Chiral Hydroxytetraphenylene-Catalyzed Asymmetric Conjugate Addition of Boronic Acids to Enones

Article abstract of DOI:10.1021/acs.orglett.9b01637

(S)-2,15-Br₂-DHTP-catalyzed asymmetric conjugate addition of boronic acids to β-trifluoromethyl α,β-unsaturated ketones and enones was studied. The reaction afforded the corresponding Michael addition products in moderate to high yields with excellent enantioselectivities (up to 99:1 er). This catalytic system features mild reaction conditions, high efficiency, and tolerance to heteroarylboronic acids.

Full text of DOI:10.1021/acs.orglett.9b01637

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chiral Hydroxytetraphenylene-Catalyzed Asymmetric Conjugate
Addition of Boronic Acids to Enones
Guo-Li Chai,*,† A-Qiang Sun,† Dong Zhai,‡ Juan Wang,† Wei-Qiao Deng,†,‡ Henry N. C. Wong,†,§
and Junbiao Chang†
†Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, School of Chemistry and Chemical Engineering,
Henan Normal University, Xinxiang, Henan 453007, China
‡Institute of Molecular Sciences and Engineering, Shandong University, Qingdao 266237, China
§Shanghai−Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: (S)-2,15-Br2-DHTP-catalyzed asymmetric con-
jugate addition of boronic acids to β-trifluoromethyl α,β-
unsaturated ketones and enones was studied. The reaction
afforded the corresponding Michael addition products in
moderate to high yields with excellent enantioselectivities (up
to 99:1 er). This catalytic system features mild reaction
conditions, high efficiency, and tolerance to heteroarylboronic
acids.
symmetric conjugate addition is an important synthetic
Rh(I)-catalyzed asymmetric conjugate addition of arylboronic
acids to β-trifluoromethyl α,β-unsaturated ketones in the
presence of (S)-BINAP to give the corresponding addition
products in high yields and enantioselectives; however, the
selectivities were found to be poor for alkenylboronic acids
(one example with 40% ee).11 In 2014, Pedro reported the first
enantioselective conjugate addition of terminal alkynes to β-
trifluoromethyl enones using a taniaphos-Cu(I) complex as the
catalyst, and also achieved the alkynylation of β-aryl-β-
trifluoromethyl enones using diethylzinc and 3,3′-(C6F5)2-
BINOL with satisfactory enantioselectivities.12 To date there
are very few reports regarding the enantioselective conjugate
addition of alkenylboronic acids to β-trifluoromethyl enones in
high yields and enantioselectivities in the absence of a
transition metal catalyst.
Wong introduced chiral tetraphenylene scaffolds to asym-
metric synthesis and achieved good results.13 Recently, our
group has reported the asymmetric allylboration of ketones
using (S)-2,15-Br2-DHTP (Cat 1, Scheme 1a) as a sufficiently
reactive catalyst, affording optically pure tertiary alcohols in
moderate to good yields with up to 99% ee (Scheme 1a).14
These results have led us to believe that the (S)-2,15-Br2-
DHTP-catalyzed asymmetric conjugate addition of easy-to-
handle boronic acids to α,β-unsaturated ketones can be
accomplished. Herein, we report our hydroxytetraphenylene-
catalyzed approach toward the construction of enantioenriched
β-trifluoromethyl ketones from boronic acids and β-trifluor-
omethyl-α,β-unsaturated ketones (Scheme 1b).
A
method for constructing new C−C bonds.1 Although
transition-metal-catalyzed conjugate additions of boronic acids
and their derivatives to α,β-unsaturated carbonyl compounds
making use of Rh(I), Ir(I), Pd(I), and Cu(I) catalysts have
been realized,2 transition-metal-free conjugate addition reac-
tions are still an important alternative method due to their low
toxicity, functional-group tolerance, operational simplicity, and
high selectivity.3,4 After the pioneering study of the non-
stereoselective conjugate addition of vinyl boronates to α,β-
unsaturated ketones was reported by Suzuki and Hara,5 the
Chong group was the first to report the enantioselective
conjugate addition of alkynyl boronates to chalcones using
3,3′-disubstituted-BINOL as the catalyst, which was sub-
sequently applied to alkenylboronates and arylboronates.6
However, alkenylboronic acids afforded lower stereoselectiv-
ities, and arylboronic esters required harsh reaction conditions.
