Catalytic asymmetric intra- and intermolecular haloetherification of enones: An efficient approach to (?)-Centrolobine

Article abstract of DOI:10.1021/acscatal.6b02048

A catalytic asymmetric intra- and intermolecular haloetherification of electron-deficient alkenes (halogen = Cl, Br, I) has been realized by the use of chiral metal complexes of N,N′-dioxides. In the presence of a chiral Fe(III) complex, a series of tetrahydropyran derivatives were obtained in good yields (up to 99% yield) with a high level of enantioselectivities (up to 97% ee). Promoted by a chiral Ce(III) complex, chiral oxepane derivatives could be given in good results. Moreover, the intermolecular haloetherification of chalcones catalyzed by Sc(III) complex using MeOH as nucleophile is demonstrated. This methodology also can be successfully applied to the synthesis of (?)-Centrolobine. Meanwhile, a reasonable reaction mechanism was proposed.

Full text of DOI:10.1021/acscatal.6b02048

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Letter
Catalytic Asymmetric Intra- and Intermolecular Haloetherification
of Enones: An Efficient Approach to (-)-Centrolobine
Pengfei Zhou, Yunfei Cai, Xia Zhong, Weiwei Luo, Tengfei
Kang, Jun Li, Xiaohua Liu, Lili Lin, and Xiaoming Feng
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02048 • Publication Date (Web): 12 Oct 2016
Downloaded from http://pubs.acs.org on October 12, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Catalysis is published by the American Chemical Society. 1155 Sixteenth Street
N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
ACS Catalysis
1
2
3
4
5
6
7
8
9
Catalytic Asymmetric Intraꢀ and Intermolecular Haloetherificaꢀ
tion of Enones: An Efficient Approach to (−)ꢀCentrolobine
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pengfei Zhou, Yunfei Cai, Xia Zhong, Weiwei Luo, Tengfei Kang, Jun Li, Xiaohua Liu,* Lili Lin, and
Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China
ABSTRACT: A catalytic asymmetric intraꢀ and intermolecular haloetherification of electronꢀdeficient alkenes (halogen = Cl, Br, I)
has been realized by the use of chiral metal complexes of N,N′ꢀdioxides. In the presence of a chiral Fe(III) complex, a series of tetꢀ
rahydropyran derivatives were obtained in good yields (up to 99% yield) with high level of enantioselectivities (up to 97% ee).
Promoted by a chiral Ce(III) complex, chiral oxepane derivatives could be given in good results. Moreover, the intermolecular haꢀ
loetherification of chalcones catalyzed by Sc(III) complex using MeOH as nucleophile is demonstrated. This methodology also can
been successfully applied to the synthesis of (−)ꢀCentrolobine. Meanwhile, a reasonable reaction mechanism was proposed.
KEYWORDS asymmetric catalysis• enones• haloetherification• Lewis acid• oxaꢀheterocycles
Catalytic asymmetric halofunctionalization of olefins is an
attractive transformation to install two functional groups
across C−C double bonds in one step.1 In recent years, enantiꢀ
of chalcones by employing MeOH as nucleophile is also realꢀ
ized.
Our attention was initially paid to the intramolecular haꢀ
loetherification. Using 1a as model substrate in the bromocyꢀ
clization reaction and after systematically screening the reacꢀ
tion parameters (see SI), we gratifyingly found that employing
Fe(acac)3 complex of chiral N,N′ꢀdioxide ligand LꢀPiPr2 as
the catalyst and BsNMeBr (Bs = benzosulfonyl) as the elecꢀ
trophilic bromine reagent, 1a could be successfully transꢀ
formed into the desired THP product 2ba in good yield with
high level of enantioselectivity and diastereoselectivity (Table
1, entry 1). This optimal reaction conditions could also be
applied to the chloroꢀ and iodocyclization using pꢀNsNCl2 and
NIS as chlorine and iodine source instead of BsNMeBr (Table
1, entry 1 and Scheme 1).
oselective
haloesterification,2,3
haloamination4
and
haloetherification5,6 of electronꢀrich alkenes, such as styrene
2ꢀ7
derivatives, have been studied extensively
with substantial
efforts on mechanistic insight8 and methodology development.
