer ansa chains (nꢃ12), the enantiomers of
monosubstituted compounds interconvert to each other at rt.
However, disubstituted [n]paracyclophanes can be resolved into
enantiomers when the ansa chain cannot be flipped.2d Due to their
unique bridged structure, planar-chiral paracyclophanes have been
widely applied as chiral motifs in functional materials and chiral
reagents.3a,b,4 Miyano used a planar-chiral paracyclophane as
a chiral stationary phase for HPLC and a chiral auxiliary.4a,b They
also reported the stereospecific conversion of planar-chiral naph-
thalenophane into axial-chiral binaphthyl.4c Scherf synthesized
chiral poly(para-phenylene) polymers containing planar-chiral
paracyclophane moieties and investigated their chiroptical prop-
erties.4d,e Kanomata used planar-chiral pyridinophanes as co-
enzyme NADH models,4f,g and their planar-chiral pyridinium ylides
in an enantioselective cyclopropanation.4h Recently, Inoue and
Kanomata reported the enantiodifferentiating photoisomerization
prepared by the optical resolution of a racemic mixture or the
asymmetric crystallization of diastereomers. For example, Kano-
mata achieved efficient stereocontrol of the planar chirality of [10]
pyridinophanes and [11]paracyclophanes with a thermodynami-
cally flexible ansa chain by the crystallization-induced or
adsorption-induced dynamic resolution of diastereomeric
mixtures.5aec
On the other hand, a more straightforward approach to the
synthesis of planar-chiral paracyclophanes is an enantioselective
reaction.6 A pioneering study by Zhu described an intramolecular
SNAr etherification using a stoichiometric amount of chiral qua-
ternary ammonium salt (up to 20% ee).6a The chiral Rh- or Pd-
catalyzed coupling of dithiol with dibromide has been reported
as another protocol by Tanaka (up to 60% ee).6b,c We previously
reported a dynamic kinetic resolution of diiodoparacyclophanes
possessing a flippable ansa chain through the use of asymmetric
consecutive Sonogashira coupling (up to 79% ee).7 Recently, the
Rh-catalyzed [2þ2þ2] cycloaddition of alkynes was reported for
the synthesis of [n]paracyclophanes with short ansa chain (nꢀ9)
by Tanaka (up to 75% ee).6d Among these previous examples, our
protocol gave the best enantioselectivity,7 but it was not excellent.
Therefore, the development of a highly enantioselective and
widely convertible synthesis of planar-chiral paracyclophanes is
still a challenging topic.8,9 In this report, we describe an asym-
metric ortho-lithiation for the highly enantioselective synthesis of
various paracyclophanes.10aec,11aed The asymmetric ortho-
* Corresponding author. Tel./fax: þ81 3 5286 8098; e-mail address: tshibata@
waseda.jp (T. Shibata).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.031

1408
K. Kanda et al. / Tetrahedron 68 (2012) 1407e1416
lithiation of an achiral [n]paracyclophane with directed moieties at
the 1 and n positions of its ansa chain would proceed with a chiral
lithium reagent. Furthermore, the second lithiation would give
a C2-symmetric dilithio paracyclophane. Subsequent treatment of
these aryllithiums with various electrophiles would afford mono-
and disubstituted planar-chiral paracyclophanes, respectively
(Scheme 1).12
reaction conditions, and planar-chiral (þ)-2aa was obtained in high
yield with excellent ee (entry 2). An equivalent amount of L1 was
sufficient to achieve high yield and excellent ee (entry 3). Even
a catalytic amount of L1 was enough to realize good enantiose-
lectivity (entries 4 and 5).13aec,14aek (þ)-Sparteine surrogate L215a,b
achieved the opposite enantioinduction to give (ꢁ)-2aa (entries
6 and 7).
We next examined various electrophiles (El) other than iodine
(Table 2). Treatment of the monolithiated compound with chloro-
trimethylsilane, chlorodiphenylphosphine, iodomethane, N,N-
dimethylformamide (DMF), or benzophenone gave the corre-
sponding planar-chiral silane 2ab, phosphine 2ac, methylated
product 2ad, aldehyde 2ae, or tertiary alcohol 2af with excellent ee
(entries 1e5).16 Enantioselective ortho-lithiation of 1,10-dioxa[10]
paracyclophane 1b with a shorter ansa chain also proceeded, and
treatment of the aryllithium with iodine, chlorotrimethylsilane, or
chlorodiphenylphosphine gave the corresponding iodinated prod-
uct 2ba, silylated product 2bb, or phosphinated product 2bc with
excellent ee (entries 6e8).17
Table 2
Reaction of ortho-lithiated 1,n-dioxa[n]paracyclophane with various electrophiles
Scheme 1. Concept of asymmetric ortho-lithiation of paracyclophane.
2. Results and discussion
Entry
n
x (equiv) Electrophiles
R
Yield (%) ee (%)
75 (2ab) 97a
2.1. Enantioselective monosubstitution of 1,n-dioxa[n]
paracyclophanes
1a
2
3
4
5
6
7
8
11 (1a)
11 (1a)
11 (1a)
11 (1a)
11 (1a)
10 (1b) 1.2
10 (1b) 1.2
10 (1b) 1.2
2
2
2
2
2
Me3SiCl
Ph2PCl
MeI
SiMe3
PPh2
Me
58 (2ac)
74 (2ad)
70 (2ae)
98
95
97
95
97
First, we chose 1,11-dioxa[11]paracyclophane 1a as a substrate
for enantioselective ortho-lithiation. This paracyclophane has oxy-
gen atoms as directed moieties, and the ansa chain is unflippable at
rt.2aec We examined the ortho-lithiation of 1a using 2 equiv of sec-
butyllithium at ꢁ78 ꢂC in Et2O along with the addition of iodine as
DMF
CHO
Benzophenone C(OH)Ph2 84 (2af)
I2
I
81 (2ba)
Me3SiCl
Ph2PCl
SiMe3
PPh2
75 (2bb) 97a
35 (2bc)
98
a
ee was determined as 2aa and 2ba by the conversion of trimethylsilyl group into
iodo one using N-iodosuccinimde.
an electrophile. As
a
result, the corresponding mono-
iodoparacyclophane 2aa was obtained in moderate yield, and the
enantiomers were resolved by HPLC analysis using a chiral column
as expected (Table 1, entry 1). We next examined an enantiose-
lective lithiation using 2 equiv of (ꢁ)-sparteine L1 under the same
We further investigated the reaction of achiral 1,n-dioxa[n](1,4)
naphthalenophanes (Table 3). The enantioselective lithiation of
1,11-dioxa[11](1,4)naphthalenophane 3a along with the addition of
iodine gave the corresponding planar-chiral 20-iodo product 4a in
high yield with excellent ee (entry 1). The catalytic reaction of 3a
also proceeded, and 4a was obtained with good ee (entry 2).
Enantioselective lithiation of [n](1,4)naphthalenophanes 3b
(n¼12), 3c (n¼14), and 3d (n¼16) was also possible, and treatment
of the resulting aryllithiums with iodine gave the corresponding
Table 1
Investigation of reaction conditions
Table 3
Enantioselective ortho-lithiation of 1,n-dioxa[n](1,4)naphthalenophanes
Entry
Ligand
x (equiv)
Time (h)
Yield (%)
ee (%)a
Entry
n
x (equiv)
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
None
L1
L1
L1
L1
d
2
1
0.5
0.2
2
5
1
2
3
5
1
4
57
91
89
87
84
82
79
d
98 (þ)
97 (þ)
93 (þ)
76 (þ)
91 (ꢁ)
74 (ꢁ)
1
2
3
4
5
6
11 (3a)
11 (3a)
12 (3b)
12 (3b)
14 (3c)
16 (3d)
1
0.2
1
0.2
2
2
2
5
10
10
24
72
95 (4a)
93 (4a)
88 (4b)
17 (4b)
82 (4c)
76 (4d)
97
81
93
NDa
94
92
L2
L2
0.2
a
a
Signs of optical rotation are shown in the parentheses.
Not determined.

K. Kanda et al. / Tetrahedron 68 (2012) 1407e1416
1409
planar-chiral 20-iodo products 4b, 4c, and 4d18 with more than 90%
ee (entries 3, 5, and 6). However, the lithiation of [n](1,4)naph-
thalenophanes with longer ansa chains (nꢃ12) was sluggish, and
a catalytic reaction gave the product 4b in low yield (entry 4).
In the case of enantioselective dilithiation, a catalytic amount
of L1 achieved higher ee (around 90%) than that in mono-
lithiation (entries 2 and 4), since kinetic resolution occurred at
the second lithiation. In fact, the ee of the monoiodo products
2ba and 2aa, which were obtained as by-products, was low
(2ba: 11% ee in entry 2, 2aa: 53% ee in entry 4). We also ex-
amined the enantioselective disubstitution of 1a by using vari-
ous electrophiles under the same reaction conditions: C2-
symmetrical diphosphine 5ac, para-xylene derivative 5ad, dia-
ldehyde 5ae, and diol 5af were obtained with almost perfect
enantioselectivity (entries 5e8). Next, we investigated the dili-
thiation of 1,n-dioxa[n]paracyclophane with a longer ansa chain
(nꢃ12). In these cases, the reactivity and enantioselectivity of
lithiation were lower than those with 1,n-dioxa[n]para-
cyclophane (nꢀ11). When 1,12-dioxa[12]paracyclophane 1c was
used, the ee was still high (82%) but the yield was low (38%) in
the presence of 1 equiv of (ꢁ)-sparteine for 12 h (entry 9). The
use of 4 equiv of (ꢁ)-sparteine with a longer reaction time
drastically improved the yield and slightly increased the ee
2.2. Enantioselective disubstitution via dilithiation
We next investigated dilithiation for the synthesis of planar-
chiral disubstituted [n]paracyclophanes (n¼10 or 11) with C2
symmetry (Table 4). After the first lithiation at ꢁ78 ꢂC, the second
lithiation was examined by the addition of 2 equiv of sec-butyl-
lithium at ꢁ20 ꢂC along with treatment with iodine. The reaction of
1b gave C2-symmetrical planar-chiral diiododioxa[10]para-
cyclophane 5ba in high yield with excellent ee with the use of
a stoichiometric amount of sparteine (entry 1). The reaction of
diiododioxa[11]paracyclophane 5aa realized almost perfect enan-
tioselectivity (entry 3). Moreover, its recrystallization yielded
a single crystal, and the absolute configuration was determined to
be S by X-ray diffraction analysis (Fig. 1).
