Asymmetric Intramolecular Rauhut-Currier Reaction and Its Desymmetric Version via Double Thiol/Phase-Transfer Catalysis

Article abstract of DOI:10.1021/acs.joc.0c01293

An asymmetric intramolecular Rauhut-Currier reaction of linear bis(enones) has been achieved via double activation catalysis of thiols and phase transfer substances, furnishing both enantioenriched cyclohexene and cyclopentene derivatives (up to 95% ee).

Full text of DOI:10.1021/acs.joc.0c01293

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Article
Asymmetric Intramolecular Rauhut-Currier Reaction and Its
Desymmetric Version via Double Thiol/Phase-Transfer Catalysis
Ying Jiang, Yang Yang, Qing He, Wei Du, and Ying-Chun Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01293 • Publication Date (Web): 31 Jul 2020
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Asymmetric Intramolecular RauhutCurrier Reaction and
Its Desymmetric Version via Double Thiol/Phase-Transfer
Catalysis
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Ying Jiang,† Yang Yang,† Qing He,† Wei Du,*† and Ying-Chun Chen*†,‡
†Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education and
Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China
‡College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China
COR1
COR1
COR1
thiol/PTC
COR1
double activation catalysis
desymmetric RC reaction
R
R
up to 85%, 95% ee, >19:1 dr
ABSTRACT
An asymmetric intramolecular RauhutCurrier reaction of linear bis(enones) has
been achieved via double activation catalysis of thiols and phase transfer substances,
furnishing both enantioenriched cyclohexene and cyclopentene derivatives (up to 95%
ee). Furthermore, the desymmetric version of pro-chiral substrates was developed under
similar catalysis, producing the frameworks bearing an additional tertiary or even
quaternary stereogenic center with moderate to excellent diastereo- and
enantioselectivity (up to 95% ee, >19:1 dr).
Introduction
The intramolecular RauhutCurrier (RC) reaction is an efficient protocol for the
construction of cyclic compounds by forming a CC bond between two electron
deficient alkene groups.1 It has gained much attention since the pioneering work
reported simultaneously by Roush2 and Krische.3 It also has important application in
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the synthesis of many natural products.4 The catalytic asymmetric RC reaction of linear
bis(enones) substrates has been investigated extensively, mainly relying on the catalysis
of chiral Lewis basic phosphines (Scheme 1a).5 Besides, stoichiometric chiral N-
protected cysteine was applied with excellent enantiocontrol, and excess strong bases
were required for good conversions (Scheme 1b).6 On the other hand, the Lu group
designed a new kind of cyclohexadienone derivatives bearing a side enone motif, and
realized an elegant intramolecular desymmetric RC reaction to construct fused
frameworks under chiral phosphine catalysis (Scheme 1c).7 Such a desymmetric
strategy further enriches the structural diversity and complexity of the chiral RC
adducts.8
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Very recently, our group uncovered a double activation system by combining 2-
mercaptobenzoic acid9 and suitable chiral Brønsted bases, which efficiently catalyzed
the asymmetric intermolecular cross-RC reaction of 2-cyclopentenone and activated
alkenes.9a Considering the high efficiency of this novel catalytic system, we envisioned
that it would be applicable to asymmetric intramolecular RC reaction of linear
bis(enones) precursors.5,10 Moreover, as outlined in Scheme 1d, the reversible sulfur-
addition of thiol catalysts to pro-chiral bis(enones) would lead to the different early
desymmetric generation of the key ion pair intermediates IV in a potentially
stereoenriched manner under chiral phase-transfer catalysis (PTC), thus the following
cyclization would deliver the expected cyclic products diastereoselectively, finally
furnishing a previously unreported desymmetric intramolecular RC reaction process for
linear bis(enones).
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Scheme 1. Asymmetric Intramolecular RauhutCurrier Reactions of Diverse
Bis(enones) Substrates
6
7
8
9
a) Asymmetric intramolecular RC reaction of linear bis(enones)
COR
O
COR
COR
COR
*
R
*
LB*
COR
*
LB
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I
b) N-protected cysteine-promoted asymmetric intramolecular RC reaction
NHAc
COR
K
O
SH
COR
COR
MeO2C
(1 equiv)
t-BuOK (6 equiv)
AcHN
COR
R
ROC
*
S
II
CO2Me
c) Desymmetric intramolecular RC reaction
O
O
O
O
O
O
R2
R2
R2
*
PR3
*
*
*
PR3 desymmetrization
*
R1
X
X
R1
X
R1
III
d) This work: Desymmetric intramolecular RC reaction of pro-chiral bis(enones)
chiral ion pair
COR1
COR1
*
COR1
COR1
NR
4 O
ArSH
COR1
R1
*
*
NR4, base
*
R3
R2
*
*
R2 R3
ArS
sulfur-addition
desymmetrization
R2 R3
IV
Results and Discussion
Based on the above considerations, initially, we investigated the asymmetric
intramolecular RC reaction of simple bis(enones) 1a to establish the suitability of the
double activation catalytic system.5 It was pleasing that the combination of 2-
mercaptobenzoic acid T1 and chiral PTC C1 derived from cinchonine could smoothly
promote the conversion of substrate 1a at 50 ºC, and the expected RC product 2a was
isolated in a moderate yield albeit with low enantioselectivity (Table 1, entry 1).
Interestingly, the reaction was significantly improved by using 2-mercaptophenol T2
as the catalytic partner (entry 2). It is also notable that the ortho-hydroxyl group of thiol
T2 is crucial for the reaction probably because it could assist the release of the thiol
catalyst,10 as no reaction occurred when 4-mercaptophenol T3 was applied (entry 3).
More PTCs in combination with thiol T2 were tested (entries 47), and excellent
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enantioselectivity with a good yield could be achieved by employing PTC C5 having a
bulky 3,5-di-t-butylbenzyl substitution (entry 7). Slightly improved data were obtained
at room temperature (entry 8), but incomplete conversion was observed at 4 C even by
extending the reaction time (entry 9). Inferior results were attained in other solvents
(entries 10 and 11). In addition, the loadings of catalysts and bases were further
investigated (entries 1215), and the optimal data were afforded with 20 mol % C5, 40
mol % T2 and 60 mol % K2CO3 (entry 14).
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Table 1. Screening Conditions of Intramolecular RC Reactions of Bis(enones) 1aa
O
C
T
(20 mol %)
(40 mol %)
COPh
COPh
O
Ph
K2CO3 (80 mol %)
Ph
Br
solvent, 50 °C
1a
2a
X
N
OMe
Br
N
N
Ph
R
HO
OH
C3
C4
C5
R = H
R = CF3
R = tBu
C1
C2
X = H
X= OCH3
N
R
SH
SH
SH
OH
CO2H
HO
T1
T2
T3
entry
1
C
T
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
EtOAc
CHCl3
t (h)
yield (%)b ee (%)c
C1
C1
C1
C2
C3
C4
C5
C5
C5
C5
C5
T1
T2
T3
T2
T2
T2
T2
T2
T2
T2
T2
72
24
72
24
24
24
24
48
72
48
48
57
79
NR
83
83
78
86
91
53
95
89
9
32
/
2
3
4
59
77
90
89
91
97
83
84
5
6
7
8d
9e
10d
11d
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12d,f
13d,g
14d,h
15d,i
C5
C5
C5
C5
T2
T2
T2
T2
toluene
toluene
toluene
toluene
72
48
48
48
60
91
92
80
93
87
91
89
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aUnless noted otherwise, reactions were performed with 1a (0.05 mmol), phase
transfer catalysts C (20 mol %), thiol T (40 mol %) and K2CO3 (80 mol %) in
b
c
solvent (1 mL) at 50 C. Yield of the isolated product. Determined by chiral
d
HPLC analysis on a chiral stationary phase. At room temperature. eAt 4 C.
g
h
i
fWith C5 (10 mol %). With T2 (20 mol %). With K2CO3 (60 mol %). With
K2CO3 (40 mol %). NR = No reaction.
Consequently, we briefly investigated the substrate scope of this known reaction.
