Chiral Rh- and Ir-catalyzed intramolecular cycloaddition of hexaynes for the construction of new chiral skeletons

Article abstract of DOI:10.1002/hc.20691

Enantioselective intramolecular cycloaddition of hexaynes with 1,3-diyne moiety was examined. Chiral Rh catalyst provided axially chiral 1,1′ -bis(biphenylenyl) derivatives by consecutive [2+2+2] cycloaddition. In contrast, chiral Ir catalyst provided axi

Full text of DOI:10.1002/hc.20691

Heteroatom Chemistry
Volume 22, Number 3/4, 2011
Chiral Rh- and Ir-Catalyzed Intramolecular
Cycloaddition of Hexaynes for the Construction
of New Chiral Skeletons
Takanori Shibata,1 Tatsuya Chiba,1 Hiroyuki Hirashima,1
Yasunori Ueno,1 and Kohei Endo2
1Department of Chemistry and Biochemistry, School of Advanced Science and Engineering,
Waseda University, Shinjuku, Tokyo, 169-8555, Japan
2Waseda Institute for Advanced Study, Shinjuku, Tokyo, 169-8050, Japan
Received 3 September 2010; revised 29 October 2010
Ir-catalyzed intermolecular enantioselective [2 +
ABSTRACT: Enantioselective intramolecular cy-
2 + 2] cycloaddition of diynes with monoalkynes
cloaddition of hexaynes with 1,3-diyne moiety was
[3a,4]. We further used this protocol in the consec-
examined. Chiral Rh catalyst provided axially chiral
utive reaction for the preparation of axially chiral
1,1ꢀ-bis(biphenylenyl) derivatives by consecutive
polyaryl compounds [3b,c] and in the intramolec-
[2 + 2 + 2] cycloaddition. In contrast, chiral Ir cata-
ular reaction for the preparation of axially chiral
lyst provided axially chiral macrocyclic compounds
ortho-diaryl benzene compounds [3d]. Recently, we
with 1,3-diyne moiety by single [2 + 2 + 2] cycload-
reported an intramolecular and consecutive reac-
ꢁ
C
dition.
2011 Wiley Periodicals, Inc. Heteroatom
tion, where axially chiral biaryl compounds were
prepared in a pot from linear hexaynes possessing
1,3-diyne moiety [3e].
Chem 22:363–370, 2011; View this article online at
wileyonlinelibrary.com. DOI 10.1002/hc.20691
On the basis of these backgrounds, we hit
upon an intramolecular and consecutive reaction
of hexaynes with two ortho-phenylene tethers,
which would provide axially chiral bis(biphenylenyl)
derivatives as a new chiral skeleton (Scheme 1) [5].
INTRODUCTION
Transition metal-catalyzed [2 + 2 + 2] cycloaddition
of unsaturated motifs, such as alkyne and alkene,
is the most atom-economical and facile protocol for
the construction of a six-membered ring system [1].
Enantioselective [2 + 2 + 2] cycloaddition is also a
fascinating protocol for the construction of chiral
cyclic skeletons [2]. In 2004, we reported a new ap-
proach to the construction of axial chiralities by
RESULTS AND DISCUSSION
As a preliminary experiment, we ascertained the con-
struction of a biphenylene skeleton by intramolec-
ular cycloaddition of an ortho-phenylene tethered
triyne. Both cationic Rh- and neutral Ir-rac-BINAP
complexes catalyzed the reaction, and triyne 1 was
transformed into substituted biphenylene 2 in good
yield (Scheme 2) [6,7].
We next examined an intramolecular reaction
of hexayne 3a using (S)-BINAP as a chiral ligand.
When the cationic Rh catalyst was used, the reac-
tion smoothly proceeded for 2 h at 60◦C and expected
bis(biphenylenyl) 4a was obtained in excellent yield
Dedicated to Professor Kin-ya Akiba on the occasion of his 75th
birthday.
Correspondence to: Takanori Shibata; e-mail: tshibata@
waseda.jp.
Contract grant sponsor: Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Contract grant number: 22350046.
2011 Wiley Periodicals, Inc.
c
ꢀ
363

364 Shibata et al.
TABLE 1 Screening of Chiral Ligands for Rh-Catalyzed
Reaction of Hexayne 3a
Z
R
Z
E
Me
R
E
E
E
Chiral catalyst
[Rh(cod)2]BF4 (10 mol%)
Chiral Ligand (10 mol%)
Z
The first
cycloaddition
Me
Me
1,2-Dichloroethane
R
60°C, 2 h
Z
Achiral
E = CO2Me
E
E
R
Z
E
Me
E
3a
4a
Chiral catalyst
R
R
Entry Chiral Ligand Yield (%)
ee (%)
The second
cycloaddition
1
2
3
4
(S)-BINAP
(S)-tolBINAP
(S)-H8-BINAPa
94
95
97
61
62
55
59
Z
(S)-SEGPHOSb 99
Axially chiral
aBis(diphenylphospino)-5,5ꢀ,6,6ꢀ,7,7ꢀ,8,8ꢀ-octahydro-1,1ꢀ-binaphthyl.
b5,5ꢀ-Bis(diphenylphosphino)-4,4ꢀ-bi-1,3-benzodioxole.
SCHEME 1 Proposed scheme for the construction of axially
chiral 1,1ꢀ-bis(biphenylenyl) skeleton from hexayne.
n-Bu
and 4h, respectively, by the expected intramolecular
and consecutive reaction (Table 2, entries 6 and 7).
We next examined the reaction of carbon-
tethered hexayne 3a using neutral Ir catalyst pre-
pared from [IrCl(cod)]2 and rac-BAINAP, but no
cycloadduct was obtained even under reflux in xy-
lene, and the hexayne was recovered. In contrast,
when oxygen-tethered hexayne 3c was submitted,
the reaction proceeded under reflux in xylene and
cycloadduct 5c was obtained in moderate yield in
place of 4c (Scheme 3). Compound 5c has an ax-
ial chirality in a 16-membered ring system, and its
structure is very unique because adamant 1,3-diyne
moiety was included in a macrocyclic system [8].
