Azetidine-Derived Dinuclear Zinc-Catalyzed Asymmetric Conjugate Addition of Bioactive Heterocycles to β,γ-Unsaturated α-Keto esters

Article abstract of DOI:10.1021/acs.joc.9b02046

A general AzePhenol dinuclear zinc catalytic system has been successfully developed and applied into the asymmetric Michael addition of 4-hydroxyl pyrones and 4-hydroxycoumarins to β,γ-unsaturated α-keto esters. Excellent yields (up to 99%) and high enantioselectivities (up to 94% ee) are obtained for a wide range of substrates under mild conditions in the absence of additives. This bimetallic catalytic approach represents a new and effective asymmetric synthetic protocol to access a variety of bioactive compounds with pharmacological interest. The possible mechanism is proposed to explain the origin of the asymmetric induction.

Full text of DOI:10.1021/acs.joc.9b02046

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Article
Azetidine Derived Dinuclear Zinc Catalyzed Asymmetric Conjugate
Addition of Bioactive Heterocycles to #,#-Unsaturated #-Ketoesters
Shanshan Liu, Zhi-Hua Xu, Xi Wang, Hao-Ran Zhu, and Min-Can Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02046 • Publication Date (Web): 19 Sep 2019
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Azetidine Derived Dinuclear Zinc Catalyzed Asymmetric
Conjugate Addition of Bioactive Heterocycles to
β,γ-Unsaturated α-Ketoesters
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Shanshan Liu,† Zhi-Hua Xu,‡ Xi Wang,‡ Hao-Ran Zhu,‡ Min-Can Wang*,‡
†Shaanxi Key Laboratory of Chemical Additives for Industry, College of Chemistry and Chemical
Engineering, Shaanxi University of Science and Technology, 6 Xuefu Road, Weiyang District, Xi’an,
Shaanxi 710021, People’s Republic of China
‡College of Chemistry and Molecular Engineering, Zhengzhou University, 100 Science Avenue,
Zhengzhou, Henan 450001, People’s Republic of China
E-mail: wangmincan@zzu.edu.cn
Abstract:
A general AzePhenol dinuclear zinc catalytic system has successfully developed and
applied into the asymmetric Michael addition of 4-hydroxyl pyrones and 4-hydroxy
coumarins to β,γ-unsaturated α-keto esters. Excellent yields (up to 99%) and high
enantioselectivities (up to 94% ee) are obtained for a wide range of substrates under
mild conditions in absence of additives. This bimetallic catalytic approach represents
a new and effective asymmetric synthetic protocol to access a variety of bioactive
compounds with pharmacological interest. The possible mechanism is proposed to
explain the origin of the asymmetric induction.
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Introduction
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Coumarin and pyranone moieties have been well recognized as the key structural
scaffolds in several bioactive compounds.1 In particular, their derivatives have been
established as potential antimalarial, anticoagulant, and anti-HIV agents.2 As a
consequence of the structural importance, methods for the synthesis of this kind of
heterocycles have gained considerable attention. The direct asymmetric Michael
addition of coumarins/pyranones to α,β-unsaturated carbonyl compound is
considered as one of the most convenient approaches to furnish the chiral drug,
warfarin, which is an effective anticoagulant for preventing thrombosis and embolism.3
As a class of activated α,β-unsaturated carbonyl systems, β,γ-unsaturated
α-ketoesters are very attractive Michael acceptors due to their high reactivity and their
potential to transform into a range of different functionalities. Furthermore, the α-oxo
ester moiety can form multiple effective associations with chiral catalysts.
Numerous
catalytic
strategies
for
enantioselective
modifications
of
coumarins/pyranones have been developed over the past decades. Among them,
organocatalytic process has proved to be efficient.4 As a subfield of organocatalysis,
bifunctional catalyst has emerged as an especially important tool for this
transformation. The previous work has disclosed the highly enantioselective Michael
addition of 4-hydroxycoumarins and β,γ unsaturated α-ketoesters catalyzed by an
array of chiral squaramide and thiourea-derived organocatalysts.5−13 The privilege of
bifunctional systems probably associates with the compatibility for simultaneous
activation of both the electrophile and the nucleophile. In contrast, the application of
metal catalyst in enantioselective Michael addition of coumarins/pyranones appears
scarce. In 2003, Jørgensen and co-workers reported the first transition metal
catalyzed asymmetric Michael addition of 4-hydroxycoumarins to β,γ-unsaturated
α-ketoesters by using chiral bisoxazoline-copper(II) complexes,14 moderate to good
enantioselectivities (up to 86% ee) were obtained in the presence of diethyl ether in
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the reflux condition. While a significant decrease both in yield and enantioselectivity
was observed under ambient condition and using other solvents, which limited the
application of this approach in practical utility. Subsequently, N,N’-dioxide–nickel(II)
complex was employed as a metal catalyst for this type of reaction by the Feng group
to afford good enantioselectivities ranging from 85% to 90% ee in the presence of 4Å
MS (molecular sieve).15 Despite the achievements to date, the metal catalytic system
towards this transformation still have some drawbacks in terms of general limitation to
mononuclear metallic catalyst, relatively lower stereoselectivity, and the requirements
of extra additives. Additionally, enantioselective manipulation of pyrones via metal
catalysis has not been well documented. Therefore, the development of novel and
effective activation strategies for the metal catalytic process to access a wide range of
bioactive heterocycles with coumarin and pyranone structure units is highly desirable
in this area.
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In recent years, our group has developed a dinuclear zinc-AzePhenol catalyst and it
has demonstrated remarkable catalytic efficiency and stereoselectivities in a number
of catalytic enantioselective transformations.16 Enlightened by this, we envisaged that
coumarins/pyrones and β,γ-unsaturated α-ketoesters might be suitably activated and
orientated by our dual Lewis acid/Lewis base functionality, and it is possible that the
azetidine ring skeleton provides the appropriate sterically hindered microenvironment
to promote the stereoselectivity of the target Michael addition. Herein, we report the
successful application of a trifluoromethyl substituted dinuclear zinc-AzePhenol in the
asymmetric Michael addition of 4-hydroxycoumarins and a 4-hydroxypyrones to
β,γ-unsaturated α-ketoesters. The combination of broad substrates scope, high
enantioselectivities, and mild conditions, represent an efficient metallic catalytic
approach for the synthesis of bioactive warfarin analogues.
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Results and Discussion
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Figure 1. Chiral Ligands Candidates
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Table 1. Optimization of Reaction Conditionsa
Entry
1
L*
L1
L2
L3
L4
L5
L6
L7
L8
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
Cat.
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnMe2
MgBu2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
Temp. (oC)
Additive
-
Yield (%)b ee (%)c
rt
rt
82
86
80
82
2
3
rt
89
63
4
rt
83
81
5
rt
81
71
6
rt
68
60
7
rt
89(87d)
86(85d)
8
rt
74
70
9
rt
92
82
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17
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20
21
22
23
rt
94
43
rt
68
84
CHCl3
rt
91
82
CH3CN
1,4-dioxane
DCE
rt
78
75
rt
57
62
rt
74
71
benzene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
rt
76
78
rt
96
89
-20
0
81
81
95
85
40
rt
89
78
4Å MS (25 mg)
Et3N
92
84
rt
86
56
rt
Na2CO3
K2CO3
89
84
24
rt
83
83
a
Unless noted, all reactions were conducted with 1 (0.125 mmol), 2a (0.125 mmol), and
b
c
catalyst (20 mol%) in toluene (1.5 mL) under N2 at room temperature (rt). Isolated yield.
Determined by HPLC analysis, the absolute configurations were assigned by comparison to
literature values. d10 mol% catalyst was used.
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Initially, the addition of 4-hydroxycoumarin 1 to the α-ketoester 2a was employed as a
model reaction to explore the effect of the various chiral dinuclear zinc catalysts.
Notably, an equilibrium between Michael adduct 3a and cyclic hemiketal 3a’ was
observed in NMR, which existed predominantly in their open (keto-3a) form. However,
The equilibrium was sufficiently rapid that only two peaks from enantiomers were
detected during chiral HPLC analysis, which was in accordance with earlier
observations by Jørgensen for similar compounds.14 A series of chiral ligands were
prepared in our laboratory (Figure 1, L1−L8).17 Our previous work showed the
reaction was ineffective by using Trost’s ligand in THF,18 therefore the preliminary
study was conducted in DCM. As shown in Table 1, the results revealed that good
yield and moderate ee were observed in the presence of L1 (entry 1). However,
additional efforts to modulate the electronic and steric effect on aryl framework did not
increase the enantiomeric excess significantly (entries 2−5). To our delight, replacing
the AzePhenol L1 by L6, the enantioseletivity was improved (entry 6). Encouraged by
this result, the different substitution on aryl ring of L6 was investigated, the
electron-withdrawing trifluoromethyl substitution was superior to electron-donating
methyl substitution with 87% yields and 85% ee, which probably owing to the effective
activation of α-ketoester by the increased electrophility of zinc catalyst (entry 7).
Accordingly, ligand L7 was then used for further reaction conditions screening. The
reaction was found to be dependent on metal counterion. A dramatic diminishment in
both yield and enantioselectivity was observed when alkali magnesium counterion
was employed (entry 10). It was worth to mention that the high yield and
enantioselectivity were maintained with a reduced catalyst loading from 20 to 10
mol% (entry 7). The solvent effect was subsequent to be assessed. In general, the
reaction in polar solvent led to a reduction of the asymmetric induction compared to
that in non-polar solvent. Toluene was identified as the choice of solvent to deliver the
adducts in excellent enantiomeric excess. Further screening of the reaction
temperature and additives for stereoselectivity enhancement was conducted.
Gratifyingly, the reaction proceeded smoothly at room temperature in the absence of
additives without any detriment of yield as well as enantiomeric excess, 96% yield and
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89% ee were achieved in the optimal conditions, which exhibited the effective and
convenience of our approach (entry 17).
