Enantioselective Synthesis of anti-syn-Trihalides and anti-syn-anti-Tetrahalides via Asymmetric β-Elimination

Article abstract of DOI:10.1021/jacs.7b02076

Structural motifs containing contiguous halide-bearing stereocenters are common in natural products as well as bioactive molecules. A few successful examples have been reported in the area of asymmetric vicinal dihalogenation of alkenes for accessing diha

Full text of DOI:10.1021/jacs.7b02076

Subscriber access provided by University of Newcastle, Australia
Article
Enantioselective Synthesis of anti-syn-Trihalides and
anti-syn-anti-Tetrahalides via Asymmetric #-Elimination
Yu Tan, Shilong Luo, Dongmei Li, Nan Zhang, Shiqi Jia,
Yidong Liu, Wenling Qin, Choong Eui Song, and Hailong Yan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b02076 • Publication Date (Web): 17 Apr 2017
Downloaded from http://pubs.acs.org on April 18, 2017
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.
Journal of the American Chemical Society 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 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Enantioselective Synthesis of anti-syn-Trihalides and anti-
syn-anti-Tetrahalides via Asymmetric β-Elimination
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
Yu Tan,a Shilong Luo,a Dongmei Li,a Nan Zhang,a Shiqi Jia,a Yidong Liu,a Wenling Qin,a Choong
Eui Songb and Hailong Yan*,a
aInnovative Drug Research Centre (IDRC), School of Pharmaceutical Sciences, Chongqing University, Chongqing
401331, China
bDepartment of Chemistry, Sungkyunkwan University, Suwon, 440-746, Korea
ABSTRACT: Structural motifs containing contiguous halide-bearing stereocenters are common in natural products as
well as bioactive molecules. A few successful examples have been reported in the area of asymmetric vicinal dihalogena-
tion of alkenes for accessing dihalogenated products; in this report, an alternative generation method of contiguous hal-
ide-bearing stereocenters α,β,γ,δ relative to carbonyl group in excellent enantioselectivity is proposed by utilizing a Song’s
oligoEG catalyst-catalyzed asymmetric β-elimination. According to this methodology, a wide range of anti-syn-trihalides
and anti-syn-anti-tetrahalides with high levels of enantioselectivity were synthesized. The synthetic utility of the contigu-
ous halide-bearing stereocenters was demonstrated by several transformations. The results of high-resolution mass spec-
trometry indicated that the favorable interaction between catalyst and one of the enantiomers of racemic contiguously
multi-halogenated ketone contributed to the original enantioselectivity of dehydrohalogenation. Deuterium kinetic iso-
tope effect experiment revealed that this β-elimination reaction proceeds by the E2 mechanism. This strategy opens a new
pathway for the asymmetric synthesis of contiguous halide-bearing stereocenters of great complexity.
(DHQD)2PHAL. Moreover, the research groups of Den-
INTRODUCTION
mark,8 Vanderwal,9 Carreira,10 and Tanaka11 et al. also con-
tributed to the development of dihalogenating agents,
methods and total synthesis of halogenated natural prod-
ucts. However, those methodologies mainly focused on
the synthesis of either anti-dihalides from easily accessi-
ble E-alkenes or syn-dihalides from Z-alkenes. The asym-
metric synthesis of syn-dihalides from E-alkenes has not
been reported, although syn-dihalides are an important
privileged structure in halogenated natural products (Fig-
ure 1).1b In particular, to date, the asymmetric method
regarding the direct enantioselective preparation of con-
tiguous 1,2,3-trihalides and/or 1,2,3,4-tetrahalides contain-
ing syn-dihalides has not been reported due to two chal-
lenges. Firstly, sequential chiral centers increase the diffi-
culty in steric control. Secondly, multiple diastereoiso-
mers are obtained in these reactions. Therefore, it is nec-
essary to develop asymmetric variants for the direct prep-
aration of contiguous halogen-dense compounds, espe-
cially the compounds containing syn-dihalides.