We next examined Ir-catalyzed enantioselective
cycloaddition using chiral ligands (Table 3, entries 1
and 2). In the case of BINAP, almost no asymmetric
[Rh(cod)2]BF4(5 mol%)
or [IrCl(cod)]2 (2.5 mol%)
with rac-BINAP (5 mol%)
E
E
E
E
1,2-Dichloroethane for Rh
or xylene for Ir catalyst
60oC, 2 h
n-Bu
Me
Me
2 92% (Rh), 79% (Ir)
1 (E= CO2Me)
SCHEME 2 Rh- or Ir-catalyzed synthesis of biphenylene.
with moderate enantiomeric excess (ee) (Table 1, en-
try 1). We further screened the BINAP derivatives
in the Rh-catalyzed reaction, but a drastic improve-
ment in enantioselectivity could not be achieved (en-
tries 2–4).
We chose tolBINAP as the best chiral ligand
and examined various hexaynes (Table 2). When
phenyl groups were installed at the hexayne ter-
mini, the enantioselectivity was drastically improved
and bis(biphenylenyl) 4b was obtained in the high-
est ee of 96% (Table 2, entry 1). Oxygen-tethered
hexaynes 3c and 3d were good substrates, and
the cycloaddition proceeded at room temperature
(rt) (Table 2, entries 2 and 3). Also, in these sub-
strates phenyl-substitution at hexayne termini real-
ized the higher selectivity than methyl-substitution.
Electron-withdrawing and electron-donating groups
on the aryl rings could be available, and high enan-
tioselectivities were achieved (Table 2, entries 4 and
5). Nitrogen-tethered hexaynes 3g and 3h were also
transformed into bis(biphenylenyl) compounds 4g
O
Me
[IrCl(cod)]2 (5 mol%)
Me
O
rac-BINAP (10 mol%)
Xylene, reflux, 29 h
3c
4c
Not obtained
5c 38%
SCHEME 3 Ir-catalyzed cycloaddition of oxygen-tethered
hexayne 3c.
Heteroatom Chemistry DOI 10.1002/hc

Chiral Rh- and Ir-Catalyzed Intramolecular Cycloaddition of Hexaynes for the Construction of New Chiral Skeletons 365
TABLE 2 Rh-Catalyzed Reaction of Various Hexaynes for the Preparation of Axially Chiral Bis(biphenylenyl) Derivatives
R
Z
Z
[Rh(cod)2]BF4 (10 mol%)
(S)-tolBINAP (10 mol%)
R
R
1,2-Dichloroethane
Z
Z
R
3
4
Entry
Z
R
Temperature (◦C)
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
CEa2
O
O
O
O
Ph
Me
Ph
3b
3c
3d
3e
3f
3g
3h
60
rt
rt
40
rt
rt
4
3
4
5
2
7
10
57 (4b)
70 (4c)
67 (4d)
45 (4e)
84 (4f)
84 (4g)
82 (4h)
96
75
89
94
94
74
92
p-BrC6H4
p-MeOC6H4
NTs
NTs
Me
Ph
60
aE = CO2Me.
TABLE 3 Ir-Catalyzed Reaction Using Chiral Ligands
Z
R
Z
R
Z
[IrCl(cod)]2 (5 mol%)
R
(S,S)-Me-DUPHOS (10 mol%)
Xylene
Z
R
5
3
Entry
Z
R
Temperature (◦C)
Time (h)
Yield (%)
ee (%)
1a
2
3
4
5
O
O
O
O
O
Me
Me
Ph
3c
3c
3d
3e
3f
Reflux
40
60
100
80
80
4
10
19
48
18
49
48 (5c)
24 (5c)
46 (5d)
24 (5e)
44 (5f)
41 (5h)
3
61
87
95
96
97
p-BrC6H4
p-MeOC6H4
Ph
6
NTs
3h
a(S)-BINAP was used in place of (S,S)-MeDUPHOS (1,2-bis(2,5-dimethylphospholano)benzene).
induction was observed. In contrast, MeDUPHOS,
which was the best ligand for the generation of ax-
ial chirality in the Ir-catalyzed alkyne-trimerization
[3], realized moderate enantioselectivity. When aryl-
substituted hexayne 3d was submitted, enantiose-
lectivity was significantly improved to ca. 90% ee
(Table 3, entry 3). When hexayne 3e was used, cy-
cloadduct 5e was obtained in excellent ee (Table 3,
entry 4) and its structure was ascertained by X-ray
analysis (Fig. 1). Anisyl-substituted and nitrogen-
tethered hexaynes 3f and 3h were also transformed
into the corresponding cycloadducts 5f and 5h with
excellent ee (Table 3, entries 5 and 6). In all entries,
unidentified by-products were formed and the yields
remained moderate.
We depicted two different reaction pathways for
Rh- and Ir-catalyzed intramolecular cycloaddition of
the hexayne (Scheme 4). The first oxidative coupling
Heteroatom Chemistry DOI 10.1002/hc

366 Shibata et al.
CONCLUSION
We examined the intramolecular cycloaddition
of hexaynes possessing 1,3-diyne moiety. Chiral
cationic Rh complex catalyzed the consecutive
[2 + 2 + 2] cycloadditions, and the first synthesis
of axially chiral bis(biphenylenyl) derivatives was
achieved. In the chiral neutral Ir complex cat-
alyzed reaction, a [2 + 2 + 2] cycloaddition pro-
ceeded to give axially chiral macrocyclic com-
pounds. In both cases, excellent enantioselectivity
was achieved when aryl-substituted hexaynes were
used. The use of bis(biphenylenyl) derivatives as new
chiral scaffold is under way at our laboratory.
EXPERIMENTAL
General Data
FIGURE 1 ORTEP diagram of 5e.
Anhydrous 1,2-dichloroethane and xylene were pur-
chased and dried over activated molecular sieves
4A. Solvent was degassed by argon bubbling prior
to use. All reactions were carried out under an at-
mosphere of argon in oven-dried glassware with a
magnetic stirring bar. Takasago International Corp.
provided (S)-H8-BINAP and (S)-SEGPHOS. Other
ligands were purchased from Strem Chemicals Inc.
IR spectra were recorded with a JASCO FT/IR-4100
spectrometer. NMR spectra were recorded with a
JEOL AL-400 (400 MHz), Lambda-500 (500 MHz),
or Bruker Avance-600 (600 MHz) spectrometer us-
ing tetramethylsilane as an internal standard and
CDCl3 as a solvent. High-resolution mass spectra
(HRMS) were measured on a JEOL JMS-SX102A
with fast atomic bombardment (FAB) method or
electron impact (EI) method at a JEOL GC-mate II.