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Table 2. Variation of the α-Ketoesters for the Asymmetric Conjugate Addition with
Coumarin Catalyzed by Dinuclear Zinc Catalysta
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Entry
1
2
2a
2b
2c
2d
2e
2f
Ar
R
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
t (h)
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Product
3a
Yield (%)b
96
ee (%)c
89
C6H5
2
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
3-ClC6H4
3-BrC6H4
3-MeC6H4
3-OMeC6H4
2-ClC6H4
2-BrC6H4
2-naphthyl
2-thienyl
C6H5
3b
3c
76
92
3
70
93
4
3d
3e
86
90
5
99
92
6
3f
70
83
7
2g
2h
2i
3g
3h
3i
78
84
8
90
92
9
99
88
10
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12
13
14
15
16
2j
3j
85
86
2k
2l
3k
84
91
3l
72
92
2m
2n
2o
2p
3m
3n
3o
3p
63
83
96
94
C6H5
i-Pr
t-Bu
98
93
C6H5
96
94
a. Unless noted, all reactions were conducted with 1 (0.125 mmol), 2a−2p (0.125 mmol), and
catalyst (10 mol%) in toluene (1.5 mL) under N2 at room temperature. b. Isolated yield. c.
Determined by HPLC analysis. The absolute configurations were assigned by comparison to
literature values. In all cases, the product chromatograms were compared against a known
racemic mixture. The absolute configuration of 3a was assigned by comparison of optical
rotation and chiral HPLC traces with the literature.14 The other products were tentatively
assigned by analogy.
Under the optimized conditions, we explored the generality of this reaction with a
spectrum of β,γ-unsaturated α-ketoesters. The results are summarized in Table 2.
The similar high level of enantioselectivities were achieved by employing a wide array
of aromatic β,γ-unsaturated α-oxoesters. It appears that the electronic nature and
position on aryl substitution had negligible effects on either the yields or
stereoselectivities (entries 2−11). However, the methoxyl and thienyl substituents on
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phenyl ring afforded slightly lower enantiomeric excess, which might be attributed to
the competitive coordination interaction between the methoxyl or thienyl group and
the catalyst (entries 9 and 13). Notably, the reactivity was sensitive to the electronic
property of the substituents on the phenyl ring, the electron-deficient halogen
substituted α-ketoesters were outperformed by the electron-rich methyl substituent to
deliver the products in lower yields (entries 2−6). Gratifyingly, the β,γ-unsaturated
α-ketoesters bearing various ester groups provided warfarin analogues in nearly
quantitative yields and excellent enantioselectivities, irrespective of the steric property
of the ester substitution (entries 14−16).
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Table 3. Variation of the α-Ketoesters for the Asymmetric Conjugate Addition with Pyrones
Catalyzed by Dinuclear Zinc Catalysta
Entry
1
2
2a
2b
2c
2d
2e
2f
Ar
R
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
t (h)
15
15
18
15
15
24
15
15
15
18
12
15
20
15
15
15
Product
5a
Yield (%)b
96
ee (%)c
83
C6H5
2
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
3-ClC6H4
3-BrC6H4
3-MeC6H4
3-OMeC6H4
2-ClC6H4
2-BrC6H4
2-naphthyl
2-thienyl
C6H5
5b
5c
84
75
3
98
81
4
5d
5e
86
76
5
92
88
6
5f
95
75
7
2g
2h
2i
5g
5h
5i
81
84
8
95
90
9
92
80
10
11
12
13
14
15
16
2j
5j
68
60
2k
2l
5k
68
72
5l
93
80
2m
2n
2o
2p
5m
5n
5o
5p
94
78
94
81
C6H5
i-Pr
t-Bu
86
80
C6H5
91
76
a. Unless otherwise noted, all reactions were conducted with 4 (0.125 mmol), 2a, 2b, 2d, 2e,
o
2g−2j, 2l−2p (0.125 mmol), and catalyst (10 mol%) in DCM (1.5 mL) under N2 at 0 C. b.
Isolated yield. c. Determined by chiral HPLC. The absolute configurations were assigned by
comparison to literature values. In all cases, the product chromatograms were compared
against a known racemic mixture. The absolute configuration of 4aa was assigned by
comparison of optical rotation and chiral HPLC traces with the literature.14
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4-Hydroxyl pyrones are less nucleophilic compared to 4-hydroxy coumarins, which led
to the lower reactivity of Michael-addition. Consequently, only 72% yield and 70% ee
was observed in this case. High yield and enantioselectivity was restored after a
screening of reaction conditions (see the Supporting Information for detail), 96% yield
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o
and 83% ee was obtained in DCM and 0 C (Table 3, entry 1). With the optimal
reaction conditions, various pyrones were prepared in high yields and good
enantioselectivities. Satisfyingly, the β,γ-unsaturated α-ketoesters bearing naphthyl
and thienyl substituents (5l and 5m), respectively, were compatible in this reaction.
The electron-donating methyl substituents on the phenyl ring (5e and 5h) had a
pronounced effect on both the asymmetric induction and the reactivity compared to
the electron-withdrawing halogen group (5b, 5c, 5d and 5f), since the α-ketoesters
bearing electron-rich substituents would facilitate the electrons shift to carbonyl group,
which made it more easier to coordinate with chiral zinc catalyst. In addition, the steric
effect was obvious as well, a diminishment of ee was observed when bulkyl tert-butyl
ester group 5p was used. It was found that ortho- halogen substitution 5j or 5k
resulted in a reduced yield and ee, which probably was attributed to the steric effect
and thus led to a competing 1,2-addition process (entry 8).
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Scheme 1. Proposed Catalytic Cycle of the Asymmetric Conjugate Addition
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To explain the high levels of stereoselectivity, we propose the following plausible
mechanism based on bifunctional activation strategy. As illustrated in Scheme 1, the
deprotonation occurred by the other Brønsted basic zinc nucleus to form the zinc
enolate B. On the other hand, the β,γ-unsaturated α-ketoester was activated and
oriented by the Lewis acidic zinc nucleus via bidentate coordination of the
1,2-dicarbonyl moiety to form the intermediate C. The benzo-fused conjugation
system of 4-hydroxy coumarin facilitates the deprotonation step, which account for the
observed higher enantioselectivities compared to 4-hydroxyl pyrones. Ultimately, the
well-induced transition state promotes the nucleophile 1 to attack the oxoester 2a
from the Re face and to justify the observed stereochemical outcome.
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Conclusion
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In conclusion, we have developed a dinuclear zinc catalyzed enantioselective Michael
addition of 4-hydroxyl pyrones and 4-hydroxy coumarins to β,γ-unsaturated
α-ketoesters. This catalytic method allows access to a series of optically active
coumarin and pyrone derivatives with pharmaceutical interest. Compared to the
previous metallic process, the higher yields and enantioselectivities can be achieved
under mild reaction conditions and in the absence of additives. Further applications of
the dinuclear metal catalytic system for the preparation of valuable chiral products are
currently underway.
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Experimental Section
General Remarks. All reactions were performed in flame-dried glassware using
conventional Schlenk techniques under a static pressure of argon. All starting
materials, ligands, and racemic products were prepared according to known
procedures. Liquids and solutions were transferred with (micro)syringes. Solvents
were purified and dried following standard procedures. Technical grade solvents for
extraction and chromatography were distilled prior to use. Analytical thin-layer
chromatography (TLC) and flash column chromatography were performed on silica
gel using the indicated solvents. 1H, 13C{1H}, and 19F{1H} NMR spectra were recorded
in CDCl3 on Bruker DPX 400 (400 MHz). Chemical shifts are reported in parts per
million (ppm) downfield from tetramethylsilane and are referenced to the residual
solvent resonance as the internal standard (δ = 7.26 ppm for 1H and δ = 77.16 ppm for
13C{1H}). Data are reported as follows: chemical shift, multiplicity (br s = broad singlet,
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz)
and integration. Optical rotations were recorded on a Perkin-Elmer 341 polarimeter.
Infrared (IR) spectra were recorded on a Thermo Nicolet IR 200 spectrophotometer
and reported in wavenumbers (cm–1). High resolution mass spectrometry (HRMS)
analyses were performed on an Agilent LC-MSAD-Trap-XCT instrument. Melting
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points (m.p.) were determined with a Stuart SMP20 apparatus and are not corrected.
The ee value determination was carried out using chiral HPLC on a Chiralcel ID, AD-H,
or OD-H Column (for all the columns: 4.6 mmφ × 250 mm, Daicel Chemical Ind., LTD,
Japan) combined with a JASCO model PU-1580 intelligent HPLC pump and a JASCO
model UV-1575 intelligent UV-vis detector (254nm).
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General Procedure for the Catalytic Asymmetric Conjugate Addition of
Bioactive Heterocycles to β,γ-Unsaturated α-Ketoesters: In a flame-dried 10 mL
Schlenk tube equipped with a magnetic stir bar, chiral ligand L7 (0.00625 mmol, 5
mol%) in dry toluene or DCM (0.8 mL) is added under nitrogen. Then a solution of
dimethylzinc (0.0105 mL, 1.2 mol/L in hexane, 0.0125 mmol, 10 mol%) is added
o
through a micro syringe to the system at 0 C and the resulting mixture is stirred at
o
room temperature for 30 min. Afterwards, cooling the system to 0 C again and
4-hydroxy coumarins 1 or 4-hydroxyl pyrones 4 (0.125 mmol, 1.0 equiv.),
β,γ-unsaturated α-keto esters (2a–2p, 0.125 mmol, 1.0 equiv.) and dry toluene or
DCM (0.7 mL) are added successively. The solution is stirred at indicated temperature
for indicated reaction time. After complete consumption of the imine starting material,
as monitored by TLC analysis, saturated NH4Cl (2.0 mL) is added and the mixture is
extracted with ethyl acetate (3 × 10 mL). The combined organic phases are washed
with brine (5.0 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent
under reduced pressure, purification of the residue by column chromatography on
silica gel using mixtures of petroleum ether and ethyl acetate as eluents affords the
analytically pure title compounds.
(R)-Methyl 4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-4-phenylbutanoate14 (3a):
Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to afford a white
20
solid, 42.4 mg, 96% yield, exists in an equilibrium with cyclic hemiketal 3a’; [α]D
=
-24.6 (c 1.0, CHCl3); HPLC (Chiralpak ID column, hexane/i-PrOH = 70/30, flow rate =
2.0 mL/min, λ = 254 nm; Retention time: tr(major) = 5.33 min, tr(minor) = 7.20 min,
1
89% ee); H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 7.8 Hz, 0.3H), 7.78 (d, J = 7.8
Hz, 0.7H), 7.53 (dd, J = 17.3, 8.8 Hz, 1H), 7.26 (dt, J = 17.1, 6.5 Hz, 7H), 5.00 (s,
0.7H), 4.66 (s, 0.3H), 4.33 (d, J = 6.4 Hz, 0.3H), 4.19 (t, J = 9.0 Hz, 0.7H), 3.86 (d, J =
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27.9 Hz, 3H), 2.78 (dd, J = 14.2, 7.4 Hz, 0.3H), 2.53 (dd, J = 14.3, 3.0 Hz, 0.3H), 2.45
(d, J = 8.9 Hz, 1.4H) ppm. HRMS (ESI) exact mass for [M+Na]+ (C20H16O6Na): calcd
m/z 375.0839, found: 375.0838; IR (neat) ṽ/cm–1 = 3440, 3132, 2854, 1741, 1626,
1400, 1159, 1091, 827, 766, 699, 595; m.p.: 170 – 172 oC.