However, compared with simple electronꢀrich alkenes which
facilitate the formation of key halonium ion intermediates, the
enantioselective halofunctionalization of electronꢀdeficient
alkenes (e.g. enones) is less explored and still limited to
haloamination and carbochlorination reactions developed by
our9 and MacMillan’s10 group employing sulfonamides and
aromatic πꢀnucleophiles as nitrogen and carbon sources, reꢀ
spectively. The asymmetric intramolecular haloetherification
of olefins is one of the most straightꢀforward methods to conꢀ
struct enantioenriched oxaꢀheterocycles (e.g. tetrahydropyran
and oxepane) which are common motifs in natural products. 11
Previous works in this field focused on the structural favored
fiveꢀ and sixꢀmembered ones5 and the asymmetric synthesis of
larger heterocycles through this protocol remains a challenge
owing to both entropic and enthalpic barriers.12 To the best of
our knowledge, the synthesis of chiral oxepanes via halocyꢀ
clization has not been reported to date.13 For the intermolecular
process, despite haloetherification of chalcone has long been
known, the catalytic asymmetric version of this reaction
remains elusive.14
Then, the generality of sixꢀmembered halocyclization was
evaluated. Considering the chloroetherification is less exꢀ
plored, compared with bromoꢀ and iodoetherification, and the
chlorine containing compounds play important roles in mediꢀ
cine science,16 we surveyed the scope of chloroꢀ and bromocyꢀ
clization in parallel (Table 1). In general, chlorocyclization
products are generated in lower enantioselectivities than broꢀ
mocyclization products but with higher diastereoselectivities
(2aa–2ah vs. 2ba–2bh). The substituents on the benzoyl group
of enones 1 with different electronic property and at varied
position have no obvious effect on the reactivity and stereoseꢀ
lectivities. Furthermore, disubstituted enones 1i and 1j can
also tolerate, even at a gramꢀscale, affording the corresponding
chloroetherification products in 87% ee and 92% ee and
bromoetherification products in 95% ee and 97% ee,
respectively. 2ꢀNaphthylꢀsubstituted substrate 1k also
undergoes the catalytic asymmetric reaction well to give the
chloroetherification product 2ak in 94% yield and 87% ee, and
the bromoetherification product 2bk in 93% yield and 94% ee.
However, 2ꢀfuryl substituent appears to have a negative effect
on the stereoselectivities. To our delight, both 2ꢀthienyl and 3ꢀ
Herein, we document a method for the asymmetric haꢀ
loetherification of electronꢀdeficient enones mediated by chiral
N,N′ꢀdioxide/metal complexes.15 Sixꢀ and sevenꢀmembered
halocyclizations (Cl, Br, I) are achieved, delivering chiral
THPs and oxepanes in good yields with high diastereoꢀ and
enantioselectivities. Tetrahydrobenzopyran is also available
using phenol as the nucleophile. Employing secondary alcohol
as nucleophile in sixꢀmembered halocyclization, an excellent
kinetic resolution was observed and the product can be applied
to the total synthesis of (−)ꢀCentrolobine. Notably, the first
catalytic asymmetric intermolecular haloetherification (Cl, Br)
thienyl
substituted
substrates
are
capable
of
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 6
Table 1. Substrate scope of chloroetherification and bromoetherificationa
1
2
3
4
5
6
7
8
9
entry
yield (%)b
ee (%)c
drd
yield (%)b
ee (%)c
drd
R; Y
1
91 (2aa)
92 (2ab)
98 (2ac)
91 (2ad)
95 (2ae)
80 (2af)
93 (2ag)
97 (2ah)
82 (2ai)
75 (2aj)
85
85
86
77
76
91
90
89
87
92
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
Ph; CH2 (1a)
97 (2ba)
96 (2bb)
98 (2bc)
89 (2bd)
99 (2be)
98 (2bf)
90 (2bg)
99 (2bh)
83 (2bi)
96
96:4
95:5
98:2
95:5
96:4
99:1
93:7
96:4
96:4
96:4
2
2ꢀFC6H4; CH2 (1b)
2ꢀMeOC6H4; CH2 (1c)
3ꢀClC6H4; CH2 (1d)
3ꢀMeC6H4; CH2 (1e)
4ꢀFC6H4; CH2 (1f)
4ꢀClC6H4; CH2 (1g)
4ꢀMeOC6H4; CH2 (1h)
3,4ꢀCl2C6H3; CH2 (1i)
95
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
