Dinuclear zinc catalyzed asymmetric tandem Michael addition/acetalization reactions of cyclic diketones and β,γ-unsaturated α-ketoesters

Article abstract of DOI:10.1016/j.tet.2014.06.109

The dinuclear zinc-ProPhenol complex is applied as efficient catalyst in the highly stereoselective tandem Michael addition/acetalization reactions of cyclic 1,3-diketones and β,γ-unsaturated α-ketoesters. A variety of substrates are well-tolerated, and a broad range of synthetically and pharmaceutically useful chiral chromene derivatives are directly produced in good yields of up to 96% and good enantioselectivities of up to 96% ee.

Full text of DOI:10.1016/j.tet.2014.06.109

Tetrahedron 70 (2014) 5468e5474
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Dinuclear zinc catalyzed asymmetric tandem Michael addition/
acetalization reactions of cyclic diketones and
-ketoesters
b
,g
-unsaturated
a
*
Xixi Song, Jing Liu, Meng-Meng Liu, Xi Wang, Zhao-Fei Zhang, Min-Can Wang ,
*
Junbiao Chang
The College of Chemistry and Molecular Engineering, Zhengzhou University, No. 75 Daxue Road, Zhengzhou, Henan 450052, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 May 2014
Received in revised form 20 June 2014
Accepted 26 June 2014
Available online 30 June 2014
The dinuclear zinceProPhenol complex is applied as efficient catalyst in the highly stereoselective tan-
dem Michael addition/acetalization reactions of cyclic 1,3-diketones and b,g-unsaturated a-ketoesters. A
variety of substrates are well-tolerated, and a broad range of synthetically and pharmaceutically useful
chiral chromene derivatives are directly produced in good yields of up to 96% and good enantiose-
lectivities of up to 96% ee.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Michael addition
Dinuclear zinc complex
Tandem reaction
Oxygen heterocycles
1. Introduction
Michael addition/acetalization reactions of cyclic 1,3-dicarbonyl
compounds and b,g-unsaturated a-ketoesters catalyzed by chiral
The six-membered oxygenated heterocycles, such as tetrahy-
dropyrans, chromenes, and flavanones, are one of the most com-
mon natural product frameworks, which exhibit numerous
biological and physiological activities.1 The structural motifs, es-
pecially the optically active ones, are widely utilized as important
building blocks for natural product syntheses and pharmaceutical
elaborations.1aed,f Among various asymmetric synthetic strategies
developed to prepare the chiral motifs, the catalytic tandem Mi-
chael addition/acetalization reaction of cyclic 1,3-dicarbonyl com-
bisoxazolineecopper(II) complexes.3 By using (S)-t-Bu-Box (Fig. 1)
as the optimal chiral ligand, a variety of synthetically and phar-
maceutically useful chiral chromene derivatives4 were directly
produced in almost quantitative yields and good stereoselectivities
up to 92% ee.3 Following the early pioneering work, the asymmetric
tandem processes have drawn intensive studies in recent years.5
Calter and co-worker demonstrated that cinchona alkaloid-
derived pyrimidine organocatalysts could efficiently catalyze the
tandem reactions to afford excellent enantioselectivities ranging
from 94% to 99% ee.5a Subsequently, a variety of chiral squaramide-
pound with a,b-unsaturated carbonyl compound is considered as
one of the highly efficient approaches.1d,e
Comparing with other commonly used
bonyl derivatives, such as alkenals and enones, the b,g
a
,
b
-unsaturated car-
-unsaturated
-ketoesters demonstrate specific advantages in substrate activa-
a
tion and stereo-induction owing to the presence of bidentate 1,2-
dicarbonyl moiety, which can form multiple effective associations
with different types of chiral catalysts.2 As early as in 2003,
Jørgensen and co-workers reported the asymmetric tandem
* Corresponding authors. Tel./fax: þ86 371 67769024 (M.C.W.); tel./fax: þ86 371
67781788 (J.C.); e-mail addresses: wangmincan@zzu.edu.cn (M.-C. Wang), chang-
junbiao@zzu.edu.cn (J. Chang).
Fig. 1. Previously used chiral ligands for the asymmetric tandem reactions of 1,3-
dicarbonyl compounds and b,g-unsaturated a-ketoesters.
http://dx.doi.org/10.1016/j.tet.2014.06.109
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

X. Song et al. / Tetrahedron 70 (2014) 5468e5474
5469
Table 1
or/and thiourea-derived H-bonding organocatalysts have also been
utilized as effective catalyst by the groups of Cao, Wang, and Xu,
respectively.5bed,g However, the development of chiral metal cata-
lysts is yet to be investigated. In 2011, Feng and co-workers com-
municated the highly enantioselective tandem Michael addition/
acetalization reactions of various cyclic 1,3-dicarbonyl compounds
Optimization of reaction conditions for the cascade Michael reaction of 2a and 1aa
and
deenickel(II)/copper(II) complexes (Fig. 1).5e,f Recently, Govender
and co-workers also described the application of
b
,g-unsaturated
a
-ketoesters catalyzed by N,N0-dioxi-
tetrahydroisoquinoline-derived N,N0-dioxide ligands (Fig. 1) to the
tandem transformations, but only moderate to good enantiose-
lectivities were obtained.5h Since the effective metal catalysts are
majorly limited to bisoxazoline and N,N0-dioxide mononuclear
metal complexes, the development of efficient metal catalysts is in
demand and rewarding, given the synthetic usefulness of chiral
chromene products.
Entry
L
Metal reagent
Solvent
Time (h)
Yield (%)b
ee (%)c
1
2
3
L1
L2
L3
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
Et2Zn
Et2Zn
Et2Zn
Me2Zn
Et2ZnþBu2Mg
Bu2Mg
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
THF
THF
THF
THF
THF
THF
Toluene
CH2Cl2
CHCl3
Et2O
MeCN
1,4-Dioxane
THF
20
15
15
21
21
21
20
20
20
20
20
20
20
24
26
94
62
90
90
54
80
53
46
48
50
42
92
80
94
87
93
4
89
91
36
5
81
75
70
61
76
77
92
94
89
Meanwhile, as a well-developed bifunctional metal catalyst, the
Trost’s dinuclear zinceProPhenol complex (Fig. 2) has demon-
strated remarkable catalytic efficiency and stereoselectivity in
asymmetric Michael additions of carbo- and phospho-nucleophiles
4
5d
6
7
8
9
10
11
12
13e
14f
15g
to a,b
-unsaturated carbonyl compounds and nitroalkenes.6,7 The
self-assembled dinuclear metal complex displays complementary
reactivity at the two metal centers, and allows for dual activation of
both Michael donor and acceptor. Comparing with the broad ap-
plications of the dinuclear metal catalyst in single-step reactions,
its use in synthetically useful tandem processes has been rarely
reported. Recently, Trost and Hirano demonstrated that the dinu-
clear zinc complex was capable of catalyzing tandem Michael ad-
dition/transesterification reactions to produce spirocyclic oxindoles
in good yields and excellent stereoselectivities.6e Moreover,
THF
THF
a
Unless otherwise noted, the reaction were performed with 1a (0.125 mmol), 2a
ꢀ
(0.125 mmol), ligand L (5 mol %), metal reagent (10 mol %), and 10 mg 4 A MS in
solvent (1.3 mL) at 25 ꢀC.
b
a
-hydroxyketone,6a
Yield of the isolated product 3a.
Determined by chiral HPLC analysis using the Chiralpak AD column. And the
bidentate enolate surrogate, for example,
c
2(5H)-furanone,6c or 3-hydroxyoxindole,6e is usually required as
effective Michael donor, and the use of monodentate one is less
documented. In these contexts, we herein report the dinuclear
zinceProPhenol-catalyzed highly enantioselective tandem Michael
absolute configuration of 3a was determined by comparison to literature data.5b
d
The 5 mol % Et2Zn and 5 mol % Bu2Mg were used as metal reagents.
e
The 3 mol % ligand L1 and 6 mol % Et2Zn were used.
f
The reaction was performed at 10 ꢀC.
g
The reaction was performed at 0 ꢀC.
addition/acetalization reactions of cyclic 1,3-diketones and
b,g-
unsaturated -ketoesters, and a wide range of optically active
a
chromene derivatives are directly produced in good yields (up to
96%) and good enantioselectivities (up to 96% ee) with a catalyst
loading of 5 mol %.
also screened, and anhydrous THF gave the optimal results in both
yield and enantioselectivity (Table 1, entries 7e12). When the
catalyst loading was decreased from 5 to 3 mol %, reaction yield was
decreased to 80% with a slight sacrifice in stereoselectivity (Table 1,
entry 13). When reaction temperature was lowered to 10 ꢀC, the
enantioselectivity increased to 94% ee, but at the cost of extended
reaction time (Table 1, entry 14). Furthermore, when the reaction
was performed at 0 ꢀC, the decreases of both reaction efficiency and
stereoselectivity were observed (Table 1, entry 15).