Table 4
Enantioselective dilithiation of 1,n-dioxa[n]paracyclophanes
Entry
n
x (equiv)
Time (h)
El
R
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
10 (1b)
10 (1b)
11 (1a)
11 (1a)
11 (1a)
11 (1a)
11 (1a)
11 (1a)
12 (1c)
12 (1c)
13 (1d)
14 (1e)
15 (1f)
16 (1g)
17 (1h)
17 (1h)
1
0.2
1
0.2
1
1
1
1
1
4
4
4
4
4
4
4
12
24
12
24
12
12
12
12
12
24
48
48
48
48
72
72
I2
I2
I2
I2
I
I
I
I
91 (5ba)
82 (5ba)
79 (5aa)
53 (5aa)
55 (5ac)
76 (5ad)
73 (5ae)
84 (5af)
38 (5ca)
60 (5ca)
62 (5da)
65 (5ea)
48 (5fa)
50 (5ga)
53 (5ha)
73 (5hc)
98
87
99
89
99a
99
99
99
82
88
89
86
84
77
db
55a
Ph2PCl
MeI
DMF
benzophenone
I2
I2
I2
I2
PPh2
Me
CHO
C(OH)Ph2
I
I
I
I
9
10
11
12
13
14
15
16
I2
I2
I2
I
I
I
Ph2PCl
PPh2
a
The obtained diphosphine were oxidized by hydrogen peroxide, and their ee was determined as the corresponding diphosphine oxides.
HPLC analyses of racemic 5ha using various chiral columns showed a single peak, and the value of optical rotation of the obtained 5ha in entry 15 was almost zero.
b
(entry 10). The enantioselectivity gradually decreased along with
the elongation of the ansa chain (entries 11e13). In particular, in
the reaction of 1,16-dioxa[16]paracyclophane 1g, the ee of the
obtained product 5ga was significantly decreased (entry 14).
This difference in enantioselectivity depending on the length of
the ansa chain can be explained as follows: monolithiated
product with a short ansa chain (nꢀ11) is unflippable, and pla-
nar chirality was induced at the first lithiation at low tempera-
ture in
a highly enantioselective manner. Therefore the
subsequent second lithiation gave dilithiated product with ex-
cellent ee with the aid of kinetic resolution. On the other hand,
monolithiated product with a longer ansa chain (nꢃ12) is con-
sidered to be flippable2d and chirality was not induced. There-
fore, planar chirality was induced at the second lithiation at
higher temperature only by dynamic kinetic resolution, which
could not achieve excellent enantioselectivity (Scheme 2).
Therefore, lithiation at low temperature is crucial for the in-
duction of high enantioselectivity.
Fig. 1. ORTEP diagram of (S)-5aa.

1410
K. Kanda et al. / Tetrahedron 68 (2012) 1407e1416
chlorotrimethylsilane gave monosilylated paracyclophanes
2cbegb. Next, we examined the second ortho-lithiation of these
silyl paracyclophanes using sec-butyllithium and (ꢁ)-sparteine as
a
chiral amine, and subsequent treatment with chloro-
trimethylsilane gave a C2-symmetrical disilylated product. In the
case of [12]paracyclophane 2cb, the enantioselective induction in
the obtained disilylated product 5cb was ascertained (18% ee),19 but
the ee was much lower than that of the diiodo product via dili-
thiation (entry 1). The reason for the low selectivity is that the ansa
chain of 2cb flips slowly at ꢁ78 ꢂC, and dynamic kinetic resolution
of 2cb did not proceed selectively. On the other hand, the lithiation
of monosilylated paracyclophane with a longer ansa chain, such as
2db, 2eb, 2fb, and 2gb, proceeded with excellent enantioselectivity,
and C2-symmetric disubstituted paracyclophanes were obtained
(entries 2e5).
Scheme 2. Different asymmetric induction dependent on the length of ansa chains.
In the case of [17]paracyclophane, diiodo product 5ha was
probably flippable, and we did not observe planar chirality (entry
15). Therefore, we introduced diphenylphosphinyl groups as bulk-
ier substituents than iodo groups. As a result, the induction of
planar chirality was ascertained, and diphosphine 5hc was ob-
tained in 55% ee (entry 16). These results mean that dilithium
complex derived from [17]paracyclophane could induce planar
chirality.
2.4. Enantioselective disubstitution using different
electrophiles via stepwise monolithiation
Finally, we demonstrated disubstitution by stepwise mono-
lithiation for the enantioselective synthesis of unsymmetrical par-
acyclophanes with two different substituents (Table 6). We
synthesized chiral silylated paracyclophanes 2ab and 2bb under
the conditions in Table 2. We next examined the ortho-lithiation of
2ab and 2bb using sec-butyllithium and TMEDA at ꢁ20 ꢂC and
treatment with various electrophiles, such as iodine, iodomethane,
dimethylformamide, and benzophenone (entries 1e5). As a result,
chiral paracyclophanes with iodo, methyl, formyl, and diphe-
nylhydroxymethyl groups in addition to a silyl group were obtained
without any loss of enantiopurity.
2.3. Enantioselective disubstitution via stepwise
monolithiation
We focused on the enantioselective disubstitution of 1,n-dioxa
[n]paracyclophane with a flippable ansa chain (nꢃ12) via stepwise
monolithiation (Table 5). ortho-Lithiation of 1ceg using sec-butyl-
lithium and N,N,N0,N0-tetramethylethylenediamine (TMEDA) as
an achiral amine at ꢁ78 ꢂC along with treatment with
Table 5
Stepwise monolithiation of 1,n-dioxa[n]paracyclophane with a flippable ansa chain
Entry
n
Yield of 2 %
Time (h)
Yield of 5 (%)
ee of 5 (%)
1
2
3
4
5
12 (1c)
13 (1d)
14 (1e)
15 (1f)
16 (1g)
76 (2cb)
57 (2db)
92 (2eb)
53 (2fb)
27 (2gb)
72
48
48
48
48
66 (5cb)
73 (5db)
84 (5eb)
95 (5fb)
64 (5gb)
18a
95a
93a
93b
91b
a
The disilylparacyclophanes were treated with NBS, and their ee was determined as the corresponding dibrominated products.
The disilylparacyclophanes were treated with NIS, and their ee was determined as the corresponding diiodinated products.
b
Table 6
Stepwise lithiation for asymmetric synthesis of planar-chiral 1,n-dioxa[n]paracyclophane with two different substituents
Entry
n
Electrophile (El)
R
Yield of 6 (%)
ee of 6 (%)
1
2
3
4
5
10 (2bb)
11 (2ab)
11 (2ab)
11 (2ab)
11 (2ab)
I2
I2
MeI
DMF
I
I
71 (6ba)
70 (6aa)
78 (6ad)
73 (6ae)
82 (6af)
97
97
96
97
97
Me
CHO
C(OH)Ph2
Benzophenone

K. Kanda et al. / Tetrahedron 68 (2012) 1407e1416
1411
2.5. Use of obtained phosphines as chiral ligands
PerkineElmer PE2400II. Optical rotations were measured with
Jasco DIP-1000 polarimeter. X-ray crystallographic analyses were
measured on a Rigaku R-AXIS RAPID diffractometer using graphite
As a preliminary application of the obtained planar-chiral par-
acyclophanes as chiral ligands, we used monophosphines 2ac and
2bc in silver-catalyzed allylation of imine (Scheme 3).20 As a result,
moderate enantioselectivity was achieved by both of them.
monochromated Mo Ka radiation. Physical properties of the com-
pounds, which were already listed in the precedent communica-
tion,12 were omitted.
4.2. Syntheses of 1,n-dioxa[n]paracyclophanes and 1,n-dioxa
[n](1,4)naphthalenophanes 1
Hydroquinone or 1,4-dihydroxynaphthalene (5.0 mmol) and the
corresponding dibromide (5.0 mmol) in dehydrated DMF (30 mL)
were added dropwise over 12 h to
a suspension of K2CO3
(12.5 mmol) in dehydrated DMF (50 mL) at 140 ꢂC. The reaction
mixture was cooled to rt and filtered with Celite. The filtrate was
treated with saturated NH4Cl aqueous solution and extracted with
ethyl acetate. The organic layer was washed with water and brine.
The extract was dried over Na2SO4 and evaporated under reduced
pressure. The residue was filtered through a short plug of silica gel
with dichloromethane and the filtrate was evaporated under re-
duced pressure. The crude products were purified by flash column
chromatography (hexane/AcOEt¼30/1w20/1) and GPC (1,2-
dichloroethane) to give dioxaparacyclophanes 1.
Scheme 3. Ag-catalyzed enantioselective allylation of imine using monophosphines
2ac and 2bc as chiral ligands.
3. Conclusions
We have developed a highly enantioselective synthesis of
planar-chiral 1,n-dioxa[n]paracyclophanes via asymmetric ortho-
lithiation and dilithiation. In the case of paracyclophane with
a short ansa chain (nꢀ11), which is unflippable, enantioselective
ortho-lithiation using sec-butyllithium and sparteine at ꢁ78 ꢂC and
further lithiation at ꢁ20 ꢂC gave planar-chiral monolithiated and
C2-symmetric dilithiated paracyclophanes, respectively, with ex-
cellent ee. Subsequent treatment of these lithium salts with various
electrophiles gave planar-chiral mono- and disubstituted para-
cyclophanes. In the case of paracyclophane with a long ansa chain
(nꢃ12), which is flippable, disubstitution by stepwise lithiation is
required for high enantioselectivity: monosubstituted para-
cyclophanes were lithiated at ꢁ78 ꢂC in the presence of sparteine
and treated with various electrophiles to give disubstituted para-
cyclophanes with high ee. These protocols gave various planar-
chiral 1,n-dioxa[n]paracyclophane derivatives with excellent ee,
which could undergo further transformation.
4.2.1. 1,12-Dioxa[12]paracyclophane (1c). White solid. Mp 60 ꢂC; IR
(KBr) 2929, 2854, 1504, 1200, 843 cmꢁ1 1H NMR (400 MHz)
;
d
0.71e0.83 (m, 4H), 0.90e1.02 (m, 4H), 1.12e1.24 (m, 4H),
1.58e1.69 (m, 4H), 4.16e4.28 (t, J¼5.6 Hz, 4H), 6.93 (s, 4H); 13C NMR
(100 MHz)
d
23.8, 27.0, 27.3, 28.2, 69.5, 119.5, 153.4; HRMS (FABþ)
for Mþ found m/z 248.1770, calcd for C16H24O2 248.1776.
