Experimental and theoretical investigation of stable diastereomeric conformations of biscarboline amides in solution

Article abstract of DOI:10.1016/j.tet.2018.06.037

Stable axial conformations generally exist only when the single bond's (axis’) rotation was sterically hindered in solution. Herein, we firstly show that two stable conformations could be observed in solution by ¹H and ¹³C NMR experiments when the single bond rotates freely. Its coalescence temperature was measured up to 120 °C when we took compound 13 as an example. The ratio of the two stable conformations was computed using quantum methods. The predicted results matched with the experimental results well. The conversion barrier between two conformers was estimated by potential energy scan (PES) and transition state (TS) calculations at the B3LYP/6-311 + G(d) level. Furthermore, its stereochemistry was also well studied by comparing theoretical electronic circular dichroism (ECD) spectra with the experimental one.

Full text of DOI:10.1016/j.tet.2018.06.037

Accepted Manuscript
Experimental and theoretical investigation of stable diastereomeric conformations of
biscarboline amides in solution
Miao-Miao Liang, Yang-Yang Ma, Liang Zhu, Yun-Jing Jia, Hua-Jie Zhu, Wan Li, Bei-
Dou Zhou
PII:
S0040-4020(18)30737-3
10.1016/j.tet.2018.06.037
TET 29633
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 April 2018
Revised Date: 13 June 2018
Accepted Date: 15 June 2018
Please cite this article as: Liang M-M, Ma Y-Y, Zhu L, Jia Y-J, Zhu H-J, Li W, Zhou B-D, Experimental
and theoretical investigation of stable diastereomeric conformations of biscarboline amides in solution,
Tetrahedron (2018), doi: 10.1016/j.tet.2018.06.037.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Experimental and Theoretical Investigation of Stable
Diastereomeric Conformations of Biscarboline Amides in
Solution
Miao-Miao Liang, Yang-Yang Ma, Liang Zhu, Yun-Jing Jia,
Hua-Jie Zhu, Wan Li, Bei-Dou Zhou

ACCEPTED MANUSCRIPT
Experimental and Theoretical Investigation of Stable
Diastereomeric Conformations of Biscarboline Amides in
Solution
Miao-Miao Liang a,†, Yang-Yang Ma a,†, Liang Zhu a, Yun-Jing Jia a, Hua-Jie Zhu a,*,
Wan Li a, Bei-Dou Zhou b,*
aCollege of Pharmacy, Chinese Center for Chirality, Hebei University, 071002, China.
bSchool of Pharmacy and Medical Technology, Putian University, 351100, Putian,
Fujian, China
† These authors contributed equally to this work
*Correspondence and requests for materials should be addressed to H.-J. Z.
(zhuhuajie@hotmail.com,
(beidouzhou@ptu.edu.cn)
hjzhu2017@163.com)
or
B.-D.
Z.
1

ACCEPTED MANUSCRIPT
Abstract
Stable axial conformations generally exist only when the single bond's (axis') rotation was
sterically hindered in solution. Herein, we firstly show that two stable conformations could be
1
observed in solution by H and 13C NMR experiments when the single bond rotates freely. Its
o
coalescence temperature was measured up to 120 C when we took compound 13 as an example.
The ratio of the two stable conformations was computed using quantum methods. The predicted
results matched with the experimental results well. The conversion barrier between two
conformers was estimated by potential energy scan (PES) and transition state (TS) calculations at
the B3LYP/6-311+G(d) level. Furthermore, its stereochemistry was also well studied by
comparing theoretical electronic circular dichroism (ECD) spectra with the experimental one.
Keywords: axial conformations, biscarboline amides, experimental investigation, theoretical
investigation
2

ACCEPTED MANUSCRIPT
Introduction
Conformational distributions of chiral compounds in solution contribute significantly to their
functions like catalysis in enantioselective additions,1 bioactivities2 and the others.3 In terms of
bioactivities, atropisomer chirality of anthranilic acid derivatives can lead to distinct entities with
specific property. In many cases, it is difficult to record the NMR signals of two different stable
conformations in solution since the exchange rate between two conformations is very fast. Many
valuable studies reported conformational conversions at very low temperatures, such as −80 oC, 4
because of the low conversion barriers like 12.4 kcal/mol.5,6 It is also difficult to observe the
1
isolated H NMR spectra at room temperature. Taking compound 1 as an example,7 in order to
record two sets of 1H NMR clearly, the temperature was cooled as low as −60 oC. If the substituent
is bulky enough to block the single bond’s rotation, it is possible to isolate the atropisomers and
use one of them, such as 2 as a chiral auxiliary in asymmetric reactions.8 Caryophyllene C (3) was
1
isolated from the fungus of Trichodermasp., which has two sets of H NMR at room temperature
with the calculated transition barrier being 19.6 kcal/mol at the B3LYP/6-311+G(d) level in the
gas phase at room temperature. This energy barrier could restrict 9-membered ring
interconversion.9 Indeed, the temperature in NMR spectrometers ranged from 95 K to 450 K. In
this study, we report the 1H NMR study of biscarboline amides at room temperature in chloroform
and the results that the single bond (axis) can rotate freely. Two sets of recorded 1H and 13C NMR
spectra exhibit that there are two stable conformers in chloroform.
AcO
HO
iPr
3
O
P
iPr
N
O
4
H
R
O
1
O
5
OH
6
O
1 Coalescence
HO
3, Pestalotiopsins C, (r.t.)
2
Chiral catalyst
temperature
(used at 0 oC to r.t.)
o
(-80 C)
3