After the optimal reaction conditions were established, the
substrate scope and limitation of the tandem reaction were further
investigated by using various
b,g-unsaturated a-ketoesters and
Fig. 2. Trost’s dinuclear zinceProPhenol complex.
cyclic 1,3-diketones (Table 2). It was found that the catalytic tan-
dem process is sensitive to spatial hindrance. If a substrate, either
a Michael donor or acceptor, possesses even a small steric hin-
drance group, a change of reaction efficiency or/and stereo-
selectivity would be observed.
2. Results and discussion
We started our investigations by examining the cascade Michael
reaction of cyclic 1,3-diketone 2a and
b
,
g
-unsaturated
a
-ketoester
The b,g-unsaturated a-ketoesters bearing different substituent
1a under the catalysis of dinuclear metaleProPhenol complex
(Table 1). The chiral complex was in situ generated by treating (S,S)-
Bis-ProPhenol ligand L with 2 equiv metal reagent in the presence
on ester moiety (R2) was initially examined. A relative big sub-
stituent, such as ethyl or isopropyl, would result in decreased yield
and prolonged reaction time comparing with methyl substituent
(Table 2, entries 1e3). The substrates 1 bearing para- or/and meta-
6
ꢀ
of 4 A MS. Early optimization with various ligandemetal combi-
nations (Table 1, entries 1e6) proved that the complex of ligand L1
and Et2Zn was the optimal catalyst in promoting the desired con-
jugate addition in anhydrous THF at 25 ꢀC. The Michael reaction
was followed with a favored tandem acetalization to afford hex-
ahydrochromene 3a in 94% yield and 93% ee (Table 1, entry 1).8
Some typical solvents, such as toluene and acetonitrile, which
had been previously used in the dinuclear catalytic system, were
substituted
g
-aryl moiety (R1) could smoothly react with 1,3-
cyclohexanedione (R3¼H) to afford chiral chromene derivatives 3
in good yields and excellent enantioselectivities of more than 90%
ee (Table 2, entries 4e14). A broad range of substituents on the g-
aromatic ring were well tolerated, including both electronic do-
nating groups, such as methyl and methoxyl, and electronic with-
drawing groups, such as fluoro, chloro, and bromo. Whereas,

5470
X. Song et al. / Tetrahedron 70 (2014) 5468e5474
Table 2
under the optimal reaction conditions. But, surprisingly, no signifi-
cant conversion was observed in each case, and the reactants were
almost untouched even after prolonged reaction time. Additionally,
the reaction of 4-hydroxycoumarine 5 was examined, and the cor-
responding cascade product 6 was obtained in 80% yield, but the
enantioselectivity is as low as 24% ee (Scheme 1). When 2-hydroxy-
1,4-naphthoquinone 7 was utilized as 1,3-diketone surrogate, the
reaction could not be driven to a completion even after three days,
and the tandem product 8 was isolated in very poor yield and
enantioselectivity (Scheme 2).
Substrate scope of the catalytic asymmetric Michael addition/acetalization reactions
of cyclic diketones and -unsaturated
b
,
g
a
-ketoestersa
Entry R1
R2
R3
Time (h)
3
Yield (%)b ee (%)c
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Me
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
24
27
30
26
28
21
24
26
30
30
28
27
24
28
48
48
72
28
30
3a
3b
3c
3d
3e
3f
3g
3h
3i
94
79
79
95
89
96
87
96
67
65
87
77
94
91
92
91
91
91
90
92
91
89
93
91
91
91
16
12
n.d.d
93
96
89
76
74
75
76
iPr
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-MeC6H4
3-MeOC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
3j
3k
3l
3,4-OCH2OeC6H3
3-ClC6H4
Scheme 1. Asymmetric cascade Michael reaction by using 4-hydroxycoumarin as
Michael donor.
3-BrC6H4
3m 87
3-Bre4-CleC6H3
2-ClC6H4
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
75
16
7
2-BrC6H4
2,6-(MeO)2eC6H3 Me
0
2-Naphthyl
2-Thienyl
Ph
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
Me
Me
80
84
98
90
94
85
85
Me Me 20
Me Me 28
Me Me 30
Me Me 30
Me Me 30
Scheme 2. Asymmetric cascade Michael reaction by using 2-hydroxy-1,4-
naphthoquinone as Michael donor.
a
Unless otherwise noted, the reaction were performed with 1 (0.125 mmol), 2
ꢀ
(0.125 mmol), ligand L1 (5 mol %), Et2Zn (10 mol %), and 10 mg 4 A MS in anhydrous
In order to understand the catalytic process, the transition state
model of the conjugate addition process (Scheme 3) was proposed
based on the dual activation mechanism of dinuclear zinc cata-
THF (1.3 mL) at 10 ꢀC.
b
Yield of the isolated product 3.
Determined by chiral HPLC analysis using the Chiralpak AD or OD column. And
c
lysis6aec,e,7a and the bidentate coordination mode of
b
,
g
-un-
-ketoesters.2 As illustrated, the cyclic 1,3-diketone was
activated by the Brønsted basic zinc nucleus, and the zinc enolate
was formed. Meanwhile, the -unsaturated -ketoester was ac-
the absolute configurations of 3 were determined by comparison to literature
data.5a,b,f,g
saturated
a
d
Not determined.
b
,
g
a
compared with para-substituted substrate, the meta-substituted
one usually gave reduced yield (Table 2, entry 4 vs 9, entry 5 vs 10,
entry 7 vs 12, and entry 8 vs 13).
tivated by the other Lewis acidic zinc nucleus via bidentate co-
ordination of the 1,2-dicarbonyl moiety. With the spatial alignment,
the zinc enolate would attack from the Re face of the coordinated
Michael acceptor to give the observed stereo-chemical outcome.
If the spatial hindrance of g-aryl moiety was large enough, the
conjugate addition could be severely prohibited. When either or-
tho-chloro or ortho-bromo substituted substrate was used, a com-
peting 1,2-addition/condensation process was identified as major
reaction, and the desired Michael addition/acetalization product
was afforded in very poor yield and enantioselectivity (Table 2,
entries 15 and 16). Moreover, the 2,6-dimethoxyl substituted
b,g-
unsaturated -ketoester was not able to react with 1,3-
a
cyclohexanedione, and reactants were almost fully recovered af-
ter days (Table 2, entry 17).
The scope of cyclic 1,3-diketone was also extended to dimedone
(R3¼Me) to further explore the potential of the catalytic system.
Compared with the results obtained by using 1,3-cyclohexanedione,
the reaction efficiency of dimedone remained almost the same, but
the enantioselectivities were decreased (Table 2, entries 20e24).
Furthermore, a series of different 1,3-dicarbonyl compounds (Fig. 3),
such as 2-methyl-1,3-cyclohexanedione 4a, 1,3-cyclopentanedione
4b, 2,4-pentanedione 4c, and Meldrum’s acid 4d were also applied
Scheme 3. Proposed transition state model.
3. Conclusion
In summary, we reported the dinuclear zinceProPhenol complex
catalyzed highly efficient asymmetric tandem Michael addition/
as Michael donors to react with
b,g-unsaturated a-ketoester 1a
acetalization reactions of cyclic 1,3-diketones and
b,g-unsaturated
a-ketoesters. A broad range of substrates are well-tolerated, and
synthetically and pharmaceutically useful chiral chromene de-
rivatives were directly produced in good yields up to 96% and good
enantioselectivities up to 96% ee. In the detailed study of substrate
scope, a steric hindrance effect was observed. If a substrate, either
Fig. 3. A series of 1,3-dicarbonyl compounds.

X. Song et al. / Tetrahedron 70 (2014) 5468e5474
5471
a Michael donor or acceptor, possesses a spatial hindrance group,
the reaction efficiency or/and stereoselectivity would decrease.
Besides six-membered cyclic 1,3-diketones, the 4-hydroxycoumarin
was also used as an alternative Michael donor to produce the desired
six-membered oxygenated heterocycle. The stereoselective out-
come of the asymmetric catalysis was also explained by a proposed
transition state model of the conjugate addition process.
20.2 ppm; IR (neat): 3433, 3130, 2927, 2852, 1744, 1615, 1400, 1162,
776, 561 cmꢁ1; MS (ESI): m/z¼303.1 [MþH]þ.