As summarized in Table 2, bis(enones) 1 with different aryl and heteroaryl groups
underwent the RC reaction smoothly to give the corresponding six-membered RC
products 2ai in good to excellent results (Table 2, entries 19), even on a larger scale
(entry 1, data in parentheses), whereas C4 was employed instead of C5 in some cases
for better enantiocontrol. In addition, an unsymmetric bis(enones) bearing both an
electron-withdrawing group and an electron-donating group afforded the corresponding
2j as a single product with excellent regio- and stereocontrol, which is superior to that
under phosphine catalysis (entry 10).5 Moreover, an aromatic/aliphatic hybrid
bis(enones) also proceeded smoothly to give product 2k exclusively, albeit with lower
enantioselectivity (entry 11).
Table 2. Substrate Scope for Intramolecular RC Reactions of Bis(enones) 1a
O
COAr
COR
C5
T2
(20 mol %)
(40 mol %)
O
R
K2CO3 (60 mol %)
Ar
toluene, rt, 1248 h
X
X
1
X = CH2, C(CH3)2, O
2
entry Ar
R
X
n
t (h) yield (%)b ee (%)c
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1d
2
Ph
Ph
CH2
CH2
CH2
CH2
CH2
CH2
CH2
C(CH3)2
O
1
1
1
1
1
1
1
1
1
1
1
48 2a, 91 (73) 91 (91)e
4-CH3C6H4
3-CH3OC6H4
4-BrC6H4,
3-BrC6H4
2-naphthyl
2-thienyl
Ph
4-CH3C6H4
3-CH3OC6H4
4-BrC6H4,
3-BrC6H4
2-naphthyl
2-thienyl
Ph
48 2b, 88
48 2c, 83
24 2d, 91
24 2e, 72
48 2f, 68
48 2g, 81
48 2h, 65
48 2i, 73
48 2j, 92
48 2k, 73
95
92
84
79
81
82
83
78
93
80
3
4f
5f
6
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7
8
9f
10
11
Ph
Ph
4-NO2C6H4
Ph
4-CH3C6H4
CH3
CH2
CH2
aUnless noted otherwise, reactions were performed with bis(enones) 1 (0.1 mmol, X =
CH2, R1 = R2), PTC C5 (20 mol %), thiol T2 (40 mol %) and K2CO3 (60 mol %) in
b
c
toluene (1 mL) at room temperature. Yield of the isolated product. Determined by
HPLC analysis on a chiral stationary phase. dData in parentheses were obtained on a 1.0
e
mmol scale. The absolute configuration of product 2a was determined by comparing
rotation data with literature reports.5 The other products were assigned by analogy. fWith
C4 (20 mol %).
On the other hand, compared to bis(enones) 1 from glutaraldehyde-type precursors,
succinaldehyde-derived ones 3 have been less investigated, and the related asymmetric
RC reactions usually suffered from low reactivity and enantioselectivity.5a,c In contrast,
we pleasingly found that the intramolecular RC reaction of such a type of substrates 3
proceeded very well under the double activation of an axial chiral thiol T4 derived from
R-BINOL10a and chiral PTC C6,11 and a few five-membered ring products 4ae were
efficiently constructed in moderate to excellent enantioselectivity (Scheme 2).
Scheme 2. Substrate Scope for Intramolecular RC Reactions of Bis(enones) 3a
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SH
C6
T4
ROC
COR
(10 mol %)
(10 mol %)
K2CO3 (60 mol %)
toluene, rt, 1224 h
O
OH
OH
3
7
O
SH
8
9
T4
R
R
10
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OMe
4
N
Br
4a
4b
4c
4d
4e
R = Ph, 90%, 93% ee
Ph
R = 4-MeC6H4, 82%, 94% ee
R = 4-BrC6H4, 79%, 85% ee
R = 2-naphthyl, 74%, 85% ee
R = 2-thienyl, 64%, 71% ee
OH
N
OTBS
C6
Ph
Inspired by the promising results based on the easily tunable thiol-PTC system, we
intended to explore the more challenging desymmetric RC reaction with linear
bis(enones) having a -substitution. Under the catalysis of thiol T5 and PTC C7,11 pro-
chiral bis(enones) 5a delivered the diastereomerically pure product 6a with excellent
enantioselectivity (Table 3, entry 1), whereas slightly lower diastereocontrol was
observed on a larger scale (entry 2). For comparison, much lower catalytic efficacy was
obtained by using a bifunctional phosphine C8 (entry 3),5b further showing the
superiority of the current double activation system. As summarized in Table 3, an array
of bis(enones) 5 bearing diverse substituents were investigated, and the corresponding
desymmetric RC products 6bm were generally obtained with good to excellent
stereoselectivity (entries 415), whereas inferior data were observed for the substrates
with electron-withdrawing or heteroaryl groups, probably due to the electronic effects
(entries 6, 7 and 9).
Table 3. Substrate Scope of Desymmetric Intramolecular RC Reaction of
Bis(enones) 5a
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O
COR
COR
C7
T5
(20 mol %)
(40 mol %)
O
R
K2CO3 (60 mol %)
R
toluene, rt
Et
R1
R1
6
5
OMe
N
SH
OH
10
11
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H
N
H
N
Br
tBu
nC4H9
OH
Br
S
N
Ph2P
T5
C8
C7
tBu
entry
1
R, R1
t (h)
72
72
96
72
72
48
24
72
72
48
48
48
36
36
yield (%)b ee (%)c
drd
Ph, CH3
Ph, CH3
Ph, CH3
6a, 76
6a, 78
6a, 34
6b, 66
6c, 75
6d, 66
6e, 82
6f, 75
6g, 62
6h, 73
6i, 82
6j, 82
6k, 75
6l, 85
6m, 70
92
90
97
94
95
79
70
80
75
84
86
85
83
84
81
>19:1
14:1
2e
3f
>19:1
>19:1
>19:1
13:1
4
4-CH3C6H4, CH3
5
3-CH3OC6H4, CH3
4-BrC6H4, CH3
3-ClC6H4, CH3
2-naphthyl, CH3
2-thienyl, CH3
Ph, Ph
6
7
14:1
8
>19:1
3:1
9
10
11
12
13
14
15g
>19:1
>19:1
>19:1
10:1
Ph, 4-ClC6H4
Ph, CO2Et
Ph, OTBS
Ph, iBu
>19:1
>19:1
2-naphthyl, 4-ClC6H4 48
aUnless noted otherwise, reactions were performed with bis(enones) 5 (0.1 mmol),
PTC C7 (20 mol %), thiol T5 (40 mol %) and K2CO3 (60 mol %) in toluene (1
b
c
mL) at room temperature. Yield of the isolated product. Determined by HPLC
analysis on a chiral stationary phase. dDetermined by 1H NMR analysis. eWith 5a
(0.5 mmol). fWith phosphine C8. gIn CHCl3; the absolute configuration of product
6m was determined by X-ray analysis after conversion to product 15 (see Scheme
4).12 The other products were assigned by analogy.
In addition, a bis(enones) 7 having a ,-disubstituted pattern underwent the
desymmetric RC reaction smoothly under the double catalysis of PTC C6 and thiol
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T4,11 producing product 8 bearing a quaternary stereogenic center in a good yield with
moderate stereocontrol (Scheme 3). Even the highly challenging desymmetric RC
reaction of substrate 9 (as an inseparable cis/trans mixture) could be realized, and the
bridged product 10 was obtained with good stereoselectivity under the catalysis of PTC
C5 and thiol T2, albeit in a fair yield, probably because the trans-precursor could not
undergo the cyclization.13 Interestingly, the substrate 1l could undergo intramolecular
RC reaction followed by a cascade aldol process under similar catalytic conditions, and
a bicyclic framework 11 was furnished in a fair yield with moderate
enantioselectivity.14 Finally, our thiol-based double activation strategy was applicable
to the asymmetric RC reaction of substrates 12;15 in this case, a bifunctional thiourea-
tertiary amine C9 was found to be a more reliable choice,11 and the desired products
13a and 13b were constructed in good yields with high ee values.
