Organocatalytic Asymmetric Atroposelective Construction of Axially Chiral 1,4-Distyrene 2,3-Naphthalene Diols

Article abstract of DOI:10.1021/acs.orglett.8b03398

An efficient organocatalytic construction of enantioenriched axially chiral 1,4-distyrene 2,3-naphthalene diols through the nucleophilic addition of α-amido sulfone to in situ generated vinylidene o-quinone methide is described. The reaction pathway was investigated by isolating reaction intermediates and performing a kinetic resolution process. Axially chiral 1,4-distyrene 2,3-naphthalene diol was used as the chiral ligand for the enantioselective addition of diethylzinc to naphthalene formaldehyde. The preliminary results revealed that these adducts could be potentially used as ligands in asymmetric synthesis.

Full text of DOI:10.1021/acs.orglett.8b03398

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Organocatalytic Asymmetric Atroposelective Construction of Axially
Chiral 1,4-Distyrene 2,3-Naphthalene Diols
Shan Li, Da Xu, Fangli Hu, Dongmei Li, Wenling Qin, and Hailong Yan*
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing
University, Chongqing 401331, P. R. China
*
S Supporting Information
ABSTRACT: An efficient organocatalytic construction of enantioenriched axially chiral 1,4-distyrene 2,3-naphthalene diols
through the nucleophilic addition of α-amido sulfone to in situ generated vinylidene o-quinone methide is described. The
reaction pathway was investigated by isolating reaction intermediates and performing a kinetic resolution process. Axially chiral
1
,4-distyrene 2,3-naphthalene diol was used as the chiral ligand for the enantioselective addition of diethylzinc to naphthalene
formaldehyde. The preliminary results revealed that these adducts could be potentially used as ligands in asymmetric synthesis.
iols are prominent feature of a number of biologically
Scheme 1. Reported C -Symmetric Axis Diols and This
Work
2
D
active natural products such as Taxol, isolobophytolide,
1
and TAN-1085. In addition, chiral diols are also widely used
as chiral ligands and auxiliaries in stereoselective synthesis such
as cyclohexyl glycol, hydrobenzoin, and axially chiral diaryl
2
diols. As a result, synthetic approaches toward the
construction of these scaffolds have attracted considerable
attention, and many practical methods have already been
3
achieved. The chiral diols commonly used as catalysts or
ligands are C -symmetric diols that bear two hydroxyl groups
2
in a tunable dihedral angle to meet the coordination
requirements and one rigid C -symmetric axis to play a
2
fundamental cooperative role in the stereochemical control
4
(
Scheme 1a). To our knowledge, chiral diols bearing two
hydroxyl groups in a single plane (no angle) along with two
chiral axes remain largely unaddressed, probably due to a lack
of reliable synthetic routes to atroposelectively construct two
contiguous enantioenriched chiral axes. Therefore, it is
necessary to develop a synthetic approach to construct two
chiral axes surrounding the diols to afford novel axial chirality
compounds.
In order to develop new and practical organocatalytic
atroposelective methods for the preparation of highly function-
alized axially chiral styrene, we envisaged that two units of
axially chiral styrene could be installed into the positions 1 and
an operationally simple and scalable fashion. The current
strategies include palladium-catalyzed enantioselective aryla-
6
tion of hydrazones and aryl bromide, organocatalytic
7
atroposelective direct Michael reaction of diones to alkynals,
and organocatalytic nucleophilic addition of the vinylidene o-
8
quinone methide (VQM) intermediate by sulfone. However,
all of the reported methods afforded products bearing only a
single chiral styrene axis. A method for constructing two
continuous chiral styrene axes has not yet been reported. Our
research group has been engaged in developing new and
4
of naphthalene 2,3-diols to accomplish the introduction of
chiral circumvents to vicinal diols. The key to this scenario is
the construction of the axially chiral styrene skeleton, which
represents a formidable challenge in asymmetric synthesis due
to the relatively low-rotation energy to racemization and the
5
difficulty in controlling the enantioselectivity. Consequently,
Received: October 23, 2018
few methods are available for their atroposelective synthesis in
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03398
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
practical methods for the construction of axially chiral
compared to catalyst A. Both catalysts C and D showed
excellent stereoselectivity. Nevertheless, the yields of reactions
catalyzed by thiourea-based catalysts were generally low.
