Enantioselective Construction of Vicinal Diaxial Styrenes and Multiaxis System via Organocatalysis

Article abstract of DOI:10.1021/jacs.8b09893

A highly diastereo- and enantioselective methodology for the asymmetric synthesis of vicinal diaxial styrenes and multiaxis system was achieved by organocatalysis. Various vicinal diaxial styrenes and multiaxis systems were obtained in excellent enantioselective manners. The mechanism studies revealed that a new tetra-substituted vinylidene ortho-quinone methide (VQM) intermediate was likely involved and accounted for the excellent enantioselectivity.

Full text of DOI:10.1021/jacs.8b09893

Subscriber access provided by UNIV OF ALABAMA BIRMINGHAM
Communication
Enantioselective Construction of Vicinal Diaxial
Styrenes and Multiaxis System via Organocatalysis
Yu Tan, Shiqi Jia, Fangli Hu, Yidong Liu, Lei Peng, Dongmei Li, and Hailong Yan
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 21 Nov 2018
Downloaded from http://pubs.acs.org on November 21, 2018
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 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 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.
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 Construction of Vicinal Diaxial Styrenes and
Multiaxis System via Organocatalysis
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, Shiqi Jia, Fangli Hu, Yidong Liu, Lei Peng, Dongmei Li and Hailong Yan*
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing
University, Chongqing 401331, P. R. China
Supporting Information Placeholder
requirements, E/Z selectivity of tetra-substituted olefin is
generally the critical issue, since their syntheses are of great
challenges6 due to the highly steric congestion of four substituents
and the difficulties in controlling the stereochemistry. In addition,
the generation of geometric isomers may also result in the failure
of reaction design. All the mentioned difficulties probably caused
the absence of successful reports.
ABSTRACT:
A
highly diastereo- and enantioselective
methodology for the asymmetric synthesis of vicinal diaxial
styrenes and multiaxis system was achieved by organocatalysis.
Various vicinal diaxial styrenes and multiaxis systems were
obtained in excellent enantioselective manners. The mechanism
studies revealed that a new tetra-substituted vinylidene ortho-
quinone methide (VQM) intermediate was likely involved and
accounted for the excellent enantioselectivity.
Scheme 1. Background and Project Synopsis
a) Contiguous stereocenters (well known)
Y
X
Y

X
Y
X

Y
R


Compounds with contiguous elements of chirality,1 which can
offer a particularly broad range of topologies, are important
scaffolds as various chiral ligands, catalysts and optical resolution
agents. Accordingly, their syntheses have attracted wide attention
from chemists and great progresses have been made in the
construction of contiguous stereocenters (Scheme 1a). However,
compared to various methods controlling contiguous stereocenters
configuration,2 current catalytic methods of the preparation of
axially chiral scaffolds mostly focus on the single stereogenic axis
(Scheme 1b).3 Stereoselective methods of preparing the individual
compound classes with two or more stereogenic axes are rarely
reported.4 Further, only few examples of asymmetrically
generating different types of axial chirality in a single reaction
step are available.4d,4e,4g The lack of a general and straightforward
catalytic protocol to access compounds with multiple
configurational axes has also hindered their preparation and
applications in asymmetric synthetic chemistry. From the
asymmetric catalytic chemistry point of view, the combination of
different types of stereogenic axes (such as the combination of
biaryl atropisomers and axially chiral styrenes) in a single
molecule may provide geometrically chiral environments.
Therefore, it is intriguing to explore a utilitarian strategy to realize
this objective.




R1
R2


n'



n
n
n
Z
Z
X
Z
Z
b) Stereogenic axis (well known)
O
R2
NR21
R3
R1
O
R1
R3
N

R1
R3
R2
R4
R2
R4



R3
R4
R2
biaryl atropisomers axially chiral styrenes axially chiral anilides axially chiral amides
c) Contiguous axes bearing diaxial styrenes and multiaxis system (not reported)
R1
(1aR,2aR,3aR,E)
(1aR,2aR,E) (1aR,2aS,E)
(1aS,2aR,E) (1aS,2aS,E)
(1aR,2aR,Z) (1aR,2aS,Z)
(1aS,2aR,Z) (1aS,2aS,Z)
up to 8 isomers
3
(1aR,2aR,3aS,E)

R2
R3
2
2
R2
R4
R1
1
1
(1aR,2aS,3aS,Z)
(1aS,2aS,3aS,Z)
up to 16 isomers
OH
OH
Vinylidene ortho-quinone methide (VQM)7 contains multiple
reactive sites and thus exhibits diverse and interesting reactivity
for a wide variety of enantioselective transformations. Usually,
the active VQM intermediate can be generated through a
Recently, axially chiral styrenes as the new member of the
axially chiral family has received extensive attention from
synthetic chemists.5 Consequently, a few examples of the
enantioselective construction of axially chiral styrenes have been
reported by the research groups of Baker,5b Miyano,5c Gu,5d,5g
Smith,5f Tan5e and our group.7f,7h Despite these achievements, the
preparation of contiguous axially chiral styrenes has not been
realized to date, due to the following requirements: (1) the
constructions of contiguous axially chiral styrenes rely on tetra-
substituted olefin skeletons and the way to control the
corresponding E/Z selectivity is the prerequisite; (2) the diastereo-
and enantioselectivity should be controlled. Among these
prototropic
rearrangement
(tautomerization)
of
2-
(phenylethynyl)phenol under basic conditions. So far, all the
reports on VQM intermediate are focused on tri-substituted types.