Structural motifs containing contiguous halide-bearing
stereocenters are found in numerous natural products
and important bioactive compounds and their absolute
and relative configurations are often crucial for their bio-
logical activities.1 In addition, the stereogenic halides can
also undergo various selective transformations with high
fidelity to afford a range of stereodefined compounds in
chemistry and medicine.2 Accordingly, much effort has
been devoted to developing new and efficient methods for
their preparation, and great progress has been made in
recent years.3 Among several methods, metal- and/or or-
gano-catalyzed asymmetric vicinal dihalogenation of al-
kenes has been proven as the most powerful tool for ac-
cessing the vicinal dihalogenated molecules. In 2009, the
Snyder group reported the first asymmetric dichlorination
of an isolated alkene and successfully realized the total
synthesis of (−)-napyradiomycin A1 with this method.4 In
2011, the Nicolaou group demonstrated a catalytic asym-
metric dichlorination of allylic alcohols by employing
dimeric cinchona alkaloid derivatives as the catalyst.5 Re-
cently, the Burns group made a landmark achievement
not only in the asymmetric dibromination and bromo-
chlorination of allylic alcohols but also in the dichlorina-
tion of non-conjugated alkenes with TADDOL and triden-
tate Schiff base as ligands, respectively.6 Most recently,
Borhan7 and his co-workers reported an enantioselective
vicinal dihalogenation of allyl amides catalyzed by
In this study, we attempted to develop an alternative
approach to prepare those motifs containing contiguous
halide-bearing stereocenters with readily available cata-
lysts and reagents. Since racemic contiguous halide-
bearing stereocenters are easily accessible,12 kinetic reso-
lution13 is an alternative and complementary strategy for
the preparation of motifs containing contiguous halide-
bearing stereocenters. A possible drawback of this hypo-
thetical approach is that except dynamic kinetic
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
units. The 3,3'-diiodo-substituted catalyst (R)-B showed
1
2
3
4
5
6
7
8
the highest activity and enantioselectivity. Among the
tested solvents (entry 2, 5-10), toluene exhibited the best
selectivity. After further optimization of reaction condi-
tions, the equivalent of KF markedly improved the S val-
ue. Henceforth, the reaction of anti-syn-α,β,γ-tribromo
ketone (±)-2a with excess KF (1.5 equiv.) in the presence
of 10 mol% catalyst (R)-B in toluene at room temperature
resulted in the highest S value (S = 33; entry 12). After 12 h,
the remaining 2a exhibited a high enantiomeric excess
(97%) at 55% conversion.
9
Figure 1. Representative bioactive natural compounds and
related work
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
Table 1. Optimization of the Reaction Conditionsa
resolution, a mixture of the product and unreacted start-
ing material is often obtained. If these compounds are
potentially important halogenated materials produced in
high enantiomeric excess, a kinetic resolution would be-
come a more attractive strategy because it would allow
the simultaneous synthesis of two chiral halogenated tar-
gets by single transformation. We recently developed a
kinetic resolution of β-sulfonyl ketones via β-elimination14
catalyzed by Song’s oligoEG catalyst15 and envisioned that
such a strategy might enable an enantioselective dehy-
drohalogenation of β-halogenated ketones. Herein, we
report our successful development of a kinetic resolution
of contiguously multi-halogenated ketones to deliver
highly enantioenriched contiguous halide-bearing stereo-
centers via asymmetric β-elimination.
Solvent
(0.05 M)
toluene
toluene
toluene
toluene
CH2Cl2
m-xylene
o-xylene
1,4-dioxane
mesitylene
THF
KF
(equiv.)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.8
1.5
ee
(%)/2ab
14
86
6
29
61
97
78
6
64
11
41
Conv.
(%)c
20
52
11
27
45
60
51
43
45
Entry
Cat.
Sd
1
2
3
4
5
6
7
8
9
10
11
12
13
(R)-A
(R)-B
(R)-C
(R)-D
(R)-B
(R)-B
(R)-B
(R)-B
(R)-B
(R)-B
(R)-B
(R)-B
(R)-B
4
25
3
10
12
20
16
1
15
2
13
33
18
RESULTS AND DISCUSSION
To validate our hypothesis, we initiated our studies
with racemic anti-syn-α,β,γ-tribromo ketone (±)-2a as a
model substrate and confined Song’s oligoEG catalyst
which has previously identified as an excellent catalyst for
asymmetric catalysis, as the catalyst. The required race-
mic anti-syn-α,β,γ-tribromo ketones can be easily ob-
tained via Wohl-Ziegler bromination (the introduction of
a bromine substituent at the allylic position of olefins)
and subsequent dibromination of olefins with moderate
yield and excellent d.r. values (Scheme 1). To our delight,
via the kinetic resolution process, one of the enantiomers
of the racemic anti-syn-α,β,γ-tribromo ketone was con-
verted into trisubstituted allyl bromide 3a with a γ stereo-
genic center by the elimination of β-bromine and its effi-
ciency was markedly dependent on the catalyst structure
(entry 1-4) (Table 1). The subsequent studies on chiral
Song’s oligoEG catalyst revealed that the catalyst bearing
three ether units ((R)-B; S = 25; entry 2) was proved to be
a much more effective catalyst compared with the other
catalysts bearing longer (4-ether units; (R)-C; S = 3; entry
3) or shorter (2-ether units; (R)-A; S = 4; entry 1) ether
32
34
55
64
toluene
toluene
toluene
97
99
2.0
aReaction conditions: (±)-2a (0.05 mmol), catalyst (0.005 mmol) and
KF in solvent (1.0 mL) at r.t. for 12 h, unless otherwise specified.