Quinine-derived squaramides, which had a longer distance
between the two donor hydrogen atoms than that of thioureas,
had been successfully employed in a wide range of asymmetric
8c−f
compounds based on VQM intermediate.
We presumed
that two moieties of VQM could be generated in one
naphthalene, followed by a formal stereoselective nucleophilic
addition to install two chiral styrene units. Thus, a new kind of
chiral axis skeleton bearing two continuous chiral styrene axes
arose. Herein, we describe an organocatalytic atroposelective
synthesis of 1,4-distyrene compounds bearing a 2,3-diol motif
allowing the construction of novel axial chiral scaffolds for the
development of chiral ligands or catalysts for asymmetric
synthesis.
Initially, we began our studies with 1,4-bis(phenylethynyl)-
naphthalene 2,3-diol 1a and α-amido sulfone 2a as model
substrates. In the presence of dimeric cinchona alkaloid
derivative catalyst A, the reaction proceeded smoothly with
good yield, while the enantioselectivity (ee = 7%) (Table 1,
9
reactions as hydrogen-bonding donor catalysts. Cinchona
squaramide catalysts E and F gave excellent enantiocontrol and
afforded 3a in higher yields. Eventually, biscinchona
squaramide catalyst F afforded an improved chemical yield
while retaining the stereoselectivity under the same conditions
(88%, ee >99%, dr >20:1) (Table 1, entry 6). All of the
solvents tested for the reaction were catalyzed by catalyst F
(Table 1, entries 6−11), and chloroform was proven to be the
optimal solvent with respect to enantioselectivity and yield
(Table 1, entry 6). Finally, the reaction proceeded smoothly
with retained enantioselectivity by using 10 mol % of catalyst F
in chloroform at 30 °C.
a
Table 1. Optimization of Reaction Conditions
After establishing the optimal catalyst F and experimental
procedure, we expanded 1 toward the nucleophilic addition of
2
a. Substrates with electron-donating groups on the para
position of the R group proceeded smoothly to give the desired
adducts 3b, 3c, and 3d in excellent stereoselectivity (ee up to
9
9%, dr >20:1) with moderate yields. The electron-with-
drawing groups at different positions of R appeared to have a
limited effect on stereoselectivity (3e−i) (Scheme 2). All of
the substrates gave excellent enantioselectivities, and a
significantly lower reaction rate was observed. The absolute
configuration of product 3h was determined by X-ray
crystallographic analysis, while others were assigned by
analogue. The substrate with 5-fluoro-2-methyl-disubstituted
R also afforded the desired product 3j with excellent
stereocontrol (ee >99%) under the standard reaction
conditions, demonstrating that the substrate scope was not
limited to monosubstituted substrates. Changing the phenyl
group into a more useful heterocyclic ring, such as thiophene,
almost had no influence on the reaction stereoselectivity and
still gave excellent results (3k) (Scheme 2). When the
1
2
substrate was asymmetric (R = C H , R = 4-MeOC H ),
6
5
6
4
the reaction also proceeded smoothly to afford the desired
product with good results (3l) (Scheme 2).
b
c
d
entry
catalyst
solvent
yield (%)
ee (%)
dr
1
2
3
4
5
6
7
8
9
A
B
C
D
E
F
F
F
F
F
F
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH Cl
85
30
36
50
75
88
77
79
72
<5
<5
7
90
1:1
1:1
10:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
To further evaluate the substrate scope, we then investigated
a series of substitution groups on the sulfone moiety of α-
amido sulfones. The results are outlined in Scheme 3.
Regardless of the type of substituents on the aromatic rings
of sulfone, bearing electron-donating (3m) (Scheme 3) or
electron-withdrawing (3n−p) (Scheme 3) groups on the para
position, the reactions of these α-amido sulfones gave axially
chiral distyrene diols with high stereoselectivities and good
reactivities. Notably, 3-chloro-4-methyl-disubstituted α-amido
sulfone also led to the desired adduct with excellent
stereoselectivity and good yield (3q) (Scheme 3). An aliphatic
substitution group on the sulfone moiety also is tolerated to
our reaction system. A high enantioselectivity of 99% ee was
also obtained, although the diastereoselectivity and chemical
yield were decreased.