In 2011, May developed the asymmetric conjugate addition of
alkenylboronic acids and alkynylboronic esters to indole-
appended enone substrates in the presence of 3,3′-(C6F5)2-
BINOL and subsequently used heteroaryl and aryl trifluor-
oborate salts as nucleophiles.7 In addition, Sugiura used O-
monoacyltartaric acids as the catalyst for the conjugate
addition of alkenylboronic acids to enones to provide only
moderate yields and ee values,8 as compared with those
obtained from the reactions catalyzed by chiral biphenol
derivatives.
In fluorine chemistry, considerable efforts have been focused
on the catalytic asymmetric synthesis of molecules with CF3-
containing stereocenters,9 because these fluorine-containing
molecules can be converted into biologically active com-
pounds.10 In 2008, Konna and co-workers described the
Received: May 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01637
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. (S)-2,15-Br2-DHTP-Catalyzed Asymmetric
Table 1. Optimization of the Reaction Conditions
Reactions
Initially, the reaction of β-trifluoromethyl α,β-unsaturated
ketone 1a with (E)-styrylboronic acid (2a) using Cat 1 as the
catalyst in toluene at room temperature was investigated,
affording the desired product 3a in 50% yield with 95.5:4.5 er
(entry 1, Table 1). We proposed that the mechanism of the
asymmetric conjugate addition of alkenylboronic boronic acids
to β-trifluoromethyl enones was similar to that proposed by
May,7a,b Chong,6b and Goodman.6e Figure 1a illustrates the
proposed mechanism of the reaction of 1a with 2a catalyzed by
Cat 1. Cat 1 and 2a first form A by losing two water molecules.
Then A and 1a form B with a tetracoordinated boron atom. C
is produced by the cleavage of the boron−carbon bond in B.
C, Mg(OtBu)2, and another 2a react to produce D and A. The
process of A to C (red box in Figure 1a) is critical to
determining the chirality of the product. To gain molecular
insights into the mechanism, we calculated the Gibbs free
energy profile along the reaction paths by density functional
theory calculations at B3LYP-D3BJ/Def2-SVP level of theory
with the C-PCM solvation model (Figure 1b). Computational
details are described in the Supporting Information. Path 1 and
Path 2 are the paths that produce the desired product 3a and
undesired product, respectively. The isosurface plot of the
lowest unoccupied molecular orbital (LUMO) for A indicates
that the boron atom in A acts as a Lewis acid site. The oxygen
atom in 1a can be coordinated to the boron atom in A. The
overall free energy barrier of Path 1 is 4.28 kcal/mol lower than
Path 2, suggesting the desired product 3a is the more favorable
product. Subsequently, various solvents were screened in the
presence of 10 mol % of Cat 1 at 25 °C; DCE was
demonstrated to be the optimal solvent (entries 1−6, Table 1).
Notably, the addition of Mg(OtBu)2 and 4 Å MS as additives
was critical to accelerate the reaction (Table S1; see
Supporting Information).7a,b In the absence of Mg(OtBu)2,
the product yield decreased to 30% (entry 7, Table 1). In the
absence of 4 Å MS, no product was afforded (entry 8, Table
1). The decrease of the solvent volume to 0.5 mL led to 3a
with a slightly higher enantioselectivity within a shorter
reaction time (entry 9, Table 1). Next, various chiral
tetraphenylene catalysts Cat 2, Cat 3, Cat 4, and Cat 515
were examined (entries 10−13, Table 1). However, all these
catalysts afforded 3a in a significantly diminished yield as well
as lower enantioselectivities as compared to those of Cat 1.
These results revealed that substituents on the tetraphenylene
frameworks considerably affect selectivities and activities of the
catalysts. Bulky, electron-withdrawing groups at positions 2
and 15 of (S)-DHTP were found to be imperative for better
results. This can be attributed to the fact that electron-
withdrawing substituents on the DHTP effectively increase the
Lewis acidity of the boron and facilitate co-ordination of the
Yield
b
c
Entry Cat (mol %) Solvent t (h) T (°C)
(%)
er
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Cat 1 (10)
Cat 1 (10)
Cat 1 (10)
Cat 1 (10)
Cat 1 (10)
Cat 1 (10)
Cat 1 (10)
Cat 1 (10)
Cat 1 (10)
Cat 2 (10)
Cat 3 (10)
Cat 4 (10)
Cat 5 (10)
Cat 6 (10)
Cat 7 (10)
Cat 8 (10)
Cat 9 (10)
PhCH3
CH2Cl2
THF
36
45
45
48
48
40
40
40
30
40
40
40
48
48
48
72
48
72
84
20
72
46
30
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
50
78
<10
30
82
90
30
N.R.
