Enantiopure (P)- and (M)-3,14-bis(o-hydroxyaryl)tetrahydrobenzo[5]helicenediols and their helicene analogues: Synthesis, amplified circularly polarized luminescence and catalytic activity in asymmetric hetero-Diels–Alder reactions

Article abstract of DOI:10.1016/j.tet.2018.10.047

Three pairs of enantiopure (P)- and (M)-3,14-bis(o-hydroxyaryl)tetrahydrobenzo[5]helicenediols (ArOH-H[5]HOLs), and enantiomers (P)- and (M)-3,14-bis(o-hydroxyphenyl)benzo[5]helicene-diols (PhOH-[5]HOLs) were designed and synthesized. It was found that co

Full text of DOI:10.1016/j.tet.2018.10.047

Accepted Manuscript
Enantiopure (P)- and (M)-3,14-bis(o-hydroxyaryl)tetrahydrobenzo[5]helicenediols and
their helicene analogues: Synthesis, amplified circularly polarized luminescence and
catalytic activity in asymmetric hetero-Diels–Alder reactions
Lei Fang, Meng Li, Wei-Bin Lin, Chuan-Feng Chen
PII:
S0040-4020(18)31269-9
https://doi.org/10.1016/j.tet.2018.10.047
TET 29880
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 8 September 2018
Revised Date: 17 October 2018
Accepted Date: 19 October 2018
Please cite this article as: Fang L, Li M, Lin W-B, Chen C-F, Enantiopure (P)- and (M)-3,14-bis(o-
hydroxyaryl)tetrahydrobenzo[5]helicenediols and their helicene analogues: Synthesis, amplified
circularly polarized luminescence and catalytic activity in asymmetric hetero-Diels–Alder reactions,
Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.10.047.
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Enantiopure (P)- and (M)-3,14-bis(o-
hydroxyaryl)tetrahydrobenzo[5]helicenediols
and their helicene analogues: synthesis,
amplified circularly polarized luminescence
and catalytic activity in asymmetric hetero-
Diels–Alder reactions
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Lei Fang,a,b Meng Li,*,a Wei-Bin Lina,b and Chuan-Feng Chen*,a,b
a Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and
Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
b University of Chinese Academy of Sciences, Beijing 100049, China

1
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Tetrahedron
journal homepage: www.elsevier.com
Enantiopure (P)- and (M)-3,14-bis(o-hydroxyaryl)tetrahydrobenzo[5]helicenediols
and their helicene analogues: synthesis, amplified circularly polarized luminescence
and catalytic activity in asymmetric hetero-Diels–Alder reactions
Lei Fang,a,b Meng Li,*,a Wei-Bin Lina,b and Chuan-Feng Chen*,a,b
a
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China.
b University of Chinese Academy of Sciences, Beijing 100049, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Three pairs of enantiopure (P)- and (M)-3,14-bis(o-hydroxyaryl)tetrahydrobenzo[5]helicenediols
(ArOH-H[5]HOLs), and enantiomers (P)- and (M)-3,14-bis(o-hydroxyphenyl)benzo[5]helicene-
diols (PhOH-[5]HOLs) were designed and synthesized. It was found that compared with ArOH-
H[5]HOLs, PhOH-[5]HOLs not only showed obvious red-shifts in both absorption and emission
spectra, but also exhibited more intense CPL with amplified glum, which might be attributed to
the more rigid structure of PhOH-[5]HOLs. However, rigid PhOH-[5]HOLs was less e ective in
the catalytic asymmetric hetero-Diels–Alder (HAD) reactions than those of ArOH-H[5]HOLs
with the flexible tetrahydro[5]helicene backbone that could adjust conformation to suit the
substrates. Therefore, the helical chirality amplification and chirality transfer could be efficiently
achieved by adjusting the rigid and flexible structures of helical molecules, which might provide
a useful strategy to optimize the structure of helicence derivatives for their applications in
chiroptical materials and asymmetric catalysis.
Available online
eywords:
helicenediol
asymmetric catalysis
hetero-Diels–Alder reaction
amplified CPL
2018 Elsevier Ltd. All rights reserved
.
1. Introduction
and IR are the intensity of the left- and right-handed circularly
polarized emissions, respectively [19]. However, the general
method to obtain higher glum was based on the supramolecular
assembly of chiral organic molecules [20-24]. The reports about
utilizing structural adjustment to increase glum, especially for the
Helicences, a kind of π conjugated compounds with helical
structure, were composed of ortho-fused polycyclic aromatic
rings [1]. Helicenes and their analogues could be not only applied
in a broad range of functional material fields as a result of their
expanded π conjugated systems and excellent chiral optical
properties [2-8], but also used as asymmetric catalysts due to
their helical chirality [9,10]. However, convenient synthesis of
multifunctional helicenes and their analogues is a challenge [11].
To improve performance, multifunctional helical molecules could
be obtained by introducing functional groups to the precursors.
Thus, rational design of the structure of helicenes and their
analogues to optimize their properties and functions was still an
attractive task.
Helicenes and their analogues were good chromophores as
well as important small organic molecules with CPL properties
due to their helical π conjugated skeleton [12-18]. For CPL
organic materials,
luminescence dissymmetry factor (glum), which is used to
evaluate the level of CPL, glum = 2 × (IL − IR)/(IL + IR), where IL
helical molecules, were very limited. Therefore,
a deep
understanding of the relationship between rigid-flexible
molecular structure and glum was particularly significant for the
rational design of CPL organic molecules with high glum
.
Since the pioneered work reported by Reetz et al. in 1997
[25], many helical catalysts have been reported with different
functional groups. Compared with helical catalysis with
phosphine groups [26-40] and nitrogenous groups [41-48], the
research about hydroxyl-functional helical catalysts [49] was
relatively lacking. However, other chiral hydroxy-functional
catalysts, such as BINOL and VAPOL, exhibited efficient
catalytic activity in many asymmetric catalysis reactions [50,51].
We envisaged that helical structure could be a suitable skeleton
to construct a chiral environment efficiently around hydroxyl
functional groups, which would make the helicenoidal phenolic
catalysts be a fascinating study direction.
a key goal is to achieve their high
Corresponding author. fax: +86-10-62554449; e-mail: cchen@iccas.ac.cn; limeng@iccas.ac.cn

2
Tetrahedron Letters
ACCEPTED MANUSCRIPT
To evaluate the relationship between the rigid-flexible
structures and the chiroptical properties as well as catalytic
activities, the enantiomers with different rigid or flexible helical
skeletons were designed (Fig. 1). Inspired by the structure of
BINOL, we introduced the hydroxyl groups into the helical
skeletons to construct the tetrahydrobenzo[5]helicenediol
derivatives which were supposed to achieve better catalytic
activity. Moreover, the more rigid benzo[5]helicenediol
derivatives with a helicene core were also synthesized to
optimize the chiroptical properties. Herein, we report the
synthesis of a series of ArOH-H[5]HOLs (P)-/(M)-3a-c with
flexible tetrahydro[5]helicene backbone and ArOH-[5]HOLs (P)-
/(M)-3d with rigid [5]helicene backbone by
a
post-
functionalization strategy. The photophysical and chiroptical
properties of 3a-d were investigated by UV/Vis, fluorescence,
CD, and CPL spectra. It was found that compared with (P)-3a-c,
(P)-3d with more rigid structure showed not only red-shifts in
both absorption and emission spectra, but also more intense CPL
with amplified glum. Conversely, it was also found that ArOH-
H[5]HOLs 3a-c with more flexible hydrogenated [5]helicene
backbone showed better catalytic activity than the [5]helicene
derivative 3d in the catalytic asymmetric HDA reactions. These
results indicated that the amplified CPL properties and efficient
catalytic activity of the helicene derivatives could be achieved by
regulating their rigid-flexible structures.