In view of these potential challenges, we aim to develop a new
variant of VQM intermediate to solve these issues. Theoretically,
a new type of tetra-substituted VQM species may be produced in
the presence of a suitable electrophilic reagent during the process
of prototropic rearrangement. Therefore, selecting the appropriate
electrophilic reagent is the primary task of our project. Firstly, N-
Iodosuccinimide (NIS),8 which was widely used in organic
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
Scheme 2. Previous Work and Our Strategy
Table 1. Optimization of the Reaction Conditionsa
1
2
3
4
1) Previous work: single axially chiral styrene
R
H
H
PhSO2H (1.0 equiv)
catalyst (10 mol%)
NIS (1.0 equiv)
Nu
OH
SO2Ph
R
I
Nu
OH
OH
O
solvent, 6 h, rt
5
6
1a
2a
VQM
Tri-substutited
intermediate
Single axially chiral styrene
7
8
9
2) Our strategy: multiaxis system
OMe
OMe
N
OMe
H
O
H
N
N
H
H
N
N
NH
NH
OH
OH
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
X
N
S
NH
Ar
N
N
NH
Ar
Nu
X
Nu
A
B
C
D
O
OH
O
OH
N
S
N
N
N
N
H
N
H
H
VQM
Multiaxis system
Tetra-substutited
intermediate
Ar
O
O
N
N
H
H
H
H
NH
N
MeO
OMe
O
NH
Ar
Ar = 3,5-(CF3)2C6H3
transformations, was selected as the potential electrophile.
Combined with our findings on enantioselective addition of
sulfone to in situ generated VQM intermediate,7f a reaction of
PhSO2Na, NIS and 1a in the presence of catalyst A, L-proline and
H3BO3 as additives was tested. As we envisaged, the desired
product was successfully obtained while the yield and
enantioselectivity were poor. Next, simplifying the reaction
condition (condition B) did not improve the enantioselectivity and
yield. Interestingly, the yield of the reaction was increased by
replacing PhSO2Na with PhSO2H, despite the enantioselectivity
was still poor.
N
N
G
E
F
O
yield
(%)b
ee
entry catalyst
solvent
E/Z
dr
(%)c
11
0
1
2
A
B
C
D
E
F
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCM
55
43
53
89
92
41
37
93
69
62
55
78
80
61
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
3
1
4
92
94
9
5
Scheme 3. Initial Attempt
6
7
G
E
E
E
E
E
E
E
3
8
95
5
SO2Ph
OH
A
, Conditions
CHCl3, rt
9
toluene
1,4-dioxane
EA
I
PhSO2X
+
NIS
+
OH
10
11
12
13
14
89
55
8
1a
2a
yield ee E/Z
dr
Et2O
Condition A: PhSO2Na, L-proline, H3BO3
Condition B: PhSO2Na
22% 15% >20 >20:1
19% 17% >20 >20:1
55% 11% >20 >20:1
DCE
30
Condition C: PhSO2H
CCl4
2
aConditions: 1a (0.1 mmol), PhSO2H (0.1 mmol), catalyst (10 mol%) and
NIS (0.1 mmol) in solvent (2.0 mL) at rt for 6 h. bIsolated yield.
cDetermined by HPLC analysis.
The following survey was focused on identifying a suitable
organocatalyst9 for this asymmetric induction. The reaction with
catalyst A, B and C gave poor enantioselectivities, albeit
moderate yields of 2a were obtained (Table 1, entries 1-3). The
results obtained with catalysts D and E revealed that the quinine-
derived squaramide catalysts realized the enantiomeric excess up
to 92% and 94% as well as excellent yields (Table 1, entries 4, 5).
Further investigation on Takemoto’s thiourea catalyst F resulted
in a significant decrease in atropselectivity (9% ee) and yield
(Table 1, entry 6). Dimeric cinchona alkaloid derivative
(DHQD)2PHAL almost did not work in this reaction. Catalysts
screening results indicated that the squaramide species was crucial
for this transformation. This is because of the low pKa value of
the squaramide moiety and the extended distance between the
squaramide N-H bonds. In addition, the distal N-aryl of the
squaramide is also extended out compared to thioureas, which
could also allow it to better control the stereo induction of the
distal axis.10 With the best catalyst in hand, the effect of the
solvent on this reaction was also examined. A series of solvents
were tested. DCM was found to be the best solvent since it
ultimately delivered the product in excellent yield,
diastereoselectivity, E/Z selectivity and enantioselectivity (93%
yield, >20:1 dr, E/Z > 20, 95% ee).
the scope of the atroposelective addition reaction. First, a panel of
substituents on ortho position of naphthalene (R1 groups) were
tested (1b-1f). Phenyl groups with para methyl and phenyl
substituents gave excellent enantioselectivities and yields (2b, 2c).