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(R)-Methyl 4-(4-fluorophenyl)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxobuta-
noate6 (3b): Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to
afford a white solid, 35.2 mg, 76% yield, exists in an equilibrium with cyclic hemiketal
3b’; HPLC (Chiralpak AD-H, hexane/i-PrOH = 80/20, flow rate = 0.5 mL/min, λ = 254
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nm; Retention time: tr(major) = 16.02 min, tr(minor) = 34.20 min, 92% ee); [α]D
=
1
-10.2 (c 0.3, in CHCl3); H NMR (400 MHz, CDCl3): δ = 7.88 – 7.76 (m, 1H), 7.64 –
7.53 (m, 1H), 7.40 – 7.27 (m, 4H), 7.23 – 7.16 (m, 2H), 4.32 (dd, J = 7.3, 2.6 Hz, 0.3H),
4.20 (dd, J = 11.1, 7.2 Hz, 0.7H), 3.97 – 3.90 (m, 3H), 2.81 (dd, J = 14.3, 7.6 Hz, 0.3H),
2.53 – 2.38 (m, 1.7H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ = 169.0, 168.9, 162.8,
161.7, 159.5 (d, J = 210 Hz), 159.4 (d, J = 260 Hz),152.8, 138.0, 137.3, 132.3, 132.1,
129.0 (d, J = 10 Hz), 128.5 (d, J = 11 Hz), 124.1, 123.9, 122.9, 116.7, 116.6, 115.5 (d,
J = 21 Hz), 115.1 (d, J = 21 Hz), 104.6, 102.8, 96.0, 95.5, 54.1, 54.0, 38.1, 35.5, 33.9,
33.1 ppm; 19F{1H} NMR (376 MHz, CDCl3): δ = -116.2, -116.5 ppm; HRMS (ESI) exact
mass for [M+H]+ (C20H16FO6): calcd m/z 371.0925, found: 371.0926; IR (neat) ṽ/cm–1
= 3421, 3132, 2923, 1746, 1715, 1698, 1624, 1399, 1224, 760; m.p.: 195 – 197 oC.
(R)-Methyl 4-(4-chlorophenyl)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxobuta-
noate6 (3c): Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to
afford a white solid, 33.8 mg, 70% yield, exists in an equilibrium with cyclic hemiketal
3c’; HPLC (Chiralpak AD-H, hexane/i-PrOH = 80/20, flow rate = 0.5 mL/min, λ = 254
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nm; Retention time: tr(major) = 16.27 min, tr(minor) = 36.27 min, 93% ee); [α]D
=
-27.7 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3): δ = 7.88 – 7.76 (m, 1H), 7.64 – 7.53
(m, 1H), 7.41 – 7.27 (m, 4H), 7.23 – 7.18 (m, 2H), 4.32 (dd, J = 7.3, 2.6 Hz, 0.3H),
4.20 (dd, J = 11.1, 7.2 Hz, 0.7H), 3.97 – 3.91 (m, 3H), 2.81 (dd, J = 14.3, 7.6 Hz, 0.4H),
2.53 – 2.37 (m, 1.6H) ppm; HRMS (ESI) exact mass for [M+H]+ (C20H16ClO6): calcd
m/z 387.0630, found: 387.0631; IR (neat) ṽ/cm–1 = 3184, 2954, 2926, 2853, 1750,
1716, 1697, 1625, 1437, 1111, 1108, 759; m.p.: 191 – 193 oC.
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(R)-Methyl 4-(4-bromophenyl)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxobuta-
noate6 (3d): Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to
afford a white solid, 46.2 mg, 86% yield, exists in an equilibrium with cyclic hemiketal
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3d’; HPLC (Chiralpak ID column, hexane/i-PrOH = 70/30, flow rate = 2.0 mL/min, λ =
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254 nm; Retention time: tr(major) = 4.79 min, tr(minor) = 7.66 min, 90% ee); [α]D
=
-28.6 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3): δ = 7.88 – 7.76 (m, 1H), 7.63 – 7.52
(m, 1H), 7.46 – 7.27 (m, 4H), 7.18 – 7.12 (m, 2H), 4.29 (dd, J = 7.3, 2.7 Hz, 0.3H),
4.22 – 4.11 (m, 0.7H), 3.92 (d, J = 12.1 Hz, 3H), 2.80 (dd, J = 14.3, 7.5 Hz, 0.3H), 2.55
– 2.33 (m, 1.7H) ppm; HRMS (ESI) exact mass for [M+H]+ (C20H16BrO6): calcd m/z
431.0125, found: 431.0126; IR (neat) ṽ/cm–1 = 3420, 3143, 1715, 1696, 1683, 1624,
1488, 1400, 1111, 759; m.p.: 197 – 199 oC.
(R)-Methyl 4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-4-(p-tolyl)butanoate6 (3e):
Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to afford a white
solid, 45.3 mg, 99% yield, exists in an equilibrium with cyclic hemiketal 3e’; HPLC
(Chiralpak OD-H, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm;
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Retention time: tr(major) = 7.30 min, tr(minor) = 13.59 min, 92% ee); [α]D = -20.3 (c
0.3, CHCl3); 1H NMR (400 MHz, CDCl3): δ = 7.90 – 7.76 (m, 1H), 7.71 – 7.43 (m, 2H),
7.29 (dd, J = 12.0, 7.5 Hz, 1H), 7.13 (d, J = 11.1 Hz, 4H), 4.32 (s, 0.3H), 4.19 (t, J =
8.9 Hz, 0.7H), 3.89 (s, 3H), 2.52 (d, J = 23.5 Hz, 0.3H), 2.51 (dd, J = 29.3, 11.3 Hz,
1.7H), 2.34 (s, 3H) ppm; HRMS (ESI) exact mass for [M+H]+ (C21H19O6): calcd m/z
367.1176, found: 367.1174; IR (neat) ṽ/cm–1 = 3420, 3133, 2956, 2854, 1731, 1715,
1625, 1574, 1491, 1455, 1399, 1111, 759; m.p.: 171 – 173 oC.
(R)-Methyl 4-(3-chlorophenyl)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxobuta-
noate6 (3f): Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to
afford a white solid, 33.8 mg, 70% yield, exists in an equilibrium with cyclic hemiketal
3f’; HPLC (Chiralpak AD-H, hexane/i-PrOH = 80/20, flow rate = 0.5 mL/min, λ = 254
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nm; Retention time: tr(major) = 13.49 min, tr(minor) = 26.75 min, 83% ee); [α]D
=
-19.6 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3): δ = 7.89 – 7.75 (m, 1H), 7.67 – 7.52
(m, 1H), 7.44 – 7.12 (m, 6H), 4.31 (dd, J = 7.2, 2.5 Hz, 0.3H), 4.20 (dd, J = 11.0, 7.2
Hz, 0.7H), 3.92 (d, J = 11.3 Hz, 3H), 2.81 (dd, J = 14.3, 7.5 Hz, 0.3H), 2.60 – 2.38 (m,
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1.7H) ppm; HRMS (ESI) exact mass for [M+H]+ (C20H16ClO6): calcd m/z 387.0630,
found: 387.0631; IR (neat) ṽ/cm–1 = 3339, 3016, 2954, 2852, 1753, 1715, 1626, 1574,
1327, 1112, 760, 736; m.p.: 140 – 142 oC.
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(R)-Methyl 4-(3-bromophenyl)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxobuta-
noate15 (3g): Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to
afford a white solid, 41.9 mg, 78% yield, exists in an equilibrium with cyclic hemiketal
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3g’; HPLC (Chiralpak AD-H, hexane/i-PrOH = 80/20, flow rate = 0.5 mL/min, λ = 254
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nm; Retention time: tr(major) = 15.99 min, tr(minor) = 29.50 min, 84% ee); [α]D
=
-22.8 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 7.2 Hz, 1H), 7.54 (dd,
J = 23.0, 17.0 Hz, 1H), 7.42 – 7.29 (m, 4H), 7.20 (s, 2H), 4.29 (s, 0.27H), 4.13 (q, J =
7.1 Hz, 0.73H), 3.89 (s, 3H), 2.78 (s, 0.3H), 2.43 (dd, J = 21.0, 9.8 Hz, 1.7H) ppm;
HRMS (ESI) exact mass for [M+H]+ (C20H16BrO6): calcd m/z 431.0125, found:
431.0126; IR (neat) ṽ/cm–1 = 3419, 3143, 2953, 2953, 2924, 1747, 1714, 1624, 1573,
1398, 1165, 1111, 759; m.p.: 130 – 132 oC.
(R)-Methyl
4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-4-(m-tolyl)butanoate15
(3h): Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to afford a
white solid 41.2 mg, 90% yield, exists in an equilibrium with cyclic hemiketal 3h’;
HPLC (Chiralpak OD-H, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm;
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Retention time: tr(major) = 8.06 min, tr(minor) = 16.06 min, 92% ee); [α]D = -13.2 (c
1
0.2, CHCl3); H NMR (400 MHz, CDCl3) δ 7.89 – 7.79 (m, 1H), 7.57 (dddd, J = 17.4,
8.6, 7.4, 1.6 Hz, 1H), 7.42 – 7.29 (m, 2H), 7.25 – 7.03 (m, 4H), 4.18 (dd, J = 16.1, 7.5
Hz, 0.67H), 4.09 – 3.99 (m, 0.33H), 3.95 – 3.85 (m, 3H), 2.60 – 2.53 (m, 0.33H), 2.49
– 2.44 (m, 1.67H), 2.33 (d, J = 4.3 Hz, 3H) ppm; HRMS (ESI) exact mass for [M+H]+
(C21H19O6): calcd m/z 367.1176, found: 367.1175; IR (neat) ṽ/cm–1 = 3147, 2955, 2925,
2854, 1715, 1625, 1574, 1435, 1398, 1111, 759, 703; m.p.: 167 – 169 oC.