10
11
12
13
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Scheme 3. More Exploration on Intramolecular RC Reactions of Diversely
Structured Substrates
O
COPh
COPh
C6
T4
(20 mol %)
(40 mol %)
O
Ph
K2CO3 (60 mol %)
Ph
toluene, 50 C, 18 h
CO2tBu
NC CO2tBu
CN
7
8
85%, 75% ee, 11:1 dr
COPh
O
C5
T2
(20 mol %)
(40 mol %)
O
Ph
K2CO3 (1 equiv)
Ph
PhOC
9
toluene, 50 C, 48 h
10
28%, 82% ee, >19:1 dr
O
C5
T2
(20 mol %)
(40 mol %)
O
O
K2CO3 (2 equiv)
3
CH3
43%, 71% ee
toluene, 60 C, 48 h
1l
11
C9
T2
(20 mol %)
(40 mol %)
NO2
NO2
CO2R toluene, 50 C, 48 h
O
O
Ph
Ph
CO2R
12a
12b
R = Et
R = Me
S
13a
13b
81%, 91% ee
75%, 89% ee
HN
N
Ar
HN
C9
Ar = 4-CH3C6H4
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As illustrated in Scheme 4, the multifunctional RC adduct 2c could undergo
Nazarov cyclization to afford the fused hexahydro-9H-fluoren-9-one architecture 14 in
a moderate yield with exclusive diastereocontrol promoted by FeCl36H2O.16 Besides，
product 6m was similarly transformed to framework 15, albeit in a fair yield.
Scheme 4. Transformation of RC Products 2c and 6m
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O
O
O
H
MeO
FeCl36H2O
(1 equiv)
O
Ar
Ar
toluene, 50 C, 5 h
H
MeO
70%, 91% ee, >19:1 dr
2c
Ar = 3-MeOC6H4, 92% ee
O
14
O
O
H
FeCl36H2O
O
Ar
(1 equiv)
Ar
toluene, 40 C, 24 h
H
Cl
Cl
6m
Ar = 2-naphthyl, 81% ee
15
27%, 81% ee, >19:1 dr
In conclusion, we have further developed the double activation system combining
thiols and phase transfer catalysts, which was successfully applied to the asymmetric
intramolecular RauhutCurrier reaction of linear bis(enones) substrates, including the
previously unreported desymmetric version for the unsaturated substrates with pro-
chiral centers. This easily tunable catalytic system is highly efficient under mild
conditions, and enables straightforward access to a broad spectrum of six- and five-
membered frameworks with structural diversity in moderate to high yields with fair to
excellent stereoselectivity. We believe that this catalytic strategy could be applicable to
more challenging asymmetric reactions. The results will be reported in due course.
EXPERIMENTAL SECTION
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General Method. Unless otherwise noted, all reactions were carried out under
ambient atmosphere; when the reactions required heating, the heat source was oil bath.
1H NMR and 13C NMR spectra were recorded on Varian INOVA-400/54, Agilent DD2-
600/54 or Bruker AscendTM 400 instruments. Chemical shifts were reported in ppm
from tetramethylsilane with the solvent resonance as the internal standard in CDCl3
solution. High resolution mass spectra (HRMS) was recorded on a Waters SYNAPT
G2 or Agilent G1969-85000 or Shimadzu LCMS-IT-TOF using an electrospray (ESI)
ionization source. X-ray diffraction experiments were carried out on an Agilent Gemini
and the data obtained were deposited at the Cambridge Crystallographic Data Centre.
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1
In each case, diastereomeric ratio was determined by H NMR analysis and
enantiomeric ratio was determined by HPLC (Agilent Technologies: 1220 Infinity Ⅱ,
1200 Series, 1260 Infinity) analysis on a chiral column in comparison with the authentic
racemate, using a Daicel Chiralpak AD-H Column (250  4.6 mm), Chiralpak IC
Column (250  4.6 mm), Chiralpak ID Column (250  4.6 mm), Chiralpak IH Column
(250  4.6 mm), Chiralpak OD-H Column (250  4.6 mm); UV detection was
monitored at 254 nm. Optical rotation was obtained from Rudolph Research Analytical
Autopol Ⅰ automatic polarimeter in CHCl3 solution at 25 °C. The melting point was
obtained from WRX-4 Mel-Temp apparatus. Column chromatography was performed
on silica gel (200-300 mesh) eluting with EtOAc and petroleum ether. TLC was
performed on glass-backed silica plates. UV light, I2, and solution of potassium
permanganate were used to visualize products or starting materials. All chemicals were
used without purification as commercially available unless otherwise noted. Petroleum
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ether and EtOAc were distilled. THF was freshly distilled from sodium/benzophenone
before use. Experiments involving moisture and/or air sensitive components were
performed under a positive pressure of argon in oven-dried glassware equipped with a
rubber septum inlet.
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The bis(enones) 1 and 3 were synthesized according to the literature
procedures.5b,c,17 The axial chiral mercaptophenol T4 was synthesized following the
literature procedures.10a The substituted mercaptophenol T5, T14 and T15 were
synthesized according to the literature procedures.18 The bis(enones) 9 was synthesized
according to the literature procedures.19 The absolute configuration of chiral 2a, 4a and
13b was assigned by comparison with the experimental data in the literatures.5b,5c,6,15
General Procedure for preparation of bis(enones) 5 and 7. General procedure
A: A solution of 3-substituted glutaric acid (10 mmol) in anhydrous THF (20 mL) was
added dropwise to a cooled suspension of LiAlH4 (20 mmol, 2.0 equiv) in anhydrous
THF (20 mL) at 0 ºC. The mixture was heated to 60 C and monitored by TLC. After
completion, the mixture was cooled to 0 C, and quenched by NaOH (1 M). The
precipitate was filtered, and the filtrate was extracted with EtOAc. The combined
organic layers were washed with brine, dried and evaporated to provide the diol without
further purification.
Oxalyl chloride (30 mmol, 3.0 equiv) was added dropwise to a solution of DMSO
(50 mmol, 5.0 equiv) in DCM (30 mL) at 78 C. The mixture was stirred at 78 C
for 15 min, and a solution of the obtained diol (10 mmol) in DCM (20 mL) was added
dropwise. The mixture was stirred at 78 C for 30 min and then triethylamine (70
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mmol, 7.0 equiv) was added. The mixture was allowed to warm to room temperature
for 30 min, and sodium bicarbonate solution was added. The mixture was extracted
with DCM. The combined organic layers were washed with brine, dried and evaporated
to provide 3-substituted glutaric dialdehyde without further purification.
A solution of 3-substituted glutaric dialdehyde in THF (20 mL) was added to a
solution of the ylide reagent (25 mmol, 2.5 equiv) in THF (20 mL). Then magnesium
sulfate (40 mmol, 4.0 equiv) was added. The mixture was stirred under reflux and
monitored by TLC. After removing the precipitate and solvent, the residue was purified
by column chromatography (petroleum ether/EtOAc = 15/1) to afford the 5-substituted
bis(enones) 5.
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General procedure B: The 4-substituted 1,6-heptadiene (5 mmol) was dissolved
in tBuOH/H2O (1:1, 50 mL), and K2OsO42H2O (0.025 mmol, 0.005 equiv) and NaIO4
(25 mmol, 5.0 equiv) were added. The mixture was stirred at room temperature
overnight. The reaction was quenched with saturated NaS2O3, and the mixture was
extracted with EtOAc. The combined organic layers were washed with brine, dried over
Na2SO4, filtered and evaporated to provide 3-substituted glutaric dialdehyde without
further purification. Subsequently, the 5-substituted bis(enones) 5 was similarly
prepared with the ylide reagent.
Bis(enones) 5ai, 5m were obtained according to the general procedure A, and
bis(enones) 5j, 5k and 7 were obtained according to the general procedure B.
(2E,7E)-5-Methyl-1,9-diphenylnona-2,7-diene-1,9-dione (5a). Purification by
flash chromatography on silica gel (EtOAc/petroleum ether = 1/20) gave 5a: 670 mg,
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42% yield (for three steps), colorless oil; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.96–
7.87 (m, 4H), 7.58–7.52 (m, 2H), 7.50–7.41 (m, 4H), 7.10–6.99 (m, 2H), 6.96–6.86 (d,
J = 14.8 Hz, 2H), 2.43–2.34 (m, 2H), 2.29–2.20 (m, 2H), 2.04–1.89 (m, 1H), 1.02 (d, J
= 6.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 190.5, 147.5, 137.8, 132.8,
128.59, 128.55, 127.6, 39.8, 32.5, 19.7; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C22H22O2Na 341.1512; found 341.1518.