Optical rotations were measured on a JASCO DIP-
370 polarimeter.
R
Z
X
Z
M
Z
M
Oxidative
coupling
R
Y
R
Z
A
R
3
Cationic
Rh catalyst
eutral
Ir catalyst
N
Insertion of X
and reductive elimination
Insertion of Y
and
reductive elimination
The second
cycloaddition
4
5
SCHEME 4
catalysts.
Two different pathways using Rh- and Ir
Hexaynes 3a–3h
of 1,6-diyne moiety is common, and metallacy-
clopentadiene A is obtained. In the case of cationic
Rh catalyst, the coordination site is vacant and re-
active because counter anion (BF4) is relatively far
from the metal center [9], and insertion of proximal
alkyne X occurs even if strained benzocyclobutadi-
ene skeleton is constructed. Then, reductive elimi-
nation of the metal catalyst provides a biphenylene
compound and the first cycloaddition concludes.
The second intramolecular cycloaddition further
proceeds to give the bis(biphenylenyl) derivative 4.
In contrast, in the case of neutral Ir catalyst, the coor-
dination site is less reactive because counter anion
(Cl) is near the metal center [10], and insertion of
distal alkyne Y precedes. The reductive elimination
furnishes macrocyclic compound 5 (see Scheme 4).
1,4-Bis(2-(4,4-dimethoxycarbonylocta-1,6-diynyl) ph-
enyl)buta-1,3-diyne (3a). Pale yellow solid; mp 134◦C;
IR (CH2Cl2) 1739, 760 cm−1; 1H NMR δ 1.74 (bs, 6H),
3.08 (bs, 4H), 3.29 (s, 4H), 3.79 (s, 12H), 7.23–7.30
(m, 4H), 7.39–7.41 (m, 2H), 7.52–7.54 (m, 2H); 13C
NMR δ 3.5, 23.2, 23.9, 53.0, 57.2, 73.1, 77.4, 79.2,
81.0, 81.7, 89.1, 124.3, 126.6, 127.8, 128.7, 132.4,
133.0, 170.0; HRMS (FAB, positive) m/z Calcd. for
C40H35O8 643.2332 ([M + 1]+); found, 643.2335 ([M
+ 1]+).
1,4-Bis(2-(4,4-dimethoxycarbonyl-7-phenylhepta-
1,6-diynyl)phenyl)buta-1,3-diyne (3b). White solid;
mp 52◦C; IR (KBr) 1743, 757 cm−1; 1H NMR
δ 3.37 (s, 4H), 3.38 (s, 4H), 3.81 (s, 12H), 7.19–7.28
(m, 10H), 7.34–7.36 (m, 4H), 7.40 (d, J = 7.2 Hz,
2H), 7.50 (d, J = 7.2 Hz, 2H); 13C NMR δ 23.9, 24.2,
Heteroatom Chemistry DOI 10.1002/hc

Chiral Rh- and Ir-Catalyzed Intramolecular Cycloaddition of Hexaynes for the Construction of New Chiral Skeletons 367
53.1, 57.3, 77.5, 81.1, 81.9, 83.8, 84.1, 88.9, 123.1,
1,4-Bis(2-(3-(N-(3-phenylprop-2-ynyl)-N-tosyl-
124.3, 126.5, 127.8, 127.9, 128.1, 128.7, 131.7, 132.4,
133.1, 169.3; HRMS (FAB, positive) m/z Calcd. for
C50H39O8 767.2645 ([M + 1]+); found, 767.2651
([M +1]+).
amino)prop-1-ynyl)phenyl)buta-1,3-diyne
(3h).
White solid; mp 172–174◦C; IR (KBr) 1352, 1165,
1
756 cm−1; H NMR δ 2.20 (s, 6H), 4.51 (s, 4H), 4.56
(s, 4H), 7.18–7.26 (m, 20H), 7.44–7.46 (m, 2H), 7.78
(d, J = 8.5 Hz, 4H); 13C NMR δ 21.3, 37.5, 37.6, 81.3,
81.8, 84.1, 85.8, 86.4, 122.3, 124.1, 125.9, 127.9,
128.1, 128.2, 128.4, 128.8, 129.6, 131.7, 132.0, 132.9,
135.2, 143.8 (two alkyne peaks are overlapped);
HRMS (FAB, positive) m/z Calcd. for C54H41N2O4S2
845.2508 ([M + 1]+); found, 845.2520 ([M + 1]+).
1,4-Bis(2-(3-(but-2-ynyloxy)prop-1-ynyl)phenyl)
buta-1,3-diyne (3c). Yellow solid; mp 80◦C; IR (KBr)
1
2843, 1475, 1074, 756 cm−1; H NMR δ 1.82 (t, J =
2.1Hz, 6H), 4.39 (q, J = 2.1 Hz, 4H), 4.56 (s, 4H),
7.27–7.34 (m, 4H), 7.45–7.47 (m, 2H), 7.53–7.56
(m, 2H); 13C NMR δ 3.6, 57.1, 57.1, 74.6, 77.5, 81.1,
83.1, 84.7, 89.3, 124.5, 126.3, 128.1, 128.8, 132.0,
132.9; HRMS (FAB, positive) m/z Calcd. for C30H23O2
A Typical Experimental Procedure of Rh-Catalyzed
Consecutive Cycloaddition of Hexaynes (Table 2).
[Rh(cod)2]BF4 (2.0 mg, 0.005 mmol) and tolBINAP
(3.4 mg, 0.005 mmol) were placed in a Schlenk tube,
which was then evacuated and backfilled with argon
(×3). To the reaction vessel, dichloromethane (1.0
mL) was added. Then it was filled with hydrogen,
and the mixture was stirred at ambient temperature
for 30 min under hydrogen atmosphere. After re-
moval of the solvent and hydrogen under reduced
pressure, the reaction vessel was filled with argon.
1,2-Dichloroethane (1.4 mL) was added to the flask,
and the solution was stirred to give a red solution.
Then, a 1,2-dichloroethane solution (0.6 mL) of hex-
ayne (0.05 mmol) was added to the solution and the
mixture was stirred at the appropriate temperature
listed in Table 2. After the completion of the reaction,
the volatiles were removed under reduced pressure,
and the crude products were purified by thin-layer
chromatography to give a chiral product. The ee was
determined by HPLC analysis using a chiral column.