(R)-Methyl 4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-4-(3-methoxyphenyl)-2-oxobu-
tanoate15 (3i): Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to
afford a white solid, 47.3 mg, 99% yield, exists in an equilibrium with cyclic hemiketal
3i’; HPLC (Chiralpak OD-H, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254
nm; Retention time: tr(major) = 6.70 min, tr(minor) = 10.98 min, 88% ee); [α]D20 = -12.8
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(c 0.3, CHCl3); H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.0 Hz, 1H), 7.63 – 7.49 (m,
0.8H), 7.36 – 7.19 (m, 3.2H), 6.91 – 6.73 (m, 3H), 4.52 (s, 0.2H), 4.18 – 4.06 (m, 2.8H),
3.88 – 3.75 (m, 4H), 2.78 (s, 0.2H), 2.48 (d, J = 8.1 Hz, 1,8H) ppm; HRMS (ESI) exact
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mass for [M+H]+ (C21H19O7): calcd m/z 383.1125, found: 383.1126; IR (neat) ṽ/cm–1
=
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3338, 3196, 3005, 2954, 1717, 1626, 1554, 1394, 1265, 1111, 761, 736; m.p.: 147 –
149 oC.
(S)-Methyl 4-(2-chlorophenyl)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxobuta-
noate8 (3j): Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to
afford a white solid, 41.0 mg, 85% yield, exists in an equilibrium with cyclic hemiketal
3j’; HPLC (Chiralpak OD-H, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254
nm; Retention time: tr(major) = 9.36 min, tr(minor) = 19.77 min, 86% ee); [α]D20 = -13.1
(c 0.3, in CHCl3); 1H NMR (400 MHz, CDCl3): δ = 7.83 (dd, J = 12.3, 8.0 Hz, 1H), 7.63
– 7.53 (m, 1H), 7.43 – 7.25 (m, 3H), 7.15 (dt, J = 14.3, 6.6 Hz, 3H), 4.75 (s, 0.47H),
4.66 (d, J = 5.7 Hz, 0.51H), 3.90 (d, J = 35.0 Hz, 3H), 2.78 (dd, J = 14.4, 7.6 Hz,
0.46H), 2.68 – 2.36 (m, 1.51H) ppm; HRMS (ESI) exact mass for [M+Na]+
(C20H15ClNaO6): calcd m/z 409.0449, found: 409.0448; IR (neat) ṽ/cm–1 = 3422, 3134,
2917, 2850, 1735, 1725, 1698, 1693, 1625, 1399, 757; m.p.: 149 – 151 oC.
(S)-Methyl 4-(2-bromophenyl)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxobuta-
noate (3k): Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to
afford a white solid, 45.2 mg, 84% yield, exists in an equilibrium with cyclic hemiketal
20
3k’; [α]D = -10.2 (c 0.3, in CHCl3); HPLC (Chiralpak OD-H, hexane/i-PrOH = 80/20,
flow rate = 1.0 mL/min, λ = 254 nm; Retention time: tr(major) = 10.74 min, tr(minor) =
1
22.06 min, 91% ee); H NMR (400 MHz, CDCl3): δ = 7.81 (dd, J = 15.8, 7.9 Hz, 1H),
7.56 (dd, J = 16.1, 7.5 Hz, 2H), 7.37 (d, J = 8.0 Hz, 0.5H), 7.35 – 7.28 (m, 1.5H), 7.16
(d, J = 5.9 Hz, 1H), 7.11 – 7.06 (m, 1H), 4.83 (s, 1H), 4.61 (s, 1H), 3.94 (s, 1H), 3.90 (s,
1H), 2.77 (dd, J = 14.5, 7.6 Hz, 0.5H), 2.63 (d, J = 16.9 Hz, 1H), 2.21 (s, 1H), 2.02 (s,
0.5H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ = 169.2, 168.8, 161.3, 160.4, 157.3,
152.8, 140.1, 139.9, 133.0, 132.2, 132.0, 131.1, 129.9, 129.4, 128.4, 128.3, 127.8,
126.9, 124.0, 124.0, 123.9, 122.9, 122.7, 116.7, 116.6, 115.2, 114.9, 102.6, 96.0, 95.5,
54.1, 54.0, 33.5, 29.3, 27.2, 22.7 ppm; HRMS (ESI) exact mass for [M+H]+
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(C20H16BrO6): calcd m/z 431.0125, found: 431.0126; IR (neat) ṽ/cm–1 = 3420, 3134,
2924, 2853, 1746, 1715, 1626, 1574, 1459, 1166, 1109, 757, 721; m.p.: 86 – 87 oC.
(R)-Methyl 4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-4-(naphthalen-2-yl)-2-oxobuta-
noate15 (3l): Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to
afford a white solid, 36.2 mg, 72% yield, exists in an equilibrium with cyclic hemiketal
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3l’; HPLC (Chiralpak OD-H, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254
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nm; Retention time: tr(major) = 11.44 min, tr(minor) = 22.10 min, 92% ee); [α]D
=
1
-10.1 (c 0.2, in CHCl3); H NMR (400 MHz, CDCl3): δ = 7.91 – 7.68 (m, 5H), 7.64 –
7.53 (m, 1H), 7.48 – 7.29 (m, 5H), 4.52 (dd, J = 7.4, 3.4 Hz, 0.3H), 4.39 (dd, J = 10.7,
7.3 Hz, 1.7H), 3.87 (d, J = 44.1 Hz, 3H), 2.87 (dd, J = 14.3, 7.4 Hz, 0.3H), 2.69 – 2.48
(m, 1.7H) ppm; HRMS (ESI) exact mass for [M+H]+ (C24H19O6): calcd m/z 403.1176,
found: 403.1176; IR (neat) ṽ/cm–1 = 3420, 3134, 2925, 2852, 1747, 1715, 1624, 1399,
1110, 819, 759; m.p.: 107 – 108 oC.
(S)-Methyl
4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-4-(thiophen-2-yl)buta-
noate6 (3m): Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to
afford a white solid, 28.2 mg, 63% yield, exists in an equilibrium with cyclic hemiketal
3m’; HPLC (Chiralpak AD-H, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254
nm; Retention time: tr(major) = 5.89 min, tr(minor) = 7.80 min, 83% ee); [α]D20 = +22.7
(c 0.3, in CHCl3); 1H NMR (400 MHz, CDCl3): δ = 7.82 (dd, J = 14.1, 7.9 Hz, 1H), 7.65
– 7.52 (m, 1H), 7.32 (tt, J = 14.4, 7.3 Hz, 2H), 7.21 – 7.15 (m, 1H), 6.93 (dd, J = 8.6,
4.2 Hz, 2H), 4.65 – 4.53 (m, 1H), 3.95 – 3.85 (m, 3H), 2.80 (dd, J = 14.4, 6.9 Hz, 0.3H),
2.73 – 2.52 (m, 1.7H) ppm; HRMS (ESI) exact mass for [M+H]+ (C18H15SO6): calcd
m/z 359.0584, found: 359.0586; IR (neat) ṽ/cm–1 = 3430, 3132, 2849, 1683, 1624,
1399, 1172, 1024, 761; m.p.: 112 – 114 oC.
(R)-Ethyl 4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-4-phenylbutanoate14 (3n):
Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to afford a white
solid, 43.9 mg, 96% yield,exists in an equilibrium with cyclic hemiketal 3n’; HPLC
(Chiralpak OD-H, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm;
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Retention time: tr(major) = 9.12 min, tr(minor) = 21.24 min, 94% ee); [α]D = -30.1 (c
1
0.3, in CHCl3); H NMR(400 MHz, CDCl3): δ = 7.80 (dd, J = 19.5, 7.7 Hz, 1H), 7.65 –
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7.45 (m, 1H), 7.39 – 7.15 (m, 7H), 4.39 – 4.24 (m, 2H), 4.20 (dd, J = 10.3, 7.9 Hz,
0.3H), 4.07 – 3.95 (m, 0.7H), 2.80 (dd, J = 14.2, 7.4 Hz, 0.3H), 2.57 – 2.37 (m, 1.7H),
1.33 (dd, J = 15.3, 8.1 Hz, 3H) ppm; HRMS (ESI) exact mass for [M+H]+ (C21H19O6):
calcd m/z 367.1176, found: 367.1174; IR (neat) ṽ/cm–1 = 3420, 3333, 3145, 3028,
1746, 1695, 1625, 1398, 1111, 758, 700. m.p.: 167 – 169 oC.
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(R)-Isopropyl
4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-4-phenylbutanoate6
(3o): Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to afford a
white solid, 46.6 mg, 98% yield, exists in an equilibrium with cyclic hemiketal 3o’;
HPLC (Chiralpak OD-H, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm;
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Retention time: tr(major) = 6.71 min, tr(minor) = 16.24 min, 93% ee); [α]D = -13.5 (c
0.3, in CHCl3); 1H NMR (400 MHz, CDCl3): δ = 7.79 (dd, J = 22.7, 7.8 Hz, 1 H), 7.62 –
7.46 (m, 1H), 7.40 – 7.17 (m, 7H), 5.16 (dt, J = 11.4, 5.7 Hz, 1H), 4.33 (d, J = 4.7 Hz,
0.3H), 4.20 (dd, J = 11.3, 7.2 Hz, 0.7H), 2.79 (dd, J = 14.2, 7.5 Hz, 0.3H), 2.56 – 2.32
(m, 0.7H), 1.28 – 1.15 (m, 6H) ppm; HRMS (ESI) exact mass for [M+H]+ (C22H21O6):
calcd m/z 381.1333, found: 381.1333; IR (neat) ṽ/cm–1 = 3443, 3132, 1734, 1716,
1698, 1614, 1440, 780, 720; m.p.: 140 – 142 oC.