4.3.2. (4R)-Ethyl 2-hydroxy-5-oxo-4-phenyl-3,4,5,6,7,8-hexahydro-
2H-chromene-2-carboxylate (3b).5a,f Purified by flash chromatog-
raphy (petroleum ether/EtOAc¼2/1) to afford a white solid in 79%
yield; HPLC (Chiralpak AD, hexane/i-PrOH¼80/20, flow
rate¼1.0 mL/min,
l
¼254 nm): tR(major)¼7.40 min, tR(minor)¼
10.00 min, 90.3% ee; 1H NMR (400 MHz, CDCl3):
d
¼7.28e7.23 (m,
4. Experimental
2.17H), 7.17e7.15 (m, 3.0H), 4.78 (br s, 0.54H), 4.40 (br s, 0.26H),
4.29e4.11 (m, 2.42H), 3.89 (m, 0.69H), 2.58e2.34 (m, 6.30H),
2.28e1.99 (m, 2.18H), 1.33e1.30 (m, 1.15H), 1.27e1.24 (m, 2.15H)
4.1. General methods
ppm; 13C NMR (100 MHz, CDCl3):
d¼197.1, 196.5, 169.5, 169.0, 168.9,
NMR spectra (1H and 13C) were performed on a commercial
spectrometer (400 MHz for 1H NMR and 100 MHz for 13C NMR)
using solution in CDCl3 (referenced internally to Me4Si); the J values
were given in Hertz. IR Spectra were determined on a commercial
spectrophotometer. TLC was performed on dry silica gel plates
developed with petroleum ether (60e90 ꢀC) and ethyl acetate, and
spots were visualized with UV light. The mass spectra were ob-
tained using a commercial instrument with an electrospray ioni-
zation source (ESI). The ionization method for HRMS was
electrospray ionization (ESI), and the mass analyzer type was the
time of flight (TOF). All the mass spectra were performed using
anhydrous MeOH as solvent. Melting points were determined using
melting point apparatus. The chiral ProPhenol ligands (L1,6d L2,7d
168.8, 144.1, 142.8, 128.4,128.2,127.2, 126.9, 126.2,126.1, 115.3, 113.1,
95.6, 94.7, 63.2, 63.0, 38.3, 37.0, 36.9, 35.8, 33.3, 31.8, 29.7, 28.9, 28.8,
20.7, 20.2, 14.0, 13.9 ppm; IR (neat): 3439, 3131, 2853, 1741, 1662,
1400, 1161, 910, 880, 776, 561 cmꢁ1; MS (ESI): m/z¼317.1 [MþH]þ,
339.1 [MþNa]þ, 655.2 [2MþNa]þ.
4.3.3. (4R)-Isopropyl 2-hydroxy-5-oxo-4-phenyl-3,4,5,6,7,8-hexahy
dro-2H-chromene-2-carboxylate (3c). Purified by flash chromatogra-
phy (petroleum ether/EtOAc¼2/1) to afford a white solid in 79% yield;
HPLC (Chiralpak AD, hexane/i-PrOH¼80/20, flow rate¼1.0 mL/min,
25
l
¼254 nm): tR(major)¼6.68 min, tR(minor)¼9.16 min, 91.4% ee; [
a
]
D
þ16.4 (c 0.52, CH2Cl2); 1H NMR (400 MHz, CDCl3):
¼7.29e7.24 (m,
d
2.22H), 7.20e7.16 (m, 3.06H), 5.12e5.02 (m, 0.99), 4.81 (s, 0.55H), 4.48
(s, 0.21H),4.08e4.09 (m, 0.32H), 3.91e3.87 (m, 0.67H), 2.59e2.17 (m,
6.36H), 2.08e1.99 (m, 2.26H), 1.31e1.25 (m, 6.37H) ppm; 13C NMR
and L36d) and various
g-aryl b,g-unsaturated a
-ketoesters 19
were synthesized according to reported procedures.
(100 MHz, CDCl3):
d
¼197.0,196.5,169.6,168.9,168.5,168.4,144.3,142.9,
4.2. Representative procedure for the dinuclear zincePro-
Phenol complex catalyzed tandem Michael addition/acetali-
zation reactions
128.4,128.2, 127.2, 126.9, 126.2, 126.1, 115.4, 113.2, 95.6, 94.6, 38.3, 37.0,
36.9, 35.8, 33.4, 31.9, 28.9, 28.8, 25.3, 21.6, 21.5, 21.4, 20.7, 20.2 ppm; IR
(neat): 3423, 3131, 2927, 2853, 1744, 1662, 1619, 1400, 1225, 1078, 828,
561 cmꢁ1; MS (ESI): m/z¼331.1 [MþH]þ, 353.1 [MþNa]þ; HRMS (ESI-
TOF): m/z [MþH]þ, calcd for C19H23Oþ5 331.1545, found 331.1541.
Diethylzinc (1 M in hexane, 13
mL, 13
mmol, 10 mol %) was added
via microsyringe to a stirred solution of chiral ligand L1 (6
m
mol,
4.3.4. (4R)-Methyl 2-hydroxy-5-oxo-4-p-tolyl-3,4,5,6,7,8-hexahy
dro-2H-chromene-2-carboxylate (3d).5f Purified by flash chroma-
tography (petroleum ether/EtOAc¼2/1) to affordawhitesolid in 95%
yield; HPLC (Chiralpak AD, hexane/i-PrOH¼80/20, flow
5 mol %) in freshly distilled anhydrous THF (0.3 mL) under a nitro-
gen atmosphere, and the mixture was stirred at room temperature
for 30 min to generate the zinc catalyst. The resulting solution was
cooled to 10 ꢀC, and was quickly added into a stirred solution of
b,g-
rate¼1.0 mL/min,
l¼254 nm): tR(major)¼8.72 min, tR(minor)¼
unsaturated
a-ketoester 1 (0.125 mmol), cyclic 1,3-diketone 2
10.42 min, 91.5% ee; 1H NMR (400 MHz, CDCl3):
0.59H), 4.51 (s, 0.29H),4.07 (br s, 0.37H), 3.88e3.82 (m, 0.57H), 3.82
(s, 1.01H), 3.70 (s, 1.95H), 2.58e2.33 (m, 4.13H), 2.28(s, 3H),
2.25e2.20 (m, 1.66H), 2.07e1.97 (m, 2.29H) ppm; 13C NMR
d
¼7.05 (s, 4H), 5.0(s,
ꢀ
(0.125 mmol), and 10 mg 4 A MS in freshly distilled anhydrous THF
(1.0 mL) at 10 ꢀC under a nitrogen atmosphere. The reaction mix-
ture was stirred at 10 ꢀC, and was monitored by TLC analysis. After
total consumption of reactants, the reaction was quenched using
saturated aqueous solution of NH4Cl, and was extracted with ethyl
acetate for three times. The combined organic layer was washed
with saturated aqueous solution of Na2CO3 and brine, and dried
over anhydrous Na2SO4, and concentrated under vacuum. The
residue was purified by flash column chromatography on silica gel
using a mixture of petroleum ether and ethyl acetate as eluent.
Absolute configurations of the tandem reaction products were
assigned by correlation to literature data and considering the
similarity in the stereochemical reaction pathway.5a,b,f,g
(100 MHz, CDCl3):
d
¼197.2, 196.6, 196.5, 169.4, 169.3, 168.8, 140.9,
139.6, 135.8, 135.5, 129.1, 127.0, 126.8, 115.4, 113.2, 95.7, 94.8, 38.3,
36.9, 35.8, 32.8, 31.2, 28.9, 28.8, 21.0, 20.7, 20.2 ppm; IR (neat): 3423,
3131, 2958, 2927, 2853, 1744, 1615, 1400, 1162, 1080, 775, 561 cmꢁ1
;
MS (ESI): m/z¼317.1 [MþH]þ, 339.1 [MþNa]þ, 655.3 [2MþNa]þ.