>−99
>99
>99
>99
>99
>99
99
2
2
toluene
CH CN
3
1
1
0
1
Et O
2
THF
a
Reaction conditions: 1a (0.05 mmol), 2a (0.1 mmol), catalyst (10
mol %) in solvent (1.0 mL) at 30 °C for 24 h, unless otherwise
specified. Isolated yield. The ee value was determined by HPLC
b
c
d
1
analysis. Diastereomeric ratio (dr) was determined by H NMR.
In order to gain insight into the reaction process, we
performed an experiment to monitor the reaction with thin-
layer chromatography (TLC). We found that, at an early stage
of the reaction, two new spots appeared simultaneously. At the
beginning of the reaction, intermediate (S)-3aa with high
enantioselectivity (ee = 97%) was isolated, and product (S,S)-
3a was also formed with excellent enantioselectivity (ee >99%)
entry 1) and diastereoselectivity were quite poor (Table 1,
entry 1). This might be ascribed to a lack of hydrogen-bonding
donors. Therefore, we turned our attention to cinchona-
derived catalysts with hydrogen-bonding donors. Thiourea-
based catalysts B−D were selected for further screening. The
enantioselectivities of the reactions were dramatically increased
B
DOI: 10.1021/acs.orglett.8b03398
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. Substrate Scope
Scheme 3. Substrate Scope
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), F (10 mol %) in
CHCl (2.0 mL) at 30 °C for 24 h, unless otherwise specified.
3
a
Scheme 4. Mechanistic Experiments
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), F (10 mol %) in
CHCl (2.0 mL) at 30 °C for 24 h, unless otherwise specified.
3
(Scheme 4a). In the later stage, the reaction experienced a
change in two different trends. The intermediate (S)-3aa
disappeared with the increase in final product (S,S)-3a. To
further understand the reaction process of the second step, we
performed a kinetic resolution reaction with racemic (±)-3aa
as substrate. As shown in Scheme 4b, the racemic (±)-3aa was
treated with 0.5 equiv of 2a under the standard reaction
conditions. After 40 min, optically pure (S,S)-3a (ee = 94%)
was successfully formed. The s value of this kinetic resolution
process was 50 (see the Supporting Information (SI) for
details). This observation indicated that this reaction could be
explored as a kinetic resolution process. Our catalytic system
has a strong stereocontrol even in the second reaction step.
Mechanistically, we assume a stepwise process initiated by a
conjugate addition of the in situ generated sulfone anion to the
VQM which is generated through an enantioselective
prototropic rearrangement (tautomerization) in the presence
of quinine-derived squaramide catalyst F (Scheme 5). The
activation of the α-amido sulfone with quinine-derived
squaramide catalyst F appears necessary for increasing its
nucleophilicity and facilitating the conjugate addition. Next,
repeating the above-mentioned reaction pathway gives the final
product (S,S)-3a with excellent enantioselectivity.
a
For reaction conditions, see the SI. The ee value was determined by
HPLC analysis.
Additionally, to further demonstrate the utility of the
obtained chiral 1,4-distyrene 2,3-naphthalene diols in syn-
thesis, especially used as organocatalysts or ligands, we first
performed a scaled-up experiment (see the SI for details). The
reaction proceeded smoothly to give the product on gram scale
without the loss of stereoselectivity and yield. Next, we tested
the configurational stability of the product by heating a
solution of (S,S)-3a in DCE at 80 °C for 24 h. Chiral HPLC
analysis showed that the ee was unaffected (see the SI for
details). Thus, we further investigated the obtained chiral 1,4-
distyrene 2,3-naphthalene diol (S,S)-3a as a ligand for the
enantioselective addition of diethylzinc to naphthalene form-
aldehyde, which was considered to be one of standard
reactions to test the reactivity and enantioselectivity of newly
10
designed chiral ligands. As a result, product (S,S)-3a showed
C
DOI: 10.1021/acs.orglett.8b03398
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Proposed Mechanism
Accession Codes
CCDC 1864091 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: yhl198151@cqu.edu.cn.
ORCID
Hailong Yan: 0000-0003-3378-0237
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was supported by the Scientific Research
Foundation of China (Grant No. 21772018) and the
Chongqing Science and Technology Commission
(
cstc2017jcyjAX0389).
the role as ligand in this reaction and gave chiral sec-alcohols
with an enantiomeric excess of 27% under unmodified reaction
conditions (Scheme 6).
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