415.1698 ([M +1]+); found, 415.1692 ([M + 1]+).
1,4-Bis(2-(3-(3-phenylprop-2-ynyloxy)prop-1-ynyl)
phenyl)buta-1,3-diyne (3d). Pale yellow oil; IR (neat)
1
1489, 1078, 756 cm−1; H NMR δ 4.63 (s, 4H), 4.67
(s, 4H), 7.20–7.30 (m, 10H), 7.40–7.42 (m, 4H),
7.44–7.51 (m, 4H); 13C NMR δ 57.2, 57.4, 77.5, 81.2,
84.6, 85.1, 86.7, 89.2, 122.4, 124.4, 126.2, 128.2,
128.4, 128.8, 131.8, 132.0, 132.9 (two aromatic
peaks are overlapped); HRMS (FAB, positive) m/z
Calcd. for C40H26O2Na 561.1830 ([M + Na]+); found,
561.1815 ([M + Na]+).
1,4-Bis(2-(3-(3-(4-bromophenyl)prop-2-ynyloxy)
prop-1-ynyl)phenyl)buta-1,3-diyne (3e). Pale yellow
solid; mp 133◦C; IR (KBr) 1484, 1083, 750 cm−1;
1H NMR δ 4.62 (s, 4H), 4.65 (s, 4H), 7.21–7.37 (m,
12H), 7.43–7.45 (m, 2H), 7.47–7.50 (m, 2H); 13C
NMR δ 57.2, 57.4, 77.5, 81.2, 85.2, 85.6, 85.8, 89.0,
121.5, 122.7, 124.4, 126.1, 128.2, 128.9, 131.5, 132.0,
132.9, 133.2; HRMS (FAB, positive) m/z Calcd. for
C40H25O2Br2 697.0221 ([M + 1]+); found, 697.0200
([M + 1]+).
1,4-Bis(2-(3-(3-(4-methoxyphenyl)prop-2-ynyloxy)
Tetramethyl
4,4ꢀ-Dimethyl-1,3,1ꢀ,3ꢀ-tetrahydro-
prop-1-ynyl)phenyl)buta-1,3-diyne (3f). Pale yellow
solid; mp 103◦C; IR (KBr) 1510, 1252 cm−1; 1H NMR
δ 3.78 (s, 6H), 4.63 (s, 4H), 4.65 (s, 4H), 6.75–6.79
(m, 4H), 7.20–7.37 (m, 8H), 7.44–7.52 (m, 4H);
13C NMR δ 55.2, 57.3, 57.4, 77.5, 81.2, 83.2, 85.0,
86.7, 89.3, 113.8, 114.7, 124.4, 126.2, 128.2, 128.8,
132.0, 133.0, 133.3, 159.7; HRMS (FAB, positive)
m/z Calcd. for C42H30O4 598.2144 ([M]+); found,
598.2128 ([M]+).
2H,2ꢀH-cyclopenta[a]-5,5ꢀ-bis(biphenylene)-2,2,2ꢀ,2ꢀ-
tetracarboxylate (4a). Pale yellow solid, mp; 280◦C;
IR (CH2Cl2) 1736, 739 cm−1; 1H NMR δ 1.95 (s, 6H),
3.36 (s, 2H), 3.37 (s, 2H), 3.44 (s, 2H), 3.45 (s, 2H),
3.78 (s, 6H), 3.79 (s, 6H), 6.25–6.27 (m, 2H),
6.53–6.54 (m, 2H), 6.58–6.67 (m, 4H); 13C NMR
δ 16.3, 37.8, 39.6, 53.1, 59.9, 116.6, 117.3, 126.2,
127.6, 127.7, 129.0, 131.8, 140.7, 142.4, 148.8, 150.6,
151.1, 172.0; HRMS (FAB, positive) m/z Calcd. for
C40H34O8 ([M]+), 642.2254; found, 642.2260 ([M]+);
[α]1D3 = −93.1 (c 1.45, CHCl3, 61% ee). The ee was
determined by HPLC analysis using a chiral column
(Daicel Chiralpak AD-H: 4 × 250 mm, 254 nm UV
detector, rt, eluent: 5% 2-propanol in hexane, flow
rate: 0.5 mL /min−1, retention time: 15 min for
minor isomer and 17 min for major isomer).
1,4-Bis(2-(3-(N-(but-2-ynyl)-N-tosylamino)prop-
1-ynyl)phenyl)buta-1,3-diyne (3g). Brown solid; mp
1
127◦C; IR (KBr) 1346, 1163 cm−1; H NMR δ 1.66
(t, J = 2.4 Hz, 6H), 2.25 (s, 6H), 4.26 (bs, 4H),
4.45 (s, 4H), 7.19–7.23 (m, 6H), 7.26–7.30 (m, 4H),
7.50–7.52 (m, 2H), 7.75 (d, J = 8.4 Hz, 4H); 13C
NMR δ 3.5, 21.4, 37.1, 37.2, 71.7, 77.2, 81.2, 81.9,
83.9, 86.4, 124.0, 126.0, 127.9, 128.2, 128.8, 129.4,
132.0, 132.8, 135.3, 143.7; HRMS (FAB, positive)
m/z Calcd. for C44H37O4N2S2 721.2194 ([M + 1]+);
found, 721.2203 ([M + 1]+).
Tetramethyl4,4ꢀ-Diphenyl-1,3,1ꢀ,3ꢀ-tetrahydro-2H,
2ꢀH-cyclopenta[a]-5,5ꢀ-bis(biphenylene)-2,2,2ꢀ,2ꢀ-tetr-
acarboxylate (4b). Yellow solid; 260◦C (decomp);
IR (KBr) 1739, 1270, 740 cm−1; 1H NMR δ 2.79
Heteroatom Chemistry DOI 10.1002/hc