bEnantiomeric excesses were determined by HPLC analysis. cConver-
sion ratio was calculated by the methods of Fiaud: Conv.
=
ee/(ee+ee’). dSelectivity values were calculated by the methods of
Fiaud: S = ln[(1-Conv.)(1-ee)]/ln[(1-Conv.)(1+ee)].
After establishing the optimal reaction conditions, a
wide range of anti-syn-α,β,γ-tribromo ketones (±)-2a-(±)-
2j with different aromatic substituents were then tested
under the optimized reaction conditions (1.5 equiv. of KF,
and 10 mol% of catalyst in toluene at room temperature)
to verify the generality of the reaction, and the results are
summarized in Table 2. The reaction of α,β,γ-tribromo
ketones (±)2a-(±)2j bearing different aryl substituents of
either electron-donating or electron-withdrawing groups
proceeded smoothly to afford the trisubstituted allyl
bromide 3a-3j with excellent E/Z selectivity (E:Z > 20:1)
and good enantioselectivity (see Supporting Information
for details), meanwhile the unreacted α,β,γ-tribromo ke-
tones 2a-2j were recovered in 40-47% yield with 90-99%
ee. For the heteroaromatic α,β,γ-tribromo ketones, only
(±)-2k in which the thiophene is known isostere of phenyl
Scheme 1. Synthesis of Racemic Substrates
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
compound 2a.16 By analogy, the same configuration was
can underwent the kinetic resolution process with useful
1
2
3
4
5
6
7
S factor (S = 17). Other heteroaromatic α,β,γ-tribromo
ketones (pyridine and furan) led to dramatically reduced
S factor (Table 2, 2l, 2m). The relative and absolute con-
figurations were determined to be ‘anti-syn’ and (S,R,S)
by single crystal X-ray crystallographic analysis of the
assigned to all 2 compounds.
We then investigated the applicability of this catalytic
system to the other classes of substrates. Gratifyingly,
when R2 group of (±)-2n-(±)-2x was an aliphatic substitu-
ent, the reaction also showed excellent enantioselectivity.
Table 2. Substrate Scopea
8
9
(R)-B (10 mol%)
KF (1.5 equiv.)
O
Br
O
Br
R1
Br
O
Br
R2
R2
+
R1
R1
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
solvent (0.05 M), r.t.
R2
Br Br
Br Br
(±)-2
2
3
O
Br
O
Br
O
Br
O
Br
O
Br
Br Br
Br Br
Br Br
Br Br
Br Br
2a
97% ee
44% yield
2b
95% ee
43% yield
2c
98% ee
2d
99% ee
40% yield
2e
97% ee
40% yield
CCDC 1527201
42% yield
(58% conv.)
S = 27
(58% conv.)
S = 31
(59% conv.)
S = 20
(55% conv.)
S = 33
(56% conv.)
S = 25
F
O
Br
O
Br
O
Br
O
Br
O
Br
O
Br
Br Br
Br Br
Br Br
S
Br Br
Br Br
Br Br
Cl
MeO
F
2g
97% ee
44% yield
(55% conv.)
S = 37
2i
2k
2h
95% ee
2f
2j
92% ee
90% ee
>99% ee
43% yield
(54% conv.)b
S > 50
93% ee
45% yield
(54% conv.)
S = 37
42% yield
(56% conv.)b
S = 17
45% yield
(52% conv.)b
S = 40
47% yield
(52% conv.)b
S = 44
O
Br
O
Br
O
Br
O
Br
O
Br
O
Br
R1
3
2
Br Br
Br Br
Br Br
Br Br
Br Br
Br Br
2l
2n
94% ee
43% yield
(55% conv.)
S = 28
2r
2p
98% ee
41% yield
2q
97% ee
2o
93% ee
43% yield
(55% conv.)