Next, we explored the substrate scope by examining various ether
substituents (R1 groups) at naphthalene (ring A). All the substrates
(1d-1f) were converted into the desired products with similar
efficiencies and selectivities. Under acidic conditions,
deprotection of 2f afforded (1aS,2aR)-Bi-2-Naphthol (2g) which
could be used as new naphthalenediol skeleton in the design of
catalysts. Heterocyclic substituent at the naphthalene (ring A) was
well tolerated to our reaction system and thiophene substituent
successfully led to the desired product 2h with excellent
stereoselectivity and yield. Furthermore, substrates with the alkyl
substituents on ring A of naphthalene were found to be
employable for the reaction and gave axially chiral adducts 2i-2k
with excellent enantioselectivities (91-95% ee). Next, a series of
substituents at different positions of naphthalene (ring B) were
tested and tolerated in this reaction, thus allowing the preparation
Having defined the optimal reaction conditions, we next tested
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
Table 2. Substrate Scopea
1
A
B
2
3
4
5
A
B
R1
R1
E
O
S
(10 mol%)
O
2
S
R3
NIS (1.0 equiv)
I
OH
+
O
1
OH
OH
DCM, 6 h, rt
R3
R2
R2
X
X
1
3
2
6
7
8
9
R
HO
2f,
R= -OMOM
SO2Ph
OH
SO2Ph
OH
SO2Ph
I
SO2Ph
OH
SO2Ph
OH
I
I
I
I
HCl, DCM, MeOH
rt, 12 h, 81%
OH
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
2d
R = -OMe
2e
R = -OBn
92%, 94% ee
E/Z > 20, >20:1 dr
2f
(1aS,2aR)-
R = -OMOM
92%, 95% ee
E/Z > 20, >20:1 dr
(1aS,2aR)-
(1aS,2aR)-
2a
(1aS,2aR)-
2b
(1aS,2aR)-2c
90%, 96% ee
E/Z > 20, >20:1 dr
(1aS,2aR)-
(1aS,2aR)-2g
93% ee
E/Z > 20, >20:1 dr
93%, 95% ee
E/Z > 20, >20:1 dr
91%, 97% ee
E/Z > 20, >20:1 dr
CCDC 1865046
90%, 87% ee
E/Z > 20, >20:1 dr
nBu
F
S
SO2Ph
OH
SO2Ph
I
SO2Ph
OH
SO2Ph
I
SO2Ph
OH
SO2Ph
OH
SO2Ph
I
I
Cl
I
I
I
OH
OH
OH
2h
(1aS,2aR)-
(1aS,2aR)-
2i
(1aS,2aR)-2j
92%, 95% ee
E/Z > 20, >20:1 dr
(1aS,2aR)-2k
91% , 95% ee
E/Z > 20, >20:1 dr
(1aS,2aS)-
92%, 96% ee
E/Z > 20, >20:1 dr
2l
(1aS,2aS)-2m
91%, 95% ee
E/Z > 20, >20:1 dr
(1aS,2aS)-2n
90% , 95% ee
E/Z > 20, >20:1 dr
90%, 92% ee
E/Z > 20, >20:1 dr
94%, 91% ee
E/Z > 20, >20:1 dr
Cl
Cl
Cl
F
F
SO2Ph
SO2Ph
OH
SO2Ph
I
SO2Ph
OH
SO2Ph
SO2Ph
OH
SO2Ph
OH
I
I
I
F
I
I
I
OH
OH
OH
Br
OMe
(1aS,2aR)-2u
93%, 90% ee
2ob
2r
2s
(1aS,2aR)-
(1aS,2aS)-
2pb
(1aS,2aS)-
(1aS,2aR)-
93%, 94% ee
E/Z > 20, >20:1 dr
2t
(1aS,2aS)-
2q
(1aS,2aS)-
91%, 94% ee
E/Z > 20, >20:1 dr
93%, 98% ee
E/Z > 20, >20:1 dr
92%, 96% ee
E/Z > 20, >20:1 dr
93%, 95% ee
94%, 96% ee
E/Z > 20, >20:1 dr
E/Z > 20, >20:1 dr
E/Z > 20, >20:1 dr
O
F3C
Br
Br
O
O
O
S
S
Cl
S
Br
SO2Ph
OH
SO2Ph
OH
Ts
SO2Ph
OH
I
I
I
I
I
I
I
O
OH
O
O
OH
OH
OH
2y,
91%
2aa
2v
2w
(1aS,2aR)-
2bb
(1aS,2aR)-
84%, 93% ee
E/Z > 20, 10:1 dr
(1aS,2aR)-
(1aS,2aR)-
2z
(1aS,2aR)-
81%, 96% ee
E/Z > 20, 8:1 dr
2x
(1aS,2aR)-
89%, 93% ee
E/Z > 20, >20:1 dr
95% ee (major)
91% ee (minor)
E/Z > 20, 1.2:1 dr
82%, 97% ee
E/Z > 20, 9:1 dr
93%, 96% ee
E/Z > 20, >20:1 dr
88%, 94% ee
E/Z > 20, >20:1 dr
BocHN
Br
Cl
Br
Br
O
O
O
SO2Ph
I
SO2Ph
OH
S
Cl
SO2Ph
OH
S
Br
S
Br
I
I
I
I
I
O
OH
O
O
OH
OH
OH
N
2ggb
(1aS,2aR)-
2cc
83%, 91% ee
E/Z > 20, 9:1 dr
2dd
(1aS,2aR)-
(1aS,2aR)-
2ff
(1aS,2aR)-
63%, 91% ee
E/Z > 20, >20:1 dr
2ee
2ee'
(1aS,2aR)-
(1aS,2aS)-
9%, 92% ee (minor)
E/Z > 20
79%, 90% ee
E/Z > 20, 8:1 dr
52%, 92% ee
80%, 90% ee (major)
E/Z > 20, 9:1 dr
CCDC 1865048
CCDC 1865047
E/Z > 20, >20:1 dr
aConditions: 1 (0.1 mmol), 3 (0.1 mmol), E (10 mol%) and NIS (0.1 mmol) in DCM (2.0 mL) at rt. bDue to poor solubility of the substrate in DCM, 4.0 mL
DCM was used.
of structurally diverse, enantioenriched axially chiral adducts 2l-
2r (95-98% ee). Among the tested substrates, the substituents on
both of R1 and naphthalene ring were well tolerated. The
introduction of three substituents on naphthalene also worked well
to give high enantioselectivity (2s, 94% ee). To further investigate
the scope of our reaction, substituents such as bromine and
methoxy were introduced to the naphthol ring (R2 substituents).
Gratifyingly, the products 2t and 2u were formed with excellent
enantioselectivities and high yields. To expand the utility of this
synthetic method, different substituted PhSO2H compounds were
also examined. Not only methyl substituent but also para chloride
and bromide were employable for the reaction and gave axially
chiral products with excellent enantioselectivities and high yields.