(R)-tert-Butyl
4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-4-phenylbutanoate6
(3p): Purified by flash chromatography (petroleum ether : EtOAc = 2 : 1) to afford a
white solid, 47.3 mg, 96% yield, exists in an equilibrium with cyclic hemiketal 3p’;
HPLC (Chiralpak OD-H, hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm;
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Retention time: tr(major) = 5.89 min, tr(minor) = 12.63 min, 94% ee); [α]D = -14.2 (c
0.3, in CHCl3); 1H NMR (400 MHz, CDCl3): δ = 7.78 (dd, J = 24.8, 7.9 Hz, 1H), 7.61 –
7.47 (m, 1H), 7.41 – 7.15 (m, 7H), 4.32 (dd, J = 7.3, 3.2 Hz, 0.3H), 4.19 (dd, J = 12.0,
6.8 Hz, 0.7H), 2.76 (dd, J = 14.3, 7.5 Hz, 0.3H), 2.53 – 2.28 (m, 1.7H), 1.53 (d, J = 9.7
Hz, 9H) ppm; HRMS (ESI) exact mass for [M+H]+ (C23H23O6): calcd m/z 395.1489,
found: 395.1490; IR (neat) ṽ/cm–1 = 3394, 3131, 2925, 2850, 1733, 1716, 1698, 1624,
1136, 758; m.p.: 151 – 153 oC.
(R)-Methyl 4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-4-phenylbutanoa-
te14 (5a): Purified by flash chromatography using petroleum ether with EtOAc to afford
a colorless oil 37.9 mg, 96% yield, exists in an equilibrium with cyclic hemiketal 5a’;
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[α]D = +17.1 (c 1.72, in CHCl3); HPLC (Chiralpak OD, hexane/i-PrOH = 70/30, flow
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rate = 2.0 mL/min, λ = 254 nm; Retention time: tr(major) = 6.50 min, tr(minor) = 10.06
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min, 83% ee); H NMR (400 MHz, CDCl3): δ = 7.34 – 7.16 (m, 5H), 5.88 (s, 0.3H),
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5.82 (s, 0.7H), 4.95 (s, 0.7H), 4.56 (s, 0.3H), 4.18 – 3.99 (m, 1H), 3.85 (s, 1H), 3.74 (s,
2H), 2.66 (dd, J = 14.3, 7.4 Hz, 0.3H), 2.41 (dd, J = 14.3, 3.7 Hz, 0.3H), 2.32 (d, J =
8.8 Hz, 1.4H), 2.24 (s, 1H), 2.20 (s, 2H) ppm. HRMS (ESI) exact mass for [M+H]+
(C17H16O6): calcd m/z 317.1020, found: 317.1023; IR (neat) ṽ/cm–1 = 3268, 2916,
2847, 1683, 1574, 1449, 1230, 1194, 1141, 757, 696.
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(R)-Methyl
4-(4-fluorophenyl)-4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-
oxobutanoate (5b): Purified by flash chromatography using petroleum ether with
EtOAc to afford a colorless oil, 35.1 mg, 84% yield, exists in an equilibrium with cyclic
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hemiketal 5b’; [α]D
= +23 (c 0.034, in CHCl3); HPLC (Chiralpak OD-H,
hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm; Retention time: tr(major)
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= 8.65 min, tr(minor) = 14.63 min, 75% ee); H NMR (400 MHz, CDCl3): δ = 7.20 –
7.10 (m, 2H), 7.02 – 6.93 (m, 2H), 5.87 (s, 0.3H), 5.82 (s, 0.7H), 4.81 (s, 0.7H), 4.52 (s,
0.3H), 4.19 – 3.99 (m, 1H), 3.87 (s, 1H), 3.81 (s, 2H), 2.66 (dd, J = 14.3, 7.4 Hz, 0.3H),
2.37 (dd, J = 11.5, 2.8 Hz, 0.3H), 2.34 – 2.27 (m, 1.4H), 2.25 (s, 1H), 2.20 (s, 2H) ppm;
13C{1H} NMR (101 MHz, CDCl3): δ = 169.0, 168.9, 163.5, 163.1, 162.6, 161.7, 161.6
(d, J = 243 Hz) , 161.5 (d, J = 241 Hz), 137.9, 137.8, 137.4, 137.3, 130.0, 129.9, 129.0
(d, J = 8 Hz), 128.6 (d, J = 8 Hz), 115.4 (d, J = 21 Hz), 115.1 (d, J = 21 Hz), 101.5,
99.9, 99.8, 95.7, 95.2, 53.9, 53.8, 38.1, 35.5, 33.2, 32.4, 29.3, 19.9 ppm; 19F{1H} NMR
(376 MHz, CDCl3): δ = -116.4, -116.7 ppm; HRMS (ESI) exact mass for [M+H]+
(C17H16FO6): calcd m/z 335.0925, found: 335.0924; IR (neat) ṽ/cm–1 = 3276, 2957,
2920, 2847, 1687, 1574, 1509, 1444, 1222, 1137, 1036, 1012, 826, 802, 781.
(R)-Methyl
4-(4-chlorophenyl)-4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-
oxobutanoate (5c): Purified by flash chromatography using petroleum ether with
EtOAc to afford a yellow solid, 42.9 mg, 98% yield, exists in an equilibrium with cyclic
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hemiketal 5c’; [α]D = +27.1 (c 0.034, in CHCl3); HPLC (Chiralpak ID, hexane/i-PrOH
= 70/30, flow rate = 2.0 mL/min, λ = 254 nm; Retention time: tr(major) = 5.47 min,
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tr(minor) = 8.86 min, 81% ee); H NMR (400 MHz, CDCl3): δ = 7.28 – 7.23 (m, 2H),
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7.14 (d, J = 8.3 Hz, 2H), 5.87 (s, 0.3H), 5.82 (s, 0.7H), 4.83 (s, 0.7H), 4.55 (s, 0.3H),
4.12 (dd, J = 7.2, 2.7 Hz, 0.3H), 4.02 (dd, J = 11.0, 7.0 Hz, 0.7H), 3.87 (s, 1H), 3.82 (s,
2H), 2.66 (dd, J = 14.2, 7.5 Hz, 0.3H), 2.38 (d, J = 3.1 Hz, 0.3H), 2.35 – 2.32 (m, 0.3H),
2.32 – 2.28 (m, 0.7H), 2.26 (s, 1.4H), 2.21 (s, 2H) ppm; 13C{1H} NMR (101 MHz,
CDCl3): δ = 169.0, 168.8, 163.5, 163.2, 163.0, 162.6, 161.8, 140.8, 140.3, 132.3,
132.2, 128.9, 128.8, 128.5, 128.4, 101.2, 100.0, 99.9, 99.5, 95.7, 95.1, 77.1, 53.9,
53.8, 37.9, 35.4, 33.3, 32.5, 19.9. ppm; HRMS (ESI) exact mass for [M+H]+
(C17H16ClO6): calcd m/z 351.0630, found: 351.0634; IR (neat) ṽ/cm–1 = 3321, 2950,
2930, 2867, 1687, 1570, 1512, 1444, 1222, 1137, 1076, 1012, 846, 791; m.p.: 97 – 99
oC.
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(R)-Methyl
4-(4-bromophenyl)-4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-
oxobutanoate (5d): Purified by flash chromatography using petroleum ether with
EtOAc to afford a colorless oil, 37.4 mg, 86% yield, exists in an equilibrium with cyclic
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hemiketal 5d’; [α]D
= +17.2 (c 0.318, in CHCl3); HPLC (Chiralpak OD-H,
hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm; Retention time: tr(major)
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= 9.15 min, tr(minor) = 15.66 min, 76% ee); H NMR (400 MHz, CDCl3): δ = 7.44 –
7.35 (m, 2H), 7.09 (d, J = 8.4 Hz, 2H), 5.87 (s, 0.3H), 5.81 (s, 0.7H), 4.77 (s, 0.7H),
4.51 (s, 0.3H), 4.17 – 4.07 (m, 1H), 3.87 (s, 1H), 3.82 (s, 2H), 2.66 (dd, J = 14.3, 7.5
Hz, 0.3H), 2.36 (dd, J = 11.9, 2.4 Hz, 0.3H), 2.34 – 2.28 (m, 1.4H), 2.25 (s, 1H), 2.21
(s, 2H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ = 168.9, 168.7, 163.4, 163.2, 162.9,
162.4, 161.8, 141.3, 140.8, 131.7, 131.3, 129.2, 128.8, 120.3, 120.2, 101.1, 99.9, 99.9,
99.4, 95.6, 95.0, 53.9, 53.8, 37.8, 35.2, 33.4, 32.5, 19.9, 19.8 ppm; HRMS (ESI) exact
mass for [M+H]+ (C17H16BrO6): calcd m/z 395.0125, found: 395.0122; IR (neat) ṽ/cm–1
= 3292, 2956, 2916, 2851, 1683, 1582, 1485, 1440, 1230, 1194, 1141, 1008, 818,
781.
(R)-Methyl 4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-4-(p-tolyl)butanoa-
te (5e): Purified by flash chromatography using petroleum ether with EtOAc to afford a
white solid, 37.9 mg, 92% yield, exists in an equilibrium with cyclic hemiketal 5e’;
[α]D20 = +44.2 (c 1.99, in CHCl3); HPLC (Chiralpak OD-H, hexane/i-PrOH = 80/20, flow
rate = 1.0 mL/min, λ = 254 nm; Retention time: tr(major) = 8.41 min, tr(minor) = 15.58
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min, 88% ee); H NMR (400 MHz, CDCl3): δ = 7.10 (s, 4H), 5.87 (s, 0.3H), 5.80 (s,
0.7H), 4.66 (s, 0.7H), 4.35 (s, 0.3H), 4.12 – 4.00 (m, 1H), 3.86 (s, 1H), 3.79 (s, 2H),
2.65 (dd, J = 14.3, 7.3 Hz, 0.3H), 2.41 (dd, J = 14.4, 3.0 Hz, 0.3H), 2.36 – 2.27 (m,
4.4H), 2.25 (s, 1H), 2.20 (s, 2H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ = 169.0,
168.9, 163.5, 163.0, 162.6, 162.5, 161.4, 139.1, 138.4, 136.1, 129.3, 129.2, 127.1,
126.9, 101.8, 99.9, 95.8, 95.1, 53.8, 53.7, 38.2, 35.6, 33.3, 21.1, 19.9, 19.8 ppm;
HRMS (ESI) exact mass for [M+H]+ (C18H19O6): calcd m/z 331.1176, found: 331.1179;
IR (neat) ṽ/cm–1 = 3264, 2952, 2924, 2856, 1683, 1574, 1444, 1400, 1230, 1190, 1141,
1036, 814, 781; m.p.: 99 – 101 oC.