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(2E,7E)-5-Methyl-1,9-di-p-tolylnona-2,7-diene-1,9-dione (5b). Purification by
flash chromatography on silica gel (EtOAc/petroleum ether = 1/20) gave 5b: 504 mg,
29% yield (for three steps), colorless oil; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.84 (d,
J = 7.9 Hz, 4H), 7.28–7.23 (d, J = 7.9 Hz, 4H), 7.08–6.98 (m, 2H), 6.91 (d, J = 15.4
Hz, 2H), 2.41 (s, 6H), 2.39–2.34 (m, 2H), 2.28–2.18 (m, 2H), 2.02–1.89 (m, 1H), 1.02
13
(d, J = 6.7 Hz, 3H); C{1H} NMR (150 MHz, CDCl3): δ (ppm) 189.0, 146.9, 143.6,
135.3, 129.3, 128.7, 127.5, 39.7, 32.5, 21.6, 19.7; HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C24H26O2Na 369.1825; found 369.1818.
(2E,7E)-1,9-Bis(3-methoxyphenyl)-5-methylnona-2,7-diene-1,9-dione
(5c).
Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/10)
gave 5c: 336 mg, 18% yield (for three steps), colorless oil;1H NMR (400 MHz, CDCl3):
δ (ppm) 7.53–7.44 (m, 4H), 7.37 (t, J = 7.9 Hz, 2H), 7.14–7.08 (m, 2H), 7.08–6.99 (m,
2H), 6.94–6.86 (m, 2H), 3.86 (s, 6H), 2.46–2.33 (m, 2H), 2.30–2.18 (m, 2H), 2.03–1.92
(m, 1H), 1.03 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 190.2,
159.9, 147.5, 139.2, 129.5, 127.6, 121.1, 119.3, 112.8, 55.5, 39.8, 32.5, 19.7; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C24H26O4Na 401.1723; found 401.1717.
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(2E,7E)-1,9-Bis(4-bromophenyl)-5-methylnona-2,7-diene-1,9-dione
(5d).
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Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/25)
gave 5d: 150 mg, 32% yield (for three steps), colorless oil;1H NMR (400 MHz, CDCl3):
δ (ppm) 7.84–7.75 (m, 4H), 7.67–7.55 (m, 4H), 7.12–7.00 (m, 2H), 6.87 (d, J = 15.3
Hz, 2H), 2.46–2.34 (m, 2H), 2.31–2.21 (m, 2H), 2.04–1.93 (m, 1H), 1.03 (d, J = 6.7
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 189.2, 147.9, 136.5, 131.9, 130.0,
127.9, 127.1, 39.8, 32.5, 19.8; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
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C22H20Br79Br81O2Na 498.9702; found 498.9695; calcd for C22H20Br79 O2Na 496.9722;
2
found 496.9721; calcd for C22H20Br81 O2Na 500.9681; found 500.9691.
2
(2E,7E)-1,9-Bis(3-chlorophenyl)-5-methylnona-2,7-diene-1,9-dione
(5e).
Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/30)
gave 5e: 297 mg, 16% yield (for three steps), colorless oil;1H NMR (400 MHz, CDCl3):
δ (ppm) 7.90 (t, J = 1.9 Hz, 2H), 7.80 (dt, J = 7.8, 1.3 Hz, 2H), 7.58–7.50 (m, 2H), 7.42
(t, J = 7.7 Hz, 2H), 7.14–7.02 (m, 2H), 6.92–6.84 (m, 2H), 2.45–2.35 (m, 2H), 2.32–
2.22 (m, 2H), 2.05–1.93 (m, 1H), 1.05 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 189.0, 148.4, 139.4, 134.9, 132.7, 129.9, 128.6, 127.1, 126.6, 39.9,
32.5, 19.8; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C22H20Cl35 O2Na 409.0733;
2
found 409.0721; calcd for C22H20Cl35Cl37O2Na 411.0703; found 411.0705.
(2E,7E)-5-Methyl-1,9-di(naphthalen-2-yl)nona-2,7-diene-1,9-dione
(5f).
Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/20)
gave 5f: 444 mg, 19% yield (for three steps), colorless oil;1H NMR (400 MHz, CDCl3):
δ (ppm) 8.44 (d, J = 1.7 Hz, 2H), 8.03 (dd, J = 8.6, 1.8 Hz, 2H), 7.98–7.73 (m, 6H),
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7.65–7.55 (m, 2H), 7.55–7.45 (m, 2H), 7.22–7.00 (m, 4H), 2.52–2.40 (m, 2H), 2.37–
2.26 (m, 2H), 2.10–1.97 (m, 1H), 1.08 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (150 MHz,
CDCl3): δ (ppm) 190.2, 147.4, 135.5, 135.1, 132.5, 130.0, 129.5, 128.5, 128.4, 127.8,
127.5, 126.8, 124.5, 39.8, 32.6, 19.8; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C30H26O2Na 441.1825; found 441.1826.
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(2E,7E)-5-Methyl-1,9-di(thiophen-2-yl)nona-2,7-diene-1,9-dione
(5g).
Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/20)
gave 5g: 253 mg, 15% yield (for three steps), colorless oil;1H NMR (400 MHz, CDCl3):
δ (ppm) 7.76 (dd, J = 3.8, 1.1 Hz, 2H), 7.66 (dd, J = 4.9, 1.1 Hz, 2H), 7.18–7.13 (m,
2H), 7.13–7.05 (m, 2H), 6.87–6.80 (m, 2H), 2.44–2.34 (m, 2H), 2.30–2.20 (m, 2H),
2.04–1.93 (m, 1H), 1.04 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
182.0, 146.6, 145.1, 133.8, 131.9, 128.2, 127.1, 39.5, 32.5, 19.7; HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C18H18S2O2Na 353.0640; found 353.0645.
(2E,7E)-1,5,9-Triphenylnona-2,7-diene-1,9-dione (5h). Purification by flash
chromatography on silica gel (EtOAc/petroleum ether = 1/15) gave 5h: 976 mg, 28%
yield (for three steps), colorless oil; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.82–7.70
(m, 4H), 7.55–7.47 (m, 2H), 7.44–7.35 (m, 4H), 7.35– 7.29 (m, 2H), 7.23–7.16 (m,
3H), 6.95–6.84 (m, 2H), 6.79 (d, J = 15.5 Hz, 2H), 3.09–2.97 (m, 1H), 2.76–2.62 (m,
13
4H); C{1H} NMR (150 MHz, CDCl3): δ (ppm) 190.6, 146.5, 142.8, 137.7, 132.7,
128.8, 128.6, 128.5, 128.0, 127.6, 126.9, 44.6, 39.4; HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C27H24O2Na 403.1669; found 403.1675.
(2E,7E)-5-(4-Chlorophenyl)-1,9-diphenylnona-2,7-diene-1,9-dione
(5i).
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Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/10)
gave 5i: 564 mg, 28% yield (for three steps), as a white solid; 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.83–7.77 (m, 4H), 7.57–7.51 (m, 2H), 7.47–7.40 (m, 4H), 7.33–7.28
(m, 2H), 7.17– 7.11 (m, 2H), 6.92–6.83 (m, 2H), 6.79 (d, J = 15.4 Hz, 2H), 3.08–2.98
(m, 1H), 2.78–2.58 (m, 4H); 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 190.4, 145.8,
141.2, 137.6, 132.8, 132.6, 128.9, 128.6, 128.51, 128.48, 128.1, 44.1, 39.2; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C27H23Cl35O2Na 437.1279; found 437.1284; calcd
for C27H23Cl37O2Na 439.1249; found 439.1260.
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(E)-Ethyl 6-oxo-2-((E)-4-oxo-4-phenylbut-2-en-1-yl)-6-phenyl hex-4-enoate (5j).
Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/10)
gave 5j: 108 mg, 15% yield (in two steps), colorless oil; 1H NMR (600 MHz, CDCl3):
δ (ppm) 7.97–7.86 (m, 4H), 7.60–7.53 (m, 2H), 7.52–7.42 (m, 4H), 7.02–6.91 (m, 4H),
4.16 (q, J = 7.1 Hz, 2H), 2.87–2.80 (m, 1H), 2.75–2.68 (m, 2H), 2.61–2.54 (m, 2H),
1.23 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 194.9, 178.3, 149.5, 142.3,
137.6, 133.33, 133.27, 132.8, 65.7, 48.3, 39.4, 19.0; HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C24H24O4Na 399.1567; found 399.1571.
(2E,7E)-5-Isobutyl-1,9-diphenylnona-2,7-diene-1,9-dione (5l). Purification by
flash chromatography on silica gel (EtOAc/petroleum ether = 1/20) gave 5l: 560 mg,
31% yield (for three steps), white semisolid; 1H NMR (400 MHz, CDCl3): δ (ppm)
7.96–7.90 (m, 4H), 7.59–7.52 (m, 2H), 7.50–7.42 (m, 4H), 7.12–7.01 (m, 2H), 6.93 (d,
J = 15.3 Hz, 2H), 2.44–2.26 (m, 4H), 2.03–1.90 (m, 1H), 1.76–1.67 (m, 1H), 1.25 (t, J
13
= 7.2 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H); C{1H} NMR (150 MHz, CDCl3): δ (ppm)
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190.3, 147.5, 137.8, 132.8, 128.6, 128.5, 127.6, 43.2, 37.1, 34.8, 25.2, 22.7; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C25H28O2Na 383.1982; found 383.1987.
(2E,7E)-5-(4-Chlorophenyl)-1,9-di(naphthalen-2-yl)nona-2,7-diene-1,9-dione
(5m). Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/10)
gave 5m: 539 mg, 21% yield (for three steps), white solid;1H NMR (400 MHz, CDCl3):
δ (ppm) 8.28 (s, 2H), 8.00–7.80 (m, 8H), 7.64–7.49 (m, 4H), 7.40–7.31 (m, 2H), 7.24–
7.18 (m, 2H), 7.04–6.86 (m, 4H), 3.16–3.07 (m, 1H), 2.86–2.66 (m, 4H); 13C{1H} NMR
(100 MHz, CDCl3): δ (ppm) 190.2, 145.7, 141.3, 135.5, 134.9, 132.7, 132.5, 130.1,
129.5, 129.0, 128.6, 128.5, 128.2, 127.8, 126.8, 124.4, 44.2, 39.3; HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C35H27Cl35O2Na 537.1592; found 537.1591; calcd for
C35H27Cl37O2Na 539.1562; found 539.1604.
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tert-Butyl (E)-2-cyano-6-oxo-2-((E)-4-oxo-4-phenylbut-2-en-1-yl)-6-phenylhex-
4-enoate (7). Purification by flash chromatography on silica gel (EtOAc/petroleum
ether = 1/10) gave 7: 359 mg, 28% yield (for two steps), white semisolid;1H NMR (400
MHz, CDCl3): δ (ppm) 7.98–7.88 (m, 4H), 7.61–7.53 (m, 2H), 7.52–7.42 (m, 4H), 7.07
(d, J = 15.5 Hz, 2H), 7.02–6.89 (m, 2H), 2.93 (dd, J = 14.2, 7.4 Hz, 2H), 2.82 (dd, J =
14.1, 7.3 Hz, 2H), 1.47 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 189.7, 166.0,
138.9, 137.2, 133.2, 130.9, 128.74, 128.68, 117.9, 85.6, 48.9, 39.5, 27.8; HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C27H27NO4Na 452.1832; found 452.1835.
General procedure for intramolecular RC reaction of bis(enones) 1.
Bis(enones) 1 (0.1 mmol), 2-mercaptophenol T2 (0.04 mmol), catalyst C5 or C4 (0.02
mmol) and K2CO3 (0.06 mmol) were added into a vial equipped with a magnetic stir
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bar. Toluene (1.0 mL) was added. The mixture was stirred at room temperature for 24
to 72 h. Purification by flash chromatography on silica gel (EtOAc/petroleum ether =
1:40) gave the product 2.
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The racemic products were prepared following the general procedure, using an
achiral TBAB as the phase transfer catalyst.
(S)-2-(2-Benzoylcyclohex-2-en-1-yl)-1-phenylethanone (2a). Purification by flash
chromatography on silica gel (EtOAc/petroleum ether = 1/40) gave 2a: 27.6 mg, 91%
yield, colorless oil; [α]D25 = 30.6; [c = 0.85 in CHCl3; data in the references: 95% ee,
[α]D25 = 38.6 (c = 0.76 in CHCl3);6 99% ee, [α]D25 = +30.0 (c = 0.35 in CHCl3);5b 91%
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ee, [α]D = +25.1 (c = 0.90 in CHCl3)5c]; 91% ee, determined by HPLC analysis:
[Daicel chiralpak ID, n-hexane/i-PrOH = 60/40, 1.0 mL/min, λ = 254 nm, t (major) =
8.63 min, t (minor) = 12.69 min]; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.11–8.01 (m,
2H), 7.73–7.63 (m, 2H), 7.54–7.35 (m, 6H), 6.64–6.56 (m, 1H), 3.58–3.46 (m, 1H),
3.39 (dd, J = 15.0, 3.2 Hz, 1H), 2.84 (dd, J = 15.0, 10.5 Hz, 1H), 2.38–2.24 (m, 1H),
2.22–2.09 (m, 1H), 1.79–1.66 (m, 3H), 1.66–1.53 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 199.5, 197.9, 144.8, 141.5, 138.8, 136.9, 132.9, 131.6, 129.2, 128.6,
128.4, 128.1, 42.4, 30.3, 26.6, 26.1, 18.1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C21H20O2Na 327.1356; found 327.1355.
(S)-2-(2-(4-Methylbenzoyl)cyclohex-2-en-1-yl)-1-(p-tolyl)
ethanone
(2b).
Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/40)
gave 2b: 29.2 mg, 88% yield, colorless oil; [α]D25 = 15.8 (c = 0.33 in CHCl3); 95% ee,
determined by HPLC analysis: [Daicel chiralpak ID, n-hexane/i-PrOH = 60/40, 1.0
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mL/min, λ = 254 nm, t (major) = 11.17 min, t (minor) = 18.53 min]; H NMR (400
MHz, CDCl3): δ (ppm) 7.97 (d, J = 7.6 Hz, 2H), 7.62 (d, J = 7.6 Hz, 2H), 7.32–7.19
(m, 4H), 6.63–6.55 (m, 1H), 3.53–3.43 (m, 1H), 3.38 (dd, J = 14.6 Hz, 3.2 Hz, 1H),
2.76 (dd, J = 14.5 Hz, 10.8 Hz, 1H), 2.42 (s, 3H), 2.41(s, 3H), 2.38–2.29 (m, 1H), 2.25–
2.14 (m, 1H), 1.81–1.68 (m, 3H), 1.671.57 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3):
δ (ppm) 199.5, 198.0, 143.9, 143.8, 142.4, 141.6, 136.0, 134.3, 129.6, 129.3, 128.9,
128.7, 42.5, 30.7, 26.5, 26.1, 21.7, 21.6, 18.2; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C23H24O2Na 355.1669; found 355.1670.
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(S)-2-(2-(3-Methoxybenzoyl)cyclohex-2-en-1-yl)-1-(3-methoxyphenyl)ethanone
(2c). Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/20)
gave 2c: 30.2 mg, 83% yield, colorless oil; [α]D25 = 21.7 (c = 0.41 in CHCl3); 92% ee,
determined by HPLC analysis: [Daicel chiralpak ID, n-hexane/i-PrOH = 60/40, 1.0
1
mL/min, λ = 254 nm, t (major) = 12.51 min, t (minor) = 16.10 min]; H NMR (400
MHz, CDCl3): δ (ppm) 7.67 (d, J = 7.6 Hz, 1H), 7.62–7.57 (m, 1H), 7.41–7.29 (m, 2H),
7.28–7.16 (m, 2H), 7.13–7.00 (m, 2H), 6.68–6.59 (m, 1H), 3.86 (s, 3H), 3.83 (s, 3H),
3.53–3.43 (m, 1H), 3.38 (dd, J = 14.8, 3.2 Hz, 1H), 2.76 (dd, J = 14.8, 10.7 Hz, 1H),
2.40–2.26 (m, 1H), 2.26–2.11 (m, 1H), 1.79–1.67 (m, 3H), 1.65–1.57 (m, 1H); 13C{1H}
NMR (150 MHz, CDCl3): δ (ppm) 199.5, 197.7, 159.8, 159.4, 145.1, 141.4, 140.1,
138.0, 129.6, 129.1, 121.8, 121.2, 119.8, 117.7, 114.0, 112.4, 55.5, 55.4, 42.7, 30.5,
26.4, 26.1, 18.0; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C23H24O4Na 387.1567;
found 387.1565.