4.2.2. 1,13-Dioxa[13]paracyclophane (1d). White solid. Mp 68 ꢂC; IR
(KBr) 2925, 2858, 1506, 1045, 837 cmꢁ1 1H NMR (400 MHz)
;
d
0.66e0.78 (m, 2H), 0.88e1.01 (m, 4H), 1.02e1.14 (m, 4H),
1.16e1.29 (m, 4H), 1.55e1.67 (m, 4H), 4.21 (t, J¼5.6 Hz, 4H), 6.90 (s,
4H); 13C NMR (100 MHz)
d 24.1, 26.8, 27.3, 28.0, 28.4, 68.9, 118.5,
152.9; HRMS (FABþ) for Mþ found m/z 262.1940, calcd for C17H26O2:
4. Experimental section
4.1. General
262.1933.
4.2.3. 1,14-Dioxa[14]paracyclophane (1e). White solid. Mp 47 ꢂC; IR
(KBr) 2927, 2854, 1506, 1460, 1241, 1224, 1205, 1011, 831 cmꢁ1 1H
;
All reactions were examined under an argon atmosphere in
oven-dried glassware with a magnetic stirring bar. Hexane and
cyclohexane solution of sec-butyllithium (1.0 M) were purchased
from Kanto Chemical Co., Inc. Dehydrated diethyl ether, tetrahy-
drofuran (THF), and dichloromethane were purchased from Wako
Pure Chemical Industries Ltd. (Wako), and purified by the method
by Grubbs21 before use. Other dehydrated solvents were purchased
NMR (400 MHz) d 0.89e1.01 (br s, 8H), 1.08e1.20 (m, 4H), 1.27e1.38
(m, 4H), 1.59e1.68 (m, 4H), 4.17 (t, J¼5.7 Hz, 4H), 6.87 (s, 4H); 13C
NMR (100 MHz)
d 23.9, 27.2, 27.5, 27.8, 28.4, 68.4, 117.7, 152.4;
HRMS (FABþ) for Mþ found m/z 276.2082, calcd for C18H28O2:
276.2089.
4.2.4. 1,15-Dioxa[15]paracyclophane (1f). Colorless oil; IR (neat)
2925, 2854, 1504, 1205, 827 cmꢁ1; 1H NMR (400 MHz)
d 0.88e1.13
ꢀ
from Kanto or Wako, and dried over activated molecular sieves 3 A
ꢀ
or 4 A. (ꢁ)-Sparteine L1 was purchased from Tokyo Chemical In-
(m, 10H), 1.15e1.28 (m, 4H), 1.32e1.42 (m, 4H), 1.58e1.69 (m, 4H),
dustry Co., Ltd. (TCI) and distilled from CaH2 before use. Chiral di-
amine ligands L2 was prepared according to the literature.15 Other
reagents were purchased from Wako, Kanto, TCI, or Aldrich and
were used without further purification. Flash column chromatog-
raphy was performed with silica gel (Kanto Chemical Co., Inc. 60 N
4.14 (t, J¼5.6 Hz, 4H), 6.85 (s, 4H); 13C NMR (100 MHz)
d 23.8, 27.4,
27.4, 28.0, 28.1, 29.5, 68.0, 117.2, 152.4; HRMS (FABþ) for Mþ found
m/z 290.2248, calcd for C19H30O2: 290.2246.
4.2.5. 1,16-Dioxa[16]paracyclophane (1g). White solid. Mp 49 ꢂC; IR
40e50
mm). Preparative thin-layer chromatography (PTLC) was
(KBr) 2924, 2854, 1508, 1211, 1059, 820 cmꢁ1 1H NMR (400 MHz)
;
performed with silica gel-precoated glass plates (Merck 60 GF254
)
d 0.97e1.19 (m, 12H), 1.19e1.32 (m, 4H), 1.34e1.64 (m, 4H),
prepared in our laboratory. Gel permeation chromatography (GPC)
was performed on JAI LC-908. IR spectra were recorded with Horiba
FT730 spectrophotometer. NMR spectra were measured with JEOL
AL-400 (400 MHz), JEOL ECS400 (400 MHz), JEOL ECX500
(500 MHz), or JEOL Lambda 500 (500 MHz) using TMS as an in-
ternal standard and CDCl3 was used as a solvent. High-resolution
mass spectra (HRMS) were measured on a JEOL JMS-SX102A with
FAB (Fast Atomic Bombardment) method or JMS-T100CS with ESI
(Electro Spray Ionization) method, and elemental analyses with
1.60e1.71 (m, 4H), 4.10 (t, J¼5.9 Hz, 4H), 6.84 (s, 4H); 13C NMR
(100 MHz) d 24.0, 27.1, 27.4, 27.9, 28.3, 28.8, 67.9, 116.6, 152.4; HRMS
(FABþ) for Mþ found m/z 304.2416, calcd for C20H32O2: 304.2402.
4.2.6. 1,17-Dioxa[17]paracyclophane (1h). Colorless oil; IR (neat)
2925, 2854, 1506, 1236, 1207, 835 cmꢁ1 1H NMR (400 MHz)
;
d
1.01e1.23 (m, 14H), 1.23e1.34 (m, 4H), 1.37e1.48 (m, 4H),
1.62e1.73 (m, 4H), 4.07 (t, J¼6.1 Hz, 4H), 6.83 (s, 4H); 13C NMR
(100 MHz)
d 24.1, 27.3, 27.7, 28.1, 28.3, 28.8, 29.2, 68.0, 116.4, 152.7;

1412
K. Kanda et al. / Tetrahedron 68 (2012) 1407e1416
HRMS (FABþ) for Mþ found m/z 318.2574, calcd for C21H34O2:
318.2559.
4.4. Enantioselective synthesis of 12-trimethylsilyl-1,10-dioxa
[10]paracyclophane and 13-trimethylsilyl-1,11-dioxa[11]
paracyclophane
4.2.7. 1,16-Dioxa[16](1.4)naphthalenophane (3e). Colorless oil; IR
(neat) 2925, 2854, 1595, 1460, 1269, 1234, 1093, 764 cmꢁ1; 1H NMR
A cyclohexane/hexane solution of sec-butyllithium (1.0 M,
(400 MHz)
d
0.67e0.78 (m, 4H), 0.80e0.92 (m, 4H), 0.93e1.04 (m,
1.2 mL, 1.2 mmol) was added dropwise to an Et2O solution (5.0 mL)
of a 1,n-dioxa[n]paracyclophane 1 (n¼8 or 9, 1.0 mmol) and
(ꢁ)-sparteine L1 (0.23 mL, 1.0 mmol) at ꢁ78 ꢂC, and the reaction
mixture was stirred for 3 h at ꢁ78 ꢂC. To the mixture was added
dropwise chlorotrimethylsilane (76.1 mL, 2.0 mmol) at ꢁ78 ꢂC and
the mixture stirred for overnight at rt. It was treated with saturated
NH4Cl aqueous solution, and extracted with ethyl acetate. The or-
ganic layer was washed with water and brine. The extract was dried
over Na2SO4 and evaporated under reduced pressure. The resulting
residue was purified by flash column chromatography (hexane/
dichloromethane¼3/1) to give trimethylsilyl-1,n-dioxa[n]para-
cyclophane 2.
4H), 1.16e1.27 (m, 4H), 1.41e1.51 (m, 4H), 1.73e1.83 (m, 4H), 4.23 (t,
J¼6.0 Hz, 4H), 6.77 (s, 2H), 7.48 (dd, J¼3.2, 6.4 Hz, 2H), 8.23 (dd,
J¼3.2, 6.4 Hz, 2H); 13C NMR (100 MHz)
d 24.6, 27.1, 27.3, 27.9, 28.3,
28.5, 68.1, 106.0, 122.0, 125.5, 127.4, 148.1 HRMS (FABþ) for Mþ
found m/z 354.2569, calcd for C24H34O2: 354.2559.
4.3. Experimental procedure for enantioselective
monolithiation
A
cyclohexane/hexane solution of sec-butyllithium (1.0 M,
0.2 mL, 0.2 mmol) was added dropwise to an ether solution
4.4.1. 13-(Trimethylsilyl)-1,11-dioxa[11]paracyclophane (2ab). Color
less oil; IR (neat) 2952, 2925, 2856, 1567, 1473, 1475, 1390, 1373, 1254,
1246, 1194, 1130, 1063, 1037, 1012, 1007, 893, 883, 839, 766, 700,
(0.5 mL) of 1,n-dioxa[n]paracyclophane
1
(0.1 mmol) and
(ꢁ)-sparteine L1 (23
m
L, 0.1 mmol) at ꢁ78 ꢂC and the reaction
mixture was stirred for the hours cited in Tables 2 and 3 at ꢁ78 ꢂC.
To the mixture was added dropwise iodine (76.1 mg, 0.3 mmol) in
Et2O (0.6 mL) at ꢁ78 ꢂC, and the reaction mixture stirred for 2 h at
rt. It was treated with saturated Na2S2O3 aqueous solution, and
extracted with ethyl acetate. The organic layer was washed with
water and brine. The extract was dried over Na2SO4 and evaporated
under reduced pressure. The resulting residue was purified by PTLC
to give a monoiodo-1,n-dioxa[n]paracyclophane 2.
625 cmꢁ1 1H NMR (400 MHz)
; d 0.30 (s, 9H), 0.58e0.75 (m, 1H),
0.75e1.11 (m, 9H), 1.49e1.78 (m, 4H), 4.09e4.27 (m, 3H), 4.30e4.43
(m, 1H), 6.94 (d, J¼8.5 Hz, 1H), 7.00e7.09 (m, 2H); 13C NMR
(100 MHz)
d
ꢁ0.3, 25.4, 26.1, 26.3, 26.8, 27.8, 29.3, 29.9, 69.9, 72.1,
117.3, 121.9, 127.0, 131.6, 153.5, 159.2; HRMS (FABþ) for Mþ found m/z
306.2028, calcd for C18H30O2Si: 306.2015. ½a D23
ꢁ23.2 (c 1.39, CHCl3,
ꢄ
97% ee). Compound 2ab was treated with NIS, and the ee was de-
termined as the corresponding iodinated products 2aa. (Daicel
Chiralpak IB: 4ꢅ250 mm, 254 nm UV detector, rt, eluent: 20%
dichloromethane in hexane, flow rate: 1.0 mL/min, retention time:
5.1 min for minor isomer and 6.3 min for major isomer).