S = 24
R
1 = pyridine; S = 3
91% ee
45% yield
(53% conv.)
2m
41% yield
(57% conv.)
S = 27
R1 = furan; S = 2
(57% conv.)
S = 31
S = 30
O
Br
O
Br
O
Br
O
Br
O
Br
O
Br
4
5
7
Br Br
Br Br
Br Br
Br Br
Br Br
Br Br
F
2s
2t
90% ee
43% yield
(54% conv.)
S = 22
2u
90% ee
2x
99% ee
2v
96% ee
2w
93% ee
47% yield
(52% conv.)
S = 45
91% ee
46% yield
(53% conv.)
S = 32
42% yield
(56% conv.)
S = 18
44% yield
(55% conv.)
S = 46
43% yield
(56% conv.)
S = 30
aUnless otherwise indicated, the reactions were carried out with (±)-2 (0.1 mmol), KF (1.5 equiv.) and catalyst (R)-B (10 mol%) in toluene (2a–2k,
2.0 mL) or CH2Cl2 (2l–2x, 2.0 mL) at r.t.; enantiomeric excesses were determined by HPLC analysis; yield was determined after chromatographic
purification; conversion ratio was calculated by the methods of Fiaud: Conv. = ee/(ee+ee’); selectivity values were calculated by the methods of
Fiaud: S = ln[(1-Conv.)(1-ee)]/ln[(1-Conv.)(1+ee)]. bDetermined by 1H NMR.
The chain length of R2 group slightly affected the S value.
The trisubstituted allyl bromides 3n-3x with good enanti-
oselectivity and excellent E:Z selectivity (E:Z > 20:1) were
obtained, meanwhile unreacted anti-syn-2n-2x were re-
covered in 90-99% ee and 41-47% yield (Table 2).
tion, however, led to poor selectivity (see Supporting In-
formation for details). The relative and absolute configu-
ration of 4a was unambiguously established by X-ray crys-
tallographic analysis.16 The wide substrate scope showed
the power of this approach for the asymmetric induction.
Furthermore, we envisioned that this methodology
might also be used in the resolution of some more chal-
lenging substrates, such as the substrate containing dif-
ferent halogen atoms. The resolution of α,β,γ-trichloro
ketones, α,β-dibromo-γ-chloro ketones and α-bromo-β,γ-
dichloro ketone proceeded as efficiently as that of anti-
syn-α,β,γ-tribromo ketones (Table 3, 4a–4j). Gratifyingly,
extension to ester substituent at R1 position such as 4k
also worked out well with a useful S factor (S = 15) (Table
3, 4k). The substrate bearing alkyl substituent at R1 posi-
To demonstrate the practicality of this process, we car-
ried out a preparative scale synthesis of 4a under the op-
timal reaction conditions. As displayed in Scheme 2, the
chemical yield and enantioselectivity almost showed no
change. Next, a few transformations were selected and
performed on 4a to further demonstrate the synthetic
potential of the chiral anti-syn-trihalogenated ketone.
The carbonyl group of 4a could be reduced stereoselec-
tivitively without affecting enantiopurity to provide the
resulting alcohol 6 containing four contiguous stereogen-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
ic centers. The relative configuration of the compound 7 product was not detected. This can be ascribed to the
1
2
3
4
5
6
7
8
derived from 6 was established by single crystal X-ray
crystallographic analysis.16 Motivated by many bioactive
natural products containing a sulfate functional moiety
attached to the chiral halides,17 sulfation of the secondary
alcohol on 6 was conducted according to Carreira’s condi-
tion10 to provide sulfated product 8 in almost quantitative
yield. Epoxide formation by treatment of 6 with NaH pro-
vided enantiomerically enriched epoxide 9. For the elimi-
nation product 3o, the γ-bromide could be substituted by
NaN3 to provide azide product 10 in excellent yield.
adequate acidity of Amberlite CG 50 for rapid protonation
of the potassium salt of (R)-B, releasing the insoluble pol-
ymeric potassium salt of Amberlite CG 50 as a by-product
without interfering with the catalysis. Thus a combination
of excessive KF and Amberlite CG 50 provided the best
result. The preliminary results of this transformation were
shown in Table 4. Irrespective of the electronic and steric
nature of the substituents, the anti-syn-anti 11a-11d were
recovered with excellent enantioselectivity. The absolute
configuration of 11a was determined to be (S,S,S,S) by X-
ray crystallography.16
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
Table 3. Substrate Scopea
Scheme 2. Gram-scale Preparation and Synthetic Ap-
plications
O
X2
O
X2
(R)-B (10 mol%)
KF (1.5 equiv.)
