Enantioselective Michael addition of cyclic β-diones to α,β-unsaturated enones catalyzed by quinine-based organocatalysts

Article abstract of DOI:10.3390/molecules22071096

An enantioselective (52–98% ee) Michael addition between cyclic β-diones and α,β-unsaturated enones was established in the presence of quinine-based primary amine or squaramide. A variety of cinnamones were smoothly converted into the desired 3,4-dihydropyrans in moderate to high yields (63–99%). Chalcones were also suitable acceptors and gave rise to the expected adducts in satisfactory yields (31–99%). The resulting adducts readily underwent further modification to form fused 4H-pyran or 2,3-dihydrofuran.

Full text of DOI:10.3390/molecules22071096

molecules
Article
Enantioselective Michael Addition of Cyclic
β-Diones to α,β-Unsaturated Enones Catalyzed by
Quinine-Based Organocatalysts
Qingqing Wang 1, Wei Wang 1, Ling Ye 2, Xuejun Yang 1, Xinying Li 1, Zhigang Zhao 1
and Xuefeng Li 1,
1
*
College of Chemistry and Environment Protection Engineering, Southwest Minzu University,
Chengdu 610041, China; wqqing767@163.com (Q.W.); m18328594286@163.com (W.W.);
yangxuejun@swun.cn (X.Y.); lixinying1984@163.com (X.L.); zzg63129@163.com (Z.Z.)
Faculty of Geosciences and Environmental Engineering, Southwest Jiaotong University,
Chengdu 610031, China; yeling_2004@126.com
2
*
Correspondence: lixuefeng@swun.edu.cn; Tel.: +86-28-8552-2315
Received: 16 May 2017; Accepted: 26 June 2017; Published: 30 June 2017
Abstract: An enantioselective (52–98% ee) Michael addition between cyclic
β-diones and
α,β-unsaturated enones was established in the presence of quinine-based primary amine or
squaramide. A variety of cinnamones were smoothly converted into the desired 3,4-dihydropyrans
in moderate to high yields (63–99%). Chalcones were also suitable acceptors and gave rise to the
expected adducts in satisfactory yields (31–99%). The resulting adducts readily underwent further
modification to form fused 4H-pyran or 2,3-dihydrofuran.
Keywords: cyclic β-dione; cinnamone; chalcone; michael addition; enantioselective
1. Introduction
The Michael addition of
bond-forming reaction in organic synthesis, and the development of the enantioselective catalytic
approach for this transformation, has attracted intensive attention [ ]. Among the often-used
acceptors, unactivated -unsaturated enones always exhibit relatively sluggish reactivity and emerge
as a class of historically challenging substrates for metal- and organocatalytic approaches [ 11].
α,β-unsaturated compounds is an atom-economic carbon-carbon
1–4
α,β
5
–
In this context, the elegantly-designed chiral primary amines, especially those based on cinchona
alkaloids, provide a particularly efficient LUMO-lowering (LUMO: lowest unoccupied molecular
orbital) activation mode through the formation of iminium ions with these unsaturated enones [12–14]
Therefore, a broad range of conjugate additions of -unsaturated enones with various different
nucleophiles have been successfully established with constantly high enantiocontrol [15 19].
However, the asymmetric Michael addition of cyclic 1,3-dicarbonyl compounds [20 27], except for
4-hydroxycoumarin and its analogues [ 28 36], to -unsaturated enones, especially chalcones,
generally draws less attention in comparison with other type of donors [37 39], albeit the adducts
of such a conjugate addition reaction are versatile precursors to construct several classes of
compounds possessing enormous bioactivities [40 41]. Liu and Feng have successfully developed
.
α,β
–
–
7,
–
α,β
–
,
an efficient Michael addition between dimedone and cinnamones employing the unmodified chiral
diphenylethylenediamine (DPEN) [37]. In contrast, only moderate enantioselectivity was obtained
for the Michael addition of dimedone to unfunctionalized chalcone according to Singh’s protocol [38].
Consequently, the development of the enantioselective Michael addition of cyclic
β-diones to
α,β-unsaturated enone is still highly sought.
Based on our continuous interest in asymmetric Michael reactions involving
α
,
β-unsaturated
enones [42 45], herein we would like to further extend the scope of donor to cyclic -diones [20
–
β
–
23,46–
Molecules 2017, 22, 1096; doi:10.3390/molecules22071096
www.mdpi.com/journal/molecules

Molecules 2017, 22, 1096
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49]. Dimedone and its analogues smoothly react with a variety of
α
,β-unsaturated enones, furnishing
the corresponding adducts in good yields and high levels of optical purities. The synthetic potential of
the desired Michael adduct is demonstrated by the easy formation of enantioenriched 4H-pyran and
2,3-dihydrofuran.
2. Results and Discussion
We were pleased to find that the Michael addition of dimedone 1a to cinnamone 2a proceeded
smoothly in the presence of 9-amino(9-deoxy)-epi-quinine 3a (Figure 1) in combination with a series
of different acid co-catalysts. It was documented that the acid co-catalyst had a great influence on
the yield and enantioinduction [16]. The aromatic carboxylic acids displayed superior catalytic effect
compared with sulfonic acid and aliphatic acids (Table 1, entries 4–9 vs. entries 1–3). The desired
3,4-dihydropyran 4a was generated with good to excellent enantioselectivities (87–90% ee) in the
presence of various aromatic acids. In contrast, salicylic acid (SA) afforded an optimal yield (99%) and
a superior enantioselectivity (90% ee) (entry 9 vs. entries 4–8) [50]. Having identified salicylic acid
as the preferential acid co-catalyst, we turned our attention to evaluate the effect of other primary
amines 3b and 3c (Figure 1) derived from naturally occurring cinchona alkaloids [51]. Both 3b and 3c
delivered the expected 3,4-dihydropyran 4a possessing opposite configurations to the adduct afforded
by 3a (entries 10 and 11). Moreover, these two pseudo-enantiomers displayed poorer catalytic activities
and enantioselectivities compared with 9-amino(9-deoxy)-epi-quinine 3a (entries 10 and 11 vs. entry
9). Subsequently, we examined the effect of the solvent with a combination of 3a and salicylic acid.
Tetrahydrofuran (THF) emerged as the favorable one in terms of reactivity and enantioselectivity (entry
15 vs. entries 9, 12–14). Notably, the model process proceeded equally smoothly when the amount of
cinnamone was decreased to 1.2 equivalents (entry 16 vs. entry 15). Reducing the reaction temperature
(0 ◦C) led to a slightly higher enantioselectivity (97% ee) (entry 17).
a
Table 1. Optimization of reaction conditions for the Michael addition of dimedone 1a to cinnamone 2a.
Yield (%) b
Entry
Cat.
Acid
Solvent
Time (h)
ee (%) c
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3a
3a
3a
3a
3a
3a
TsOH
TFA
AcOH
BA
ONBA
PNBA
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
PhCF3
DCM
48
48
48
24
36
36
24
36
24
96
36
24
24
24
24
24
96
60
65
82
89
91
96
96
91
99
89
89
96
55
99
99
99
99
66
75
85
90
90
89
88
87
90
−82
−82
85
83
69
94
94
97
OFBA
p-MeOC6H4CO2H
SA
SA
SA
SA
SA
SA
SA
SA
SA
10
11
12
13
14
15
16 d
17 d,e
EtOH
THF
THF
THF
a
Unless otherwise noted, the reaction was performed with 0.1 mmol of 1a, 0.15 mmol of 2a, 20 mol % of 3a, and 40
mol % of acid in 1 mL of solvent at room temperature (r.t.). TsOH = p-toluenesulfonic acid, TFA = trifluoroacetic
acid, BA = benzoic acid, ONBA = o-nitrobenzoic acid, PNBA = p-nitrobenzoic acid, OFBA = o-fluorobenzoic acid,
b
c
DCM = dichloromethane. Isolated yield after flash chromatography on silica gel. Determined by HPLC analysis
on a chiral stationary phase (Chiralcel AD-H). d 0.12 mmol of 2a was employed. Carried out at 0 ◦C.
e

Molecules 2017, 22, 1096
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Figure 1. Structures of the chiral primary amine catalysts used.
With the optimal reaction conditions in hand, various cinnamones
1a to determine the scope and generality of this Michael addition. As presented in Table 2, the electronic
property exerted marginal impact on this asymmetric process. The electron-deficient cinnamones 2c 2f
2 were treated with dimedone
–
generally provided the corresponding 3,4-dihydropyrans in slightly higher chemical yields, in contrast
with the electron-rich acceptors 2g and 2h (Table 2, entries 3–6 vs. entries 7 and 8). Meanwhile, all these
enones gave rise to the desired adducts with excellent enantioselectivities (96–97% ee) irrespective of
electronic nature (entries 3–8). On the other hand, the steric hindrance slightly impaired the reactivity
of this conjugate addition reaction. In this context, the ortho-substituted enone 2b afforded somewhat
poorer conversion (87% yield) in comparison with other electron-poor cinnamones 2c
(entry 2 vs. entries 3–6). Gratifyingly, 2i and 2j, both possessing a bulky naphthyl group at the
–
2f (96–99% yield)
-site,
β
were also compatible with this catalytic system (entries 9 and 10). The resulting adducts 4ai and 4aj
were formed in excellent yields and with high levels of enantioselectivities. The heteroaromatic enones
2k and 2l were all suitable partners for this Michael reaction (entries 11 and 12). The alkyl-substituted
enones 2m and 2n were found to react relatively slowly with dimedone, however, synthetically useful
yields and satisfactory enantiocontrol were still obtained (entries 13 and 14). Remarkably, cyclic enone
2o was also a competent acceptor, furnishing the bridged-ring compound 4ao in 91% yield and 98% ee
(entry 15) [37]. The ketone substituent (R2) could also be varied from methyl group to ethyl group.
Although relatively poorer conversion was detected, excellent enantioselectivity was maintained for
this sterically more hindered acceptor (entry 16). It seemed to be an effect of increased steric bulk
on the ketone, retarding the acceptor to approach the catalyst, thereby slowing down the reaction
rate. On the other hand, the unsubstituted cyclic β-dione, 1,3-cyclohexanedione, was also tolerated by
this catalytic system. Acceptable yields (67–78%) and high degrees of enantiomeric excesses (94–96%
ee) were successfully achieved (entries 17–19), despite its relatively lower reactivity in contrast with
dimedone [20,52]. Notably, a one mmole-scale Michael addition of cinnamone 2a and dimedone 1a
was performed under optimal reaction conditions. Excellent chemical yield (95%) and enantiopurity
(94% ee) were both obtained (entry 1).
a
Table 2. Substrate scope of the Michael addition of cyclic β-diones to cinnamones and its analogues.
Yield (%) b
Entry
1
R2
R3
2
4
ee (%) c
99 (95) d
97 (94) d
91
1
2
3
4
1a
1a
1a
1a
Ph
Me
Me
Me
Me
2a
2b
2c
4aa
4ab
4ac
4ad
o-ClC6H4
m-ClC6H4
p-ClC6H4
87
99
99
96
2d
97 (S) e