96
4
95
5
95
6
97
7
96
8
97
9
10e
95
98 (96) (2bj)
97 (93)
; CH2 (1j)
2ꢀnaphthyl; CH2 (1k)
2ꢀfuryl; CH2 (1l)
2ꢀthienyl; CH2 (1m)
3ꢀthienyl; CH2 (1n)
PhCH2CH2; CH2 (1o)
Ph; O (1p)
11
12
13
14f
15
16
17
18
94 (2ak)
71 (2al)
85 (2am)
90 (2an)
54 (2ao)
88 (2ap)
85 (2aq)
86 (2ar)
87
44
81
82
73
87
40
90
> 99:1
> 99:1
> 99:1
> 99:1
88:12
> 99:1
93:7
93 (2bk)
93 (2bl)
94 (2bm)
98 (2bn)
90 (2bo)
97 (2bp)
93 (2bq)
ꢀꢀ
94
95:5
94:6
95:5
96:4
95:5
96:4
88:12
ꢀꢀ
78
95
94 (R, R)
93
95
77
ꢀꢀ
Ph; NTs (1q)
80:20
(1r)
19
ꢀꢀ
ꢀꢀ
ꢀꢀ
68 (2bs)
73
94:6
Me; CH2 (1s)
a
All reactions were performed with 1 (0.1 mmol), halogen reagent (for BsNMeBr 0.2 mmol, for pꢀNsNCl2 0.1 mmol), and Fe(acac)3/LꢀPiPr2 (1:1, 5
mol%) in oꢀxylene (0.05 M) at 0 °C for 4 h, unless otherwise stated. b Yield of the isolated product. c Determined by HPLC. d Determined by HPLC and 1H
NMR. The value in parentheses was conducted on a gram scale (4.0 mmol of 1j). The absolute configuration of 2bn was verified by Xꢀray crystallogꢀ
raphy as (2R,3R).
e
f
bromine reagent BsNMeBr undergoes oxaꢀMichael reaction
accompanied by direct bromination of phenol unit (see SI).
Furthermore, simple acetone derived substrate 1s could aslo
tolerate this reaction and generate the bromoetherification 2bs
in 68% yield with 73% ee.
Scheme 1. Catalytic asymmetric iodocycloetherification of
1a.
Next, we tried to apply this protocol for the asymmetric
synthesis of chiral oxepanes. Under the standard reaction
conditions of sixꢀmembered halocyclization, the sevenꢀ
tolerating the reaction, giving the haloetherification products
membered bromocyclization of 3a delivering 2ꢀsubstituted
in similar results in comparison with the standard substrate 1a.
oxepane in 92% yield but with only 40% ee for the major
A conceivable interpretation is that the oxygen atom on the
isomer (see SI). Then we reoptimized several catalysts
furyl group coordinates competitively to Fe(III) center, leading
variables for catalysis of sevenꢀmembered bromocyclization
to the erosion of the enantioselectivity. The absolute
and found the enantioselectivities could be highly enhanced to
configuration of 2bn is unambiguously verified by Xꢀray
98% and >99% ee by changing central metal from Fe(acac)3 to
crystallography to be (2R,3R). In these cases, the transꢀ
Ce(OTf)3 and using 5 mol% mꢀchloroperbenzoic acid (mꢀ
products are given in no less than 93:7 dr Notably, enone 1o
CPBA) as proton additive. Under the optimized reaction
derived from benzyl acetone also furnishes the
conditions, the scope of the sevenꢀmembered chloroꢀ and
haloetherification products 2ao and 2bo with good
bromocyclization was investigated and the outcomes indicated
stereocontrol. Enones embed a heteroatom (O, NTs) into the
that many representative cases could give excellent
carbon chain are also compatible with this methodology,
enantioselectivities. The diastereoselectivity is moderate, but
although afford the products 2aq and 2bq in lower
both isomers can be isolated by flash chromatography in most
stereoselectivities. It is worth pointing out that the
cases (see SI). Particularly, the αꢀbromine can be removed
chloroetherification of substrate 1r bearing
a phenolic
easily in the presence of BnSH and Et3N at room temperature.
As shown in Table 2, various substituted enones 3 including
aryl, heteroaryl and alkylꢀgroups could be efficiently
converted into the optically active γꢀketone oxepanes 4
nucleophile is equally successful under the chiral Fe(III)/Lꢀ
PiPr2 catalytic system. Tetrahydrobenzopyran 2ar was
obtained in 86% yield and 80:20 dr with 90% ee for the major
isomer. However, the related bromoetherification using
ACS Paragon Plus Environment

Page 3 of 6
ACS Catalysis
with good yields and excellent enantioselectivities (95–99%
Table 2. Synthesis of chiral oxepane 4.a
1
ee) after two sequential bromocyclization and debromination
2
transformations.
