Asymmetric annulation of 3-alkynylacrylaldehydes with styrene-type olefins by synergetic relay catalysis from agoac and chiral phosphoric acid

Article abstract of DOI:10.1021/jo501196n

Asymmetric annulation of 3-alkynylacrylaldehydes with 2-hydroxystyrenes has been studied and achieved by synergetic catalysis from AgOAc and chiral phosphoric acid, providing the corresponding multiring products with decent total yields and moderate to ex

Full text of DOI:10.1021/jo501196n

Article
pubs.acs.org/joc
Asymmetric Annulation of 3‑Alkynylacrylaldehydes with Styrene-
Type Olefins by Synergetic Relay Catalysis from AgOAc and Chiral
Phosphoric Acid
Hao Zhang, Le Zhu, Shaozhong Wang, and Zhu-Jun Yao*
State Key Laboratory of Coordination Chemistry, Nanjing National Laboratory of Microstructures, School of Chemistry and
Chemical Engineering, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
S
* Supporting Information
ABSTRACT: Asymmetric annulation of 3-alkynylacrylalde-
hydes with 2-hydroxystyrenes has been studied and achieved
by synergetic catalysis from AgOAc and chiral phosphoric acid,
providing the corresponding multiring products with decent
total yields and moderate to excellent enantioselectivities (up
to 95% ee). The developed mild multibond-formation cascade
reaction involves in situ generation of pyrylium intermediate by Ag(I)-catalyzed alkyne/carbonyl cycloisomerization,
counteranion-directed asymmetric oxa [4 + 2]-cycloaddition, and intramolecular nucleophilic substitution.
10 mol % Pd(OAc)2 and 10 mol % (S)-TRIP at room
temperature (P-1, Table 1, entry 1). Disappointedly, such a
binary catalysis mode was proven to be less effecient for this
reaction, affording two products 3aa (the expected product,
12%, 65% ee) and 4aa containing a quaternary carbon (an
isomer of 3aa, 6%, 59% ee) with low yields and moderate
enantioselectivities after 26 h. The relative structures of these
two products were determined by 2D NMR methods, and their
absolute configurations were finally confirmed by the X-ray
single crystal analysis of products 3cd and 4ag in a late stage of
this study (see Supporting Information). Analysis of these
results indicated that poor efficiency in generating the active
pyrylium intermediate through Pd(OAc)2 activation of the
alkyne functionality might be a main reason. Once the pyrylium
intermediate was produced, the subsequent [4 + 2]-cyclization
of pyrylium with styrene 2a proceeded as expected. To improve
the results, several other bivalent metal catalysts were further
screened together with (S)-TRIP (Table 1, entries 2−4). The
reaction with Cu(OAc)2 gave similar unsatisfactory results in a
much longer reaction time (entry 2), and both Fe(OAc)2 and
Zn(OAc)2 were found to be insufficiently active to trigger the
reaction (entries 3 and 4).
The failure in achieving the type 1 mechanism turned our
attention to the alternative ACDC mode8,9 with a relay catalysis
design (Figure 1, type 2).10,11 A number of steps was expected
to synergetically occur under such a mechanism, including
converting substrate 1 into the corresponding metallopyrylium,
protonolysis of the C−M bond with chiral phosphoric acid and
forming a tight chiral ionic pair, assembling olefin 2 into the
chiral environment through a hydrogen bond with the PO
bond, and triggering the key [4 + 2]-cycloaddition. To favor the
production of pyrylium intermediate, new metal catalysts
INTRODUCTION
■
Pyryliums, a unique type of reactive cyclic oxonium
intermediate with erratic aromaticity, have been commonly
applied as inseparable intermediates to the synthesis of various
heterocycles.1 For high reactivity, pure pyryliums (without any
stabilizing structural factors) have been rarely reported in
complicated transformations,2 and enantioselective reaction
involving a pure pyrylium intermediate has remained as an
unresolved challenge. To expand the application scope, several
types of stabilized pyryliums have been developed and applied
to enantioselective transformations in recent years, including
benzopyrylium,3 isobenzopyrylium,4 and oxidopyryliums5,6
(Figure 1). Inspired by our recent achievement in the
enantioselective transformations of isobenzopyryliums (also
called isochromenyliums, a type of pyrylium stabilized with a
fused benzene ring) with a supramolecular binary catalysis
mode,7 we tried to expand the developed binary catalytic
methodology to the reactions involving a pure pyrylium
intermediate. Two theoretical catalytic modes were accordingly
proposed to achieve such an asymmetric transformation
(Figure 1, types 1 and 2). Type 1 mechanism was deduced
through the same supramolecular catalysis as our previous
study on isochromenyliums,7 while type 2, based on the
asymmetric counterion-directed catalysis (ACDC) theory,8,9
was considered as an alternative option to generate the required
asymmetric environment. Herein, we report our results on the
first catalytic enantioseletive reaction involving a pure
unstabilized pyrylium via an asymmetric counterion-directed
mechanism.
RESULTS AND DISCUSSION
■
As shown in the hypothesis in Figure 1, we first examined the
reaction of 3-alkynylacrylaldehyde 1a and 2-hydroxystyrene 2a
under our previous conditions7 with a catalyst combination of
Received: May 29, 2014
Published: July 9, 2014
© 2014 American Chemical Society
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Figure 1. (A) Typical structures of pyrylium, benzopyrylium, isobenzopyrylium, and oxidopyrylium. (B) Initial design of asymmetric annulation of 3-
alkynylacrylaldehydes 1 with 2-hydroxystyrenes 2.
a
Table 1. Screening of Metal Catalysts
b
b
entry
metal catal.
time
3aa (yield, ee) (%)
4aa (yield, ee) (%)
1
2
Pd(OAc)2
Cu(OAc)2
Zn(OAc)2
Fe(OAc)2
AuCl
26 h
8 d
12 (65)
6 (59)
13 (50)
0
16 (60)
c
3
4 d
0
c
4
4 d
0
0
5
6
7
60 h
1.5 h
6 h
0
0
AgOTf
42 (0)
28 (63)
36 (0)
32 (63)
AgOAc
a
Unless otherwise noted, the reaction was conducted between 1a (0.5 mmol) and 2a (0.75 mmol), the metal catalyst (10 mol %), and P-1 (10 mol
b
%) in 1,2-dichloroethane (5 mL) at room temperature under nitrogen atmosphere. Isolated yields and ee values were determined by chiral HPLC.
c
No reaction occurred.
should have stronger ability to activate the alkyne functionality
of substrate 1a than Pd(OAc)2. The monovalent gold(I) and
silver(I) catalysts were therefore examined in the reaction
together with chiral phosphoric acid P-1 (Table 1, entries 5−
7). To our delight, the two products could be obtained under
cocatalysis from AgOAc and (S)-TRIP with moderate yields
and enantioselectivities in a shorter reaction time (Table 1,
entry 7). A parallel reaction catalyzed with AgOTf and (S)-
TRIP gave the racemic products in similar yields (entry 6). It is
suggested that exchange of the counterion of metal catalysts
with chiral phosphoric acid was crucial in the reaction. Because
the acidity of phosphoric acid P-1 is stronger than that of acetic
acid, the combination of AgOAc and (S)-TRIP would be
favorable to produce Ag-(S)-TRIP in the reaction, and similar
anionic exchange was forbidden for the catalyst combination of
AgOTf and (S)-TRIP. Therefore, AgOAc was determined as
the π-Lewis acid for our further optimization.
Because the enantioselectivity was controlled through the
chiral phosphoric acid, we further screened a number of chiral
phosphoric acids having various 3,3′-subsitituents (10 mol %)
at room temperature (Table 2). The experiments showed that
(S)-TRIP (P-1) was the best Brønsted acid catalyst for this
asymmetric transformation (entry 1). The reactions with other
binaphthol-based chiral phosphoric acids (P-2 to P-8) and
chiral spirophosphoric acids (P-9 and P-10) could not afford
better results.
With the catalyst combination of AgOAc and (S)-TRIP (P-
1), other reaction parameters were then investigated (Table 3).
The experiments indicated that DCE was the best solvent
(entry 10), and the reaction cannot be completed in MeCN,
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a
Table 2. Optimization of Chiral Phosphoric Acids
b
b
entry
acid
time
conversion rate of 1a (%)
3aa (yield, ee) (%)
4aa (yield, ee) (%)
1
2
P-1
P-2
P-3
P-4
P-5
P-6
P-7
P-8
P-9
P-10
6 h
4 d
4 d
4 d
4 d
4 d
4 d
4 d
4 d
5 d
100
50
28 (63)
12 (22)
27 (28)
26 (21)
7.2 (5)
32 (63)
20 (20)
28 (17)
27 (10)
trace
3
60
4
60
5
20
6
trace
trace
20
7
8
7.3 (17)
15 (−19)
32 (−40)
3.6 (11)
11 (−11)
29 (−27)
9
40
10
100
a
Unless otherwise noted, the reaction was conducted between 1a (0.5 mmol) and 2a (0.75 mmol), AgOAc (10 mol %), and the phosphoric acid (10
b
mol %) in 1,2-dichloroethane (5 mL) at room temperature under nitrogen atmosphere. Isolated yields and ee values were determined by chiral
HPLC.
a
Table 3. Optimization of Reaction Parameters
b
b
entry
x
y
solvents
MeCN
time
3aa (yield, ee) (%)
4aa (yield, ee) (%)
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
10
4 d
0
0
10
1,4-dioxane
4 d
0
0
10
THF
4 d
0
0
10
DMF
4 d
0
0
10
toluene
33 h
12 h
25 h
43 h
2.5 d
6 h
7 (85)
19 (70)
16 (71)
10 (81)
6.1 (85)
28 (63)
15 (75)
22 (63)
27 (68)
26 (66)
30 (72)
29 (73)
19 (67)
18 (67)
8 (70)
19 (57)
22 (63)
14 (63)
4.4 (65)
32 (63)
12 (70)
38 (62)
31 (61)
39 (62)
35 (69)
34 (71)
18 (60)
18 (59)
10
DCM
10
DCE:toluene (5:1)
10
DCE:toluene (1:1)
10
DCE:toluene (1:5)
10
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
c
11
10
6.5 d
3 h
d
12
10
13
14
15
16
15
8 h
30
27 h
16 h
28 h
20 h
36 h
7.5
3.75
3.75
3.75
2.5
2.5
2.5
e
17
f
18
a
Unless otherwise noted, the reaction was conducted between 1a (0.5 mmol) and 2a (0.75 mmol) with indicated catalysts in 5 mL of solvent at
b
c
room temperature (23 °C) under nitrogen atmosphere. Isolated yields and ee values were determined by chiral HPLC. The reaction was
performed at 0 °C. The reaction was performed at 40 °C. The reaction was performed without N2 protection. The reaction was conducted with
d
e
f
the addition of water (1 equiv).
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a
Table 4. Examination of the Reaction Scope of 3-Alkynylacrylaldehyde 1
b
b
entry
1
time
24 h
3 (yield, ee) (%)
4 (yield, ee) (%)
1
1b (R1 = 4-NO2C6H4)
1c (R1 = 4-CNC6H4)
1d (R1 = 4-CO2MeC6H4)
1e (R1 = 4-FC6H4)
3ab (0)
4ab (0)
2
72 h
70 h
14 h
42 h
28 h
15 h
44 h
60 h
6.5 d
44 h
3d 10 h
3ca (32, 92)
3da (28, 87)
3ea (45, 83)
3fa (34, 88)
3ga (33, 82)
3ha (25, 78)
3ia (23, 15)
3ja (30, 58)
3ka (30, 65)
3la (29, 17)
3ma (27, 0)
4ca (34, 92)
4da (30, 84)
4ea (37, 83)
4fa (30, 86)
4ga (41, 82)
4ha (67, 78)
4ia (40, 9)
4ja (32, 57),
4ka (53, 65)
4la (42, 20)
4ma (37, 0)
3
4
5
1f (R1 = 4-BrC6H4)
6
1g (R1 = 4-MeC6H4)
1h (R1 = 4-MeOC6H4)
1i (R1 = 3-MeOC6H4)
1j (R1 = 2-MeOC6H4)
1k (R1 = 3,4-(MeO)2C6H3)
1l (R1 = 3, 4,5-(MeO)3C6H2)
1m (R1 = n-C5H11)
7
8
9
10
11
12
a
Unless otherwise noted, the reaction was conducted between 1 (0.5 mmol) and 2a (0.75 mmol), AgOAc (2.5 mol %), and (S)-TRIP (3.75 mol %)
b
in 5 mL of anhydrous DCE at room temperature (23 °C) under nitrogen atmosphere. Isolated yields and ee values were determined by chiral
HPLC.
1,4-dioxane, THF, and DMF (entries 1−4). Though the
reaction afforded products with higher enantioselectivity in
toluene (entry 5), severe side reactions were observed. We also
tried to improve the enantioselectivity in the mixed solvents of
toluene and DCE, but the results were unsatisfactory (entries
7−9). A slightly better enantioselectivity was observed when
the reaction was performed at 0 °C but with much lower yields
and in a much longer reaction time (entry 11). Higher reaction
temperature could shorten the reaction time but could not
improve the enantioselectivity (entry 12). Increasing the
loading of (S)-TRIP over AgOAc showed a little improvement
in the enantioselectivity, and 50% excess (0.5 equiv more than
that of AgOAc) was found to be sufficient (entries 10, 13, and
14). To our surprise, lowering the catalyst loadings down to 2.5
mol % of AgOAc and 3.75 mol % of (S)-TRIP further improved
the enantioselectivities of products up to 73% and 71% ee,
respectively (entries 16). Water was found to be detrimental
but not fatal to this reaction (entries 17 and 18), and anhydrous
solvent is therefore preferred. Therefore, the optimal catalyst
combination was finally determined as AgOAc (2.5 mol %) and
(S)-TRIP (3.75 mol %).
The generality of reaction was explored under the above
optimized conditions (Tables 4−6). Significant electronic
effects of R1 were observed (Table 4). When the electron
density of the phenyl ring of R1 decreased, the enantiose-
lectivity of products turned out to be better (entries 2−5). In
particular, the NO2 group of substrate 1b did not afford the
desired products (entry 1). A significant effect of the R1
substituent position(s) on the phenyl ring was also observed
on the enantioselectivity. The meta-position substituent caused
a dramatic decrease in the enantioselectivity (entries 8, 10, and
11). Unsatisfactory results also occurred for substrate 1 with an
aliphatic substituent (entry 12). We guess that sufficient π−π
interactions11c between the R1 functionality of substrate 1 and
the chiral catalyst P-1 might be helpful for enantioselective
control of the reactions (for more discussion on the
mechanism, see text below).
Unfortunately, the reactions of 3-alkynyl-2-enones 5 did not
work at all with this catalytic system (Figure 2). No desired
Figure 2. Examined 3-alkynyl-2-enone 5.
products were obtained under standard conditions. Consider-
ing possible self-reaction of the pyrylium intermediate
generated from ketones 5 with the aromatic ring of R2 (5a
and 5b), we also tried to decrease the possible side reactions by
introduction of alkyls into the substrate (5c and 5d) or by
running the reaction at lower temperatures. However, these
attempts gave no desirable results.
The reactions of multisubstituted o-hydroxystyrene 2 were
also examined (Table 5). A much slower reaction and a low
conversion rate (ca. 30%) were observed when 3-alkynylacry-
laldehyde 1a reacted with olefin 2b bearing a strong, electron-
rich phenyl group (Table 5, entry 1, R3 = p-OMe). The
reactions with the styrenes 2 having a weak electronic-donating
group or an electronic-withdrawing group afforded reasonable
combined yields of products 3 and 4 with moderate ee values
(entries 2−4, R3 = p-Me, p-Br, or p-CO2Me). Under standard
conditions, the reactions of 1,2-disubstituted olefins were
carried out for longer reaction times and gave compounds 4 as
the major products (entries 5 and 6), while no reaction could
be detected for the trisubstituted olefins after 4 days (entries 7
and 8).
On the basis of the above results (Tables 4 and 5), we
reorganized a number of substrates for further examination
(Table 6). The 3-alkynylacrylaldehyde 1 with an electron-rich
phenyl group (1g, R1 = 4-MeC6H4, entry 6; 1h, R1 = 4-
MeOC6H4, entries 7−11) and an electron-poor phenyl group
(1c, R1 = 4-CNC6H4, entries 1−5) were applied to the reaction
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a
Table 5. Examination of the Scope of Olefin 2
b
b
entry
2
time
3 (yield, ee) (%)
4 (yield, ee) (%)
1
2
3
4
5
6
7
8
2b (R3 = 4-OMe, R4 = H, R5 = H)
2c (R3 = 4-Me, R4 = H, R5 = H)
2d (R3 = 4-Br, R4 = H, R5 = H)
2e (R3 = 4-CO2Me, R4 = H, R5 = H)
2f (R3 = H, R4 = CH3, R5 = H)
2g (R3 = 4-Br, R4 = CH3, R5 = H)
2h (R3 = H, R4 = CH3, R5 = CH3)
2i (R3 = H, R4/R5 = c-C5H10)
8 d
3ab (9.6, 80)
3ac (24, 72)
3ad (44, 83)
3ae (36, 80)
3af (12, 63)
3ag (9.4, 75)
3ah (0)
4ab (15, 76)
4ac (40, 66)
4ad (38, 63)
4ae (39, 60)
4af (71, 60)
60 h
19 h
16 h
8 d
c
5 d
4ag (63, 53)
4ah (0)
4 d
4 d
3ai (0)
4ai (0)
a
Unless otherwise noted, the reaction was conducted between 1a (0.5 mmol) and 2 (0.75 mmol), AgOAc (2.5 mol %), and (S)-TRIP (3.75 mol %)
b
in 5 mL of anhydrous DCE at room temperature (23 °C) under nitrogen atmosphere. Isolated yields and ee values were determined by chiral
HPLC. The absolute structure of 4ag was determined by X-ray single crystal analysis (see Supporting Information).
c
a
Table 6. Further Examination of the Catalytic Asymmetric Reactions
b
b
entry
1
2
time
3 (yield, ee) (%)
4 (yield, ee) (%)
1
1c (R1 = 4-CNC6H4)
1c (R1 = 4-CNC6H4)
1c (R1 = 4-CNC6H4)
1c (R1 = 4-CNC6H4)
1c (R1 = 4-CNC6H4)
1g (R1 = 4-Me C6H4)
1h (R1 = 4-MeOC6H4)
1h (R1 = 4-MeOC6H4)
1h (R1 = 4-MeOC6H4)
1h (R1 = 4-MeOC6H4)
1h (R1 = 4-MeOC6H4)
2b (R3 = 4-OMe, R4 = H)
2c (R3 = 4-Me, R4 = H)
2d (R3 = 4-Br, R4 = H,)
2e (R3 = 4-CO2Me, R4 = H)
2f (R3 = H, R4 = CH3)
2d (R3 = 4-Br, R4= H)
2b (R3 = 4-OMe, R4 = H)
2c (R3 = 4-Me, R4 = H)
2d (R3 = 4-Br, R4 = H)
2e (R3 = 4-CO2Me, R4 = H)
2f (R3 = H, R4 = CH3)
48 h
72 h
60 h
4 d
3cb (0)
4cb (0)
2
3cc (trace)
4cc (trace)
4cd (33, 86)
4ce (12, 91)
4cf (trace)
c
3
3cd (36, 95)
4
3ce (50, 94)
3cf (trace)
5
14 d
23 h
9.5 d
8.5 d
53 h
4d 4h
12 d
6
3gd (34, 91)
3hb (29, 85)
3hc (24, 77)
3hd (40, 88)
3he (29, 88)
3hf (trace)
4gd (52, 82)
4hb (38, 85)
4hc (58, 70),
4hd (45, 81)
4he (30, 88)
4hf (80, 71)
7
8
9
10
11
a
Unless otherwise noted, the reaction was conducted between 1 (0.5 mmol) and 2 (0.75 mmol), AgOAc (2.5 mol %), and (S)-TRIP (3.75 mol %)
b
in 5 mL of anhydrous DCE at room temperature (23 °C) under nitrogen atmosphere. Isolated yields and ee values were determined by chiral
HPLC. The absolute structure of 3cd was determined by X-ray single crystal analysis (see Supporting Information).
c
with the styrenes under standard reaction conditions,
respectively. The results show that 3-alkynylacrylaldehyde 1c
only reacted with the styrenes having an electron-poor phenyl
group (entries 3 and 4). The reaction of 1c and 2d afforded
36% yield of 3ce (95% ee) and 33% yield of 4ce (86% ee), and
the reaction of 1c and 2e afforded 50% yield of 3ce (94% ee)
and 12% yield of 4ce (91% ee) while 3-alkynylacrylaldehyde 1h
was found to react with all the styrenes and afforded the
products with moderate to good enantioselectivity (entries 7−
11). It is deduced that the relative stability of pyrylium
intermediate and the acidity of the phenol group of 2, as well as
mutual reactivities of both substrates, might be all regulated by
the electronic density of the involved phenyl rings.
acid are essential for this reaction (entries 1 and 2). When Ag-
(S)-TRIP alone was used as the only catalyst, the desired
products could be obtained in lower yield and low
enantioselectivity after a relatively longer reaction time (entry
3). This means that Ag-(S)-TRIP could not sufficiently achieve
this transformation in a highly enantioselective fashion. Further
addition of (S)-TRIP (1.25 mol %) and acetic acid (2.5 mol %)
to the same reaction (entry 4) resulted in similar yields and
enantiopurities of the products as those under standard
conditions with AgOAc (2.5 mol %) and (S)-TRIP (3.75 mol
%) (entry 5). In addition, treatment of the pure single products
3aa and 4aa was also examined, in parallel, under the standard
catalytic reaction conditions, with AgOAc (2.5 mol %) and (S)-
TRIP (3.75 mol %) in 1,2-dichloroethane at room temperature.
Both substrates were unchanged after 3 days. Such results
excluded the possibility of mutual transformation between these
two products during the reaction process.
To better understand the mechanism, several control
experiments were conducted (Table 7). Failure of the cascade
transformations at rt in the absence of either AgOAc or (S)-
TRIP reveals that both the metal salt and the chiral phosphoric
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a
limited cavity of the ion pair results in the hindrance effects of
the R4 in the reactions. The larger the size of the R4 group, the
more difficult the delivery of styrene 2 to the cavity. That is
why trisubstituted olefins cannot undergo this reaction. The
resulting carbocation C is finally attacked by the internal
phenolic hydroxyl group through a SN2 (attack at C1 position)
or a SN2′ (attack at C3 position) mechanism, providing the
final products 3 and 4, respectively. In the meanwhile, one
molecule of chiral phosphoric acid is regenerated in the last
step and returns to the synergetic catalytic cycle. In total, three
new bonds and two rings are enantioselectively produced
through this catalytic asymmetric cascade reaction starting from
the two prochiral substrates 1 and 2.
Table 7. Control Experiments for Mechanism Study
Ag(I)
entry (2.5 mol %)
(S)-TRIP,
mol %
3aa (yield,
b
4aa (yield,
b
time
ee) (%)
ee) (%)
1
2
3
4
5
AgOAc
−
3.75
7 d
0
0
−
7 d
0
0
Ag-(S)-TRIP
Ag-(S)-TRIP
AgOAc
−
1.25
3.75
3 d
18, 62
26, 70
29, 73
17, 59
28, 65
34, 71
c
30 h
26 h
a
Unless otherwise noted, the reactions were carried out between 1a
CONCLUSION
■
(0.5 mmol) and 2a (0.75 mmol) with the indicated catalysts in 5 mL
of anhydrous DCE at room temperature (23 °C) under nitrogen
atmosphere. Isolated yields and ee values were determined by chiral
In summary, a catalytic asymmetric counterion-directed
annulation of 3-alkynylacrylaldehydes and 2-hydroxystyrenes
has been successfully developed through an in situ-generated
unstabilized pyrylium with synergetic catalysis from AgOAc and
chiral phosphoric acid (S)-TRIP under mild conditions,
providing corresponding multiring products in moderate to
excellent enantioselectivity (up to 95% ee). Three new bonds
and two rings were totally generated through the developed
cascade reaction, which is composed of an alkyne−carbonyl
cycloisomerization, an oxa [4 + 2]-cycloaddition, and an
intramolecular SN2 or SN2′ substitution. Further study on the
regioselective control of the reaction and application of the
developed methodology to the synthesis of functional
molecules will be studied in this laboratory.
b
c
HPLC. Acetic acid (2.5 mol %) was added.
A possible mechanism was proposed based on the above
results and control experiments (Figure 3). First, the alkyne
EXPERIMENTAL SECTION
General. All the reactions were conducted using oven-dried
glassware. DCE was distilled from CaH2 prior to use. Hexane and
ethyl acetate were obtained from commercial suppliers and used
■
1
without further distillation. Chemical shifts for H NMR are reported
in parts per million (ppm) downfield from tetramethylsilane as the
internal standard, and coupling constants are in hertz (Hz). The
following abbreviations are used for spin multiplicity: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, and br = broad.
Chemical shifts for 13C NMR are reported in ppm, relative to the
central line of a triplet at 77.16 ppm for deuteriochloroform.
Enantiomeric ratios of products were determined by chiral HPLC
with different chiral columns and hexane and i-PrOH as solvents.
Melting points were uncorrected.
Representative Procedure. To a solution of AgOAc (2.8 mg, 2.5
mol %) and (S)-TRIP (14.1 mg, 3.75 mol %) in dry DCE (1 mL) in a
dark reaction tube were added 3-alkynylacrylaldehyde 1a (105 mg, 0.5
mmol) in dry DCE (2 mL) and 2-hydroxystyrene 2a (90 mg, 0.75
mmol) in dry DCE (2 mL) under N2 at rt. The resulting mixture was
stirred at rt until starting material 1a was consumed (monitored by
TLC). The whole mixture was concentrated under vacuum. The
residue was purified by flash column chromatography on silica gel
(hexane/ethyl acetate = 150:1 to 100:1) to give products 3aa (47.8
mg, 29% yield, 73% ee) and 4aa (56.1 mg, 34% yield, 71% ee) as white
solids.
Figure 3. A proposed reaction mechanism.
bond of 1 is coordinated and activated by Ag(I), initiating the
cycloisomerization with the internal carbonyl oxygen to afford a
Ag(I)-pyrylium/chiral phosphate ionic pair A. Immediate
protonolysis of the C−Ag bond with HOAc delivers AgOAc
back to the first catalytic cycle and generates the key chiral
pyrylium phosphate ionic pair B. Then the phosphate PO
bond of intermediate B grasps the 2-hydroxystyrene substrate 2
through a hydrogen bond with the phenolic hydroxyl group,
and an asymmetric [4 + 2]-cycloaddition is immediately
triggered.12 We believe that certain π−π interactions between
the phenyl groups of the two substrates and chiral phosphate
also contribute crucial driving forces in forming the transition
state of asymmetric [4 + 2]-cycloaddition, though it cannot yet
be precisely explained. Existence of such π−π interactions also
can explain our previous observation on significant electronic
effects of the substrates in the reactions. Furthermore, the
3aa. White solid; mp 146−148 °C; [α]D25 −102.7 (c 0.36, CHCl3);
1H NMR (400 MHz, CDCl3): δ 8.14 (dd, J = 7.6, 1.2 Hz, 2H), 7.64
(tt, J = 7.6, 2.4 Hz, 1H), 7.56 (td, J = 6.0, 1.6 Hz, 2H), 7.24 (dd, J =
7.6, 1.2 Hz, 1H), 7.16 (td, J = 7.6, 1.6 Hz, 1H), 6.91 (td, J = 7.2, 0.8
Hz, 1H), 6.82 (dd, J = 8.8, 0.8 Hz, 1H), 4.50 (s, 1H), 4.10 (s, 1H),
3.17 (d, J = 1.6 Hz, 1H), 2.40−2.35 (m, 1H), 2.19−2.09 (m, 2H),
1.88−1.72 (m, 3H), 1.69−1.50 (m, 3H), 1.48−1.37 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 199.6, 153.3, 136.6, 133.4, 131.6, 130.2,
129.0, 128.7, 128.6, 128.3, 126.4, 120.1, 117.5, 71.4, 57.4, 33.2, 29.2,
28.4, 23.4, 22.7, 22.6 ppm; IR (KBr) vmax 2924, 2828, 2358, 1676,
1578, 1219, 1046, 1113, 1021, 967, 693, 581 cm−1; HRMS (ESI, m/z)
7068
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Article
calcd for C23H22O2Na+ [M + Na]+: 353.1517, found: 353.1514; HPLC
analysis: 73% ee [Daicel CHIRALPAK AD-H column, hexane/i-PrOH
= 96:4, 0.5 mL/min, 254 nm, t1 = 10.3 min (minor), t2 = 11.9 min
(major)].
(m, 1H), 1.55−1.45 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 198.7,
166.2, 153.0, 140.2, 135.2, 134.1, 130.1, 128.5, 128.3, 128.2, 127.1,
121.9, 120.3, 117.1, 74.1, 52.6, 49.5, 34.9, 33.6, 31.9, 31.8, 25.8, 21.3
ppm; IR (KBr) vmax 2934, 2862, 1726, 1726, 1684, 1282, 1240, 1225,
1110, 955, 819, 750 cm−1; HRMS (ESI, m/z) calcd for C25H23O4− [M
− H]−: 387.1602, found: 387.1605; HPLC analysis: 84% ee [Daicel
CHIRALPAK AD-H column, hexane/i-PrOH = 90:10, 0.5 mL/min,
254 nm, t1 = 13.4 min (major), t2 = 17.3 min (minor)].
4aa. White solid; mp 125−128 °C; [α]D25 77.6 (c 0.36, CHCl3); 1H
NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.4 Hz, 2H), 7.56 (t, J = 7.2
Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.16 (t, J = 8.0 Hz, 1H), 7.02 (d, J =
7.6 Hz, 1H), 6.89−6.84 (m, 2H), 5.52 (d, J = 5.2 Hz, 1H), 3.88 (d, J =
3.2 Hz, 1H), 3.27 (brs, 1H), 2.35−2.31 (m, 1H), 2.21−2.12 (m, 3H),
2.05−1.95 (m, 2H), 1.83−1.76 (m, 2H), 1.69−1.66 (m, 1H), 1.60−
1.46 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 199.0, 153.0, 137.0,
135.2, 133.3, 128.9, 128.5, 128.29, 128.24, 127.4, 121.9, 120.2, 117.0,
74.3, 49.0, 35.0, 33.5, 31.9, 31.8, 25.8, 21.3 ppm; IR (KBr) vmax 2959,
1681, 1594, 1579, 1261, 1069, 1033, 958, 771, 700, 626, 590 cm−1;
HRMS (ESI, m/z) calcd for C23H22O2Na+ [M + Na]+:353.1517,
found: 353.1512; HPLC analysis: 71% ee [Daicel CHIRALPAK AD-H
column, hexane/i-PrOH = 98:2, 0.5 mL/min, 254 nm, t1 = 10.4 min
(major), t2 = 11.7 min (minor)].
25
3ea. White solid, 78.3 mg, 45% yield; mp 162−164 °C; [α]D
1
−156.6 (c 0.36, CHCl3); H NMR (400 MHz, CDCl3): δ 8.19−8.15
(m, 2H), 7.26−7.14 (m, 4H), 6.92 (dt, J = 7.2, 1.2 Hz, 1H), 6.83 (dd, J
= 8.0, 1.6 Hz, 1H), 4.50 (s, 1H), 4.04 (s, 1H), 3.14 (d, J = 1.2 Hz, 1H),
2.36−2.35 (m, 1H), 2.17−2.08 (m, 2H), 1.86 (dt, J = 13.2, 3.6 Hz,
1H), 1.81−1.73 (m, 2H), 1.68−1.65 (m, 1H), 1.58−1.54 (m, 2H),
1.45−1.42 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 198.1, 167.2,
164.7, 153.4, 133.05, 133.02, 131.8, 131.3, 131.2, 130.0, 128.7, 128.4,
126.3, 120.1, 117.5, 116.3, 116.1, 71.4, 57.3, 33.3, 29.2, 28.4, 23.4, 22.7,
22.6 ppm; IR (KBr) vmax 2936, 2902, 2834, 1678, 1595, 1502, 1272,
1219, 1158, 1045, 874, 599 cm−1; HRMS (ESI, m/z) calcd for
C23H21FO2Na+ [M + Na]+: 371.1423, found: 371.1421; HPLC
analysis: 83% ee [Daicel CHIRALPAK AD-H column, hexane/i-PrOH
= 95:5, 0.5 mL/min, 254 nm, t1 = 9.6 min (minor), t2 = 11.1 min
(major)].
25
3ca. White solid, 56.8 mg, 32% yield; mp 137−141 °C; [α]D
1
−301.1 (c 0.36, CHCl3); H NMR (400 MHz, CDCl3): 8.21 (dd, J =
8.8, 2.0 Hz, 2H), 7.88 (dd, J = 8.8, 2.0 Hz, 2H), 7.20−7.15 (m, 2H),
6.92 (dt, J = 7.2, 1.6 Hz, 1H), 6.83 (dd, J = 8.0, 0.4 Hz, 1H), 4.51 (s,
1H), 4.05 (s, 1H), 3.11 (d, J = 1.6 Hz, 1H), 2.41−2.36 (m, 1H), 2.19−
2.11 (m, 1H), 2.05 (dt, J = 13.2, 2.4 Hz, 1H), 1.88 (dt, J = 13.2, 4.0
Hz, 1H), 1.79−1.72 (m, 2H), 1.68−1.62 (m, 1H), 1.59−1.52 (m, 2H),
1.47−1.39 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 198.4, 153.3,
139.6, 132.9, 132.3, 129.3, 128.9, 128.61, 128.60, 125.7, 120.2, 117.9,
117.6, 116.7, 71.1, 57.7, 33.0, 29.3, 28.4, 23.2, 22.6, 22.5 ppm; IR
(KBr) vmax 2923, 2853, 2231, 1685, 1579, 1483, 1216, 1139, 1043, 889,
4ea. White solid, 64.3 mg, 37% yield; mp 168−170 °C; [α]D25 78.3
(c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.00−7.96 (m, 2H),
7.19−7.11 (m, 3H), 7.03 (dd, J = 8.0, 1.6 Hz, 1H), 6.89−6.85 (m,
2H), 5.52 (d, J = 4.8 Hz, 1H), 3.83 (d, J = 2.8 Hz, 1H), 3.25 (brs, 1H),
2.35−2.30 (m, 1H), 2.21−2.19 (m, 2H), 2.12 (qd, J = 13.2, 4.0 Hz,
1H), 2.06−2.00 (m, 1H), 1.96 (qt, J = 13.2, 3.2 Hz, 1H), 1.83−1.76
(m, 2H), 1.70−1.66 (m, 1H), 1.56−1.45 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 197.4, 167.2, 164.6, 153.0, 135.2, 133.45, 133.42,
131.0, 130.9, 128.5, 128.3, 127.3, 121.9, 120.3, 117.1, 116.1, 115.9,
74.2, 49.0, 35.1, 33.6, 31.9, 31.8, 25.8, 21.3 ppm; IR (KBr) vmax 2923,
2862, 2836, 1679, 1595, 1503, 1227, 1205, 1160, 755, 580, 519 cm−1;
HRMS (ESI, m/z) calcd for C23H22FO2+ [M + H]+: 349.1604, found:
349.1597; HPLC analysis: 83% ee [Daicel CHIRALPAK AD-H
column, hexane/i-PrOH = 96:4, 0.5 mL/min, 254 nm, t1 = 9.9 min
(major), t2 = 11.1 min (minor)].
−
754, 719, 642 cm−1; HRMS (ESI, m/z) calcd for C24H20NO2 [M −
H]−: 354.1500, found: 354.1499; HPLC analysis: 92% ee [Daicel
CHIRALPAK AD-H column, hexane/i-PrOH = 90:10, 0.5 mL/min,
254 nm, t1 = 15.0 min (minor), t2 = 19.6 min (major)].
4ca. White solid, 60.3 mg, 34% yield; mp 123−126 °C; [α]D25 41.6
(c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.04 (dt, J = 8.4, 1.6
Hz, 2H), 7.79 (dt, J = 8.4, 1.6 Hz, 2H), 7.18 (td, J = 8.2, 1.2 Hz, 1H),
7.04 (dd, J = 8.0, 2.0 Hz, 1H), 6.91−6.87 (m, 2H), 5.53 (d, J = 5.6 Hz,
1H), 3.85 (d, J = 3.2 Hz, 1H), 3.23 (brs, 1H), 2.30−2.20 (m, 3H),
2.13−2.05 (m, 2H), 1.97 (qt, J = 12.8, 3.2 Hz, 1H), 1.83−1.78 (m,
2H), 1.70 (dt, J = 12.8, 3.6 Hz, 1H), 1.55−1.43 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 197.8, 152.9, 139.9, 135.1, 132.8, 128.7, 128.55,
128.52, 126.8, 121.8, 120.4, 117.9, 117.2, 116.6, 74.0, 49.5, 34.8, 33.7,
31.88, 31.83, 25.7, 21.3 ppm; IR (KBr) vmax 2936, 2227, 1687, 1594,
1486, 1238, 1122, 1090, 965, 770, 750, 648 cm−1; HRMS (ESI, m/z)
calcd for C24H20NO2− [M − H]−: 354.1500, found: 354.1500; HPLC
analysis: 92% ee [Daicel CHIRALPAK AD-H column, hexane/i-PrOH
= 87:13, 0.5 mL/min, 254 nm, t1 = 15.6 min (major), t2 = 18.7 min
(minor)].
25
3fa. White solid, 69.3 mg, 34% yield; mp 118−120 °C; [α]D
−151.6 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J =
8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.19−7.14 (m, 2H), 6.91 (t, J =
7.2 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.50 (s, 1H), 4.02 (s, 1H), 3.12
(d, J = 1.2 Hz, 1H), 2.40−2.35 (m, 1H), 2.16−2.07 (m, 2H), 1.88−
1.71 (m, 3H), 1.66−1.42 (m, 4H); 13C NMR (100 MHz, CDCl3): δ
198.7, 153.4, 135.3, 132.4, 131.9, 130.1, 129.9, 128.7, 128.6, 128.4,
126.2, 120.1, 117.6, 71.4, 57.4, 33.2, 29.3, 28.4, 23.3, 22.7, 22.6 ppm;
IR (KBr) vmax 2929, 2857, 2831, 1676, 1583, 1275, 1215, 1174, 1157,
905, 748 cm−1; HRMS (ESI, m/z) calcd for C23H21BrO2Na+ [M +
Na]+: 431.0623, found: 431.0622; HPLC analysis: 88% ee [Daicel
CHIRALPAK AD-H column, hexane/i-PrOH = 97:3, 0.5 mL/min,
254 nm, t1 = 11.9 min (minor), t2 = 13.1 min (major)].
25
3da. White solid, 54.3 mg, 28% yield; mp 154−158 °C; [α]D
1
−122.2 (c 0.36, CHCl3); H NMR (400 MHz, CDCl3): δ 8.24−8.16
(m, 4H), 7.22−7.14 (m, 2H), 6.92 (dt, J = 7.6, 1.6 Hz, 1H), 6.82 (dd, J
= 8.0, 0.8 Hz, 1H), 4.51 (s, 1H), 4.09 (s, 1H), 3.98 (s, 3H), 3.14 (d, J =
1.6 Hz, 1H), 2.40−2.36 (m, 1H), 2.19−2.06 (m, 1H), 2.08 (dt, J =
13.2, 2.4 Hz, 1H), 1.87 (dt, J = 13.2, 3.6 Hz, 1H), 1.83−1.72 (m, 2H),
1.70−1.63 (m, 1H), 1.60−1.51 (m, 2H), 1.48−1.41 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 199.3, 166.2, 153.3, 139.9, 134.2, 132.0,
130.3, 129.8, 128.7, 128.5, 128.4, 126.1, 120.2, 117.5, 71.3, 57.8, 52.6,
33.0, 29.2, 28.4, 23.3, 22.68, 22.62 ppm; IR (KBr) vmax 2932, 2860,
1723, 1680, 1608, 1580, 1277, 1216, 1114, 905, 754, 581 cm−1; HRMS
4fa. White solid, 61.2 mg, 30% yield; mp 146−148 °C; [α]D25 114.4
(c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.81 (dt, J = 8.8, 2.0
Hz, 2H), 7.60 (dt, J = 8.4, 2.4 Hz, 2H), 7.17 (td, J = 7.6, 1.6 Hz, 1H),
7.03 (dd, J = 7.6, 1.6 Hz, 1H), 6.89−6.86 (m, 2H), 5.51 (d, J = 5.2 Hz,
1H), 3.81 (d, J = 3.2 Hz, 1H), 3.24 (brs, 1H), 2.32−2.28 (m, 1H),
2.21−2.19 (m, 2H), 2.11−1.91 (m, 3H), 1.82−1.76 (m, 2H), 1.70−
1.66 (m, 1H), 1.53−1.47 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
198.0, 153.0, 135.7, 135.2, 132.2, 129.8, 128.6, 128.5, 128.3, 127.2,
121.9, 120.3, 117.1, 74.2, 49.1, 35.0, 33.6, 31.9, 31.8, 25.8, 21.3 ppm;
IR (KBr) vmax 2931, 2860, 1678, 1580, 1261, 1242, 1151, 1126, 1096,
1070, 1021, 752 cm−1; HRMS (ESI, m/z) calcd for C23H22BrO2+ [M +
H]+: 409.0803, found: 409.0794; HPLC analysis: 86% ee [Daicel
CHIRALPAK AD-H column, hexane/i-PrOH = 97:3, 0.5 mL/min,
254 nm, t1 = 11.5 min (major), t2 = 14.2 min (minor)].
−
(ESI, m/z) calcd for C25H23O4 [M − H]−: 387.1602, found:
387.1605; HPLC analysis: 87% ee [Daicel CHIRALPAK AD-H
column, hexane/i-PrOH = 90:10, 0.5 mL/min, 254 nm, t1 = 12.5 min
(minor), t2 = 13.9 min (major)].
4da. White solid, 58.2 mg, 30% yield; mp 135−137 °C; [α]D25 60.6
(c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.13−8.11 (m, 2H),
8.00−7.98 (m, 2H), 7.17 (td, J = 7.2, 2.0 Hz, 1H), 7.03 (dd, J = 8.0,
1.6 Hz, 1H), 6.90−6.88 (m, 2H), 5.52 (d, J = 5.2 Hz, 1H), 3.95 (s,
3H), 3.89 (d, J = 3.2 Hz, 1H), 3.25 (brs, 1H), 2.33−2.28 (m, 1H),
2.22−2.20 (m, 2H), 2.17 (td, J = 13.2, 4.0 Hz, 1H), 2.07−2.01 (m,
1H), 1.97 (qt, J = 13.2, 3.2 Hz, 1H), 1.85−1.78 (m, 2H), 1.70−1.67
25
3ga. White solid, 56.7 mg, 33% yield; mp 149−151 °C; [α]D
−216.0 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.04 (dt, J =
6.4, 1.6 Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H), 7.24 (dd, J = 7.2, 1.6 Hz,
1H), 7.16 (dt, J = 7.4, 2.0 Hz, 1H), 6.91 (dt, J = 7.2, 1.2 Hz, 1H), 6.82
(dd, J = 8.4, 1.2 Hz, 1H), 4.50 (s, 1H), 4.07 (s, 1H), 3.16 (d, J = 1.6
7069
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Article
Hz, 1H), 2.46 (s, 3H), 2.39−2.35 (m, 1H), 2.18−2.10 (m, 2H), 1.87−
1.70 (m, 3H), 1.67−1.51 (m, 3H), 1.47−1.38 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 199.3, 153.4, 144.3, 134.1, 131.5, 130.4, 129.7,
128.7, 128.3, 126.5, 120.0, 117.5, 71.5, 57.2, 33.3, 29.2, 28.4, 23.4, 22.7,
22.6, 21.8 ppm; IR (KBr) vmax 2942, 2901, 1672, 1604, 1578, 1220,
1199, 1183, 1113, 1046, 909, 756 cm−1; HRMS (ESI, m/z) calcd for
C24H24O2Na+ [M + Na]+: 367.1674, found: 367.1675; HPLC analysis:
82% ee [Daicel CHIRALPAK OD-H column, hexane/i-PrOH = 97:3,
0.5 mL/min, 254 nm, t1 = 10.1 min (major), t2 = 11.9 min (minor)].
4ga. White solid, 70.5 mg, 41% yield; mp 130−133 °C; [α]D25 76.6
(c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 8.8 Hz,
2H), 7.26 (d, J = 8.0 Hz, 2H), 7.16 (td, J = 7.6, 1.2 Hz, 1H), 7.03 (dd,
J = 7.2, 0.8 Hz, 1H), 6.89−6.84 (m, 2H), 5.51 (d, J = 4.4 Hz, 1H), 3.86
(d, J = 2.8 Hz, 1H), 3.26 (brs, 1H), 2.41 (s, 3H), 2.35−2.31 (m, 1H),
2.21−2.11 (m, 3H), 2.04−1.90 (m, 2H), 1.82−1.75 (m, 2H), 1.69−
1.66 (m, 1H), 1.55−1.46 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
198.6, 153.1, 144.2, 135.2, 134.5, 129.6, 128.5, 128.4, 128.2, 127.6,
121.9, 120.2, 117.1, 74.3, 48.9, 35.2, 33.5, 31.96, 31.90, 25.8, 21.7, 21.4
ppm; IR (KBr) vmax 2920, 2887, 2862, 2835, 1681, 1604, 1582, 1240,
Hz, 1H), 7.44 (td, J = 8.0, 2.0 Hz, 1H), 7.13 (td, J = 7.6, 1.6 Hz, 1H),
7.03−6.99 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.85−6.82 (m, 2H), 5.52
(d, J = 4.8 Hz, 1H), 3.96 (d, J = 2.8 Hz, 1H), 3.80 (s, 3H), 3.19 (brs,
1H), 2.42−2.37 (m, 1H), 2.24−2.18 (m, 3H), 2.04−1.87 (m, 3H),
1.79−1.57 (m, 2H), 1.54−1.46 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 202.6, 157.7, 153.1, 135.3, 133.1, 129.9, 129.6, 128.5, 128.1,
127.9, 122.2, 120.9, 120.0, 116.9, 111.6, 74.4, 55.7, 53.2, 33.8, 33.5,
32.1, 31.9, 25.8, 21.4 ppm; IR (KBr) vmax 2963, 2859, 1683, 1598,
1481, 1377, 1237, 1080, 965, 860, 782, 765, 681 cm−1; HRMS (ESI,
+
m/z) calcd for C24H25O3 [M + H+]: 361.1804, found: 361.1815;
HPLC analysis: 9% ee [Daicel CHIRALPAK OD-H column, hexane/i-
PrOH = 65:35, 0.5 mL/min, 254 nm, t1 = 9.1 min (major), t2 = 11.3
min (minor)].
25
3ja. White solid, 54.0 mg, 30% yield; mp 92−95 °C; [α]D −91.6
(c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.0 Hz,
1H), 7.62 (dd, J = 2.8, 2.4 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.23 (dd,
J = 7.6, 1.6 Hz, 1H), 7.19−7.14 (m, 2H), 6.91 (td, J = 7.6, 0.8 Hz, 1H),
6.82 (dd, J = 8.0, 0.8 Hz, 1H), 4.50 (s, 1H), 4.07 (s, 1H), 3.91 (s, 3H),
3.18 (d, J = 1.6 Hz, 1H), 2.40−2.35 (m, 1H), 2.19−2.09 (m, 2H),
1.88−1.72 (m, 3H), 1.70−1.62 (m, 1H), 1.57−1.49 (m, 2H), 1.48−
1.38 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 199.5, 160.2, 153.4,
138.0, 131.6, 130.2, 130.0, 128.7, 128.3, 126.4, 121.0, 120.1, 119.8,
117.5, 113.1, 71.5, 57.5, 55.6, 33.2, 29.2, 28.4, 23.4, 22.7, 22.6 ppm; IR
(KBr) vmax 2930, 2832, 1660, 1595, 1458, 1343, 1244, 1142, 1043, 869,
775, 760, 666 cm−1; HRMS (ESI, m/z) calcd for C24H24O3Na+ [M +
Na]+: 383.1623, found: 383.1623; HPLC analysis: 58% ee [Daicel
CHIRALPAK AD-H column, hexane/i-PrOH = 96:4, 0.5 mL/min,
254 nm, t1 = 12.3 min (minor), t2 = 13.6 min (major)].
+
1202, 1190, 750, 580 cm−1; HRMS (ESI, m/z) calcd for C24H25O2
[M + H]+: 345.1855, found: 345.1847; HPLC analysis: 82% ee [Daicel
CHIRALPAK OD-H column, hexane/i-PrOH = 96:4, 0.45 mL/min,
254 nm, t1 = 13.2 min (major), t2 = 14.0 min (minor)].
25
3ha. White solid, 45.0 mg, 25% yield; mp 150−154 °C; [α]D
−152.2 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.13 (dt, J =
9.2, 2.4 Hz, 2H), 7.24 (dd, J = 7.6, 1.6 Hz, 1H), 7.16 (td, J = 7.6, 2.4
Hz, 1H), 7.04 (dt, J = 9.2, 2.4 Hz, 2H), 6.91 (td, J = 7.6, 1.2 Hz, 1H),
6.82 (dd, J = 8.0, 1.2 Hz, 1H), 4.50 (s, 1H), 4.04 (s, 1H), 3.91 (s, 3H),
3.16 (d, J = 1.2 Hz, 1H), 2.39−2.35 (m, 1H), 2.17−2.12 (m, 2H),
1.88−1.70 (m, 3H), 1.68−1.58 (m, 2H), 1.55−1.50 (m, 1H), 1.48−
1.37 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 198.2, 163.8, 153.4,
131.5, 130.9, 130.5, 129.6, 128.8, 128.3, 126.7, 120.0, 117.5, 114.2,
71.6, 57.0, 55.7, 33.5, 29.2, 28.4, 23.5, 22.75, 22.71 ppm; IR (KBr) vmax
2931, 2833, 1666, 1595, 1485, 1344, 1215, 1173, 1044, 998, 840, 759,
598 cm−1; HRMS (ESI, m/z) calcd for C24H24O3Na+ [M + Na]+:
383.1623, found: 383.1624; HPLC analysis: 78% ee [Daicel
CHIRALPAK OD-H column, hexane/i-PrOH = 80:20, 0.5 mL/min,
254 nm, t1 = 10.8 min (major), t2 = 14.6 min (minor)].
25
4ja. Pale yellow wax, 57.6 mg, 32% yield; [α]D 50.5 (c 0.36,
CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.52−7.49 (m, 2H), 7.36 (t,
J = 8.0 Hz, 1H), 7.17 (td, J = 7.8, 2.0 Hz, 1H), 7.12 (ddd, J = 8.0, 2.4,
1.2 Hz, 1H), 7.03 (dd, J = 8.4, 1.6 Hz, 1H), 6.89−6.85 (m, 2H), 5.52
(d, J = 4.8 Hz, 1H), 3.86 (d, J = 3.2 Hz, 1H), 3.84 (s, 3H), 3.28 (brs,
1H), 2.35−2.30 (m, 1H), 2.22−2.10 (m, 3H), 2.05−1.89 (m, 2H),
1.84−1.77 (m, 2H), 1.71−1.66 (m, 1H), 1.55−1.46 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 198.9, 160.2, 153.0, 138.4, 135.2, 129.9,
128.5, 128.2, 127.4, 121.9, 120.8, 120.2, 119.7, 117.0, 112.6, 74.3, 55.5,
49.2, 35.1, 33.6, 32.0, 31.9, 25.8, 21.4 ppm; IR (KBr) vmax 2963, 2859,
1683, 1598, 1481, 1377, 1237, 1080, 965, 860, 782, 765, 681 cm−1;
25
4ha. White solid, 120.6 mg, 67% yield; mp 180−181 °C; [α]D
1
+
66.6 (c 0.36, CHCl3); H NMR (400 MHz, CDCl3): δ 7.94 (dt, J =
HRMS (ESI, m/z) calcd for C24H25O3 [M + H]+: 361.1804, found:
8.8, 2.4 Hz, 2H), 7.17 (td, J = 8.0, 1.2 Hz, 1H), 7.04 (dd, J = 8.0, 1.2
Hz, 1H), 6.93 (dt, J = 9.2, 2.0 Hz, 2H), 6.89−6.85 (m, 2H), 5.52 (d, J
= 4.8 Hz, 1H), 3.86 (s, 3H), 3.83 (d, J = 3.2 Hz, 1H), 3.26 (brs, 1H),
2.37−2.33 (m, 1H), 2.21−2.11 (m, 3H), 2.04−1.90 (m, 2H), 1.82−
1.75 (m, 2H), 1.69−1.65 (m, 1H), 1.55−1.49 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 197.5, 163.7, 153.1, 135.3, 130.6, 130.1, 128.5,
128.2, 127.7, 122.0, 120.1, 117.1, 114.0, 74.4, 55.6, 48.7, 35.3, 33.6,
31.98, 31.92, 25.8, 21.4 ppm; IR (KBr) vmax 2935, 2836, 1670, 1599,
1482, 1243, 1182, 1018, 954, 867, 753, 619, 583 cm−1; HRMS (ESI,
361.1814; HPLC analysis: 57% ee [Daicel CHIRALPAK AD-H
column, hexane/i-PrOH = 96:4, 0.5 mL/min, 254 nm, t1 = 11.1 min
(major), t2 = 12.4 min (minor)].
25
3ka. White solid, 58.5 mg, 30% yield; mp 176−178 °C; [α]D
−110.0 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.85 (dd, J =
8.4, 2.0 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.24 (dd, J = 7.6, 1.2 Hz,
1H),7.16 (dt, J = 7.4, 2.0 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.91 (dt, J
= 7.2, 0.8 Hz, 1H), 6.83 (dd, J = 8.0, 0.4 Hz, 1H), 4.51 (s, 1H), 4.07 (s,
1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.18 (brs, 1H), 2.40−2.35 (m, 1H),
2.18−2.14 (m, 2H), 1.86 (dt, J = 13.2, 3.2 Hz, 1H), 1.82−1.72 (m,
2H), 1.69−1.51 (m, 3H), 1.47−1.35 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 198.2, 153.6, 153.4, 149.4, 131.5, 130.4, 129.7, 128.6, 128.2,
126.6, 123.0, 120.0, 117.5, 110.8, 110.3, 71.5, 56.8, 56.2, 56.1, 33.6,
29.2, 28.4, 23.4, 22.7, 22.6 ppm; IR (KBr) vmax 2937, 2893, 1671, 1580,
1278, 1216, 1173, 1132, 1047, 1021, 852, 756 cm−1; HRMS (ESI, m/
z) calcd for C25H26O4Na+ [M + Na]+: 413.1729, found: 413.1724;
HPLC analysis: 65% ee [Daicel CHIRALPAK AD-H column, hexane/
i-PrOH = 85:15, 0.5 mL/min, 254 nm, t1 = 13.0 min (minor), t2 = 15.3
min (major)].
+
m/z) calcd for C24H25O3 [M + H]+: 361.1804, found: 361.1799;
HPLC analysis: 78% ee [Daicel CHIRALPAK AD-H column, hexane/
i-PrOH = 85:15, 0.5 mL/min, 254 nm, t1 = 11.5 min (major), t2 = 15.8
min (minor)].
25
3ia. White solid, 41.4 mg, 23% yield; mp 154−156 °C; [α]D
1
−16.6 (c 0.36, CHCl3); H NMR (400 MHz, CDCl3): 7.64 (dt, J =
8.0, 1.6 Hz, 1H), 7.51 (td, J = 8.0, 2.0 Hz, 1H), 7.11 (td, J = 8.0, 1.6
Hz, 1H), 7.08−7.04 (m, 3H), 6.85 (td, J = 7.2, 1.2 Hz, 1H), 6.78 (d, J
= 8.0 Hz, 1H), 4.46 (s, 1H), 4.18 (s, 1H), 4.01 (s, 3H), 3.14 (d, J = 1.2
Hz, 1H), 2.37−2.32 (m, 1H), 2.16−2.06 (m, 2H), 1.99−1.95 (m, 1H),
1.84 (dt, J = 13.2, 3.6 Hz, 1H), 1.76−1.63 (m, 2H), 1.59−1.53 (m,
2H), 1.47−1.36 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 203.1,
157.9, 153.5, 133.5, 131.2, 130.7, 130.4, 129.0, 128.9, 128.0, 126.7,
121.2, 119.8, 117.2, 111.7, 71.7, 61.7, 55.7, 32.7, 29.4, 28.3, 23.7, 22.8,
22.7 ppm; IR (KBr) vmax 2929, 2830, 1678, 1597, 1484, 1344, 1271,
1043, 890, 839, 752, 695, 575 cm−1; HRMS (ESI, m/z) calcd for
C24H24NaO3+ [M + Na]+: 383.1623, found: 383.1621; HPLC analysis:
15% ee [Daicel CHIRALPAK OD-H column, hexane/i-PrOH = 70:30,
0.5 mL/min, 254 nm, t1 = 9.1 min (major), t2 = 12.0 min (minor)].
4ia. White solid, 72.0 mg, 40% yield; mp 162−164 °C; [α]D25 10.0
(c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.53 (dd, J = 7.6, 2.0
25
4ka. White solid, 103.3 mg, 53% yield; mp 75−77 °C; [α]D 41.6
(c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.57−7.55 (m, 2H),
7.17 (td, J = 7.8, 1.6 Hz, 1H), 7.04 (dd, J = 8.4, 1.6 Hz, 1H), 6.90−6.85
(m, 3H), 5.52 (d, J = 4.8 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.85 (d, J
= 2.8 Hz, 1H), 3.28 (brs, 1H), 2.39−2.34 (m, 1H), 2.22−2.09 (m,
3H), 2.06−1.90 (m, 2H), 1.83−1.76 (m, 2H), 1.70−1.66 (m, 1H),
1.59−1.46 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 197.6, 153.5,
153.1, 149.4, 135.3, 130.1, 128.5, 128.2, 127.6, 122.9, 121.9, 120.2,
117.0, 110.3, 110.1, 74.4, 56.2, 56.0, 48.5, 35.5, 33.6, 32.0, 31.9, 25.8,
21.4 ppm; IR (KBr) vmax 2931, 2833, 1678, 1581, 1454, 1413, 1324,
1240, 1127, 1003, 900, 812, 753 cm−1; HRMS (ESI, m/z) calcd for
7070
dx.doi.org/10.1021/jo501196n | J. Org. Chem. 2014, 79, 7063−7074

The Journal of Organic Chemistry
Article
+
C25H27O4 [M + H]+: 391.1909, found: 391.1905; HPLC analysis:
1674, 1596, 1580, 1261, 1219, 1002, 906, 739, 690 cm−1; HRMS (ESI,
m/z) calcd for C24H24O3Na+ [M + Na]+: 383.1623, found: 383.1620;
HPLC analysis: 80% ee [Daicel CHIRALPAK OD-H column, hexane/
i-PrOH = 65:35, 0.5 mL/min, 254 nm, t1 = 8.8 min (major), t2 = 17.5
min (minor)].
65% ee [Daicel CHIRALPAK AD-H column, hexane/i-PrOH = 85:15,
0.5 mL/min, 254 nm, t1 = 12.2 min (major), t2 = 17.7 min (minor)].
3la. White solid, 60.9 mg, 29% yield; mp 197−199 °C; [α]D
25
−25.5 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.14 (s, 2H),
7.21 (td, J = 6.4, 2.8 Hz, 1H), 7.17 (dd, J = 8.4, 1.6 Hz, 1H), 6.90 (dt, J
= 7.2, 1.2 Hz, 1H), 6.83 (dd, J = 8.4, 0.8 Hz, 1H), 4.51 (s, 1H), 4.05 (s,
1H), 4.00 (s, 6H), 3.96 (s, 3H), 3.20 (d, J = 1.6 Hz, 1H), 2.40−2.36
(m, 1H), 2.19−2.10 (m, 2H), 1.87 (dt, J = 13.2, 3.2 Hz, 1H), 1.83−
1.73 (m, 2H), 1.70−1.67 (m, 1H), 1.63−1.49 (m, 2H), 1.48−1.38 (m,
1H); 13C NMR (100 MHz, CDCl3): δ 198.3, 153.42, 153.40, 142.9,
131.6, 130.2, 128.3, 126.4, 120.0, 117.6, 106.1, 71.4, 61.1, 57.1, 56.4,
33.4, 29.2, 28.4, 23.3, 22.7, 22.6 ppm; IR (KBr) vmax 2924, 2859, 2834,
1664, 1584, 1503, 1128, 1005, 979, 772, 704, 617 cm−1; HRMS (ESI,
m/z) calcd for C26H28O5Na+ [M + Na]+: 443.1834, found: 443.1830;
HPLC analysis: 17% ee [Daicel CHIRALPAK AD-H column, hexane/
i-PrOH = 75:25, 0.5 mL/min, 254 nm, t1 = 10.5 min (minor), t2 = 14.1
min (major)].
4ab. White solid, 27.0 mg, 15% yield; mp 152−154 °C; [α]D25 45.5
(c 0.18, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.96−7.94 (m, 2H),
7.58 (tt, J = 7.0, 1.2 Hz, 1H), 7.49−7.45 (m, 2H), 6.81 (d, J = 8.8 Hz,
1H), 6.75 (dd, J = 8.8, 3.2 Hz, 1H), 6.59 (d, J = 3.2 Hz, 1H), 5.53 (d, J
= 4.4 Hz, 1H), 3.88 (d, J = 2.8 Hz, 1H), 3.74 (s, 3H), 3.23 (brs, 1H),
2.35−2.31 (m, 1H), 2.21−2.10 (m, 3H), 2.06−1.89 (m, 2H), 1.89−
1.76 (m, 2H), 1.69−1.65 (m, 1H), 1.57−1.45 (m, 1H.); 13C NMR
(100 MHz, CDCl3): δ 199.1, 153.2, 147.0, 137.0, 135.2, 133.3, 128.9,
128.3, 127.9, 121.7, 117.5, 114.1, 113.2, 74.1, 55.8, 49.0, 35.3, 33.5,
31.88, 31.87, 25.8, 21.3 ppm; IR (KBr) vmax 2926, 2866, 2833, 1680,
1593, 1233, 1219, 1144, 1036, 865, 693 cm−1; HRMS (ESI, m/z) calcd
for C24H25O3 [M + H]+: 361.1804, found: 361.1814; HPLC analysis:
76% ee [Daicel CHIRALPAK AD-H column, hexane/i-PrOH = 50:50,
0.5 mL/min, 254 nm, t1 = 8.5 min (major), t2 = 10.0 min (minor)].
4la. White solid, 88.2 mg, 42% yield; mp 65−67 °C; [α]D25 13.8 (c
0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.20 (s, 2H), 7.17 (dd,
J = 7.2, 2.0 Hz, 1H), 7.06 (dd, J = 8.0, 1.6 Hz, 1H), 6.90−6.87 (m,
2H), 5.52 (d, J = 4.8 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 6H), 3.82 (d, J =
3.2 Hz, 1H), 3.30 (brs, 1H), 2.38−2.33 (m, 1H), 2.22−2.20 (m, 2H),
2.13 (td, J = 13.2, 4.4 Hz, 1H), 2.06−1.91 (m, 2H), 1.85−1.77 (m,
2H), 1.71−1.67 (m, 1H), 1.56−1.45 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 197.9, 153.3, 153.1, 142.9, 135.2, 132.3, 128.5, 128.2, 127.5,
121.9, 120.3, 117.0, 105.8, 74.4, 61.0, 56.5, 48.7, 35.2, 33.6, 32.1, 31.9,
25.8, 21.4 ppm; IR (KBr) vmax 2929, 2860, 2833, 1676, 1595, 1513,
1417, 1262, 1241, 1163, 1022, 955, 813, 755 cm−1; HRMS (ESI, m/z)
25
3ac. White solid, 41.2 mg, 24% yield; mp 156−159 °C; [α]D
1
−108.3 (c 0.36, CHCl3); H NMR (400 MHz, CDCl3): δ 8.15−8.13
(m, 2H), 7.65 (tt, J = 7.6, 1.6 Hz, 1H), 7.60−7.56 (m, 2H), 7.00 (d, J =
2.0 Hz, 1H), 6.96 (dd, J = 8.4, 2.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H),
4.47 (s, 1H), 4.09 (s, 1H), 3.12 (d, J = 1.6 Hz, 1H), 2.39−2.33 (m,
4H), 2.16−2.08 (m, 2H), 1.86−1.63 (m, 4H), 1.56−1.50 (m, 2H),
1.48−1.36 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 199.8, 151.1,
136.7, 133.4, 131.6, 130.1, 129.19, 129.11, 129.0, 128.6, 126.0, 117.2,
71.3, 57.3, 33.2, 29.2, 28.4, 23.5, 22.7, 22.6, 20.8 ppm; IR (KBr) vmax
2930, 2857, 1676, 1593, 1495, 1342, 1239, 1154, 1025, 908, 810, 726,
691 cm−1; HRMS (ESI, m/z) calcd for C24H24O2Na+ [M + Na]+:
367.1674, found: 367.1673; HPLC analysis: 72% ee [Daicel
CHIRALPAK AS-H column, hexane/i-PrOH = 98:2, 0.5 mL/min,
254 nm, t1 = 9.5 min (major), t2 = 11.9 min (minor)].
+
calcd for C26H29O5 [M + H]+: 421.2015, found: 421.2009; HPLC
analysis: 20% ee [Daicel CHIRALPAK AS-H column, hexane/i-PrOH
= 85:15, 0.65 mL/min, 254 nm, t1 = 7.4 min (minor), t2 = 10.1 min
(major)].
3ma. White solid, 43.7 mg, 27% yield; mp 74−76 °C; H NMR
4ac. White solid, 68.8 mg, 40% yield; mp 137−140 °C; [α]D25 80.0
(c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.96−7.94 (m, 2H),
7.59−7.55 (m, 1H), 7.48−7.44 (m, 2H), 6.98 (dd, J = 8.4, 2.0 Hz,
1H), 6.83 (d, J = 2.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.53 (d, J = 4.4
Hz, 1H), 3.87 (d, J = 3.2 Hz, 1H), 3.22 (brs, 1H), 2.34−2.30 (m, 1H),
2.26 (s, 3H), 2.21−2.18 (m, 2H), 2.13 (dd, J = 13.6, 4.0 Hz, 1H),
2.04−1.90 (m, 2H), 1.82−1.76 (m, 2H), 1.70−1.57 (m, 1H), 1.55−
1.45 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 199.1, 150.8, 137.0,
135.2, 133.3, 129.4, 129.0, 128.95, 128.92, 128.3, 127.1, 121.9, 116.8,
74.2, 49.2, 35.0, 33.6, 31.9, 25.8, 21.3, 20.8 ppm; IR (KBr) vmax 2925,
2853, 1686, 1595, 1494, 1362, 1262, 1198, 1143, 1093, 958, 860, 777
cm−1; HRMS (ESI, m/z) calcd for C24H24O2Na+ [M + Na]+:
367.1674, found: 367.1671; HPLC analysis: 66% ee [Daicel
CHIRALPAK AD-H column, hexane/i-PrOH = 97:3, 0.5 mL/min,
254 nm, t1 = 8.7 min (major), t2 = 9.9 min (minor)].
1
(400 MHz, CDCl3): δ 7.14−7.10 (m, 2H), 6.87 (dt, J = 7.6, 1.2 Hz,
1H), 6.78 (dd, J = 8.0, 0.8 Hz, 1H), 4.43 (s, 1H), 3.14 (s, 1H), 3.08 (d,
J = 1.6 Hz, 1H), 2.75−2.67 (m, 1H), 2.60−2.52 (m, 1H), 2.34−2.30
(m, 1H), 2.12−2.01 (m, 2H), 1.89 (dt, J = 13.2, 3.6 Hz, 1H), 1.78−
1.47 (m, 7H), 1.45−1.28 (m, 5H), 0.92 (t, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 210.7, 153.3, 131.2, 130.0, 128.9, 128.2, 126.3,
120.0, 117.3, 71.4, 62.8, 42.9, 32.7, 31.6, 29.2, 28.3, 28.8, 23.7, 22.66,
22.64, 22.60, 14.0 ppm; IR (KBr) vmax 2941, 2866, 2831, 1700, 1605,
1579, 1215, 1127, 1002, 891, 766, 591 cm−1; HRMS (ESI, m/z) calcd
for C22H27O2− [M − H]−: 323.2017, found: 323.2015; HPLC analysis:
0% ee [Daicel CHIRALPAK OD-H column, hexane/i-PrOH = 98:2,
0.45 mL/min, 254 nm, t1 = 10.2 min, t2 = 11.0 min].
1
4ma. White solid, 59.9 mg, 37% yield; mp 77−78 °C; H NMR
(400 MHz, CDCl3): δ 7.14 (td, J = 8.4, 1.6 Hz, 1H), 7.07 (dd, J = 7.2,
1.2 Hz, 1H), 6.87 (td, J = 7.6, 1.2 Hz, 1H), 6.83 (dd, J = 8.0, 0.8 Hz,
1H), 5.46 (d, J = 4.4 Hz, 1H), 3.24 (brs, 1H), 3.03 (d, J = 3.2 Hz, 1H),
2.58 (dt, J = 16.8, 7.6 Hz, 1H), 2.42 (dt, J = 16.8, 7.2 Hz, 1H), 2.36−
2.30 (m, 1H), 2.15−2.13 (m, 2H), 2.07−2.01 (m, 1H), 1.98−1.85 (m,
2H), 1.77−1.72 (m, 2H), 1.66−1.56 (m, 3H), 1.49−1.41 (m, 1H),
1.35−1.24 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 209.9, 152.9, 134.9, 128.5, 128.1, 127.5, 122.0, 120.2, 117.0,
73.6, 53.7, 43.5, 34.1, 33.6, 32.1, 31.8, 31.5, 25.7, 23.5, 22.6, 21.3, 14.0
ppm; IR (KBr) vmax 2927, 2852, 2359, 1704, 1581, 1484, 1431, 1240,
1131, 899, 772, 749 cm−1; HRMS (ESI, m/z) calcd for C22H28O2Na+
[M + Na]+: 347.1987, found: 347.1983; HPLC analysis: 0% ee [Daicel
CHIRALPAK OD-H column, hexane/i-PrOH = 98:2, 0.45 mL/min,
254 nm, t1 = 12.6 min, t2 = 13.5 min].
25
3ad. White solid, 89.7 mg, 44% yield; mp 185−187 °C; [α]D
1
−183.3 (c 0.36, CHCl3); H NMR (400 MHz, CDCl3): δ 8.11−8.09
(m, 2H), 7.65 (tt, J = 7.2, 2.2 Hz, 1H), 7.60−7.56 (m, 2H), 7.31 (d, J =
2.4 Hz, 1H), 7.23 (dd, J = 8.8, 2.4 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H),
4.49 (s, 1H), 4.06 (s, 1H), 3.12 (d, J = 1.2 Hz, 1H), 2.36−2.32 (m,
1H), 2.15−2.10 (m, 2H), 1.83−1.68 (m, 4H), 1.60−1.53 (m, 2H),
1.44−1.40 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 199.4, 152.6,
136.5, 133.6, 131.4, 131.27, 131.21, 130.4, 129.2, 128.58, 128.50,
119.4, 111.8, 71.6, 57.1, 33.1, 29.3, 28.4, 23.1, 22.68, 22.64 ppm; IR
(KBr) vmax 2928, 2880, 1681, 1593, 1475, 1341, 1216, 1117, 1000, 908,
817, 770, 691 cm−1; HRMS (ESI, m/z) calcd for C23H21BrO2Na+ [M
+ Na]+: 431.0623, found: 431.0618; HPLC analysis: 83% ee [Daicel
CHIRALPAK AD-H column, hexane/i-PrOH = 96:4, 0.65 mL/min,
254 nm, t1 = 7.4 min (minor), t2 = 8.3 min (major)].
25
3ab. White solid, 17.2 mg, 9.6% yield; mp 145−147 °C; [α]D
−136.6 (c 0.18, CHCl3); H NMR (400 MHz, CDCl3): δ 8.13−8.11
4ad. White solid, 77.5 mg, 38% yield; mp 158−160 °C; [α]D25 91.1
(c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.93 (dd, J = 7.8, 1.2
Hz, 2H), 7.58 (dt, J = 7.0, 1.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.24
(dd, J = 8.8, 2.8 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 6.76 (d, J = 8.4 Hz,
1H), 5.53 (d, J = 5.6 Hz, 1H), 3.84 (d, J = 3.2 Hz, 1H), 3.24 (brs, 1H),
2.35−2.30 (m, 1H), 2.20−2.10 (m, 3H), 2.03−1.90 (m, 2H), 1.82−
1.76 (m, 2H), 1.70−1.66 (m, 1H), 1.54−1.49 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 198.6, 152.3, 136.8, 135.1, 133.5, 131.13,
1
(m, 2H), 7.63 (tt, J = 7.6, 1.6 Hz, 1H), 7.57−7.53 (m, 2H), 6.79 (t, J =
1.6 Hz, 1H), 6.75 (d, J = 2.0 Hz, 2H), 4.46 (s, 1H), 4.09 (s, 1H), 3.80
(s, 3H), 3.12 (d, J = 1.6 Hz, 1H), 2.37−2.34 (m, 1H), 2.17−2.07 (m,
2H), 1.87−1.69 (m, 3H), 1.66−1.52 (m, 3H), 1.62−1.37 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 199.6, 153.1, 147.3, 136.6, 133.4, 131.6,
130.1, 129.1, 128.6, 127.0, 117.7, 114.5, 113.2, 71.3, 57.3, 55.9, 33.5,
29.3, 28.4, 23.3, 22.75, 22.70 ppm; IR (KBr) vmax 2923, 2858, 2845,
7071
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131.11, 129.6, 129.0, 128.3, 121.9, 118.9, 112.1, 74.7, 48.6, 34.9, 33.4,
31.8, 25.7, 21.3 ppm; IR (KBr) vmax 2928, 2859, 1684, 1595, 1485,
1350, 1288, 1149, 1034, 991, 812, 786, 691 cm−1; HRMS (ESI, m/z)
calcd for C23H21BrO2Na+ [M + Na]+: 431.0623, found: 431.0615;
HPLC analysis: 63% ee [Daicel CHIRALPAK AD-H column, hexane/
i-PrOH = 96:4, 0.65 mL/min, 254 nm, t1 = 7.5 min (major), t2 = 8.6
min (minor)].
MHz, CDCl3): δ 201.0, 152.0, 137.6, 133.0, 131.2, 130.8, 130.5, 129.7,
129.1, 128.9, 128.3, 119.4, 111.8, 76.7, 57.2, 38.8, 31.3, 29.27, 29.24,
22.9, 22.7, 14.8 ppm; IR (KBr) vmax 2929, 2882, 1685, 1596, 1474,
1321, 1218, 1178, 1092, 987, 814, 750, 692 cm−1; HRMS (ESI, m/z)
calcd for C24H23BrO2Na+ [M + Na]+: 445.0779, found: 445.0767;
HPLC analysis: 75% ee [Daicel CHIRALPAK AS-H column, hexane/
i-PrOH = 95:5, 0.5 mL/min, 254 nm, t1 = 8.5 min (major), t2 = 9.6
min (minor)].
25
3ae. White solid, 69.8 mg, 36% yield; mp 106−108 °C; [α]D
1
25
−96.1 (c 0.36, CHCl3); H NMR (400 MHz, CDCl3): δ 8.15−8.13
4ag. White solid, 133.2 mg, 63% yield; mp 192−194 °C; [α]D
(m, 2H), 7.96 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 8.4, 2.0 Hz, 1H),
7.68−7.64 (m, 1H), 7.61−7.57 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 4.57
(s, 1H), 4.10 (s, 1H), 3.91 (s, 3H), 3.23 (d, J = 1.6 Hz, 1H), 2.37−2.33
(m, 1H), 2.20−2.13 (m, 2H), 1.87−1.72 (m, 3H), 1.68−1.62 (m, 1H),
1.58−1.50 (m, 2H), 1.47−1.37 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 199.5, 167.2, 157.8, 136.5, 133.6, 131.5, 131.0, 130.7, 130.1,
129.2, 128.6, 126.3, 122.0, 117.5, 72.2, 57.1, 52.0, 33.1, 29.3, 28.4, 23.2,
22.65, 22.64 ppm; IR (KBr) vmax 2926, 2857, 1680, 1604, 1475, 1261,
1223, 1117, 1004, 907, 818, 793, 593 cm−1; HRMS (ESI, m/z) calcd
for C25H24O4Na+ [M + Na]+: 411.1572, found: 411.1570; HPLC
analysis: 80% ee [Daicel CHIRALPAK OD-H column, hexane/i-PrOH
= 80:20, 0.65 mL/min, 254 nm, t1 = 7.3 min (major), t2 = 12.5 min
(minor)].
98.8 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.92−7.90 (m,
2H), 7.58 (dt, J = 8.2, 1.2 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.22 (dd, J
= 8.4, 2.8 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H),
5.48 (d, J = 4.0 Hz, 1H), 3.75 (d, J = 3.2 Hz, 1H), 3.23 (d, J = 2.4 Hz,
1H), 2.40−2.20 (m, 4H), 1.95 (qt, J = 13.2, 3.2 Hz, 1H), 1.80−1.56
(m, 4H), 0.91(d, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
200.2, 151.7, 137.0, 134.4, 133.4, 131.3, 131.0, 130.9, 129.0, 128.4,
126.7, 119.1, 111.9, 74.4, 47.7, 42.2, 40.7, 33.7, 31.9, 25.5, 21.4, 18.9
ppm; IR (KBr) vmax 2926, 2867, 2830, 1684, 1594, 1572, 1258, 1243,
+
1210, 657, 618, 528 cm−1; HRMS (ESI, m/z) calcd for C24H24BrO2
[M + H]+: 423.0960, found: 423.0951; HPLC analysis: 53% ee [Daicel
CHIRALPAK OD-H column, hexane/i-PrOH = 97:3, 0.5 mL/min,
254 nm, t1 = 9.3 min (major), t2 = 10.1 min (minor)].
4ae. White solid, 75.9 mg, 39% yield; mp 173−177 °C; [α]D25 75.5
(c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.95−7.93 (m, 2H),
7.86 (dd, J = 8.8, 2.0 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.59 (tt, J =
7.2, 1.2 Hz, 1H), 7.48 (t, J = 8.0 Hz, 2H), 6.91 (d, J = 8.4 Hz, 1H),
5.54 (d, J = 5.6 Hz, 1H), 3.87−3.86 (m, 4H), 3.34 (brs, 1H), 2.37−
2.32 (m, 1H), 2.22−2.14 (m, 3H), 2.08−1.89 (m, 2H), 1.85−1.77 (m,
2H), 1.72−1.69 (m, 1H), 1.58−1.49 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 198.5, 167.0, 157.3, 136.7, 135.2, 133.5, 130.8, 130.0, 129.0,
128.3, 127.4, 122.1, 117.1, 75.4, 51.9, 48.8, 35.0, 33.4, 31.8, 31.7, 25.8,
21.3 ppm; IR (KBr) vmax 2930, 2825, 1709, 1681, 1609, 1437, 1288,
1264, 11130, 954, 772, 688, 532 cm−1; HRMS (ESI, m/z) calcd for
C25H24O4Na+ [M + Na]+: 411.1572, found: 411.1567; HPLC analysis:
60% ee [Daicel CHIRALPAK OD-H column, hexane/i-PrOH = 80:20,
0.65 mL/min, 254 nm, t1 = 9.4 min (minor), t2 = 11.3 min (major)].
3cd. White solid, 78.1 mg, 36% yield; mp 221−224 °C; [α]D
25
−210.5 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.18 (dd, J =
8.8, 2.0 Hz, 2H), 7.90 (dd, J = 8.8, 2.0 Hz, 2H), 7.27−7.24 (m, 2H),
6.72−6.70 (m, 1H), 4.50 (s, 1H), 4.01 (s, 1H), 3.06 (d, J = 2.0 Hz,
1H), 2.37−2.33 (m, 1H), 2.17−2.05 (m, 2H), 1.86−1.69 (m, 4H),
1.64−1.47 (m, 2H), 1.45−1.37 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 198.3, 152.5, 139.6, 133.1, 132.1, 131.5, 131.0, 129.6, 128.9,
127.7, 119.5, 117.8, 116.9, 112.0, 71.3, 57.4, 32.9, 29.3, 28.2, 23.0, 22.6,
22.5 ppm; IR (KBr) vmax 2943, 2859, 2228, 1679, 1447, 1284, 1216,
1126, 1018, 905, 849, 774, 584 cm−1; HRMS (ESI, m/z) calcd for
C24H20BrNO2 [M − H]−: 432.0605, found: 432.0601; HPLC
−
analysis: 95% ee [Daicel CHIRALPAK AD-H column, hexane/i-
PrOH = 90:10, 0.5 mL/min, 254 nm, t1 = 14.2 min (minor), t2 = 19.2
min (major)].
25
25
3af. White solid, 20.6 mg, 12% yield; mp 158−159 °C; [α]D
4cd. White solid, 71.6 mg, 33% yield; mp 216−219 °C; [α]D
1
1
−213.3 (c 0.18, CHCl3); H NMR (400 MHz, CDCl3): δ 8.04−8.02
116.6 (c 0.36, CHCl3); H NMR (400 MHz, CDCl3): δ 8.02 (dt, J =
(m, 2H), 7.65−7.55 (m, 3H), 7.24 (td, J = 7.6, 2.0 Hz, 1H), 7.15 (dd, J
= 7.8, 1.6 Hz, 1H), 6.91 (td, J = 7.2, 1.2 Hz, 1H), 6.81 (dd, J = 8.0, 1.2
Hz, 1H), 4.17 (s, 1H), 3.85 (s, 1H), 3.25 (t, J = 1.6 Hz, 1H), 2.43−
2.39 (m, 1H), 2.25−2.08 (m, 3H), 1.83−1.75 (m, 1H), 1.73−1.49 (m,
4H), 0.97 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 201.2,
152.8, 137.7, 132.9, 129.5, 129.0, 128.8, 128.4, 128.3, 128.0, 120.0,
117.5, 76.6, 57.3, 38.9, 31.5, 29.3, 29.1, 22.9, 22.8, 15.0 ppm; IR (KBr)
vmax 2937, 2857, 1678, 1593, 1496, 1326, 1219, 1180, 991, 751, 690,
566 cm−1; HRMS (ESI, m/z) calcd for C24H24O2Na+ [M + Na]+:
367.1674, found: 367.1670; HPLC analysis: 63% ee [Daicel
CHIRALPAK AD-H column, hexane/i-PrOH = 97:3, 0.5 mL/min,
254 nm, t1 = 8.6 min (minor), t2 = 10.9 min (major)].
8.8, 2.0 Hz, 2H), 7.79 (dt, J = 8.8, 2.0 Hz, 2H), 7.26 (dd, J = 8.8, 2.4
Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 6.77 (d, J = 6.4 Hz, 1H), 5.53 (d, J
= 6.4 Hz, 1H), 3.80 (d, J = 3.6 Hz, 1H), 3.20 (brs, 1H), 2.30−2.20 (m,
3H), 2.10−2.03 (m, 2H), 1.93 (qt, J = 13.2, 3.2 Hz, 1H), 1.82−1.77
(m, 2H), 1.70−1.68 (m, 1H), 1.54−1.43 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 197.4, 152.1, 139.7, 135.0, 132.9, 131.3, 131.0, 128.9,
128.7, 121.8, 119.0, 117.6, 116.8, 112.3, 74.4, 49.1, 34.6, 33.5, 31.7,
25.6, 21.2 ppm; IR (KBr) vmax 2929, 2860, 2231, 1689, 1474, 1243,
1209, 1172, 1093, 959, 805, 777, 538 cm−1; HRMS (ESI, m/z) calcd
−
for C24H19BrNO2 [M − H]−: 432.0605, found: 432.0609; HPLC
analysis: 86% ee [Daicel CHIRALPAK AD-H column, hexane/i-PrOH
= 80:20, 0.65 mL/min, 254 nm, t1 = 9.6 min (major), t2 = 11.4 min
(minor)].
4af. White solid, 122.1 mg, 71% yield; mp 94−96 °C; [α]D25 107.2
(c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.94−7.92 (m, 2H),
7.55 (tt, J = 7.2, 1.2 Hz, 1H), 7.48−7.45 (m, 2H), 7.15 (td, J = 7.6, 1.6
Hz, 1H), 7.02 (dd, J = 7.6, 1.6 Hz, 1H), 6.87−6.83 (m, 2H), 5.47 (d, J
= 4.4 Hz, 1H), 3.81 (d, J = 2.8 Hz, 1H), 3.26 (d, J = 2.8 Hz, 1H),
2.41−2.26 (m, 4H), 1.98 (qt, J = 12.8, 3.6 Hz, 1H), 1.81−1.58 (m,
4H), 0.92 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 200.6,
152.5, 137.1, 134.5, 133.2, 129.2, 128.9, 128.4, 128.1, 126.8, 120.0,
117.2, 73.9, 48.0, 42.3, 40.8, 33.8, 32.0, 25.6, 21.5, 18.9 ppm; IR (KBr)
vmax 2931, 2866, 1683, 1582, 1240, 1216, 1092, 1016, 963, 859, 753,
693 cm−1; HRMS (ESI, m/z) calcd for C24H24O2Na+ [M + Na]+:
367.1674, found: 367.1679; HPLC analysis: 60% ee [Daicel
CHIRALPAK AS-H column, hexane/i-PrOH = 95:5, 0.5 mL/min,
254 nm, t1 = 8.1 min (minor), t2 = 8.9 min (major)].
25
3ce. White solid, 103.2 mg, 50% yield; mp 195−197 °C; [α]D
−135.7 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.22 (dt, J =
8.4, 1.6 Hz, 2H), 7.91−7.88 (m, 3H), 7.85 (dd, J = 8.8, 2.4 Hz, 1H),
6.85 (d, J = 8.8 Hz, 1H), 4.57 (brs, 1H), 4.05 (brs, 1H), 3.91 (s, 3H),
3.17 (d, J = 2.0 Hz, 1H), 2.39- 2.34 (m, 1H), 2.20−2.11 (m, 2H), 1.87
(dt, J = 13.6, 3.6 Hz, 1H), 1.79−1.71 (m, 2H), 1.68−1.66 (m, 1H),
1.62−1.53 (m, 2H), 1.47−1.36 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 198.3, 167.0, 157.7, 139.5, 133.1, 132.1, 130.8, 130.3, 129.9,
129.0, 125.7, 122.2, 117.9, 117.6, 116.9, 71.9, 57.4, 52.1, 32.9, 29.4,
28.4, 23.1, 22.59, 22.53 ppm; IR (KBr) vmax 2938, 2856, 2234, 1708,
1683, 1578, 1493, 1283, 1220, 1116, 844, 767, 543 cm−1; HRMS (ESI,
−
m/z) calcd for C26H22NO4 [M − H]−: 412.1554, found: 412.1557;
HPLC analysis: 94% ee [Daicel CHIRALPAK AD-H column, hexane/
i-PrOH = 65:35, 0.5 mL/min, 254 nm, t1 = 9.5 min (minor), t2 = 11.4
min (major)].
25
3ag. White solid, 19.8 mg, 9.4% yield; mp 61−65 °C; [α]D
−138.3 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.98 (d, J =
6.8 Hz, 2H), 7.66−7.57 (m, 3H), 7.31 (d, J = 2.0 Hz, 1H), 7.22 (dd, J
= 8.8, 2.4 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.16 (s, 1H), 3.80 (s, 1H),
3.21 (s, 1H), 2.39−2.35 (m, 1H), 2.25−2.07 (m, 3H), 1.81−1.77 (m,
1H), 1.71−1.52 (m, 4H), 0.95 (d, J = 7.2 Hz, 3H); 13C NMR (100
4ce. White solid, 24.7 mg, 12% yield; mp 235−237 °C; [α]D25 97.8
(c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.4 Hz,
2H), 7.86 (dd, J = 8.4, 1.6 Hz, 1H), 7.80−7.78 (m, 3H), 6.91 (d, J =
8.4 Hz, 1H), 5.54 (d, J = 4.8 Hz, 1H), 3.86 (s, 3H), 3.83 (d, J = 2.8 Hz,
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1H), 3.30 (brs, 1H), 2.31−2.19 (m, 3H), 2.13−1.91 (m, 3H), 1.85−
1.69 (m, 3H), 1.56−1.47 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
197.3, 166.9, 157.1, 139.6, 135.1, 132.9, 130.7, 130.2, 128.7, 126.8,
122.4, 122.0, 117.8, 117.2, 116.8, 75.1, 52.0, 49.3, 34.7, 33.5, 31.74,
31.72, 25.6, 21.2 ppm; IR (KBr) vmax 2930, 2860, 2231, 1716, 1691,
1581, 1435, 1262, 1226, 1150, 981, 804, 567 cm−1; HRMS (ESI, m/z)
calcd for C26H22NO4− [M − H]−: 412.1554, found: 412.1559; HPLC
analysis: 91% ee [Daicel CHIRALPAK AD-H column, hexane/i-PrOH
= 70:30, 0.5 mL/min, 254 nm, t1 = 15.1 min (major), t2 = 18.4 min
(minor)].
1H), 6.96 (dd, J = 8.4, 2.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 4.74 (s,
1H), 4.03 (s, 1H), 3.92 (s, 3H), 3.10 (d, J = 1.2 Hz, 1H), 2.38−2.33
(m, 4H), 2.17−2.10 (m, 2H), 1.86−1.61 (m, 4H), 1.58−1.38 (m, 3H);
13C NMR (100 MHz, CDCl3): δ 198.3, 163.8, 151.1, 131.4, 130.9,
130.4, 129.6, 129.1, 129.09, 129.03, 126.2, 117.2, 114.2, 71.4, 57.0,
55.7, 33.5, 29.2, 28.4, 23.6, 22.75, 22.70, 20.8 ppm; IR (KBr) vmax
2912, 2850, 1669, 1601, 1572, 1493, 1256, 1172, 1029, 818, 680, 609
cm−1; HRMS (ESI, m/z) calcd for C25H26O3Na+ [M + Na]+:
397.1780, found: 397.1771; HPLC analysis: 77% ee [Daicel
CHIRALPAK AS-H column, hexane/i-PrOH = 85:15, 0.5 mL/min,
254 nm, t1 = 9.3 min (major), t2 = 11.1 min (minor)].
25
3gd. White solid, 71.9 mg, 34% yield; mp 211−215 °C; [α]D
−160.0 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J =
8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 2.0 Hz, 1H), 7.23
(dd, J = 8.0, 2.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 4.49 (s, 1H), 4.04
(s, 1H), 3.11 (d, J = 1.6 Hz, 1H), 2.47 (s, 3H), 2.35−2.31 (m, 1H),
2.14−2.11 (m, 2H), 1.82−1.63 (m, 4H), 1.58−1.50 (m, 2H), 1.49−
1.36 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 199.0, 152.6, 144.5,
134.0, 131.3, 131.23, 131.21, 130.6, 129.8, 128.7, 128.6, 119.4, 111.8,
71.6, 56.9, 33.3, 29.2, 28.3, 23.1, 22.68, 22.66, 21.8 ppm; IR (KBr) vmax
2939, 2857, 1701, 1674, 1576, 1490, 1263, 1115, 1039, 999, 769, 688
cm−1; HRMS (ESI, m/z) calcd for C24H23BrO2Na+ [M + Na]+:
445.0779, found: 445.0771; HPLC analysis: 91% ee [Daicel
CHIRALPAK AD-H column, hexane/i-PrOH = 97:3, 0.5 mL/min,
254 nm, t1 = 10.3 min (minor), t2 = 11.8 min (major)].
25
4hc. White solid, 108.4 mg, 58% yield; mp 164−165 °C; [α]D
1
80.0 (c 0.36, CHCl3); H NMR (400 MHz, CDCl3): δ 7.94 (dt, J =
9.2, 2.0 Hz, 2H), 6.98 (dd, J = 8.4, 2.0 Hz, 1H), 6.93 (dt, J = 8.8, 2.0
Hz, 2H), 6.84 (d, J = 1.6 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 5.52 (d, J
= 4.8 Hz, 1H), 3.86 (s, 3H), 3.82 (d, J = 3.2 Hz, 1H), 3.21 (brs, 1H),
2.36−2.31 (m, 1H), 2.26 (s, 3H), 2.20−2.18 (m, 2H), 2.12 (dd, J =
13.6, 4.4 Hz, 1H), 2.04−1.88 (m, 2H), 1.80−1.75 (m, 2H), 1.69−1.64
(m,1H), 1.56−1.46 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 197.6,
163.7, 150.8, 135.3, 130.6, 130.0, 129.3, 128.95, 128.92, 127.3, 121.9,
116.8, 114.0, 74.3, 55.6, 48.8, 35.3, 33.5, 31.9, 25.8, 21.4, 20.6 ppm; IR
(KBr) vmax 2933, 2837, 1668, 1599, 1574, 1494, 1243, 1177, 1018, 959,
804, 595 cm−1; HRMS (ESI, m/z) calcd for C25H26O3Na+ [M + Na]+:
397.1780, found: 397.1775; HPLC analysis: 70% ee [Daicel
CHIRALPAK AD-H column, hexane/i-PrOH = 60:40, 0.5 mL/min,
254 nm, t1 = 8.7 min (major), t2 = 10.7 min (minor)].
25
4gd. White solid, 109.9 mg, 52% yield; mp 141−144 °C; [α]D
1
77.7 (c 0.36, CHCl3); H NMR (400 MHz, CDCl3): δ 7.84 (dt, J =
25
8.0, 1.8 Hz, 2H), 7.28−7.23 (m, 3H), 7.15 (d, J = 2.4 Hz, 1H), 6.76 (d,
J = 8.4 Hz, 1H), 5.52 (d, J = 5.6 Hz, 1H), 3.81 (d, J = 3.2 Hz, 1H),
3.23 (brs, 1H), 2.42 (s, 3H), 2.35−2.30 (m, 1H), 2.20−2.09 (m, 3H),
2.02−1.86 (m, 2H), 1.80−1.75 (m, 2H), 1.69−1.66 (m, 1H), 1.56−
1.45 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 198.1, 152.3, 144.4,
135.1, 134.3, 131.1, 129.74, 129.71, 128.4, 121.9, 118.9, 112.1, 74.8,
48.4, 35.1, 33.4, 31.8, 25.7, 21.7, 21.3 ppm; IR (KBr) vmax 2931, 2861,
1678, 1605, 1570, 1475, 1245, 1183, 1091, 951, 774, 656 cm−1; HRMS
(ESI, m/z) calcd for C24H23BrO2Na+ [M + Na]+: 445.0779, found:
445.0777; HPLC analysis: 82% ee [Daicel CHIRALPAK AD-H
column, hexane/i-PrOH = 97:3, 0.5 mL/min, 254 nm, t1 = 8.8 min
(major), t2 = 10.5 min (minor)].
3hd. White solid, 87.8 mg, 40% yield; mp 153−156 °C; [α]D
−199.4 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.10 (dt, J =
8.8, 2.4 Hz, 2H), 7.31 (d, J = 2.4 Hz, 1H), 7.24 (dd, J = 8.8, 2.4 Hz,
1H), 7.05 (dt, J = 8.8, 2.4 Hz, 2H), 6.70 (d, J = 8.8 Hz, 1H), 4.99 (s,
1H), 4.01 (s, 1H), 3.92 (s, 3H), 3.11 (d, J = 1.6 Hz, 1H), 2.35−2.31
(m, 1H), 2.17−2.10 (m, 2H), 1.82−1.62 (m, 4H), 1.59−1.49 (m, 2H),
1.46−1.36 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 197.8, 163.9,
152.6, 131.28, 131.21, 131.1, 130.9, 130.7, 129.4, 128.7, 119.4, 114.3,
111.8, 71.7, 56.73, 55.74, 33.4, 29.2, 28.3, 23.1, 22.69, 22.66 ppm; IR
(KBr) vmax 2916, 2838, 1667, 1600, 1572, 1472, 1279, 1177, 1030, 998,
865, 578 cm−1; HRMS (ESI, m/z) calcd for C24H23BrO3Na+ [M +
Na]+: 461.0728, found: 461.0725; HPLC analysis: 88% ee [Daicel
CHIRALPAK AD-H column, hexane/i-PrOH = 70:30, 0.5 mL/min,
254 nm, t1 = 9.2 min (minor), t2 = 10.0 min (major)].
25
3hb. White solid, 56.5 mg, 29% yield; mp 174−175 °C; [α]D
−165.5 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.11 (dt, J =
8.8, 2.0 Hz, 2H), 7.03 (dt, J = 9.2, 2.0 Hz, 2H), 6.80 (t, J = 1.6 Hz,
1H), 6.75 (d, J = 2.0 Hz, 2H), 4.46 (s, 1H), 4.04 (s, 1H), 3.91 (s, 3H),
3.81 (s, 3H), 3.11 (d, J = 2.0 Hz, 1H), 2.37−2.33 (m, 1H), 2.16−2.10
(m, 2H), 1.86−1.65 (m, 4H), 1.59−1.47 (m, 2H), 1.45−1.39 (m, 1H);
13C NMR (100 MHz, CDCl3): δ 198.1, 163.8, 153.0, 147.3, 131.4,
130.9, 130.3, 129.5, 127.3, 117.7, 114.5, 114.2, 113.1, 71.4, 56.9, 55.9,
55.7, 33.8, 29.2, 28.3, 23.5, 22.75, 22.71 ppm; IR (KBr) vmax 2921,
2838, 1667, 1597, 1517, 1495, 1225, 1171, 1044, 838, 816, 595 cm−1;
HRMS (ESI, m/z) calcd for C25H26O4Na+ [M + Na]+: 413.1729,
found: 413.1723; HPLC analysis: 85% ee [Daicel CHIRALPAK OD-H
column, hexane/i-PrOH = 75:25, 0.5 mL/min, 254 nm, t1 = 11.0 min
(minor), t2 = 19.6 min (major)].
4hd. White solid, 98.8 mg, 45% yield; mp 90−93 °C; [α]D25 78.8 (c
1
0.36, CHCl3); H NMR (400 MHz, CDCl3): δ 7.92 (dt, J = 9.2, 2.0
Hz, 2H), 7.24 (dd, J = 8.4, 2.4 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 6.94
(dt, J = 9.2, 2.0 Hz, 2H), 6.76 (d, J = 8.8 Hz, 1H), 5.53 (d, J = 5.2 Hz,
1H), 3.87 (s, 3H), 3.78 (d, J = 3.2 Hz, 1H), 3.22 (brs, 1H), 2.36−2.32
(m, 1H), 2.19−2.11 (m, 3H), 2.03−1.86 (m, 2H), 1.80−1.76 (m, 2H),
1.69−1.65 (m,1H), 1.55−1.45 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 197.0, 163.8, 152.3, 135.2, 131.1, 131.0, 130.6, 129.84,
129.82, 122.0, 118.9, 114.1, 112.1, 74.9, 55.6, 48.2, 35.2, 33.4, 31.8,
25.7, 21.3 ppm; IR (KBr) vmax 2937, 2861, 1667, 1599, 1574, 1474,
1245, 1180, 1019, 954, 817, 590 cm−1; HRMS (ESI, m/z) calcd for
+
C24H24BrO3 [M + H]+: 439.0909, found: 439.0901; HPLC analysis:
4hb. White solid, 74.1 mg, 38% yield; mp 135−137 °C; [α]D25 67.7
(c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.94 (dt, J = 8.8, 2.0
Hz, 2H), 6.93 (dt, J = 9.2, 2.0 Hz, 2H), 6.81 (d, J = 8.8 Hz, 1H), 6.75
(dd, J = 8.8, 2.8 Hz, 1H), 6.59 (d, J = 2.8 Hz, 1H), 5.52 (d, J = 4.4 Hz,
1H), 3.87 (s, 3H), 3.83 (d, J = 3.6 Hz, 1H), 3.73 (s, 3H), 3.21 (brs,
1H), 2.37−2.33 (m, 1H), 2.20−2.09 (m, 3H), 2.05−1.91 (m, 2H),
1.80−1.74 (m, 2H), 1.68−1.64 (m,1H), 1.56−1.45 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 197.6, 163.7, 153.2, 147.0, 135.2, 130.6,
130.0, 128.1, 121.8, 117.5, 114.08, 114.06, 113.3, 74.2, 55.8, 55.6, 48.7,
35.6, 33.5, 31.9, 25.8, 21.3 ppm; IR (KBr) vmax 2923, 2833, 1673, 1601,
1570, 1495, 1236, 1171, 1036, 954, 806, 582 cm−1; HRMS (ESI, m/z)
calcd for C25H26O4Na+ [M + Na]+: 413.1729, found: 413.1727; HPLC
analysis: 85% ee [Daicel CHIRALPAK AD-H column, hexane/i-PrOH
= 70:30, 0.5 mL/min, 254 nm, t1 = 10.8 min (major), t2 = 16.0 min
(minor)].
81% ee [Daicel CHIRALPAK AD-H column, hexane/i-PrOH = 75:25,
0.5 mL/min, 254 nm, t1 = 9.5 min (major), t2 = 11.6 min (minor)].
25
3he. White solid, 60.6 mg, 29% yield; mp 175−178 °C; [α]D
−220.5 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.14 (dt, J =
8.8, 2.0 Hz, 2H), 7.96 (d, J = 2.4 Hz, 1H), 7.83 (dd, J = 8.4, 2.0 Hz,
1H), 7.06 (dt, J = 8.8, 2.0 Hz, 2H), 6.83 (d, J = 8.8 Hz, 1H), 4.56 (s,
1H), 4.05 (s, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.22 (d, J = 1.2 Hz, 1H),
2.38−2.32 (m, 1H), 2.23−2.11 (m, 2H), 1.87−1.72 (m, 3H), 1.66−
1.50 (m, 3H), 1.46−1.36 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
197.9, 167.2, 163.9, 157.8, 131.3, 131.04, 131.01, 130.0, 129.4, 126.5,
121.9, 117.5, 114.3, 72.3, 56.7, 55.7, 52.0, 33.4, 29.3, 28.4, 23.3, 22.6
ppm; IR (KBr) vmax 2940, 2836, 1717, 1664, 1603, 1573, 1421, 1262,
1177, 1039, 837, 604 cm−1; HRMS (ESI, m/z) calcd for C26H26O5Na+
[M + Na]+: 441.1678, found: 441.1677; HPLC analysis: 88% ee
[Daicel CHIRALPAK AD-H column, hexane/i-PrOH = 70:30, 0.5
mL/min, 254 nm, t1 = 9.5 min (minor), t2 = 11.1 min (major)].
25
3hc. White solid, 44.8 mg, 24% yield; mp 172−175 °C; [α]D
25
−163.3 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.13 (dt, J =
9.2, 2.0 Hz, 2H), 7.05 (dd, J = 8.8, 2.0 Hz, 2H), 7.00 (d, J = 1.6 Hz,
4he. White solid, 62.7 mg, 30% yield; mp 214−216 °C; [α]D
1
158.3 (c 0.36, CHCl3); H NMR (400 MHz, CDCl3): δ 7.93 (dt, J =
7073
dx.doi.org/10.1021/jo501196n | J. Org. Chem. 2014, 79, 7063−7074

The Journal of Organic Chemistry
Article
8.8, 2.0 Hz, 2H), 7.85 (dd, J = 8.8, 2.4 Hz, 1H), 7.78 (d, J = 2.0 Hz,
1H), 6.94 (dt, J = 8.8, 2.0 Hz, 2H), 6.90 (d, J = 8.8 Hz, 1H), 5.53 (d, J
= 5.6 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.81 (d, J = 3.2 Hz, 1H),
3.33 (brs, 1H), 2.38−2.34 (m, 1H), 2.21−2.13 (m, 3H), 2.08−1.89
(m, 2H), 1.83−1.68 (m, 3H), 1.55−1.49 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 196.9, 167.1, 163.8, 157.4, 135.3, 130.8, 130.6, 130.0,
129.7, 127.6, 122.2, 122.0, 117.1, 114.1, 75.5, 55.6, 52.0, 48.4, 35.3,
33.4, 31.82, 31.81, 25.6, 21.3 ppm; IR (KBr) vmax 2909, 2833, 1708,
1674, 1599, 1575, 1436, 1259, 1174, 1036, 877, 675 cm−1; HRMS
(ESI, m/z) calcd for C26H26O5Na+ [M + Na]+: 441.1678, found:
441.1679; HPLC analysis: 88% ee [Daicel CHIRALPAK AD-H
column, hexane/i-PrOH = 70:30, 0.5 mL/min, 254 nm, t1 = 11.6 min
(major), t2 = 14.8 min (minor)].
Chem.Asian J. 2010, 5, 2047−2052. (b) Moquist, P. N.; Kodama, T.;
Schaus, S. E. Angew. Chem., Int. Ed. 2010, 49, 7096−7100. (c) Maity,
P.; Srinivas, H. D.; Watson, M. P. J. Am. Chem. Soc. 2011, 133, 17142−
17145. (d) Rueping, M.; Volla, M. R.; Atodiresei, C. I. Org. Lett. 2012,
́
14, 4642−4645. (e) Fananas, F. J.; Mendoza, A.; Arto, T.; Temelli, B.;
̃
Rodríguez, F. Angew. Chem., Int. Ed. 2012, 51, 4930−4933. (f) Wang,
H. H.; Kuang, Y. Y.; Wu, J. Asian J. Org. Chem. 2012, 1, 302−312.
(g) Terada, M.; Yamanaka, T.; Toda, Y. Chem.Eur. J. 2013, 19,
13658−13662. (h) Hsiao, C.-C.; Liao, H.-H.; Sugiono, E.; Atodiresei,
I.; Rueping, M. Chem.Eur. J. 2013, 19, 9775−9779.
(4) For a recent review on enantioselective reactions of
benzopyrylium intermediates, see: Chen, J.-R.; Hu, X.-Q.; Xiao, W.-J.
Angew. Chem., Int. Ed. 2014, 53, 4038−4040.
25
4hf. White solid, 149.6 mg, 80% yield; mp 146−148 °C; [α]D
(5) For representative enantioselective [3 + 2] reactions via
oxidopyrylium intermediates, see: (a) Garnier, E.C.; Liebeskind, L.
S. J. Am. Chem. Soc. 2008, 130, 7449−7458. (b) Burns, N. Z.; Witten,
M. R.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 14578−14581.
(6) For a recent example on enantioselective [5 + 2] reactions via
oxidopyrylium intermediates, see: Witten, M. R.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2014, 53, 5912−5916.
1
116.6 (c 0.36, CHCl3); H NMR (400 MHz, CDCl3): δ 7.92 (dt, J =
8.8, 2.0 Hz, 2H), 7.14 (td, J = 8.0, 2.4 Hz, 1H), 7.03 (dd, J = 8.4, 1.6
Hz, 1H), 6.93 (dt, J = 8.8, 2.0 Hz, 2H), 6.87−6.83 (m, 2H), 5.46 (d, J
= 4.0 Hz, 1H), 3.87 (s, 3H), 3.75 (d, J = 2.8 Hz, 1H), 3.25 (d, J = 2.8
Hz, 1H), 2.41−2.26 (m, 4H), 1.97 (qt, J = 13.2, 3.2 Hz, 1H), 1.86−
1.76 (m, 2H), 1.73−1.59 (m, 2H), 0.92 (d, J = 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 199.1, 163.5, 152.5, 134.6, 130.7, 130.3, 129.4,
128.4, 128.1, 126.7, 120.0, 117.2, 114.0, 74.0, 55.6, 47.7, 42.6, 40.8,
33.9, 32.0, 25.6, 21.5, 18.9 ppm; IR (KBr) vmax 2927, 2858, 1680, 1597,
1509, 1455, 1266, 1174, 1021, 837, 757, 604 cm−1; HRMS (ESI, m/z)
calcd for C25H26O3Na+ [M + Na]+: 397.1780, found: 397.1797; HPLC
analysis: 71% ee [Daicel CHIRALPAK AD-H column, hexane/i-PrOH
= 97:3, 0.5 mL/min, 254 nm, t1 = 10.8 min (major), t2 = 12.3 min
(minor)].
(7) Yu, S.-Y.; Zhang, H.; Gao, Y.; Mo, L.; Wang, S. Z.; Yao, Z.-J. J.
Am. Chem. Soc. 2013, 135, 11402−11407.
(8) For reviews on ACDC, see: (a) Phipps, R. J.; Hamilton, G. L.;
Toste, F. D. Nat. Chem. 2012, 4, 603−614. (b) Mahlau, M.; List, B.
Angew. Chem., Int. Ed. 2013, 52, 518−533. (c) Brak, K.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2013, 52, 534−561.
(9) For selected examples of chiral-anion catalysis by chiral
phosphates, see: (a) Rueping, M.; Antonchick, A. P.; Dipl.-Chem, C.
B. Angew. Chem., Int. Ed. 2007, 46, 6903−6906. (b) Hamilton, G. L.;
Kanai, T.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 14984−14986.
(c) Wang, Y.; Zheng, K.; Hong, R. J. Am. Chem. Soc. 2012, 134, 4096−
4099. (d) Shi, S.-H.; Huang, F.-P.; Zhu, P.; Dong, Z.-W.; Hui, X.-P.
Org. Lett. 2012, 14, 2010−2013.
(10) For reviews on relay catalysis system of transition metals and
organocatalysts, see: (a) Wu, X.; Li, M. L.; Gong, L. Z. Acta Chim. Sin.
2013, 8, 1091−1100. (b) Lv, F. P.; Liu, S. Y.; Hu, W. H. Asian J. Org.
Chem. 2013, 2, 824−836.
ASSOCIATED CONTENT
* Supporting Information
■
S
Copies of 1H and 13C NMR spectra for all new compounds, 2D
NMR copies for compounds 3aa and 4aa, chiral HPLC
analyses for all the products (PDF), and X-ray crystal data of
compounds 3cd and 4ag (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(11) For selected recent examples of enantioselective reaction in
relay catalysis mode, see: (a) Chen, D.-F.; Wu, P.-Y.; Gong, L.-Z. Org.
Lett. 2013, 15, 3958−3961. (b) Qian, D. Y.; Zhang, J. L. Chem.Eur.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yaoz@nju.edu.cn.
Notes
■
́ ́
J. 2013, 19, 6984−6988. (c) Calleja, J.; Gonzalez-Perez, A. B.; Lera, A.
́
́
R.; Alvarez, R.; Fananas, F. J.; Rodríguez, F. Chem. Sci. 2014, 5, 996−
̃
1007. (d) Wu, X.; Li, M.-L.; Wang, P.-S. J. Org. Chem. 2014, 79, 419−
425. (e) Horino, Y.; Takahashi, Y.; Nakashima, Y.; Abe, H. RSC Adv.
2014, 4, 6215−6218.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(12) A mechanism of multistep cascade process could not be
completely excluded for this oxa [4 + 2]-cyclization.
Research grants from MOST (nos. 2010CB833202 and
2013AA092903), NSFC (nos. 21272112 and 21032002), and
National Science Fund for Talent Training in Basic Science
(J1103310) are greatly appreciated.
REFERENCES
■
(1) For a recent review of pyrylium and its benzo-derivatives, see:
Alvarez-Builla, J.; Vaquero, J. J.; Barluenga, J. Modern heterocyclic
chemistry, 1st ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim,
Germany, 2011; Chapter 18, pp 1631−1682.
(2) For selected recent transformations involving a pyrylium
intermediate, see: (a) Liang, S.; Zhu, L. Y.; Hurst, J. K. Langmuir
2012, 28, 12171−12181. (b) Velde, N. A.; Korbitz, H. T.; Garner, C.
M. Tetrahedron Lett. 2012, 53, 5742−5744. (c) Velde, N. A.; Korbitz,
H. T.; Bellert, D. J.; Garner, C. M. J. Org. Chem. 2013, 78, 11698−
11706. (d) Carta, F.; Vullo, D.; Maresca, A.; Scozzafava, A.; Supuran,
C. T. Bioorg. Med. Chem. 2013, 21, 1564−1569. (e) Farcasi̧ u, D.;
̆
Lezcano, M. J. Labelled Compd. Radiopharm. 2013, 56, 637−638.
(f) Yang, L. J.; Ye, J. W.; Gao, Y.; Deng, D.; Lin, Y.; Ning, G. L. Eur. J.
́
Org. Chem. 2014, 3, 515−522. (g) Sola, A.; Tarraga, A.; Molina, P. Org.
Biomol. Chem. 2014, 12, 2547−2551.
(3) For representative enantioselective reactions of benzopyrylium
intermediates, see: (a) Benfatti, F.; Benedetto, E.; Cozzi, P. G.
7074
dx.doi.org/10.1021/jo501196n | J. Org. Chem. 2014, 79, 7063−7074