Scheme 1. Synthesis of enantiomers (P)-3a-c and (M)-3a-c.
For a comparison, enantiotopic benzo[5]helicene derivative
PhOH-[5]HOL was also synthesized. As shown in Scheme 2,
(P)-3d and (M)-3d could be obtained by the oxidation of MOM-
protected tetrahydrobenzo[5]helicene 5 with DDQ, and then
followed by their Suzuki-Miyaura cross-coupling reactions with
o-hydroxyphenylboronic acid, and the deprotected reactions. The
specific rotations ([α]D25 in DCM, c = 1.0 mg mL-1) of enantiopure
compounds (P)-3d and (M)-3d were +1032° and –1056°,
respectively, which were larger than those of (P)-3a and (M)-3a
with a tetrahydro[5]helicene structure.
Fig. 1. Design of the enantiomers with different rigid or flexible helical
skeletons.
2. Results and discussions
2.1 Synthesis of (P)-3a-d and (M)-3a-d.
The synthetic routes to (P)-3a-c and (M)-3a-c are shown in
Scheme 1. Starting from the enantiopure Br-H[5]HOL (P)-4 and
(M)-4 [3], ArOH-H[5]HOLs (P)-3a-c and (M)-3a-c could be
conveniently obtained in good yields by Suzuki-Miyaura cross-
coupling reaction, respectively. Specific optical rotations of the
enantiomeric tetrahydro-benzo[5]helicenes were measured in
dichloromethane (DCM), and the enantiomers all showed
specific optical rotations of about ±500°. The reaction process
does not lead to the racemization of the products and helical
tetraols (P)- and (M)-3a-c was identified as enantiomerically pure
products by HPLC (ee >99%, Fig. S45-S50, ESI†).
Scheme 2. Synthesis of enantiomers (P)-3d and (M)-3d.
2.2 Photophysical and chiroptical properties of (P)-3a-d and
(M)-3a-d.
The UV-vis and fluorescence spectra of enantiomers (P)-3a
and (M)-3a were identical (Fig. S1). Therefore, (P)-3a-d were
then used to investigate their photophysical properties, and the
results were summarized in Table 1. It was found that although
(P)-3a-c had different substituted-hydroxyphenyl functional
groups at 3,14-positions, no obvious changes of the maximum
absorption wavelength for (P)-3a-c were observed in DCM with
the absorption maxima at about 310 nm (Fig. S2 and Table 1).
However, compared with tetrahydro[5]helicene analogue (P)-3a,
the enantiotopic helicenoidal tetraols (P)-3d exhibited obvious
red-shift in both absorption and emission spectra. (P)-3d
exhibited the maximum absorption bands at 330 nm with large
molar absorptivity (log ε = 4.71), which was 25 nm red-shift
compared with that of (P)-3a. Moreover, (P)-3a-c all showed a
red shift of emission maxima compared with (P)-4, and exhibited

3
almost the same emission spectra at about 425 nm with large
ACCEPTED MANUSCRIPT
stokes shifts. Compared with (P)-3a, the emission spectrum of
(P)-3d exhibited further 31 nm red-shift with stokes shift up to
125 nm (Fig. 2 and Table 1). The fluorescence quantum yields of
compounds (P)-3a-c were all larger than 0.30, with the highest
one up to 0.41 of (P)-3c in DCM upon excitation at the
maximum absorption wavelength. For (P)-3d, its fluorescence
quantum yield was 0.19. The partially quenched fluorescence of
(P)-3d might indicate the enhanced π-π stacking interaction and
more intense intermolecular electron transfer of the helicene
derivatives [52].
(a) 100
(
(
(
P
P
P
)
)
)
-
-
-
3a
3b
3c
50
0
-50
(
(
(
M
M
M
)
)
)
-3a
-
-
3b
3c
1.2
-100
(P
(P
(P
(P
(P
)-3a
)-3b
)-3c
)-3d
)-4
250
300
350
400
1.0
0.8
0.6
0.4
0.2
0.0
Wavelength (nm)
(b)
(P)-3d
(M)-3d
100
50
0
-50
-100
350
400
450
500
550
600
Wavelength (nm)
Fig. 2 Fluorescence spectra (excited at corresponding λabs,max) of (P)-3a-d
and (P)-4 in DCM (c = 1.0 ×10-5 M).
250
300
350
400
450
Wavelength (nm)
Table 1. Photophysical properties of (P)-3a-d
Fig. 3 (a) CD spectra of (P)-3a-c and (M)-3a-c in DCM (c = 8.0 ×10-5
M); and (b) CD spectra of (P)-3d and (M)-3d in DCM (c = 8.0 ×10-5 M).
λabs
(nm)b
Compounda
log
ε
ꢀλstokes
(nm)e
λem (nm)c Φf (%)d
(M-1 cm-1)
(P)-3a
(P)-3b
(P)-3c
(P)-3d
305
4.74
424
425
425
455
32.6
41.0
39.1
18.7
119
115
124
125
As shown in Fig. 4a, it was further found the enantiomers 3a-c
showed CPL signals, matching with the region of emission
spectra. It was noteworthy that the enantiomers exhibited glum
with values of –2.5×10-4 to –4.1×10-4 for the P configuration
enantiomers and +2.6×10-4 to +4.2×10-4 for M configuration
enantiomers, respectively (Table S2, ESI†). These indicated that
the chirality also existed in excited states of enantiomers 3a-c.
Similarly, Fig. 4b showed the mirror-imaged CPL spectra of (P)-
3d and (M)-3d in DCM. Interestingly, it was found that (P)-3d
and (M)-3d exhibited CPL emissions with glum of –4.52×10-3 and
+4.43×10-3 at 455 nm, respectively. The glum value of which were
20-fold larger than that of PhOH-H[5]HOL (Fig. 4c), which
might be attributed to its rigid helical structures that could
remained the chirality effectively in the excited states. The results
indicated that the CPL amplification can be achieved successfully
by the strategy of improving the helical molecular rigidity.
310
4.73
4.74
4.71
301
330
a All spectra were recorded in DCM (c = 1.0×10-5 M).
b The maximum absorption bands.
c Excited at the maxima absorption.
d Absolute fluorescence quantum yield.
e Stokes shift =λem − λmax,abs
.