When naphthalene was replaced by benzofuran, the reaction still
proceeded smoothly to give desired axially chiral adduct, albeit
the diastereoselectivity of the product decreased. Finally,
replacing naphthalene ring with a series of ortho substituted
phenyl groups gave the enantioenriched adducts 2z-2ee in slightly
lower yields and satisfying diastereoselectivities with excellent
enantioselectivities. Substrates with nitrogen atom at different
positions were also investigated. Although those substrates gave
moderate yields, the ee values remained at an excellent level (2ff,
2gg). The absolute configuration of 2a was determined to be
(1aS,2aR) by single crystal X-ray crystallographic analysis, others
were assigned by analogue.
Motivated by the obtained results, we further expanded this
methodology to the preparation of adducts with three elements of
axial chirality. We regarded the compounds containing vicinal
diaxial styrenes and a biaryl axis as our target molecule. First, a
rotating hindered biaryl axis was constructed by introducing two
sterically hindered substituents (R1 and R2 groups) on the basis of
1a skeleton. With this strategy, we envisaged a kinetic resolution
process, in which one of the enantiomers of the racemic (±)-4 was
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
To gain insight into the reaction mechanism, a series of control
Table 3. Substrate Scope and Transformations
1
2
3
4
5
6
7
8
experiments were performed. For example, the reaction did not
lead to any axially chiral styrenes when 1a', in which the
hydroxyl was protected thus not capable of generating the VQM
intermediate, was used as substrate. This result excluded the
possibility of direct activation of alkynes by NIS and proved that
VQM intermediate participated in the reaction. When the reaction
was performed with 0.5 equiv of NIS, the conversion of substrate
1a remained at 46%. However, compound 8, which was believed
to be generated through tri-substituted VQM intermediate, was
not obtained. Additionally, in the absence of NIS, the reaction did
not occur, indicating that NIS was essential for both generating
the active tetra-substituted VQM intermediate and activating
PhSO2H. Finally, replacing NIS by succinimide did not provide
any product. All the above experimental results implied that the
active tetra-substituted VQM intermediate was involved in our
reaction.
a) Substrate Scopea
R1
R1
R2
R2
R1
3
R2
PhSO2H (0.55 equiv)
E
(10 mol%)
2
NIS (0.55 equiv)
SO2Ph
OH
I
+
1
OH
DCM, 6 h, rt
OH
R3
R3
R3

(aR)-4
(1aS,2aR,3aS)-5
Cl
Cl
Cl
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
SO2Ph
OH
SO2Ph
OH
SO2Ph
OH
I
I
I
Br
OMe
5b
(1aS,2aR,3aS)-
5c
5a
(1aS,2aR,3aS)-
(1aS,2aR,3aS)-
94% ee
95% ee
96% ee
CCDC 1865049
E/Z > 20, >20:1 dr
E/Z > 20, >20:1 dr
40% yield, (41% conv.)
S = 79
E/Z > 20, >20:1 dr
43% yield, (45% conv.)
S = 117
42% yield, (43% conv.)
S = 70
Scheme 4. Preliminary Mechanistic Studies
nBu
Br
Cl
Cl
Br
SO2Ph
I
SO2Ph
OH
SO2Ph
I
SO2Ph
I
I
PhSO2H (1.0 equiv)
OH
OH
OH
NIS (1.0 equiv)
No reaction
DCM, rt
OMOM
Br
5d
(1aS,2aR,3aS)-5e
96% ee
E/Z > 20, >20:1 dr
38% yield, (38% conv.)
S = 90
5f
5g
(1aS,2aR,3aS)-
(1aS,2aR,3aS)-
(1aS,2aR,3aS)-
96% ee
95% ee
94% ee
E/Z > 20, >20:1 dr
42% yield, (44% conv.)
S = 113
E/Z > 20, >20:1 dr
41% yield, (44% conv.) 42% yield, (43% conv.)
S = 88 S = 68
E/Z > 20, >20:1 dr
1a'
PhSO2H (1.0 equiv)
NIS (0.5 equiv)
nPr
nPr
2a,
46% yield
DCM, rt
SO2Ph
I
SO2Ph
OH
SO2Ph
OH
I
I
PhSO2H (1.0 equiv)
DCM, rt
SO2Ph
OH
OH
No reaction
No reaction
H
OH
Br
5h
5i
(1aS,2aR,3aS)-
(1aS,2aR,3aS)-
5j
(1aS,2aR,3aS)-
PhSO2H (1.0 equiv)
Succinimide (1.0 equiv)
95% ee
95% ee
96% ee
8
E/Z > 20, >20:1 dr
38% yield, (39% conv.)
S = 73
E/Z > 20, >20:1 dr
41% yield, (43% conv.)
S = 83
E/Z > 20, >20:1 dr
43% yield, (43% conv.)
S = 106
1a
Not observed
DCM, rt
b) Synthetic Transformations
Br
Based on the experimental results, a plausible reaction pathway
is outlined in Scheme 5. Catalyst E quickly reacts with 1a and
generates tetra-substituted VQM intermediate I in the presence of
NIS. Meanwhile, the released succinimide anion captures a proton
from PhSO2H thus giving the corresponding PhSO2H anion with
nucleophilic property. Finally, a nucleophilic addition of the
activated sulfinate anion to the highly active tetra-substituted
VQM intermediate I occurs thus furnishing the product 2a.
Another reaction pathway involving a tri-substituted VQM
intermediate II is suppressed maybe due to the competitive
reactions in the process of generating tri-substituted VQM
intermediate II and tetra-substituted VQM intermediate I.