4.3.1. 12-(Diphenylphosphino)-1,10-dioxa[10]paracyclophane
(2bc). After monolithiation of 1b, chlorodiphenylphosphine (56 mL,
0.3 mmol) was added at ꢁ78 ꢂC. Then the mixture was stirred for
2 h at rt. It was filtered through a short plug of silica gel with
dichloromethane and the filtrate was evaporated under reduced
pressure. The crude products were purified by PTLC (hexane/
dichloromethane¼3/1) to give 2bc. White solid. Mp 110 ꢂC; IR (KBr)
4.4.2. 12-(Trimethylsilyl)-1,10-dioxa[10]paracyclophane (2bb). Co-
lorless oil; IR (neat) 2954, 2925, 2856, 1567, 1473, 1244, 1390, 1365,
1190, 1126, 1033, 839, 767, 700, 625 cmꢁ1 1H NMR (400 MHz)
;
d
0.08e0.25 (m, 1H), 0.29 (s, 9H), 0.53e0.71 (m, 1H), 0.71e1.07 (m,
3052, 2925, 2866, 1473, 1456, 1192, 1028, 742, 696 cmꢁ1
;
1H NMR
6H), 1.18e1.34 (m, 1H), 1.35e1.49 (m, 1H), 1.51e1.64 (m, 1H),
1.82e1.98 (m, 1H), 3.95e4.04 (m, 1H), 4.09e4.25 (m, 2H), 4.32e4.41
(m, 1H), 6.85 (d, J¼8.2 Hz, 1H), 6.98 (dd, J¼3.7, 8.2 Hz, 1H), 7.09 (d,
(400 MHz)
d 0.32e0.50 (m, 1H), 0.55e1.08 (m, 6H), 1.28e1.66 (m,
4H), 1.67e1.83 (m, 1H), 3.71e3.86 (m, 1H), 3.99e4.12 (m, 1H),
4.19e4.37 (m, 2H), 6.35e5.39 (m, 1H), 6.95e7.01 (m, 2H), 7.26e7.39
J¼3.7 Hz, 1H); 13C NMR (100 MHz)
d
ꢁ0.53, 22.8, 24.8, 26.0, 26.5,
(m, 10H); 13C NMR (100 MHz)
d
24.0 (d, J¼2.9 Hz), 24.1, 26.3, 26.6,
26.7, 29.4, 69.7, 73.1, 118.3, 123.0, 127.5, 132.6, 152.3, 158.1; HRMS
27.5 (d, J¼2.9 Hz), 28.0, 71.7 (d, J¼2.9 Hz), 72.0, 120.6 (d, J¼2.9 Hz),
123.0, 125.7, 128.3 (d, J¼6.7 Hz), 128.5, 128.5 (d, J¼6.7 Hz), 129.0,
131.8 (d, J¼13.4 Hz), 133.0 (d, J¼19.2 Hz), 134.6 (d, J¼21.1 Hz), 136.5
(d, J¼45.1 Hz), 136.6 (d, J¼47.9 Hz), 153.2, 155.2 (d, J¼16.6 Hz); 31P
(FABþ) for Mþ found m/z 202.1849, calcd for C17H28O2Si: 292.1859.
½
a 3D3
ꢄ
ꢁ22.3 (c 1.03, CHCl3, 97% ee). Compound 2bb was treated with
NIS, and the ee was determined as the corresponding iodinated
products 2ba. (Daicel Chiralpak IB: 4ꢅ250 mm, 254 nm UV de-
tector, rt, eluent: 20% dichloromethane in hexane, flow rate: 1.0 mL/
min, retention time: 5.2 min for minor isomer and 6.0 min for
major isomer).
NMR (160 MHz)
d
ꢁ20.2; HRMS (FABþ) for Mþ found m/z 404.1906,
calcd for C26H29O2P: 404.1905. ½a D27
þ7.1 (c 1.13, CHCl3, 98% ee). ee
ꢄ
was determined by HPLC analysis using a chiral column (Daicel
Chiralpak IA: 4ꢅ250 mm, 254 nm UV detector, rt, eluent: 20%
dichloromethane in hexane, flow rate: 0.5 mL/min, retention time:
8.9 min for minor isomer and 9.5 min for major isomer).
4.5. Synthesis of trimethylsilyl-1,n-dioxa[n]paracyclophane
(n‡12)
4.3.2. 18-Iodo-1,16-dioxa[16](1.4)naphthalenophane (4d). Pale yel-
A cyclohexane/hexane solution of sec-butyllithium (1.0 M,
2.0 mL, 2.0 mmol) was added dropwise to an Et2O solution
(5.0 mL) of 1,n-dioxa[n]paracyclophane 1 (1.0 mmol) and TMEDA
(0.23 mL, 1.0 mmol) at ꢁ78 ꢂC, and the reaction mixture was
stirred for 3 h at ꢁ78 ꢂC. To the mixture was added dropwise
low viscous oil; IR (neat) 2925, 2854, 1572, 1458, 1444, 1321, 1269,
1259, 1097, 960, 765, 709 cmꢁ1; 1H NMR (400 MHz)
d 0.60e1.50 (m,
20H), 1.59e1.83 (m, 3H), 1.90e2.07 (m, 1H) 4.14e4.45 (m, 4H), 7.11
(s, 1H), 7.43e7.55 (m, 2H), 8.06e8.14 (m, 1H), 8.18e8.26 (m, 1H); 13C
NMR (100 MHz)
d
24.6, 26.4, 27.3, 27.4, 27.7, 27.9, 28.0, 28.2, 28.2,
chlorotrimethylsilane (76
m
L, 0.3 mmol) at ꢁ78 ꢂC and the mixture
28.4, 28.7, 31.6, 67.7, 74.3, 85.9, 115.0, 122.4, 122.6, 125.7, 126.6,
stirred for overnight at rt. It was treated with saturated NH4Cl
aqueous solution, and extracted with ethyl acetate. The organic
layer was washed with water and brine. The extract was dried
over Na2SO4 and evaporated under reduced pressure. The result-
ing residue was purified by flash column chromatography (hex-
ane/dichloromethane¼3/1) to give a trimethylsilyl-1,n-dioxa[n]
paracyclophane 2.
126.8, 129.4, 148.9, 151.1; HRMS (FABþ) for Mþ found m/z 480.1519,
calcd for C24H33IO2: 480.1525. ½a D26
ꢄ
6.6 (c 1.82, CHCl3, 92% ee). ee
was determined by HPLC analysis using a chiral column (Daicel
Chiralpak IB: 4ꢅ250 mm, 254 nm UV detector, rt, eluent: 20%
dichloromethane in hexane, flow rate: 1.0 mL/min, retention time:
6.3 min for minor isomer and 9.1 min for major isomer).

K. Kanda et al. / Tetrahedron 68 (2012) 1407e1416
1413
4.5.1. 14-(Trimethylsilyl)-1,12-dioxa[12]paracyclophane (2cb). Co-
lorless oil; IR (neat) 2949, 2929, 2898, 2856, 1573, 1473, 1259, 1246,
1196, 1136, 1072, 1045, 1022, 1004, 860, 837, 764, 704, 625 cmꢁ1; 1H
2 h at rt. It was treated with Na2S2O3 aqueous solution, and extracted
with ethyl acetate. The organic layer was washed with water and
brine. The extract was dried over Na2SO4 and evaporated under
reduced pressure. The resulting residue was purified by thin-layer
chromatography to give a diiodo-1,n-dioxa[n]paracyclophane 5.
NMR (400 MHz)
d 0.27 (s, 9H), 0.48e0.65 (m, 1H), 0.70e1.23 (m,
11H), 1.45e1.62 (m, 2H), 1.62e1.75 (m, 1H), 1.75e1.89 (m, 1H),
4.06e4.16 (m, 1H), 4.20 (t, J¼5.7 Hz, 2H), 4.37e4.47 (m, 1H), 6.83 (d,
J¼8.7 Hz, 1H), 6.95 (dd, J¼2.7, 8.7 Hz, 1H), 7.01 (d, J¼2.7 Hz, 1H); 13C
4.6.1. (S)-13,16-Diiodo-1,11-dioxa[11]paracyclophane (5aa). White
NMR (100 MHz)
d
ꢁ0.5, 23.5, 24.2, 27.2, 27.3, 27.3, 27.5, 28.4, 67.6,
solid. Mp 70 ꢂC; IR (KBr) 2924, 2854, 1471, 1448, 1335, 1187,
69.7, 114.6, 119.8, 125.8, 130.0, 152.4, 157.6 (A pair of peaks at the
aliphatic region is overlapped.); HRMS (FABþ) for Mþ found m/z
320.2184, calcd for C19H32O2Si: 320.2172.
1043 cmꢁ1; 1H NMR (400 MHz)
d
0.69e0.85 (m, 2H), 0.86e1.08 (m,
8H), 1.47e1.64 (m, 2H), 1.74e1.90 (m, 2H), 4.16e4.25 (m, 2H),
4.31e4.40 (m, 2H), 7.37 (s, 2H); 13C NMR (100 MHz)
25.3, 25.9,
d
28.0, 29.7, 72.7, 90.5, 129.6, 154.6; Anal. Calcd for C15H20I2O2: C,
4.5.2. 15-(Trimethylsilyl)-1,13-dioxa[13]paracyclophane (2db). Co-
37.06; H, 4.15. found: C, 37.23; H, 4.04.; HRMS (FABþ) for Mþ found
lorless oil; IR (neat) 2925, 2900, 2856, 1576, 1473, 1259, 1244, 1200,
m/z 485.9557, calcd for C15H20I2O2: 485.9553. ½a D25
þ58.9 (c 1.87,
ꢄ
1138, 1061, 1045, 1002, 870, 837, 764, 704, 625 cmꢁ1
;
1H NMR
CHCl3, 99% ee). ee was determined by HPLC analysis using a chiral
column (Daicel Chiralpak IA: 4ꢅ250 mm, 254 nm UV detector, rt,
eluent: 20% dichloromethane in hexane, flow rate: 1.0 mL/min,
retention time: 4.5 min for minor isomer and 5.8 min for major
isomer). Crystal data for C15H20I2O2, M¼486.13, orthorhombic,
(400 MHz)
d 0.27 (s, 9H), 0.61e0.76 (m, 2H), 0.87e1.26 (m, 12H),
1.49e1.74 (br s, 4H), 4.12e4.33 (m, 4H), 6.72 (d, J¼9.0 Hz, 1H), 6.90
(dd, J¼3.2, 9.0 Hz, 1H), 6.99 (d, J¼3.2 Hz, 1H); 13C NMR (100 MHz)
d
ꢁ0.5, 24.3, 26.7, 27.4, 27.6, 27.8, 28.3, 28.3, 28.5, 67.1, 69.3, 112.9,
ꢀ
ꢀ
119.0, 124.8, 129.7, 151.8, 157.2 (A pair of peaks at the aliphatic re-
gion is overlapped.); HRMS (FABþ) for Mþ found m/z 334.2321,
calcd for C20H34O2Si: 334.2328.
space group P212121 (no. 19), a¼10.2806(9) A, b¼10.712(1) A,
3
ꢀ ꢀ
c¼14.605(2) A, V¼1608.4(3) A , T¼173 K, Z¼4,
m(Mo
K
a
)¼
39.085 cmꢁ1; number of reflections measured: total 25,616 and
unique 3682, R1¼0.0785, wR2¼0.2027, Flack parameter (Friedel
pairs¼1579) 0.02(8). CCDC 852454.