Moreover, it was found that (P)-3a-c and (M)-3a-c exhibited
mirror images of CD and CPL spectra in DCM. All of the
enantiomers showed similar Cotton effects (Fig. 3a), by virtue of
the same helical backbones, with strong Cotton effects at about
330 nm, in which the negative signals for (P)-3a-c and the
positive signals for (M)-3a-c were found. The absorption
dissymmetry factors (gabs) were –4.7×10-4 to –8.3×10-4 for the P
configuration enantiomers, and +4.9×10-4 to +8.7×10-4 for the M
configuration enantiomers, respectively (Table S1, ESI†).
Meanwhile, Fig. 3b showed the mirror-imaged CD spectra of
(P)-3d and (M)-3d in DCM. The gabs value of (P)-3d and (M)-3d
were –3.28×10-4 and +3.57×10-4 at 425 nm, respectively, which
were similar to their tetrahydro[5]helicene analogues.

4
Tetrahedron Letters
H[5]HOL (P)-3a was used as ligand in the presence of Ti(OiPr)4
ACCEPTED MANUSCRIPT
for the HDA reaction, it was found that product 8a could be
10
8
obtained in 68% yield and 23% ee (Table 2, entry 2). We also
tested the HDA reaction with the 2,2’-biphenol 2 as ligand, and
found that racemic product 8a was only obtained in 26% yield
(Table 2, entry 3). These results indicated that the
enantioselectivity of the product with PhOH-H[5]HOL (P)-3a as
ligand was derived from the chirality of helical skeleton.
(
(
(
P
P
P
)
)
)
-3a
-3b
-3c
6
4
2
0
-2
-4
-6
-8
-10
Table 2. Ligands screening for the enantioselective HDA reaction of
Danishefsky’s diene 6 and benzaldehyde 7aa
(
(
(
M
M
M
)
)
)
-3a
-3b
-3c
400
450
500
550
Wavelength (nm)
100
80
(P)-3d
(M)-3d
(P)-3a
(M)-3a
60
40
20
0
-20
-40
-60
-80
-100
Lewis
acid
entry Ligand
solvent yield (%)b ee (%)c
1
2
3
(P)-4
(P)-3a
2
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
toluene
toluene
toluene
23
68
26
0
23
0
400
450
500
550
600
Wavelength (nm)
a All reactions were carried out at 0 °C using 10 mol % of ligand. The
ratio of Ti(OiPr)4 and ligand is 2:1. The reaction time was 24 h.
b All yields are isolated yields.
0.006
0.005
0.004
0.003
0.002
0.001
0.000
(M)-3a
(M)-3d
c Absolute configurations were R, which determined in all cases ee was
determined by HPLC using a chiral column (Chiracel OD-H).
Besides Ti(OiPr)4, other Lewis acids were also screened for
the (P)-3a catalytic asymmetric HDA reaction of benzaldehyde
7a with Danishefsky’s diene 6, and the results are shown in Table
3. It was found that butyl magnesium as the Lewis acid decreased
the yield and the enantioselectivity (Table 3, entry 2). With
trimethylaluminum as the lewis acid, a dramatic improvement in
yield (82%) was observed but the enantioselectivity (7%) was
poor (Table 3, entry 3). Taking both enantioselectivity and yield
into account, Ti(OiPr)4 was chosen as Lewis acid for the catalytic
asymmetric HDA reaction.
The effect of the molar ratio of Ti(OiPr)4 to (P)-3a on the
enantioselectivity was examined as well. Stoichiometry ratio of
(P)-3a/Ti was tested from 1:1 to 1:6, the enantioselectivity
showed appreciably variation with stoichiometry of Ti(OiPr)4.
When the molar ratio of Ti(OiPr)4 to (P)-3a was 4:1, the best
result of 75% yield and 47% ee was achieved (Table 3, entries 1,
4-8). More Ti(OiPr)4 would lead to a decline in enantioselectivity
as a result of background reaction.
Different solvents under 1:4 stoichiometry of (P)-3a/Ti were
also screened, which revealed a dramatic solvent effect (Table 3,
entries 9-11). It was found toluene was more favorable than other
solvents in the Ti(IV)-ArOH-H[5]HOL catalyzed HDA reaction.
Reactions with dichloromethane, ether, or dioxane as solvent all
gave very low yield as well as poor enantiomeric excess of the
product.
We further studied the effect of the amount of catalyst on the
HDA reaction. It was found that there was a small decline in the
enantioselectivity and yield when the amount of (P)-3a was
increased to 20 mol % or more, which might be due to poor
400
425
450
475
500
Wavelength (nm)
Fig. 4 (a) Mirror image CPL spectra of (P)- and (M)-3a-c in DCM; (b)
mirror image CPL spectra of (P)- and (M)-3a and 3d in DCM; (c)
dissymmetry factor glum versus wavelength of (M)-3a and (M)-3d in
DCM (c = 8.0×10-5 M).
2.3 Asymmetric catalysis of the helicenoidal tetraols in hetero-
Diels–Alder reactions
In view of the successes achieved with Ti/BINOL [53-58], we
envisaged helicenoidal phenolic compounds could also be used
as asymmetric ligands in HDA reactions. Therefore, we started
the catalytic screening by HDA reaction between Danishefsky’s
diene 6 and benzaldehyde 7a (Table 2). As a comparison, we first
tested the HAD reaction in neat condition with only 10 mol %
Br-H[5]HOL (P)-4 as the catalyst, which gave 8a in 15% yield
and no enantioselectivity (Table S3, entry 1). It was also found
there was no obvious improvement in yield even when the
reaction temperature or solvent was changed (Table S3). By the
combination of (P)-4 and Ti(OiPr)4 in toluene, the reaction yield
could be increased to 23%, but still no enantioselectivity was
shown (Table 2, entry 1). When the post-functionalized PhOH-

5
solubility of the (P)-3a and excessive amount of Lewis acid
causing the background reaction (Table 3, entries 12-13). The
temperature profile of the Ti(IV)-ArOH-H[5]HOL catalytic HAD
reaction was also performed, and it was found that both yield and
enantiomeric excess of the product decreased with increase of the
temperature (Table 3, entries 14-15). The optimal temperature
ACCEPTED MANUSCRIPT
of 0 °C could provide the product of the HDA reaction in 79%
yield and 53% ee when reaction were pre-activated at 110 oC for
1 h. (Table 3, entry 16).