R2
R2
R1
X1
O
R1
R1
X3
+
X1 X3
X1 X3
CH2Cl2 (0.05 M), r.t.
4a
a) Gram scale synthesis and synthetic transfornations of
R2
±
4
( )-
4
5
O
Cl
O
Cl
KF
O
(R)-B (10 mol%)
Cl
+
Cl
Cl
Cl Cl
toluene, r.t.
O
Cl
O
Cl
Cl
65% Conv.
S = 23
4a
0.7 g
> 99% ee
5a
1.1 g
55% ee
(±)-4a
2.0 g
2
Cl
4a
Cl
Cl Cl
4b
96% ee
42% yield
(57% conv.)
S = 23
91% ee
Br
CCDC 1527202
A
44% yield
(56% conv.)
S = 20
OSO3
Cl
OH Cl
O
Cl
O
Cl
O
Br
O
O
Cl
C
B
Cl
Cl
Cl
Cl
3
7
Cl Cl
Cl Cl
Cl Cl
Br Cl
4e
96% ee
44% yield
(56% conv.)
S = 30
6
8
-18.7° [a]2D0
96% yield
> 99% ee
95% yield
7
4c
99% ee
40% yield
(59% conv.)
S = 26
4d
99% ee
40% yield
(60% conv.)
S = 23
D
O
A
B
: L-Selectride, THF, -78 to 25 °C, 3 h;
: 4-Bromobenzoyl chloride, DMAP,
Et3N, CH2Cl2, 0 °C to r.t.;
O
Br
O
Br
O
Br
2
3
7
Cl
C: SO3•Py, DMF, 100 °C, 5 h;
D: NaH, THF, r.t..
Br Cl
Br Cl
Br Cl
9
> 99% ee
92% yield
7
(±)-
4f
4g
4h
90% ee
43% yield
(56% conv.)
S = 18
90% ee
44% yield
(54% conv.)
S = 24
91% ee
43% yield
(55% conv.)
S = 21
CCDC 1533845
b) Synthetic transformation of 3o
O
Cl
O
Br
O
Br
O
O
EtOH
Br
N3
O
NaN3
+
3
Br Cl
Br Cl
Br
4k
Cl
Br
Br
3o
90% ee
10
90% ee
85% yield
4i
99% ee
40% yield
(59% conv.)
S = 26
4j
98% ee
96% ee
40% yield
(58% conv.)
S = 21
33% yield
(65% conv.)
S = 15
To gain insight into the reaction mechanism, a series of
experiments and spectroscopic studies were carried out
(Scheme 3). An intermolecular competition between (±)-
2a and (±)-D-2a demonstrated a kinetic isotope effect
(kH/kD = 4.43), which suggested that the deprotonation of
α-proton was probably involved in the rate-determining
step. Based on the kinetic isotope effect studies and addi-
tional experimental results (see Supporting Information
for details), we speculated that the C-H and C-halogen
bonds broke simultaneously.18 Furthermore, we also con-
ducted an in situ electrospray ionization mass spectros-
copy (ESI-MS) analysis with the reaction mixture contain-
ing (R)-B, KF, 4a and 4c’ (1:1:1:1 mixture). Gratifyingly, the
proposed intermediate I could be observed in the meas-
urements of ESI-MS (positive ion mode). This result sug-
gested that the complexation between the (2R,3S,4R)-4c’
aUnless otherwise indicated, the reactions were carried out with (±)-
4 (0.1 mmol), KF (1.5 equiv.) and catalyst (R)-B (10 mol%) in CH2Cl2
(2.0 mL) at r.t.; enantiomeric excesses were determined by HPLC
analysis; yield was determined after chromatographic purification;
conversion ratio was calculated by the methods of Fiaud: Conv. =
ee/(ee+ee’); selectivity values were calculated by the methods of
Fiaud: S = ln[(1-Conv.)(1-ee)]/ln[(1-Conv.)(1+ee)].
We were further interested in expanding this method-
ology to the kinetic resolution of α,β,γ,δ-tetrahalogenated
ketones. In theory, the kinetic resolution of α,β,γ,δ-
tetrahalogenated ketones is challenging because the dou-
ble elimination may occur and produce the dienone
product. After screening the reaction conditions, we find
that the addition of the Amberlite CG 50 can improve the
performance of catalyst (R)-B, meanwhile the dienone
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
a) Kinetic isotope effect study
enantiomer and catalyst (R)-B (found, m/z 1548.8676) was
1
2
3
4
5
6
7
better than that between the (2S,3R,4S)-4a enantiomer
Table 4. Substrate Scopea
O
Br
O
Br
O
(R)-B (10 mol%)
KF (1.5 equiv.)