ACCEPTED MANUSCRIPT
Results and Discussion
Synthesis of chiral biscarboline derivatives is illustrated below on the basis of our previous
reports.10,11 The reaction condition is mild, and the over yield is up to 60% (Scheme 1).
O
O
O
OCH3
OH
OCH3
CH3OH
(CH3O)2CHCHO
NH
O
o
NH2
NH2
SOCl2, reflux
DCM, 4A MS, r.t.
N
N
N
H
H
H
O
4
5 (98.5%)
6 (99%)
O
O
OCH3
OCH3
(1) 4 (1.0 equiv.)
DCM, M.S, r.t., 12 h
TCCA
DMF
TSOHꢀH2O
N
N
acetone, r.t., 4 h
0 oC, 2 h
(2) TFA, r.t., 12 h
N
N
H
O
H
CHO
O
7 (97%)
8 (80%)
O
O
O
OCH3
OCH3
OCH3
CH3I,
NaH
TCCA
DMF
NH
N
N
N
N
N
H
H
DMF
0 oC
2 h
H
H
0 oC,
2 h
N
N
N
N
N
N
H3CO
O
H3CO
H3CO
O
O
O
9 (78%)
10 (70%)
11 (95%)
O
O
O
O
NH
OH
Cl
O
1
R
NaOH
2
N
N
N
N
Et3N,DCM,r.t.
CH3OH
Reflux
N
N
2'
N
N
NH2
R
1'
R
H
N
HO
O
CO2CH3
O
O
O
12 (96%)
H
N
17:R =
13:R = ꢀMe (85%)
14:R = ꢀiPr (89%)
(65%)
15:R = ꢀCH(CH3)CH2CH3 (86%)
16:R = ꢀBn (84%)
18:R = ꢀ(OH)Bn (54%)
19:R = ꢀ(CH2) iPr (50%)
Scheme 1. Synthesis of biscarboline amides 13 to 19.
Chiral biscarboline amides 13 to 19 may have one set of H and 13C NMR spectra
theoretically since there is no any atom or group adjacent to the single bond (C1-C1') to sterically
hinder its rotation. However, two sets of 1H and 13C NMR spectra were recorded in CDCl3 at room
temperature (Fig. 1). For example, the methyl 1H NMR signals of –OMe and >NMe displayed two
1
1
sets of signals. Mostly, other protons also exhibited two sets of signals although some H NMR
signals overlapped severely. Majority of carbons had two sets of 13C NMR signals too. There were
likely two main chiral isomers in solution.
4

ACCEPTED MANUSCRIPT
Fig. 1 The recorded partial two sets of 1H NMR and 13C NMR spectra for –OMe and >NMe of 13
1
to 19, respectively. The data listed near the proton signals of H NMR spectra are the integration
1
value of this signal. The green lines that cross the proton signals are the integration lines in H
NMR spectra
To investigate the phenomena, compound 13 was chosen as a typical example for further
study. One HPLC peak of 13 was recorded through chiral columns (Chiralcel series of -OB-H,
-OD-H, -IA, -IB, -IC and –ID) and diethyl pyridine column (see SI for details). Only single peak
was recorded. Therefore, it may be only one product existed in solution instead of two stable
epimers or two compounds.
1
Theoretically, the two sets of H and 13C NMR spectra might be caused by partial
racemization of the L-alanine ester. To exclude the possibility, racemic L-alanine was used for
esterification firstly. The racemic esters then reacted with 12. Compound 12 had two −CO2H
groups which could react with either single L-alanine ester (L-13) or D-alanine ester (D-13), or the
complex of one L-alanine ester and one D-alanine ester (D,L-13 or L,D-13). Thus, it afforded a
mixture (M-13) of three diastereomeric compounds. Theoretically, the ratio of the three
compounds of L-13: (D,L)/ (L,D)-13:D-13 should be 1:2:1. Indeed, this was confirmed by HPLC
5

ACCEPTED MANUSCRIPT
analysis using Chiracel IC column (Fig. 2). Once L-13 was added into the racemic sample (M-13),
the relative area of the third signal increased. This confirmed that the sample 13 obtained in
Scheme 1 was an optically pure L-type structure. It showed the reaction condition is quite mild.
No partial racemization of 13 happened when the corresponding L-amino acid ester reacted with
the intermediate 12 under the reaction conditions we used.
Lꢀ13
b
Mꢀ13
a
c
Mꢀ13
+ Lꢀ13
c
b
a
19
21
23
25
Retention time (min.)
Fig. 2 HPLC analyses for L-13, mixture (M-13) of products derived from racemic L-alanine ester
reacted with 12 and a mixture of M-13 and L-13. The mixture of CH2Cl2 and EtOH (v/v=70:30)
was used as an eluent by Chiracel IC column. Upper: HPLC signals of the obtained pure product
L-13 in experiment. Only one signal was recorded at a retention time of 23.9 min. Middle: HPLC
signals of the mixture (M-13) of racemic L-alanine ester reacted with compound 12. Three signals
(a, b, and c) were recorded with a relative area ratio namely 1:2:1. The retention times were 20.8,
21.9 and 23.5 min., respectively. Bottom: HPLC signals of the mixture of M-13 and L-13. The
retention times were 20.6, 21.7 and 23.2 min., respectively. The relative area of signal c increased
when L-13 was added.
As a typical characteristic of the two stable conformations in solution, the temperature
(coalescence temperature) can be raised to “fuse” the two sets of NMR into one. Solvent was
replaced then by DMSO-d6 since it needed a high temperature to “fuse” them. When the
o
1
temperature was 50 C, the H NMR signals of –OMe contained two isolated peaks. The two
o
signals gradually became one peak till the measurement temperature raised up to 80 C (Fig. 3,
TMS as an internal standard)(Fig. 3), but the frequency differences between the two
o
o
conformations decreased from 49.2 Hz at 50 C to 43.8 Hz at 80 C, while the frequency
differences of protons was 51.6 Hz at room temperature. When the temperature raised to 100oC,
the 1H NMR signal became sharp. However, the proton signals of >NMe were still a bit wide.
6

ACCEPTED MANUSCRIPT
1
Fig. 3 Chemical shift changes of protons of –OMe when H NMR measurement temperature
o
o
o
raised from 298 K (25 C) to 323 K (50 C), 353 K (80 C), 373 K ( 100oC) and 393 K (120oC),
respectively.
Most reports about conformational studies were carried out at low temperatures as mentioned
above,3,4 and in those cases low transition state energy like 12.4 kcal/mol could be computed by
o
Eyring equation.4,12 In our case, the coalescence temperature was as high as about 80 C. The
computed transition barrier in free energy (∆G≠) was 18.4 kcal/mol when the frequency difference
of–OMe protons changed from 16.2 Hz (room temperature) to 0 Hz (80 oC) in DMSO-d6. Eyring
equation is listed as following:
Where Tc is the coalescence temperature (K), kc= π∆ν/2−1/2 , ∆ν is difference in the chemical shift
of the –OMe protons between two conformations.
However, the protons of >NCH3 also exhibited two signals when the temperature was 353 K
o
1
(80 C) (Fig. 3C). Further H NMR experiments were performed at higher temperatures, like 373
K and 393 K. The results are illustrated in Figure 3D and 3E. It showed that the sharp signal
of >NCH3 was recorded at 393 K. It exhibited that the TS barrier was about 20.6 kcal/mol at 393
K.
To our best knowledge, both two stable conformations observed at very low temperatures are
caused by single bond’s (axis’) rotation restriction. However, in our case, the rotation resistance is
not caused by atom(s) or group(s) near the axis. It is necessary and important to investigate this
case carefully. Therefore, conformational searches were performed by using MMFF94S force field
via two different packages.13 All the conformations were optimized at the B3LYP/6-31G(d) level
in the gas phase. The optimized conformers with energy within 0-2.5 kcal/mol were selected for
re-optimization at the B3LYP/6-311+G(d) level in the gas phase. The geometry with the lowest
7