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(R)-methyl
4-(3-chlorophenyl)-4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-
oxobutanoate (5f):Purified by flash chromatography using petroleum ether with
EtOAc to afford a white solid, 42 mg, 95% yield, exists in an equilibrium with cyclic
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hemiketal 5f’; [α]D = +22.2 (c 0.034, in CHCl3); HPLC (Chiralpak ID, hexane/i-PrOH
= 70/30, flow rate = 2.0 mL/min, λ = 254 nm; Retention time: tr(major) = 5.51 min,
tr(minor) = 9.50 min, 75% ee);1H NMR (400 MHz, CDCl3): δ = 7.22 – 7.15 (m, 3H),
7.11 (d, J = 7.1 Hz, 1H), 5.88 (s, 0.3H), 5.83 (s, 0.7H), 4.91 (s, 0.7H), 4.60 (s, 0.3H),
4.12 (dd, J = 7.1, 2.7 Hz, 0.3H), 4.05 – 3.97 (m, 0.7H), 3.87 (s, 1H), 3.81 (s, 2H), 2.66
(dd, J = 14.3, 7.5 Hz, 0.3H), 2.35 (d, J = 7.2 Hz, 0.3H), 2.31 (d, J = 7.6 Hz, 1H), 2.27
(d, J = 4.7 Hz, 1.4H), 2.22 (s, 2H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ = 168.9,
168.8, 163.5, 163.4, 163.1, 162.6, 161.9, 144.4, 143.9, 134.3, 134.0, 129.9, 129.5,
127.7, 127.1, 126.9, 126.7, 125.8, 125.6, 100.9, 100.0, 99.2, 95.7, 95.1, 77.1, 53.9,
53.8, 37.9, 35.3, 33.6, 32.8, 20.0, 19.9 ppm; HRMS (ESI) exact mass for [M+H]+
(C17H16ClO6): calcd m/z 351.0630, found: 351.0626; IR (neat) ṽ/cm–1 = 3266, 2986,
2920, 2847, 1687, 1574, 1522, 1444, 1222, 1137, 1036, 1022, 832, 802, 781; m.p.: 92
– 94 oC.
(R)-Methyl
4-(3-bromophenyl)-4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-
oxobutanoate (5g): Purified by flash chromatography using petroleum ether with
EtOAc to afford a colorless oil, 39.9 mg, 81% yield, exists in an equilibrium with cyclic
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hemiketal 5g’; [α]D
= +25.3 (c 0.44, in CHCl3); HPLC (Chiralpak OD-H,
hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm; Retention time: tr(major)
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= 11.25 min, tr(minor) = 22.82 min, 84% ee); H NMR (400 MHz, CDCl3): δ = 7.40 –
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7.28 (m, 2H), 7.20 – 7.10 (m, 2H), 5.87 (s, 0.3H), 5.82 (s, 0.7H), 4.15 – 3.96 (m, 2H),
3.87 (s, 1H), 3.83 (s, 2H), 2.66 (dd, J = 14.3, 7.5 Hz, 0.3H), 2.42 – 2.29 (m, 1.7H),
2.26 (s, 1H), 2.22 (s, 2H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ = 168.7, 163.4,
163.2, 162.4, 161.8, 144.7, 144.2, 130.6, 130.2, 129.9, 129.8, 129.7, 129.6, 126.2,
126.1, 122.6, 122.3, 100.9, 99.9, 99.2, 95.6, 95.0, 53.9, 53.8, 37.9, 35.2, 33.6, 32.7,
19.9, 19.9 ppm; HRMS (ESI) exact mass for [M+H]+ (C17H16BrO6): calcd m/z 395.0125,
found: 395.0127; IR (neat) ṽ/cm–1 = 3248, 2952, 2924, 2847, 1679, 1578, 1440, 1230,
1190, 1137, 781, 692.
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(R)-Methyl
4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-4-(m-tolyl)buta-
noate (5h): Purified by flash chromatography using petroleum ether with EtOAc to
afford a white solid, 39.2 mg, 95% yield, exists in an equilibrium with cyclic hemiketal
5h’; [α]D20 = +43.6 (c 1.60, in CHCl3); HPLC (Chiralpak OD-H, hexane/i-PrOH = 80/20,
flow rate = 1.0 mL/min, λ = 254 nm; Retention time: tr(major) = 9.15 min, tr(minor) =
19.20 min, 90% ee); 1H NMR (400 MHz, CDCl3): δ = 7.21 – 7.11 (m, 1H), 7.00 (t, J =
7.0 Hz, 3H), 5.88 (s, 0.3H), 5.82 (s, 0.7H), 4.86 (s, 0.7H), 4.48 (s, 0.3H), 4.16 – 4.07
(m, 0.3H), 4.00 (t, J = 8.9 Hz, 0.7H), 3.85 (s, 1H), 3.77 (s, 2H), 2.65 (dd, J = 14.3, 7.3
Hz, 0.3H), 2.42 (dd, J = 14.3, 3.7 Hz, 0.3H), 2.31 (t, J = 4.2 Hz, 4.4H), 2.25 (s, 1H),
2.21 (s, 2H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ = 169.0, 168.9, 163.5, 163.1,
162.8, 162.6, 161.5, 161.4, 142.1, 141.4, 138.0, 138.0, 128.4, 128.3, 128.0, 127.8,
127.6, 127.5, 124.2, 124.1, 101.6, 100.0, 99.9, 95.9, 95.2, 53.8, 53.6, 38.2, 35.9, 33.7,
32.9, 21.5, 19.9, 19.8 ppm; HRMS (ESI) exact mass for [M+H]+ (C18H19O6): calcd m/z
331.1176, found: 331.1176; IR (neat) ṽ/cm–1 = 3292, 2956, 2920, 2847, 1687, 1578,
1444, 1400, 1181, 1137, 1040, 1008, 987, 777, 701; m.p.: 105 – 107 oC.
(R)-Methyl 4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-4-(3-methoxyphenyl)-2-
oxobutanoate (5i): Purified by flash chromatography using petroleum ether with
EtOAc to afford a colorless oil 39.8 mg, 92% yield, exists in an equilibrium with cyclic
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hemiketal 5i’; [α]D = +32.2 (c 0.466, in CHCl3); HPLC (Chiralpak ID, hexane/i-PrOH
= 70/30, flow rate = 2.0 mL/min, λ = 254 nm; Retention time: tr(major) = 9.74 min,
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tr(minor) = 16.62 min, 80% ee); H NMR (400 MHz, CDCl3): δ = 7.25 – 7.18 (m, 1H),
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6.87 – 6.72 (m, 3H), 5.87 (s, 0.3H), 5.80 (s, 0.7H), 4.70 (s, 0.7H), 4.40 (s, 0.3H), 4.17
– 3.94 (m, 1H), 3.87 (s, 1H), 3.81 (s, 2H), 3.77 (d, J = 5.1 Hz, 3H), 2.66 (dd, J = 14.3,
7.4 Hz, 0.3H), 2.44 (dd, J = 14.3, 3.3 Hz, 0.3H), 2.37 – 2.30 (m, 1.4H), 2.25 (s, 1H),
2.21 (s, 2H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ = 169.0, 168.9, 163.4, 163.1,
162.7, 162.5, 161.5, 159.7, 159.6, 144.0, 143.2, 129.6, 129.4, 119.7, 119.5, 113.8,
113.2, 111.7, 111.5,101.6, 99.9, 99.7, 95.8, 95.1, 55.2, 53.8, 53.8, 38.1, 35.6, 33.8,
32.9,19.9, 19.9 ppm; HRMS (ESI) exact mass for [M+H]+ (C18H19O7): calcd m/z
347.1125, found: 347.1130; IR (neat) ṽ/cm–1 = 3252, 2956, 2920, 2839, 1683, 1578,
1440, 1226, 1186, 1137, 1036, 777, 696.
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(S)-Methyl
4-(2-chlorophenyl)-4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-
oxobutanoate (5j): Purified by flash chromatography using petroleum ether with
EtOAc to afford a colorless oil, 29.8 mg, 68% yield, exists in an equilibrium with cyclic
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hemiketal 5j’; [α]D
= +44.4 (c 1.04, in CHCl3); HPLC (Chiralpak OD-H,
hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm; Retention time: tr(major)
= 11.29 min, tr(minor) = 19.68 min, 60% ee); 1H NMR (400 MHz, CDCl3): δ = 7.35 (d, J
= 7.2 Hz, 1H), 7.20 – 7.08 (m, 3H), 5.88 (s, 0.5H), 5.83 (s,0.5H), 4.58 (s, 0.5H), 4.47
(d, J = 7.5 Hz, 0.5H), 4.12 (q, J = 7.1 Hz, 0.5H), 3.89 (s, 1.5H), 3.81 (s, 2H), 2.64 (dd,
J = 14.5, 7.6 Hz, 0.5H), 2.56 – 2.41 (m, 1H), 2.26 (s, 1.5H), 2.22 (s, 2H) ppm; 13C{1H}
NMR (101 MHz, CDCl3): δ = 169.1, 168.8, 163.4, 163.1, 162.2, 161.7 161.6, 138.4,
133.3, 129.6, 129.2, 127.9, 127.8, 127.0, 126.2, 100.0, 99.9, 99.3, 95.7, 95.2, 53.9,
53.8, 32.6, 30.4, 19.9, 19.8 ppm; HRMS (ESI) exact mass for [M+H]+ (C17H16ClO6):
calcd m/z 351.0630, found: 351.0634; IR (neat) ṽ/cm–1 = 3276, 2956, 2924, 2851,
1683, 1578, 1440, 1230, 1190, 1141, 1032, 943, 814, 757, 692.