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Table 2. Cont.
Yield (%) b
Entry
1
R2
R3
2
4
ee (%) c
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
p-FC6H4
p-BrC6H4
p-MeC6H4
p-MeOC6H4
1-naphthyl
2-naphthyl
2-furanyl
2-thiophenyl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2a
2d
2f
4ae
4af
4ag
4ah
4ai
4aj
4ak
4al
4am
4an
4ao
4ap
4ba
4bd
4bf
96
99
95
89
89
98
78
97
69
75
91
63
71
78
67
96
97
97
97
96
98
95
91
91
94
98
98
94
95
96
n-Bu
-C3H6-
Ph
Ph
p-ClC6H4
p-BrC6H4
Et
Me
Me
Me
a
Unless otherwise noted, the reaction was performed with 0.1 mmol of 1a, 0.12 mmol of 2a, 20 mol% of 3a, and 40
mol % of salicylic acid in 1 mL of THF at 0 ◦C for 96 h. Isolated yield after flash chromatography on silica gel.
b
c
d
Determined by HPLC analysis on a chiral stationary phase. Data within parentheses is that performed on an
e
one-mmole scale. Configuration of 4ad.
Having identified cinnamones as the suitable acceptors, we successively turned our attention to
chalcone (Scheme 1), a class of challenging substrates for iminium ion activation [16]. Different than
cinnamones, the bulky benzene group might retard the later annulation process, therefore only the
initial Michael adduct was accessed. Considering the unstability of the Michael adduct due to aerobic
oxidation [53], a subsequent acetylation was conducted after the initial conjugate addition in a one-pot
manner. To our disappointment, the titled process allowed access to the final acetyl derivative 6aa in
fairly low yield (<20%), even when the initial Michael addition was performed at room temperature.
Scheme 1. Michael addition of dimedone to chalcone.
Fortunately, we finally found that the Michael addition of chalcone worked properly in the
presence of squaramide
7 derived from quinine (see supporting material) [54,55]. As outlined in
Table 3, this Michael addition was independent of the electronic nature of the substituents on the
aromatic rings. Both the electron-rich acceptors 5b and 5f and the electron-deficient acceptors 5c
and 5g generated the expected adducts in satisfactory yields and excellent optical purities (Table 3,
entries 2 and 6 vs. entries 3 and 7). Moreover, the steric hindrance exerted influence on this
Michael addition to a certain extent. The enone 5e possessing a naphthyl group afforded relatively
lower isolated yield (68%) even after a prolonged reaction time, albeit accompanied by outstanding
enantioselectivity (entry 5). Heteroaromatic chalcones 5d and 5h were also favorable partners, giving
rise to the final acetyl derivatives with high levels of enantiopurities (entries 4 and 8). Except
for dimedone, 1,3-cyclohexanedione 1b was a competent donor as well, albeit a longer reaction
time was required in order to achieve complete conversion (entry 9). In contrast with Singh’s
precedent study (72% ee for 6aa) [38], our protocol efficiently improved the enantioselectivity and
displayed a wide substrate generality for this Michael addition of cyclic β-dione to chalcone [56].

Molecules 2017, 22, 1096
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Moreover, a one mmole-scale Michael addition of chalcone 5a with dimedone 1a proceeded smoothly
as well. The expected acetyl derivate 6aa was formed in an almost quantitative yield and with
satisfactory enantioselectivity (entry 1). The alkyl-substituted enone 5i was also a suitable acceptor,
albeit unsatisfactory enantioselectivity was obtained for the resulting Michael adduct (entry 10).
a
Table 3. Substrate scope of the Michael addition of cyclic β-diones to chalcones.
Yield (%) b
Entry
1
R2
Ar1
5
6
ee (%) c
95 (99) d
99
93 (91) d (R) e
1
2
3
1a
1a
1a
1a
1a
1a
1a
1a
1b
1a
Ph
p-ClC6H4
p-MeC6H4
2-thiophenyl
2-naphthyl
Ph
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5a
5i
6aa
6ab
6ac
6ad
6ae
6af
6ag
6ah
6ba
6ai
94
93
91
91
87
95
97
91
52
96
95
68
98
99
99
93
93
4 f
5 f
6
Ph
p-ClC6H4
p-MeC6H4
2-thiophenyl
Ph
7
8
Ph
Ph
Ph
n-Pr
9 f
10 g
Ph
a
Unless otherwise noted, the Michael addition was performed with 0.1 mmol of
1
, 0.12 mmol of
5
, and 20 mol % of
b
c
7
in 1 mL of chloroform at rt for 120 h. Isolated yield after flash chromatography on silica gel. Determined by
d
HPLC analysis on a chiral stationary phase. Data within parentheses is that performed on a one-mmole scale.
e
f
g
Configuration of 6aa. Performed with 168 h. Performed with 72 h.
The five-membered cyclic dione, 1,3-cyclopentadione 1c, was also tolerated by our catalytic
protocol (Scheme 2). However, it proved to be an inferior donor in terms of reactivity and
enantioselectivity, in contrast with the six-membered cyclic dione. The related acetyl derivative
6ca was obtained in an unsatisfactory yield and with moderate optical purity.
Scheme 2. Michael addition of 1,3-cyclopentadione to chalcone.
To demonstrate the synthetic potential of this Michael reaction, product modification was
performed on the Michael adducts. 3,4-Dihydropyran 4aa readily underwent a dehydrating procedure
to afford 4H-pyran
8 without the loss of optical purity (Scheme 3a) [20]. The Michael adduct of

Molecules 2017, 22, 1096
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chalcone could be utilized for the facile preparation of the biologically interesting 2,3-dihydrofuran
via a successive stereoselective oxidative cyclization process (Scheme 3b) [57]. The fused
2,3-dihydrofuran was obtained as a single trans-diastereomer in a synthetically useful yield and with
excellent enantioselectivity.
9
9
Scheme 3. Synthetic elaborations of the Michael adducts.
The absolute configuration of the Michael adduct 4ad (Table 2, entry 4) was determined to be
S via comparison of the optical rotation value and HPLC traces with that of the previous literature
reports [37]. On the other hand, the absolute configuration of 6aa (Table 3, entry 1) was established as
R by the analysis of the optical rotation value with Singh’s protocol [38]. To account for the observed
stereochemical outcome of these Michael reactions, the corresponding transition state models were
proposed and described in Scheme 4. The primary amine motif of 9-amino(9-deoxy)-epi-quinine
3a was engaged in iminium formation with the carbonyl group of benzalacetone 1a. Meanwhile,
dimedone was deprotonated by the tertiary amine moiety of aminocatalyst 3a and orientated via
hydrogen-bonding, thereby leading to a favorable attack toward the si-face of cinnamon 1a. As a result,
the desired S-configured product 4a was obtained. On the other hand, chalcone 5a was efficiently
activated via hydrogen-bonding interactions between the NH moiety of the squaramide
7 and the
carbonyl group of chalcone. Furthermore, the re-face approach of dimedone was induced by the
tertiary amine of the squaramide
configuration [58].
7 and led to the formation of the major stereoisomer with the R
Scheme 4. Proposed transition state models.

Molecules 2017, 22, 1096
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3. Materials and Methods
3.1. General Remarks
1H- and 13C-NMR spectra were recorded on Varian 400 MHz spectrometers. Chemical shifts (
are reported in ppm downfield from CDCl3 (
= 7.26 ppm) for 1H-NMR and relative to the central
CDCl3 resonance (
= 77.0 ppm) for 13C-NMR spectroscopy. Coupling constants (J) are given in
δ)
δ
δ
Hz. ESI-HRMS spectrometry was performed with a Bruker Daltonics LCQDECA ion trap mass
spectrometer. Enantiomeric excess was determined by HPLC analysis on Chiralpak AD-H, OD-H,
and IC columns in comparison with the authentic racemates. Optical rotation data were recorded on a
Rudolph Autopol I automatic polarimeter. Commercial grade solvents were dried and purified by
standard procedures as specified in reference [59]. THF (AR grade) was used as received. All other
reagents were purchased from commercial sources and were used without further purification.
3.2. General Procedure for the Asymmetric Michael Reaction of Cinnamones
9-Amino-epi-quinine 3a (6.5 mg, 0.02 mmol), α,β-unsaturated enones (0.12 mmol), dimedone
(14.0 mg, 0.1 mmol), and salicylic acid (4.9 mg, 0.04 ◦mmol) were dissolved in THF (1 mL) without
stirring. Once the solution was cooled down to 0 C, the reaction mixture was stirred for 96 h.
After the solvent was removed in vacuo, the residue was purified by flash chromatography on silica
gel (EtOAc/petroleum ether) to afford the desired 3,4-dihydropyran.
2-Hydroxy-2,7,7-trimethyl-4-phenyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4aa) [37]. Colorless oil; 99%
yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ (ppm) 7.30–7.23 (m,
2H), 7.19–7.12 (m, 3H), 4.03 (br s, 0.6H), 3.84 (t, J = 8.4 Hz, 0.6H), 3.31 (br s, 0.4H), 3.16–3.12 (m, 0.4H),
2.50–2.15 (m, 6H), 1.48 (s, 1.7H), 1.46 (s, 1.3H), 1.19 (s, 1.7H), 1.16 (s, 1.3H), 1.11 (s, 1.7H), 1.07 (s, 1.3H);
13C-NMR (100 MHz, CDCl3)
δ (ppm) 197.3, 196.9, 169.6, 168.6, 144.9, 142.9, 128.8, 128.2, 127.8, 127.7,
126.9, 126.8, 126.5, 125.7, 113.0, 110.5, 99.8, 99.2, 50.6, 50.5, 42.9, 42.8, 42.7, 40.5, 33.9, 32.8, 31.9, 31.4,
29.5, 28.6, 28.3, 27.8, 27.4, 27.1; 97% ee was determined by HPLC on AD-H column, hexane/i-propanol
(80/20), 1.0 mL/min, UV 254 nm, tminor = 4.820 min, tmajor = 7.627 min; [α]D20
=
−
4.2 (c = 0.028, EtOH).
◦
4-(2-Chlorophenyl)-2-hydroxy-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ab) [60]. Colorless
oil; 87% yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
(ppm) 7.36–7.29
δ
(m, 1H), 7.10–7.05 (m, 3H), 4.36–4.24 (m, 1H), 3.83 (br s, 0.5H), 3.43 (br s, 0.5H), 2.49–2.11 (m, 6H), 1.49
(s, 1.4H), 1.48 (s, 1.6H), 1.18 (s, 1.6H), 1.16 (s, 1.4H), 1.09 (s, 1.6H), 1.07 (s, 1.4H); 13C-NMR (100 MHz,
CDCl3) δ (ppm) 196.7, 196.5, 169.7, 140.5, 133.6, 129.9, 129.5, 127.8, 127.6, 126.9, 126.7, 126.6, 112.6, 110.4,
99.7, 98.1, 50.7, 50.6, 42.9, 42.8, 37.7, 31.9, 31.5, 29.4, 28.9, 28.2, 27.9, 27.6, 27.3; 91% ee was determined
by HPLC on AD-H column, hexane/i-propanol (90/10), 1.0 mL/min, UV 254 nm, tminor = 7.703 min,
tmajor = 9.353 min; [α]20 = −32.8◦ (c = 0.021, EtOH).
D
4-(3-chlorophenyl)-2-hydroxy-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ac) [37]. Colorless
oil; 99% yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ (ppm) 7.19–7.09
(m, 3H), 7.02 (t, J = 7.8 Hz, 1H), 4.34 (br s, 0.5H), 3.89 (t, J = 4.8 Hz, 0.5H), 3.82–3.77 (m, 1H), 2.48–2.09
(m, 6H), 1.44 (s, 3H), 1.18 (s, 1.3H), 1.15 (s, 1.7H), 1.09 (s, 1.3H), 1.07 (s, 1.7H); 13C-NMR (100 MHz,
CDCl3)
δ (ppm) 197.3, 197.0, 169.9, 169.1, 147.3, 145.9, 134.2, 133.9, 129.6, 129.5, 129.1, 127.9, 127.5,
127.1, 126.4, 125.9, 125.27, 125.25, 112.6, 110.3, 99.6, 98.1, 50.6, 50.5, 42.9, 42.8, 42.5, 40.5, 33.9, 33.3,
31.9, 31.5, 29.9, 29.5, 28.6, 28.3, 27.8, 27.4, 26.9; 96% ee was determined by HPLC on AD-H column,
hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, tminor = 5.267 min, tmajor = 7.583 min; [α]D20
+5.5◦ (c = 0.039, EtOH).
=
4-(4-Chlorophenyl)-2-hydroxy-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ad) [37]. Colorless
oil; 99% yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
(ppm) 7.23
δ
(d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 3.95
(d, J = 4.4 Hz, 0.5H), 3.81 (d, J = 8.6 Hz, 0.5H), 3.16–3.09 (m, 0.5H), 2.95 (br s, 0.4H), 2.49–2.17 (m,