368 Shibata et al.
(d, J = 17.5 Hz, 2H), 3.29 (d, 17.5 Hz, 2H), 3.33
(d, J = 17.0 Hz, 2H), 3.44 (d, J = 17.0 Hz, 2H), 3.63
(s, 6H), 3.73 (s, 6H), 6.47–6.48 (m, 6H), 6.62–6.74
(m, 6H), 7.03–7.12 (m, 6H). 13C NMR δ 37.6, 40.1,
52.9, 52.9, 60.1, 116.9, 118.2, 125.4, 126.2, 127.3,
127.8, 128.2, 129.3, 129.7, 136.7, 138.0, 140.5, 143.8,
149.8, 150.2, 150.7, 171.6, 171.8; HRMS (FAB,
positive) m/z Calcd. for C50H38O8 766.2567 ([M]+);
found, 766.2532 ([M]+); [α]D28 = −418.2 (c 1.18,
CHCl3, 96% ee). The ee was determined by HPLC
analysis using a chiral column (Daicel Chiralcel
OD-H: 4 × 250 mm, 254 nm UV detector, rt, eluent:
5% 2-propanol in hexane, flow rate: 1.0 mL /min−1,
retention time: 13 min for minor isomer and 15 min
(d, J = 13.2 Hz, 2H), 4.89 (d, J = 13.2 Hz, 2H),
4.93 (d, J = 13.2 Hz, 2H), 6.40–6.42 (m, 4H), 6.50
(d, J = 6.8 Hz, 2H), 6.65–6.80 (m, 6H), 7.21–7.23
(m, 4H); 13C NMR δ 70.9, 72.6, 117.5, 118.7, 120.9,
124.1, 128.4, 128.7, 129.4, 130.4, 130.9, 132.7,
136.7, 140.8, 142.1, 149.5, 150.3, 150.6; HRMS
(FAB, positive) m/z Calcd. for C40H24Br2O2 696.0143
([M]+); found, 696.0142 ([M]+); [α]1D5 = −262.4
(c 0.69, CHCl3, 94% ee). The ee was determined
by HPLC analysis using a chiral column (Daicel
Chiralpak IC: 4 × 250 mm, 254 nm UV detector, rt,
eluent: 20% 2-propanol in hexane, flow rate: 0.5 mL/
min−1, retention time: 14 min for minor isomer and
15 min for major isomer).
4,4ꢀ-Bis(4-methoxyphenyl)-1,3,1ꢀ,3ꢀ-tetrahydro-2H,
for major isomer).
4,4ꢀ-Dimethyl-1,3,1ꢀ,3ꢀ-tetrahydro-2H,2ꢀH-2-oxacy-
2ꢀH-2-oxacyclopenta[a]-5,5ꢀ-bis(biphenylenyl)
(4f).
Yellow solid; 185◦C (decomp); IR (KBr) 1516,
1248 cm−1; 1H NMR
3.78 (s, 6H), 4.31
clopenta[a]-5,5ꢀ-bis(biphenylene)
(4c).
Yellow
solid; 225◦C (decomp) IR (KBr) 1410, 1059, 739
cm−1; 1H NMR δ 1.93 (s, 6H), 4.90 (s, 4H), 4.96
(s, 4H), 6.33 (d, J = 6.4 Hz, 2H), 6.55 (d, J = 6.4
Hz, 2H), 6.62–6.71 (m, 4H); 13C NMR δ 16.0, 71.3,
72.6, 116.9, 117.4, 125.7, 128.0, 128.0, 128.5, 129.1,
140.0, 140.2, 149.3, 150.1, 151.0; HRMS (FAB,
positive) m/z Calcd. for C30H22O2 414.1612 ([M]+);
found, 414.1612 ([M]+); [α]D15 = −232.6 (c 0.62,
CHCl3, 75% ee). The ee was determined by HPLC
analysis using a chiral column (Daicel Chiralpak
AD-H: 4 × 250 mm, 254 nm UV detector, rt, eluent:
5% 2-propanol in hexane, flow rate: 0.5 mL/ min−1,
retention time: 14 min for major isomer and 20 min
δ
(d, J = 12.8 Hz, 2H), 4.78 (d, J = 12.8 Hz,
2H), 4.90 (s, 4H), 6.46–6.51 (m, 6H), 6.60–6.77 (m,
10H); 13C NMR δ 55.2, 70.9, 72.8, 113.0, 117.1,
118.4, 125.0, 128.1, 128.4, 129.0, 130.0, 130.4,
134.1, 140.4, 141.1, 150.0, 150.2, 150.7, 158.3;
HRMS (FAB, positive) m/z Calcd. for C42H31O4
599.2222 ([M + 1]+); found, 599.2195 ([M + 1]+);
[α]2D2 = −623.9 (c 1.27, CHCl3, 94% ee). The ee
was determined by HPLC analysis using a chiral
column (Daicel Chiralpak IC: 4 × 250 mm, 254 nm
UV detector, rt, eluent: 50% dichloromethane in
hexane, flow rate: 0.5 mL/ min−1, retention time: 15
for minor isomer).
min for major isomer and 16 min for minor isomer).
4,4ꢀ-Diphenyl-1,3,1ꢀ,3ꢀ-tetrahydro-2H,2ꢀH-2-oxacy-
4,4ꢀ-Dimethyl-1,3,1ꢀ,3ꢀ-tetrahydro-2H,2ꢀH-2,2ꢀ-
clopenta[a]-5,5ꢀ-bis(biphenylenyl)
(4d).
Yellow
ditosyl-2-azacyclopenta[a]-5,5ꢀ-bis(biphenylenyl) (4g).
Yellow solid; 160◦C (decomp) IR (KBr) 1348,
1163, 740 cm−1; 1H NMR δ 1.83 (s, 6H), 2.43
(s, 6H), 4.31–4.48 (m, 8H), 6.23 (d, J = 6.4 Hz, 2H),
6.53 (d, J = 6.4 Hz, 2H), 6.60–6.71 (m, 4H), 7.36
(d, J = 7.8 Hz, 4H), 7.80 (d, J = 7.8 Hz, 4H); 13C
NMR δ 15.9, 21.5, 51.3, 52.6, 117.1, 117.6, 125.4,
125.7, 127.6, 128.2, 128.3, 129.9, 130.6, 133.6,
136.7, 141.5, 143.8, 149.4, 149.5, 150.3; HRMS
(FAB, positive) m/z Calcd. for C44H37O4N2S2
721.2194 ([M]+); found, 721.2149 ([M]+); [α]1D3
= −102.0 (c 2.63, CHCl3, 74% ee). The ee was
determined by HPLC analysis using a chiral column
(Daicel Chiralcel OD-H: 4 × 250 mm, 254 nm UV
detector, rt, eluent: 20% 2-propanol in hexane, flow
rate: 1.0 mL/ min−1, retention time: 10 min for major
isomer and 11 min for minor isomer).