ACCEPTED MANUSCRIPT
energy was selected for potential energy scan (PES) and transition state (TS) calculations,
respectively.14 PES was performed firstly via rotation around C1-C1' at the B3LYP/6-311+G(d)
level.15 The energy reached up to 26.6 kcal/mol via overcoming the conversion barrier from (aS,S)
to (aR,S). The PES curve is illustrated in Fig. 4A. This estimation of rotation resistance around
C1-C1' is higher than the free energy barrier (20.6 kcal/mol) using Eyring equation.
Fig. 4 (A) The PES scan curve via C1-C1' rotation using B3LYP/6-311+G(d) method. (B) The
orthographic TS views obtained at the B3LYP/6-311+G(d) level using the lowest energy
conformation as an initial TS structure in computations, and the up-right is its planar TS structure.
Meanwhile, TS barrier energy for conversion from (aS,S)-13 to (aR,S)-13 was calculated at
the B3LYP/6-311+G(d) level in the gas phase. The predicted barrier was 24.4 kcal/mol in total
electron energy at the B3LYP/6-311+G(d) level. Considering the computed barrier in the gas
phase is different from that in liquid by about 0.5-2 kcal/mol using PCM model, or by about 3-6
kcal/mol through adding specific polar solvent in TS structures,16 we did single point energy
computations
at
the
B3LYP/6-311++G(2d,p)
level
in
CHCl3
using
the
B3LYP/6-311+G(d)-optimized TS structure and PCM model. This barrier decreased to 23.9
kcal/mol. We then re-computed its barrier at the B3LYP/6-311+G(d,p) level in CHCl3 using PCM
8

ACCEPTED MANUSCRIPT
model, and the geometries were then used for single point energy computations at the
B3LYP/6-311++G(2d,p) level in liquid using PCM model. The predicted barrier decreased from
24.4 kcal/mol to 24.0 kcal/mol. The difference of TS barrier between the computed barrier using
Eyring equation (based on experimental results) and the predicted barrier using quantum theory
was about 4 Kcal/mol. Therefore, the barrier near 20.6 kcal/mol predicted by Eyring equation
should be reasonable. The TS structure is illustrated in Fig. 4B. All the TS structures at different
basis sets just contained single imaginary frequency or eigenvalue.
In order to explain the ratio of 1H NMR of L-13 in CDCl3, stable conformations of L-13 were
obtained using MMFF94S force field. After B3LYP/6-31G(d)-optimized geometries were
obtained, further accurate geometries were recorded using three methods. Method 1: The
optimization was performed at the B3LYP/6-311+G(d) level in the gas phase. Method 2: The
optimization was carried out at the B3LYP/6-311++G(2d,p) level in the gas phase. Method 3: The
optimization was calculated at the B3LYP/6-311+G(d,p) level in CHCl3 using PCM model.
Different energy data for all geometries are summarized in Table 1. The most stable conformation
of (aR,S)-13 obtained at B3LYP/6-311+G(d) level in the gas phase just occupied about 3%,
namely, the ratio of (aS,S)-13 to (aR,S)-13 was about 27.8:1. It was also 27.8:1 at the
B3LYP/6-311++G(2d,p) level in the gas phase. However, the experimental ratio was 2.22:1 using
the methyl protons integration of –OMe, or 2.32:1 using the methyl protons integration of >NMe,
or 2.27:1 using their averaged value in experiments. Obviously, both predicted results in the gas
phase had big differences from the experimental result. Thus, all the geometries were further
optimized at the B3LYP/6-311+G(d,p) level in solution using PCM model. The predicted ratio of
(aS,S)-13 to (aR,S)-13 turned to be 4.8:1 via the relative energy values analyses. Apparently, the
calculated ratio 4.8:1 in solution is close to the experimental result compared to the calculated
ratio in gas phase.
Table 1 The conformational structures (from a to h) for (aS,S)-13 and (from a to f) for (aR,S)-13
obtained at different levels.
Method 1 a
Method 2 b
(in the gas phase)
Rel. Fr.
Method 3 c
(in liquid)
(in the gas phase)
Conformer
Rel. Fr.e
Rel. Fr.
d
∆E
∆E
∆E
(aS,S)-a
(aS,S)-b
(aS,S)-c
(aS,S)-d
(aS,S)-e
(aS,S)-f
(aS,S)-g
(aS,S)-h
0.000
2.066
1.743
4.221
3.852
3.580
3.588
4.145
1.000
0.0304
0.0524
0.0008
0.0015
0.0023
0.0023
0.0009
1.091
0.000
2.061
1.567
4.206
3.636
3.203
3.300
4.091
1.000
0.0306
0.0707
0.00081
0.0021
0.0044
0.0037
0.00099
1.113
0.000
0.938
0.981
1.886
1.952
2.046
2.117
1.000
0.204
0.190
0.0412
0.0368
0.0314
0.0279
f
f
-
-
Sum of fractions =
1.532
(aR,S)-a
3.386
2.514
2.456
3.870
0.0032
0.0142
0.0157
0.0014
3.368
2.585
2.336
3.514
0.0033
0.0126
0.019
1.092
-
0.157
-
(aR,S)-b
(aR,S)-c
(aR,S)-d
1.283
2.179
0.114
0.025
0.0026
9