Table 3. Optimization of the catalytic asymmetric HDA reactions of Danishefsky’s diene 6 and benzaldehyde 7aa
entry
1
Lewis acid
Ti(OiPr)4
Bu2Mg
(P)-3a: Ti(OiPr)4
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
temperature
0 oC
0 oC
0 oC
0 oC
0 oC
0 oC
0 oC
0 oC
0 oC
0 oC
0 oC
0 oC
0 oC
r.t.
yield (%)b
68
ee (%)c
23
13
7
1:2
1:2
1:2
1:1
1:3
1:4
1:5
1:6
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
2
15
3
AlMe3
82
4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
42
13
30
47
33
22
20
<1
14
43
38
25
27
53
5
73
6
75
7
72
8
70
9
15
10
11
12d
13e
14
15
16f
dioxane
Et2O
6
21
toluene
toluene
toluene
toluene
toluene
70
62
73
40 oC
0 oC
68
79
a All reactions were carried out at 0 °C. The reaction time was 24 h.
b All yields are isolated yields.
c Absolute configurations were R, which determined in all cases ee was determined by HPLC using a chiral column (Chiracel OD-H).
d The amount of ligand (P)-3a was 20 mol %.
e The amount of ligand (P)-3a was 30 mol %.
f 1:4 stoichiometry of (P)-3a/Ti(OiPr)4 with 4Å molecular sieves in toluene solution were pre-activated at 110 oC for 1 h.
Under the optimal conditions, (P)-3b-d were also examined as
the ligands for the catalytic asymmetric HDA reactions of
benzaldehyde and Danishefsky’s diene. Compared with (P)-3a,
Ti(IV) complexes prepared from (P)-3b and (P)-3c with a
tetrahydro[5]helicene core structure provided the product with
similar yields and enantioselectivities (Table 4, entries 2-3). For
(P)-3d with rigid [5]helicene skeleton, although it could also
display enantiocontrol in the HDA reaction, lower yield and
enantioselectivity than those of (P)-3a-c were obtained (Table 4,
entry 4). Enhanced enantioselective control and reaction rate in
ArOH-H[5]HOL-catalyzed HDA reaction might be attributed to
their flexible backbone which could adjust the conformation of
the helical ligands to adapt to the substrate structures.
electronic effect of the aldehydes on the enantioselectivity was
obvious. It was found the electron-donating substituent showed a
positive effect on the enantioselectivity, while the electron-
withdrawing substituent had a negative influence for both of
meta- and para-substituted benzaldehydes. Under the optimal
conditions, p-methoxybenzaldehyde afforded product 8b in 62%
yield and 43% ee, while p-nitrobenzaldehyde gave product 8f in
44% yield and significantly low enantioselectivity (11% ee).
Similarly, m-methyl substituted benzaldehyde (8g, 58% ee) gave
distinctly higher enantioselectivity than that of m-
nitrobenzaldehyde (8i, 19% ee). These results are agreed with the
previously reports of the Ti(IV)-H8-BINOL catalyzed HDA
reactions.[57] In the cases of heteroaromatic aldehydes, the
obvious electronic effect was also observed. For electron-rich 2-
furaldehyde, product 8j was obtained in a modest yield and
enantioselectivity, whereas electron-withdrawing 3-pyridine-
carboxaldehyde only led to a low enantioselectivity (8k, 14% ee).
After testing the applicability of the Ti(IV)-ArOH-H[5]HOL
catalytic asymmetric HDA reactions, we further paid our
attention to studying the scope of the reactions by utilizing
various functionalized aldehydes. The results indicated the

6
Tetrahedron
ACCEPTED MANUSCRIPT
3. Conclusions
For aliphatic aldehydes, cyclohexylcarboxaldehyde and n-nonyl
aldehyde, very poor enantioselectivities of the products were
obtained.
In conclusion, a series of optically active helicenoidal tetraols
(P)- and (M)-3a-c with flexible tetrahydro[5]helicene core and
enantiomers (P)- and (M)-3d with rigid [5]helicene core were
conveniently synthesized by the post-functionalized strategy.
Compared with 3a-c, the [5]helicene derivative 3d not only
exhibited longer absorption and emission wavelengths, but also
showed one order of magnitude amplification of the dissymmetry
factor glum due to its rigid skeleton. However, it was found that
enantiopure 3a-c with more flexible skeleton were more e ective
in the catalytic asymmetric HDA reactions than 3d with rigid
skeleton, and under the optimal conditions, 3a-c/Ti(OiPr)4 could
catalyze the asymmetric HDA reactions of aromatic aldehydes
and Danishefsky’s diene in up to 79% yields and up to 65% ee.
The results presented in this paper indicated the rigid helical
structure contributed to amplifying CPL, while flexibility was
beneficial to the asymmetric catalysis reaction, which could
render a strategy to design and optimize the helical rigid-flexible
structures to achieve amplified CPL properties and better
catalytic activities.
Table 4. HDA reactions of Danishefsky’s diene 6 and benzaldehyde 7a
catalyzed by Ti(IV)-(P)-3a-da
entry
ligand
(P)-3a
(P)-3b
(P)-3c
(P)-3d
yield (%)b
ee (%)c
53
4. Experimental section
1
2
3
4
79
72
76
60
4.1. General methods
47
All the reagents and solvents were commercially available and
used without further purification. Reactions were carried out
under inert and anhydrous conditions unless otherwise noted. 1H,
13C NMR spectra were recorded on Bruker® Avance 400MHz
and Brucker® AVIII 500 MHz NMR spectrometers in CDCl3
solutions at 298 K and the chemical shifts were reported relative
to internal standard TMS (0 ppm). The UV-vis spectra were
recorded on PerkinElmer® UV/vis/NIR spectrometer (Lambda
950), and the fluorescence spectra were recorded on HITACHI®
F-7000 Fluorescence Spectrometer at room temperature in DCM,
using 10mm cells and concentrations of 1×10-5 M. Absolute
fluorescence quantum yield, measured by Edinburgh instruments
(FLS980). CD spectra were recorded on a JASCO J810
spectropolarimeter at room temperature in DCM. During the
measurement, the instrument was thoroughly purged with
nitrogen. CPL spectra were performed with a JASCO CPL-200
spectrometer at room temperature. The optical rotation was
determined by Rudolph Autopol VI Automatic polarimeter. All
the melting points were not calibrated and determined on YuHua
X-5 digital melting point apparatus. High resolution mass spectra
were obtained on the Thermo Fisher® Exactive high-resolution
LC-MS spectrometer. HPLC analysis were performed on Agilent
1260 Infinity. Analytical injections were performed on chiral
stationary phase using the column (Chiralpak® OD 5 µm, 4.6 mm
× 250 mm, Chiralpak® IF 5 µm, 4.6 mm × 250 mm). The starting
material (P)-4 and (M)-4 was synthesized by reported method
[3].
53
37
a
1:4 stoichiometry of (P)-3/Ti(OiPr)4 (10 mol %) with 4Å molecular
sieves in toluene solution were pre-activated at 110 oC for 1 h. Then
benzaldehyde and Danishefsky’s diene were added and reaction was
processed under 0 °C for 24 h.
b All yields are isolated yields.
c Absolute configurations were R, which determined in all cases ee was
determined by HPLC using a chiral column (Chiracel OD-H).