(S)-Methyl
4-(2-bromophenyl)-4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-
oxobutanoate (5k): Purified by flash chromatography using petroleum ether with
EtOAc to afford a white solid, 33.4 mg, 68% yield, exists in an equilibrium with cyclic
hemiketal 5k’; HPLC (Chiralpak ID, hexane/i-PrOH = 70/30, flow rate = 2.0 mL/min, λ
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= 254 nm; Retention time: tr(major) = 7.39 min, tr(minor) = 6.55 min, 72% ee); [α]D
=
+59.7 (c 0.03, in CHCl3);1H NMR (400 MHz, CDCl3): δ = 7.55 (d, J = 8.9 Hz, 1H), 7.24
– 7.18 (m, 0.5H), 7.18 – 7.11 (m, 1H), 7.10 – 7.03 (m, 1.5H), 5.85 (d, J = 21.2 Hz, 1H),
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4.67 (s, 1H), 4.58 (s, 0.5H), 3.86 (d, J = 27.7 Hz, 3H), 2.64 (dd, J = 14.4, 7.6 Hz, 0.5H),
2.56 – 2.45 (m, 1H), 2.24 (d, J = 16.3 Hz, 3H), 2.20 – 2.11 (m, 1H) ppm; 13C{1H} NMR
(101 MHz, CDCl3): δ = 169.14, 168.82, 163.46, 163.19, 162.33, 161.73, 161.67,
140.97, 139.95, 133.04, 132.97, 129.98, 129.42, 128.30, 128.20, 127.75, 127.29,
126.90, 124.20, 124.01, 101.06, 100.05, 99.92, 99.52, 95.80, 95.28, 54.02, 53.80,
32.88, 29.72, 29.34, 27.23, 22.71, 19.92. ppm; HRMS (ESI) exact mass for [M+H]+
(C17H16BrO6): calcd m/z 395.0125, found: 395.0126; IR (neat) ṽ/cm–1 = 3239, 2962,
2935, 2849, 1680, 1578, 1440, 1232, 1192, 1139, 782, 692; m.p.: 117 – 119 oC.
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(R)-Methyl
4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-4-(naphthalen-2-yl)-2-
oxobutanoate (5l): Purified by flash chromatography using petroleum ether with
EtOAc to afford a yellow solid, 36.6 mg, 93% yield, exists in an equilibrium with cyclic
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hemiketal 5l’; [α]D = +17.6 (c 0.828, in CHCl3); HPLC (Chiralpak ID, hexane/i-PrOH
= 70/30, flow rate = 2.0 mL/min, λ = 254 nm; Retention time: tr(major) = 8.75 min,
1
tr(minor) = 14.83 min, 80% ee); H NMR (400 MHz, CDCl3): δ = 7.80 – 7.69 (m, 3H),
7.63 (s, 0.7H), 7.62 (s, 0.3H), 7.41 (m, 2H), 7.34 (dd, J = 8.5, 1.8 Hz, 0.3H), 7.29 (dd,
J = 8.5, 1.8 Hz, 0.7H), 5.90 (s, 0.3H), 5.83 (s, 0.7H), 4.98 (s, 0.7H), 4.57 (s, 0.3H),
4.22 – 4.08 (m, 1H), 3.83 (s, 1H), 3.67 (s, 2H), 2.70 (dd, J = 14.3, 7.4 Hz, 0.3H), 2.50
(dd, J = 14.3, 3.7 Hz, 0.3H), 2.43 – 2.30 (m, 1.4H), 2.26 (s, 1H), 2.20 (s, 2H) ppm;
13C{1H} NMR (101 MHz, CDCl3): δ = 168.9, 168.8, 163.6, 163.3, 163.1, 162.7, 161.6,
139.5, 139.1, 133.5, 133.4, 132.5, 132.4, 128.3, 128.1, 127.8, 127.7, 127.6, 125.9,
125.7, 125.4, 125.4, 125.3, 101.3, 100.0, 99.8, 95.9, 95.3, 53.8, 53.6, 38.0, 35.7, 33.9,
33.2, 19.9, 19.8 ppm; HRMS (ESI) exact mass for [M+H]+ (C21H19O6): calcd m/z
367.1176, found: 367.1174; IR (neat) ṽ/cm–1 = 3280, 2952, 2924, 2851, 1687, 1574,
1444, 1396, 1226, 1181, 1137, 1040, 959, 822, 745; m.p.: 131 – 133 oC.
(S)-Methyl 4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-4-(thiophen-2-yl)-
butanoate (5m): Purified by flash chromatography using petroleum ether with EtOAc
to afford a colorless oil, 37.8 mg, 94% yield, exists in an equilibrium with cyclic
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hemiketal 5m’; [α]D
= +78.5 (c 2.0, in CHCl3); HPLC (Chiralpak OD-H,
hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm; Retention time: tr(major)
1
= 11.36 min, tr(minor) = 14.94 min, 78% ee); H NMR (400 MHz, CDCl3): δ = 7.17 –
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7.12 (m, 1H), 6.93 – 6.85 (m, 2H), 5.86 (s, 0.3H), 5.81 (s, 0.7H), 4.95 (s, 0.7H), 4.56 (s,
0.3H), 4.43 (dd, J = 6.7, 2.7 Hz, 0.3H), 4.37 (dd, J = 10.0, 6.7 Hz, 0.7H), 4.15 – 4.09
(m, 0.3H), 3.88 (s, 1H), 3.75 (s, 1.7H), 2.66 (dd, J = 14.4, 6.9 Hz, 0.3H), 2.57 (dd, J =
14.4, 2.9 Hz, 0.3H), 2.53 – 2.36 (m, 1.4H), 2.25 (s, 1H), 2.21 (s, 2H) ppm; 13C{1H}
NMR (101 MHz, CDCl3): δ = 168.6, 162.6, 162.5, 161.9, 161.8, 145.4, 145.3, 126.5,
125.0, 124.6, 123.9, 123.4, 101.3, 99.9, 95.7, 95.2, 53.8, 53.7, 38.5, 35.6, 29.4, 28.4,
19.9, 19.8 ppm; HRMS (ESI) exact mass for [M+H]+ (C15H15O6S): calcd m/z 323.0584,
found: 323.0580; IR (neat) ṽ/cm–1 = 3260, 2952, 2920, 2847, 1683, 1574, 1440, 1404,
1185, 1137, 1028, 801, 785, 696.
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(R)-Ethyl 4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-4-phenylbutanoate8
(5n): Purified by flash chromatography using petroleum ether with EtOAc to afford a
white solid, 38.7 mg, 94% yield, exists in an equilibrium with cyclic hemiketal 5n’; m.p.
= 57−60 oC; [α]D20 = +34.1 (c 1.0, in CHCl3); HPLC (Chiralpak OD-H, hexane/i-PrOH =
80/20, flow rate = 1.0 mL/min, λ = 254 nm; Retention time: tr(major) = 8.61 min,
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tr(minor) = 17.30 min, 81% ee); H NMR (400 MHz, CDCl3): δ = 7.32 – 7.26 (m, 2H),
7.24 – 7.18 (m, 3H), 5.88 (s, 0.3H), 5.82 (s, 0.7H), 4.90 (s, 0.7H), 4.55 (s, 0.3H), 4.34
– 4.17 (m, 2.3H), 4.06-4.00 (m, 0.7H), 2.67 (dd, J = 14.3, 7.4 Hz, 0.3H), 2.41 (dd, J =
14.3, 3.5 Hz, 0.3H), 2.35 – 2.28 (m, 1.4H), 2.25 (s, 1H), 2.20 (s, 2H), 1.32 (t, J = 7.1
Hz, 1H), 1.28 (t, J = 7.1 Hz, 2H) ppm. HRMS(EI): calcd for C18H19O6 [M+H]+: 331.1176,
found 331.1179; IR (neat) ṽ/cm–1 = 3284, 2920,2852, 1683, 1574, 1449, 1396, 1226,
1190, 1141, 1040, 1004, 757, 696; m.p.: 95 – 97 oC.
(R)-Isopropyl 4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-4-phenylbuta-
noate (5o): Purified by flash chromatography using petroleum ether with EtOAc to
afford a colorless oil, 37.0 mg, 86% yield, exists in an equilibrium with cyclic hemiketal
5o’; [α]D20 = +24 (c 0.274, in CHCl3); HPLC (Chiralpak OD-H, hexane/i-PrOH = 80/20,
flow rate = 1.0 mL/min, λ = 254 nm; Retention time: tr(major) = 6.97 min, tr(minor) =
1
14.86 min, 80% ee); H NMR (400 MHz, CDCl3): δ = 7.36 – 7.16 (m, 5H), 5.88 (s,
0.3H), 5.81 (s, 0.7H), 4.68 (s, 0.7H), 4.41 (s, 0.3H), 4.24 – 3.98 (m, 1H), 2.67 (dd, J =
14.3, 7.5 Hz, 0.3H), 2.40 (dd, J = 14.3, 3.2 Hz, 0.3H), 2.35 – 2.28 (m, 1.4H), 2.25 (s,
1H), 2.20 (s, 2H), 1.30 (dt, J = 11.0, 5.5 Hz, 6H) ppm; 13C{1H} NMR (101 MHz, CDCl3):
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δ = 168.1, 168.0, 163.5, 163.2, 162.9, 162.4, 161.4, 142.5, 141.7, 128.6, 128.3, 127.3,
127.1, 126.7, 126.6, 101.8, 100.0, 99.9, 99.8, 95.6, 94.9, 71.8, 71.7, 38.0, 35.4, 33.9,
33.0, 21.6, 21.5, 21.4, 19.9, 19.8 ppm; HRMS (ESI) exact mass for [M+H]+ (C19H21O6):
calcd m/z 345.1333, found: 345.1338; IR (neat) ṽ/cm–1 = 3171, 2977, 1756, 1675,
1638, 1574, 1444, 1287, 1230, 1149, 1105, 1050, 1012, 838, 769, 701.
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(R)-tert-Butyl 4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-4-phenylbuta-
noate (5p): Purified by flash chromatography using petroleum ether with EtOAc to
afford a colorless oil, 40.7 mg, 91% yield, exists in an equilibrium with cyclic hemiketal
5p’; [α]D20 = +4.6 (c 0.828, in CHCl3); HPLC (Chiralpak OD-H, hexane/i-PrOH = 80/20,
flow rate = 1.0 mL/min, λ = 254 nm; Retention time: tr(major) = 7.73 min, tr(minor) =
15.63 min, 76% ee); 1H NMR (400 MHz, CDCl3): δ = 7.34 – 7.27 (m, 2H), 7.22 (dd, J =
16.4, 6.3 Hz, 3H), 5.88 (s, 0.3H), 5.82 (s, 0.7H), 4.67 (s, 0.7H), 4.45 (s, 0.3H),
4.25-3.87 (m, 1H), 2.64 (d, J = 6.8 Hz, 1H), 2.43 – 2.28 (m, 1H), 2.25 (s, 1H), 2.20 (s,
2H), 1.51 (s, 9H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ = 167.6, 167.5, 163.4, 163.3,
163.0, 162.4, 161.3, 142.7, 141.8, 128.6, 128.4, 128.2, 127.3, 127.0, 126.5, 126.4,
101.8, 100.1, 100.0, 99.9, 95.8, 95.1, 85.0, 84.8, 38.2, 35.6, 34.0, 33.3, 27.7, 19.9,
19.8 ppm; HRMS (ESI) exact mass for [M+H]+ (C20H23O6): calcd m/z 359.1489, found:
359.1486; IR (neat) ṽ/cm–1 = 3236, 2973, 2924, 2847, 1748, 1679, 1642, 1574, 1444,
1400, 1295, 1141, 1056, 951, 842, 773, 696.