Br
O
O
Br
S
Se
O
SO2Ph
NBS, PhSO2
Br
S
Cl
Cl
OH
H
Se
Ph
O
OH
Et3N, DCM
Et3N, DCM
OH
6
7
(1aS,2aR,3aS)-
85%, 95% ee
E/Z > 20, >20:1 dr
(1aS,2aR,3aS)-
4g'
(aS)-
95% ee
93%, 97% ee
E/Z > 20, >20:1 dr
aConditions: (±)-4 (0.1 mmol), PhSO2H (0.55 mmol), E (10 mol%) and
NIS (0.55 mmol) in DCM (2.0 mL) at rt for 6 h. All the reported S values
were the average of 3 times of repetition.
converted into tetra-substituted 5 with three stereogenic axes and
the unreacted chiral 4 remained. Under the optimal reaction
conditions, the substrates investigation showed that this
transformation tolerated a broad variety of substrates. The
substituents on R1, R2 and R3 groups with different electronic
properties were well tolerated and afforded the desired products
with excellent enantioselectivities (94%-96% ee). The absolute
configuration of the multiaxial chiral 5a was unambiguously
determined to be (1aS,2aR,3aS) by single crystal X-ray
crystallographic analysis. Although the enantioselectivities of
Scheme 5. Proposed Reaction Pathway
I
Ph
k1
SO2Ph
I
O
Pathway A
HO
k2
2a
O
I
PhSO2
H
N
O
catalyst
solvent
NIS
k2 >> k4
k1 >> k3
OH
unreacted
4 were not high (60%-78%) (see Supporting
PhSO2
Information for details), an excellent enantioselectivity could be
obtained after recrystallization. Next, various transformations of 4
were performed. When 4g' reacted with NBS and PhSO2H in the
presence of triethylamine, the corresponding multiaxial chiral 6
was obtained in high yield with excellent diastereo- and
enantioselectivity. The same level result was obtained when 4g'
reacted with Se-phenyl 4-chlorobenzenesulfonoselenoate.
1a
H
O
k4
Ph
Pathway B
SO2Ph
H
k3
HO
8
II
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
Tetrahalides via Asymmetric β-Elimination. J. Am. Chem. Soc. 2017, 139,
6431–6436. (i) Zhou, Z.; Wang, Z.-X.; Zhou, Y.-C.; Xiao, W.; Ouyang,
Q.; Du, W.; Chen, Y.-C. Switchable regioselectivity in amine-catalysed
asymmetric cycloadditions. Nat. Chem. 2017, 9, 590–594.
In conclusion, we have developed
a
diastereo- and
1
2
3
4
5
6
7
8
enantioselective catalytic method which afforded highly poly
chiral axial motifs. The reactions proceeded smoothly under mild
reaction conditions and showed broad substrate scope affording
the desired products containing two to three stereogenic axes in
good yields with excellent diastereo- and enantioselectivities. The
control experiments performed showed that the generation of
tetra-substituted VQM intermediate was the key to the excellent
enantioselectivity. The obtained unique topology may contribute
to the development of new chiral catalysts or ligands. Moreover,
the investigation of the fluorescent properties of these scaffolds is
ongoing in our laboratory.
(3) For selected reviews on atropisomers, see: (a) Bringmann, G.;
Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M.
Atroposelective Synthesis of Axially Chiral Biaryl Compounds. Angew.
Chem., Int. Ed. 2005, 44, 5384–5427. (b) Bringmann, G.; Gulder, T.;
Gulder, T. A. M.; Breuning, M. Atroposelective Total Synthesis of
Axially Chiral Biaryl Natural Products Chem. Rev. 2011, 111, 563–639.
(c) Wencel-Delord, J.; Panossian, A.; Leroux, F. R.; Colobert, F. Recent
advances and new concepts for the synthesis of axially stereoenriched
biaryls. Chem. Soc. Rev. 2015, 44, 3418–3430. (d) Kumarasamy, E.;
Raghunathan, R.; Sibi, M. P.; Sivaguru, J. Nonbiaryl and Heterobiaryl
Atropisomers: Molecular Templates with Promise for Atropselective
Chemical Transformations. Chem. Rev. 2015, 115, 11239–11300. (e)
Zilate, B.; Castrogiovanni, A.; Sparr, C. Catalyst-Controlled
Stereoselective Synthesis of Atropisomers. ACS Catal. 2018, 8, 2981–
2988.
(4) For selected examples on compounds with two or more stereogenic
axes, see: (a) Shibata, T.; Fujimoto, T.; Yokota, K.; Takagi, K. Iridium
Complex-Catalyzed Highly Enantio- and Diastereoselective [2+2+2]
Cycloaddition for the Synthesis of Axially Chiral Teraryl Compounds. J.
Am. Chem. Soc. 2004, 126, 8382–8383. (b) Shibata, T.; Arai, Y.; Takami,
K.; Tsuchikama, K.; Fujimoto, T.; Takebayashi, S.; Takagi, K. Iridium-
Catalyzed Enantioselective [2+2+2] Cycloaddition of Diynes and
Monoalkynes for the Generation of Axial Chiralities. Adv. Synth. Catal.
2006, 348, 2475–2483. (c) Tanaka, K.; Kamisawa, A.; Suda, T.; Noguchi,
K.; Hirano, M. Rh-Catalyzed Synthesis of Helically Chiral and Ladder-
Type Molecules via [2+2+2] and Formal [2+1+2+1] Cycloadditions
Involving C-C Triple Bond Cleavage. J. Am. Chem. Soc. 2007, 129,
12078–12079. (d) Oppenheimer, J.; Hsung, R. P.; Figueroa, R.; Johnson,
W. L. Stereochemical Control of Both C−C and C−N Axial Chirality in
the Synthesis of Chiral N,O-Biaryls. Org. Lett. 2007, 9, 3969–3972. (e)
Suda, T.; Noguchi, K.; Hirano, M.; Tanaka, K. Highly Enantioselective
Synthesis of N,N-Dialkylbenzamides with Aryl-Carbonyl Axial Chirality
by Rhodium-Catalyzed [2+2+2] Cycloaddition. Chem. Eur. J. 2008, 14,
6593–6596. (f) Ogaki, S.; Shibata, Y.; Noguchi, K.; Tanaka, K.