Molecules 2017, 22, 1096
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6H), 1.53 (s, 1.5H), 1.50 (s, 1.5H), 1.18 (s, 1.5H), 1.15 (s, 1.5H), 1.10 (s, 1.4H), 1.08 (s, 1.6H); 13C-NMR
(100 MHz, CDCl3) (ppm) 196.9, 196.6, 169.3, 168.3, 143.5, 141.9, 132.1, 131.3, 129.1, 128.8, 128.49,
δ
128.47, 128.3, 127.9, 112.9, 110.5, 99.5, 97.9, 50.74, 50.72, 42.9, 42.8, 42.5, 40.3, 33.6, 32.6, 32.0, 31.5, 29.5,
28.7, 28.3, 28.1, 27.5, 27.4; 97% ee was determined by HPLC on OD-H column, hexane/i-propanol
(80/20), 1.0 mL/min, UV 254 nm, tminor = 5.493 min, tmajor = 8.417 min; [α]2D0 = +13.8 (c = 0.039, EtOH),
◦
2◦
[α]D = +10.5◦ (c = 0.039, DCM).
4-(4-Fluorophenyl)-2-hydroxy-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ae) [37]. Colorless
oil; 96% yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ (ppm) 7.13
(t, J = 6.4 Hz, 1H), 7.08 (t, J = 6.4 Hz, 1H), 6.94 (t, J = 9.4 Hz, 1H), 6.92 (t, J = 8.8 Hz, 1H), 3.94 (br s,
0.5H), 3.82 (dd, J = 9.8, 8.2 Hz, 0.5H), 3.51–3.27 (m, 1H), 2.48–2.11 (m, 6H), 1.47 (s, 3H), 1.78 (s, 1.4H),
1.14 (s, 1.6H), 1.09 (s, 1.4H), 1.07 (s, 1.6H); 13C-NMR (100 MHz, CDCl3)
δ
(ppm) 197.2, 196.9, 169.5,
168.6, 161.2 (d, J1
= 243.3 Hz), 160.9 (d, J1
= 241.8 Hz), 140.6 (d, J4
= 3.2 Hz), 139.0 (d, J4
C-F
C-F
C-F
C-F
= 3.3 Hz), 129.2, 129.1, 128.5 (d, J3
= 7.8 Hz), 128.2 (d, J3
= 7.8 Hz), 115.4 (d, J2
= 21.1 Hz),
C-F
C-F
C-F
115.0 (d, J2C-F = 21.2 Hz), 114.6, 114.4, 113.0, 110.7, 99.6, 98.1, 60.4, 50.7, 50.6, 42.9, 42.8, 42.7, 40.6, 33.4,
32.6, 31.9, 31.4, 29.5, 28.6, 28.3, 27.9, 27.3, 27.0, 20.9, 14.1; 96% ee was determined by HPLC on AD-H
column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, tminor = 5.043 min, tmajor = 9.330 min;
[α]2D0 = −5.4◦ (c = 0.041, EtOH).
4-(4-Bromophenyl)-2-hydroxy-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4af) [37]. Colorless
oil; 99% yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ (ppm) 7.37 (d,
J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 3.90 (t, J = 5.4 Hz,
0.5H), 3.72 (pseudo triple, J = 5.4 Hz, 0.6H), 3.50 (br s, 0.5H), 3.19 (br s, 0.4H), 2.48–2.07 (m, 6H), 1.49
(s, 1.6H), 1.48 (s, 1.4H), 1.17 (s, 1.4H), 1.14 (s, 1.6H), 1.09 (s, 1.4H), 1.07 (s, 1.6H); 13C-NMR (100 MHz,
CDCl3) δ (ppm) 197.0, 196.7, 169.4, 168.4, 144.1, 142.6, 131.6, 131.4, 130.9, 129.6, 128.9, 128.7, 120.0, 119.4,
112.8, 110.4, 99.5, 97.9, 50.7, 50.6, 42.9, 42.8, 42.4, 40.3, 33.7, 32.8, 31.9, 31.5, 29.5, 28.7, 28.3, 28.1, 27.4,
27.3; 97% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV
254 nm, tminor = 5.720 min, tmajor = 10.570 min; [α]20 = +13.9◦ (c = 0.010, EtOH).
D
2-Hydroxy-2,7,7-trimethyl-4-(p-tolyl)-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ag) [60]. Colorless oil; 95%
yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ (ppm) 7.16–7.01 (m,
4H), 3.99 (br s, 0.6H), 3.80 (pseudo triple, J = 8.8 Hz, 0.6H), 3.33 (pseudo double, J = 9.6 Hz, 0.8H),
2.50–2.13 (m, 9H), 1.47 (s, 3H), 1.19 (s, 1.7H), 1.15 (s, 1.3H), 1.10 (s, 1.7H), 1.07(s, 1.3H); 13C-NMR (100
MHz, CDCl3)
δ (ppm) 197.1, 196.7, 169.2, 169.1, 141.8, 139.6, 136.2, 135.1, 129.8, 129.0, 128.7, 127.5,
126.8, 126.7, 113.3, 110.5, 99.7, 98.1, 50.7, 42.9, 42.8, 42.7, 40.3, 33.6, 31.9, 31.5, 29.5, 28.8, 28.3, 27.9, 27.4,
27.3, 21.0, 20.9; 97% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0
mL/min, UV 254 nm, tminor = 5.313 min, tmajor = 7.733 min; [α]20 = +6.2◦ (c = 0.041, EtOH).
D
2-Hydroxy-4-(4-methoxyphenyl)-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one
Colorless oil; 89% yield purified by flash column chromatography; H-NMR (400 MHz, CDCl3)
(
4ah
)
[37].
1
δ
(ppm) 7.10 (d, J = 8.8 Hz, 1.1H), 7.05 (d, J = 8.8 Hz, 0.9H), 6.82 (d, J = 7.6 Hz, 1.1H), 6.79 (d, J = 8.4
Hz, 0.9H), 3.99 (br s, 0.6H), 3.80 (pseudo triple, J = 8.8 Hz, 0.6H), 3.75 (s, 3H), 3.59 (br s, 0.4H), 3.31
(br s, 0.6H), 2.49–2.11 (m, 6H), 1.47 (s, 1.7H), 1.46 (s, 1.3H), 1.19 (s, 1.7H), 1.15 (s, 1.3H), 1.10 (s, 1.7H),
1.07 (s, 1.3H); 13C-NMR (100 MHz, CDCl3) δ (ppm) 197.0, 196.7, 169.1, 167.9, 158.2, 157.6, 136.8, 134.4,
128.7, 127.9, 127.8, 114.5, 113.8, 113.4, 113.3, 110.6, 99.7, 88.1, 55.2, 55.1, 50.8, 42.9, 42.8, 42.7, 40.1, 33.2,
31.9, 31.49, 31.47, 29.5, 28.8, 28.3, 27.9, 27.5; 97% ee was determined by HPLC on AD-H column,
hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, tminor = 6.353 min, tmajor = 12.270 min; [α]D20
+6.5◦ (c = 0.030, EtOH).
=
2-Hydroxy-2,7,7-trimethyl-4-(naphthalen-1-yl)-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ai). Colorless oil;
89% yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
(ppm) 8.18 (d,
δ
J = 8.0 Hz, 0.3H), 8.13 (d, J = 8.4 Hz, 0.7H), 7.90 (d, J = 8.0 Hz, 0.7H), 7.85 (d, J = 7.6 Hz, 0.3H), 7.74 (d,
J = 8.4 Hz, 0.7H), 7.68 (d, J = 8.0 Hz, 0.3H), 7.65–7.54 (m, 2.5H), 7.34 (t, J = 7.2 Hz, 1H), 7.27 (d, J = 5.6