4.5.3. 16-(Trimethylsilyl)-1,14-dioxa[14]paracyclophane (2eb). Color-
less oil; IR (neat) 2925, 2854, 1576, 1475, 1396, 1268, 1257, 1243,
1200, 1140, 1072, 1051, 1007, 883, 839, 763, 706, 627 cmꢁ1; 1H NMR
4.6.2. 14,17-Diiodo-1,12-dioxa[12]paracyclophane (5ca). White solid.
(400 MHz)
d
0.27 (s, 9H), 0.84e0.97 (m, 6H), 0.97e1.06 (m, 2H),
Mp 98 ꢂC; IR (KBr) 2927, 2854,1471,1456,1336,1263,1192,1045, 981,
1.06e1.15 (m, 2H), 1.15e1.23 (m, 2H), 1.23e1.39 (m, 4H), 1.54e1.76
(m, 4H), 4.11e4.25 (m, 4H), 6.76 (d, J¼8.3 Hz, 1H), 6.88 (dd, J¼3.2,
872, 804, 739 cmꢁ1
;
1H NMR (400 MHz)
d
0.63e0.83 (br s, 4H),
0.83e1.04 (m, 2H), 1.04e1.35 (m, 6H), 1.57e1.77 (m, 4H), 4.17e4.30
(m, 2H), 4.30e4.43 (m, 2H), 7.30 (s, 2H); 13C NMR (100 MHz)
23.8,
8.3 Hz, 1H), 6.97 (d, J¼3.2 Hz, 1H); 13C NMR (100 MHz)
d
ꢁ0.6, 23.9,
d
24.2, 27.1, 27.4, 27.5, 27.6, 27.7, 28.1, 28.3, 28.5, 66.5, 68.7, 111.8, 118.5,
124.1, 129.1, 151.4, 156.9; HRMS (FABþ) for Mþ found m/z 348.2474,
calcd for C21H36O2Si: 348.2485.
27.4, 27.4, 27.6, 70.6, 89.1,127.0,152.7; HRMS (FABþ) for Mþ found m/z
499.9710, calcd for C16H22I2O2: 499.9709. ½a D24
þ54.6 (c 1.40, CHCl3,
ꢄ
88% ee). ee was determined by HPLC analysis using a chiral column
(Daicel Chiralpak IA: 4ꢅ250 mm, 254 nm UV detector, rt, eluent: 20%
CH2Cl2 in hexane, flow rate: 1.0 mL/min, retention time: 4.8 min for
minor isomer and 7.3 min for major isomer).
4.5.4. 17-(Trimethylsilyl)-1,15-dioxa[15]paracyclophane (2fb). Co-
lorless oil; IR (neat) 2925, 2854, 1577, 1473, 1396, 1269, 1244, 1203,
1147, 1068, 1045, 1005, 881, 839, 764, 710, 627 cmꢁ1 1H NMR
;
(400 MHz)
d
0.26 (s, 9H), 0.85e1.47 (m,18H),1.54e1.81 (m, 4H), 4.14
4.6.3. 15,18-Diiodo-1,13-dioxa[13]paracyclophane (5da). White solid.
(t, J¼5.9 Hz, 4H), 6.74 (d, J¼9.0 Hz, 1H), 6.85 (dd, J¼2.9, 9.0 Hz, 1H),
Mp 115 ꢂC; IR (KBr) 2924, 2852, 1473, 1456, 1338, 1196, 1045, 839,
6.96 (d, J¼2.9 Hz, 1H); 13C NMR (100 MHz)
d
ꢁ0.61, 23.9, 24.0, 27.4,
744 cmꢁ1 1H NMR (400 MHz)
; d 0.67e0.84 (m, 2H), 0.84e1.12 (m,
6H), 1.12e1.34 (m, 6H), 1.52e1.67 (m, 2H), 1.67e1.83 (m 2H), 4.29 (t,
27.4, 27.6, 27.6, 27.8, 28.1, 28.2, 28.2, 29.6, 66.3, 68.4, 111.0, 117.4,
124.0,1129.2,151.5,157.0; HRMS (FABþ) for Mþ found m/z 362.2649,
calcd for C22H38O2Si: 362.2641.
J¼5.4 Hz, 4H), 7.30 (m, 2H); 13C NMR (100 MHz)
d 24.1, 27.1, 27.1,
28.4, 28.6, 70.5, 88.3, 125.8, 153.0; HRMS (FABþ) for Mþ found m/z
513.9885, calcd for C17H24I2O2: 513.9866. ½a D24
þ54.1 (c 1.46, CHCl3,
ꢄ
4.5.5. 18-(Trimethylsilyl)-1,16-dioxa[16]paracyclophane (2gb). Co-
95% ee). ee was determined by HPLC analysis using a chiral column
(Daicel Chiralpak IA: 4ꢅ250 mm, 254 nm UV detector, rt, eluent:
20% CH2Cl2 in hexane, flow rate: 1.0 mL/min, retention time: 4.4 min
for minor isomer and 6.4 min for major isomer).
lorless oil; IR (neat) 2925, 2854, 1577, 1468, 1396, 1271, 1244, 1205,
1142, 1058, 1045, 883, 839, 763, 713, 686, 627 cmꢁ1 1H NMR
;
(400 MHz)
d 0.27 (s, 9H), 0.95e1.50 (m, 20H), 1.57e1.80 (m, 4H),
4.08 (t, J¼5.9 Hz, 2H), 4.13 (t, J¼5.9 Hz, 2H), 6.74 (d, J¼9.0 Hz, 1H),
6.85 (dd, J¼3.4, 9.0 Hz, 1H), 6.95 (d, J¼3.4 Hz, 1H); 13C NMR
4.6.4. 16,19-Diiodo-1,14-dioxa[14]paracyclophane (5ea). White solid.
(100 MHz)
d
ꢁ0.65, 23.7, 24.1, 26.6, 27.2, 27.4, 27.4, 27.8, 28.0, 28.0,
Mp 101 ꢂC; IR (KBr) 2924, 2852, 1473, 1460, 1338, 1261, 1200, 1047,
28.6, 28.6, 29.2, 65.9, 68.0, 110.6, 117.2, 123.3, 128.9, 151.4, 157.2;
HRMS (FABþ) for Mþ found m/z 376.2809, calcd for C23H40O2Si:
376.2798.
862, 800, 736 cmꢁ1
;
1H NMR (400 MHz)
d
0.85e1.03 (br, 8H),
1.03e1.46 (m, 8H), 1.49e1.67 (m, 2H), 1.67e1.83 (m, 2H), 4.13e4.35
(m, 4H), 7.26 (s, 2H); 13C NMR (100 MHz)
24.0, 26.8, 27.5, 28.0, 28.6,
d
69.6, 87.3, 124.6, 151.8; HRMS (FABþ) for Mþ found m/z 528.0014,
4.6. Typical experimental procedure for enantioselective
dilithiation
calcd for C18H26I2O2: 528.0022. ½a D24
þ59.4 (c 1.41, CHCl3, 93% ee). ee
ꢄ
was determined by HPLC analysis using a chiral column (Daicel
Chiralpak IA: 4ꢅ250 mm, 254 nm UV detector, rt, eluent: 20%
CH2Cl2 in hexane, flow rate: 1.0 mL/min, retention time: 4.4 min for
minor isomer and 6.4 min for major isomer).
To an Et2O solution (0.5 mL) of a 1,n-dioxa[n]paracyclophane 1
(0.1 mmol) and L1 (23 mL, 0.1 mmol) was added dropwise a cyclo-
hexane/hexane solution of sec-butyllithium (1.0 M, 0.2 mL,
0.2 mmol) at ꢁ78 ꢂC and stirred for 2 h at ꢁ78 ꢂC Then a cyclohex-
ane/hexane solution of sec-butyllithium (1.0 M, 0.2 mL, 0.2 mmol)
was added dropwise to the mixture at ꢁ78 ꢂC and stirred for the
hours cited in Table 4 at ꢁ20 ꢂC. Iodine (152.3 mg, 0.6 mmol) in Et2O
(1.2 mL) was added dropwise at ꢁ78 ꢂC and the mixture stirred for
4.6.5. 17,20-Diiodo-1,15-dioxa[15]paracyclophane (5fa). White solid.
Mp 84 ꢂC; IR (KBr) 2924, 2852,1475,1460,1340,1201,1049, 987, 858,
733 cmꢁ1 1H NMR (400 MHz)
; d 0.91e1.20 (m, 10H), 1.20e1.55 (m,
8H), 1.59e1.74 (m, 4H), 4.20 (t, J¼5.5 Hz, 4H), 7.24 (s, 2H); 13C NMR
(100 MHz)
d 24.0, 27.2, 27.5, 28.1, 28.3, 29.4, 69.4, 87.2, 124.0, 152.2;

1414
K. Kanda et al. / Tetrahedron 68 (2012) 1407e1416
HRMS (FABþ) for Mþ found m/z 542.0179, calcd for C19H28I2O2:
0.54e0.72 (m, 2H), 0.74e0.90 (m, 2H), 0.90e1.20 (m, 8H), 1.37e1.56
(m, 2H),1.69e1.88 (m, 2H), 4.00e4.17 (m, 2H), 4.36e4.53 (m, 2H), 6.92
542.0179. ½a 2D4
ꢄ
þ58.9 (c 0.70, CHCl3, 91% ee). ee was determined by
HPLC analysis using
a
chiral column (Daicel Chiralpak IA:
(s, 2H); 13C NMR (100 MHz)
d
ꢁ0.4, 24.5, 27.3, 27.6, 28.0, 68.4, 120.9,
4ꢅ250 mm, 254 nm UV detector, rt, eluent: 20% CH2Cl2 in hexane,
flow rate: 1.0 mL/min, retention time: 4.4 min for minor isomer and
6.9 min for major isomer).