88
11
5
95.5:4.5
97.1:2.9
−
95.2:4.8
97.3:2.7
97:3
MTBE
PhCF3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
d
e
f
97:3
−
97.2:2.8
83.7:16.3
78:22
96.7:3.3
95.5:4.5
42.9:57.1
10.2:89.8
5.9:94.1
17.3:82.7
9:91
f
f
f
f
f
f
f
f
f
f
f
f
f
30
32
6
19
14
10
12
38
92
74
88
Cat 10 (10) DCE
Cat 1 (10)
Cat 1 (10)
Cat 1 (5)
Cat 1 (20)
DCE
DCE
DCE
DCE
98:2
60
25
25
96.3:3.7
96.8:3.2
97.7:2.3
a
Reaction conditions: β-trifluoromethyl enone 1a (0.1 mmol), (E)-
styrylboronic acid 2a (0.12 mmol), catalyst (0.01 mmol), Mg(OtBu)2
(0.01 mmol), 4 Å MS (50 mg), and 1.0 mL of dry solvent were stirred
b
c
under N2. Isolated yield. The er values were determined by chiral
d
e
f
HPLC analysis. Without Mg(OtBu)2. Without 4 Å MS. With 0.5
mL of DCE.
boron to the carbonyl oxygen of the enone. Interestingly,
commercially available catalysts (R)-BINOL Cat 6, (R)-3,3′-
Br2-BINOL Cat 7, (R)-3,3′-I2-BINOL Cat 8, (R)-3,3′-Ph2-
BINOL Cat 9, and Cat 10 bearing two 3,5-bis(trifluoro-
methyl)phenyl groups exhibited poorer catalytic effects
(entries 14−18, Table 1). Furthermore, with the decrease of
the reaction temperature to 0 °C and the extension of the
reaction time to 84 h, Cat 1 gave a lower yield with a slightly
higher er (entry 19, Table 1). Moreover, slightly diminished
product enantioselectivities were observed at 60 °C (entry 20,
Table 1). Finally, the catalyst loading was decreased to 5 mol
%, affording the desired product in moderate yield with good
er (entry 21, Table 1). However, the increase in the catalyst
loading to 20 mol % did not achieve a significantly better result
(entry 21, Table 1). Thus, the optimal reaction conditions are
therefore 1a (0.1 mmol) and 2a (0.12 mmol) in the presence
of Cat 1 (0.01 mmol, 10 mol %), 4 Å MS (50 mg), and
B
DOI: 10.1021/acs.orglett.9b01637
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrate Scope of β-Trifluoromethyl α,β-
a
Unsaturated Ketones
a
Unless otherwise noted, reactions were carried out with β-
trifluoromethyl enones 1a−1t (0.1 mmol, 1.0 equiv), (E)-styrylbor-
onic acid 2a−2c (0.12 mmol, 1.2 equiv), Cat 1 (0.01 mmol, 10 mol
%), Mg(OtBu)2 (0.01 mmol), and 4 Å MS (50 mg) in 0.5 mL of dry
DCE at 25 °C under N2 for 24−48 h. Isolated yield. The er values
Figure 1. (a) Proposed catalytic mechanism. (b) Calculated relative
Gibbs free energy profile along reaction coordinates, structures of
intermediates and transition states, and isosurface plots of the highest
occupied molecular orbital (HOMO) for 1a and the lowest
unoccupied molecular orbital (LUMO) for A.
b
were determined by chiral HPLC analysis. With (R)-2,15-Br2-DHTP
c
(0.01 mmol, 10 mol %). With Cat 1 (0.02 mmol, 20 mol %).
Mg(OtBu)2 (0.01 mmol, 10 mol %) in dry DCE (0.5 mL) at
25 °C (entry 9, Table 1).
afforded the desired product 3s in 68% yield with 98.5:1.5 er.