Molecules 2017, 22, 1096
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Hz, 0.5H), 4.82 (d, J = 6.8 Hz, 0.8H), 4.70 (br s, 0.5H), 3.39 (br s, 0.8H), 2.63–2.23 (m, 6H), 1.47 (s, 3H),
1.27 (s, 2H), 1.24 (s, 1H), 1.17 (s, 2H), 1.12 (s, 1H); 13C-NMR (100 MHz, CDCl3)
(ppm) 196.9, 196.7,
δ
169.7, 138.6, 134.7, 130.8, 129.3, 128.9, 127.9, 126.2, 125.8, 125.4, 125.3, 125.2, 123.3, 122.5, 118.8, 117.1,
110.2, 99.5, 98.3, 50.8, 50.7, 43.1, 42.9, 37.9, 32.1, 31.5, 29.4, 29.2, 28.0, 27.9, 27.83, 27.80; ESI-HRMS calcd.
for C22H24O3 + H+ 337.1804, found 337.1798; 96% ee was determined by HPLC on AD-H column,
hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, tminor = 4.927 min, tmajor = 6.790 min; [α]D20
−88.9◦ (c = 0.045, EtOH).
=
2-Hydroxy-2,7,7-trimethyl-4-(naphthalen-2-yl)-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4aj) [37]. Colorless
oil; 98% yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
(ppm) 7.81–7.69
δ
(m, 3H), 7.59 (s, 0.5H), 7.55 (s, 0.5H), 7.44–7.35 (m, 2.5H), 7.27–7.26 (m, 0.5H), 4.19 (br s, 0.5H), 4.01
(pseudo triple, J = 8.6 Hz, 0.5H), 3.29–3.17 (m, 1H), 2.57–2.17 (m, 6H), 1.49 (s, 3H), 1.26 (s, 2H), 1.19
(s, 1H), 1.13 (s, 1.6H), 1.09 (s, 1.4H); 13C-NMR (100 MHz, CDCl3)
δ (ppm) 197.2, 196.9, 169.7, 168.6,
142.3, 140.5, 133.6, 133.5, 132.3, 132.1, 128.8, 127.9, 127.7, 127.53, 127.52, 127.4, 126.1, 125.7, 125.65,
125.57, 125.52, 125.4, 124.9, 124.8, 113.0, 110.4, 99.8, 98.2, 50.7, 50.6, 42.9, 42.8, 42.5, 40.0, 34.1, 32.9,
32.0, 31.5, 29.9, 29.5, 28.7, 28.4, 27.9, 27.5, 27.2; 98% ee was determined by HPLC on AD-H column,
hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, tminor = 7.073 min, tmajor = 13.053 min; [α]D20
+60.2◦ (c = 0.051, EtOH).
=
4-(Furan-2-yl)-2-hydroxy-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ak) [37]. Colorless oil;
1
78% yield purified by flash column chromatography; H-NMR (400 MHz, CDCl3)
δ (ppm) 7.36 (s,
0.6H), 7.29 (s, 0.4H), 6.28 (dd, J = 3.0, 1.8 Hz, 1H), 6.02 (d, J = 3.2 Hz, 0.7H), 5.95 (d, J = 2.0 Hz, 0.3H),
4.15 (d, J = 6.8 Hz, 1H ), 4.04 (br s, 1H), 2.55–2.22 (m, 6H), 1.55 (s, 2.2 H), 1.41 (s, 0.8H), 1.17 (s, 3H),
1.11 (s, 3H); 13C-NMR (100 MHz, CDCl3)
δ (ppm) 196.7, 168.9, 155.5, 141.9, 140.3, 110.6, 110.3, 108.4,
106.0, 105.3, 98.3, 50.7, 42.8, 35.9, 32.0, 28.6, 28.2, 27.9, 26.1; 95% ee was determined by HPLC on AD-H
column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, tminor = 5.327 min, tmajor = 6.257 min;
[α]2D0 = −12.9◦ (c = 0.015, EtOH).
2-Hydroxy-2,7,7-trimethyl-4-(thiophen-2-yl)-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4al). Brown oil; 97%
yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ (ppm) 7.17 (d, J = 4.8
Hz, 0.6H), 7.06 (d, J = 4.8 Hz, 0.6H), 6.89–6.87 (m, 1H), 6.81 (s, 1H), 4.32 (d, J = 5.6 Hz, 0.6H), 4.23
(pseudo triple, J = 8.0 Hz, 0.4H), 3.53 (br s, 1H), 2.51-2.11 (m, 6H), 1.52 (s, 2H), 1.46 (s, 1H), 1.19 (s,
2H), 1.16 (s, 1H), 1.10 (s, 2H), 1.07 (s, 1H); 13C-NMR (100 MHz, CDCl3)
δ (ppm) 196.8, 196.7, 169.1,
168.1, 148.7, 147.2, 127.0, 126.4, 124.6, 124.2, 123.8, 123.7, 123.2, 122.4, 112.9, 110.7, 99.4, 98.4, 50.6, 42.8,
42.7, 39.9, 31.9, 31.4, 29.4, 29.3, 28.5, 28.4, 27.7, 27.66, 27.61, 27.3; ESI-HRMS calcd. for C16H20O3S +
H+ 293.1211, found 293.1206; 91% ee was determined by HPLC on AD-H column, hexane/i-propanol
(80/20), 1.0 mL/min, UV 254 nm, tminor = 5.850 min, tmajor = 7.423 min; [α]D20
=
−
18.9 (c = 0.047, EtOH).
◦
2-Hydroxy-2,4,7,7-tetramethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4am). Colorless oil; 69% yield
purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
(ppm) 3.66–3.35 (m, 1H),
2.77–2.66 (m, 1H), 2.29–2.06 (m, 6H), 1.55 (s, 1.4H), 1.50 (s, 1.6H), 1.23 (d, J = 7.6 Hz, 2H), 1.21 (d, J =
7.6 Hz, 1H), 1.05 (s, 3H), 1.02 (s, 3H); 13C-NMR (100 MHz, CDCl3)
(ppm) 213.5, 198.5, 197.9, 170.7,
δ
δ
166.7, 166.5, 117.1, 114.9, 114.3, 99.1, 97.8, 51.3, 51.2, 51.1, 49.2, 43.2, 42.8, 42.7, 41.5, 39.2, 31.9, 31.4, 29.8,
29.2, 28.4, 28.1, 28.0, 27.2, 26.9, 24.3, 22.9, 22.1, 19.7, 19.4, 18.5; ESI-HRMS calcd. for C13H20O3 + H+
225.1491, found 225.1485; 91% ee was determined by HPLC on IC column, hexane/i-propanol (95/5),
1.0 mL/min, UV 254 nm, tmino = 49.740 min, t
= 77.910 min; [α]20 = −5.5◦ (c = 0.017, EtOH).
r
major
D
4-Butyl-2-hydroxy-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4an). Colorless oil; 75% yield
purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
(ppm) 3.19–3.10 (m, 1H),
δ
2.93–2.87 (m, 0.5H), 2.64 (s, 0.3H), 2.59 (s, 0.3H), 2.30–2.09 (m, 6H), 2.01–1.89 (m, 1H), 1.79–1.73 (m, 1H),
1.65–1.45 (m, 3H), 1.35–1.19 (m, 4H), 1.06–1.02 (m, 6H), 0.89–0.81 (m, 3H); 13C-NMR (100 MHz, CDCl3)
δ
(ppm) 213.8, 198.6, 197.8, 171.5, 167.1, 166.7, 115.7, 114.2, 113.9, 99.3, 97.9, 51.4, 51.3, 51.2, 48.3, 43.2,
42.9, 42.8, 38.2, 35.1, 32.1, 31.8, 31.7, 31.3, 30.9, 30.5, 29.8, 29.7, 29.4, 29.3, 28.5, 28.3, 28.2, 28.1, 28.0, 27.9,

Molecules 2017, 22, 1096
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27.1, 26.8, 22.8, 22.7, 22.4, 14.1, 14.0; ESI-HRMS calcd. for C16H26O3 + H+ 267.1960, found 267.1964;
94% ee was determined by HPLC on IC column, hexane/i-propanol (70/30), 1.0 mL/min, UV 254 nm,
tminor = 4.440 min, tmajor = 8.093 min; [α]20 = −13.0◦ (c = 0.034, EtOH).
D
2-Hydroxy-9,9-dimethyl-2,3,4,5,6,8,9,10-octahydro-7H-2,6-methanobenzo[b]oxocin-7-one (4ao) [37]. White
solid; 91% yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ (ppm) 4.46
(s, 1H ), 3.15 (s, 1H), 2.29 (s, 2H), 2.19 (s, 2H), 2.02 (d, J = 12.8 Hz, 1H), 1.93 (d, J = 12.4 Hz, 1H), 1.74 (d,
J = 15.2 Hz, 1H), 1.16 (dd, J = 13.0, 3.8 Hz, 1H), 1.59 (d, J = 11.2 Hz, 2H), 1.45–1.33 (m, 2H), 1.04 (s, 6H);
13C-NMR (100 MHz, CDCl3)
δ (ppm) 196.7, 171.2, 112.3, 101.3, 50.3, 42.0, 38.7, 36.2, 32.3, 28.5, 28.4, 28.2,
26.9, 19.2; 98% ee was determined by HPLC on IC column, hexane/i-propanol (90/10), 1.0 mL/min,
UV 254 nm, tmajor = 12.987 min, tminor = 14.423 min; [α]20 = +4.7◦ (c = 0.023, EtOH).
D
2-Ethyl-2-hydroxy-7,7-dimethyl-4-phenyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ap) [37]. Colorless oil;
63% yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ (ppm) 7.24–7.16
(m, 2.5H), 7.12 (d, J = 7.6 Hz, 1H), 7.09–7.06 (m, 1.5H), 3.99 (br s, 0.5H), 3.76 (pseudo triple, J = 9.0 Hz,
0.5H), 3.15–3.00 (m, 1H), 2.44–2.09 (m, 6H), 1.69–1.63 (m, 2H), 1.13 (s, 1.6H), 1.09 (s, 1.4H), 1.04 (s, 1.6H),
1.00 (s, 1.4H), 0.89 (0.86) (t, J = 7.6 Hz, 3H); 13C-NMR (100 MHz, CDCl3)
δ (ppm) 196.9, 196.5, 169.3,
168.0, 145.1, 142.9, 129.0, 128.3, 126.9, 126.7, 125.8, 113.3, 110.4, 101.3, 99.7, 50.8, 42.9, 42.8, 40.3, 38.0,
33.9, 33.6, 33.2, 32.0, 31.9, 31.5, 29.5, 28.9, 28.3, 27.5, 7.3, 7.2; 98% ee was determined by HPLC on AD-H
column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, tminor = 5.247 min, tmajor = 11.667 min;
[α]2D0 = −5.4◦ (c = 0.018, EtOH).
2-Hydroxy-2-methyl-4-phenyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ba) [60]. White solid; 71% yield
purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ (ppm) 7.28 (t, J = 7.2 Hz,
1H), 7.24 (d, J = 7.2 Hz, 1H), 7.19–7.12 (m, 3H), 4.02 (br s, 0.5H), 3.84 (pseudo triple, J = 8.8 Hz, 0.5H),
3.36–3.31(m, 0.5H), 2.63–2.45 (m, 2H), 2.42–2.30 (m, 2H), 2.27–2.15 (m, 2H), 2.11–1.95 (m, 2H), 1.47 (s,
1.5H), 1.45 (s, 1.5H); 13C-NMR (100 MHz, CDCl3)
δ (ppm) 197.2, 196.9, 171.1, 170.1, 144.8, 142.7, 128.9,
128.3, 127.9, 127.7, 126.79, 126.77, 126.6, 125.8, 114.4, 111.6, 99.6, 97.9, 42.8, 40.4, 36.9, 33.9, 32.5, 29.3,
29.2, 27.9, 27.2, 20.8, 20.2; 94% ee was determined by HPLC on AD-H column, hexane/i-propanol
(80/20), 1.0 mL/min, UV 254 nm, tminor = 5.343 min, tmajor = 6.693 min; [α]D20
=
−
8.2 (c = 0.019, EtOH).
◦
4-(4-chlorophenyl)-2-hydroxy-2-methyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4bd): White solid; 78%
yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ
(ppm) 7.25 (d, J = 7.2
Hz, 0.6H), 7.21 (d, J = 8.8 Hz, 1.5H), 7.11 (d, J = 8.8 Hz, 0.6H), 7.07 (d, J = 7.6 Hz, 1.4H), 3.95 (pseudo
triple, J = 4.8 Hz, 0.5H), 3.82 (pseudo triple, J = 9.0 Hz, 0.5H), 3.33 (br s, 0.5H), 3.05 (br s, 0.5H), 2.61–2.33
(m, 4H), 2.26–2.17 (m, 2H), 2.07–1.97 (m, 2H), 1.51 (s, 1.6H), 1.49 (s, 1.4H); 13C-NMR (100 MHz, CDCl3)
δ
(ppm) 197.2, 196.8, 171.2, 170.2, 143.4, 141.8, 132.0, 131.2, 128.8, 128.4, 128.3, 128.2, 114.2, 111.6, 99.4,
97.8, 42.5, 40.3, 36.9, 33.5, 32.6, 29.3, 29.2, 28.1, 27.2, 20.7, 20.2; ESI-HRMS calcd. for C16H17ClO3 + H+
293.0944, found 293.0937; 95% ee was determined by HPLC on AD-H column, h◦exane/i-propanol
(80/20), 1.0 mL/min, UV 254 nm, tminor = 6.397 min, tmajor = 8.430 min; [α]D20
=
−
11.9 (c = 0.007, EtOH).
4-(4-Bromophenyl)-2-hydroxy-2-methyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4bf). White solid; 67%
yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ
(ppm) 7.38 (d, J = 8.8
Hz, 0.8H), 7.36 (d, J = 8.8 Hz, 1.2H), 7.05 (d, J = 10.0 Hz, 0.8H), 7.03 (d, J = 8.8 Hz, 1.2H), 3.93 (pseudo
triple, J = 5.0 Hz, 0.5H), 3.81 (pseudo triple, J = 9.2 Hz, 0.5H), 3.23 (br s, 0.5H), 2.99 (br s, 0.5H), 2.61–2.33
(m, 4H), 2.28–2.17 (m, 2H), 2.07–1.97 (m, 2H), 1.52 (s, 1.6H), 1.49 (s, 1.4H); 13C-NMR (100 MHz, CDCl3)
δ
(ppm) 197.2, 196.8, 171.2, 170.2, 143.9, 142.4, 131.7, 131.4, 130.9, 129.6, 128.8, 128.6, 120.1, 119.4, 114.2,
111.6, 99.4, 97.8, 42.5, 40.3, 36.9, 36.8, 33.6, 32.7, 29.3, 29.2, 28.1, 27.2, 20.7, 20.2; ESI-HRMS calcd. for
C16H17BrO3 + H+ 337.0439, found 337.0438; 96% ee was determined by HPLC on AD-H column,
hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, tminor = 6.780 min, tmajor = 8.967 min; [α]D20
−8.5◦ (c = 0.008, EtOH).
=