130.6, 156.3; HRMS (FABþ) for Mþ found m/z 392.2574, calcd for
24
C22H40O2Si2: 392.2567. ½
a
ꢄ
ꢁ6.3 (c 1.33, CHCl3, 18% ee). Com-
Hg435
pound 5cb was treated with NBS, and the ee was determined as the
corresponding dibrominated product. (Daicel Chiralpak IA:
4ꢅ250 mm, 254 nm UV detector, rt, eluent: 20% dichloromethane in
hexane, flow rate: 1.0 mL/min, retention time: 4.8 min for minor
isomer and 5.9 min for major isomer).
4.6.6. 18,21-Diiodo-1,16-dioxa[16]paracyclophane (5ga). White solid.
Mp 74 ꢂC; IR (KBr) 2924, 2852, 1483, 1462, 1340, 1205, 1051, 860,
746 cmꢁ1
;
1H NMR (400 MHz)
d
0.90e1.45 (m, 16H), 1.45e1.95 (m,
8H), 4.05e4.28 (m, 4H), 7.21 (s, 2H); 13C NMR (100 MHz)
d
23.7, 26.7,
27.2, 27.9, 28.3, 29.0, 68.9, 86.5, 123.3, 151.9; HRMS (FABþ) for Mþ
4.7.2. 15,18-Bis(trimethylsilyl)-1,13-dioxa[13]paracyclophane
found m/z 556.0309, calcd for C20H30I2O2: 556.0335. ½a D26
ꢄ
þ43.4 (c
(5db). Colorless oil; IR (neat) 2952, 2925, 2900, 2854, 1465, 1335,
1.00, CHCl3, 91% ee). ee was determined by HPLC analysis using
a chiral column (Daicel Chiralpak IA: 4ꢅ250 mm, 254 nm UV de-
tector, rt, eluent: 20% CH2Cl2 in hexane, flow rate: 1.0 mL/min, re-
tention time:4.0 min for minorisomerand 6.0 min for major isomer).
1246, 1186, 1107, 1057, 837, 762, 633 cmꢁ1 1H NMR (400 MHz)
;
d
0.27 (s, 18H) 0.59e0.76 (m, 2H), 0.84e1.27 (m, 12H), 1.43e1.61 (m,
2H), 1.61e1.77 (m, 2H), 4.03e4.16 (m, 2H), 4.33e4.45 (m, 2H), 6.91
(s, 2H); 13C NMR (100 MHz)
ꢁ0.34, 24.8, 26.6, 27.8, 28.6, 28.8, 67.8,
d
119.7, 130.4, 156.7; HRMS (FABþ) for Mþ found m/z 406.2704, calcd
4.6.7. 19,22-Diiodo-1,17-dioxa[17]paracyclophane (5ha). Yellowish
for C23H42O2Si2: 406.2723. ½a D23
ꢁ11.0 (c 1.29, benzene, 89% ee).
ꢄ
viscous oil; IR (KBr) 2924, 2852, 1483, 1460, 1342, 1205, 1051, 1002,
Compound 5db was treated with NBS, and the ee was determined
as the corresponding dibrominated product. (Daicel Chiralpak IA:
4ꢅ250 mm, 254 nm UV detector, rt, eluent: 20% dichloromethane
in hexane, flow rate: 1.0 mL/min, retention time: 4.3 min for minor
isomer and 5.2 min for major isomer).
856 cmꢁ1; 1H NMR (400 MHz)
d
1.00e1.45 (m, 20H), 1.47e1.71 (m,
4H), 1.71e1.91 (m, 2H), 4.04e4.21 (m, 4H), 7.21 (s, 2H); 13C NMR
(100 MHz)
d 24.3, 27.1, 27.8, 28.2, 28.3, 28.9, 29.2, 69.2, 86.6, 123.3,
152.3; HRMS (FABþ) for Mþ found m/z 570.0484, calcd for
C21H32I2O2: 570.0492.
4.7.3. 16,19-Bis(trimethylsilyl)-1,14-dioxa[14]paracyclophane
4.6.8. 19,22-Bis(diphenylphosphino)-1,17-dioxa[17]paracyclophane
(5eb). Colorless oil; IR (neat) 2952, 2925, 2900, 2856, 1468, 1336,
(5hc). After dilithiation of 1g, chlorodiphenylphosphine (112
mL,
1244,1192,1107,1055, 837, 762, 633 cmꢁ1; 1H NMR (400 MHz)
d
0.27
(s, 18H), 0.64e1.53 (m, 18H), 1.80e1.97 (m, 2H), 3.98e4.10 (m, 2H),
4.34e4.45 (m, 2H), 6.85 (s, 2H); 13C NMR (100 MHz)
ꢁ0.2, 23.9, 27.1,
0.6 mmol) was added at ꢁ78 ꢂC. Then the mixture was stirred for
2 h at rt. It was filtered through a short plug of silica gel with
dichloromethane and the filtrate was evaporated under reduced
pressure. The crude products were purified by PTLC (hexane/
dichloromethane¼3/2) to give 5hc. White solid. 50 ꢂC; IR (KBr)
d
27.8, 28.0, 28.4, 66.6, 118.1, 129.3, 155.5; HRMS (FABþ) for Mþ found
m/z 420.2862, calcd for C24H44O2Si2: 420.2880. ½a D28
þ22.6 (c 1.33,
ꢄ
CHCl3, 93% ee). Compound 5eb was treated with NBS, and the ee was
determined as the corresponding dibrominated product. (Daicel
Chiralpak IA: 4ꢅ250 mm, 254 nm UV detector, rt, eluent: 20%
dichloromethane in hexane, flow rate: 1.0 mL/min, retention time:
4.1 min for minor isomer and 5.3 min for major isomer).
2925, 2852, 1463, 1434, 1344, 1196, 724, 696 cmꢁ1
;
1H NMR
(400 MHz)
d 0.99e1.44 (m, 26H), 3.60e3.84 (m, 4H), 6.22 (t,
J¼4.6 Hz, 2H), 7.22e7.44 (m, 20H); 13C NMR (100 MHz)
d 24.3, 27.5,
27.7, 28.0, 28.5, 28.8, 29.2, 67.9, 117.4, 128.1 (d, J¼14.4 Hz), 128.3,
128.4, 128.4, 128.6 (d, J¼13.4 Hz), 133.7 (d, J¼20.1 Hz), 134.1 (d,
J¼20.1 Hz), 136.6 (d, J¼12.5 Hz), 137.3 (d, J¼11.5 Hz), 153.8 (d,
4.7.4. 17,20-Bis(trimethylsilyl)-1,15-dioxa[15]paracyclophane
J¼16.3 Hz); 31P NMR (160 MHz)
d
ꢁ16.3: HRMS (FABþ) for Mþ
(5fb). Colorless oil; IR (neat) 2951, 2925, 2902, 2854, 1466, 1338,
found m/z 686.3441, calcd for C45H52O2P2: 686.3443. ½a D27
ꢄ
þ8.2 (c
1244, 1194, 1107, 1057, 839, 762, 633 cmꢁ1 1H NMR (400 MHz)
;
1.03, CHCl3, 55% ee). Compound 5hc was treated with hydrogen
peroxide, and the ee was determined as the corresponding phos-
phine oxide. (Daicel Chiralpak IA: 4ꢅ250 mm, 254 nm UV detector,
rt, eluent: 70% 2-propanol in hexane, flow rate: 1.0 mL/min, re-
tention time: 15.2 min for major isomer and 21.5 min for minor
isomer).
d
0.28 (s, 18H), 0.76e1.20 (m, 12H), 1.20e1.42 (m, 6H), 1.48e1.65 (m,
2H), 1.66e1.83 (m, 2H), 3.96e4.10 (m, 2H), 4.26e4.39 (m, 2H), 6.87
(m, 2H); 13C NMR (100 MHz)
d
ꢁ0.40, 24.4, 27.7, 28.0, 28.2, 28.3,
29.5, 66.7, 117.7, 129.6, 156.2; HRMS (FABþ) for Mþ found m/z
24
434.3021, calcd for C25H46O2Si2: 434.3036. ½
a
ꢄ
þ30.0 (c 1.38,
Hg435
CHCl3, 93% ee). Compound 5fb was treated with NIS, and the ee was
determined as the corresponding diiodinated product 5fa.
4.7. Asymmetric lithiation of trimethylsilyl-1,n-dioxa[n]
paracyclophanes (n‡12)
4.7.5. 18,21-Bis(trimethylsilyl)-1,16-dioxa[16]paracyclophane
(5gb). Colorless oil; IR (neat) 2949, 2925, 2902, 2856, 1464, 1338,
To a solution of trimethylsilyl-1,n-dioxa[n]paracyclophanes 2
1244, 1196, 1107, 837, 762, 633 cmꢁ1; 1H NMR (400 MHz)
d 0.27 (s,
(0.2 mmol) and L1 (92
m
L, 0.4 mmol) in Et2O (1.0 mL) was added
18H), 0.80e1.02 (m, 8H), 1.05e1.32 (m, 10H); 1.37e1.53 (m, 2H),
1.56e1.69 (m, 2H), 1.70e1.84 (m, 2H), 3.94e4.03 (m, 2H), 4.23e4.32
dropwise a cyclohexane/hexane solution of sec-butyllithium (1.0 M,
0.4 mL, 0.4 mmol) at ꢁ78 ꢂC and stirred for the hours cited in Table 5
at ꢁ78 ꢂC. Then to the mixture was added dropwise trimethylsilyl-
(m, 2H), 6.84 (s, 2H); 13C NMR (100 MHz)
d
ꢁ0.5, 23.5, 26.7, 27.5,
27.8, 27.9, 29.2, 65.7, 116.8, 129.1, 156.0; HRMS (FABþ) for Mþ found
chloride (76
m
L, 0.6 mmol) at ꢁ78 ꢂC and stirred for 1 h at rt. The
m/z 448.3201, calcd for C26H48O2Si2: 448.3193. ½a D28
þ13.0 (c 1.44,
ꢄ
mixturewas added NH4Cl solution, and extracted with ethyl acetate.
The organic layer was washed with water and brine, dried over
Na2SO4. The solvent was removed under reduced pressure, and the
crude products were purified by PTLC to give bis(trimethylsilyl) 1,n-
dioxa[n]paracyclophanes 5.