These results reveal that the substituents on the β-
trifluoromethyl-α,β-unsaturated ketones do not significantly
affect the stereoselectivities of products. Unfortunately,
relevant reactions involving ethyl 4,4,4-trifluorocrotonate, β-
methyl β-trifluoromethyl α,β-unsaturated ketone, or β-phenyl
β-trifluoromethyl α,β-unsaturated ketone were unsuccessful.
Furthermore, effects of alternative boronic acids were
examined for the reaction with substrate 1a. Thus,
furanboronic acid 2b and benzofuranboronic acid 2c exhibited
acceptable reactivities, affording products 3t and 3u with good
enantioselectivities, respectively. Arylboric acids were un-
reactive under our reaction conditions. These findings reveal
that structures of boronic acids lead to a significant impact on
reactivities and enantioselectivities of these catalytic reactions.
The absolute configuration of 3b was determined to be (E,R)
by comparison of chiral HPLC data and specific rotation values
reported in the literature.11a,12a Accordingly, the R-config-
uration was assigned to the remainder of the expected products
3 by assuming a uniform stereochemical pathway.
With the optimal reaction conditions in hand, the substrate
scope of β-trifluoromethyl α,β-unsaturated ketones 1a−1s was
investigated (Scheme 2). When the enantiomer of Cat 1 (R)-
2,15-Br2-DHTP was utilized in the reaction, the corresponding
product 3a′ was obtained in 89% yield with 97.3:2.7 er. In the
case of substrate 2b, desired product 3b was generated in 93%
yield with 97.2:2.8 er, and the result was considerably better
than that reported previously ((E,S)-3b′: 66% yield, 78% ee;
(E,R)-3b: 70% yield, 40% ee).12a,11a All reactions of β-
trifluoromethyl α,β-unsaturated ketones bearing either elec-
tron-donating or electron-withdrawing groups on the phenyl
ring were performed, leading to the formation of the
corresponding products in moderate to high yields with
excellent enantioselectivities (90−98% ee). Halides, Me, OMe,
CF3, and nitro groups on the ortho, para, or meta position of
the phenyl ring were tolerated under the standard reaction
conditions (Scheme 2, 3c−3n), albeit diminished yields for
products 3i and 3j were noted. In addition, heteroaromatic
thiophene α,β-unsaturated ketones 2o and 2p and ring-fused
naphthyl α,β-unsaturated ketones 2q and 2r afforded the
corresponding products in good yields with excellent er values
(Scheme 2, 3o−3r). The use of alkyl-substituted substrate 2s
We also optimized the reaction conditions with trans-
chalcone 4a and (E)-styrylboronic acid (2a), and the desired
product 5a was obtained in 99% yield with 98.1:1.9 er using 5
mol % Cat 1 (Table S2; see Supporting Information). The
C
DOI: 10.1021/acs.orglett.9b01637
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substrate scope of enones 4b−4q was then evaluated (Scheme
3). Initially, chalcones carrying β-aryl groups with diverse
results in our system were better than those reported by
Sugiura.8a The configuration of all products was assigned by
comparison with that reported in literature.
To confirm the scalability of the current protocol, a gram-
scale reaction of β-trifluoromethyl α,β-unsaturated ketone 1i
(4 mmol) with (E)-styrylboronic acid (2a) (4.8 mmol) was
carried out, affording product 3i in an isolated yield of 75%
with 97.2:2.8 er (eq 1, Scheme 4). A gram-scale reaction of
a
Scheme 3. Substrate Scope of Enones
Scheme 4. Gram-Scale Reactions
enone 4a with boronic acid 2a in the presence of Cat 1 (1 mol
%) and Mg(OtBu)2 (1 mol %) was also conducted. To our
delight, 1.15 g of product 5a was obtained in 92% yield with
95.8:4.2 er, and after crystallization, 0.85 g of 3a was afforded
with 99.8:0.2 er (eq 2, Scheme 4). After the reaction, Cat 1
was easily recovered by flash column chromatography, which
can be reused without loss of activity.
In summary, we have developed an asymmetric conjugate
addition of boronic acids to α,β-unsaturated ketones catalyzed
by (S)-2,15-Br2-DHTP under mild reaction conditions.