4.3.5. (4R)-Methyl 2-hydroxy-4-(4-methoxyphenyl)-5-oxo-3,4,5,6,7,8-
hexahydro-2H-chromene-2-carboxylate (3e).5f Purified by flash chro-
matography (petroleum ether/EtOAc¼2/1) to afford a white solid in
89% yield; HPLC (Chiralpak AD, hexane/i-PrOH¼80/20, flow
rate¼1.0 mL/min,
l
¼254 nm): tR(major)¼12.49 min, tR(minor)¼
20.34 min, 91.2% ee; 1H NMR (400 MHz, CDCl3):
d
¼7.09e7.06 (m,
4.3. Characterization of the tandem reaction products
1.99H), 6.81e6.79 (d, J¼8.3 Hz, 2H), 4.91 (br s, 0.53H), 4.44 (br s,
0.32H), 4.05 (br s, 0.36H), 3.88e3.84 (m, 1.78H), 3.76e3.71 (m,
4.97H), 2.49e2.19 (m, 6.32H), 2.07e1.99 (m, 2.36H) ppm; 13C NMR
4.3.1. (4R)-Methyl 2-hydroxy-5-oxo-4-phenyl-3,4,5,6,7,8-hexahydro-
2H-chromene-2-carboxylate (3a).5f Purified by flash chromatogra-
phy (petroleum ether/EtOAc¼2/1) to afford a white solid in 94%
yield; HPLC (Chiralpak AD, hexane/i-PrOH¼80/20, flow rate¼1.0 mL/
(150 MHz, CDCl3):
d
¼197.2, 196.7, 169.4, 169.3, 168.8, 158.0, 157.8,
135.9, 134.8, 128.1, 127.9, 115.4, 113.8, 113.8, 113.4, 95.8, 94.9, 55.2,
55.2, 53.6, 53.5, 38.3, 37.0, 36.9, 35.9, 32.4, 30.8, 28.9, 28.8, 20.7,
20.2 ppm; IR (neat): 3423, 3130, 2957, 2924, 2853, 1745, 1614, 1615,
1245, 1400, 1225, 1078, 1040, 776, 561 cmꢁ1; MS (ESI): m/z¼333.2
[MþH]þ, 687.3 [2MþNa]þ.
min,
l
¼254 nm): tR(major)¼7.75 min, tR(minor)¼10.56 min, 94.3%
ee; 1H NMR (400 MHz, CDCl3):
d
¼7.27e7.24 (m, 2.15H), 7.17e7.14 (m,
3H), 4.83 (s, 0.64H), 4.40 (s, 0.30H), 4.09e4.13 (m, 0.33H), 3.89 (m,
0.70H), 3.84 (s, 0.97H), 3.71 (s, 2.04H), 2.56e2.22 (m, 6.26H),
2.17e1.99 (m, 2.15H) ppm; 13C NMR (100 MHz, CDCl3):
d¼197.1,196.5,
169.4,168.8,143.9,142.7, 128.4,128.3,127.2, 126.9,126.3,126.1, 115.3,
113.1, 95.7, 94.8, 38.3, 36.9, 36.9, 35.8, 33.2, 31.6, 28.8, 28.7, 20.7,
4.3.6. (4R)-Methyl 4-(4-fluorophenyl)-2-hydroxy-5-oxo-3,4,5,6,7,8-
hexahydro-2H-chromene-2-carboxylate (3f).5f Purified by flash

5472
X. Song et al. / Tetrahedron 70 (2014) 5468e5474
chromatography (petroleum ether/EtOAc¼2/1) to afford a white
solid in 96% yield; HPLC (Chiralpak AD, hexane/i-PrOH¼80/20, flow
2.10e1.98 (m, 2.22H) ppm; 13C NMR (100 MHz, CDCl3):
d¼197.1, 196.6,
169.5, 169.4, 169.3, 168.8, 159.5, 159.5, 145.7, 144.4, 129.4, 129.3, 119.5,
119.4, 115.2, 113.6, 112.9, 111.1, 95.7, 94.8, 38.3, 36.9, 36.9, 35.8, 33.2,
31.6, 28.9, 28.8, 20.7, 20.2 ppm; IR (neat): 3424, 3131, 2853, 1744,
1664, 1662,1400, 1161,1078, 776, 619, 561 cmꢁ1; MS (ESI): m/z¼333.2
[MþH]þ, 355.2 [MþNa]þ, 687.3 [2MþNa]þ.
rate¼1.0 mL/min,
l
¼254 nm): tR(major)¼9.07 min, tR(minor)¼
14.26 min, 90.9% ee; 1H NMR (400 MHz, CDCl3):
d¼7.13e7.10 (m,
2.00H), 6.96e6.92 (m, 1.94H), 4.82 (s, 0.52H), 4.50 (s, 0.37H),
4.06e4.04 (m, 0.37H), 3.90e3.89 (m, 0.71H), 3.85 (s, 1.05H), 3.76 (s,
1.95H), 2.57e2.19 (m, 6.27H), 2.09e1.99 (m, 2.49H) ppm; 13C NMR
(100 MHz, CDCl3):
d
¼196.6, 196.5, 169.4, 169.3, 169.0, 162.4, 159.9,
4.3.11. (4R)-Methyl 4-(benzo[d][1,3]dioxol-5-yl)-2-hydroxy-5-oxo-
3,4,5,6,7,8-hexahydro-2H-chromene-2-carboxylate (3k).5f Purified
by flash chromatography (petroleum ether/EtOAc¼2/1) to afford
awhite solid in 87%yield; HPLC (ChiralpakAD, hexane/i-PrOH¼80/20,
139.6, 139.5, 138.6, 128.8, 128.7, 128.3, 128.3, 115.3, 115.2, 115.0,
114.9, 114.8, 95.5, 94.7, 53.7, 53.6, 38.3, 36.9, 36.9, 36.8, 35.6, 32.6,
31.0, 28.8, 28.7, 20.7, 20.2 ppm; IR (neat): 3430, 3130, 2853, 1742,
1663, 1621, 1400, 1159, 1083, 776, 561 cmꢁ1; MS (ESI): m/z¼321.1
[MþH]þ, 343.1 [MþNa]þ, 359.1 [MþK]þ.
flow rate¼1.0 mL/min, ¼254 nm): tR(major)¼15.04 min, tR(minor)¼
l
18.78 min, 92.5% ee; 1H NMR (400 MHz, CDCl3):
d
¼6.71e6.69 (m,
0.99H), 6.66e6.63 (m, 2.03H), 5.89 (s, 2H), 4.05e3.93 (m, 0.55H), 3.84
(s, 1.19H), 3.82e3.79 (m, 0.55H), 3.79 (s, 1.95H), 2.56e2.18 (m, 6.48H),
4.3.7. (4R)-Methyl 4-(4-chlorophenyl)-2-hydroxy-5-oxo-3,4,5,6,7,8-
hexahydro-2H-chromene-2-carboxylate (3g).5f Purified by flash
chromatography (petroleum ether/EtOAc¼2/1) to afford a white
solid in 87% yield; HPLC (Chiralpak AD, hexane/i-PrOH¼80/20, flow
2.07e1.97 (m, 2.31H) ppm; 13C NMR (100 MHz, CDCl3):
d¼197.2, 196.7,
169.5, 169.4, 169.3, 168.8, 147.5, 145.7, 137.9, 136.8, 120.1, 115.4, 113.2,
108.2, 108.1, 107.9, 107.3, 100.9, 100.8, 95.7, 94.8, 53.7, 53.6, 38.3, 36.9,
36.9, 35.8, 32.8, 31.5, 28.9, 20.7, 20.2 ppm; IR (neat): 3424, 3131, 2927,
2853,1744,1659,1615,1400,1225,1078, 929, 776, 561 cmꢁ1; MS (ESI):
m/z¼347.1 [MþH]þ, 369.1 [MþNa]þ.
rate¼1.0 mL/min, ¼254 nm): tR(major)¼10.36 min, tR(minor)¼
l
15.65 min, 90.3% ee; 1H NMR (400 MHz, CDCl3):
d
¼7.22e7.18 (m,
2H), 7.10e7.07 (m, 1.99H), 4.90 (s, 0.53H), 4.58 (s, 0.27H), 4.02 (br s,
0.32H), 3.88e3.83 (m, 1.70H), 3.75 (s, 2.01H), 2.40e1.96 (m, 8.38H)
ppm; 13C NMR (100 MHz, CDCl3):
d
¼197.2, 196.6, 169.7, 169.4, 169.2,
4.3.12. (4R)-Methyl 4-(3-chlorophenyl)-2-hydroxy-5-oxo-3,4,5,6,7,8-
hexahydro-2H-chromene-2-carboxylate (3l).5f Purified by flash
chromatography (petroleum ether/EtOAc¼2/1) to afford a white
solid in 77% yield; HPLC (Chiralpak AD, hexane/i-PrOH¼80/20, flow
142.6, 141.6, 131.7, 128.8, 128.6, 128.3, 128.2, 115.0, 112.9, 95.5, 94.8,
53.8, 53.7, 38.1, 36.9, 36.9, 35.6, 32.8, 31.3, 28.9, 28.8, 20.7, 20.2 ppm;
IR (neat): 3422, 3130, 2958, 2924, 2853, 1744, 1659, 1615, 1400,
1225, 1078, 927, 776, 561 cmꢁ1; MS (ESI): m/z¼337.1 [MþH]þ.