solid; 270◦C (decomp); IR (KBr) 1055, 737, cm−1;
1H NMR δ 4.29 (d, J = 13.2 Hz, 2H), 4.77
(d, J = 13.2 Hz, 2H), 4.89 (d, J = 12.7 Hz,
2H), 4.91 (d, J = 12.7, 2H), 6.45–6.53 (m, 6H),
6.63 (d, J = 6.5 Hz, 2H), 6.70 (dd, J = 7.2, 7.2
Hz, 2H), 6.76 (dd, J = 7.0, 7.0 Hz, 2H), 7.05
(dd, J = 7.2, 7.2 Hz, 4H), 7.11–7.14 (m, 2H); 13C
NMR δ 70.9, 72.4, 117.2, 118.5, 124.8, 126.6, 127.6,
128.1, 128.5, 128.9, 129.1, 134.4, 137.8, 140.5,
141.5, 149.7, 150.3, 150.7; HRMS (FAB, positive)
m/z Calcd. for C40H26O2 538.1933 ([M]+); found,
538.1923 ([M]+); [α]D27 = −649.6 (c 0.21, CHCl3,
89% ee). The ee was determined by HPLC analysis
using a chiral column (Daicel Chiralpak AD-H: 4
× 250 mm, 254 nm UV detector, rt, eluent: 10%
2-propanol in hexane, flow rate: 0.5 mL /min−1,
retention time: 8 min for minor isomer and 10 min
4,4ꢀ-Diphenyl-1,3,1ꢀ,3ꢀ-tetrahydro-2H,2ꢀH-2,2ꢀ-
for major isomer).
ditosyl-2-azacyclopenta[a]-5,5ꢀ-bis(biphenylenyl)
(4h). Yellow solid; 144◦C (decomp); IR (KBr)
1350, 1165, 741 cm−1; 1H NMR δ 2.40 (s, 6H),
3.74 (d, J = 13.8 Hz, 2H), 4.23 (d, J = 14.5 Hz, 2H),
4.35 (d, J = 14.5 Hz, 2H), 4.40 (d, J = 13.8 Hz, 2H),
4,4ꢀ-Bis(4-bromophenyl)-1,3,1ꢀ,3ꢀ-tetrahydro-2H,
2ꢀH-2-oxacyclopenta[a]-5,5ꢀ-bis(biphenylenyl) (4e).
Yellow solid; 187◦C (decomp); IR (KBr) 1491, 1057,
741 cm−1; 1H NMR δ 4.28 (d, J = 13.2 Hz, 2H), 4.79
Heteroatom Chemistry DOI 10.1002/hc

Chiral Rh- and Ir-Catalyzed Intramolecular Cycloaddition of Hexaynes for the Construction of New Chiral Skeletons 369
6.40–6.41 (m, 6H), 6.59–6.76 (m, 6H), 7.04–7.07 (m,
1H), 6.98–7.01 (m, 1H), 7.12 (d, J = 8.2 Hz, 1H),
7.15 (d, J = 8.2 Hz, 1H), 7.23–7.48 (m, 12H), 7.68 (d,
J = 7.5 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H); 13C NMR
δ 57.1, 67.2, 74.2, 74.4, 77.9, 78.2, 80.9, 82.7, 84.0,
91.5, 121.4, 125.5, 126.3, 126.5, 126.7, 127.1, 127.2,
127.5, 128.0, 128.1, 128.4, 128.7, 128.7, 128.9, 129.5,
129.6, 131.0, 131.1, 132.0, 132.7, 133.0, 133.2, 133.6,
136.6, 137.5, 138.4, 138.5, 138.7, 143.1, 143.6; HRMS
(FAB, positive) m/z Calcd. for C40H25O2 537.1855
4H), 7.14–7.17 (m, 2H), 7.29 (d, J = 7.5 Hz, 4H),
7.64 (d, J = 8.0 Hz, 4H); 13C NMR δ 21.5, 51.0, 52.8,
117.4, 118.5, 125.1, 125.9, 127.0, 127.6, 127.8, 128.5,
128.7, 129.0, 130.0, 133.7, 135.9, 136.8, 136.9, 142.8,
143.6, 149.1, 150.1, 150.6; HRMS (FAB, positive)
m/z Calcd. for C54H41O4N2S2 845.2508 ([M + 1]+);
found, 845.2535 ([M + 1]+); [α]3D1 = −149.8 (c 0.67,
CHCl3, 92% ee). The ee was determined by HPLC
analysis using a chiral column (Daicel Chiralpak
IC: 4 × 250 mm, 254 nm UV detector, rt, eluent:
80% dichloromethane in h exane, flow rate: 1.0 mL/
min−1, retention time: 14 min for major isomer and
16 min for minor isomer).
([M − 1]+); found, 537.1865 ([M − 1]+); [α]2D9
=
−138.2 (c 1.37, CHCl3, 87% ee). The ee was deter-
mined by HPLC analysis using a chiral column (Dai-
cel Chiralpak AD-H: 4 × 250 mm, 254 nm UV detec-
tor, rt, eluent: 10% 2-propanol in hexane, flow rate:
1.0 mL/ min−1, retention time: 6 min for major iso-
mer and 17 min for minor isomer).
A Typical Experimental Procedure of Ir-Catalyzed
Cycloaddition of Hexaynes (Table 3) . [IrCl(cod)]2
(1.7 mg, 0.0025 mmol) and Me-DUPHOS (1.5 mg,
0.005 mmol) were placed in a Schlenk tube, which
was then evacuated and backfilled with argon (×3).
To the reaction vessel xylene (1.4 mL) was added.
Then, a xylene solution (0.6 mL) of hexayne (0.05
mmol) was added to the solution and the mixture
was stirred at the appropriate temperature listed in
Table 3. After the completion of the reaction, the
volatiles were removed under reduced pressure and
the crude products were purified by thin-layer chro-
matography to give a chiral macrocyclic compound.
The eewas determined by HPLC analysis using a chi-
ral column.