3
4
5
6
7
8
9
On the basis of intramolecular haloetherification, we started
tackling a more ambitious proposal, wherein intermolecular
haloetherification would be facilitated directly from chalcone
and external alcohol nucleophile. Further survey of reaction
conditions lead to the following optimal reaction conditions:
0.5 mol% chiral Sc(OTf)3/LꢀRaPr2 complex as catalyst, 10.0
equiv MeOH as nucleophile, toluene as solvent and 35 °C as
the reaction temperature (see SI). Under these reaction
conditions, various enones were surveyed (Table 3). The
electronic nature of substituents on the phenyl group of R1 and
benzoyl group affect the reactivity slightly. By improving the
catalyst loading, aryl substituted substrates underwent
bromoetherification smoothly with high levels of stereocontrol
(entries 1ꢀ7). Nonetheless, the method was less tolerant with
alkyl substituted enones 5h and 5i. Substrate with a electronꢀ
withdrawing cyano group at αꢀposition also gave the
corresponding addition product 6j although with lower
stereoselectivity. It was proven that rigid enone 5k did not
apparently affect the reaction course and excellent results were
maintained. However, (E)ꢀ4ꢀphenylbutꢀ3ꢀenꢀ2ꢀone failed to
give the bromomethoxylation prodcut (entry 12). Notably,
using pꢀNsNCl2 as chlorine reagent could furnish the
chloromethoxylation product 6a in 64% yield with 88% ee as
a single diastereoisomer. Regretfully, this system was not
suitable for other alcohol nucleophiles.17
entry
R
drb
yield (%)c
86 (4a)
74 (4b)
57 (4c)
84 (4d)
73 (4e)
ee (%)d
98
1
2
3
4
5
Ph
57:43
57:43
57:43
57:43
57:43
4ꢀFC6H4
4ꢀMeOC6H4
4ꢀPhC6H4
98
95
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
99
97
6
3ꢀthienyl
50:50
66:34
74 (4f)
98
95
7
PhCH2CH2
38 (4g)
c
a
For details, see SI. b Determine by 1H NMR. Yield of the isolated 4
after two step transformations. d Determined by HPLC.
Table 3. Substrate scope of intermolecular haloetherificaꢀ
tion.a
enꢀ
1d
R1
Ph
R2;
H;
x
yield
(%)b
ee (%)c
try
R3
H
0.
92
(91)(6a)
96
(94)
(R, R)
The synthetic utility of this reaction was demonstrated by
the manipulation of generated bromine atom in the products.
C–Br bond of 2bj routinely transformed into C–N bond by a
SN2 reaction, affording αꢀazideketone 10. In the presence of
Et3N and BnSH, bromine atom of 6a was easily removed to
furnish βꢀmethoxy carbonyl compound 11 in 95% yield with
maintenance of the enantioselectivity. Direct reduction of the
2ꢀbromoꢀ3ꢀmethoxy ketone product 6a with LiBH4 affords the
corresponding alcohol product which can be transformed into
optically active epoxide 12 without losing of any enantioselecꢀ
tivity.