Enantioenriched products bearing a trifluoromethylated stereo-
center were obtained in moderate to high yields and good to
excellent enantioselectivities (up to 99:1 er). In addition,
heteroarylboronic acids were tolerated under these reaction
conditions, and gram-scale reactions were achieved without
loss of enantioselectivities. Additional investigations to extend
the scope to other substrates and applications of the resulting
products are underway in our laboratories.
a
Unless otherwise noted, enones 1a−1q (0.1 mmol), boronic acid
2a−2d (0.12 mmol), Cat 1 (0.005 mmol, 5 mol %), Mg(OtBu)2
(0.005 mmol, 5 mol %), 4 Å MS (100 mg), and dry MTBE (1.0 mL)
were stirred at 25 °C under N2. Isolated yield. The er values were
determined by chiral HPLC analysis. With Cat 1 (0.1 mmol, 10 mol
%).
b
substituents were examined. Various electron-donating groups
(OMe, Me) and electron-withdrawing groups (F, Cl, Br, CF3,
NO2) on the phenyl ring were well tolerated, delivering
adducts in excellent yields and enantioselectivities (5b−5i,
92−99% yields, 96−98% ee). Moreover, phenyl-type enones
bearing a fused ring and heteroaromatic ring at the β-position
were also applicable, affording the corresponding products with
excellent results (5j−5m). Then, enones bearing α′-aryl groups
with different substituents (OMe, Br) were allowed to react
with (E)-styrylboronic acid (2a) to give the expected products
in good yields and er values (5n and 5o). Of particular note is
that enone 4p bearing a methyl group and enone 4q bearing an
ester group both reacted with boronic acid 2a smoothly, and
the desired products 5p and 5q were obtained in quantitative
yields with 98.2:1.8 and 96.5:3.5 er, respectively. Finally, this
catalytic reaction also worked well with other boronic acids,
such as furanboronic acid 2b, benzofuranboronic acid 2c, and
alkenylboronic acid 2d. In the case of 2b and 2c, the
corresponding reactions provided the desired products 5r and
5s in excellent yields with 91.1:8.9 and 92.4:7.6 er under the
standard reaction condition, while the er values increased to
93:7 and 93.9:6.1 when the catalyst loading was increased to
10 mol %. Product 5t was afforded in 57% yield with 98.7:1.3
er, and the moderate yield is likely due to the lower reactivity
of alkenylboronic acid 2d as compared with that of 2a. All
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01637.
Experimental details; computational details; copies of
1H, 13C, 19F NMR spectra; and chromatograms of
racemic and optically active products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: guolichai@126.com.
ORCID
Guo-Li Chai: 0000-0002-1342-6217
Dong Zhai: 0000-0003-3155-4607
Henry N. C. Wong: 0000-0002-3763-3085
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b01637
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
tion of Enones. Org. Lett. 2011, 13, 5796−5799. For a theoretical
study, see: (d) Pellegrinet, S. C.; Goodman, J. M. Asymmetric
Conjugate Addition of Alkynylboronates to Enones: Rationale for the
Intriguing Catalysis Exerted by Binaphthols. J. Am. Chem. Soc. 2006,
128, 3116−3117. (e) Paton, R. S.; Goodman, J. M.; Pellegrinet, S. C.
Theoretical Study of the Asymmetric Conjugate Alkenylation of
Enones Catalyzed by Binaphthols. J. Org. Chem. 2008, 73, 5078−
5089.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (NSFC) (Project No. U1804283 and
21525315), National Key R@D Program of China (Grant
2017YFA0204800), the 111 Project (No. D17007), and a
start-up fund from Henan Normal University (qd 18005).
(7) (a) Lundy, B. J.; Jansone-Popova, S.; May, J. A. Enantioselective
Conjugate Addition of Alkenylboronic Acids to Indole-Appended
Enones. Org. Lett. 2011, 13, 4958−4961. (b) Le, P. Q.; Nguyen, T. S.;
May, J. A. A General Method for the Enantioselective Synthesis of α-
Chiral Heterocycles. Org. Lett. 2012, 14, 6104−6107. (c) Shih, J. L.;
Nguyen, T. S.; May, J. A. Organocatalyzed Asymmetric Conjugate
Addition of Heteroaryl and Aryl Trifluoroborates: A Synthetic
Strategy for Discoipyrrole D. Angew. Chem., Int. Ed. 2015, 54,
9931−9935. (d) Nguyen, T. S.; Yang, M. S.; May, J. A. Experimental
Mechanistic Insight into the BINOL-Catalyzed Enantioselective
Conjugate Addition of Boronates to Enones. Tetrahedron Lett.