Br
+
D
Br
H
Br
Br
Br
Br
toluene
10 min, 16% Conv.
(±)-2a
(±)-D-2a
3a
B
R
O
(R)- (10 mol%)
O
Br
Br
O
Br
Br
Br
KF (3.0 equiv.), CG 50
(1 : 1)
kH/kD = 4.43
+
R
R
Br
CHCl3 (0.13 M), 35 °C
Br
Br
Br
11
Br
Br
b) High-resolution mass spectrometry analysis
(
±
)-11
12
O
Cl
O
Cl
8
9
+
O
Br
Br
O
Br
Br
Cl Cl
Cl Cl
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
4c'
4a
(1 : 1)
Br
Br
Br
Br
KF, (R)-B
11a
99% ee
25% yield
(73% conv.)
S = 10
11b
92% ee
34% yield
(64% conv.)
S = 10
KF
without
no observation of the desired complex
CH2Cl2, -20 o
C
CCDC 1527200
I
I
O
O
O
O
Br
Br
O
Br
Br
O
K
H
O
H
Br
Br
Br
Br
F
α
O
I
F
Cl
Cl
O
H
I
β
11d
95% ee
30% yield
(68% conv.)
S = 9
11c
97% ee
30% yield
(69% conv.)
S = 10
R
Ph
H
favored
Complex I R =
Cl
aUnless otherwise indicated, the reactions were carried out with (±)-
11 (0.1 mmol), KF (3.0 equiv.), CG 50 (8.0 mg) and catalyst (R)-B (10
mol%) in CHCl3 (0.75 mL) at 35 °C; enantiomeric excesses were de-
termined by HPLC analysis; yield was determined after chromato-
graphic purification; conversion ratio was calculated by the methods
of Fiaud: Conv. = ee/(ee+ee’); selectivity values were calculated by
the methods of Fiaud: S = ln[(1-Conv.)(1-ee)]/ln[(1-Conv.)(1+ee)].
Calcd [C61H53Cl3I4KO7]+ = 1548.8667
Observed [C61H53Cl3I4KO7]+ = 1548.8676
in HRMS. The difference can be explained by the essential
role of K+ (potassium fluoride) in promoting the for-
mation of the complex. Taking the results described
above and our previous report into consideration, we
proposed the mode of stereoinduction, as shown in
Scheme 3b. The carbonyl group of substrate is presumably
hydrogen bonded to one of OH groups of (R)-B, thus
placing the α-halide stereocenter in its close vicinity. The
formation of hydrogen bond between the β-halide and
another OH group of (R)-B is the enantio-discriminating
step in our reaction.
and the catalyst (R)-B. This finding revealed that the in-
teraction between the chiral catalyst and its favored enan-
tiomers of racemic substrates contributed to the original
enantioselectivity of dehydrohalogenation. In contrast, in
the absence of KF, the desired complex was not observed
Scheme 3. Preliminary Mechanistic Studies
CONCLUSIONS
In summary, we have successfully developed an effi-
cient catalytic asymmetric reaction for the synthesis of
the derivatives of anti-syn-trihalides and anti-syn-anti-
tetrahalides by β-elimination. According to this method, a
wide range of motifs containing contiguous halide-
bearing stereocenters with excellent enantioselectivity are
synthesized, delivering a practical and straightforward
approach to this fundamental and important privileged
structure. The method can be readily scaled up to a pre-
parative scale (2.0 gram). The HRMS studies suggest that
the formation of complex between the chiral polyether,
potassium fluoride and α,β,γ-trihalogenated ketone is
responsible for the high stereoselectivity. Kinetic isotope
effect experiment revealed that this β-elimination reac-
tion proceeds by the E2 mechanism. Further efforts re-
garding the synthetic utility of this approach to other im-
portant organic transformations are ongoing.
ASSOCIATED CONTENT
Supporting Information.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
(9) (a) Shibuya, G. M.; Kanady, J. S.; Vanderwal, C. D. J. Am.
Experimental procedure and characterization data for all the
products. This material is available free of charge via the In-
ternet at http://pubs.acs.org.