Enantioselective Synthesis of Axially Chiral Hydroxy Carboxylic Acid
Derivatives by Rhodium-Catalyzed [2+2+2] Cycloaddition. J. Org. Chem.
2011, 76, 1926–1929. (g) Barrett, K. T.; Metrano, A. J.; Rablen, P. R.;
Miller, S. J. Spontaneous transfer of chirality in an atropisomerically
enriched two-axis system. Nature 2014, 509, 71–75. (h) Lotter, D.;
Neuburger, M.; Rickhaus, M.; Häussinger, D.; Sparr, C. Stereoselective
Arene-Forming Aldol Condensation: Synthesis of Configurationally
Stable Oligo-1,2-naphthylenes. Angew. Chem., Int. Ed. 2016, 55, 2920–
2923. (i) Lotter, D.; Castrogiovanni, A.; Neuburger, M.; Sparr, C.
Catalyst-Controlled Stereodivergent Synthesis of Atropisomeric Multiaxis
Systems. ACS Cent. Sci. 2018, 4, 656–660.
(5) (a) Kawabata, T.; Yahiro, K.; Fuji, K. Memory of Chirality:
Enantioselective Alkylation Reactions at an Asymmetric Carbon Adjacent
to a Carbonyl Group. J. Am. Chem. Soc. 1991, 113, 9694–9696. (b) Baker,
R. W.; Hambley, T. W.; Turner, P.; Wallace, B. J. Central to axial
chirality transfer via double bond migration: asymmetric synthesis and
determination of the absolute configuration of axially chiral 1-(3’-
indenyl)naphthalenes. Chem. Commun. 1996, 2571–2572. (c) Hattori, T.;
Date, M.; Sakurai, K.; Morohashi, N.; Kosugi, H.; Miyano, S. Highly
stereospecific conversion of C-centrochirality of a 3,4-dihydro-2H-1,1’-
binaphthalen-1-ol into axial chirality of a 3,4-dihydro-1,1’-binaphthalene.
Tetrahedron Lett. 2001, 42, 8035–8038. (d) Feng, J.; Li, B.; He, Y.; Gu, Z.
Enantioselective Synthesis of Atropisomeric Vinyl Arene Compounds by
Palladium Catalysis: A Carbene Strategy. Angew. Chem., Int. Ed. 2016,
55, 2186–2190. (e) Zheng, S.-C.; Wu, S.; Zhou, Q.; Chung, L. W.; Ye, L.;
Tan, B. Organocatalytic atroposelective synthesis of axially chiral
styrenes. Nat. Commun. 2017, 8, 15238. (f) Jolliffe, J. D.; Armstrong, R.
J.; Smith, M. D. Catalytic enantioselective synthesis of atropisomeric
biaryls by a cation-directed O-alkylation. Nat. Chem. 2017, 9, 558–562.
(g) Feng, J.; Li, B.; Jiang, J.; Zhang, M.; Ouyang, W.; Li, C.; Fu, Y.; Gu,
Z. Visible Light Accelerated Vinyl C–H Arylation in Pd-Catalysis:
Application in the Synthesis of ortho Tetra-substituted Vinylarene
Atropisomers. Chinese J. Chem. 2018, 36, 11–14.
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
ASSOCIATED CONTENT
Supporting Information
Experimental procedure and characterization data for all the
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*yhl198151@cqu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This study was supported by the Scientific Research Foundation
of China (Grant 21772018).
REFERENCES
(1) For selected reviews, see: (a) Volla, C. M. R.; Atodiresei, I.;
Rueping, M. Catalytic C-C Bond-Forming Multi-Component Cascade or
Domino Reactions: Pushing the Boundaries of Complexity in Asymmetric
Organocatalysis. Chem. Rev. 2014, 114, 2390–2431. (b) Wang, Y.; Lu, H.;
Xu, P.-F. Asymmetric Catalytic Cascade Reactions for Constructing
Diverse Scaffolds and Complex Molecules. Acc. Chem. Res. 2015, 48,
1832–1844. (c) Desimoni, G.; Faita, G.; Quadrelli, P. Forty Years after
“Heterodiene Syntheses with α,β-Unsaturated Carbonyl Compounds”:
Enantioselective Syntheses of 3,4-Dihydropyran Derivatives. Chem. Rev.
2018, 118, 2080–2248.
(2) For selected examples on contiguous stereocenters, see: (a) Liu, X.;
Fox, J. M. Enantioselective, Facially Selective Carbomagnesation of
Cyclopropenes. J. Am. Chem. Soc. 2006, 128, 5600–5601. (b) Tan, B.;
Shi, Z.; Chua, P. J.; Zhong, G. Control of Four Stereocenters in an
Organocatalytic Domino Double Michael Reaction: Efficient Synthesis of
Multisubstituted Cyclopentanes. Org. Lett. 2008, 10, 3425–3428. (c)
Sparr, C.; Gilmour, R. Cyclopropyl Iminium Activation: Reactivity
Umpolung in Enantioselective Organocatalytic Reaction Design. Angew.