2015, 56, 3337−3341.
(8) (a) Sugiura, M.; Tokudomi, M.; Nakajima, M. Enantioselective
Conjugate Addition of Boronic Acids to Enones Catalyzed by O-
Monoacyltartaric Acids. Chem. Commun. 2010, 46, 7799−7800.
(b) Sugiura, M.; Kinoshita, R.; Nakajima, M. O-Monoacyltartaric Acid
Catalyzed Enantioselective Conjugate Addition of a Boronic Acid to
Dienones: Application to the Synthesis of Optically Active Cyclo-
pentenones. Org. Lett. 2014, 16, 5172−5175. (c) Grimblat, N.;
Sugiura, M.; Pellegrinet, S. C. A Hydrogen Bond Rationale for the
Enantioselective β-Alkenylboration of Enones Catalyzed by O-
Monoacyltartaric Acids. J. Org. Chem. 2014, 79, 6754−6758.
(9) (a) Hiyama, T. In Organofluorine Compounds: Chemistry and
Applications; Yamamoto, H., Ed.; Springer: New York, 2000.
(b) Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal
Chemistry of Fluorine; John Wiley and Sons: Hoboken, NJ, 2000.
(c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in
REFERENCES
■
(1) Catalytic Asymmetric Conjugate Reactions; Cordova, A., Ed.;
Wiley-VCH: Weinheim, 2010.
(2) For examples, see: (a) Wu, C.; Yue, G.; Nielsen, C. D.-T.; Xu,
K.; Hirao, H.; Zhou, J. Asymmetric Conjugate Addition of
Organoboron Reagents to Common Enones Using Copper Catalysts.
J. Am. Chem. Soc. 2016, 138, 742−745. (b) Holder, J. C.; Zou, L.;
Marziale, A. N.; Liu, P.; Lan, Y.; Gatti, M.; Kikushima, K.; Houk, K.
N.; Stoltz, B. M. Mechanism and Enantioselectivity in Palladium-
Catalyzed Conjugate Addition of Arylboronic Acids to β-Substituted
Cyclic Enones: Insights from Computation and Experiment. J. Am.
Chem. Soc. 2013, 135, 14996−15007. (c) Kikushima, K.; Holder, J.
C.; Gatti, M.; Stoltz, B. M. Palladium-Catalyzed Asymmetric
Conjugate Addition of Arylboronic Acids to Five-, Six-, and Seven-
Membered β-Substituted Cyclic Enones: Enantioselective Construc-
tion of All-Carbon Quaternary Stereocenters. J. Am. Chem. Soc. 2011,
133, 6902−6905. (d) Shintani, R.; Takeda, M.; Nishimura, T.;
Hayashi, T. Chiral Tetrafluorobenzobarrelenes as Effective Ligands
for Rhodium-Catalyzed Asymmetric 1,4-Addition of Arylboroxines to
β,β-Disubstituted α,β-Unsaturated Ketones. Angew. Chem., Int. Ed.
2010, 49, 3969−3971. (e) Paquin, J.-F.; Defieber, C.; Stephenson, C.
R. J.; Carreira, E. M. Asymmetric Synthesis of 3,3-Diarylpropanals
with Chiral Diene-Rhodium Catalysts. J. Am. Chem. Soc. 2005, 127,
10850−10851.
(3) (a) Nguyen, T. N.; Chen, P.-A.; Setthakarn, K.; May, J. A. Chiral
Diol-Based Organocatalysts in Enantioselective Reactions. Molecules
2018, 23, 2317−2353. (b) Min, C.; Seidel, D. Asymmetric Bronsted
Acid Catalysis with Chiral Carboxylic Acids. Chem. Soc. Rev. 2017, 46,
5889−5902. (c) Yoshida, K.; Hayashi, T. In Boronic Acids; Hall, D. G.,
Ed.; Wiley-VCH: Weinheim, 2005; chapter 4. (d) Batey, R. A. In
Boronic Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2005; chapter
́
7. (e) Roscales, S.; Csaky, A. G. Transition-metal-free C−C Bond
̈
Forming Reactions of Aryl, Alkenyl and Alkynylboronic Acids and
Their Derivatives. Chem. Soc. Rev. 2014, 43, 8215−8225.