4.2. General procedure for the synthesis of enantiomers 3a-c by
Suzuki-Miyaura cross coupling reactions
To the mixture of Br-H[5]HOL (P)-4 or (M)-4 (67 mg, 0.1
mmol), aryl boronic acid (0.5 mmol), and K2CO3 (138 mg, 1.0
mmol) in a mixture solution of toluene (15 mL), EtOH (15 mL),
and degassed water (7.5 mL) was added Pd(PPh3)2Cl2 (0.01
mmol). The reaction mixture was refluxed for 12 h, cooled to
room temperature, and then added EA (30 mL) and water (30
mL). The organic phase was separated, dried over MgSO4, and
concentrated by reduced pressure. The crude product was
purified by flash column chromatography.
Scheme 3. The catalytic asymmetric HDA reactions of substituted
aldehydes 7 with Danishefsky’s diene 6.

7
4.2.1. Compound (P)-3a. DCM: EtOAc (v/v =100:1). Yellow
powder (48 mg, 69% yield). [α]2D5 = –528° (c = 1.0 mg mL-1,
DCM). Rf = 0.38 (DCM: EtOAc, v/v =100:1). M. p.: 67-69 °C.
1H NMR (500 MHz, CDCl3): δ 8.18 (dd, J = 6.8, 3.5 Hz, 2H),
7.57 (dd, J = 6.7, 3.3 Hz, 2H), 7.45 (d, J = 9.2 Hz, 2H), 7.35 (t, J
= 7.8 Hz, 2H), 7.28–7.20 (m, 4H), 7.13 (t, J = 8.4 Hz, 2H), 7.08
(d, J = 8.9 Hz, 2H), 7.02 (s, 2H), 6.99 (t, J = 7.6 Hz, 2H), 6.74 (d,
J = 7.9 Hz, 2H), 6.36 (s, 2H), 6.24 (d, J = 8.4 Hz, 2H), 5.76 (s,
2H), 3.40 (d, J = 19.4 Hz, 2H), 2.51 (t, J = 17.6 Hz, 2H), 2.40 (d,
J = 18.2 Hz, 2H), 1.57 (t, J = 17.2 Hz, 2H). 13C NMR (126 MHz,
CDCl3): δ 153.8, 147.1, 135.9, 135. 8, 135.2, 131.9, 131.2, 131.1,
130.9, 130.5, 130.2, 129.4, 129.2, 129.1, 127.6, 127.4, 126.4,
126.1, 125.8, 124.5, 123.0, 121.2, 117.8, 29.3, 24.9. HRMS
(APCI): calcd. for C50H35O4 [M-H]—: 699.2541, found: 699.2538.
2JC-F = 22.68 Hz), 29.3, 24.9. 19F NMR (377 MHz, CDCl3): δ -
ACCEPTED MANUSCRIPT
123.79. HRMS (APCI): calcd. for C52H33F2O4 [M-H]—:
735.2352, found: 735.2353.
4.2.6. Compound (M)-3c. DCM: EtOAc (v/v =100:1) as
eluent. Yellow powder (46 mg, 62% yield). [α]2D5 = +515° (c = 1.0
mg mL-1, DCM). Rf = 0.45 (DCM: EtOAc, v/v =100:1). M. p.:
1
72-74 °C. H NMR (500 MHz, CDCl3): δ 8.16 (dd, J = 6.4, 3.3
Hz, 2H), 7.56 (dd, J = 6.5, 3.2 Hz, 2H), 7.26–7.20 (m, 4H), 7.13
(dd, J = 9.2, 2.5 Hz, 2H), 7.07–6.97 (m, 8H), 6.66 (d, J = 6.6 Hz,
2H), 6.22 (d, J = 7.7 Hz, 2H), 5.83 (s, 2H), 3.39 (d, J = 13.2 Hz,
2H), 2.61–2.34 (m, 4H), 1.54 (t, J = 12.3 Hz, 2H). 13C NMR (126
MHz, CDCl3): δ 157.3 (d, 1JC-F = 239.40 Hz), 149.9, 146.8, 136.1,
3
3
135.5 (d, JC-F = 5.04 Hz), 132.0, 130.5 (d, JC-F = 5.04 Hz),
130.2, 129.5, 129.3, 127.7, 127.6, 127.2, 126.3, 126.0, 124.5,
2
2
4.2.2. Compound (M)-3a. DCM: EtOAc (v/v =100:1). Yellow
powder (45 mg, 65% yield). [α]2D5 = +532° (c = 1.0 mg mL-1,
DCM). Rf = 0.38 (DCM: EtOAc, v/v =100:1). M. p.: 68-69 °C.
1H NMR (500 MHz, CDCl3): δ 8.18 (dd, J = 6.8, 3.5 Hz, 2H),
7.57 (dd, J = 6.7, 3.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.36 (t, J
= 8.1 Hz, 2H), 7.27–7.20 (m, 4H), 7.13 (t, J = 7.7 Hz, 2H), 7.08
(d, J = 8.4 Hz, 2H), 7.02 (s, 2H), 6.99 (t, J = 7.8 Hz, 2H), 6.74 (d,
J = 8.0 Hz, 2H), 6.36 (s, 2H), 6.24 (d, J = 8.5 Hz, 2H), 5.76 (s,
2H), 3.40 (d, J = 18.8 Hz, 2H), 2.49 (d, J = 15.5 Hz, 2H), 2.40 (d,
J = 14.9 Hz, 2H), 1.57 (t, J = 15.0 Hz, 2H). 13C NMR (126 MHz,
CDCl3): δ 153.8, 147.1, 135.9, 135.8, 135.2, 131.9, 131.2, 131.1,
130.9, 130.5, 130.2, 129.4, 129.2, 129.1, 127.6, 127.4, 126.4,
126.1, 125.9, 124.5, 123.0, 121.2, 117.8, 29.3, 24.9. HRMS
(APCI): calcd. for C50H35O4 [M-H]—: 699.2541, found: 699.2542.
122.4, 119.2, 119.1, 116.9 (d, JC-F = 22.68 Hz), 115.6 (d, JC-F =
22.68 Hz), 29.3, 24.9. 19F NMR (377 MHz, CDCl3): δ -123.79.
HRMS (APCI): calcd. for C52H33F2O4 [M-H]—: 735.2352, found:
735.2351.
4.3. Synthesis of enantiomers 3d.
4.3.1. Compound (P)-3d. To the solution of (P)-5 (304 mg, 0.4
mmol) in xylene (100 mL) was added 2,3-dichloro-5,6-
dicyanobenzoquinone (908 mg, 4 mmol) in one portion. The
reaction mixture was refluxed with stirring overnight, cooled to
room temperature, and concentrated by reduced pressure. Crude
product was purified by flash column chromatography with DCM
and petroleum ether (1:1, v/v) as eluent to give product. To the
mixture of above product, boronic acid (276 mg, 2 mmol), and
K2CO3 (138 mg, 4 mmol) in a mixture solution of toluene (60
mL), EtOH (60 mL), and degassed water (30 mL) was added
Pd(PPh3)2Cl2 (0.04 mmol). The reaction mixture was refluxed for
12 h, cooled to room temperature, and then added EtOAc (100
mL) and water (100 mL). The organic phase was separated, dried
over MgSO4, and concentrated by reduced pressure. The crude
product was purified by flash column chromatography. To the
solution of the above product in MeOH (20 mL) and THF (20
mL) was added Amberlyst 15 resin (400 mg). After the mixture
was stirred at 65 °C overnight, the resin was filtered off, and the
solvent was removed by reduced pressure. The organic layer was
passed through a silica plug with DCM as eluent to afford the
product (108 mg, 39% yield for three steps) as a yellow powder.