5
2
4ꢀMeC6H4
4ꢀFC6H4
4ꢀF3CC6H4
3ꢀClC6H4
2ꢀnaphthyl
Ph
H;
H;
H;
H;
H;
H;
5
1
5
1
5
5
5
5
5
5
81 (6b)
94
95
95
94
92
94
75
80
H
H
H
H
H
3
99 (6c)
90 (6d)
97 (6e)
80 (6f)
98 (6g)
70 (6h)
66 (6i)
67 (6j)
64 (6k)
4
5
6
O
O
O
O
NaN3
O
O
O
O
7
DMSO, rt
4ꢀMeO
Br
N3
10
8
iꢀPr
H;
H
2bj
49% yield, 90% ee
93% ee; 96:4 dr
> 99:1 dr
9
iꢀBu
H;
H
O
OMe
OMe
Ph
O
OMe
1) LiBH4, THF, 0 °C
Ph
2) KOH, Et2O, 0 °C
Et3N, BnSH
O
10e
11
Ph
CN;
H
60/6
0
Ph
CH2Cl2, rt
Ph
Ph
Ph
Br
11
6a
12
96
95% yield
94% ee
53% yield, 94% ee
94% ee
>99:1 dr
>99:1 dr
12
5
messy
ꢀꢀ
Scheme 2. Further transformation of the products
Finally, the developed sixꢀmembered bromocyclization
methodology was applied to the enantioselective synthesis of
(−)ꢀCentrolobine (Scheme 2), which is isolated from
heartwood of Centrolobium robustum and exhibits antiꢀ
inflammatory, antibacterial, and antileishmanial activities.18
Exposing racemic substrate (±)ꢀ13 with a secondary alcohol
nucleophile to 10 mol% Fe(acac)3/LꢀPiPr2 catalyst and
BsNMeBr bromine reagent at 0 °C for 20 min, an excellent
kinetic resolution was observed and the bromocyclization
a
Reaction conditions: 5 (0.1 mmol), MeOH (1.0 mmol), bromine
reagent (0.075 mmol), Sc(OTf)3/LꢀRaPr2 (1:1, x mol%), toluene (0.05 M),
35 °C. b Yield of the isolated product.. c Determined by HPLC. d The value
in parentheses is conducted on 2.0 mmol scale of 5a using 0.5 mol%
catalyst, the absolute configuration of 6a was verified as (2R, 3R) by Xꢀ
ray crystallographic analysis. e dr = 75: 25.
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 6
product 14 and recovered (+)ꢀ13 were obtained in >93% ee returning back to the starting material (rate 1, 2 »rate 3).
1
2
3
4
5
6
7
8
and 99% ee, respectively. Debromination of 14 and cyclization
of (+)ꢀ13 gave (−)ꢀ15 and (+)ꢀ15 in 50% and 38% yield for
two steps, respectively. To the best of our knowledge, no
report regarding the kinetic resolution of secondary alcohol by
halocyclization or intramolecular oxaꢀMichael addition. Then
by treating the recrystallized (−)ꢀ15 (>99% ee) with LiBH4
prior to the addition of Et3SiH and TFA, the deoxygenated
product (−)ꢀ16 was isolated in 96% yield. Finally, an Ullmann
cross coupling reaction of (−)ꢀ16 with NaOMe in the presence
of CuI followed by the deprotection of benzyl group produced
(−)ꢀCentrolobine in 99% ee.
Without the coordinated sulfonyl group of bromine reagent,
the hydroxyl group addition step displays terrible stereocontrol
(Scheme 3A, 9% ee). Moreover, the C–O bond formation
product (oxaꢀMichael product) using 3a as substrate was not
observed in the absence of bromine reagent might be attributꢀ
ed to proton quenching enolate intermediate rate is much
slower than retro rate of enolate I to the substate 3a(n = 2; rate
3 »rate 4).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Enantioselective total synthesis of (−)ꢀ
Centrolobine.
The formation of both diastereoisomers in most cases (espeꢀ
cially in bromocyclization) casts doubt on the reaction process
and the stereocontrol elements of the asymmetric halocycloꢀ
etherification. Firstly, the reaction is unlikely to proceed
through a classical haliranium ion intermediate mechanism.
There are three phenomenons observed can support this supꢀ
pose during the course of this study. a) The low diastereoseꢀ
lectivity of most products conflict with the classical stereospeꢀ
cific ringꢀopening of halonium ion mechanism.1e b) The elecꢀ
tronꢀricher substrate 3c showed lower reactivity in this reacꢀ
tion (Table 2, entry 3, reaction temperature increased to 35
ºC). c) The configuration of the oxygenꢀjointed carbon center
is uniform for the two diastereoisomers of 8 and no epimerizaꢀ
tion19 process was observed in the reaction (see SI for details).
Secondly, in the presence of the optimized chiral catalysts
without haloꢀreagent, the Michael reactions performed slugꢀ
gishly. Intramolecular sixꢀ, sevenꢀmembered Michael adꢀ
ducts20 and intermolecular Michael adducts were given in
51%, 0% and 0% yield, respectively. Neither Michael adducts
could undergo αꢀbromination to afford the final bromoetherifiꢀ
cation products (Scheme 4A). The aforementioned results
helped ruling out the absolute stepwise Michael/αꢀ
halogenation reaction like MacMillan’s report. 10
Scheme 4. Control experiment and proposed mechanism.