1
2
3
4
5
6
7
8
Chem. Soc. 2008, 130, 12514-12518. (b) Bedke, D. K.; Shibuya, G.
M.; Pereira, A.; Gerwick, W. H.; Haines, T. H.; Vanderwal, C. D. J.
Am. Chem. Soc. 2009, 131, 7570-7572. (c) Bedke, D. K.; Shibuya,
G. M.; Pereira, A. R.; Gerwick, W. H.; Vanderwal, C. D. J. Am.
Chem. Soc. 2010, 132, 2542-2543. (d) Chung, W.-j.; Carlson, J. S.;
Bedke, D. K.; Vanderwal, C. D. Angew. Chem., Int. Ed. 2013, 52,
10052-10055. (e) Vogel, C. V.; Pietraszkiewicz, H.; Sabry, O. M.;
Gerwick, W. H.; Valeriote, F. A.; Vanderwal, C. D. Angew. Chem.,
Int. Ed. 2014, 53, 12205-12209. (f) Chung, W.-j.; Vanderwal, C. D.
Acc. Chem. Res. 2014, 47, 718-728. (g) Chung, W.-j.; Carlson, J. S.;
Vanderwal, C. D. J. Org. Chem. 2014, 79, 2226-2241.
(10) (a) Nilewski, C.; Geisser, R. W.; Carreira, E. M. Nature
2009, 457, 573-576. (b) Nilewski, C.; Geisser, R. W.; Ebert, M.-O.;
Carreira, E. M. J. Am. Chem. Soc. 2009, 131, 15866-15876. (c)
Nilewski, C.; Deprez, N. R.; Fessard, T. C.; Li, D. B.; Geisser, R.
W.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50, 7940-7943.
(d) Nilewski, C.; Chapelain, C. L.; Wolfrum, S.; Carreira, E. M.
Org. Lett. 2015, 17, 5602-5605. (e) Fischer, S.; Huwyler, N.;
Wolfrum, S.; Carreira E. M. Angew. Chem., Int. Ed. 2016, 55, 2555-
2558. (f) Bailey, A. M.; Wolfrum, S.; Carreira, E. M. Angew.
Chem., Int. Ed. 2016, 55, 639-643.
(11) (a) Yoshimitsu, T.; Fukumoto, N.; Tanaka, T. J. Org. Chem.
2009, 74, 696-702. (b) Yoshimitsu, T.; Fukumoto, N.; Nakatani,
R.; Kojima, N.; Tanaka, T. J. Org. Chem. 2010, 75, 5425-5437. (c)
Yoshimitsu, T.; Nakatani, R.; Kobayashi, A.; Tanaka, T. Org. Lett.
2011, 13, 908-911.
(12) (a) Yu, T.-Y.; Wang, Y.; Hu, X.-Q.; Xu, P.-F. Chem. Com-
mun. 2014, 50, 7817-7820. (b) Yu, T.-Y.; Wei, H.; Luo, Y.-C.;
Wang, Y.; Wang, Z.-Y.; Xu, P.-F. J. Org. Chem. 2016, 81, 2730-
2736.
(13) (a) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth.
Catal. 2001, 343, 5-26. (b) Vedejs, E.; Jure, M. Angew. Chem., Int.
Ed. 2005, 44, 3974-4001.
(14) Li, L.; Liu, Y.; Peng, Y.; Yu, L.; Wu, X.; Yan, H. Angew.
Chem., Int. Ed. 2016, 55, 331-335.
(15) (a) Yan, H.; Jang, H. B.; Lee, J.-W.; Kim, H. K.; Lee, S. W.;
Yang, J. W.; Song, C. E. Angew. Chem., Int. Ed. 2010, 49, 8915-
8917. (b) Yan, H.; Oh, J. S.; Lee, J.-W.; Song, C. E. Nat. Commun.
2012, 3, 1212. (c) Park, S. Y.; Lee, J.-W.; Song, C. E. Nat. Commun.
2015, 6, 7512. (d) Liu, Y.; Ao, J.; Paladhi, S.; Song, C. E.; Yan, H. J.
Am. Chem. Soc. 2016, 138, 16486-16492. (e) Oliveira, M. T.; Lee, J.-
W. ChemCatChem 2017, 9, 377-384. (f) Vaithiyanathan, V.; Kim,
M. J.; Liu, Y.; Yan, H.; Song, C. E. Chem. - Eur. J. 2017, 23, 1268-
1272.