Macrocyclic compound (5c). Pale yellow solid;
173◦C (decomp); IR (KBr) 1082, 758 cm−1; 1H NMR
δ 2.32 (s, 3H), 2.37 (s, 3H), 4.33 (d, J = 14.0 Hz,
1H), 4.37 (d, J = 14.0 Hz, 1H), 4.62 (d, J = 6.4 Hz,
1H), 4.73 (d, J = 12.0 Hz, 1H), 4.77 (d, J = 12.0
Hz, 1H), 5.07 (d, J = 6.4 Hz, 1H), 5.17 (s, 2H), 7.23–
7.43 (m, 7H), 7.62–7.64 (m, 1H); 13C NMR δ 16.5,
16.6, 57.0, 65.8, 74.3, 74.4, 78.2, 80.7, 81.8, 83.6, 84.7,
91.1, 122.0, 125.9, 127.2, 127.4, 128.1, 128.7, 129.3,
129.4, 130.1, 130.8, 131.4, 132.0, 133.3, 133.5, 135.9,
137.7, 138.0, 143.3; HRMS (FAB, positive) m/z Calcd.
for C30H23O2 415.1698 ([M + 1]+); found, 415.1685
([M + 1]+); [α]D14 = 18.4 (c 0.55, CHCl3, 61% ee).
The ee was determined by HPLC analysis using a
chiral column (Daicel Chiralpak AD-H: 4 × 250 mm,
254 nm UV detector, rt, eluent: 10% 2-propanol in
hexane, flow rate: 1.0 mL/ min−1, retention time: 12
min for minor isomer and 15 min for major isomer).
Macrocyclic compound (5d). White solid; 260◦C
(decomp); IR (KBr) 1081, 761 cm−1; 1H NMR δ 3.94
(d, J = 5.7 Hz, 1H), 3.96 (d, J = 2.0 Hz), 4.24 (d,
J = 5.7 Hz, 1H), 4.26 (bs, 1H), 4.72 (d, J = 12.7 Hz,
1H), 4.97 (d, J = 12.5 Hz, 1H), 5.02 (d, J = 12.5 Hz,
1H), 5.12 (d, J = 12.7 Hz, 1H), 6.79 (d, J = 7.5 Hz,
Macrocyclic compound (5e). White solid; 170◦C
(decomp); IR (KBr) 2850, 1492, 1074, 758 cm−1; H
1
NMR δ 3.87 (d, J = 9.6 Hz, 1H), 3.97 (d, J = 14.4
Hz, 1H), 4.19 (d, J = 9.6 Hz, 1H), 4.26 (d, J = 14.4
Hz, 1H), 4.67–4.70 (m, 1H), 4.88–4.91 (m, 1H), 5.02–
5.06 (m, 1H), 5.12–5.15 (m, 1H), 6.64 (dd, J = 2.2,
8.6 Hz, 1H), 7.10–7.62 (m, 14H), 8.23 (dd, J = 2.2,
8.6 Hz, 1H); 13C NMR δ 57.6, 67.5, 74.2, 74.3, 77.9,
78.2, 81.1, 82.6, 84.4, 90.9, 121.3, 121.4, 122.0, 125.2,
126.8, 127.5, 128.3, 128.8, 128.9, 129.4, 129.5, 129.7,
130.4, 131.0, 131.4, 131.6, 132.2, 132.8, 133.4, 133.4,
133.6, 134.5, 135.0, 137.0, 137.3, 137.9, 138.8, 141.7,
142.9 (two aromatic peaks are overlapped); HRMS
(FAB, positive) m/z Calcd. for C40H24O2Br2 696.0143
([M]+); found, 696.0142 ([M]+); [α]1D5 = −137.9 (c
1.16, CHCl3, 95% ee). The ee was determined by
HPLC analysis using a chiral column (Daicel Chi-
ralcel OD-H: 4 × 250 mm, 254 nm UV detector, rt,
eluent: 10% 2-propanol in hexane, flow rate: 1.0 mL/
min−1, retention time: 6 min for major isomer and 7
min for minor isomer); crystal data forC40H24O2Br2,
M = 696.44, orthorhombic, space group P212121 (no.
˚
˚
19), a = 8.0605(2) A, b = 16.9235(4) A, c = 26.6926(7)
3
˚
˚
A, V = 3641.20(15) A , T = 223 K, Z = 4, μ(Cu Kα) =
13.943 cm−1; number of reflections measured: total
6629 and unique 2072, R = 0.1304, wR2 = 0.1732,
1
Flack parameter (Friedel pairs = 2850) 0.07(14).
CCDC 790096.
Macrocyclic compound (5f). White solid; 168◦C
1
(decomp); IR (KBr) 1514, 1246, cm−1; H NMR δ
3.72 (s, 3H), 3.87 (s, 3H), 3.95 (d, J = 3.0 Hz, 1H),
3.98 (s, 1H), 4.26 (d, J = 3.0 Hz, 1H), 4.29 (bs, 1H),
4.69 (d, J = 12.8 Hz, 1H), 4.96 (d, J = 12.8 Hz, 1H),
5.04 (d, J = 12.8 Hz, 1H), 5.12 (d, J = 12.8 Hz, 1H),
6.52 (dd, J = 8.8, 2.8 Hz, 1H), 6.68 (dd, J = 8.4, 2.4
Hz, 1H), 6.89 (dd, J = 8.6, 2.6 Hz, 1H), 6.94–7.00
(m, 2H), 7.14–7.48 (m, 9H), 7.61 (d, J = 7.6 Hz, 1H),
8.22 (dd, J = 8.8, 2.4 Hz, 1H); 13C NMR δ 55.0, 55.2,
Heteroatom Chemistry DOI 10.1002/hc

370 Shibata et al.
57.1, 67.3, 74.3, 74.5, 78.3, 78.3, 80.8, 82.9, 84.0, 91.5,
111.3, 112.3, 113.6, 121.3, 125.3, 125.5, 127.1, 128.0,
128.2, 128.6, 128.8, 129.0, 129.5, 130.1, 130.8, 130.9,
132.0, 132.3, 133.1, 133.2, 133.8, 134.1, 136.3, 137.6,
138.3, 142.8, 143.8, 158.3, 158.9 (two aromatic peaks
are overlapped); HRMS (FAB, positive) m/z Calcd.
for C42H31O4 599.2222 ([M + 1]+); found, 599.2247
[2] (a) Shibata, T.; Tsuchikama, K. Org Biomol Chem
2008, 1317–1323; (b) Tanaka, K. Chem Asian J 2009,
4, 508–518.