Chem., Int. Ed. 2011, 50, 8391–8395. (d) Dell’Amico, L.; Rassu, G.;
Zambrano, V.; Sartori, A.; Curti, C.; Battistini, L.; Pelosi, G.; Casiraghi,
G.; Zanardi, F. Exploring the Vinylogous Reactivity of Cyclohexenylidene
Malononitriles: Switchable Regioselectivity in the Organocatalytic
Asymmetric Addition to Enals Giving Highly Enantioenriched
Carbabicyclic Structures. J. Am. Chem. Soc. 2014, 136, 11107–11114. (e)
Watson, C. G.; Balanta, A.; Elford, T. G.; Essafi, S.; Harvey, J. N.;
Aggarwal, V. K. Construction of Multiple, Contiguous Quaternary
Stereocenters in Acyclic Molecules by Lithiation-Borylation. J. Am.
Chem. Soc. 2014, 136, 17370–17373. (f) Kiss, E.; Campbell, C. D.;
Driver, R. W.; Jolliffe, J. D.; Lang, R.; Sergeieva, T.; Okovytyy, S.; Paton,
R. S.; Smith, M. D. A Counterion-Directed Approach to the Diels–Alder
Paradigm: Cascade Synthesis of Tricyclic Fused Cyclopropanes. Angew.
Chem., Int. Ed. 2016, 55, 13813–13817. (g) Alam, R.; Diner, C.; Jonker,
S.; Eriksson, L.; Szabó, K. J. Catalytic Asymmetric Allylboration of
Indoles and Dihydroisoquinolines with Allylboronic Acids:
Stereodivergent Synthesis of up to Three Contiguous Stereocenters.
Angew. Chem., Int. Ed. 2016, 55, 14417–14421. (h) Tan, Y.; Luo, S.; Li,
D.; Zhang, N.; Jia, S.; Liu, Y.; Qin, W.; Song, C. E.; Yan, H.
Enantioselective Synthesis of anti-syn-Trihalides and anti-syn-anti-
(6) For selected reviews, see: (a) Flynn, A. B.; Ogilvie, W. W.
Stereocontrolled Synthesis of Tetrasubstituted Olefins. Chem. Rev. 2007,
107, 4698–4745. (b) Negishi, E.; Huang, Z.; Wang, G.; Mohan, S.; Wang,
C.; Hattori, H. Recent Advances in Efficient and Selective Synthesis of
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
Di-, Tri-, and Tetrasubstituted Alkenes via Pd-Catalyzed Alkenylation-
Yuan, Y.; Jiang, K.; Liu, T.-Y.; Chen, Y.-C. Enantioselective [4+1]
Annulation Reactions of α-Substituted Ammonium Ylides To Construct
Spirocyclic Oxindoles. J. Am. Chem. Soc. 2015, 137, 9390–9399. (g) Sim,
J. H.; Song, C. E. Water-Enabled Catalytic Asymmetric Michael
Reactions of Unreactive Nitroalkenes: One-Pot Synthesis of Chiral
GABA-Analogs with All-Carbon Quaternary Stereogenic Centers. Angew.
Chem., Int. Ed. 2017, 56, 1835–1839.
(10) (a) Malerich, J. P.; Hagihara, K.; Rawal, V. H. Chiral Squaramide
Derivatives are Excellent Hydrogen Bond Donor Catalysts. J. Am. Chem.
Soc. 2008, 130, 14416–14417. (b) Chauhan, P.; Mahajan, S.; Kaya, U.;
Hack, D.; Enders, D. Bifunctional Amine-Squaramides: Powerful
Hydrogen-Bonding Organocatalysts for Asymmetric Domino/Cascade
Reactions. Adv. Synth. Catal. 2015, 357, 253–281. (c) Held, F. E.;
Tsogoeva, S. B. Asymmetric cycloaddition reactions catalyzed by
bifunctional thiourea and squaramide organocatalysts: recent advances.
Catal. Sci. Technol. 2016, 6, 645–667.
Carbonyl Olefination Synergy. Acc. Chem. Res. 2008, 41, 1474–1485. (c)
Barczak, N. T.; Rooke, D. A.; Menard, Z. A.; Ferreira, E. M.
Stereoselective Synthesis of Tetrasubstituted Olefins through a Halogen-
Induced 1,2-Silyl Migration. Angew. Chem., Int. Ed. 2013, 52, 7579–7582.
(d) Xue, F.; Zhao, J.; Hor, T. S. A.; Hayashi, T. Nickel-Catalyzed Three-
Component Domino Reactions of Aryl Grignard Reagents, Alkynes, and
Aryl Halides Producing Tetrasubstituted Alkenes. J. Am. Chem. Soc.
2015, 137, 3189–3192. (e) Dai, J.; Wang, M.; Chai, G.; Fu, C.; Ma, S. A
Practical Solution to Stereodefined Tetrasubstituted Olefins. J. Am. Chem.
Soc. 2016, 138, 2532–2535. (f) Iwamoto, T.; Nishikori, T.; Nakagawa, N.;
Takaya, H.; Nakamura, M. Iron-Catalyzed anti-Selective Carbosilylation
of Internal Alkynes. Angew. Chem., Int. Ed. 2017, 56, 13298–13301. (g)
Barrado, A. G.; Zieliński, A.; Goddard, R.; Alcarazo, M. Regio- and
Stereoselective Chlorocyanation of Alkynes. Angew. Chem., Int. Ed. 2017,
56, 13401–13405.
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) (a) Doria, F.; Percivalle, C.; Freccero, M. Vinylidene-Quinone
Methides, Photochemical Generation and β-Silicon Effect on Reactivity. J.