Molecules 2017, 22, 1096
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3.3. Procedure for the Asymmetric Michael Reaction of Chalcones
Dimedone 1a (14.0 mg, 0.1 mmol), chalcone 5a (25.0 mg, 0.12 mmol), and quinine-based
squaramide (12.5 mg, 0.02 mmol) were dissolved in chloroform (1.0 mL). After stirring at room
temperature for 120 h, triethylamine (41.7 L, 0.3 mmol) was added in one portion. Subsequently,
acetyl chloride (14.2 L, 0.2 mmol) was added dropwise. Once the reaction completed (1 h), the crude
7
µ
µ
product was purified over silica gel by column chromatography (EtOAc/petroleum ether) to afford
6aa (37.1 mg, 95 % yield) as a colorless oil.
1
5,5-Dimethyl-3-oxo-2-(3-oxo-1,3-diphenylpropyl)cyclohex-1-en-1-yl acetate (6aa) [38
CDCl3)
,
53]. H-NMR (400 MHz,
δ
(ppm) 7.96 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.28–7.22 (m, 4H),
7.15 (t, J = 6.6 Hz, 1H), 4.79 (t, J = 7.4 Hz, 1H), 3.82 (ABX, JAB = 17.2 Hz, JAX = 8.0 Hz, 1H), 3.75 (ABX,
JAB = 17.2, JBX = 6.8 Hz, 1H), 2.53 (AB, JAB = 18.0 Hz, 1H), 2.42 (AB, JAB = 17.2 Hz, 1H), 2.24 (s, 2H),
2.15 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H); 13C-NMR (100 MHz, CDCl3)
δ (ppm) 198.7, 198.6, 167.3, 163.9,
142.0, 136.8, 132.9, 128.9, 128.5, 128.2, 128.1, 127.4, 126.1, 116.4, 51.7, 42.7, 40.8, 35.7, 32.5, 28.1, 27.9, 20.9;
93% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254
nm, tminor = 7.467 min, tmajor = 10.760 min; [α]20 = +41.5◦ (c = 0.032, CHCl3).
D
2-(1-(4-Chlorophenyl)-3-oxo-3-phenylpropyl)-5,5-dimethyl-3-oxocyclohex-1-en-1-yl acetate (6ab). Colorless
oil; 99% yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ
(ppm) 7.95 (d,
J = 7.6 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.4 Hz, 2H), 7.24–7.17 (m, 4H), 4.74 (t, J = 7.2 Hz, 1H),
3.79 (ABX, JAB = 17.6 Hz, JAX = 7.2 Hz, 1H), 3.72 (ABX, JAB = 17.8 Hz, JBX = 7.8 Hz, 1H), 2.53 (AB, JAB
18.0 Hz, 1H), 2.42 (AB, JAB = 17.6 Hz, 1H), 2.24 (s, 2H), 2.20 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H); 13C-NMR
=
(100 MHz, CDCl3)
δ (ppm) 198.8, 198.3, 167.4, 164.0, 140.5, 136.7, 133.1, 131.9, 128.9, 128.7, 128.6, 128.3,
128.1, 51.7, 42.7, 40.6, 35.3, 32.6, 27.9, 27.8, 20.9; ESI-HRMS calcd. for C25H26ClO4 + H+ 425.1514, found
425.1514; 94% ee was determined by HPLC on AD-H column, hexane/i-propanol (70/30), 1.0 mL/min,
UV 254 nm, tminor = 6.560 min, tmajor = 11.080 min; [α]20 = +79.6◦ (c = 0.019, EtOH).
D
5,5-Dimethyl-3-oxo-2-(3-oxo-3-phenyl-1-(p-tolyl)propyl)cyclohex-1-en-1-yl acetate (6ac). Colorless oil; 96%
yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ (ppm) 7.96 (d, J = 7.2
Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H),
4.74 (t, J = 7.4 Hz, 1H), 3.82 (ABX, JAB = 17.2 Hz, JAX = 8.0 Hz, 1H), 3.73 (ABX, JAB = 17.2 Hz, JBX = 6.8
Hz, 1H), 2.53 (AB, JAB = 17.6 Hz, 1H), 2.43 (AB, JAB = 17.6 Hz, 1H), 2.28 (s, 3H), 2.24 (s, 2H), 2.17 (s, 3H),
1.02 (s, 3H), 1.01 (s, 3H); 13C-NMR (100 MHz, CDCl3)
δ (ppm) 198.9, 198.8, 167.5, 163.8, 138.9, 136.9,
135.7, 132.9, 129.1, 128.9, 128.5, 128.1, 127.4, 51.8 42.8, 40.9, 35.5, 32.6, 28.0, 27.9, 20.9; ESI-HRMS calcd.
for C26H29O4 + H+ 405.2060, found 405.2061; 93% ee was determined by HPLC on AD-H column,
hexane/i-propanol (70/30), 1.0 mL/min, UV 254 nm, tminor = 6.467 min, tmajor = 13.007 min; [α]D20
+70.1◦ (c = 0.018, EtOH).
=
5,5-Dimethyl-3-oxo-2-(3-oxo-3-phenyl-1-(thiophen-2-yl)propyl)cyclohex-1-en-1-yl acetate (6ad). Colorless oil;
95% yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
(ppm) 7.72–7.67
δ
(m, 1H), 7.54 (d, J = 4.0 Hz, 1H), 7.20–7.16 (m, 4H), 7.10–7.09 (m, 1H), 7.05–7.00 (m, 1H), 4.71 (t, J = 7.4
Hz, 1H), 3.72 (ABX, JAB = 16.2 Hz, JAX = 8.4 Hz, 1H), 3.57 (ABX, JAB = 16.4 Hz, JBX = 6.4 Hz, 1H), 2.45
(AB, JAB = 18.0 Hz, 1H), 2.36 (AB, JAB = 17.6 Hz, 1H), 2.16 (s, 2H), 2.12 (s, 3H), 0.93 (s, 6H); 13C-NMR
(100 MHz, CDCl3)
δ (ppm) 198.8, 191.7, 167.4, 164.1, 144.3, 141.8, 133.7, 132.1, 128.7, 128.2, 128.0, 127.4,
126.2, 51.7, 42.7, 41.3, 36.0, 32.6, 27.9, 27.8, 20.9; ESI-HRMS calcd. for C23H25O4S + H+ 397.1468, found
397.1468; 91% ee was determined by HPLC on AD-H column, hexane/i-propanol (70/30), 1.0 mL/min,
UV 254 nm, tminor = 6.903 min, tmajor = 10.567 min; [α]20 = +29.6◦ (c = 0.016, EtOH).
D
5,5-Dimethyl-2-(1-(naphthalen-2-yl)-3-oxo-3-phenylpropyl)-3-oxocyclohex-1-en-1-yl acetate (6ae). Colorless
oil; 68% yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ (ppm) 8.00 (d,
J = 8.0 Hz, 2H), 7.78–7.73 (m, 4H), 7.56 (t, J =7.4 Hz, 1H), 7.46 (t, J = 7.4 Hz, 2H), 7.43–7.39 (m, 3H), 4.97
(t, J = 7.2 Hz, 1H), 3.94 (ABX, JAB = 17.6 Hz, JAX = 8.4 Hz, 1H), 3.88 (ABX, JAB = 17.0 Hz, JBX = 7.0 Hz,
1H), 2.56 (AB, JAB = 18.0 Hz, 1H), 2.43 (AB, JAB = 18.0 Hz, 1H), 2.28 (AB, JAB = 16.8 Hz, 1H), 2.24 (AB,