CHCl3, 91% ee). Compound 5gb was treated with NIS, and the ee
was determined as the corresponding diiodinated product 5ga.
4.8. Asymmetric lithiation of planar-chiral trimethylsilyl-1,n-
dioxa[n]paracyclophanes (n£11)
4.7.1. 14,17-Bis(trimethylsilyl)-1,12-dioxa[12]paracyclophane (5cb). Co-
lorless oil; IR (neat) 2952, 2925, 2900, 2854, 1468, 1333, 1246, 1184,
To a solution of trimethylsilyl-1,n-dioxa[n]paracyclophanes 2
(0.1 mmol) and TMEDA (15 mL, 0.1 mmol) in Et2O (1.0 mL) was
1107, 1049, 839, 761, 633 cmꢁ1
;
1H NMR (400 MHz)
d
0.29 (s, 18H),

K. Kanda et al. / Tetrahedron 68 (2012) 1407e1416
1415
added dropwise a cyclohexane/hexane solution of sec-butyllithium
(1.0 M, 0.2 mL, 0.2 mmol) at ꢁ78 ꢂC and stirred for 2 h at ꢁ20 ꢂC.
ethyl acetate. The extract was dried over Na2SO4 and evaporated
under reduced pressure. The resulting residue was purified by PTLC
to give 6ae. Yellowish oil; IR (neat) 2951, 2927, 2900, 2856, 1685,
1597, 1471, 1458, 1398, 1354, 1244, 1178, 1132, 1057, 978, 841, 769,
4.8.1. 12-Iodo-15-trimethylsilyl-1,10-dioxa[10]paracyclophane
(6ba). After lithiation of 2bb, iodine (76.1 mg, 0.3 mmol) in Et2O
(0.6 mL) was added dropwise at ꢁ78 ꢂC and stirred for 1 h at rt. The
mixture was treated with Na2S2O3 aqueous solution, and extracted
with ethyl acetate. The organic layer was washed with water and
brine. The extract was dried over Na2SO4 and evaporated under
reduced pressure. The resulting residue was purified by thin-layer
chromatography to give 6ba. Yellowish viscous oil; IR (neat)
2954, 2925, 2873, 2856, 1566, 1537, 1471, 1450, 1324, 1244, 1174,
640 cmꢁ1 1H NMR (500 MHz)
; d 0.31 (s, 9H), 0.45e0.62 (m, 1H),
0.62e0.78 (m, 1H), 0.78e1.07 (m, 8H), 1.49e1.64 (m, 2H) 1.64e1.82
(m, 2H), 4.12e4.39 (m, 3H), 4.41e4.55 (m, 1H), 7.17 (s, 1H), 7.34 (s,
1H) 10.47 (s, 1H); 13C NMR (125 MHz)
27.5, 28.5, 29.8, 69.2, 73.9 112.3, 128.2, 129.4, 140.8, 156.7, 159.2,
d
ꢁ0.7, 24.2, 25.9, 26.3, 26.7,
190.0; HRMS (ESI) for MþNa found m/z 357.1853, calcd for
C19H30NaO3Si: 357.1862. ½a D18
ꢁ48.9 (c 1.22, CHCl3, 97% ee). ee was
ꢄ
determined by HPLC analysis using a chiral column (Daicel Chir-
alpak IA: 4ꢅ250 mm, 254 nm UV detector, rt, eluent: 10% CH2Cl2 in
hexane, flow rate: 1.0 mL/min, retention time: 9.2 min for minor
isomer and 12.8 min for major isomer).
839, 764, 690, 628 cmꢁ1 1H NMR (400 MHz)
; d 0.11e0.37 (m, 1H),
0.27 (s, 9H), 0.53e0.72 (m, 1H), 0.72e1.13 (m, 6H), 1.18e1.36 (m,
1H), 1.49e1.70 (m, 2H), 1.83e2.04 (m, 1H), 4.00e4.25 (m, 2H),
4.28e4.45 (m, 2H), 7.03 (s, 1H), 7.27 (s, 1H); 13C NMR (100 MHz)
d
ꢁ0.7, 22.5, 25.0, 26.0, 26.1, 26.6, 29.1, 70.1, 74.3, 92.8, 126.8, 128.2,
4.8.5. 13-(1-Hydroxy-1,1-diphenylmethyl)-16-trimethylsilyl-1,11-
dioxa[11]paracyclophane (6af). After lithiation of 2ab, benzophe-
none (54.7 mg, 0.3 mmol) in Et2O (0.6 mL) was added at ꢁ78 ꢂC.
Then the mixture was stirred for 12 h at rt. It was treated with sat-
urated NH4Cl aqueous solution and extracted with ethyl acetate. The
extract was dried over Na2SO4 and evaporated under reduced
pressure. The resulting residue was purified by PTLC to give 6af.
Colorless oil; IR (neat) 3479, 3058, 2952, 2924, 2898, 2854, 1596,
1475, 1446, 1340, 1246, 1176, 1034, 862, 839, 756, 700, 677 cmꢁ1; 1H
133.1, 152,.3, 158.3; HRMS (FABþ) for Mþ found m/z 418.0840, calcd
for C17H27IO2Si: 418.0825. ½a D23
þ42.5 (c 1.69, CHCl3, 97% ee). ee was
ꢄ
determined by HPLC analysis using a chiral column (Daicel Chir-
alpak IA: 4ꢅ250 mm, 254 nm UV detector, rt, eluent: 10% CH2Cl2 in
hexane, flow rate: 0.5 mL/min, retention time: 10.9 min for minor
isomer and 12.1 min for major isomer).
4.8.2. 13-Iodo-16-trimethylsilyl-1,11-dioxa[11]paracyclophane
(6aa). After lithiation of 2ab, iodine (76.1 mg, 0.3 mmol) in Et2O
(0.6 mL) was added dropwise at ꢁ78 ꢂC and stirred for 1 h at rt. The
mixture was treated with Na2S2O3 aqueous solution, and extracted
with ethyl acetate. The organic layer was washed with water and
brine. The extract was dried over Na2SO4 and evaporated under re-
duced pressure. The resulting residue was purified by thin-layer
chromatography to give 6aa. Pale yellow viscous oil; IR (neat) 2951,
2925, 2897, 2856, 1567, 1469, 1456, 1431, 1244, 1182, 829, 771,
NMR (500 MHz) d 0.29 (s, 9H), 0.64e1.19 (m,10H),1.33e1.64 (m, 4H),
3.79e3.91 (m, 1H), 3.92e4.04 (m, 1H), 4.07e4.19 (m, 1H), 4.29e4.42
(m, 1H), 6.03 (s, 1H), 6.11 (s, 1H), 7.03 (s, 1H), 7.14e7.42 (m, 10H); 13C
NMR (125 MHz)
d
ꢁ0.32, 25.4, 25.5, 27.0, 27.1, 27.7, 28.9, 29.2, 70.3,
71.4, 82.3, 119.5, 124.6, 127.2, 127.2, 127.7, 127.7, 127.8, 128.2, 129.9,
137.9, 145.7, 147.1, 150.5, 157.8; HRMS (ESI) for MþNa found m/z
511.2627, calcd for C31H40O3Si: 511.2644. ½a D13
þ46.3 (c 2.03, CHCl3,
ꢄ
97% ee). ee was determined by HPLC analysis using a chiral column
(Daicel Chiralpak IA: 4ꢅ250 mm, 254 nm UV detector, rt, eluent: 10%
CH2Cl2 in hexane, flow rate: 1.0 mL/min, retention time: 5 min for
major isomer and 13 min for minor isomer).
690 cmꢁ1 1H NMR (500 MHz)
; d 0.28 (s, 9H), 0.55e0.71 (m, 1H),
0.76e1.15 (m, 9H),1.43e1.58 (m,1H),1.59e1.73 (m, 2H),1.73e1.88 (m,
1H), 4.08e4.24 (m, 2H), 4.28e4.45 (m, 2H), 6.98 (s, 1H), 7.32 (s, 1H);
13C NMR (125 MHz)
d
ꢁ0.58, 24.8, 26.1, 26.2, 26.6, 27.8, 29.2, 29.6,
70.0, 72.7, 92.2, 126.3, 126.7, 131.7, 152.7, 159.7; HRMS (FABþ) for Mþ
Acknowledgements
found m/z 432.0979, calcd for C18H29IO2Si: 432.0981. ½a D14
þ31.1 (c
ꢄ
1.51, CHCl3, 97% ee). ee was determined by HPLC analysis using
a chiral column (Daicel Chiralpak IB: 4ꢅ250 mm, 254 nm UV de-
tector, rt, eluent: 10% CH2Cl2 in hexane, flow rate: 0.5 mL/min, re-
tention time:8.4 min for minorisomerand 9.7 min for major isomer).
K.K. is grateful to the Japan Society for the Promotion of Science
for the fellowship support. This work was supported by Grant-in-
Aid for Scientific Research from the Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan (No. 23655091). We
also thank Asahi Glass Foundation and the Global COE program
‘Center for Practice Chemical Wisdom’ by MEXT. We also thank
Ms. T. Koike (Waseda Univ.) for her experimental assistance in the
preliminary work.
4.8.3. 13-Methyl-16-trimethylsilyl-1,11-dioxa[11]paracyclophane
(6ad). After lithiation of 2ab, MeI (19 mL, 0.3 mmol) was added
at ꢁ78 ꢂC. Then the mixture was stirred for 12 h at rt. It was treated
with saturated NH4Cl aqueous solution and extracted with ethyl ac-
etate. The extract was dried over Na2SO4 and evaporated under re-
duced pressure. The resulting residue was purified by PTLC to give
6ad. Colorless oil; IR (neat) 2952, 2925, 2900, 2856,1600,1479,1352,
References and notes
€
1. For reviews, see: (a) Cyclophane Chemistry; Vogtle, F., Ed.; Wiley: Chichester, UK,
1993; (b) Modern Cyclophane Chemistry; Gleither, R., Hopf, H., Eds.; Wiley:
Chichester, UK, 2004.