[α]2D5 = +1025° (c = 1.0 mg mL-1, DCM). Rf = 0.45 (DCM). M. p.:
4.2.3. Compound (P)-3b. DCM as eluent. Yellow powder (52
mg, 72% yield). [α]D25 = –536° (c = 1.0 mg mL-1, DCM). Rf = 0.43
(DCM). M. p.: 70-72 °C. 1H NMR (500 MHz, CDCl3): δ 8.14
(dd, J = 6.3, 3.3 Hz, 2H), 7.53 (dd, J = 6.3, 2.9 Hz, 2H), 7.25–
7.15 (m, 6H), 7.12 (d, J = 8.2 Hz, 2H), 6.98–6.91 (m, 6H), 6.72
(d, J = 7.3 Hz, 2H), 6.19 (d, J = 7.6 Hz, 2H), 5.71 (s, 2H), 3.36
(d, J = 13.9 Hz, 2H), 2.53–2.38 (m, 10H), 1.54 (t, J = 12.6 Hz,
2H). 13C NMR (101 MHz, CDCl3): δ 151.5, 147.2, 135.9, 135.2,
131.9, 131.4, 131.0, 130.5, 130.4, 123.0, 129.1, 129.0, 127.8,
127.2, 126.4, 125.8, 125.7, 124.5, 123.1, 117.6, 7, 29.3, 25.0,
20.7. HRMS (APCI): calcd. for C52H39O4 [M-H]—: 727.2854,
found: 727.2855.
4.2.4. Compound (M)-3b. DCM as eluent. Yellow powder (54
mg, 74% yield). [α]D25 = +568° (c = 1.0 mg mL-1, DCM). Rf = 0.43
(DCM). M. p.: 70-72 °C. 1H NMR (500 MHz, CDCl3): δ 8.17
(dd, J = 6.4, 3.3 Hz, 2H), 7.55 (dd, J = 6.5, 3.1 Hz, 2H), 7.23–
7.17 (m, 6H), 7.14 (d, J = 8.1 Hz, 2H), 7.00–6.94 (d, J = 9.7 Hz,
6H), 6.75 (d, J = 7.2 Hz, 2H), 6.22 (d, J = 7.6 Hz, 2H), 5.74 (s,
2H), 3.39 (d, J = 15.3 Hz, 2H), 2.53–2.38 (m, 10H), 1.56 (t, J =
16.5 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 151.5, 147.2,
135.9, 135.2, 131.9, 131.4, 131.0, 130.5, 130.4, 123.0, 129.1,
129.0, 127.8, 127.3, 126.4, 125.8, 125.7, 124.5, 123.10 117.6,
29.3, 25.0, 20.7. HRMS (APCI): calcd. for C52H39O4 [M-H]—:
727.2854, found: 727.2855.
1
73-75°C. H NMR (500 MHz, CDCl3): δ 8.68 (dd, J = 5.8, 3.1
Hz, 2H), 8.34 (d, J = 8.5 Hz, 2H), 7.74 (dd, J = 6.7, 2.5 Hz, 2H),
7.61 (s, 2H), 7.53–7.47 (m, 4H), 7.39 (t, J = 8.8 Hz, 2H), 7.19–
7.04 (m, 6H), 6.92 (t, J = 8.2 Hz, 2H), 6.58 (t, J = 7.7 Hz, 2H),
6.20 (s, 2H), 6.13 (s, 2H), 5.64 (d, J = 7.8 Hz, 2H). 13C NMR
(126 MHz, CDCl3): δ 153.9, 148.1, 135.5, 132.3, 131.3, 130.2,
129.9, 129.7, 129.0, 128.9, 128.8, 128.5, 128.1, 127.9, 127.2,
126.3, 125.9, 125.6, 125.1, 124.9, 123.6, 121.3, 117.6, 117.4.
HRMS (APCI): calcd. for C52H39O4 [M-H]—: 695.2228, found:
695.2223.
4.3.2. Compound (M)-3d. According to the same method as the
preparation of (P)-3d, compound (M)-3d was obtained. DCM as
eluent. Yellow powder (88 mg, 32% yield). [α]2D5 = –1032° (c =
1.0 mg mL-1, DCM). Rf = 0.45 (DCM). M. p.: 74-76 °C. 1H NMR
(500 MHz, CDCl3): δ 8.68 (dd, J = 7.8, 4.7 Hz, 2H), 8.33 (d, J =
8.7 Hz, 2H), 7.73 (dd, J = 6.2, 3.1 Hz, 2H), 7.61 (s, 2H), 7.57–
7.45 (m, 4H), 7.38 (t, J = 8.8 Hz, 2H), 7.18–7.03 (m, 6H), 6.93 (t,
J = 8.3 Hz, 2H), 6.58 (t, J = 9.0 Hz, 2H), 6.20 (s, 2H), 6.13 (s,
2H), 5.64 (d, J = 8.2 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ
153.9, 148.1, 135.5, 132.3, 131.3, 130.2, 129.9, 129.7, 129.0,
128.9, 128.8, 128.5, 128.1, 127.9, 127.2, 126.3, 125.9, 125.6,
125.1, 124.9, 123.6, 121.3, 117.7, 117.4. HRMS (APCI): calcd.
for C52H39O4 [M-H]—: 695.2228, found: 695.2228.
4.2.5. Compound (P)-3c. DCM: EtOAc (v/v =100:1) as eluent.
Yellow powder (44 mg, 60% yield). [α]2D5 = –527° (c = 1.0 mg
mL-1, DCM). Rf = 0.45 (DCM: EtOAc, v/v =100:1). M. p.: 73-75
°C. 1H NMR (500 MHz, CDCl3): δ 8.16 (dd, J = 6.4, 3.3 Hz, 2H),
7.56 (dd, J = 6.5, 3.2 Hz, 2H), 7.26–7.20 (m, J = 7.3, 5.9 Hz,
4H), 7.13 (dd, J = 9.2, 2.7 Hz, 2H), 7.03–6.99 (m, 8H), 6.66 (d, J
= 6.6 Hz, 2H), 6.22 (d, J = 7.8 Hz, 2H), 5.84 (s, 2H), 3.39 (d, J =
17.6 Hz, 2H), 2.65–2.33 (m, 4H), 1.54 (t, J = 14.7 Hz, 2H). 13C
1
NMR (126 MHz, CDCl3): δ 157.3 (d, JC-F = 238.14 Hz), 149.9,
3
3
146.8, 136.1, 135.5 (d, JC-F = 5.04 Hz), 132.0, 130.6 (d, JC-F
=
5.04 Hz), 130.2, 129.5, 129.3, 127.7, 127.6, 127.2, 126.4, 126.0,
2
124.5, 122.4, 119.2, 119.1, 116.9 (d, JC-F = 22.68 Hz), 115.6 (d,

8
Tetrahedron
ACCEPTED MANUSCRIPT
4.4. General catalytic asymmetric HDA procedure.
190.8, 162.6, 143.0, 132.7, 126.5, 118.3, 112.8, 107.8, 79.9, 43.3.