Molecules 2017, 22, 1096
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J
AB = 17.6 Hz, 1H), 2.15 (s, 3H), 1.04 (s, 3H), 1.01 (s, 3H); 13C-NMR (100 MHz, CDCl3)
δ
(ppm) 198.8,
198.6, 167.4, 164.1, 139.5, 136.9, 133.3, 133.0, 132.0, 128.8, 128.5, 128.1, 127.9, 127.7, 127.5, 126.5, 125.8,
125.6, 125.3, 51.7, 42.8, 40.8, 35.9, 32.6, 27.9, 27.8, 20.9; ESI-HRMS calcd. for C29H29O4 + H+ 441.2060,
found 441.2061; 91% ee was determined by HPLC on AD-H column, hexane/i-propanol (70/30), 1.0
mL/min, UV 254 nm, tminor = 7.943 min, tmajor = 11.667 min; [α]20 = +79.7◦ (c = 0.011, EtOH).
D
2-(3-(4-Chlorophenyl)-3-oxo-1-phenylpropyl)-5,5-dimethyl-3-oxocyclohex-1-en-1-yl acetate (6af). White solid;
98% yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.90 (d, J =
8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.26–7.23 (m, 4H), 7.20–7.23 (m, 1H), 4.77 (t, J = 7.4 Hz, 1H), 3.82
(ABX, JAB = 17.2 Hz, JAX = 8.0 Hz, 1H), 3.70 (ABX, JAB = 17.2 Hz, JBX = 6.8 Hz, 1H), 2.54 (AB, JAB = 17.6
Hz, 1H), 2.42 (AB, JAB = 18.0 Hz, 1H), 2.24 (s, 2H), 2.17 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H); 13C-NMR (100
MHz, CDCl3) δ (ppm) 198.9, 197.5, 167.3, 164.0, 141.8, 139.3, 135.1, 129.5, 128.75, 128.72, 128.2, 127.4,
126.2, 51.7, 42.7, 40.7, 35.8, 32.5, 27.8, 20.9; ESI-HRMS calcd. for C25H26ClO4 + H+ 425.1514, found
425.1514; 87% ee was determined by HPLC on AD-H column, hexane/i-propanol (70/30), 1.0 mL/min,
UV 254 nm, tminor = 9.913 min, tmajor = 15.547 min; [α]20 = +57.9◦ (c = 0.016, EtOH).
D
5,5-Dimethyl-3-oxo-2-(3-oxo-1-phenyl-3-(p-tolyl)propyl)cyclohex-1-en-1-yl acetate (6ag). Colorless oil; 99%
yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ (ppm) 7.87 (d, J = 8.0 Hz,
2H), 7.29–7.23 (m, 6H), 7.19–7.11 (m, 1H), 4.79 (t, J = 7.4 Hz, 1H), 3.79 (ABX, JAB = 16.4 Hz, JAX = 7.6
Hz, 1H), 3.73 (ABX, JAB = 16.8 Hz, JBX = 6.8 Hz, 1H), 2.53 (AB, JAB = 18.0 Hz, 1H), 2.42 (AB, JAB = 17.6
Hz, 1H), 2.40 (s, 3H), 2.25 (s, 2H), 2.17 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H); 13C-NMR (100 MHz, CDCl3)
δ
(ppm) 198.8, 198.3, 167.4, 163.8, 143.7, 142.1, 134.4, 129.1, 129.0, 128.2, 128.1, 127.5, 126.1, 51.7, 42.7, 40.6,
35.7, 32.6, 27.9, 21.6, 20.9; ESI-HRMS calcd. for C26H29O4 + H+ 405.2060, found 405.2061; 95% ee was
determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, tminor
=
9.573 min, tmajor = 13.540 min; [α]20 = +77.1◦ (c = 0.018, EtOH)
D
5,5-Dimethyl-3-oxo-2-(3-oxo-1-phenyl-3-(thiophen-2-yl)propyl)cyclohex-1-en-1-yl acetate (6ah). Colorless
oil; 99% yield purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
(ppm) 7.88
δ
(d, J = 7.6 Hz, 2H), 7.47 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.4 Hz, 2H), 7.03–6.97 (m, 1H), 6.83–6.74 (m,
2H), 4.97 (t, J = 7.0 Hz, 1H), 3.82 (ABX, JAB = 17.4 Hz, JAX = 7.8 Hz, 1H), 3.70 (ABX, JAB = 17.6 Hz,
J
BX = 6.4 Hz, 1H), 2.49 (AB, JAB = 18.0 Hz, 1H), 2.38 (AB, JAB = 17.6 Hz, 1H), 2.19 (s, 2H), 2.15 (s, 3H),
0.97 (s, 3H), 0.95 (s, 3H); 13C-NMR (100 MHz, CDCl3)
δ
(ppm) 198.4, 198.0, 167.3, 164.1, 145.7, 136.6,
133.0, 128.5, 128.2, 128.1, 126.4, 124.1, 123.3, 51.6, 42.6, 42.3, 32.6, 31.5, 27.9, 27.8, 20.9; ESI-HRMS calcd.
for C23H25O4S + H+ 397.1468, found 397.1469; 97% ee was determined by HPLC on AD-H column,
hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, tminor = 7.623 min, tmajor = 9.193 min; [α]D20
+102.9◦ (c = 0.019, EtOH)
=
3-Oxo-2-(3-oxo-1,3-diphenylpropyl)cyclohex-1-en-1-yl acetate (6ba). Colorless oil; 93% yield purified by
flash column chromatography; 1H-NMR (400 MHz, CDCl3)
(ppm) 7.97 (d, J = 7.6 Hz, 2H), 7.55 (t,
δ
J = 7.2 Hz, 1H), 7.44 (t, J =7.4 Hz, 2H), 7.29–7.23 (m, 4H), 7.16 (t, J = 6.6 Hz, 1H), 4.80 (t, J = 7.2 Hz,
1H), 3.81 (ABX, JAB = 17.8 Hz, JAX = 6.6 Hz, 1H), 3.75 (ABX, JAB = 17.6 Hz, JBX = 7.6 Hz, 1H), 2.65 (dt,
J = 18.0, 6.4 Hz, 1H), 2.53 (dt, J = 18.0, 5.9 Hz, 1H), 2.37 (t, J = 6.4 Hz, 2H), 2.17 (s, 3H), 1.98–1.89 (m, 2H);
13C-NMR (100 MHz, CDCl3)
δ (ppm) 198.8, 198.7, 167.3, 165.6, 142.0, 136.8, 132.9, 130.1, 128.5, 128.1,
128.0, 127.5, 126.1, 40.8, 37.9, 35.7, 29.0, 20.9, 20.7; ESI-HRMS calcd. for C23H23O4 + H+ 363.1591, found
363.1591; 91% ee was determined by HPLC on AD-H column, hexane/i-propanol (70/30), 1.0 mL/min,
UV 254 nm, tminor = 7.667 min, tmajor = 10.660 min; [α]20 = +92.4◦ (c = 0.016, EtOH).
D
3-Oxo-2-(3-oxo-1,3-diphenylpropyl)cyclopent-1-en-1-yl acetate (6ca). Colorless oil; 31% yield purified by
flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ (ppm) 7.94 (d, J = 7.6 Hz, 2H), 7.52 (t,
J = 7.2 Hz, 1H), 7.42 (t, J = 7.0 Hz, 2H), 7.36–7.34 (m, 2H), 7.26 (t, J = 6.8 Hz, 2H), 7.18 (t, J = 7.0 Hz, 1H),
4.49 (t, J = 7.2 Hz, 1H), 4.06 (ABX, JAB = 17.6 Hz, JBX = 8.8 Hz, 1H), 3.56 (ABX, JAB = 17.6 Hz, JBX = 6.0
Hz, 1H), 2.93–2.79 (m, 2H), 2.47–2.38 (m, 2H), 2.21 (s, 3H); 13C-NMR (100 MHz, CDCl3)
δ
(ppm) 205.3,
198.3, 176.7, 166.5, 141.9, 136.8, 133.1, 129.9, 128.6, 128.5, 128.0, 127.8, 126.7, 40.8, 35.8, 34.7, 26.9, 21.1;

Molecules 2017, 22, 1096
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ESI-HRMS calcd. for C22H22O4 + H+ 349.1440, found 349.1437; 57% ee was determined by HPLC on
AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, tminor = 8.787 min, tmajor = 12.983
min; [α]2D0 = +29.0◦ (c = 0.014, EtOH).
5,5-Dimethyl-3-oxo-2-(1-oxo-1-phenylhexan-3-yl)cyclohex-1-en-1-yl acetate (6ai). Colorless oil; 93% yield
purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ (ppm) 7.91 (d, J = 7.2 Hz,
2H), 7.52 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.4 Hz, 2H), 3.32 (ABX, JAB = 16.4 Hz, JBX = 6.8 Hz, 1H), 3.23
(ABX, JAB = 16.0 Hz, JBX = 6.4 Hz, 1H), 2.46 (AB, JAB = 18.0 Hz, 1H), 2.41 (AB, JAB = 18.0 Hz, 1H), 2.27
(AB, JAB = 15.6 Hz, 1H), 2.21 (AB, JAB = 15.2 Hz, 1H), 2.20 (s, 3H), 1.77–1.68 (m, 2H), 1.54–1.47 (m, 1H),
1.21–1.16 (m, 2H), 1.06 (s, 3H), 0.99 (s, 3H), 0.85 (t, J = 7.2 Hz, 3H); 13C-NMR (100 MHz, CDCl3)
δ (ppm)
199.7, 199.4, 167.7, 163.8, 137.2, 132.8, 128.6, 128.4, 128.1, 52.1, 42.7, 42.0, 35.0, 32.4, 31.6, 28.0, 27.9, 21.1,
20.9, 13.9; ESI-HRMS calcd. for C22H29O4 + H+ 357.2066, found 357.2064; 52% ee was determined by
HPLC on IC column, hexane/i-propanol (99/1), 1.0 mL/min, UV 254 nm, tmajor = 39.457 min, tminor
42.963 min; [α]D20 = +4.75◦ (c = 0.022, EtOH).
=
3.4. Preparation of 4H-Pyran via Dehydrating
Thionyl chloride (7.3
µL, 11.9 mg, 0.1 mmol) was added dropwise to a solution of 4a (28.6 mg,
0.1 mmol, 97% ee) and pyridine (14.1
µL, 15.8 mg, 0.2 mmol) in DCM (1.0 mL) at rt. After the reaction
completed, the solvent was removed under reduced pressure. The residue was subjected to silica gel
flash chromatography (EtOAc/petroleum ether) to provide 8 (19.3 mg, 72% yield) as a white solid.
1
2,7,7-Trimethyl-4-phenyl-4,6,7,8-tetrahydro-5H-chromen-5-one (
8
): H-NMR (400 MHz, CDCl3)
δ
(ppm)
7.29–7.24 (m, 4H), 7.17–7.13 (m, 1H), 4.90 (d, J = 4.8 Hz, 2H), 4.28 (d, J = 4.0 Hz, 1H), 2.39 (s, 2H), 2.22
(AB, JAB = 16.0 Hz, 1H), 2.16 (AB, JAB = 16.4 Hz, 1H), 1.88 (s, 3H), 1.09 (s, 3H), 1.03 (s, 3H); 13C-NMR
(100 MHz, CDCl3) δ (ppm) 197.3, 164.7, 145.8, 145.6, 128.2, 127.8, 126.2, 112.2, 104.5, 50.8, 41.4, 35.2, 31.9,
29.1, 27.6, 18.6; ESI-HRMS calcd. for C18H20O2 + H+ 269.1542, found 269.1541; 98% ee was determined
by HPLC on OD-H column, hexane/i-propanol (90/10), 1.0 mL/min, UV 254 nm, tminor = 5.880 min,
tmajor = 8.550 min; [α]20 = −182.7◦ (c = 0.024, EtOH).
D
3.5. Preparation of Fused Dihydrofuran via Stereoselective Oxidative Cyclization
After the initial Michael addition between 5a (49.9 mg, 0.24 mmol) and 1a (28.0 mg, 0.2 mmol) was
completed, the corresponding adduct was purified via flash column chromatography. Subsequently,
the mixture of PhIO (66 mg, 0.3 mmol) and Michael adduct (69.6 mg, 0.2 mmol) in H2O◦(1 mL)
was treated with Bu4NI (111 mg, 0.3 mmol). The reaction mixture was warmed up to 30 C and
allowed to stir for 16 h. The reaction was followed by TLC until completion. The reaction mixture was
successively quenched with saturated Na2S2O3 (25 mL) and extracted by dichloromethane (25 mL × 3).
The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (EtOAc/petroleum ether) to furnish 2,3-dihydrobenzofuran
61% yield as a colorless oil.
9 in
2-Benzoyl-6,6-dimethyl-3-phenyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (
9
) [61]. White solid; 61% yield
purified by flash column chromatography; 1H-NMR (400 MHz, CDCl3)
δ
(ppm) 7.82 (d, J = 7.2 Hz,
2H), 7.61 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.36 (t, J =7.2 Hz, 2H), 7.30–7.28 (m, 1H), 7.25–7.23
(m, 2H), 5.89 (d, J = 4.8 Hz, 1H), 4.40 (d, J = 4.0 Hz, 1H), 2.63 (ABX, JAB = 18.0 Hz, JAX = 1.6 Hz, 1H),
2.53 (AB, JAB = 17.6 Hz, 1H), 2.25 (AB, JAB = 16.4 Hz, 1H), 2.18 (AB, JAB = 16.4 Hz, 1H), 1.17 (s, 6H);
13C-NMR (100 MHz, CDCl3)
δ (ppm) 193.5, 192.8, 176.3, 141.2, 134.1, 133.1, 129.0, 128.89, 128.86, 127.6,
127.3, 115.1, 91.8, 51.1, 48.9, 37.6, 34.3, 29.0, 28.3; 93% ee was determined by HPLC on AD-H column,
hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, tminor = 10.843 min, tmajor = 15.107 min; [α]D20
−44.6◦ (c = 0.021, EtOH).
=

Molecules 2017, 22, 1096
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4. Conclusions
In summary, we have successfully developed an enantioselective Michael addition of cyclic
-diones to -unsaturated enones in the presence of quinine-based primary amine or squaramide.
β
α,β
These asymmetric processes displayed especially broad substrate generalities, and various cinnamones
and chalcones furnished the desired adducts in good to high yields. Although chalcones proved to be a
class of challenging acceptors in the precedent study [38], good reactivities and excellent enantiopurities
were achieved in the case of their Michael addition with cyclic β-diones via our protocol.
Supplementary Materials: The supplementary materials are available online.
Acknowledgments: This work is financially supported by the National Natural Science Foundation of China
(
No. 21402163) and the Fundamental Research Funds for the Central Universities of Southwest Minzu University
(No. 2016NGJPY02). Wang Qingqing gratefully acknowledges the Graduate Innovation Project of Southwest
Minzu University (No. CX2016SZ058).
Author Contributions: Q.W. and X.L. (Xuefeng Li) designed and planned the research. Q.W. and W.W. performed
the experiments and analyzed the data. L.Y., X.Y., X.L. (Xinying Li), and Z.Z. characterized the compounds.
X.L. (Xuefeng Li) prepared the manuscript for publication. All authors discussed the results and commented on
the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
Sibi, M.P.; Manyem, S. Enantioselective conjugate additions. Tetrahedron 2000, 56, 8033–8061. [CrossRef]
Christoffers, J.; Koripelly, G.; Rosiak, A.; Rössle, M. Recent advances in metal-catalyzed asymmetric conjugate
additions. Synthesis 2007, 9, 1279–1300. [CrossRef]
3.
4.
5.
Krause, N.; Hoffmann-Röder, A. Recent advances in catalytic enantioselective Michael additions. Synthesis
2001, 2, 171–196. [CrossRef]
Almas¸i, D.; Alonso, D.A.; Najera, C. Organocatalytic asymmetric conjugate additions. Tetrahedron Asymmetry
2007, 18, 299–365. [CrossRef]
Halland, N.; Hazell, R.G.; Jørgensen, K.A. Organocatalytic asymmetric conjugate addition of nitroalkanes to
α,β-unsaturated enones using novel imidazoline catalysts. J. Org. Chem. 2002, 67, 8331–8338. [CrossRef]
[PubMed]
6.
7.
Halland, N.; Aburel, P.S.; Jørgensen, K.A. Highly Enantioselective Organocatalytic Conjugate Addition of
Malonates toAcyclic
Halland, N.; Hansen, T.; Jørgensen, K.A. Organocatalytic Asymmetric Michael Reaction of Cyclic
1,3-Dicarbonyl Compounds and -Unsaturated Ketones—A Highly Atom-Economic Catalytic One-Step
α,β-Unsaturated Enones. Angew. Chem. Int. Ed. 2003, 42, 661–665. [CrossRef] [PubMed]
α,β
Formation of Optically Active Warfarin Anticoagulant. Angew. Chem. Int. Ed. 2003, 42, 4955–4957. [CrossRef]
[PubMed]
8.
9.
Halland, N.; Aburel, P.S.; Jørgensen, K.A. Highly Enantio- and Diastereoselective Organocatalytic
Asymmetric Domino Michael-Aldol Reaction of β-Ketoesters and α,β-Unsaturated Ketones. Angew. Chem.
Int. Ed. 2004, 43, 1272–1277.
Pulkkinen, J.; Aburel, P.S.; Halland, N.; Jørgensen, K.A. Highly Enantio-and Diastereoselective
Organocatalytic Domino Michael-Aldol Reactions of -Diketone and -Ketosulfone Nucleophiles with
α,β-Unsaturated Ketones. Adv. Synth. Catal. 2004, 346, 1077–1080. [CrossRef]
β
β
10. Prieto, A.; Halland, N.; Jørgensen, K.A. Novel imidazolidine-tetrazole organocatalyst for asymmetric
conjugate addition of nitroalkanes. Org. Lett. 2005, 7, 3897–3900. [CrossRef] [PubMed]
˙
11. Kwiatkowski, P.; Dudzinski, K.; Łyzwa, D. Effect of High Pressure on the Organocatalytic Asymmetric
Michael Reaction: Highly Enantioselective Synthesis of γ-Nitroketones with Quaternary Stereogenic Centers.
Org. Lett. 2011, 13, 3624–3627. [CrossRef] [PubMed]
12. Melchiorre, P. Cinchona-based Primary Amine Catalysis in the Asymmetric Functionalization of Carbonyl
Compounds. Angew. Chem. Int. Ed. 2012, 51, 9748–9770. [CrossRef] [PubMed]
13. Xu, L.-W.; Luo, J.; Lu, Y. Asymmetric catalysis with chiral primary amine-based organocatalysts.
Chem. Commun. 2009, 1807–1821. [CrossRef] [PubMed]

Molecules 2017, 22, 1096
15 of 17
14. Chen, Y.-C. The Development of AsymmetricPrimary Amine Catalysts Based on Cinchona Alkaloids. Synlett
2008, 2008, 1919–1930. [CrossRef]
15. Xie, J.W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.C.; Wu, Y.; Zhu, J.; Deng, J.G. Highly Asymmetric
Michael Addition to α,β-Unsaturated Ketones Catalyzed by 9-Amino-9-deoxyepiquinine. Angew. Chem.
Int. Ed. 2007, 46, 389–392. [CrossRef] [PubMed]
16. Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Organocatalytic asymmetric
Friedel-Crafts alkylation of indoles with simple
[CrossRef] [PubMed]
α,β-unsaturated ketones. Org. Lett. 2007, 9, 1403–1405.
17. Pesciaioli, F.; De Vincentiis, F.; Galzerano, P.; Bencivenni, G.; Bartoli, G.; Mazzanti, A.; Melchiorre, P.
Organocatalytic Asymmetric Aziridination of Enones. Angew. Chem. Int. Ed. 2008, 47, 8703–8706. [CrossRef]
[PubMed]
18. Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L. Catalytic Enantioselective Peroxidation of α,β-Unsaturated
Ketones. J. Am. Chem. Soc. 2008, 130, 8134–8135. [CrossRef] [PubMed]
19. McCooey, S.H.; Connon, S.J. Readily accessible 9-epi-amino cinchona alkaloid derivatives promote efficient,
highly enantioselective additions of aldehydes and ketones to nitroolefins. Org. Lett. 2007, 9, 599–602.
[CrossRef] [PubMed]
20. Calter, M.A.; Wang, J. Catalytic, asymmetric Michael reactions of cyclic diketones with β, γ-unsaturated
α-ketoesters. Org. Lett. 2009, 11, 2205–2208. [CrossRef] [PubMed]
21. Yu, C.; Zheng, F.; Ye, H.; Zhong, W. Enantioselective synthesis of functionalized 3,4-dihydropyran derivatives
organocatalyzed by a novel fluorinated-diphenylprolinolether. Tetrahedron 2009, 65, 10016–10021. [CrossRef]
22. Dong, Z.; Feng, J.; Fu, X.; Liu, X.; Lin, L.; Feng, X. Highly Enantioselective Conjugate Addition of Cyclic
0
Diketones to
β,
γ
-Unsaturated
α
-Ketoesters Catalyzed by an N,N -Dioxide-Cu(OTf)2 Complex. Chem. Eur. J.
2011, 17, 1118–1121. [CrossRef] [PubMed]
23. Zhang, G.; Wang, Y.; Zhang, W.; Xu, X.; Zhong, A.; Xu, D. Organocatalytic Michael Addition of
Naphthoquinone with
α,β-Unsaturated Ketones: Primary Amine Catalyzed Asymmetric Synthesis of
Lapachol Analogues. Eur. J. Org. Chem. 2011, 2011, 2142–2147. [CrossRef]
24. Tan, B.; Lu, Y.; Zeng, X.; Chua, P.J.; Zhong, G. Facile Domino Access to Chiral Bicyclo[3.2.1]octanes and
Discovery of a New Catalytic Activation Mode. Org. Lett. 2010, 12, 2682–2685. [CrossRef] [PubMed]
25. Tsakos, M.; Elsegood, M.R.J.; Kokotos, C.G. Organocatalytic asymmetric domino Michael-Henry reaction
for the synthesis of substituted bicyclo[3.2.1]octan-2-ones. Chem. Commun. 2013, 49, 2219–2221. [CrossRef]
[PubMed]
26. Franke, P.T.; Richter, B.; Jørgensen, K.A. Organocatalytic Asymmetric Synthesis of Functionalized
3,4-Dihydropyran Derivatives. Chem. Eur. J. 2008, 14, 6317–6321. [CrossRef] [PubMed]
27. Rueping, M.; Sugiono, E.; Merino, E. Asymmetric Organocatalysis: An Efficient Enantioselective Access to
Benzopyranes and Chromenes. Chem. Eur. J. 2008, 14, 6329–6332. [CrossRef] [PubMed]
28. Kim, H.; Yen, C.; Preston, P.; Chin, J. Substrate-directed stereoselectivity in vicinal diamine-catalyzed
synthesis of warfarin. Org. Lett. 2006, 8, 5239–5242. [CrossRef] [PubMed]
29. Xie, J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.-G.; Chen, Y.-C. Highly enantioselective Michael addition
of cyclic 1, 3-dicarbonyl compounds to
[PubMed]
α,β-unsaturated ketones. Org. Lett. 2007, 9, 413–415. [CrossRef]
30. Dong, Z.; Wang, L.; Chen, X.; Liu, X.; Lin, L.; Feng, X. Organocatalytic Enantioselective Michael Addition of
4-Hydroxycoumarin to -Unsaturated Ketones: A Simple Synthesis of Warfarin. Eur. J. Org. Chem. 2009
2009, 5192–5197. [CrossRef]
α
,
β
,
31. Kristensen, T.E.; Vestli, K.; Hansen, F.K.; Hansen, T. New Phenylglycine-Derived Primary Amine
Organocatalysts for the Preparation of Optically Active Warfarin. Eur. J. Org. Chem. 2009, 2009, 5185–5191.
[CrossRef]
32. Zhu, X.; Lin, A.; Shi, Y.; Guo, J.; Zhu, C.; Cheng, Y. Enantioselective Synthesis of Polycyclic Coumarin
Derivatives Catalyzed by an in Situ Formed Primary Amine-Imine Catalyst. Org. Lett. 2011, 13, 4382–4385.
[CrossRef] [PubMed]
33. Mei, R.-Q.; Xu, X.-Y.; Li, Y.-C.; Fu, J.-Y.; Huang, Q.-C.; Wang, L.-X. Highly effective and enantioselective
Michael addition of 4-hydroxycoumarin to
α,β-unsaturated ketones promoted by simple chiral primary
amine thiourea bifunctional catalysts. Tetrahedron Lett. 2011, 52, 1566–1568. [CrossRef]