rate¼1.0 mL/min,
l
¼254 nm): tR(major)¼8.63 min, tR(minor)¼
11.87 min, 90.3% ee; 1H NMR (400 MHz, CDCl3):
d
¼7.19e7.12 (m,
4.3.8. (4R)-Methyl 4-(4-bromophenyl)-2-hydroxy-5-oxo-3,4,5,6,7,8-
hexahydro-2H-chromene-2-carboxylate (3h).5f Purified by flash
chromatography (petroleum ether/EtOAc¼2/1) to afford a white solid
in 96% yield; HPLC (Chiralpak AD, hexane/i-PrOH¼80/20, flow
2.94H), 7.06e7.05 (m, 1H), 5.00 (s, 0.60H), 4.58 (s, 0.30H), 4.03 (br s,
0.39H), 3.88e3.84 (m, 1.68H), 3.77 (s, 2H), 2.56e2.18 (m, 6.25H),
2.09e1.99 (m, 2.25H) ppm; 13C NMR (150 MHz, CDCl3):
d¼197.0,
196.5, 169.8, 169.3, 169.3, 146.3, 145.3, 134.1, 133.8, 129.7, 129.3,
127.6, 126.9, 126.3, 126.3, 125.7, 125.4, 114.8, 112.6, 95.5, 94.7, 53.8,
53.7, 38.0, 36.9, 36.8, 35.5, 33.2, 31.6, 28.9, 28.7, 20.7, 20.1 ppm; IR
(neat): 3424, 3131, 2958, 2923, 2853, 1744, 1615, 1400, 1225, 1078,
928, 776, 629, 561 cmꢁ1; MS (ESI): m/z¼337.1 [MþH]þ.
rate¼1.0 mL/min,
l¼254 nm): tR(major)¼10.84 min, tR(minor)¼
16.51 min, 90.5% ee; 1H NMR (400 MHz, CDCl3):
d¼7.38e7.34 (m, 2H),
7.05e7.03 (m, 2H), 4.77e4.70 (br s, 0.64H), 4.13e4.12 (m, 0.39H),
4.02e4.00 (br s, 0.32H), 3.85 (s, 1.69H), 3.75 (s, 2.01H), 2.56e1.97 (m,
8.49H) ppm; 13C NMR (150 MHz, CDCl3):
d¼196.0, 195.5, 170.3, 168.8,
168.3, 168.1, 142.0, 141.1, 130.4, 130.1, 128.1, 127.7, 118.7, 118.6, 113.8,
111.8, 94.5, 93.7, 52.7, 52.5, 37.0, 35.8, 35.8, 34.5, 31.8, 30.4, 27.8, 27.7,
19.6,19.1 ppm; IR (neat): 3421, 3130, 2927, 2853,1744,1615,1400,1225,
1078, 776, 561 cmꢁ1; MS (ESI): m/z¼381.0 [MþH]þ, 402.9 [MþNa]þ.
4.3.13. (4R)-Methyl 4-(3-bromophenyl)-2-hydroxy-5-oxo-3,4,5,6,7,8-
hexahydro-2H-chromene-2-carboxylate (3m).5f Purified by flash
chromatography (petroleum ether/EtOAc¼2/1) to afford a white
solid in 87% yield; HPLC (Chiralpak AD, hexane/i-PrOH¼80/20, flow
rate¼1.0 mL/min,
l
¼254 nm): tR(major)¼9.48 min, tR(minor)¼
4.3.9. (4R)-Methyl 2-hydroxy-5-oxo-4-m-tolyl-3,4,5,6,7,8-
hexahydro-2H-chromene-2-carboxylate (3i).5f Purified by flash
chromatography (petroleum ether/EtOAc¼2/1) to afford a white
solid in 67% yield; HPLC (Chiralpak AD, hexane/i-PrOH¼80/20, flow
12.92 min, 91.7% ee; 1H NMR (400 MHz, CDCl3):
d
¼7.29e7.26 (m,
2H), 7.13e7.09 (m, 1.89H), 4.88 (s, 0.53H), 4.56 (br s, 0.25H),
4.03e4.02 (m, 0.46H), 3.85 (s, 1.57H), 3.78 (s, 1.89H), 2.57e1.99 (m,
7.85H) ppm; 13C NMR (100 MHz, CDCl3):
d¼197.1, 196.5, 169.8,
rate¼1.0 mL/min,
l
¼254 nm): tR(major)¼7.12 min, tR(minor)¼
169.3, 169.3, 146.5, 130.5, 130.0, 129.8, 129.6, 129.3, 129.1, 126.1,
125.9, 122.4, 122.2, 114.7, 112.6, 95.5, 94.7, 53.8, 53.7, 38.1, 36.9, 36.8,
35.4, 33.1, 31.5, 28.9, 28.7, 20.6, 20.1 ppm; IR (neat): 3432, 3130,
2852, 1744, 1662, 1618, 1400, 1225, 1078, 776, 561 cmꢁ1; MS (ESI):
m/z¼381.1 [MþH]þ, 403.1 [MþNa]þ.
11.16 min, 89.9% ee; 1H NMR (400 MHz, CDCl3):
d¼7.16e7.12(m,
1.03H), 6.98e6.93(m, 3H), 4.73 (s, 0.65H), 4.31 (s, 0.33H), 4.07e4.06
(m, 0.47H), 3.88e3.87 (m, 0.62H), 3.83(s, 1.18H), 3.75 (s, 2.11H),
2.57e2.35 (m, 4.37H), 2.30 (s, 3.16H), 2.22 (d, J¼9.0 Hz, 1.62H),
2.02e1.99(m, 2.18H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼197.0,
196.5, 169.4, 168.7, 143.9, 142.5, 137.8, 128.3, 127.7, 127.0, 124.0,
123.9, 115.4, 113.1, 95.8, 94.8, 38.3, 37.0, 36.9, 35.9, 33.1, 31.5, 28.9,
28.8, 21.6, 20.2 ppm; IR (neat): 3423, 3131, 2927, 2853, 1744, 1661,
1617, 1400, 1159, 1078, 776, 662, 561 cmꢁ1; MS (ESI): m/z¼317.1
[MþH]þ, 339.1 [MþNa]þ, 655.3 [2MþNa]þ.
4.3.14. (4R)-Methyl 4-(3-bromo-4-chlorophenyl)-2-hydroxy-5-oxo-
3,4,5,6,7,8-hexahydro-2H-chromene-2-carboxylate (3n). Purified by
flash chromatography (petroleum ether/EtOAc¼2/1) to afford
a white solid in 75% yield; HPLC (Chiralpak AD, hexane/i-PrOH¼80/
20, flow rate¼1.0 mL/min,
tR(minor)¼15.49 min, 90.7% ee; [
(400 MHz, CDCl3):
l
¼254 nm): tR(major)¼11.30 min,
a]
D
25 ꢁ13.6 (c 0.67, CH2Cl2); 1H NMR
4.3.10. (4R)-Methyl 2-hydroxy-4-(3-methoxyphenyl)-5-oxo-3,4,5,6,7,8-
hexahydro-2H-chromene-2-carboxylate (3j).5f Purified by flash chro-
matography (petroleum ether/EtOAc¼2/1) to afford a white solid in
65% yield; HPLC (Chiralpak AD, hexane/i-PrOH¼80/20, flow
d
¼7.40 (m, 0.99H), 7.34e7.27(m,1.15H), 7.08e7.05
(m, 1H), 4.93 (br s, 0.52H), 4.67 (br s, 0.30H), 4.05e3.99 (m, 0.58H),
3.85 (s, 1.28H), 3.81 (s, 2.03H), 2.56e2.14 (m, 6.31H), 2.10e2.00 (m,
2.29H) ppm; 13C NMR (100 MHz, CDCl3):
d¼197.1, 196.5,169.9,169.5,
rate¼1.0 mL/min,
l¼254 nm): tR(major)¼10.67 min, tR(minor)¼
169.3, 169.2, 144.7, 143.7, 132.8, 132.0, 131.8, 130.2, 129.7, 127.8, 127.4,
122.3, 121.9, 116.0, 114.6, 112.4, 95.3, 94.7, 38.0, 36.9, 36.8, 35.2, 32.7,
28.9, 28.8, 25.3, 20.7, 20.1 ppm; IR (neat): 3426, 3130, 2927, 2852,
1743, 1659, 1620, 1400, 1225, 1078, 928, 777, 561 cmꢁ1; MS (ESI): m/
14.30 min, 86.1% ee; 1H NMR (400 MHz, CDCl3):
d¼7.19e7.15 (m, 1H),
6.77e6.70(m, 3.05H), 4.84 (br s, 0.47H), 4.41 (br s, 0.22H), 4.07e3.88
(m, 0.99H), 3.84 (s, 1.14H), 3.78e3.75 (m, 5H), 2.58e2.22 (m, 6.27H),

X. Song et al. / Tetrahedron 70 (2014) 5468e5474
5473
z¼414.9 [MþH]þ, 436.9 [MþNa]þ; HRMS (ESI-TOF): m/z [MþH]þ,
1622, 1400, 774, 561 cmꢁ1; MS (ESI): m/z¼309.1 [MþH]þ, 331.1
[MþNa]þ, 347.1 [MþK]þ, 639.1 [2MþNa]þ.
calcd for C17H17BrClO5þ 414.9948, found 414.9943.