HPLC analysis: Daicel Chiralpak OD-H, Hexane/IPA = 90:10,
flow rate = 1.0 mL/min, retention time: 27.28 min (minor) and
32.49 min (major).
A mixture of PhOH-H[5]HOL (35.0 mg, 0.05 mmol), 1.0 M
Ti(OiPr)4 in CH2Cl2 (100 µL, 0.10 mmol), and activated 4 Å
molecular sieves (240 mg) in toluene (5 mL) was heated at 110
°C for 1 h. The yellow mixture was cooled to rt, and arylaldehyde
(0.5 mmol) was added. The mixture was stirred for 10 min and
cooled to 0 °C. Danishefsky’s diene (120 µL, 0.60 mmol) was
added. The mixture was allowed to stir at 0 °C for 24 h, and then
treated with 5 drops of trifluoroacetic acid (TFA). After the
mixture was stirred at 0 °C for 15 min, saturated NaHCO3 (5.0
mL) was added. The mixture was stirred for 10 min, and then
filtered through a plug of Celite. The organic layer was separated,
and the aqueous layer was extracted with ether (5 × 3 mL). The
combined organic layer was dried over anhydrous MgSO4 and
concentrated. The crude residue was purified by flash
chromatography (EtOAc: petroleum ether = 1:4, Rf = 0.52) to
yield product.
4.4.6. Compound (R)-8f. White solid (48 mg, 44% yield); Yield:
43%; M. p.: 101-102 °C; [lit. [58] M. p.: 100-102 °C];
Enantiomeric excess: 11%. H NMR (500 MHz, CDCl3): δ 8.30
(d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 6.0 Hz,
1H), 5.62 – 5.51 (m, 2H), 2.85 (dd, J = 16.7, 14.2 Hz, 1H), 2.75
(d, J = 3.6 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 190.7, 162.5,
148.1, 144.9, 126.7, 124.2, 107.9, 43.4. HPLC analysis: Daicel
Chiralpak OD-H, Hexane/IPA = 90:10, flow rate = 1.0 mL/min,
retention time: 29.36 min (minor) and 40.16 min (major).
1
4.4.7. Compound (R)-8g. Colorless oil (52 mg, 55% yield);
Enantiomeric excess: 58%. H NMR (500 MHz, CDCl3): δ 7.45
1
(d, J = 6.0 Hz, 1H), 7.34–7.23 (m, 1H), 7.23–7.11 (m, 3H), 5.54–
5.43 (m, 1H), 5.37 (dd, J = 14.5, 3.2 Hz, 1H), 2.89 (dd, J = 16.8,
14.6 Hz, 1H), 2.63 (d, J = 19.5 Hz, 1H), 2.38 (s, 3H). 13C NMR
(126 MHz, CDCl3): δ 192.1, 163.2, 138.6, 137.8, 129.7, 128.7,
126.8, 123.2, 107.3, 81.2, 43.4, 21.4. HPLC analysis: Daicel
Chiralpak OD-H, Hexane/IPA = 90:10, flow rate = 1.0 mL/min,
retention time: 8.83 min (minor) and 10.05 min (major).
4.4.1. Compound (R)-8a. Colorless oil (69 mg, 79% yield);
Enantiomeric excess: 53%; H NMR (500 MHz, CDCl3): δ 7.28
1
(d, J = 6.0 Hz, 1H), 7.25–7.16 (m, 5H), 5.33 (d, J = 6.0 Hz, 1H),
5.23 (d, J = 14.4 Hz, 1H), 2.78–2.59 (m, 1H), 2.46 (dd, J = 18.5,
2.6 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 191.1, 162.2, 136.8,
127.9, 125.1, 106.3, 80.1, 76.3, 76.1, 75.8, 42.4. HPLC analysis:
Daicel Chiralpak OD-H, Hexane/IPA = 99:1, flow rate = 1.0
mL/min, retention time: 24.60 min (minor) and 29.33 min
(major).
4.4.8. Compound (R)-8h. White solid (57 mg, 55% yield); M. p.:
73-74 °C; [lit. [57] M. p.: 74-75 °C]; Enantiomeric excess: 25%.
1H NMR (500 MHz, CDCl3): δ 7.57 (d, J = 7.7 Hz, 1H), 7.50 (d,
J = 6.0 Hz, 1H), 7.42–7.23 (m, 3H), 5.79 (dd, J = 13.9, 3.9 Hz,
1H), 5.53 (d, J = 6.0 Hz, 1H), 2.84–2.58 (m, 2H). 13C NMR (126
MHz, CDCl3): δ 191.3, 163.0, 135.8, 131.5, 129.7, 129.7, 127.4,
127.1, 107.5, 77.9, 42.1. HPLC analysis: Daicel Chiralpak OD-
H, Hexane/IPA = 90:10, flow rate = 1.0 mL/min, retention time:
15.13 min (minor) and 16.63 min (major).
4.4.2. Compound (R)-8b. White solid (63 mg, 62% yield);
Enantiomeric excess: 43%; M. p.: 51-53 °C; [lit. [58] M. p.: 50-
51 °C]; H NMR (500 MHz, CDCl3): δ 7.40 (d, J = 6.0 Hz, 1H),
7.28 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.45 (d, J = 6.0
Hz, 1H), 5.31 (dd, J = 14.4, 3.2 Hz, 1H), 3.76 (s, 3H), 2.86 (dd, J
= 16.8, 14.5 Hz, 1H), 2.56 (dd, J = 16.8, 2.5 Hz, 1H). 13C NMR
(126 MHz, CDCl3): δ 192.3, 163.3, 160.0, 129.9, 127.8, 114.1,
107.2, 80.8, 55.3, 43.1. HPLC analysis: Daicel Chiralpak OD-H,
Hexane/IPA = 90:10, flow rate = 1.0 mL/min, retention time:
14.30 min (minor) and 15.52 min (major).
1
4.4.9. Compound (R)-8i. Colorless oil (73 mg, 66% yield); Yield:
67%; Enantiomeric excess: 19%. H NMR (500 MHz, CDCl3): δ
1
8.05 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.76 (t, J = 7.6
Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 6.1 Hz, 1H), 6.06
(dd, J = 14.1, 3.1 Hz, 1H), 5.58 (d, J = 6.0 Hz, 1H), 2.99–2.96
(m, 1H), 2.84–2.69 (m, 1H). 13C NMR (126 MHz, CDCl3): δ
190.8, 162.6, 147.2, 133.8, 129.5, 128.1, 124.9, 107.9, 43.1.
HPLC analysis: Daicel Chiralpak OD-H, Hexane/IPA = 90:10,
flow rate = 1.0 mL/min, retention time: 16.81 min (minor) and
20.20 min (major).