(4) For examples, see: (a) Inokuma, T.; Takasu, K.; Sakaeda, T.;
Takemoto, Y. Hydroxyl Group-Directed Organocatalytic Asymmetric
Michael Addition of α,β-Unsaturated Ketones with Alkenylboronic
Acids. Org. Lett. 2009, 11, 2425−2428. (b) Lee, S.; MacMillan, D. W.
C. Organocatalytic Vinyl and Friedel-Crafts Alkylations with
Trifluoroborate Salts. J. Am. Chem. Soc. 2007, 129, 15438−15439.
(c) Luan, Y.; Schaus, S. E. Enantioselective Addition of Boronates to
o-Quinone Methides Catalyzed by Chiral Biphenols. J. Am. Chem. Soc.
2012, 134, 19965−19968.
(5) (a) Hara, S.; Hyuga, S.; Aoyama, M.; Sato, M.; Suzuki, A. Boron
Trifluoride Etherate Mediated 1,4-Addition of 1-Alkenyldialkoxybor-
anes to α,β-Unsaturated Ketones. A Stereoselective Synthesis of γ,δ-
Unsaturated Ketones. Tetrahedron Lett. 1990, 31, 247−250. (b) Hara,
S.; Ishimura, S.; Suzuki, A. Cyanuric Fluoride-Induced 1,4-Addition
Reaction of Alkenylboronic Acids to α,β-Unsaturated Ketones.
Stereoselective Synthesis of Functionalized γ,δ-Unsaturated Ketones.
Synlett 1996, 1996, 993−994. (c) Hara, S.; Shudoh, H.; Ishimura, S.;
Suzuki, A. The Regioselective 1,4-Addition Reaction of Alkenylbor-
onic Acids to α,β,α’,β’-Unsaturated Ketones. Bull. Chem. Soc. Jpn.
1998, 71, 2403−2408.
(6) (a) Wu, T. R.; Chong, J. M. Ligand-Catalyzed Asymmetric
Alkynylboration of Enones: A New Paradigm for Asymmetric
Synthesis Using Organoboranes. J. Am. Chem. Soc. 2005, 127,
3244−3245. (b) Wu, T. R.; Chong, J. M. Asymmetric Conjugate
Alkenylation of Enones Catalyzed by Chiral Diols. J. Am. Chem. Soc.
2007, 129, 4908−4909. (c) Turner, H. M.; Patel, J.; Niljianskul, N.;
Chong, J. M. Binaphthol-Catalyzed Asymmetric Conjugate Arylbora-
Medicinal Chemistry. Chem. Soc. Rev. 2008, 37, 320−330. (d) Muller,
̈
K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking
Beyond Intuition. Science 2007, 317, 1881−1886.
(10) (a) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Asymmetric
Construction of Stereogenic Carbon Centers Featuring a Trifluor-
omethyl Group from Prochiral Trifluoromethylated Substrates. Chem.
Rev. 2011, 111, 455−529. (b) Ma, J.-A.; Cahard, D. Update 1 of:
Asymmetric Fluorination, Trifluoromethylation, and Perfluoroalkyla-
tion Reactions. Chem. Rev. 2008, 108, PR1−PR4. (c) Ma, J.-A.;
Cahard, D. Asymmetric Fluorination, Trifluoromethylation, and
Perfluoroalkylation Reactions. Chem. Rev. 2004, 104, 6119−6146.
(d) Kawai, H.; Tachi, K.; Tokunaga, E.; Shiro, M.; Shibata, N.
Cinchona Alkaloid-Catalyzed Asymmetric Trifluoromethylation of
Alkynyl Ketones with Trimethylsilyl Trifluoromethane. Org. Lett.
2010, 12, 5104−5107. (e) Chinkov, N.; Warm, A.; Carreira, E. M.
Asymmetric Autocatalysis Enables an Improved Synthesis of
Efavirenz. Angew. Chem., Int. Ed. 2011, 50, 2957−2961. (f) Zhang,
G.-W.; Meng, W.; Ma, H.; Nie, J.; Zhang, W.-Q.; Ma, J.-A. Catalytic
Enantioselective Alkynylation of Trifluoromethyl Ketones: Pro-
nounced Metal Fluoride Effects and Implications of Zinc-to-Titanium
Transmetallation. Angew. Chem., Int. Ed. 2011, 50, 3538−3542.