(S)-2-(2-(4-Bromobenzoyl)cyclohex-2-en-1-yl)-1-(4-bromophenyl) ethanone (2d).
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Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/60)
gave 2d: 41.8 mg, 91% yield, colorless oil; [α]D25 = +8.44 (c = 0.45 in CHCl3); 84% ee,
determined by HPLC analysis: [Daicel chiralpak ID, n-hexane/i-PrOH = 60/40, 1.0
mL/min, λ = 254 nm, t (major) = 9.27 min, t (minor) = 12.15 min]; 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.94 (d, J = 8.4 Hz, 2H), 7.677.50 (m, 6H), 6.68–6.57 (m, 1H), 3.50–
3.38 (m, 1H), 3.34 (dd, J = 14.8 Hz, 3.2 Hz, 1H), 2.80 (dd, J = 14.8 Hz, 10.3 Hz, 1H),
2.43–2.30 (m, 1H), 2.29–2.17 (m, 1H), 1.80–1.69 (m, 3H), 1.68–1.62 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 198.7, 196.9, 145.6, 141.2, 137.4, 135.4, 132.0,
131.5, 130.9, 130.1, 128.3, 126.6, 42.4, 30.4, 26.5, 26.2, 18.1; HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C21H18Br79Br81O2Na 484.9545; found 484.9548; calcd for
C21H18Br79 O2Na 482.9566; found 482.9568; calcd for C21H18Br81 O2Na 486.9525;
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found 486.9535.
(S)-2-(2-(3-Bromobenzoyl)cyclohex-2-en-1-yl)-1-(3-bromophenyl)ethanone (2e).
Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/60)
gave 2e: 33.1 mg, 72% yield, colorless oil; [α]D25 = 17.1 (c = 0.46 in CHCl3); 79% ee,
determined by HPLC analysis: [Daicel chiralpak ID, n-hexane/i-PrOH = 60/40, 1.0
mL/min, λ = 254 nm, t (major) = 8.70 min, t (minor) = 11.00 min]; 1H NMR (400 MHz,
CDCl3): δ (ppm) 8.17 (t, J = 1.8 Hz, 1H), 8.01 (dt, J = 7.8, 1.3 Hz, 1H), 7.78 (t, J = 1.8
Hz, 1H), 7.72–7.62 (m, 2H), 7.58 (dt, J = 7.7, 1.3 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H),
7.32 (t, J = 7.8 Hz, 1H), 6.70–6.62 (m, 1H), 3.51–3.40 (m, 1H), 3.32 (dd, J = 15.2, 3.3
Hz, 1H), 2.84 (dd, J = 15.2, 10.2 Hz, 1H), 2.45–2.31 (m, 1H), 2.30–2.17 (m, 1H), 1.80–
13
1.69 (m, 3H), 1.70–1.63 (m, 1H); C{1H} NMR (100 MHz, CDCl3): δ (ppm) 198.1,
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123.0, 122.4, 42.4, 30.1, 26.5, 26.3, 18.0; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
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C21H18Br79Br81O2Na 484.9545; found 484.9559; calcd for C21H18Br79 O2Na 482.9566;
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found 482.9572; calcd for C21H18Br81 O2Na 486.9525; found 486.9524.
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(S)-2-(2-(2-Naphthoyl)cyclohex-2-en-1-yl)-1-(naphthalen-2-yl) ethanone (2f).
Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/40)
gave 2f: 27.4 mg, 68% yield, colorless oil; [α]D25 = +13.6 (c = 0.25 in CHCl3); 81% ee,
determined by HPLC analysis: [Daicel chiralpak ID, n-hexane/i-PrOH = 60/40, 1.0
1
mL/min, λ = 254 nm, t (major) = 13.31 min, t (minor) = 19.60 min]; H NMR (400
MHz, CDCl3): δ (ppm) 8.69 (s, 1H), 8.19 (s, 1H), 8.11 (dd, J = 8.6, 1.8 Hz, 1H), 8.01
(d, J = 8.0 Hz, 1H), 7.98–7.78 (m, 6H), 7.63–7.46 (m, 4H), 6.76–6.67 (m, 1H), 3.69–
3.55 (m, 2H), 3.02–2.91 (m, 1H), 2.47–2.31 (m, 1H), 2.31–2.15 (m, 1H), 1.88–1.74 (m,
3H), 1.72–1.63 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 199.8, 198.1,
144.9, 141.8, 136.1, 135.6, 134.9, 134.1, 132.7, 132.3, 130.5, 130.3, 129.8, 129.2,
128.41, 128.38, 128.2, 127.9, 127.8, 127.7, 126.7, 126.6, 125.7, 124.2, 42.8, 30.9, 26.7,
26.3, 18.3; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C29H24O2Na 427.1669; found
427.1670.
(S)-1-(Thiophen-2-yl)-2-(2-(thiophene-2-carbonyl)cyclohex-2-en-1-yl)ethanone
(2g). Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/40)
gave 2g: 25.6 mg, 81% yield, colorless oil; [α]D25 = 19.0 (c = 0.21 in CHCl3); 82% ee,
determined by HPLC analysis: [Daicel chiralpak ID, n-hexane/i-PrOH = 60/40, 1.0
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mL/min, λ = 254 nm, t (major) = 10.44 min, t (minor) = 17.52 min]; H NMR (400
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MHz, CDCl3): δ (ppm) 7.92 (d, J = 4.0 Hz, 1H), 7.63 (d, J = 4.8 Hz, 1H), 7.62–7.56
(m, 2H), 7.15–7.05 (m, 2H), 6.87–6.81 (m, 1H), 3.55–3.40 (m, 1H), 3.27 (dd, J = 14.2,
3.1 Hz, 1H), 2.68 (dd, J = 14.2, 10.8 Hz, 1H), 2.42–2.29 (m, 1H), 2.27–2.15 (m, 1H),
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1.77–1.71 (m, 3H), 1.68–1.60 (m, 1H); C{1H} NMR (100 MHz, CDCl3): δ (ppm)
192.5, 189.3, 144.3, 143.9, 141.7, 141.5, 133.6, 133.34, 133.26, 132.8, 128.3, 127.7,
43.2, 31.6, 26.5, 26.0, 18.3; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H16O2S2Na
339.0484; found 339.0483.
(S)-2-(2-Benzoyl-5,5-dimethylcyclohex-2-en-1-yl)-1-phenylethanone
(2h).
Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/40)
gave 2h: 21.6 mg, 65% yield, colorless oil; [α]D25 = 80.0 (c = 0.25 in CHCl3); 83% ee,
determined by HPLC analysis: [Daicel chiralpak ID, n-hexane/i-PrOH = 60/40, 1.0
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mL/min, λ = 254 nm, t (major) = 10.03 min, t (minor) = 13.41 min]; H NMR (400
MHz, CDCl3): δ (ppm) 8.07–7.97 (m, 2H), 7.82–7.72 (m, 2H), 7.59–7.51 (m, 2H),
7.50–7.40 (m, 4H), 6.53–6.43 (m, 1H), 3.52 (dd, J = 15.3, 3.1 Hz, 1H), 3.46–3.34 (m,
1H), 2.83 (dd, J = 15.3, 9.5 Hz, 1H), 2.26–2.16 (m, 1H), 2.02–1.90 (m, 1H), 1.73–1.63
(m, 1H), 1.47–1.35 (m, 1H), 1.00 (s, 3H), 0.87 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 199.7, 198.2, 142.2, 140.9, 138.5, 136.9, 133.0, 132.0, 129.6, 128.6,
128.3, 128.2, 42.4, 41.7, 39.8, 31.3, 30.6, 29.4, 25.3; IR (CH2Cl2)  2961, 2923, 1680,
1597, 1579, 1448, 1365, 1261, 754, 691 (cm−1); HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C23H24O2Na 355.1669; found 355.1670.