Org. Chem. 2012, 77, 3615–3619. (b) Furusawa, M.; Arita, K.; Imahori,
T.; Igawa, K.; Tomooka, K.; Irie, R. Base-catalyzed Schmittel
cycloisomerization of o-phenylenediyne-linked bis(arenol)s to indeno[1,2-
c]chromenes. Tetrahedron Lett. 2013, 54, 7107–7110. (c) Wu, X.; Xue,
L.; Li, D.; Jia, S.; Ao, J.; Deng, J.; Yan, H. Organocatalytic Intramolecular
[4+2] Cycloaddition between In Situ Generated Vinylidene ortho-Quinone
Methides and Benzofurans. Angew. Chem., Int. Ed. 2017, 56, 13722–
13726. (d) Beppu, S.; Arae, S.; Furusawa, M.; Arita, K.; Fujimoto, H.;
Sumimoto, M.; Imahori, T.; Igawa, K.; Tomooka, K.; Irie, R.
Stereoselective Intramolecular Dearomatizative [4+2] Cycloaddition of
Linked Ethynylnaphthol–Benzofuran Systems. Eur. J. Org. Chem. 2017,
2017, 6914–6918. (e) Liu, Y.; Wu, X.; Li, S.; Xue, L.; Shan, C.; Zhao, Z.;
Yan, H. Organocatalytic Atroposelective Intramolecular [4+2]
Cycloaddition: Synthesis of Axially Chiral Heterobiaryls. Angew. Chem.,
Int. Ed. 2018, 57, 6491–6495. (f) Jia, S.; Chen, Z.; Zhang, N.; Tan, Y.;
Liu, Y.; Deng, J.; Yan, H. Organocatalytic Enantioselective Construction
of Axially Chiral Sulfone-Containing Styrenes. J. Am. Chem. Soc. 2018,
140, 7056–7060. (g) Arae, S.; Beppu, S.; Kawatsu, T.; Igawa, K.;
Tomooka, K.; Irie, R. Asymmetric Synthesis of Axially Chiral
Benzocarbazole Derivatives Based on Catalytic Enantioselective
Hydroarylation of Alkynes. Org. Lett. 2018, 20, 4796–4800. (h) Li, D.;
Tan, Y.; Peng, L.; Li, S.; Zhang, N.; Liu, Y.; Yan, H. Asymmetric
Mannich Reaction and Construction of Axially Chiral Sulfone-Containing
Styrenes in One Pot from α-Amido Sulfones Based on the Waste–Reuse
Strategy. Org. Lett. 2018, 20, 4959–4963.
(8) (a) Lü, B.; Jiang, X.; Fu, C.; Ma, S. Highly Regio- and
Stereoselective Cyclic Iodoetherification of 4,5-Alkadienols. An Efficient
Preparation of 2-(1’(Z)-Iodoalkenyl)tetrahydrofurans. J. Org. Chem. 2009,
74, 438–441. (b) Pradal, A.; Nasr, A.; Toullec, P. Y.; Michelet, V. Room-
Temperature
Metal-Free
Electrophilic
5-endo-Selective
Iodocarbocyclization of 1,5-Enynes. Org. Lett. 2010, 12, 5222–5225. (c)
Dobish, M. C.; Johnston, J. N. Achiral Counterion Control of
Enantioselectivity in a Brønsted Acid-Catalyzed Iodolactonization. J. Am.
Chem. Soc. 2012, 134, 6068–6071. (d) Okamoto, N.; Sueda, T.; Minami,
H.; Miwa, Y.; Yanada, R. Regioselective Iodoazidation of Alkynes:
Synthesis of α,α-Diazidoketones. Org. Lett. 2015, 17, 1336–1339. (e)
Grandclaudon, C.; Michelet, V.; Toullec, P. Y. Synthesis of
Polysubstituted 2-Iodoindenes via Iodonium-Induced Cyclization of
Arylallenes. Org. Lett. 2016, 18, 676–679. (f) Ni, S.; Sha, W.; Zhang, L.;
Xie, C.; Mei, H.; Han, J.; Pan, Y. N-Iodosuccinimide-Promoted Cascade
Trifunctionalization of Alkynoates: Access to 1,1-Diiodoalkenes. Org.
Lett. 2016, 18, 712–715. (g) Pan, R.; Hu, L.; Han, C.; Lin, A.; Yao, H.
Cascade Radical 1,6-Addition/Cyclization of para-Quinone Methides:
Leading to Spiro[4.5]deca-6,9-dien-8-ones. Org. Lett. 2018, 20, 1974–
1977.
(9) For selected reviews and book on organocatalysis, see: (a) Tian, S.-
K.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Asymmetric
Organic Catalysis with Modified Cinchona Alkaloids. Acc. Chem. Res.
2004, 37, 621–631. (b) Doyle, A. G.; Jacobsen, E. N. Small-Molecule H-
Bond Donors in Asymmetric Catalysis. Chem. Rev. 2007, 107, 5713–
5743. (c) MacMillan, D. W. C. The advent and development of
organocatalysis. Nature 2008, 455, 304–308. (d) Cinchona Alkaloids in
Synthesis and Catalysis: Ligands, Immobilization and Organocatalysis;
Song, C. E., Ed.; Wiley-VCH: Weinheim, Germany, 2009. For selected
examples, see: (e) Lifchits, O.; Reisinger, C. M.; List, B. Catalytic
Asymmetric Epoxidation of α-Branched Enals. J. Am. Chem. Soc. 2010,
132, 10227–10229. (f) Zheng, P.-F.; Ouyang, Q.; Niu, S.-L.; Shuai, L.;
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
1
2
3
Tetra-substutited VQM
intermediate
4
5
6
X
7
8
O
Y
X
9
OH
OH
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
 Mild reaction conditions
 Up to 98% ee, E/Z > 20, >20:1 dr
 Up to 3 stereogenic axes in one single molecule
 Different types of stereogenic axes in one single molecular
ACS Paragon Plus Environment