In summary, we have developed a general method for the
catalytic asymmetric haloetherification of enones by using
metal complexes of chiral N,N′ꢀdioxides as the catalysts. The
mild reaction conditions and broad substrate scope of
halocyclization permit a rapid and efficient access to chiral
THPs and oxepanes incorporating a pendant halogen even on a
gram scale. The synthetic utility was demonstrated by the
enantioselective synthesis of (−)ꢀCentrolobine. In addition, a
similar Sc(III)/N,N'ꢀdioxide catalytic system can also be
applied to realize the first catalytic asymmetric intermolecular
haloetherificaiton of chalcones. Meanwhile, a reasonable
mechanism was proposed to evalute the reaction process.
Further studies on the detailed reaction mechanism and
development of other enantioselective halofunctionalization
reactions are ongoing.
The detailed reaction process is not fully understood until
now. We proposed a possible reaction mechanism to explain
the reason why the addition of electrophilic halogen reagent is
crucial for the C–O bond formation and the stereocontrol eleꢀ
ment (Scheme 4B). Originally, the carbonyl group and sulꢀ
fonyl group coordinated with the central metal of catalyst.
Then the hydroxyl nucleophile proceed a reversible21 addition
(favoring starting material for substrate 3) on the activated
carbon carbon double bond, thus forming an enolate intermeꢀ
diate I, which is the enantioselectivityꢀdetermine step. In the
presence of electrophilic bromine reagent, diastereoselective
capture of enolate intermediate I by Br+ generating the bromoꢀ
etherification product is much faster than the rate of enolate I
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, full spectroscopic data for all new comꢀ
pounds, and copies of 1H, 13C NMR, and HPLC spectra (PDF)
Xꢀray crystallographic data for 2bn (CIF)
Xꢀray crystallographic data for 6a(CIF)
AUTHOR INFORMATION
ACS Paragon Plus Environment

Page 5 of 6
ACS Catalysis
2014, 16, 2426–2429. (d) Xia, Z.; Hu, J.; Shen, Z.; Wan, X.; Yao, Q.;
Corresponding Author
Lai, Y.; Gao, J.ꢀM.; Xie, W. Org. Lett. 2016, 18, 80–83.
(8) (a) Brown, R. S. Acc. Chem. Res. 1997, 30, 131–137. (b) Denꢀ
mark, S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc. 2010, 132,
1232–1233.
1
2
3
4
5
6
7
8
* liuxh@scu.edu.cn
* xmfeng@scu.edu.cn
Notes
(9) (a) Cai, Y. F.; Liu, X. H.; Hui, Y. H.; Jiang, J.; Wang, W. T.;
Chen, W. L.; Lin, L. L.; Feng, X. M. Angew. Chem. Int. Ed. 2010, 49,
6160–6164. (b) Huang, S.ꢀX.; Ding, K. Angew. Chem. Int. Ed. 2011,
50, 7734–7736. (c) Cai, Y. F.; Liu, X. H.; Jiang, J.; Chen, W. L.; Lin,
L. L.; Feng, X. M. J. Am. Chem. Soc. 2011, 133, 5636–5639. (d) Cai,
Y. F.; Liu, X. H.; Chen, W. L.; Wang, W. T.; Lin, L. L.; Feng, X. M.
Chem. Eur. J. 2011, 17, 14916–14921. (e) Cai, Y. F.; Liu, X. H.;
Zhou, P. F.; Kuang, Y. L.; Lin, L. L.; Feng, X. M. Chem. Commun.
2013, 49, 8054–8056. (f) Cai, Y. F.; Zhou, P. F.; Liu, X. H.; Zhao, J.
N.; Lin, L. L.; Feng, X. M. Chem. Eur. J. 2015, 21, 6386–6389.
(10) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2005, 127, 15051–15053.
(11) (a) Inoue, M. Chem. Rev. 2005, 105, 4379–4405. (b) Bielitza,
M.; Pietruszka, J. Angew. Chem. Int. Ed. 2013, 52, 10960–10985.
(12) (a) Galli, C.; Illuminati, G.; Mandolini, L.; Tamborra, P. J .Am.
Chem. Soc. 1977, 99, 2591–2597. (b) Illuminati, G.; Mandolini, L.
Acc. Chem. Res. 1981, 14, 95–102. (c) Rousseau, G.; Homsi, F.
Chem. Soc. Rev. 1997, 26, 453–461.
(13) (a) Brunel, Y.; Rousseau, G. J. Org. Chem. 1996, 61, 5793–
5800. (b) Cheng, Y. A.; Chen, T.; Tan, C. K.; Heng, J. J.; Yeung, Y.ꢀ
Y. J. Am. Chem. Soc. 2012, 134, 16492–16495.
(14) (a) Agrawal, M. K.; Adimurthy, S.; Ganguly, B.; Ghosh, P. K.