Molecules 2017, 22, 1096
16 of 17
34. Ray, S.K.; Singh, P.K.; Molleti, N.; Singh, V.K. Enantioselective Synthesis of Coumarin Derivatives by
PYBOX-DIPH-Zn(II) Complex Catalyzed Michael Reaction. J. Org. Chem. 2012, 77, 8802–8808. [CrossRef]
[PubMed]
35. Dong, J.; Du, D.-M. Highly enantioselective synthesis of Warfarin and its analogs catalysed by primary
amine-phosphinamide bifunctional catalysts. Org. Biomol. Chem. 2012, 10, 8125–8131. [CrossRef] [PubMed]
˙
36. Is¸ık, M.; Akkoca, H.U.; Akhmedov, I.M.; Tanyeli, C. A bis-Lewis basic 2-aminoDMAP/prolinamide
organocatalyst for application to the enantioselective synthesis of Warfarin and derivatives. Tetrahedron
Asymmetry 2016, 27, 384–388. [CrossRef]
37. Liu, Y.; Liu, X.; Wang, M.; He, P.; Lin, L.; Feng, X. Enantioselective Synthesis of 3,4-Dihydropyran Derivatives
via Organocatalytic Michael Reaction of
[CrossRef] [PubMed]
α,β-Unsaturated Enones. J. Org. Chem. 2012, 77, 4136–4142.
38. Molleti, N.; Allu, S.; Ray, S.K.; Singh, V.K. Bifunctional chiral urea catalyzed highly enantioselective Michael
addition of cyclic 1,3-dicarbonyl compounds to 2-enoylpyridines. Tetrahedron Lett. 2013, 54, 3241–3244.
[CrossRef]
39. Ray, S.K.; Rout, S.; Singh, V.K. Enantioselective synthesis of 3, 4-dihydropyran derivatives via a Michael
addition reaction catalysed by chiral pybox–diph–Zn (II) complex. Org. Biomol. Chem. 2013, 11, 2412–2416.
[CrossRef] [PubMed]
40. Kumar, A.; Sharma, S.; Tripathi, V.D.; Maurya, R.A.; Srivastava, S.P.; Bhatia, G.; Tamrakar, A.K.; Srivastava, A.K.
Design and synthesis of 2,4-disubstituted polyhydroquinolines as prospective antihyperglycemic and lipid
modulating agents. Biorg. Med. Chem. 2010, 18, 4138–4148. [CrossRef] [PubMed]
41. Rodrigo, G.; Standen, N. ATP-sensitive potassium channels. Curr. Pharm. Des. 2005, 11, 1915–1940.
[CrossRef] [PubMed]
42. Li, X.; Cun, L.; Lian, C.; Zhong, L.; Chen, Y.; Liao, J.; Zhu, J.; Deng, J. Highly enantioselective Michael
addition of malononitrile to alpha,beta-unsaturated ketones. Org. Biomol. Chem. 2008, 6, 349–353. [CrossRef]
[PubMed]
43. Li, X.; Ma, Y.; Xing, Z.; Tang, N.; Zhu, J.; Deng, J. The asymmetric addition of malononitrile to α,β-unsaturated
ketones catalyzed by RuCl2[(R,R)-DPEN](PPh3)2 as the precatalyst. Tetrahedron Lett. 2014, 55, 3868–3872.
[CrossRef]
44. Zheng, Y.; Yao, Y.; Ye, L.; Shi, Z.; Li, X.; Zhao, Z.; Li, X. Highly enantioselective Michael addition of
malononitrile to
973–978. [CrossRef]
45. Liu, S.; Wang, Q.; Ye, L.; Shi, Z.; Zhao, Z.; Yang, X.; Ding, K.; Li, X. A general, highly enantioselective
Michael addition of nitroalkanes to -unsaturated enones catalyzed by 9-amino (9-deoxy)-epi-quinine:
α,β-unsaturated pyrazolamides catalyzed by a bifunctional thiourea. Tetrahedron 2016, 72,
α,β
A remarkable additive effect. Tetrahedron 2016, 72, 5115–5120. [CrossRef]
46. Chen, X.K.; Zheng, C.W.; Zhao, S.L.; Chai, Z.; Yang, Y.Q.; Zhao, G.; Cao, W.G. Highly Enantioselective
Michael Addition of Cyclic 1, 3-Dicarbonyl Compounds to β, γ-Unsaturated α-Keto Esters. Adv. Synth.
Catal. 2010, 352, 1648–1652. [CrossRef]
47. Wang, Y.F.; Wang, K.; Zhang, W.; Zhang, B.B.; Zhang, C.X.; Xu, D.Q. Enantioselective Asymmetric Michael
Addition of Cyclic Diketones to
[CrossRef]
β, γ-Unsaturated α-Keto Esters. Eur. J. Org. Chem. 2012, 2012, 3691–3696.
48. Zhang, G.; Zhang, Y.; Yan, J.; Chen, R.; Wang, S.; Ma, Y.; Wang, R. One-Pot Enantioselective Synthesis of
Functionalized Pyranocoumarins and 2-Amino-4H-chromenes: Discovery of a Type of Potent Antibacterial
Agent. J. Org. Chem. 2012, 77, 878–888. [CrossRef] [PubMed]
49. Gao, Y.; Du, D.-M. Enantioselective synthesis of 2-amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitriles
using squaramide as the catalyst. Tetrahedron Asymmetry 2012, 23, 1343–1349. [CrossRef]
50. Feng, X.; Zhou, Z.; Zhou, R.; Zhou, Q.-Q.; Dong, L.; Chen, Y.-C. Stereodivergence in Amine-Catalyzed
Regioselective [4 + 2] Cycloadditions of β-Substituted Cyclic Enones and Polyconjugated Malononitriles.
J. Am. Chem. Soc. 2012, 134, 19942–19947. [CrossRef] [PubMed]
51. Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Highly enantioselective conjugate addition of nitromethane to
chalcones using bifunctional cinchona organocatalysts. Org. Lett. 2005, 7, 1967–1969. [CrossRef] [PubMed]
52. Rueping, M.; Parra, A.; Uria, U.; Besselievre, F.; Merino, E. Catalytic asymmetric domino Michael addition–
alkylation reaction: Enantioselective synthesis of dihydrofurans. Org. Lett. 2010, 12, 5680–5683. [CrossRef]
[PubMed]

Molecules 2017, 22, 1096
17 of 17
53. Wang, G.-W.; Lu, Q.-Q.; Xia, J.-J. Three Types of Products Obtained Unexpectedly from the Reaction of
Dimedone with Chalcones. Eur. J. Org. Chem. 2011, 2011, 4429–4438. [CrossRef]
54. Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K.A. Squaramides: Bridging from Molecular Recognition to
Bifunctional Organocatalysis. Chem. Eur. J. 2011, 17, 6890–6899. [CrossRef] [PubMed]
55. Tsakos, M.; Kokotos, C.G. Primary and secondary amine-(thio)ureas and squaramides and their applications
in asymmetric organocatalysis. Tetrahedron 2013, 69, 10199–10222. [CrossRef]
56. Wang, J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.; Wang, W. Organocatalytic enantioselective conjugate
additions to enones. J. Am. Chem. Soc. 2006, 128, 12652–12653. [CrossRef] [PubMed]
57. Ye, Y.; Wang, L.; Fan, R. Aqueous iodine (III)-mediated stereoselective oxidative cyclization for the synthesis
of functionalized fused dihydrofuran derivatives. J. Org. Chem. 2010, 75, 1760–1763. [CrossRef] [PubMed]
58. Yang, W.; Jia, Y.; Du, D.-M. Squaramide-catalyzed enantioselective Michael addition of malononitrile to
chalcones. Org. Biomol. Chem. 2012, 10, 332–338. [CrossRef] [PubMed]
59. Armarego, W.L.F.; Chai, C. Purification of Laboratory Chemicals, 7th ed.; Butterworth-Heinemann: Oxford, UK,
2012.
60. Jiang, L.; Wang, B.; Li, R.-R.; Shen, S.; Yu, H.-W.; Ye, L.-D. Catalytic promiscuity of Escherichia coli BioH
esterase: Application in the synthesis of 3,4-dihydropyran derivatives. Process Biochem. 2014, 49, 1135–1138.
[CrossRef]
61. Ye, Y.; Wang, L.; Fan, R. Aqueous Iodine(III)-Mediated Stereoselective Oxidative Cyclization for the Synthesis
of Functionalized Fused Dihydrofuran Derivatives. J. Org. Chem. 2010, 75, 1760–1763. [CrossRef] [PubMed]
Sample Availability: Samples of the compounds 4, 6, 8 and 9 are available from the authors.
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