(g) Ohshima, T.; Kawabata, T.; Takeuchi, Y.; Kakinuma, T.; Iwasaki,
T.; Yonezawa, T.; Murakami, H.; Nishiyama, H.; Mashima, K. C1-
Symmetric Rh/Phebox-Catalyzed Asymmetric Alkynylation of α-
Ketoesters. Angew. Chem., Int. Ed. 2011, 50, 6296−6300.
(11) (a) Konno, T.; Tanaka, T.; Morigaki, A.; Ishihara, T. A First
High Enantiocontrol of an Asymmetric Tertiary Carbon Center
Attached with a Fluoroalkyl Group via Rh(I)-Catalyzed Conjugate
Addition Reaction. Tetrahedron Lett. 2008, 49, 2106−2110.
(b) Morigaki, A.; Tanaka, T.; Miyabe, T.; Ishihara, T.; Konno, T.
Rhodium(I)-Catalyzed 1,4-Conjugate Arylation toward β-Fluoroalky-
lated Electron-Deficient Alkenes: a New Entry to a Construction of a
Tertiary Carbon Center Possessing a Fluoroalkyl Group. Org. Biomol.
Chem. 2013, 11, 586−595. (c) Boz, E.; Hasļ ak, Z. P.; Tuzun, N. Ş.;
̈ ̈
E
DOI: 10.1021/acs.orglett.9b01637
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Konuklar, F. A. S. A Theoretical Study on Rh(I) Catalyzed
Enantioselective Conjugate Addition Reactions of Fluoroalkylated
Olefins. Organometallics 2014, 33, 5111−5119.
(12) (a) Sanz-Marco, A.; Garcia-Ortiz, A.; Blay, G.; Pedro, J. R.
Catalytic Asymmetric Conjugate Addition of Terminal Alkynes to β-
Trifluoromethyl α,β-Enones. Chem. Commun. 2014, 50, 2275−2278.
(b) Sanz-Marco, A.; Blay, G.; Vila, C.; Pedro, J. R. Catalytic
Enantioselective Conjugate Alkynylation of β-Aryl-β-trifluoromethyl
Enones Constructing Propargylic All-Carbon Quaternary Stereogenic
Centers. Org. Lett. 2016, 18, 3538−3541.
(13) (a) Peng, H.-Y.; Lam, C.-K.; Mak, T. C. W.; Cai, Z.; Ma, W.-T.;
Li, Y.-X.; Wong, H. N. C. Chiral Rodlike Platinum Complexes,
Double Helical Chains, and Potential Asymmetric Hydrogenation
Ligand Based on “Linear” Building Blocks: 1,8,9,16-Tetrahydroxyte-
traphenylene and 1,8,9,16-Tetrakis(diphenylphosphino) tetrapheny-
lene. J. Am. Chem. Soc. 2005, 127, 9603−9611. (b) Hau, C.-K.; He,
H.; Lee, A. W. M.; Chik, D. T. W.; Cai, Z.; Wong, H. N. C.
Enantioselective Brønsted Base Catalyzed [4 + 2] Cycloaddition
Using Novel Amino-Substituted Tetraphenylene Derivatives. Tetrahe-
dron 2010, 66, 9860−9874. (c) Chai, G.-L.; Han, J.-W.; Wong, H. N.
C. Hydroxytetraphenylenes as Chiral Ligands: Application to
Asymmetric Darzens Reaction of Diazoacetamide with Aldehydes.
Synthesis 2017, 49, 181−187. (d) Chai, G.-L.; Han, J.-W.; Wong, H.
N. C. Asymmetric Darzens Reaction of Isatins with Diazoacetamides
Catalyzed by Chiral BINOL−Titanium Complex. J. Org. Chem. 2017,
82, 12647−12654.
(14) Chai, G.-L.; Zhu, B.; Chang, J. Synthesis and Application of
Substituted 1,16- Dihydroxytetraphenylenes in Catalytic Asymmetric
Allylboration of Ketones. J. Org. Chem. 2019, 84, 120−127.
(15) Xiong, X.; Yeung, Y.-Y. Ammonium Salt-Catalyzed Highly
Practical Ortho-Selective Monohalogenation and Phenylselenation of
Phenols: Scope and Applications. ACS Catal. 2018, 8, 4033−4043.
F
DOI: 10.1021/acs.orglett.9b01637
Org. Lett. XXXX, XXX, XXX−XXX