4.3.15. (4S)-Methyl 4-(2-chlorophenyl)-2-hydroxy-5-oxo-3,4,5,6,7,8-
hexahydro-2H-chromene-2-carboxylate (3o).5f Purified by flash
chromatography (petroleum ether/EtOAc¼2/1) to afford a white
solid in 16% yield; HPLC (Chiralpak AD, hexane/i-PrOH¼90/10,
4.3.19. (4R)-Methyl 2-hydroxy-7,7-dimethyl-5-oxo-4-phenyl-3,4,5,6,7,
8-hexahydro-2H-chromene-2-carboxylate (3t).5f Purified by flash
chromatography (petroleum ether/EtOAc¼2/1) to afford a white solid
in 98% yield; HPLC (Chiralpak AD, hexane/i-PrOH¼80/20, flow
flow rate¼1.0 mL/min,
l¼254 nm): tR(major)¼16.18 min,
rate¼1.0 mL/min,
l
¼254 nm): tR(major)¼6.48 min, tR(minor)¼
tR(minor)¼18.89 min, 16.7% ee; 1H NMR (400 MHz, CDCl3):
10.45 min, 90.1% ee; 1H NMR (400 MHz, CDCl3):
d
¼7.27e7.24 (t,
d
¼7.34e7.32 (d, J¼6.64 Hz, 1H), 7.13e7.07 (m, 2.91H), 4.69 (s,
J¼7.2 Hz, 2.26H), 7.17e7.13 (t, J¼7.2 Hz, 3.09H), 5.00 (s, 0.54H), 4.50 (s,
0.37H), 4.07 (br s, 0.37H), 3.91e3.87 (m, 0.72H), 3.84 (s, 0.98H), 3.70 (s,
1.95H), 2.58e2.21 (m, 6.36H), 1.19 (d, J¼9.6 Hz, 3.25H), 1.10 (d,
0.48H), 4.39e4.37 (m, 1.32H), 3.87 (s, 1.26H), 3.78 (s, 1.68H),
2.59e2.28 (m, 5.70H), 2.12e2.00 (m, 2.40H) ppm; 13C NMR
(100 MHz, CDCl3):
d
¼196.6, 196.1, 169.7, 169.6, 169.3, 133.3, 129.7,
J¼9.2 Hz, 3.05H) ppm; 13C NMR (100 MHz, CDCl3):
¼198.3, 197.9,
d
129.5, 129.0, 127.5, 127.3, 126.8, 126.1, 114.8, 112.6, 95.5, 94.8, 53.8,
53.6, 37.0, 36.9, 32.7, 29.2, 28.9, 28.8, 20.7, 20.2 ppm; IR (neat):
3421, 3130, 2927, 2853, 1744, 1662, 1621, 1400, 1225, 1078, 772,
563 cmꢁ1; MS (ESI): m/z¼337.1 [MþH]þ, 359.1 [MþNa]þ, 375.0
[MþK]þ.
170.7, 169.0, 168.5, 145.2, 144.2, 129.7, 129.6, 128.6, 128.4, 127.5, 127.4,
115.1, 97.2, 97.2, 96.3, 96.3, 54.9, 54.7, 52.1, 52.1, 43.8, 43.7, 39.6, 37.4,
37.4, 34.6, 33.4, 33.3, 33.2, 33.0, 31.0, 30.6, 30.1, 29.6, 29.0 ppm; IR
(neat): 3418, 3130, 2927, 2853, 1742, 1661, 1621, 1400, 1161, 1074, 776,
562 cmꢁ1; MS (ESI): m/z¼331.2 [MþH]þ, 683.3 [2MþNa]þ.
4.3.16. (4S)-Methyl 4-(2-bromophenyl)-2-hydroxy-5-oxo-3,4,5,6,7,8-
4.3.20. (4R)-Methyl
2-hydroxy-7,7-dimethyl-5-oxo-4-p-tolyl-3,4,5,6,
hexahydro-2H-chromene-2-carboxylate (3p). Purified by flash
chromatography (petroleum ether/EtOAc¼2/1) to afford a white
7,8-hexahydro-2H-chromene-2-carboxylate (3u). Purified by flash
chromatography (petroleum ether/EtOAc¼2/1) to afford a white solid
in 90% yield; HPLC (Chiralpak AD, hexane/i-PrOH¼80/20, flow
25
solid in 7% yield; [
a
]
þ8.5 (c 0.75, CH2Cl2); HPLC (Chiralpak AD,
D
hexane/i-PrOH¼90/10, flow rate¼1.0 mL/min,
l
¼254 nm):
rate¼1.0 mL/min,
l
¼254 nm): tR(major)¼7.34 min, tR(minor)¼
tR(major)¼16.75 min, tR(minor)¼19.88 min, 6.5% ee; 1H NMR
10.62 min, 75.7% ee; [
a
]
25 ꢁ11.4 (c 0.39, CH2Cl2); 1H NMR (400 MHz,
D
(400 MHz, CDCl3):
d
¼7.53e7.51 (d, J¼6.64 Hz, 1H), 7.17e7.00 (m,
CDCl3):
d
¼7.07e7.01 (m, 4H), 4.97 (s, 0.50H), 4.56 (s, 0.27H), 4.07e3.99
3.05H), 4.86 (s, 0.49H), 4.52 (s, 0.35H), 4.34e4.33 (m, 0.98H), 3.87
(s, 1.28H), 3.76 (s, 1.80H), 2.58e2.28 (m, 5.78H), 2.10e2.01 (m,
(m, 0.69H), 3.84e3.88 (m, 0.51H), 3.83 (s, 1.07H), 3.69 (s, 1.88H),
2.56e2.29 (m, 3.39H), 2.28 (m, 3.16H), 2.25e2.20 (m, 2.6H), 1.19 (d,
J¼9.6 Hz, 3.45H), 1.10 (d, J¼9.2 Hz, 2.85H) ppm; 13C NMR (100 MHz,
2.49H) ppm; 13C NMR (100 MHz, CDCl3):
d¼196.6, 196.1, 169.7,
169.6,169.3,141.2,132.9,132.8,129.1,127.8,127.6,127.5, 126.7,124.0,
114.8, 112.9, 95.5, 94.8, 53.8, 53.6, 37.0, 36.9, 33.1, 31.8, 29.7, 28.9,
28.8, 25.3, 20.7, 20.2 ppm; IR (neat): 3431, 3131, 2584, 1741, 1658,
1628, 1400, 1227, 1078, 922, 776, 561 cmꢁ1; MS (ESI): m/z¼381.0
[MþH]þ, 402.9 [MþNa]þ; HRMS (ESI-TOF): m/z [MþH]þ, calcd for
CDCl3):
d
¼198.2, 197.8, 170.7, 170.6, 168.9, 168.3, 142.2, 141.2, 137.0,
136.8, 130.4, 128.4, 128.3, 115.3, 113.5, 97.3, 96.4, 54.9, 54.8, 52.1, 43.7,
43.7, 39.7, 37.5, 34.2, 33.4, 33.0, 31.0, 30.6, 30.1, 29.6, 29.0, 26.6,
22.4 ppm; IR (neat): 3426, 3132, 2956, 2923, 1750, 1617, 1400, 1225,
1072, 819, 793, 561 cmꢁ1; MS (ESI): m/z¼345.1 [MþH]þ, 367.1
[MþNa]þ, 383.0 [MþK]þ; HRMS (ESI-TOF): m/z [MþH]þ, calcd for
C
17H18BrOþ5 381.0338, found 381.0332.
C
20H25Oþ5 345.1702, found: 345.1698.