[3] (a) Shibata, T.; Fujimoto, T.; Yokota, K.; Takagi,
K. J Am Chem Soc 2004, 126, 8382–8383; (b)
Shibata, T.; Arai, Y.; Takami, K.; Tsuchikama,
K.; Fujimoto, T.; Takebayashi, S.; Takagi, K. Adv
Synth Catal 2006, 348, 2475–2483; (c) Shibata, T.;
Tsuchikama, K. Chem Commun 2005, 6017–6019;
(d) Shibata, T.; Tsuchikama K.; Otsuka, M. Tetra-
hedron: Asymmetry 2005, 17, 614–619; (e) Shibata,
T.; Yoshida, S.; Arai, Y.; Otsuka, M.; Endo, K. Tetra-
hedron 2008, 64, 821–830.
[4] In 2004, chiral Co and Rh-catalyzed enantioselective
[2 + 2 + 2] cycloadditions for the generation of axial
chirality were independently reported: (a) Gutnov, A.;
Heller, B.; Fischer, C.; Drexler, H.-J.; Spannenberg,
A.; Sundermann B.; Sundermann, C. Angew Chem,
Int Ed 2004, 43, 3795–3797; (b) Tanaka, K.; Nishida,
G.; Wada, A.; Noguchi, K. Angew Chem, Int Ed 2004,
43, 6510–6512.
[5] Synthesis and use of biphenylenes: Vollhardt, K. P.
C.; Mohler, D. L. Adv Strain Org Chem 1996, 5 121–
160.
[6] Cocatalyzed [2 + 2 + 2] cycloaddition of ortho-
phenylene tethered diyne with alkyne is an estab-
lished protocol for the construction of biphenyne
skeleton: (a) Berris, B. C.; Lai, Y. H.; Vollhardt, K.
P. C. J Chem Soc Chem Commun 1982, 16, 953–954;
(b) Vollhardt, K. P. C. Pure Appl Chem 1993, 65, 153–
156.
23
([M + 1]+); [α] = −104.3 (c 0.67, CHCl3, 96% ee).
]D
The ee was determined by HPLC analysis using a
chiral column (Daicel Chiralpak IC: 4 × 250 mm, 254
nm UV detector, rt, eluent: 50% dichloromethane in
hexane, flow rate: 0.5 mL/ min−1, retention time: 10
min for minor isomer and 11 min for major isomer).
Macrocyclic compound (5h). Pale yellow solid;
160◦C (decomp); IR (KBr) 1350, 1163, 756 cm−1; 1H
NMR δ 2.33 (s, 3H), 2.39 (s, 3H), 3.52 (d, J = 18.0
Hz, 1H), 3.70 (d, J = 18.0 Hz, 1H), 3.92 (d, J =
12.0 Hz, 1H), 4.20–4.50 (m, 5H), 6.86–6.91 (m, 2H),
7.04–7.20 (m, 10H), 7.26–7.43 (m, 12H), 7.62 (m,
2H); 13C NMR δ 21.4, 21.6, 35.8, 46.7, 54.1, 54.3, 77.8,
78.1, 80.9, 82.1, 82.7, 90.0, 121.4, 125.1, 127.1, 127.3,
127.4, 127.5, 127.7, 127.8, 128.0, 128.1, 128.1, 128.2,
128.7, 128.8, 128.8, 129.0, 129.1, 129.2, 129.8, 129.8,
130.0, 130.6, 130.6, 131.4, 131.9, 133.4, 133.9, 135.2,
135.7, 136.6, 137.2, 137.3, 139.3, 143.3, 143.4, 143.5,
143.6 (two aromatic peaks are overlapped); HRMS
(FAB, positive) m/z Calcd. for C54H41N2O4S2 845.2508
([M + 1]+); found, 845.2482 ([M + 1]+); [α]2D8 = 55.8
(c 1.41, CHCl3, 97% ee). The ee was determined by
HPLC analysis using a chiral column (Daicel Chiral-
pak IA: 4 × 250 mm, 254 nm UV detector, rt, eluent:
50% dichloromethane in hexane, flow rate: 0.5 mL/
min−1, retention time: 9 min for major isomer and
11 min for minor isomer).
[7] Triynes with alkyne terminus were transformed
into tetraphenylenes by consecutive inter- and in-
tramolecular [2 + 2 + 2] cycloaddition: Shibata, T.;
Chiba, T.; Hirashima, H.; Ueno, Y.; Endo, K. Angew
Chem, Int Ed 2009, 48, 8066–8069.
[8] Intramolecular and enantioselective [2 + 2 + 2] cy-
cloaddition of triynes for the generation of other-
than-axial chiralities: (a) Stara´, I. G.; Stary´, I.;
ˇ
ˇ
Kolla´rovicˇ, A.; Teply´, F.; Vyskocˇil, S.; Saman, D.
Tetrahedron Lett 1999, 40, 1993–1996; (b) Tanaka,
K.; Sagae, H.; Toyoda, K.; Noguchi, K.; Hirano, M. J
Am Chem Soc 2007, 129, 1522–1523; (c) Tanaka, K.;
Kamisawa, A.; Suda, T.; Noguchi, K.; Hirano, M. J
Am Chem Soc 2007, 129, 12078–12079; (d) Shibata,
T.; Uchiyama, T.; Endo, K. Org Lett 2009, 11, 3906–
3908.
ACKNOWLEDGMENTS
We thank Takasago International Corporation for
the gift of H8-BINAP and SEGPHOS.
[9] Structural analyses of cationic Rh-BINAP complexes
with BF4 as a counter anion: Preetz, A.; Drexler,
H. -J.; Shulz, S.; Heller, D. Tetrahedron: Asymmetry
2010, 21, 1226–1231.
[10] Structural analyses of Ir-BINAP complexes with Cl
as a counter anion: (a) Yamagata, T.; Iseki, A.;
Tani, K. Chem Lett 1997, 1215–1216; (b) Tani, K.;
Nakajima, K.; Iseki, A.; Yamagata, T. Chem Commun
2001, 1630–1631.
REFERENCES
[1] Recent reviews: (a) Yamamoto, Y. Curr Org Chem
2005, 9, 503–509; (b) Kotha, S.; Brahmachary, E.;
Lahiri, K. Eur J Org Chem 2005, 4741–4761; (c)
Chopade, P. R.; Louie, J. Adv Synth Catal 2006, 348,
2307–2327.
Heteroatom Chemistry DOI 10.1002/hc