Supporting Information
Chiral HPLC chromatograms data and copies of NMR spectra for the asymmetric
conjugate adducts. This material is available free of charge via the Internet at
http://pubs.acs.org.
Notes
The authors declare no competing financial interest.
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Acknowledgments
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We are grateful to the National Natural Science Foundation of China (NSFC:
21871237, 21901150) and the China Postdoctoral Science Foundation
(2018M643806XB) for financial support.
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References
(1) (a) Moskvina, V. S.; Khilya, V. P. Recent Progress in the Synthesis of 4-Arylcoumarins,
Chem. Nat. Compd. 2019, 55, 401−427. (b) Polamreddy, P.; Vishwakarma, V.; Gundla, R. A
Review on Anti-HCV Agents Targeting Active Site and Allosteric Sites of Nonstructural Protein
5B [NS5B]. Int. J. Pharm. Pharm. Sci. 2016, 8, 1−18. (c) McDonald, B. R.; Scheidt, K. A.
Pyranone Natural Products as Inspirations for Catalytic Reaction Discovery and Development.
Acc. Chem. Res. 2015, 48, 1172−1183.
(2) Li, X.; Zeng, H.; Wang, P.; Lin, L.; Liu, L.; Zhen, P.; Fu, Y.; Lu, P.; Zhu, H. Reactivation of
Latent HIV-1 in Latently Infected Cells by Coumarin Compounds: Hymecromone and
Scoparone. Curr. HIV. Res. 2016, 14, 484−490.
(3) Tavares, L.; Marcatto, L.; Soares, R.; Krieger, J.; Pereira, A.; Santos, P. J. L. Association
between ABCB1 Polymorphism and Stable Warfarin Dose Requirements in Brazilian Patients.
Front. Pharmacol. 2018, 9, 542/1-542/8.
(4) (a) Calter, M. A.; Wang, J. Catalytic, Asymmetric Michael Reactions of Cyclic Diketones
with γ-Unsaturated r-Ketoesters, Org. Lett. 2009, 11, 2205–2208. (b) Halland, N.; Hansen, T.;
Jørgensen, K. A. Organocatalytic Asymmetric Michael Reaction of Cyclic 1,3-Dicarbonyl
Compounds and α,β-Unsaturated Ketones - A Highly Atom-Economic Catalytic One-Step
Formation of Optically Active Warfarin Anticoagulant. Angew. Chem. Int. Ed. 2003, 42,
4955–4957. (c) Rueping, M.; Merino, E.; Sugiono, E. Enantioselective Organocatalytic
Reactions of 4-Hydroxycoumarin and 4-Hydroxypyrone with α,β-Unsaturated Aldehydes - An
Efficient Michael Addition-Acetalization Cascade to Chromenones, Quinolinones and
Pyranones. Adv. Synth. Catal. 2008, 350, 2127–2131.
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6
7
8
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(5) Modrocka, V.; Veverkova, E.; Meciarova, M.; Sebesta, R. Bifunctional Amine-
Squaramides as Organocatalysts in Michael/Hemiketalization Reactions of β,γ-Unsaturated
α-Ketoesters and α,β-Unsaturated Ketones with 4-Hydroxycoumarins. J. Org. Chem. 2018, 83,
13111−13120.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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35
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53
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55
56
57
58
59
60
(6) Wang, J.-j.; Lao, J.-h.; Hu, Z.-p.; Lu, R.-J.; Nie, S.-z.; Du, Q.-s.; Yan, M. Organocatalytic
Asymmetric Conjugate Addition of Cyclic 1,3-Dicarbonyl Compounds to β,γ-Unsaturated
α-Ketoesters. ARKIVOC 2010, 229−243.
(7) Wang, Y.-F.; Zhang, W.; Luo, S.-P.; Zhang, G.-C.; Xia, A.-B.; Xu, X.-S.; Xu, D.-Q. Highly
Enantioselective Organocatalytic Michael Addition of 2-Hydroxy-1,4-naphthoquinone to
β,γ-Unsaturated α-Oxo Esters. Eur. J. Org. Chem. 2010, 4981–4985.
(8) Xu, D.-Q.; Wang, Y.-F.; Zhang, W.; Luo, S.-P. Zhong, A.-G.; Xia, A.-B.; Xu, Z.-Y. Chiral
Squaramides as Highly Enantioselective Catalysts for Michael Addition Reactions of
4-Hydroxycoumarins and 4-Hydroxypyrone to β,γ-Unsaturated α-Keto Esters. Chem. Eur. J.
2010, 16, 4177–4180.
(9) Gao, Y.; Ren, Q.; Wang, L.; Wang, J. Enantioselective Synthesis of Coumarins Catalyzed
by a Bifunctional Amine–Thiourea Catalyst. Chem. Eur. J. 2010, 16, 13068–13071.
(10) Chen, X.-K.; Zheng, C.-W.; Zhao, S.-L.; Chai, Z.; Yang, Y.-Q.; Zhao, G.; Cao, W.-G.
Highly Enantioselective Michael Addition of Cyclic1,3-Dicarbonyl Compounds to
β,γ-Unsaturated α-Keto Esters. Adv. Synth. Catal. 2010, 352, 1648–1652.
(11) Wang, Y.-F.; Wang, K.; Zhang, W.; Zhang, B.-B.; Zhang, C.-X.; Xu, D.-Q.
Enantioselective Asymmetric Michael Addition of Cyclic Diketones to β,γ-Unsaturated α-Keto
Esters. Eur. J. Org. Chem. 2012, 3691–3696.
(12) Zhao, B.-L.; Du, D.-M. Enantioselective Synthesis of Enol Lactones from Tandem Michael
Addition/Lactonization Catalyzed by a Chiral Squaramide Catalyst. Tetrahedron: Asymmetry
2014, 25, 310–317.
(13) 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.
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(14) Halland, N.; Velgaard, T.; Jørgensen, K. A. Direct Asymmetric Michael Reactions of
Cyclic 1,3-Dicarbonyl Compounds and Enamines Catalyzed by Chiral Bisoxazoline-Copper(II)
Complexes. J. Org. Chem. 2003, 68, 5067–5074.
9
(15) Dong, Z.; Feng, J.; Cao, W.; Liu, X.; Lin, L.; Feng, X. N,N’-Dioxide–Nickel(II) Complex
Catalyzed Asymmetric Michael Addition of Cyclic 1,3-Dicarbonyl Compounds to
β,γ-Unsaturated α-Ketoesters. Tetrahedron Lett. 2011, 52, 3433– 3436.
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(16) (a) Liu, S.; Gao, W.-C.; Miao, Y.-H.; Wang, M.-C. Dinuclear Zinc-AzePhenol Catalyzed
Asymmetric Aza-Henry Reaction of N-Boc Imines and Nitroalkanes under Ambient Conditions.
J. Org. Chem. 2019, 84, 2652−2659. (b) Liu, S.; Li, G.-W.; Yang, X.-C.; Zhang, D.-Y.; Wang,
M.-C. Dinuclear Zinc Complex Catalyzed Asymmetric Methylation and Alkynylation of
Aromatic Aldehydes. Org. Biomol. Chem. 2017, 15, 7147−7156. (c) Liu, S.; Shao, N.; Li, F.-Z.;
Yang, X.-C.; Wang, M.-C. Azetidine Derived Dinuclear Zinc Catalyzed Asymmetric
Phospha-Michael Addition of Dialkyl Phosphite to α,β-Unsaturated Carbonyl Compounds. Org.
Biomol. Chem. 2017, 15, 9465−9474. (d) Hua, Y.-Z.; Liu, M.-M.; Huang, P.-J.; Song, X.; Wang,
M.-C.; Chang, J.-B. A New Strategy for Enantioselective Construction of Multisubstituted
Five-Membered Oxygen Heterocycles via a Domino Michael/Hemiketalization Reaction.
Chem.–Eur. J. 2015, 21, 11994–11998. (e) Hua, Y.-Z.; Han, X.-W.; Yang, X.-C.; Song, X.;
Wang, M.-C.; Chang, J.-B. Enantioselective Friedel–Crafts Alkylation of Pyrrole with
Chalcones Catalyzed by a Dinuclear Zinc Catalyst. J. Org. Chem. 2014, 79, 11690–11690. (f)
Liu, M.-M., Yang, X.-C., Hua, Y.-Z., Chang, J.-B., Wang, M.-C. Synthesis of Chiral
Bispirotetrahydrofuran Oxindoles by Cooperative Bimetallic-Catalyzed Asymmetric Cascade
Reaction. Org. Lett. 2019, 21, 2111. (g) Yang, X.-C., Liu, M.-M., Mathey, F., Yang, H., Hua,
Y.-Z., Wang, M.-C. Access to Chiral 2,5-Pyrrolidinyl Dispirooxindoles via Dinuclear
Zinc-Catalyzed Asymmetric Cascade Reactions. J. Org. Chem. 2019, 84, 7762.
(17) (a) Shao, N.; Luo, Y.-Y.; Lu, H.-J.; Hua, Y.-Z.; Wang, M.-C. Enantioselective Phospha-
Michael Reaction of Diethyl Phosphonate with Exocyclic α,β-Unsaturated Benzocyclic Ketones
Catalyzed by a Dinuclear Zinc-AzePhenol Catalyst. Tetrahedron 2018, 74, 2130-2142. (b) Hua,
Y.-Z.; Chen, J.-W.; Yang, H.; Wang, M.-C. Asymmetric Friedel−Crafts Alkylation of Indoles
with Trifluoromethyl Pyruvate Catalyzed by a Dinuclear Zinc Catalyst. J. Org. Chem. 2018, 83,
1160−1166.
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(18) Song, X.; Liu, J.; Liu, M.-M.; Wang, X.; Zhang, Z.-F.; Wang, M.-C.; Chang, J. Dinuclear
Zinc Catalyzed Asymmetric Tandem Michael Addition/Acetalization Reactions of Cyclic
Diketones and β,γ-Unsaturated α-Ketoesters. Tetrahedron 2014, 70, 5468−5474.
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