4.3.17. (4R)-Methyl 2-hydroxy-4-(naphthalen-2-yl)-5-oxo-3,4,5,6,7,8-
hexahydro-2H-chromene-2-carboxylate (3r).5f Purified by flash
chromatography (petroleum ether/EtOAc¼2/1) to afford a white
solid in 80% yield; HPLC (Chiralpak AD, hexane/i-PrOH¼80/20, flow
4.3.21. (4R)-Methyl 2-hydroxy-4-(4-methoxyphenyl)-7,7-dimethyl-
5-oxo-3,4,5,6,7,8-hexahydro-2H-chromene-2-carboxylate
(3v). Purified by flash chromatography (petroleum ether/EtOAc¼2/
1) to afford a white solid in 94% yield; HPLC (Chiralpak AD, hexane/i-
rate¼1.0 mL/min,
l¼254 nm): tR(major)¼13.68 min, tR(minor)¼
20.61 min, 93.3% ee; 1H NMR (400 MHz, CDCl3):
2.94H), 7.60e7.56 (d, 1H), 7.41e7.25 (m, 3.17H), 4.90 (br s, 0.56H),
4.44 (s, 0.23H), 4.23 (br s, 0.23H), 4.12e4.05 (m, 1.06H), 3.82 (s,
0.91H), 3.67 (s, 1.95H), 2.60e2.26 (m, 6.09H), 2.04e1.99 (m, 2.18H)
d¼7.76e7.71 (m,
PrOH¼80/20, flow rate¼1.0 mL/min,
l
¼254 nm): tR(major)¼
9.48 min, tR(minor)¼18.23 min, 76.5% ee;[
a
]
D
25 ꢁ19.7 (c 0.55, CH2Cl2);
1H NMR (400 MHz, CDCl3):
d
¼7.10e7.06 (m, 2H), 6.82e6.79 (d,
J¼8.3 Hz, 2H), 4.61 (s, 0.57H), 4.29 (s, 0.36H), 4.13e4.04 (m, 0.55H),
3.87e3.83 (m, 1.48H), 3.76e3.75 (m, 5.16H), 2.52e2.20 (m, 6.14H),
1.17 (d, J¼9.6 Hz, 3.18H), 1.10 (d, J¼9.2 Hz, 3.15H) ppm; 13C NMR
ppm; 13C NMR (100 MHz, CDCl3):
d
¼197.2, 196.6, 169.7, 169.4, 169.0,
141.4, 140.4, 133.6, 133.4, 132.3, 128.1, 128.0, 127.8, 127.6, 125.9, 125.8,
125.6, 125.5, 125.4, 125.3, 125.2, 115.2, 113.2, 95.7, 94.8, 53.7, 53.7,
38.2, 37.0, 36.9, 35.8, 33.4, 32.0, 28.9, 28.8, 20.7, 20.2 ppm; IR (neat):
3422, 3131, 2958, 2927, 2853, 1744, 1659, 1615, 1400, 1225, 1078,
1043, 928, 770, 559 cmꢁ1; MS (ESI): m/z¼353.2 [MþH]þ, 727.3
[2MþNa]þ.
(100 MHz, CDCl3):
d¼198.2, 197.8, 170.7, 170.6, 168.7, 168.1, 159.3,
159.1,137.3,136.1,129.6,129.3,115.5,115.2,115.1, 97.1, 96.3, 56.5, 56.5,
54.9, 54.8, 52.2, 43.7, 43.7, 39.6, 37.1, 33.8, 33.4, 33.0, 32.2, 31.0, 30.6,
30.1, 29.5, 29.0 ppm; IR (neat): 3425, 3133, 2957, 2925, 2853, 1750,
1615,1510,1400,1245,1078, 828, 764, 611 cmꢁ1; MS (ESI): m/z¼361.1
[MþH]þ, 383.1 [MþNa]þ, 399.0 [MþK]þ; HRMS (ESI-TOF): m/z
[MþH]þ, calcd for C20H25Oþ6 361.1651, found: 361.1649.
4.3.18. (4S)-Methyl 2-hydroxy-5-oxo-4-(thiophen-2-yl)-3,4,5,6,7,8-
hexahydro-2H-chromene-2-carboxylate (3s).5f Purified by flash
chromatography (petroleum ether/EtOAc¼2/1) to afford a white
solid in 84% yield; HPLC (Chiralpak AD, hexane/i-PrOH¼90/10, flow
4.3.22. (4R)-Methyl 4-(4-chlorophenyl)-2-hydroxy-7,7-dimethyl-5-
oxo-3,4,5,6,7,8-hexahydro-2H-chromene-2-carboxylate
(3w). Purified by flash chromatography (petroleum ether/EtOAc¼2/
1) to afford a white solid in 85% yield; HPLC (Chiralpak AD, hexane/i-
rate¼0.5 mL/min,
l
¼254 nm) tR(major)¼53.21 min, tR(minor)¼
63.20 min, 95.9% ee; 1H NMR (400 MHz, CDCl3):
d
¼7.12e7.07 (dd,
J¼5.1 Hz, 1H), 6.89e6.85 (m, 1.05H), 6.79e6.77 (m, 0.99H), 5.18 (s,
0.46H), 4.56 (s, 0.35H), 4.38 (br s, 0.41H), 4.28e4.23 (m, 0.62H), 3.85
(s, 1.27H), 3.68 (s, 1.85H), 2.58e2.26 (m, 6.32H), 2.09e1.99 (m,
PrOH¼80/20, flow rate¼1.0 mL/min,
l
¼254 nm): tR(major)¼7.79 min,
tR(minor)¼15.53 min, 72.1% ee; [
a
]
25 ꢁ31.7 (c 0.89, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3):
d
¼7.26e7.19 (m, 2.05H), 7.10e7.08 (d, 2H), 4.71 (s,
2.21H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼197.0,196.7,169.2,169.1,
0.57H), 4.46 (s, 0.57H), 4.13e4.11 (m, 0.31H), 4.04e4.02 (m, 0.41H),
3.84 (s, 1.24H), 3.78 (s, 1.90H), 2.58e2.19 (m, 6.77H), 1.17 (d, J¼9.6 Hz,
3.23H), 1.10 (d, J¼9.2 Hz, 3.05H) ppm; 13C NMR (100 MHz, CDCl3):
169.0, 168.9, 147.2, 146.9, 126.6, 126.4, 124.2, 124.1, 123.6, 122.9,
115.0, 113.4, 95.6, 95.0, 53.7, 53.5, 38.5, 36.9, 35.7, 28.8, 28.7, 28.7,
26.8, 20.6, 20.1 ppm; IR (neat): 3423, 3131, 2927, 2853, 1741, 1663,
d¼198.1,197.6,170.7,170.6,169.1,168.5,143.9,143.0,133.0,132.9,130.2,

5474
X. Song et al. / Tetrahedron 70 (2014) 5468e5474
129.8, 129.7, 129.5, 114.9, 113.1, 96.8, 96.1, 55.0, 54.9, 52.0, 43.7, 43.7,
39.4, 36.8, 34.2, 33.4, 33.0, 32.8, 31.0, 30.6, 30.1, 29.5, 29.0 ppm; IR
(neat): 3423, 3130, 2927, 2852,1743,1662,1621,1400,1226,1078, 828,
776, 561 cmꢁ1; MS (ESI): m/z¼365.1 [MþH]þ, 387.1 [MþNa]þ, 403.1
[MþK]þ; HRMS (ESI-TOF): m/z [MþH]þ, calcd for C17H18ClOþ5
365.1153, found: 365.1153.
Supplementary data
Copies of 1H NMR and 13C NMR spectra of products of tandem
reactions are available. Supplementary data related to this article
can be found at http://dx.doi.org/10.1016/j.tet.2014.06.109.
References and notes
4.3.23. (4R)-Methyl 4-(4-bromophenyl)-2-hydroxy-7,7-dimethyl-5-
oxo-3,4,5,6,7,8-hexahydro-2H-chromene-2-carboxylate
(3x). Purified by flash chromatography (petroleum ether/EtOAc¼2/
1) to afford a white solid in 85% yield; HPLC (Chiralpak AD, hexane/
1. For selected recent reviews on six-membered oxygenated heterocycles, see: (a)
Clarke, P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2045e2053; (b) Tang, Y.; Op-
penheimer, J.; Song, Z.; You, L.; Zhang, X.; Hsung, R. P. Tetrahedron 2006, 62,
10785e10813; (c) Larrosa, I.; Romea, P.; Urpí, F. Tetrahedron 2008, 64,
i-PrOH¼80/20, flow rate¼1.0 mL/min,
8.23 min, tR(minor)¼16.65 min, 77.5% ee; [
CH2Cl2); 1H NMR (400 MHz, CDCl3):
l
¼254 nm): tR(major)¼
ꢁ~
2683e2723; (d) Shen, H. C. Tetrahedron 2009, 65, 3931e3952; (e) Nunez, M. G.;
25
a
]
ꢁ25.5 (c 0.49,
D
García, P.; Moro, R. F.; Díez, D. Tetrahedron 2010, 66, 2089e2109; (f) Litvinov, Y.