(S)-2-(4-Benzoyl-3,6-dihydro-2H-pyran-3-yl)-1-phenylethanone (2i). Purification
by flash chromatography on silica gel (EtOAc/petroleum ether = 1/10) gave 2i: 22.2
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mg, 73% yield, colorless oil; [α]D25 = 9.35 (c = 0.54 in CHCl3); 78% ee, determined
by HPLC analysis: [Daicel chiralpak AD-H, n-hexane/i-PrOH = 80/20, 1.0 mL/min, λ
= 254 nm, t (major) = 12.74 min, t (minor) = 17.47 min]; 1H NMR (400 MHz, CDCl3):
δ (ppm) 8.04–7.94 (m, 2H), 7.72–7.62 (m, 2H), 7.59–7.49 (m, 2H), 7.50–7.38 (m, 4H),
6.63–6.55 (m, 1H), 4.42 (dd, J = 19.1, 3.3 Hz, 1H), 4.32–4.22 (m, 1H), 4.07–4.00 (m,
1H), 3.72–3.64 (m, 1H), 3.51–3.43 (m, 1H), 3.35–3.27 (m, 1H), 3.27–3.20 (m, 1H);
13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 198.7, 195.9, 141.8, 138.7, 137.9, 136.9,
133.1, 132.0, 129.2, 128.6, 128.3, 128.2, 67.7, 65.3, 39.9, 29.9; HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C20H18O3Na 329.1148; found 329.1150.
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(S)-2-(2-(4-Nitrobenzoyl)cyclohex-2-en-1-yl)-1-(p-tolyl)ethanone
(2j).
Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/40)
gave 2j: 33.4 mg, 92% yield, colorless oil; [α]D25 = 5.30 (c = 0.42 in CHCl3); 93% ee,
determined by HPLC analysis: [Daicel chiralpak ID, n-hexane/i-PrOH = 60/40, 1.0
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mL/min, λ = 254 nm, t (major) = 15.41 min, t (minor) = 21.42 min]; H NMR (400
MHz, CDCl3) δ (ppm) 8.33–8.24 (m, 2H), 7.98–7.90 (m, 2H), 7.85–7.76 (m, 2H), 7.27
(d, J = 7.0 Hz, 2H), 6.64–6.56 (m, 1H), 3.53–3.41 (m, 1H), 3.33 (dd, J = 15.0, 3.7 Hz,
1H), 2.93 (dd, J = 15.0, 9.7 Hz, 1H), 2.41 (s, 3H), 2.39–2.31 (m, 1H), 2.30–2.18 (m,
1H), 1.84–1.70 (m, 3H), 1.70–1.62 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
199.2, 196.0, 149.3, 147.1, 144.4, 144.0, 141.8, 134.4, 130.0, 129.4, 128.5, 123.4, 42.0,
30.1, 26.6, 26.4, 21.7, 18.0; IR (CH2Cl2)  2921, 2851, 1679, 1604, 1524, 1347, 1270,
1183, 967, 805, 721 (cm−1); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C22H21NO4Na
386.1363; found 386.1361.
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(S)-1-(2-benzoylcyclohex-2-en-1-yl)propan-2-one (2k). Purification by flash
chromatography on silica gel (EtOAc/petroleum ether = 1/30) gave 2k: 18.0 mg, 73%
yield, colorless oil; [α]D25 = 62.8 (c = 0.96 in CHCl3); 80% ee, determined by HPLC
analysis: [Daicel chiralpak ID, n-hexane/i-PrOH = 60/40, 1.0 mL/min, λ = 254 nm, t
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(major) = 10.17 min, t (minor) = 11.17 min]; H NMR (400 MHz, CDCl3) δ (ppm)
7.68–7.62 (m, 2H), 7.54–7.48 (m, 1H), 7.45–7.39 (m, 2H), 6.59–6.53 (m, 1H), 3.41–
3.32 (m, 1H), 2.70 (dd, J = 15.7, 3.6 Hz, 1H), 2.46 (dd, J = 15.7, 9.7 Hz, 1H), 2.37–
2.26 (m, 1H), 2.25–2.17 (m 1H), 2.17 (s, 3H), 1.82–1.72 (m, 1H), 1.70–1.64 (m, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 208.2, 197.9, 144.5, 141.3, 138.7, 131.7,
129.3, 128.1, 47.4, 29.9, 29.3, 27.0, 26.1, 18.2; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C16H18O2Na 265.1199; found 265.1168.
Asymmetric reaction of 2a on a large scale. (2E,7E)-1,9-Diphenylnona-2,7-
diene-1,9-dione (304.0 mg, 1 mmol), 2-mercaptophenol T2 (50.4 mg, 0.4 mmol),
catalyst C5 (125.2 mg, 0.2 mmol) and K2CO3 (82.8 mg, 0.6 mmol) were stirred in
toluene (10 mL) at rt for 72 h. After completion, purification by flash chromatography
on silica gel (EtOAc/petroleum ether = 1/40) gave 2a: 221.0 mg, 73% yield, colorless
oil; 91% ee.
General procedure for intramolecular RC reaction of bis(enones) 3.
Bis(enones) 3 (0.1 mmol), chiral thiol T4 (0.01 mmol), catalyst C6 (0.01 mmol) and
K2CO3 (0.06 mmol) were added into a vial equipped with a magnetic stir bar. Toluene
(1.0 mL) was added. The mixture was stirred at room temperature for 24 h. Purification
by flash chromatography on silica gel (EtOAc/petroleum ether = 1:40) gave the product
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90% yield, colorless oil; [α]D25 = +91.1 [c = 0.38 in CHCl3; data in the reference: 94%
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ee, [α]D = +108.1 (c = 0.60 in CHCl3)5c]; 93% ee, determined by HPLC analysis:
[Daicel chiralpak ID, n-hexane/i-PrOH = 60/40, 1.0 mL/min, λ = 254 nm, t (minor) =
9.64 min, t (major) = 19.14 min]; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.08–7.99 (m,
2H), 7.80–7.71 (m, 2H), 7.57–7.49 (m, 2H), 7.49–7.39 (m, 4H), 6.61–6.53 (m, 1H),
3.80–3.68 (m, 2H), 2.89–2.76 (m, 1H), 2.75–2.60 (m, 1H), 2.59–2.44 (m, 1H), 2.39–
13
2.23 (m, 1H), 1.86–1.70 (m, 1H); C{1H} NMR (100 MHz, CDCl3): δ (ppm) 199.7,
194.2, 147.9, 146.2, 139.0, 137.0, 133.0, 132.0, 128.9, 128.6, 128.3, 128.2, 42.4, 41.7,
32.7, 29.6; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H18O2Na 313.1199; found
313.1201.
(R)-2-(2-(4-Methylbenzoyl)cyclopent-2-en-1-yl)-1-(p-tolyl)
ethanone
(4b).
Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/40)
gave 4b: 25.9 mg, 82% yield, colorless oil; [α]D25 = +44.4 (c = 0.73 in CHCl3); 94% ee,
determined by HPLC analysis: [Daicel chiralpak ID, n-hexane/i-PrOH = 60/40, 1.0
mL/min, λ = 254 nm, t (minor) = 12.50 min, t (major) = 25.22 min]; 1H NMR (400
MHz, CDCl3): δ (ppm) 7.96–7.87 (m, 2H), 7.70–7.60 (m, 2H), 7.29–7.15 (m, 4H),
6.58–6.48 (m, 1H), 3.78–3.64 (m, 2H), 2.80–2.69 (m, 1H), 2.69–2.59 (m, 1H), 2.57–
2.45 (m, 1H), 2.41 (s, 3H), 2.38 (s,3H), 2.34–2.23 (m, 1H), 1.82–1.69 (m, 1H);13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 199.5, 194.0, 146.9, 146.3, 143.7, 142.7, 136.4,
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134.5, 129.3, 129.1, 128.9, 128.5, 42.4, 41.9, 32.6, 29.5, 21.62, 21.58; HRMS (ESI-
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TOF) m/z: [M + Na]+ calcd for C22H22O2Na 341.1512; found 341.1511.