1244, 1178, 1033, 839, 750, 636 cmꢁ1; 1H NMR (400 MHz)
d 0.21 (s,
9H), 0.49e0.66 (m,1H), 0.67e1.06 (m, 9H),1.35e1.64 (m, 4H), 2.20 (s,
2. The monosubstituted [11]paracyclophanes were resolved into the enantiomers at
rt, see:(a)Hochmuth, D. H.; Konig,W. A. LiebigsAnn.1996, 947e951;(b)Hochmuth,
3H), 4.00e4.17(m3H), 4.21e4.32 (m,1H), 6.69(s,1H), 6.92(s,1H); 13C
€
€
€
D. H.; Konig, W. A. Tetrahedron: Asymmetry 1999, 10,1089e1097; (c) Scharwachter,
NMR (100 MHz)
d
ꢁ0.2,16.7, 25.1, 25.9, 26.1, 26.6, 28.1, 29.9, 30.1, 69.8,
€
K. P.; Hochmuth, D. H.; Dittmann, H.; Konig, W. A. Chirality 2001, 13, 679e690; (d)
Luttringhaus, A.; Gralheer, H. Liebigs Ann. Chem. 1942, 550, 67e98.
71.8,119.0,126.6,128.2,131.9,151.8,159.6; HRMS (FABþ) for Mþ found
€
m/z 320.2166, calcd for C19H32O2Si: 320.2172. ½a D23
ꢁ19.0 (c 1.39,
ꢄ
3. (a) Pye, P. J.; Rossen, K.; Reamer, R. A.; Tsou, N. N.; Volante, R. P.; Reider, P. J. J.
Am. Chem. Soc. 1997, 119, 6207e6208 For a review of [2.2]paracyclophane de-
rivatives for asymmetric syntheses, see: (b) Gibson, S. E.; Knight, J. D. Org. Bi-
omol. Chem. 2003, 1, 1256e1269.
4. (a) Oi, S.; Miyano, S. Chem. Lett. 1992, 987e990; (b) Hattori, T.; Harada, N.; Oi, S.;
Abe, H.; Miyano, S. Tetrahedron: Asymmetry 1995, 6, 1043e1046; (c) Hattori, T.;
Koike, N.; Okaishi, Y.; Miyano, S. Tetrahedron Lett. 1996, 37, 2057e2060; (d)
Fiesel, R.; Huber, J.; Scherf, U. Angew. Chem., Int. Ed. 1996, 35, 2113e2116; (e)
Fiesel, R.; Huber, J.; Apel, U.; Enkelmann, V. ,; Hentschke, R.; Scherf, U. Mac-
romol. Chem. Phys. 1997, 198, 2623e2650; (f) Kanomata, N.; Nakata, T. Angew.
Chem., Int. Ed. 1997, 36, 1207e1211; (g) Kanomata, N.; Nakata, T. J. Am. Chem. Soc.
2000, 122, 4563e4568; (h) Kanomata, N.; Sakaguchi, R.; Sekine, K.; Yamashita,
S.; Tanaka, H. Adv. Synth. Catal. 2010, 352, 2966e2978; (i) Maeda, R.; Wada, T.;
CHCl3, 97% ee). ee was determined by HPLC analysis using a chiral
column (Daicel Chiralpak IA: 4ꢅ250 mm, 254 nm UV detector, rt,
eluent: 10% CH2Cl2 in hexane, flow rate: 0.5 mL/min, retention time:
10.6 min for minor isomer and 11.3 min for major isomer).
4.8.4. 13-(16-Trimethylsilyl-1,11-dioxa[11]paracyclophane)carbalde-
hyde (6ae). After lithiation of 2ab, DMF (23 mL, 0.3 mmol) was
added at ꢁ78 ꢂC. Then the mixture was stirred for 2 h at rt. It was
treated with saturated NH4Cl aqueous solution and extracted with

1416
K. Kanda et al. / Tetrahedron 68 (2012) 1407e1416
Mori, T.; Kono, S.; Kanomata, N.; Inoue, Y. J. Am. Chem. Soc. 2011, 133,
10379e10381.
Commun. 2008, 3750e3752; (c) Canipa, S. J.; O’Brien, P.; Taylor, S. Tetrahedron:
Asymmetry 2009, 20, 2407e2412.
5. (a) Kanomata, N.; Ochiai, Y. Tetrahedron Lett. 2001, 42, 1045e1048; (b) Ka-
nomata, N.; Oikawa, J. Tetrahedron Lett. 2003, 44, 3625e3628; (c) Ueda, T.;
Kanomata, N.; Machida, H. Org. Lett. 2005, 7, 2365e2368.
6. (a) Islas-Gonzalez, G.; Bois-Choussy, M.; Zhu, J. Org. Biomol. Chem. 2003, 1,
30e32; (b) Tanaka, K.; Hori, T.; Osaka, T.; Noguchi, K.; Hirano, M. Org. Lett. 2007,
9, 4881e4884; (c) Hori, T.; Shibata, Y.; Tanaka, K. Tetrahedron: Asymmetry 2010,
21, 1303e1306; (d) Araki, T.; Hojo, D.; Noguchi, K.; Tanaka, K. Synlett 2011,
539e542.
14. Examples of enantioselective lithiation using a catalytic amount of chiral di-
amines and a stoichiometric amount of achiral amines including lithium amide,
see: (a) Asami, M.; Ishizaki, T.; Inoue, S. Tetrahedron: Asymmetry 1994, 5,
793e796; (b) Yamashita, T.; Sato, D.; Kiyoto, T.; Kumar, A.; Koga, K. Tetrahedron
1997, 33, 16987e16998; (c) Sdergren, M. J.; Andersson, P. G. J. Am. Chem. Soc.
1998, 120, 10760e10761; (d) Lill, S. O. N.; Pettersen, D.; Amedjkouh, M.; Ahl-
berg, P. J. Chem. Soc., Perkin Trans. 1 2001, 3054e3063; (e) Amedjkouh, M.;
€
Pettersen, D.; Lill, S. O. N.; Davidsson, O; Ahlberg, P. Chem.dEur. J. 2001, 7,
7. Kanda, K.; Koike, T.; Endo, K.; Shibata, T. Chem. Commun. 2009, 1870e1872.
8. Although it is not a paracyclophane synthesis, enantioselective synthesis of
planar-chiral azamacrocycles via Pd-catalyzed BuchwaldeHartwig reaction of
1,5-dichloroanthraquinone and 1,5-dichloroanthracene with a diamine was
recently reported: Ranyuk, E. R.; Averin, A. D.; Beletskaya, I. P. Adv. Synth. Catal.
2010, 352, 2299e2305.
4368e4377; (f) Pettersen, D.; Amedjkouh, M.; Ahlberg, P. Tetrahedron 2002, 58,
4669e4673; (g) Malhotra, S. V. Tetrahedron: Asymmetry 2003, 14, 645e647; (h)
McGrath, M. J.; O’Brien, P. J. Am. Chem. Soc. 2005, 127, 16378e16379; (i)
McGrath, M. J.; Bilke, J. L.; O’Brien, P. Chem. Commun. 2006, 2607e2609; (j)
Bilke, J. L.; O’Brien, P. J. Org. Chem. 2008, 73, 6452e6454; (k) Bilke, J. L.; Moore,
S. P.; O’Brien, P.; Gilday, J. Org. Lett. 2009, 11, 1935e1938.
9. It is not an enantioselective synthesis, but enantiomerically pure para-
cyclophanes was synthesized from hydrogen-bond-controlled axially chiral
substrates using olefin metathesis: Mori, K.; Ohmori, K.; Suzuki, K. Angew.
Chem., Int. Ed. 2009, 48, 5638e5641.
15. (a) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P. J. Am. Chem. Soc. 2002,
124, 11870e11871; (b) Dixon, A. J.; McGrath, M. J.; O’Brien, P. Org. Synth. 2006,
83, 141e154.
16. Monosubstituted 1,11-dioxa[11]paracyclophanes 2ab, 2ad, and 2ae, which are
oil, were slowly racemized at rt (2ab: from 97% ee to 87% ee for 8 months, 2ad:
from 95% ee to 88% ee for 2 years, 2ae: from 97% ee to 62% ee for 2 years). On
the other hand, monosubstituted 1,11-dioxa[11]paracyclophanes 2ac and 2af,
which are solid, was not racemized at all at rt for as long as 2 years.
17. Monosubstituted 1,10-dioxa[10]paracyclophanes 2ba and 2bc, which are solid,
and 2bb, which is oil, were not racemized at all at rt for as long as 8 months.
18. 20-Iodo[16](1,4)naphthalenophane 4d, which is amorphous, was gradually
racemized at rt (from 92% ee to 72% ee for 10 days).
19. When 1c was first lithiated by using sparteine, and the obtained 2c was further
lithiated by using TMEDA (inverse procedure against entry 1 in Table 5), the ee
of 5cb was almost zero. This result means that dynamic kinetic resolution
occurred in the reaction of 1,12-dioxa[12]paracyclophane 2cb.
10. Examples of enantioselective ortho-lithiation of chromium-arene complex, see:
(a) Uemura, M.; Hayashi, Y.; Hayashi, Y. Tetrahedron: Asymmetry 1994, 5,
1427e1430; (b) Alexakis, A.; Kanger, T.; Mangeney, P.; Rose-Munch, F.; Perrotey,
A.; Rose, E. Tetrahedron: Asymmetry 1995, 6, 2135e2138; (c) Pache, S.; Botuha,
€
C.; Franz, R.; Kundig, P.; Einhorn, J. Helv. Chim. Acta 2000, 83, 2436e2451.
11. Examples of enantioselective ortho-lithiation of ferrocene, see: (a) Nishibayashi,
Y.; Aikawa, Y.; Ohe, K.; Uemura, S. J. Org. Chem. 1996, 61, 1172e1174; (b) Tsu-
kazaki, M.; Tinkl, M.; Roglans, A.; Chapell, B. J.; Taylor, N. J.; Snieckus, V. J. Am.
Chem. Soc. 1996, 118, 685e686; (c) Iftime, G.; Daran, J.-C.; Manoury, E.; Bala-
voine, G. G. A. Angew. Chem., Int. Ed. 1998, 37, 1698e1701; (d) Metallinos, C.;
Szillat, H.; Taylor, N. J.; Snieckus, V. Adv. Synth. Catal. 2003, 345, 370e382.
12. The preliminary communication of this work, see: Kanda, K.; Endo, K.; Shibata,
T. Org. Lett. 2010, 12, 1980e1983.
20. Monophosphine MOP was used as a chiral ligand: Marina, N.; Wadamoto, M.;
Yamamoto, H. Eur. J. Org. Chem. 2009, 5129e5131.
21. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518e1520.
13. Examples of lithiation using a catalytic amount of chiral diamines, see: (a)
Genet, C.; Canipa, S. J.; O’Brien, P.; Taylor, S. J. Am. Chem. Soc. 2006, 128,
9336e9337; (b) Gammon, J. J.; Canipa, S. J.; O’Brien, P.; Kelly, B.; Taylor, S. Chem.