ACCEPTED MANUSCRIPT
(aR,S)-e
(aR,S)-f
3.862
3.406
0.0014
0.0031
0.0393
27.8:1
3.652
-
0.0021
-
2.256
-
0.022
-
Sum of fractions =
0.0400
27.8:1
0.3192
4.8:1
Ratio of (aS,S):(aR,S)
a
b
Method 1: optimization at the B3LYP/6-311+G(d) level in the gas phase. Method 2:
c
optimization at the B3LYP/6-311++G(2d,p) level in the gas phase. Method 3: optimization at
d
e
the B3LYP/6-311+G(d,p) level in CHCl3 using PCM model. Unit: Kcal/mol for all ∆E data.
The relative fraction (Rel. Fr.) means the relative ratio based on their energies. The lowest
energy conformation had −2095.3774786 a.u. for (aS,S)-13 using method 1, −2095.4772563 a.u.
using method 2, and −2095.444776 a.u via using method 3. These data were used as the
reference zero for relative ratio calculation. fThe conformation had energy degeneration with
others.
The lowest energy geometries (aS,S)-13a and (aR,S)-13c, are illustrated in Fig. 5. It is clearly
found that the ester moiety (red moiety, Fig. 5, left) of (aR,S)-13c tended to block the indole
moiety rotation (red section, right figure) around the C1-C1' axis. This sterically hindered rotation
leads two results. One is the rotation rate is very slow. This is valid for NMR machine determining
the shielding constants. The second is leading to the rotation energy barrier increase.
O
NH
2
1
N
O
N
1'
2'
O
N
N
H
N
O
(aS,S)ꢀ13a
(aR,S)ꢀ13c
dihedral angle N2ꢀC1ꢀC1'ꢀN'
dihedral angle N2ꢀC1ꢀC1'ꢀN'
in the gas phase: 122.4 o In liquid: 112.6 o
O
in the gas phase: ꢀ115.7 o
O
Fig. 5 The most stable conformations of (aS,S)-13a and (aR,S)-13c. The big repulsive between the
indole moiety and the ester moiety sterically hindered its rotation around C1-C1'.
Electronic circular dichroism (ECD) spectra were also investigated for 13.9,14,16 All the
B3LYP/6-311++G(2d,p)-optimized geometries were used for their ECD calculations at the
B3LYP/6-311+G(d) level in the gas phase and in liquid, respectively (Fig. 6). Firstly, the
simulated ECD spectra for single conformation (aS,S)-13a (geometry number in Table 1) and
single conformation (aR,S)-13c, which both had the lowest energy in each series of configurations,
were compared to each other. They had almost the mirror-image-like curves (Fig. 6A-C). It
seemed that the effect of the stereogenic center of amino acid moiety had very small effect on its
ECD curve in single conformation even if this stereogenic center was close to the chromophore
of >C=O. The ECD curve of single conformation depends on each single conformation’s axial
chirality (aS or aR).
10

ACCEPTED MANUSCRIPT
Fig. 6(A) Predicted ECD for single conformation (aS,S)-13a with the lowest energy. (B) Predicted
ECD for single conformation (aR,S)-13c with the lowest energy. (C) Comparison of the ECD
spectra between the (aS,S)-13a and (aR,S)-13c. (D) Comparison of the predicted ECD spectrum
using all geometries in the gas phase and the experimental ECD spectrum. (E) Comparison of the
predicted ECD spectrum using all geometries in liquid and the experimental ECD spectrum. The
standard derivation is 0.25 eV.
Finally, the simulated ECD spectra using all conformations in the gas phase was compared
with the experimental ECD spectrum in Fig. 5(D). Then the B3LYP/6-311+G(d)-optimized
conformations in CHCl3 were used in ECD simulations again at the B3LYP/6-311+G(d) level in
liquid using PCM model. Both ECD spectra were compared with each other (Fig. 5(E)). The ECD
curve predicted that 13 in the gas phase (Fig. 5(D) has less similarity than the one in liquid (Fig. 5
(E)) when they were compared to the experimental results.
Conclusion
We showed two stable chiral axial conformations of biscarboline amides without single
bond’s (axis’) rotation restriction at room temperature. The results had been confirmed by 1H and
13C NMR spectra respectively, variable temperature NMR and HPLC analyses taking compound
13 as an example. Furthermore, the conversion TS barrier was obtained. Its ECD was also
investigated experimentally and theoretically, and a good agreement between the predicted and
experimental ECD spectra was obtained.
Experimental details
General methods
All reactions were monitored by GF254 thin layer chromatography (TLC). Flash
chromatography was performed using silica gel (200-300 mesh). Optical rotations were performed
on an Optical Activity AA-55 polarimeter using a 10 cm cell with a Na 589 nm filter. HPLC
11

ACCEPTED MANUSCRIPT
analysis was performed with chiral columns and normal phase chromatographic column. 1H NMR
and 13C NMR were recorded on a Bruker AV-600 spectrometer in CDCl3 or DMSO-d6 with
tetramethyl-silane (TMS) as a reference. All solvents for the reactions were of reagent grade and
were dried and distilled before used.
General procedure for preparation of 13-19
To the solution of 12 (0.45 g, 1 mmol) and Et3N (0.41 ml, 3.0 mmol) in anhydrous CH2Cl2,
isobutyl-chloroformate was added drop-wisely (0.31 ml, 2.4 mmol) at 0oC. Amino acid ester (2.4
mmol) was added after 30 mins. The reaction was warmed to room temperature slowly and
detected by TLC until the reaction finished. Then, aqueous HCl solution (1 M) was added to
quench the reaction. Aqueous saturated NaHCO3 solution was used to adjust pH to 7-8 and the
mixture was washed with brine, dried over anhydrous Na2SO4. The solution was concentrated
under reduced pressure and the residue was purified with silica gel.
Compound 13: Following the general procedure mentioned above, it was obtained as yellow solid,
yield of 85%. MS-ESI, m/z 620.2 [M+H]+. [α]D25 -77.52 (c 2.37, CH2Cl2). 13A: 1H NMR (600 MHz,
CDCl3) δ 9.12 (s, 2H), 8.42 (d, J = 8.4 Hz, 1H), 8.33 (t, J = 7.5 Hz, 2H), 7.68 (ddd, J = 11.1, 8.2,
1.0 Hz, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.44 – 7.40 (m, 2H), 4.94 – 4.88 (m, 2H), 3.73 (s, 4H), 3.46
(s, 5H), 1.47 (d, J = 7.2 Hz, 4H). 13C NMR (151 MHz, CDCl3) δ 173.47, 164.71, 143.16, 138.45,
137.97, 137.36, 131.21, 129.34, 122.05, 121.43, 120.96, 114.94, 110.13, 52.34, 47.97, 32.67,
18.43.13B:1H NMR (600 MHz, CDCl3) δ 9.12 (s, 2H), 8.37 (d, J = 7.7 Hz, 1H), 8.33 (t, J = 7.5
Hz, 2H), 7.68 (ddd, J = 11.1, 8.2, 1.0 Hz, 2H), 7.46 (d, J = 8.3 Hz, 1H), 7.44 – 7.40 (m, 2H), 4.84
– 4.81 (m, 1H), 3.71 (s, 2H), 3.29 (s, 1H), 1.52 (d, J = 7.2 Hz, 2H).13C NMR (151 MHz, CDCl3) δ
173.17, 165.00, 142.96, 138.50, 138.23, 137.30, 130.89, 129.30, 122.13, 121.46, 120.96, 115.03,
109.92, 52.38, 48.33, 32.15, 18.29. Elemental analysis for C34H32N6O6: calcd. C: 65.80, H: 5.20,
N: 13.54, found: C:65.70, H:5.31, N:13.47.
Compound 14.Yellow solid, yield of 89%. MS-ESI, m/z 676.5 [M+H]+. [α]D25 -27.66 (c 2.41,
CH2Cl2). 14A: 1H NMR (600 MHz, CDCl3) δ 9.12 (s, 1H), 8.49 (d, J = 9.3 Hz, 1H), 8.34 (d, J =
2.9 Hz, 1H), 7.71 – 7.66 (m, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.45 – 7.41 (m, 2H), 4.82 (dd, J = 9.3,
5.3 Hz, 1H), 3.72 (s, 4H), 3.48 (s, 4H), 2.30 – 2.21 (m, 2H), 0.97 (d, J = 6.8 Hz, 4H), 0.88 (d,
J=6.8Hz, 4H). 13C NMR (151 MHz, CDCl3) δ 172.53, 165.17, 143.26, 138.53, 138.02, 137.48,
131.32, 129.31, 121.99, 121.47, 120.92, 114.94, 110.13, 57.46, 52.02, 32.81, 31.48, 19.18,
18.05.14B:1H NMR (600 MHz, CDCl3) δ 9.13 (s, 1H), 8.39 (d, J = 9.1 Hz, 1H), 8.33 (d, J = 2.9
Hz, 1H) , 7.71 – 7.66 (m, 2H), 7.47 (d, J = 8.3 Hz, 1H), 7.45 – 7.41 (m, 2H), 4.78 (dd, J = 9.1, 5.6
Hz, 1H), 3.69 (s, 2H), 3.39 (s, 2H), 2.30 – 2.21 (m, 2H), 1.01 (d, J = 6.8 Hz, 2H), 0.91 (d, J = 6.8
Hz, 2H), 13C NMR (151 MHz, CDCl3) δ 172.14, 165.17, 143.09, 138.51, 138.22, 137.44, 131.23,
129.33, 121.12, 121.53, 121.00, 115.08, 109.87, 57.59, 52.08, 32.46, 31.26, 19.27, 18.17.
Elemental analysis for C38H40N6O6: calcd. C: 67.44, H: 5.96, N: 12.42, found: C:67.28, H:6.11,
N:12.36.
Compound 15. Yellow solid, yield of 86%. MS-ESI, m/z 704.6 [M+H]+. [α]D25 -56.80 (c 2.47,
1
CH2Cl2). 15A: H NMR (600 MHz, CDCl3)δ 9.12 (s, 2H), 8.48 (d, J = 9.2 Hz, 1H), 8.34 (d, J =
3.3 Hz, 1H), 7.71 – 7.66 (m, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.43 (td, J = 7.5, 2.4 Hz, 2H), 4.86 (dd,
J = 9.2, 5.3 Hz, 1H), 3.72 (s, 4H), 3.49 (s, 4H), 1.99 – 1.94 (m, 1H), 1.50 – 1.40 (m, 2H), 0.92 (d,
J = 6.9 Hz, 4H), 0.84 (t, J = 7.4 Hz, 4H). 13C NMR (151 MHz, CDCl3) δ 172.50, 165.02, 143.29,
138.55, 138.09, 137.48, 131.36, 129.29, 121.96, 121.49, 120.91, 114.87, 110.12, 56.74, 51.92,
38.02, 32.84, 25.18, 15.64, 11.36.15B: 1H NMR (600 MHz, CDCl3) δ9.12 (s, 2H), 8.39 (d, J = 9.0
12

ACCEPTED MANUSCRIPT
Hz, 1H), 8.33 (d, J = 3.4 Hz, 1H), 7.71 – 7.66 (m, 2H), 7.46 (d, J = 8.3 Hz, 1H),7.43 (td, J = 7.5,
2.4 Hz, 2H), 4.84 – 4.80 (m, 1H), 3.68 (s, 2H), 3.40 (s, 2H), 2.05 – 2.00 (m, 1H), 1.20 – 1.13 (m,
2H), 0.97 (d, J = 6.8 Hz, 2H), 0.88 (t, J = 7.4 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ 172.02,
165.02, 143.12, 138.30, 138.09, 137.45, 131.28, 129.29, 122.10, 121.56, 120.99, 114.97, 109.82,
56.82, 51.98, 37.82, 32.49, 25.35, 15.71, 11.41. Elemental analysis for C40H44N6O6: calcd. C:
68.16, H: 6.29, N: 11.92, found: C:68.04, H:6.38, N:11.91
Compound 16. Yellow solid, yield of 84%. MS-ESI, m/z 772.6 [M+H]+. [α]D25 +48.25 (c
2.28,CH2Cl2). 16A: 1H NMR (600 MHz, CDCl3)δ9.09 (s, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.34 (dd,
J = 7.8, 4.6 Hz, 2H), 7.71 (dt, J = 15.3, 7.7 Hz, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.41 (d, J = 8.3 Hz,
1H), 7.00 (d, J = 7.4 Hz, 2H), 6.96 (t, J = 7.4 Hz, 1H), 6.75 (t, J = 7.7 Hz, 2H), 5.10 (dt, J = 8.8,
5.9 Hz, 1H), 3.72 (s, 3H), 3.11 (s, 3H), 3.29 (dd, J = 14.1, 5.4 Hz, 1H), 3.09 (dd, J = 8.0, 6.2 Hz,
2H). 13C NMR (151 MHz, CDCl3) δ 172.03, 164.89, 143.20, 138.40, 137.66, 137.18, 136.17,
131.27, 129.19, 129.02, 129.00, 128.24, 128.22, 126.85, 121.89, 121.44, 120.93, 114.63, 110.33,
52.87, 52.19, 37.92, 32.77. 16B:1H NMR (600 MHz, CDCl3) δ9.07 (s, 1H), 8.34 (dd, J = 7.8, 4.6
Hz, 2H), 8.29 (d, J = 7.6 Hz, 1H), 7.71 (dt, J = 15.3, 7.7 Hz, 2H), 7.45 (s, 1H), 7.44 (d, J = 4.2 Hz,
1H), 7.04 (d, J = 7.2 Hz, 2H), 6.89 (t, J = 7.5 Hz, 2H), 6.57 (t, J = 7.4 Hz, 1H), 5.05 (td, J = 7.7,
5.5 Hz, 1H), 3.68 (s, 3H), 3.32 (s, 3H), 3.23 (dd, J = 13.9, 5.8 Hz, 1H), 3.09 (dd, J = 8.0, 6.2 Hz,
2H). 13C NMR (151 MHz, CDCl3) δ 171.89, 164.95, 142.95, 138.33, 137.76, 137.18, 135.58,
131.03, 129.27, 129.04, 129.04, 128.40, 128.40, 126.88, 122.10, 121.42, 121.00, 114.79, 109.95,
53.35, 52.34, 37.68, 32.41. Elemental analysis for C46H40N6O6: calcd. C: 71.49, H: 5.22, N: 10.87,
found: C:71.35, H:5.33, N:10.83.
Compound 17. Yellow solid, yield of 65% (0.55g). MS-ESI, m/z 851 [M+H]+. [α]D25 -28.35 (c
3.65,CH2Cl2). 17A: 1H NMR (600 MHz, CDCl3) δ 9.10 (s, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.38 (d,
J = 7.9 Hz, 1H), 8.34 – 8.28 (m, 2H), 7.74 – 7.69 (m, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 8.3
Hz, 1H), 7.14 (s, 1H), 6.94 (dd, J = 5.8, 3.1 Hz, 1H), 6.78 (dd, J = 17.3, 8.3 Hz, 2H), 6.71 (d, J =
1.6 Hz, 1H), 5.15 (dt, J = 10.3, 5.3 Hz, 1H), 3.67 (d, J = 7.6 Hz, 3H), 3.45 (dt, J = 12.3, 5.9 Hz,
2H), 3.31 (s, 3H), 3.26 (dd, J = 15.0, 5.1Hz, 1H), 13C NMR (150 MHz, CDCl3) δ 172.42, 165.41,
142.88, 138.41, 137.24, 136.04, 130.59, 129.27, 127.11, 122.58, 122.31, 121.99, 121.41, 121.05,
119.00, 117.99, 114.57, 111.17, 110.31, 109.95, 108.77, 52.39, 52.31, 31.48, 26.87.17B:1H NMR
(600 MHz, CDCl3) δ9.07 (s, 1H), 8.55 (d, J = 7.1 Hz, 1H), 8.38 (d, J = 7.9 Hz, 1H), 8.34 – 8.28
(m, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.8 Hz, 3H), 7.32 (d, J = 8.3 Hz, 1H), 7.14 (s, 1H),
6.87 (t, J = 7.5 Hz, 1H), 6.74 (dd, J = 6.0, 3.0 Hz, 2H), 6.68 (d, J = 1.7 Hz, 1H), 5.04 (dd, J = 12.4,
5.5 Hz, 1H), 3.81 (s, 3H), 3.45 (dt, J = 12.3, 5.9 Hz, 2H), 3.36 (dd, J = 15.0, 5.3 Hz, 1H), 2.88(s,
3H). 13C NMR (150 MHz, CDCl3) δ 173.06, 164.92, 143.15, 138.44, 137.90, 137.24, 131.20,
129.31, 127.20, 122.11, 121.97, 121.84, 121.36, 120.99, 119.31, 118.34, 114.62, 111.17, 110.90,
109.75, 109.08, 52.56, 52.29, 32.82, 27.57. Elemental analysis for C46H40N6O8: calcd. C: 70.57, H:
4.98, N: 13.17, found: C:70.38, H:5.13, N:13.14.
Compound 18.Yellow solid, yield of 54% (0.43g). MS-ESI, m/z 805 [M+H]+. [α]2D5 -5.34 (c
6.87,CH2Cl2). 18A: 1H NMR (600 MHz, CDCl3)δ 8.91 (s, 2H), 8.42 (d, J = 8.3 Hz, 1H), 8.12 (t, J
= 7.6 Hz, 2H), 7.53 (dt, J = 19.6, 7.7 Hz, 2H), 7.35 (dd, J = 8.3, 4.5 Hz, 2H), 7.27 (dt, J = 17.1,
7.5 Hz, 2H), 6.74 (dd, J = 16.6, 8.4 Hz, 4H), 6.34 (d, J = 8.4 Hz, 2H), 6.27 (d, J = 8.3 Hz, 2H),
4.92 (dd, J = 13.3, 7.3 Hz, 1H), 3.67 (s, 3H), 3.26 (s, 3H), 3.09 – 3.06 (m, 1H), 3.05 (d, J = 5.9 Hz,
2H), 13C NMR (150 MHz, CDCl3) δ 171.65, 164.19, 153.96 , 141.80, 137.33, 136.85, 136.19,
130.02, 129.06, 128.26, 126.31, 120.26, 120.3, 119.94, 114.5, 113.7, 108.9, 52.13, 51.54, 35.37,
13

ACCEPTED MANUSCRIPT
1
31.53.18B: H NMR (600 MHz, CDCl3) δ 8.91 (s, 2H), 8.30 (d, J = 7.6 Hz, 1H), 8.12 (t, J = 7.6
Hz, 2H), 7.53 (dt, J = 19.6, 7.7 Hz, 2H), 7.35 (dd, J = 8.3, 4.5 Hz, 2H), 7.27 (dt, J = 17.1, 7.5 Hz,
2H), 6.34 (d, J = 8.4 Hz, 2H), 6.27 (d, J = 8.3 Hz, 2H), 4.87 (dd, J = 13.3, 5.8 Hz, 1H), 3.63 (s,
3H), 3.05 (d, J = 5.9 Hz, 2H), 2.99 (s, 3H), 2.98 – 2.95 (m, 1H). 13C NMR (150 MHz, CDCl3) δ
171.10, 164.39, 154.42 , 141.99, 137.40, 136.44, 136.11, 129.61, 129.19, 128.26, 125.61, 120.90,
120.28, 119.96, 114.5, 113.7, 108.9, 52.65, 51.34, 35.80, 30.91. Elemental analysis: calcd. C:
68.65, H: 5.01, N: 10.44, found: C:68.52, H:5.13, N:10.40.
Compound 19.Yellow solid, yield of 50% (0.35g). MS-ESI, m/z 705 [M+H]+. [α]2D5 -72.32 (c
2.95,CH2Cl2). 19A: 1H NMR (600 MHz, CDCl3) δ 9.13 (s, 1H), 8.34 – 8.30 (m, 3H), 7.69 (q, J =
7.2 Hz, 2H), 7.53 (d, J = 8.3 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 4.97 (td, J = 9.4, 4.4 Hz, 1H), 3.73
(s, 4H), 3.48 (s, 4H), 1.76 (dd, J = 11.5, 6.3 Hz, 1H), 1.72 – 1.66 (m, 4H), 0.97 (t, J = 5.4 Hz, 6H),
13C NMR (150 MHz, CDCl3) δ 173.56, 165.11, 143.20, 138.49, 138.19, 137.41, 131.23, 129.34,
1
122.13, 121.49, 121.02, 115.03, 110.18, 52.26, 51.08, 41.67, 32.78, 25.15, 22.87, 22.00. 19B: H
NMR (600 MHz, CDCl3) δ 9.12 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.69 (q, J = 7.2 Hz, 2H), 7.47 –
7.45 (m, 1H), 7.43 (t, J = 7.5 Hz, 2H), 4.86 (dd, J = 8.7, 5.2 Hz, 1H), 3.71 (s, 2H), 3.34 (s, 2H),
13
1.72 – 1.66 (m, 4H), 1.65 – 1.60 (m, 1H), 0.92 (d, J = 6.2 Hz, 2H), 0.88 (d, J = 5.9 Hz, 4H). C
NMR (150 MHz, CDCl3) δ 173.08, 165.06, 143.02, 138.47, 137.92, 137.38, 131.09, 129.34,
121.99, 121.46, 120.99, 114.98, 109.84, 52.23, 50.69, 41.30, 32.31, 24.85, 22.85, 21.69.
Elemental analysis for C40H44N6O6: calcd. C: 68.16, H: 6.29, N: 11.92, found: C:68.03, H:6.42,
N:11.89.
Variable temperature 1H NMR
Compound 13 (298 K, 25oC) 13A: 1H NMR (600 MHz, DMSO) δ 9.11 (s, H), 8.85 (d, J = 8.1 Hz,
1H), 8.59 (d, J = 2.5 Hz, 1H), 7.79 – 7.69 (m, 4H), 7.43 (td, J = 7.2, 2.7 Hz, 2H), 4.70 – 4.62 (m,
2H), 3.64 (s, 3H), 3.43 (s, 3H), 1.38 (d, J = 7.2 Hz, 3H). 13B: 1H NMR (600 MHz, DMSO) δ 9.12
(s, H), 8.88 (t, J = 8.2 Hz, 1H), 8.57 (d, J = 2.5 Hz, 1H), 7.79 – 7.69 (m, 4H), 7.43 (td, J = 7.2, 2.7
Hz, 2H), 4.70 – 4.62 (m, 2H), 3.61 (s, 3H), 3.35 (s, 3H), 1.40 (d, J = 7.2 Hz, 3H).
Compound 13 (323 K,50oC) 13A: 1H NMR (600 MHz, DMSO) δ 9.10 (s, H), 8.75 (d, J = 8.0 Hz,
1H), 8.56 (s, 1H), 7.77 – 7.71 (m, 4H), 7.44 (dd, J = 9.8, 4.9 Hz, 2H), 4.67 (dt, J = 14.8, 7.5 Hz,
2H), 3.65 (s, 3H), 3.43 (s, 3H), 1.39 (d, J = 7.2 Hz, 3H). 13B: 1H NMR (600 MHz, DMSO) δ 9.10
(s, H), 8.78 (d, J = 7.8 Hz, 1H), 8.57 (s, 1H), 7.77 – 7.71 (m, 4H), 7.44 (dd, J = 9.8, 4.9 Hz, 2H),
4.67 (dt, J = 14.8, 7.5 Hz, 2H), 3.63 (s, 3H), 3.35 (s, 3H), 1.43 – 1.40 (m, 3H).
Compound 13 (353 K, 80oC),1H NMR (600 MHz, DMSO) δ 9.09 (s, 2H), 8.65 (s, 2H), 8.54 (s,
1H), 8.53 (s, 1H), 7.72 (s, 4H), 7.44 (dt, J = 7.8, 3.8 Hz, 2H), 4.68 (s, 2H), 3.65 (s, 6H), 3.43 (s,
3H), 3.36 (s, 3H), 1.42 (s, 6H).
Compound 13 (373 K, 100 oC ),1H NMR (600 MHz, DMSO) δ 9.07 (s, 2H), 8.64 (s, 2H), 8.51 (s,
2H), 7.70 (s, 4H), 7.42 (s, 2H), 4.69 (s, 2H), 3.66 (s, 6H), 3.45 (s, 3H), 3.37 (s, 3H), 1.42 (s, 6H)
Compound 13 (393 K, 120 oC ),1H NMR (600 MHz, DMSO) δ 9.08 (s, 2H), 8.63 (s, 2H), 8.50 (s,
2H), , 7.70 (s, 4H), 7.43 (s, 2H), 4.68 (s, 2H), 3.66 (s, 6H), 3.45 (s, 3H), 3.36 (s, 3H), 1.42 (s, 6H)
Computational methods
Conformational searches were performed firstly by using MMFF94S force field via two
different packages, respectively. The stable conformations were 27 using Barista and 97 using
Compute VOA, respectively. All the conformations were optimized at the B3LYP/6-31G(d) level
in the gas phase. Total 21 conformations in 0-2.5 kcal/mol were selected for further optimizations
14

ACCEPTED MANUSCRIPT
at the B3LYP/6-311+G(d) level and the B3LYP/6-311++G(2d,p) level in the gas phase and liquid,
respectively. The geometries were then used for PES, TS computations and conformational
analyses.
Acknowledgement
Authors thank the financial support from Hebei University for “Talent Program”, the Education
Committee of Hebei Province (ZD2017004), and the computation support from the
High-Performance Computer Center in Hebei University.
References and Notes
(1) Zhu, H. J.; Jiang, J. X.; Saobo, S.; Pittman,C. U. J. Org. Chem.2005, 70, 261-267.
(2) (a) LaPlante, S. R.; Forgione, P.; Boucher, C.; Coulombe, R.;Gillard, J.; Hucke, O.; Jakalian,
A.; Joly, M.; Kukolj, G.; Lemke, C.; McCollum, R.; Titolo, S.; Beaulieu, P. L.; Stammers, T. J.
Med. Chem. 2014,57, 1944−1951. (b) LaPlante, S. R.; Fader, L. D.; Fandrick, K. R.; Fandrick, D.
R.; Hucke, O.; Kemper, R.; Miller, S. P. F.; Edwards, P. J. J. Med. Chem. 2011, 54, 7005−7022
(3) (a) Ren, J.; Cai, X. H.; Fan, H. F.; Cao, J. X.; Liao, T. G.; Luo X. D.; Zhu, H. J. Theochem.
2008, 870, 72-76. (b) Bringmann, G.; Tasler, S. Tetrahedron.2001, 57, 331-343
(4) Modarresi-Alam, A. R.; Keykha, H.; Khamooshi, F.; Dabbagh, H. A. Tetrahedron.2004, 60,
1525–1530.
(5) (a) Gunnter, H. NMR spectroscopy; 2nd ed. Wiley: New York, 1995; Chapter 9. (b) Garratt, P. J.;
Thom, S. N.; Wrigglesworth, R. Tetrahedron.1994, 50, 12219–12234. (c) Carlson, E.; Jones, F. B.;
Raban, M. Chem. Commun.1969, 1235–1237. (d) Dabbagh, H. A.; Modarresi-Alam, A. R. J.
Chem. Res. (S.) 2000, 190–192.
(6) (a) Erol, S.; Dogan, I. Chirality. 2012, 24, 493–498. (b) Isikgor, F. H.; Erol, S.; Dogan, I.;
Tetrahedron: Asymmetry. 2014, 25, 449–456. (c) Takahashi, I.; Morita, F.; Kusagaya, S.; Fukaya,
H.; Kitagawa, O. Tetrahedron: Asymmetry.2012, 23, 1657–1662. (d) Suzuki, Y.; Takahashi, I.;
Dobashi, Y.; Hasegawa, H.; Roussel, C.; Kitagawa, O. Tetrahedron Lett.2015, 56, 132–135. (e)
Suzumura, N.; Kageyama, M.; Kamimura, D.; Inagaki, T.; Dobashi, Y.; Hasegawa, H.; Fukaya, H.
Kitagawa, O. Tetrahedron Lett . 2012, 53, 4332–4336.
(7) Gasparrini, F.; Lunazzi, L.; Mazzanti, A.; Pierini, M.; Pietrusiewicz, K. M.; Villani, C. J. Am.
Chem. Soc. 2000,122,4776-4780.
(8) Zhang, Y.; Wang, Y. Q.; Dai, W. M. J. Org. Chem.2006, 71, 2445-2455.
(9) (a) Yu, H.; Li, W. X.; Wang, J. C.; Yang, Q.; Wang, H. J.; Zhang, C. C.; Ding, S. S.; Li,Y.; Zhu,
H. J. Tetrahedron. 2015, 71, 3491-3494. (b) Maurizio, P.; Fumio, S.; Hiroyuki, K.; Jun, U.; Shigeo,
Y. J. Org. Chem. 1996, 61, 2122-2124.
(10) Bai, B.; Shen, L.; Ren, J.; Zhu, H. J. Adv. Synth. &Catal.2012, 354, 354-358.
(11) Bai, B.; Zhu, H. J.; Pan, W. Tetrahedron.2012, 68, 6829-6836.
(12) Raban, M.; Jones, F. B. J. Am. Chem. Soc.1971, 93, 2692–2699.
(13) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Montgomery, J. A.; Vreven, Jr.; Kudin, T. K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.;
Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
15

ACCEPTED MANUSCRIPT
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, Klene, H. M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Adamo, C.; Jaramillo, J. R.; Gomperts, R. E.; Stratemann, O.; Yazyev, A. J.; Austin, R.; Cammi,
C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuk,
A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M.
W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03 User’s
Reference.Gaussian Inc. 2003, Carnegie, PA.15106, USA.
(14) For TS calculations, see: (a) Zhu, H. J. Organic Stereochemistry—experimental and
computational methods, Wiley-VCH, 2015. (b) Zhu, H. J. Modern Organic Stereochemistry,
Science Presses. (China), 2009. (c) Xiao, W. L.; Lei, C.; Ren, J.; Liao, T. G.; Pu, J. X.; Pittman, C.
U.; Lu, Y.; Zheng, Y. T.; Zhu, H. J.; Sun, H. D. Chem.-A J. Eur.2008, 14, 11584-11592. (d) Li, L.
C.; Jiang, J. X.; Ren, J.; Ren, Y.; Pittman, C. U.; Zhu, H. J. Eur. J. Org. Chem. 2006, 1981-1990.
(15) Foresman, J. B.; Frisch, Æ. Exploring chemistry with electronic structure method, 2nd ed.
Gaussian, Inc. Pittsburg, PA. 1996.
(16) (a) Berova, N.; Polavarapu, P. L.; Nakanish, K.; Woody, R. W. Comprehensive
ChiropticalSpectrascopy. John Wiley & Sons; Hoboken: New Jersey; 2011. (b) Batista, J. M.;
López SN, Jr.; Mota, J. S.; Vanzolini, K. L.; Cass, Q. B.;Rinaldo, D.; Vilegas, W.; Bolzani, V. S.;
Kato, M.J.; Furlan, M. Chirality . 2009, 21, 799–801. (c) Stephens, P. J.; Pan, J. J.; Devlin, F. J.;
Krohn, K.; Kurtan, T. J Org Chem.2007, 72, 3521-3536. (d) Zhu, H. J.; Li, W. X.; Hu, D. B.; Wen,
M. L. Tetrahedron.2014, 70, 8236-8238. (e) Ren, J.; Li, G. L.; Shen, L.; Zhang, G. L.; Nafie, L.;
Zhu, H. J. Tetrahedron. 2013, 69, 10351-10356. (f) Tirado-Rives, J.; Jorgensen, W. L. J Chem
Theo Comput .2008, 4, 297-306. (g) Masullo, M.; Bassarello, C.; Bifulco, G.; Piacente, S.
Tetrahedron .2010, 66, 139–145. (h) Ding, Y. Q.; Li, X. C.; Ferreira, D. J Nat Prod .2010, 73,
435–440. (i) He, P.; Wang, X. F.; Guo, X. J.; Zhou, C. Q.; Shen, S. G.; Hu, D. B.;Yang, X. L.; Luo,
D. Q.; Rina, D.; Zhu, H. J. Tetrahedron Lett . 2014, 55, 2965–2968. (j) Zhao, S. D.; Shen, L; Luo,
D. Q.; Zhu, H. J. Cur Org Chem. 2011, 15, 1843-1847. (k) Stephens, P; McCann, D. M.;
Cheeseman, J. R.; Frisch, M. J. Chirality. 2005, 17, S52-S64. (l) Nakanishi, K.; Berova, N.;
Woody, R. Ed.; VCH Publishers: New York, 1994, 361-398.
16