M.; Shestopalov, A. M. In Advances in Heterocyclic Chemistry; Alan, K., Ed.; Aca-
demic: 2011; Vol. 103, pp 175e260.
d
¼7.38e7.34 (m, 2H),
7.04e7.02 (d, 2.02H), 4.84 (s, 0.52H), 4.57 (s, 0.30H), 4.03e3.98 (m,
0.73H), 3.84 (s, 1.41H), 3.76 (s, 1.93H), 2.57e2.19 (m, 6.40H), 1.19 (d,
J¼9.6 Hz, 2.95H), 1.10 (d, J¼9.2 Hz, 3.07H) ppm; 13C NMR (100 MHz,
2. Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev. 2013, 113, 5924e5988.
3. Halland, N.; Velgaard, T.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 5067e5074.
4. For selected recent examples on the biological and pharmaceutical activities of
chromene derivatives, see: (a) Erichsen, M. N.; Huynh, T. H.; Abrahamsen, B.;
Bastlund, J. F.; Bundgaard, C.; Monrad, O.; Bekker-Jensen, A.; Nielsen, C. W.;
Frydenvang, K.; Jensen, A. A.; Bunch, L. J. Med. Chem. 2010, 53, 7180e7191; (b)
Kumar, A.; Sharma, S.; Tripathi, V. D.; Maurya, R. A.; Srivastava, S. P.; Bhatia, G.;
Tamrakar, A. K.; Srivastava, A. K. Bioorg. Med. Chem. 2010, 18, 4138e4148; (c)
Harel, D.; Schepmann, D.; Prinz, H.; Brun, R.; Schmidt, T. J.; Wunsch, B. J. Med.
Chem. 2013, 56, 7442e7448.
5. For recent examples on the asymmetric catalytic Michael addition of cyclic
1,3-dicarbonyl compounds to b,g-unsaturated a-ketoesters, see: (a) Calter, M.
CDCl3):
d
¼198.1, 197.6, 170.7, 170.6, 169.1, 168.7, 144.5, 143.7, 132.8,
132.5, 130.6, 130.2, 121.1, 121.0, 114.8, 113.0, 96.9, 96.1, 55.0, 54.9,
52.0, 43.7, 43.7, 39.3, 36.9, 34.2, 33.4, 33.0, 32.9, 31.0, 30.6, 30.1, 29.5,
29.0, 26.6 ppm; IR (neat): 3439, 3127, 2957, 2923, 2850, 1744, 1619,
1400,1225, 1071, 826, 776, 561 cmꢁ1; MS (ESI): m/z¼409.0 [MþH]þ,
431.0 [MþNa]þ, 447.0 [MþK]þ; HRMS (ESI-TOF): m/z [MþH]þ,
calcd for C17H18BrOþ5 409.0651, found: 409.0647.
€
A.; Wang, J. Org. Lett. 2009, 11, 2205e2208; (b) Chen, X.-K.; Zheng, C.-W.;
Zhao, S.-L.; Chai, Z.; Yang, Y.-Q.; Zhao, G.; Cao, W.-G. Adv. Synth. Catal. 2010,
352, 1648e1652; (c) Gao, Y.; Ren, Q.; Wang, L.; Wang, J. Chem.dEur. J. 2010,
16, 13068e13071; (d) Xu, D. Q.; Wang, Y. F.; Zhang, W.; Luo, S. P.; Zhong, A.
G.; Xia, A. B.; Xu, Z. Y. Chem.dEur. J. 2010, 16, 4177e4180; (e) Dong, Z.; Feng,
J.; Cao, W.; Liu, X.; Lin, L.; Feng, X. Tetrahedron Lett. 2011, 52, 3433e3436; (f)
Dong, Z.; Feng, J.; Fu, X.; Liu, X.; Lin, L.; Feng, X. Chem.dEur. J. 2011, 17,
1118e1121; (g) Wang, Y.-F.; Wang, K.; Zhang, W.; Zhang, B.-B.; Zhang, C.-X.;
Xu, D.-Q. Eur. J. Org. Chem. 2012, 3691e3696; (h) Cele, Z. E. D.; Sosibo, S. C.;
Andersson, P. G.; Kruger, H. G.; Maguire, G. E. M.; Govender, T. Tetrahedron:
Asymmetry 2013, 24, 191e195.
6. For examples on the dinuclear zinc catalyzed asymmetric Michael reaction of
carbo-nucleophiles, see: (a) Trost, B. M.; Hisaindee, S. Org. Lett. 2006, 8,
6003e6005; (b) Trost, B. M.; Muller, C. J. Am. Chem. Soc. 2008, 130, 2438e2439;
(c) Trost, B. M.; Hitce, J. J. Am. Chem. Soc. 2009, 131, 4572e4573; (d) Trost, B. M.;
Hirano, K. Angew. Chem., Int. Ed. 2012, 51, 6480e6483; (e) Trost, B. M.; Hirano, K.
Org. Lett. 2012, 14, 2446e2449.
7. For examples on the dinuclear zinc catalyzed asymmetric Michael reaction of
phospho-nucleophiles, see: (a) Zhao, D.; Wang, Y.; Mao, L.; Wang, R. Chem.dEur.
J. 2009, 15, 10983e10987; (b) Zhao, D.; Yuan, Y.; Chan, A. S. C.; Wang, R. Chem.
dEur. J. 2009, 15, 2738e2741; (c) Zhao, D.; Mao, L.; Wang, Y.; Yang, D.; Zhang, Q.;
Wang, R. Org. Lett. 2010, 12, 1880e1882; (d) Zhao, D.; Mao, L.; Yang, D.; Wang, R. J.
Org. Chem. 2010, 75, 6756e6763; (e) Zhao, D.; Mao, L.; Wang, L.; Yang, D.; Wang,
R. Chem. Commun. 2012, 889e891; (f) Zhao, D.; Wang, L.; Yang, D.; Zhang, Y.;
Wang, R. Chem.dAsian J. 2012, 7, 881e883.
4.3.24. (4R)-Methyl 2-hydroxy-5-oxo-4-phenyl-2,3,4,5-tetrahy
dropyrano[3,2-c]chromene-2-carboxylate (6).5b Purified by flash
chromatography (petroleum ether/EtOAc¼2/1) to afford a white
solid in 80% yield; HPLC (Chiralpak OD-H, hexane/i-PrOH¼80/20,
flow rate¼1.0 mL/min,
l¼254 nm): tR(major)¼11.69 min,
tR(minor)¼21.67 min, 23.9% ee; 1H NMR (400 MHz, CDCl3):
¼7.81
d
(dt, J¼16.4, 8.0 Hz, 1H), 7.59e7.52 (m, 1H), 7.31e7.23 (m, 7H), 4.89
(d, J¼8.8, 0.56H), 4.61 (s, 0.27H), 4.36e4.17 (m, 1H), 3.92e3.87 (dd,
J¼32.2, 9.5 Hz, 3.06H), 2.83e2.78 (dd, J¼14.0, 7.4 Hz, 0.33H),
2.57e2.45 (m, 1.76H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼168.7,
161.7,160.9,158.6,158.2,152.8,142.2,141.6,132.1,131.9,128.6,128.4,
127.4, 127.1, 126.7, 124.0, 123.8, 122.9, 116.6, 116.5, 115.2, 115.0, 104.6,
102.9, 96.2, 95.6, 53.9, 53.8, 38.1, 35.8, 34.6, 33.8 ppm; IR (neat):
3440, 3132, 2854, 1741, 1626, 1400, 1159, 1091, 827, 766, 699,
595 cmꢁ1; MS (ESI): m/z¼353.1 [MþH]þ, 375.0 [MþNa]þ.
Acknowledgements
8. The product 3a existed as an equilibrating mixture of anomers, and the cyclic
hexahydrochromene form was the major isomer, which was illustrated by
proton and carbon NMR spectra.
We thank the National Natural Science Foundation of China
(Nos. 21272216 and 21302173), and the China Postdoctoral Science
Foundation (No. 2013M541984) for financial support.
9. Vaijayanthi, T.; Chadha, A. Tetrahedron: Asymmetry 2007, 18, 1077e1084.