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(R)-2-(2-(4-Bromobenzoyl)cyclopent-2-en-1-yl)-1-(4-bromophenyl)
ethanone
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(4c). Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/40)
gave 4c: 35.1 mg, 79% yield, colorless oil; [α]D25 = +21.3 (c = 1.48 in CHCl3); 85% ee,
determined by HPLC analysis: [Daicel chiralpak ID, n-hexane/i-PrOH = 60/40, 1.0
mL/min, λ = 254 nm, t (minor) = 10.59 min, t (major) = 16.20 min]; 1H NMR (400
MHz, CDCl3): δ (ppm) 7.94–7.86 (m, 2H), 7.67–7.55 (m, 6H), 6.61–6.54 (m, 1H),
3.74–3.62 (m, 2H), 2.79 (dd, J = 16.2, 10.6 Hz), 2.74–2.62 (m, 1H), 2.61–2.48 (m, 1H),
2.38–2.25 (m, 1H), 1.82–1.70 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3): δ (ppm)
198.6, 193.0, 148.3, 145.8, 137.6, 135.5, 131.9, 131.6, 130.4, 129.8, 128.2, 127.0, 42.2,
41.5, 32.7, 29.5; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H16Br79Br81O2Na
470.9389; found 470.9392; calcd for C20H16Br79 O2Na 468.9409; found 468.9415;
2
calcd for C20H16Br81 O2Na 472.9368; found 472.9383.
2
(R)-2-(2-(2-Naphthoyl)cyclopent-2-en-1-yl)-1-(naphthalen-2-yl) ethanone (4d).
Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/40)
gave 4d: 28.8 mg, 74% yield, colorless oil; [α]D25 = 8.00 (c = 0.75 in CHCl3); 85% ee,
determined by HPLC analysis: [Daicel chiralpak ID, n-hexane/i-PrOH = 60/40, 1.0
mL/min, λ = 254 nm, t (minor) = 14.32 min, t (major) = 26.77 min]; 1H NMR (400
MHz, CDCl3): δ (ppm) 8.62 (s, 1H), 8.27 (s, 1H), 8.11 (d, J = 8.6 Hz, 1H), 8.00–7.84
(m, 7H), 7.66–7.50 (m, 4H), 6.71–6.64 (m, 1H), 4.03–3.91 (m, 1H), 3.91–3.80 (m, 1H),
3.01 (dd, J = 15.6, 10.2 Hz), 2.82–2.68 (m, 1H), 2.68–2.53 (m, 1H), 2.47–2.34 (m, 1H),
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2.00–1.82 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 199.8, 194.3, 147.9,
146.4, 136.3, 135.6, 135.2, 134.2, 132.6, 132.3, 130.3, 130.2, 129.7, 129.3, 128.42,
128.37, 128.3, 128.0, 127.8, 127.7, 126.74, 126.66, 125.1, 124.1, 42.6, 42.0, 32.8, 29.7;
IR (CH2Cl2)  2941, 1676, 1627, 1469, 1355, 1277, 1186, 751 (cm−1); HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C28H22O2Na 413.1512; found 413.1505.
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(R)-1-(Thiophen-2-yl)-2-(2-(thiophene-2-carbonyl)cyclopent-2-en-1-yl) ethanone
(4e). Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/40)
gave 4e: 19.3 mg, 64% yield, colorless oil; [α]D25 = +33.9 (c = 1.12 in CHCl3); 71% ee,
determined by HPLC analysis: [Daicel chiralpak ID, n-hexane/i-PrOH = 60/40, 1.0
mL/min, λ = 254 nm, t (minor) = 11.46 min, t (major) = 25.33 min]; 1H NMR (400
MHz, CDCl3): δ (ppm) 7.89–7.81 (m, 1H), 7.71–7.66 (m, 1H), 7.65–7.55 (m, 2H),
7.16–7.05 (m, 2H), 6.84–6.76 (m, 1H), 3.75–3.68 (m, 1H), 3.64 (dd, J = 14.9, 3.0 Hz),
2.71 (dd, J = 14.8, 10.3 Hz, 1H), 2.68–2.63 (m, 1H), 2.60–2.50 (m, 1H), 2.35–2.21 (m ,
1H), 1.88–1.75 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 192.7, 185.1,
145.9, 145.3, 144.4, 144.2, 133.5, 133.1, 132.7, 132.6, 128.2, 127.8, 43.0, 42.6, 32.7,
29.3; IR (CH2Cl2)  3097, 2936, 1655, 1618, 1515, 1413, 722 (cm−1); HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C16H14O2S2Na 325.0327; found 325.0330.
General procedure for desymmetric intramolecular RC reaction of
bis(enones) 5. Bis(enones) 5 (0.1 mmol), 2-mercaptophenol T5 (0.04 mmol), catalyst
C7 (0.02 mmol) and K2CO3 (0.06 mmol) were added into a vial equipped with a
magnetic stir bar. Toluene (1.0 mL) was added. The mixture was stirred at room
temperature for 24 to 72 h. Purification by flash chromatography on silica gel
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(EtOAc/petroleum ether = 1/40) gave the product 6.
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((1S,5R)-2-Benzoyl-5-methylcyclohex-2-en-1-yl)-1-phenylethanone
(6a).
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Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/40)
gave 6a: 24.2 mg, 76% yield, colorless oil; [α]D25 = 97.4 (c = 1.77 in CHCl3); >19:1
dr; 92% ee, determined by HPLC analysis: [Daicel chiralpak ID, n-hexane/i-PrOH =
60/40, 1.0 mL/min, λ = 254 nm, t (major) = 10.11 min, t (minor) = 12.28 min]; 1H NMR
(400 MHz, CDCl3): δ (ppm) 8.06–7.96 (m, 2H), 7.79–7.70 (m, 2H), 7.57–7.48 (m, 2H),
7.48–7.37 (m, 4H), 6.52–6.46 (m, 1H), 3.52 (dd, J = 15.1, 3.1 Hz, 1H), 3.45–3.33 (m,
1H), 2.73 (dd, J = 15.1, 9.8 Hz, 1H), 2.30–2.17 (m, 1H), 1.98–1.87 (m, 2H) , 1.71–1.56
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(m, 1H), 1.20 (q, J = 12.1 Hz, 1H), 0.96 (d, J = 6.5 Hz, 3H); C{1H} NMR (100
MHz,CDCl3): δ (ppm) 199.8, 198.3, 142.7, 142.0, 138.5, 136.9, 133.0, 132.1, 129.6,
128.6, 128.4, 128.2, 42.8, 37.6, 34.6, 33.5, 28.1, 21.7; IR (CH2Cl2)  3058, 2908, 1680,
1640, 1597, 1579, 1447, 1369, 1258, 753, 734, 711, 690 (cm−1); HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C22H22O2Na 341.1512; found 341.1512.
((1S,5R)-5-Methyl-2-(4-methylbenzoyl)cyclohex-2-en-1-yl)-1-(p-tolyl)ethanone
(6b). Purification by flash chromatography on silica gel (EtOAc/petroleum ether = 1/40)
gave 6b: 22.8 mg, 66% yield, colorless oil; [α]D25 = 93.5 (c = 0.62 in CHCl3); >19:1
dr; 94% ee, determined by HPLC analysis: [Daicel chiralpak IC, n-hexane/i-PrOH =
90/10, 1.0 mL/min, λ = 254 nm, t (minor) = 18.90 min, t (major) = 19.81 min]; 1H NMR
(400 MHz, CDCl3): δ (ppm) 7.97–7.87 (m, 2H), 7.73–7.65 (m, 2H), 7.29–7.21 (m, 4H),
6.50–6.42 (m, 1H), 3.48 (dd, J = 14.8 Hz, 2.3 Hz, 1H), 3.44–3.33 (m, 1H), 2.65 (dd, J
= 14.2 Hz, 10.2 Hz, 1H), 2.41 (s, 3H), 2.39 (s, 3H), 2.29–2.16 (m, 1H), 1.99–1.85 (m,
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