4.4.3. Compound (R)-8c. White solid (67 mg, 64% yield);
Enantiomeric excess: 67%; M. p.: 70-71 °C; [lit. [58] M. p.: 69-
71 °C]; 1H NMR (500 MHz, CDCl3): δ 7.47 (d, J = 6.0 Hz, 1H),
7.40 (d, J = 6.9 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 5.53 (d, J = 6.0
Hz, 1H), 5.41 (d, J = 14.3 Hz, 1H), 2.86 (dd, J = 16.6, 14.5 Hz,
1H), 2.65 (d, J = 19.8 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ
191.6, 162.9, 136.4, 134.8, 129.1, 127.5, 107.5, 80.3, 43.3. HPLC
analysis: Daicel Chiralpak OD-H, Hexane/IPA = 90:10, flow rate
= 1.0 mL/min, retention time: 23.34 min (minor) and 30.43 min
(major).
4.4.10. Compound (R)-8j. White solid (58 mg, 70% yield); M. p.:
70-71 °C; [lit. [58] M. p.: 72-73 °C]; Enantiomeric excess: 42%.
1H NMR (500 MHz, CDCl3): δ 7.48–7.47 (m, 1H), 7.36 (d, J =
6.1 Hz, 1H), 6.45 (d, J = 3.3 Hz, 1H), 6.40 (d, J = 1.7 Hz, 1H),
5.49–5.45 (m, 2H), 3.06 (dd, J = 16.9, 12.8 Hz, 1H), 2.73–2.69
(m, 1H). 13C NMR (126 MHz, CDCl3): δ 191.1, 162.4, 150.1,
143. 6, 110.1, 109. 7, 107.3, 73.5, 39.5. HPLC analysis: Daicel
Chiralpak OD-H, Hexane/IPA = 90:10, flow rate = 1.0 mL/min,
retention time: 21.99 min (major) and 24.18 min (minor).
4.4.4. Compound (R)-8d. Colorless oil (95 mg, 76% yield);
Enantiomeric excess: 57%; H NMR (500 MHz, CDCl3): δ 7.55
1
(d, J = 8.4 Hz, 2H), 7.47 (d, J = 6.0 Hz, 1H), 7.28 (d, J = 8.4 Hz,
2H), 5.53 (d, J = 6.0 Hz, 1H), 5.39 (dd, J = 14.3, 3.3 Hz, 1H),
2.85 (dd, J = 16.8, 14.4 Hz, 1H).13C NMR (126 MHz, CDCl3): δ
191.6, 162.9, 136.9, 132.0, 127.7, 122.9, 107.5, 80.3, 43.3. HPLC
analysis: Daicel Chiralpak OD-H, Hexane/IPA = 90:10, flow rate
= 1.0 mL/min, retention time: 11.36 min (minor) and 14.15 min
(major).
4.4.11. Compound (R)-8k. White solid (47 mg, 54% yield); M.
p.: 73-75 °C; [lit. [57] M. p.: 73-74 °C]; Enantiomeric excess:
14%. H NMR (500 MHz, CDCl3): δ 8.69–8.57 (m, 1H), 7.79 (t,
J = 7.7 Hz, 1H), 7.55–7.43 (m, 2H), 7.34–7.27 (m, 1H), 5.63–
5.46 (m, 2H), 3.07–2.94 (m, 1H), 2.92–2.78 (m, 1H). 13C NMR
(126 MHz, CDCl3): δ 191.8, 162.4, 156.7, 149.5, 137.2, 123.6,
120.9, 107.8, 81.1, 41.6. HPLC analysis: Daicel Chiralpak OD-
H, Hexane/IPA = 90:10, flow rate = 1.0 mL/min, retention time:
27.78 min (major) and 34.99 min (minor).
1
4.4.5. Compound (R)-8e. White solid (58 mg, 58% yield); Yield:
59%; M. p.: 72-73 °C; [lit. [58] M. p.: 70-72 °C]; Enantiomeric
excess: 33%. 1H NMR (500 MHz, CDCl3): δ 7.75 (d, J = 8.2 Hz,
2H), 7.53 (dd, J = 16.4, 7.1 Hz, 3H), 5.58 (d, J = 6.0 Hz, 1H),
5.52 (dd, J = 14.1, 3.5 Hz, 1H), 2.84 (dd, J = 16.7, 14.2 Hz, 1H),
2.72 (dd, J = 16.8, 3.2 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ
4.4.12. Compound (R)-8l. Colorless oil (32 mg, 36% yield);
1
Enantiomeric excess: 4%. H NMR (500 MHz, CDCl3): δ 7.38

9
(d, J = 6.0 Hz 1H), 5.38 (d, J = 6.0 Hz 1H), 4.25–4.07 (m, 1H),
16. T. Kaseyama, S. Furumi, X. Zhang, K. Tanaka and M.
Takeuchi, Angew. Chem. Int. Ed. 50 (2011) 3684-3687.
ACCEPTED MANUSCRIPT
2.62–2.47 (m, 1H), 2.38 (d, J = 16.6 Hz, 1H), 1.96–1.86 (m, 1H),
1.80 (d, J = 12.8 Hz, 2H), 1.68 (d, J = 11.0 Hz, 2H), 1.34–1.00
(m, 6H). 13C NMR (126 MHz, CDCl3): δ 193.2, 163.3, 106.8,
83.6, 77.4, 77.1, 76.9, 41.4, 39.1, 28.0, 26.1, 25.8. HPLC
analysis: Daicel Chiralpak OD-H, Hexane/IPA = 90:10, flow rate
= 1.0 mL/min, retention time: 9.87 min (major) and 10.99 min
(minor).
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4.4.13. Compound (R)-8m. Colorless oil (23 mg, 22% yield);
1
Enantiomeric excess: 3%. H NMR (500 MHz, CDCl3): δ 7.36
(d, J = 5.9 Hz, 1H), 5.40 (dd, J = 6.0, 1.1 Hz, 1H), 4.45–4.35 (m,
1H), 2.52 (dd, J = 16.8, 13.4 Hz, 1H), 2.43 (dd, J = 16.8, 3.8,
1H), 1.85–1.81 (m, 1H), 1.69–1.62 (m, 1H), 1.49–1.25 (m, 12H),
0.89 (t, J = 6.8 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 192.8,
163.3, 106.9, 79.6, 77.4, 77.1, 76.9, 41.9, 34.4, 31.8, 29.4, 29.3,
24.8, 22.7, 14.1. HPLC analysis: Daicel Chiralpak OD-H,
Hexane/IPA = 90:10, flow rate = 1.0 mL/min, retention time:
17.21 min (minor) and 18.60 min (major).
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Acknowledgement
We thank the National Natural Science Foundation of China
(21572233, 21332008), the National Basic Research Program
(2015CB856502), and the Strategic Priority Research Program of
Chinese Academy of Sciences (XDB12010400) for financial
supports.
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Conflicts of interest
There are no conflicts to declare.
Appendix A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at https://doi.org/10.1016
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