Tetrahedron 2009, 65, 2791–2797. (b) Bar, S. Can. J. Chem. 2010,
88, 605–612.
(15) (a) Liu, X. H.; Lin, L. L.; Feng, X. M. Acc. Chem. Res. 2011,
44, 574–587. (b) Liu, X. H.; Lin, L. L.; Feng, X. M. Org. Chem.
Front. 2014, 1, 298–302.
(16) Thomas, G. Medicinal Chemistry: An Introduction, Wiley,
New York, 2000.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We appreciate the National Natural Science Foundation of China
(Nos. 21290182, 21432006 and 21572136) for financial support.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES
(1) (a) Chen, G.; Ma, S. Angew. Chem. Int. Ed. 2010, 49, 8306–
8308. (b) Snyder, S. A.; Treitler, D. S.; Brucks, A. P. Aldrichimica
Acta, 2011, 44, 27–40. (c) Castellanos, A.; Fletcher, S. P. Chem. Eur.
J. 2011, 17, 5766–5776. (d) Tan, C. K.; Zhou, L.; Yeung, Y.ꢀY.
Synlett 2011, 1335–1339. (e) Denmark, S. E.; Kuester, W. E.; Burk,
M. T. Angew. Chem. Int. Ed. 2012, 51, 10938–10953. (f) Hennecke,
U. Chem. Asian, J. 2012, 7, 456–465. (g) Murai, K.; Fujioka, H. Hetꢀ
erocycles 2013, 87, 763–805. (h) Chemler, S. R.; Bovino, M. T. ACS
Catal. 2013, 3, 1076–1091. (i) Cheng, Y. A.; Yu, W. Z.; Yeung, Y.ꢀ
Y. Org. Biomol. Chem. 2014, 12, 2333–2343.
(2) (a) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J.
Am. Chem. Soc. 2010, 132, 3298–3300. (b) Veitch, G. E.; Jacobsen,
E. N. Angew. Chem. Int. Ed. 2010, 49, 7332–7335. (c) Zhang, W.;
Zheng, S.; Liu, N.; Werness, J. B.; Guzei, I. A.; Tang, W. J. Am.
Chem. Soc. 2010, 132, 3664–3665. (d) Zhou, L.; Tan, C. K.; Jiang,
X.; Chen, F.; Yeung, Y.ꢀY. J. Am. Chem. Soc. 2010, 132, 15474–
15476. (e) Murai, K.; Matsushita, T.; Nakamura, A.; Fukushima, S.;
Shimura, M.; Fujioka, H. Angew. Chem. Int. Ed. 2010, 49, 9174–
9177. (f) Jiang, X.; Tan, C. K.; Zhou, L.; Yeung, Y.ꢀY. Angew. Chem.
Int. Ed. 2012, 51, 7771–7775.
(3) (a) Nakatsuji, H.; Sawamura, Y.; Sakakura, A.; Ishihara, K. Anꢀ
gew. Chem. Int. Ed. 2014, 53, 6974–6977. (b) Toda, Y.; Pink, M.;
Johnston, J. N. J. Am. Chem. Soc. 2014, 136, 14734–14737. (c) Vara,
B. A.; Struble, T. J.; Wang, W.; Dobish, M. C.; Johnston, J. N. J. Am.
Chem. Soc. 2015, 137, 7302–7305. (d) Zhang, W.; Liu, N.; Schieneꢀ
beck, C. M.; Zhou, X.; Izhar, I. I.; Guzei, I. A.; Tang, W. Chem. Sci.
2013, 4, 2652–2656. (e) Li, L.; Su, C.; Liu, X.; Tian, H.; Shi, Y. Org.
Lett. 2014, 16, 3728–3731.
(4) (a) Chen, F.; Tan, C. K.; Yeung, Y.ꢀY. J. Am. Chem. Soc. 2013,
135, 1232–1235. (b) Huang, D.; Liu, X.; Li, L.; Cai, Y.; Liu, W.; Shi,
Y. J. Am. Chem. Soc. 2013, 135, 8101–8104. (c) Zhu, C.ꢀL.; Tian, J.ꢀ
S.; Gu, Z.ꢀY.; Xing, G.ꢀW.; Xu, H. Chem. Sci. 2015, 6, 3044–3050.