AUTHOR INFORMATION
Corresponding Author
*yhl198151@cqu.edu.cn
Funding Sources
9
This study was supported by the Fundamental Research
Funds for the Central Universities in China (Grant No:
CQDXWL-2014-Z003), the Scientific Research Foundation of
China (Grant No: 21402016), Graduate Scientific Research
and Innovation Foundation of Chongqing, China (CYB16032)
Notes
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
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful to Mr. Xiangnan Gong (Analytical and Test-
ing Center of Chongqing University) for X-ray crystallo-
graphic analysis.
REFERENCES
(1) (a) Butler, A.; Walker, J. V. Chem. Rev. 1993, 93, 1937-1944.
(b) Gribble, G. W. Acc. Chem. Res. 1998, 31, 141-152. (c) Pereira, A.
R.; Byrum, T.; Shibuya, G. M.; Vanderwal, C. D.; Gerwick, W. H.
J. Nat. Prod. 2010, 73, 279-283. (d) Wang, B. G.; Gloer, J. B.; Ji, N.
Y.; Zhao, J. C. Chem. Rev. 2013, 113, 3632-3685.
(2) (a) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790-4791. (b) Shi-
batomi, K.; Yamamoto, H. Angew. Chem., Int. Ed. 2008, 47, 5796-
5798. (c) Lundin, P. M.; Esquivias, J.; Fu, G. C. Angew. Chem., Int.
Ed. 2009, 48, 154-156. (d) Liang, Y.; Fu, G. C. J. Am. Chem. Soc.
2015, 137, 9523-9526. (e) Kainz, Q. M.; Matier, C. D.; Bartosze-
wicz, A.; Zultanski, S. L.; Peters, J. C.; Fu, G. C. Science 2016, 351,
681-684.
(3) (a) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew.
Chem., Int. Ed. 2012, 51, 10938-10953. (b) Cresswell, A. J.; Eey, S.
T.-C.; Denmark, S. E. Angew. Chem., Int. Ed. 2015, 54, 15642-
15682. (c) Chung, W.-j.; Vanderwal, C. D. Angew. Chem., Int. Ed.
2016, 55, 4396-4434.
(4) Snyder, S. A.; Tang, Z. Y.; Gupta, R. J. Am. Chem. Soc.
2009, 131, 5744-5745.
(16) CCDC 1527201 (2a), 1527202 (4a), 1533845 (7), and 1527200
(11a) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre.
(17) (a) Nilewski, C.; Carreira, E. M. Eur. J. Org. Chem. 2012,
2012, 1685-1698. (b) Umezawa, T.; Matsuda, F. Tetrahedron Lett.
2014, 55, 3003-3012.
(18) (a) Saunders, W. H., Jr.; Ashe, T. A. J. Am. Chem. Soc.
1969, 91, 4473-4478. (b) Mayer, B. J.; Spencer, T. A.; Onan, K. D.
J. Am. Chem. Soc. 1984, 106, 6343-6348. (c) Villano, S. M.; Kato,
S.; Bierbaum, V. M. J. Am. Chem. Soc. 2006, 128, 736-737.
(5) Nicolaou, K. C.; Simmons, N. L.; Ying, Y.; Heretsch, P. M.;
Chen, J. S. J. Am. Chem. Soc. 2011, 133, 8134-8137.
(6) (a) Hu, D. X.; Shibuya, G. M.; Burns, N. Z. J. Am. Chem.
Soc. 2013, 135, 12960-12963. (b) Hu, D. X.; Seidl, F. J.; Bucher, C.;
Burns, N. Z. J. Am. Chem. Soc. 2015, 137, 3795-3798. (c) Bucher,
C.; Deans, R. M.; Burns, N. Z. J. Am. Chem. Soc. 2015, 137, 12784-
12787. (d) Landry, M. L.; Hu, D. X.; McKenna, G. M.; Burns, N. Z.
J. Am. Chem. Soc. 2016, 138, 5150-5158. (e) Burckle, A. J.; Vasilev,
V. H.; Burns, N. Z. Angew. Chem., Int. Ed. 2016, 55, 11476-11479.
(7) Soltanzadeh, B.; Jaganathan, A.; Yi, Y.; Yi, H.; Staples, R. J.;
Borhan, B. J. Am. Chem. Soc. 2017, 139, 2132-2135.
(8) Cresswell, A. J.; Eey, S. T.-C.; Denmark, S. E. Nat. Chem.
2015, 7, 146-152.
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
Insert Table of Contents artwork here
1
2
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
7
ACS Paragon Plus Environment