(d) Liu, W.; Pan, H.; Tian, H.; Shi, Y. Org. Lett. 2015, 17, 3956–
3959. (e) Cheng, Y. A.; Yu, W. Z.; Yeung, Y.ꢀY. Angew. Chem. Int.
Ed. 2015, 54, 12102–12106. (f) Arai, T.; Watanabe, O.; Yabe, S.;
Yamanaka, M. Angew. Chem. Int. Ed. 2015, 54, 12767–12771. (g) Qi,
J.; Fan, G.ꢀT.; Chen, J.; Sun, M.ꢀH.; Dong, Y.ꢀT.; Zhou, L. Chem.
Commun. 2014, 50, 13841–13844.
(5) (a) Kang, S. H.; Lee, S. B.; Park, C. M. J. Am. Chem. Soc. 2003,
125, 15748–15749. (b) Hennecke, U.; Müller, C. H.; Fröhlich, R.
Org. Lett. 2011, 13, 860–863. (c) Huang, D.; Wang, H.; Xue, F.;
Guan, H.; Li, L.; Peng, X.; Shi, Y. Org. Lett. 2011, 13, 6350–6353.
(d) Denmark, S. E.; Burk, M. T. Org. Lett. 2012, 14, 256–259. (e)
Zeng, X.; Miao, C.; Wang, S.; Xia, C.; Sun, W. Chem. Commun.
2013, 49, 2418–2420. (f) Ke, Z.; Tan, C. K.; Chen, F.; Yeung, Y.ꢀY.
J. Am. Chem. Soc. 2014, 136, 5627–5630. (g) Tay, D. W.; Leung, G.
Y. C.; Yeung, Y.ꢀY. Angew. Chem. Int. Ed. 2014, 53, 5161–5164. (h)
Liu, H.; Jiang, G.; Pan, X.; Wan, X.; Lai, Y.; Ma, D.; Xie, W. Org.
Lett. 2014, 16, 1908–1911. (i) Shen, Z.; Pan, X.; Lai, Y.; Hu, J.; Wan,
X.; Li, X.; Zhang, H.; Xie, W. Chem. Sci. 2015, 6, 6986–6971.
(6) (a) Soltanzadeh, B.; Jaganathan, A.; Staples, R. J.; Borhan, B.
Angew. Chem. Int. Ed. 2015, 54, 9517–9522. (b) Zhang, X. Li, J.;
Tian, H.; Shi, Y. Chem. Eur. J. 2015, 21, 11658–11663.
(17) In the presence of bromine reagent, alcohol like nꢀBuOH,
BnOH and iꢀPrOH oxidized into the corresponding aldehyde or keꢀ
tone and the chalcone transformed into diꢀbromination product withꢀ
out enantioselectivity.
(18) Alegrio, L. V.; BrazꢀFilho, R.; Gottlieb, O. R. Phytochemistry
1989, 28, 2359–2362.
(19) Zhao, G.ꢀL.; Rios, R.; Vesely, J.; Eriksson, L.; Córdova, A.
Angew. Chem. Int. Ed. 2008, 47, 8468–8472.
(20) (a) Gu, Q.; Rong, Z.ꢀQ.; Zheng, C.; You, S.ꢀL. J. Am. Chem.
Soc. 2010, 132, 4056–4057. (b) Asano, K.; Matsubara, S. J. Am.
Chem. Soc. 2011, 133, 16711–16713. (c) Lu, Y.; Zou, G.; Zhao, G.
ACS Catal. 2013, 3, 1356–1359. (d) Miyaji, R.; Asano, K.; Matsubꢀ
ara, S. Org. Biomol. Chem. 2014, 12, 119–122.
(21).(a) Pesti, J. A.; Yin, J.; Zhang, L.ꢀH.; Anzalone, L. J. Am.
Chem. Soc. 2001, 123, 11075–11076. (b)Qian, H.; Zhao, W.; Sung, H.
HꢀY.; Williams, I. D.; Sun, J. Chem. Commun. 2013, 49, 4361–4363.
(7) (a) Tripathi, C. B.; Mukherjee, S. Angew. Chem. Int. Ed. 2013,
52, 8450–8453. (b) Zhao, Y.; Jiang, X.; Yeung, Y.ꢀY. Angew. Chem.
Int . Ed. 2013, 52, 8597–8601. (c) Yin, Q.; You, S.ꢀL. Org. Lett.
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 6
1
2
TOC
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment