Synthesis and biological activity of C-7, C-9 and C-10 modified taxane analogues from 1-deoxybaccatin VI

Article abstract of DOI:10.1016/j.bmc.2020.115736

A series of C-7, C-9 and C-10 modified taxane analogues were synthesized and their in vitro anticancer activities against three human cancer cell lines: A-549 (human lung cancer cell line), MDA-MB-231 (human breast cancer cell line), A-549/T (human lung c

Full text of DOI:10.1016/j.bmc.2020.115736

Bioorganic & Medicinal Chemistry 28 (2020) 115736
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and biological activity of C-7, C-9 and C-10 modified taxane
analogues from 1-deoxybaccatin VI
Chenghu Xie , Yongmei Cui , Lanlan Li , Minmin Zhang , Hongchun Liub,⁎, Haixia Lina,⁎
a
a
b
b
a
Department of Chemistry, Innovative Drug Research Center, College of Sciences, Shanghai University, Shanghai, China
b
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
A series of C-7, C-9 and C-10 modified taxane analogues were synthesized and their in vitro anticancer activities
against three human cancer cell lines: A-549 (human lung cancer cell line), MDA-MB-231 (human breast cancer
cell line), A-549/T (human lung cancer resistant cell line) were studied. The novel 1-deoxybaccatin VI deriva-
tives modified with carbonate group at C-9 and C-10 positions enable the behavior of these compounds to be
evidently distinct from other similar compounds. The strong cytotoxicity in the three cell lines, especially in
drug-resistant cell line, showed by the newly synthesized taxane analogues indicated them as potential lead
compounds for anticancer drug design.
Paclitaxel
Taxane analogues
1
-Deoxybaccatin VI
Synthesis
In vitro anticancer activity
1
. Introduction
glycoprotein such as cabazitaxel 4.16 In 2002, C-9 and C-10
1
7
modified taxane analogues 5, 6 and 7 were reported to be similar
1
8
Paclitaxel (PTX) 1, a diterpenoid natural compound isolated from
and more potent than docetaxel, respectively. These results suggest
that substitutions at C7-C10 positions and carbonate group at C-1, C-14
positions may have profound influence on antitumor activity. Thus
further exploration of the effects of carbonate group at C-9 and C-10
positions could be fruitful for the discovery of new candidates for drug
development.
1
,2
the stem bark of Taxus brevifolia (Pacific yew) in 1971, and its deri-
vative docetaxel 2 approved by FDA to treat breast cancer in 1996 are
active against a number of cancer types including breast, lung, prostate,
3
–5
ovarian and some leukaemias,
due to their unique mechanism of
action by bonding tubulin, promoting microtuble assembly and stabi-
6
lizing microtubules, which ultimately disrupts mitosis and causes cell
1-Deoxybaccatin VI (8), which is extracted from roots of Taxus
chinensis in relatively high yield and reserves the essential pharmaco-
7
–9
death. However, difficulties related to formulation and multiple drug
resistance (MDR) limit the application of paclitaxel and its close ana-
1
9,20
phore, proves to be the valuable starting material for research.
As
1
0
21,22
logue docetaxel in cancer treatments. Therefore, it is essential to
develop novel taxoid anticancer drugs with fewer side effects, superior
pharmacological properties and improved activity against various
an ongoing part of our research on taxane analogues,
we developed
a series of 1-deoxypaclitaxel analogues 16a-h bearing different sub-
stituted groups at the C-3′-N-acyl position, C-7, C-9 and C-10 positions
from 1-deoxybaccatin VI. The activities of these newly synthesized
compounds against three cancer cell lines and cell survival data are also
reported in this paper.
1
1–13
classes of cancers.
The bioactive conformation of paclitaxel is important since it could
provide critical information that would allow the design of novel ana-
1
4
logues with simpler structures and increased potency against cancers.
A series of analogues, which bear a 1,14-carbonate moiety, exhibited
improved clinical properties such as oral bioavailability and broader
spectrum of antitumor activity. Ortataxel 3 (Fig. 1) not only exhibited
two orders of magnitude better cytotoxicity than paclitaxel against
drug-resistant cells but also a significant improvement in water solu-
2. Results and discussion
2.1. Chemistry
As shown in Scheme 1, selective deacetylation of the C-7, C-9, C-10
and C-13 acetoxyl groups without concomitant deacylation of the C-2
and C-4 acyloxy groups of 1-deoxybaccatin VI 8 afforded 9. Subsequent
carbonation of the C-9 and C-10 hydroxyl groups using
1
5
bility, and it has been selected for clinical development. In addition, it
has been proposed that the ability of C-10 taxane analogues to over-
come MDR in vitro is the result of reduced binding affinity for P-
⁎
Corresponding authors.
E-mail addresses: hchliu@simm.ac.cn (H. Liu), haixialin@staff.shu.edu.cn (H. Lin).
https://doi.org/10.1016/j.bmc.2020.115736
Received 2 May 2020; Received in revised form 20 August 2020; Accepted 23 August 2020
Available online 29 August 2020
0968-0896/ © 2020 Published by Elsevier Ltd.

C. Xie, et al.
Bioorganic & Medicinal Chemistry 28 (2020) 115736
Table 1
Cytotoxicity (IC50 a) values for paclitaxel and its analogues 16a-h.
Compound
IC50
±
SD (μM)
A549b
A549/Tc
MDA-MB-231d
1
1
1
1
1
1
1
1
6a
6b
6c
0.068 ± 0.023
0.115 ± 0.012
0.133 ± 0.028
0.069 ± 0.024
0.022 ± 0.004
0.062 ± 0.013
0.329 ± 0.003
0.408 ± 0.073
0.013 ± 0.003
2.339 ± 0.338
4.898 ± 1.006
1.028 ± 0.069
3.024 ± 0.053
0.229 ± 0.057
0.229 ± 0.035
2.885 ± 1.074
2.885 ± 0.069
1.584 ± 0.268
0.183 ± 0.035
0.182 ± 0.029
0.209 ± 0.020
0.068 ± 0.025
0.124 ± 0.008
0.119 ± 0.005
2.016 ± 0.369
1.950 ± 0.363
0.020 ± 0.001
6d
6e
6f
6 g
6 h
Paclitaxel
a
Cytotoxicity (IC50) was assayed by CCK-8 method under growing human
tumor cell lines were exposed for 72 h.
b
c
d
Human lung cancer cell line.
Human lung cancer resistant cell line.
Human breast cancer cell line
configuration (Scheme 1).2
9,30
Cyclic protection using 4-methoxy ben-
zaldehyde dimethyl acetal in the presence of catalytic amount of pyr-
idinium para-toluenesulfonate (PPTS) afforded 14a-h in 80%-90%
yields. Compounds 14a-h, after saponification to the corresponding
carboxylic acid without further purification, were then coupled with
compound 11 in the presence of EDC and DMAP to smoothly provide
the corresponding cyclic ester intermediates 15a-h with good to ex-
Fig. 1. Paclitaxel and paclitaxel analogues.
2
0,31
cellent yield (85%-92%).
After hydrolysis of the acetonide pro-
tecting groups under p-toluenesulfonic acid, the final products 16a-h
were afforded (Scheme 1).
2.2. Cytotoxicity assay
2
.2.1. Cytotoxicity to A-549, A-549/T and MDA-MB-231
The newly synthesized compounds 16a-h and paclitaxel were sub-
sequently evaluated in cytotoxicity assays employing the A-549 (human
lung cancer), MDA-MB-231 (human breast cancer), A549/T (human
3
2
lung cancer resitent) cell line by CCK-8 method. The inhibitory ac-
tivities (IC50) are summarized in Table 1.
As reported in Table 1, it was observed that most of compounds
exhibited reduced cytotoxicities against A549 and MDA-MB-231 human
cancer cell lines in comparison with paclitaxel. Among them, four
compounds 16a, 16d and 16e-f showed potent cytotoxicity with IC50
values in the range of 22–69 nM against A549 cell line and compound
Scheme 1. Reagents and conditions: (a) H
CDI, Et N, DCM/MeOH, rt, 6 h, 75%; (c) Ac
d) SOCl , MeOH, 0 ˚C to rt, overnight, 95%; (e) Carbonyl chloride, THF, sat.
NaHCO , 0 ˚C to rt, 3 h, 85%-95%; (f) 4-Methoxybenzaldehyde dimethyl acetal,
PPTS, toluene, 110 ˚C, 80%-90%; (g) KOH, MeOH, rt, 2 h, 85%-95%; (h) EDC,
DMAP, CH Cl , 50 ˚C, 2 h, 85%-90%; (i) PTS, MeOH, rt, 5 h, 80%-85%.
2
NNH
2
·H
2
O, EtOH, rt, 40 h, 87%; (b)
1
6e exhibited the highest cytotoxicity activity with IC50 of 22 nM. For
3
2
O, DMAP, THF, rt, 1 h, 92% (11);
MDA-MB-231 cell line, all compounds showed much weaker cytotoxi-
city activities than paclitaxel in this assay.
(
2
3
Although these new taxoids 16a-h possess, in general, weaker cy-
totoxicities against A549 and MDA-MB-231 normal cancer cell lines
than paclitaxel, it can be noted that compounds 16e and 16f exert re-
markable cytotoxic effects against the drug-resistant human lung cancer
cell line, A549/T, with IC50 values 7-fold lower than that of paclitaxel.
The notable compound 16e with benzoyl substituents at the C-3′-N
shows the highest activity against both A549 and A549/T cell lines. In
our previous investigation of 1-deoxypaclitaxel analogues, we dis-
covered that compound 17 possessed a 10-fold reduced cytotoxicity
2
2
carbonyldiimidazole (CDI) gave compound 10 due to the smaller
stereo-hindrance effect on the C-9 and C-10 hydroxyl groups compared
with C-7 and C-9 hydroxyl groups, in which only two hydroxyls re-
mained at the C-7 and C-13 positions. The C-7 hydroxyl group of 10 is
more active than C-13 hydroxyl group, which is distinctly different
from the 9,10-O-isopropylidene derivative in which the C-13 hydroxyl
group is more active than the C-7 hydroxyl group due to the huge
stereo-hindrance effect on the C-7 hydroxyl group caused by the acet-
1
9
against A 549 than paclitaxel, by comparing both the structures of
1
6e and 17 (Fig. 2), it is clear that a 9,10-O-isopropylidene group at the
2
3
9,10-positions markedly decreases cytotoxicity and the carbonate sub-
stituent at C-9,10 exerts a remarkable effect on the activity especially
against the drug-resistant human lung cancer cell line, A549/T. More-
over, the 1-deoxypaclitaxel 18 synthesized from 1-deoxybaccatin VI
exhibited comparable cytotoxicity to compound 17. These results sug-
gest that different substituents at C-9 and C-10 have great influences on
the cytotoxicity.
onide protection at the C-9 and C-10 positions. Thus, the acetyl group
was selectively introduced to C-7 position to afford 11 which can be
coupled with paclitaxel side chains by the EDC-DMAP method in to-
luene.
As previously reported, paclitaxel side chains can be synthesized by
2
4–29
different methods.
In this paper, we synthesized the oxazoline side
chain precursor by using (2R,3S)-3-phenylisoserine 12 with natural
The dose–response curves for paclitaxel and compounds 16a-h are
2

C. Xie, et al.
Bioorganic & Medicinal Chemistry 28 (2020) 115736
Fig. 2. Synthesis of compounds 16e (Scheme 1), 1719 and 18 21.
shown in Fig. 3. All exponentially growing human tumor cell lines ex-
posed for 72 h to paclitaxel and the compounds formulated in DMSO
solution (CCK-8 method) exhibited characteristic dose–response
3
3–35
curves.
In A549 and MDA-MB-23 cell lines, all of the compounds
exhibited weaker inhibition of cell survival than paclitaxel when the
concentration was less than 0.1 μM. However, in A549/T cell lines, all
of the compounds exhibited greater inhibition of cell survival than
paclitaxel when the concentration was 0.01–0.1 μM, which implied that
each of the compounds exhibited better efficacy than paclitaxel at this
range of concentration. The superior cytotoxicity activity against A549/
T of these compounds may be related to structural modifications at the
C-7, C-9 and C-10 positions.
3
. Conclusion
In summary, we have synthesized 1-deoxy taxane analogues from 1-
deoxybaccatin VI and found that analogue 16e based on the 9,10-car-
bonate taxane skeleton exhibits comparable cytotoxicity in A549 cell-
based assay relative to paclitaxel and shows 7-fold more potent than
paclitaxel in the A549/T assay. The new toxoids bearing different
substituted groups at C-3′-N position showed degrees of cytotoxicity.
Most of the compounds exhibited greater inhibition of cell survival than
paclitaxel in 0.01–0.1 μM concentration in A549/T cell lines, indicating
the advantage of introduction of carbonate group at the C-9 and C-10
positions. Further modifications of these structures with the aim of
improving the potency in vitro as well as the efficacy in vivo are in
progress.
4
. Experimental section
4.1. General chemical procedures
Commercially available reagents were purchased and were used
1
without further purification unless otherwise mentioned. H NMR and
1
3
C NMR spectra were recorded on a Bruker DM-500 MHz spectrometer
at 500.134 MHz and 125.771 MHz, respectively, with TMS as an in-
ternal standard. Chemical shifts are reported in parts per million (ppm)
and coupling constants (J) are reported in Hertz (Hz). Coupling patterns
are described by abbreviations: s (singlet), d (doublet), t (triplet), m
(
multiplet) and br (broad). Chemical shifts in CDCl
3
were reported in
1
the scale relative to CHCl
3
(7.26 ppm) for H NMR, and to CDCl
3
1
3
(
77.16 ppm) for C NMR, as internal references. Mass spectra were
recorded on a Varian 320-MS TQ LC/MS in positive electrospray ioni-
zation (ESI) mode. 1-deoxybaccatin VI (8) was isolated according to
literature procedures.
Fig. 3. Survival of three human tumor cell lines after exposure to compounds
1
6a-h and paclitaxel for 72 h. (a) A-549 (human lung cancer) cell line; (b) A-
4
.2. Synthetic procedures
5
49/T (human lung cancer resistant) cell line; (c) MDA-MB-231 (human breast
cancer) cell line.
4.2.1. Synthesis of compound 9
Compound 8 (2.0 g, 2.87 mol) was dissolved in 95% ethanol
recrystallized from a mixture of methanol and water to yield 9 (1.4 g,
(
140 mL) and treated with hydrazine hydrate (75 mL) at 26 ˚C for 12 h.
1
8
7%) as a white solid. H NMR (500 MHz, CDCl
3
): δ ppm 8.02 (d,
After careful neutralization (1 N HCl, pH = 7), the mixture was ex-
tracted with EtOAc and worked up in the usual manner, then
J = 7.4 Hz, 2H), 7.69 (m, 1H), 7.58 (m, 2H), 6.27 (br, 1H), 6.08 (br,
3

C. Xie, et al.
Bioorganic & Medicinal Chemistry 28 (2020) 115736
1
H), 5.58 (dd, J = 4.4, 1.7 Hz, 1H), 4.99 (d, J = 4.6 Hz, 1H), 4.90 (d,
Na
2
SO
4
and the solvent was evaporated under reduced pressure, and
J = 9.1 Hz, 1H), 4.68 (d, J = 10.4 Hz, 1H), 4.45–4.26 (m, 2H), 4.22 (t,
J = 8.3 Hz, 1H), 4.15 (d, J = 8.0 Hz, 1H), 4.08–4.01 (br, 1H), 3.95 (d,
J = 8.0 Hz, 1H), 2.87 (d, J = 5.3 Hz, 1H), 2.37–2.26 (m, 2H), 1.84 (s,
the resulting oil was purified by silica gel column chromatography
(EtOAc: hexane = 1: 3), yielding a product 13a-h (80%-90%).
3
1
1
7
1
H), 1.72 (dd, J = 8.7, 0.8 Hz, 1H), 1.67–1.64 (m, 2H), 1.59 (s, 6H),
4.3.1. Compound 13a
1
3
1
.01 (s, 3H). C NMR (125 MHz, CDCl
3
): δ ppm 169.5, 164.8, 138.4,
H NMR (500 MHz, CDCl ): δ ppm 7.53 (d, J = 7.85 Hz, 2H), 7.48
3
36.2, 134.0, 130.0, 129.7, 129.3, 83.7, 81.0, 78.9, 76.2, 73.4, 72.2,
(d, J = 5.90 Hz, 2H), 7.43–7.31 (m, 5H), 7.03 (br, 1H), 5.77 (dd,
13
0.8, 65.6, 47.6, 44.2, 43.8, 38.1, 37.8, 32.1, 30.3, 27.0, 23.0, 15.5,
3.0.
J = 5.80 Hz, 2.00 Hz, 1H), 4.77 (d, J = 2.61 Hz, 1H), 3.85 (s, 3H).
C
NMR (125 MHz, CDCl ) δ ppm: 171.7, 171.3, 165.5, 165.5, 164.9,
3
1
63.8, 158.8, 153.1, 143.1, 136.0, 131.9, 130.4, 128.8, 128.3, 127.3,
4.2.2. Synthesis of compound 10
118.9, 73.5, 54.8, 47.5.
To a solution of 9 (530.8 mg, 1.0 mmol) in a mixture of CH
2
Cl
2
(
12 mL) and CH
3
OH (0.5 mL) were added carbonyldiimidazole
4.3.2. Compound 13b
1
(
162 mg, 4.0 mmol) followed by Et
3
N (0.25 mL, 8 mmol), and the re-
H NMR (500 MHz, CDCl ): δ ppm 7.96–7.90 (m, 1H), 7.52–7.46
3
action mixture was vigorously stirred for 4 h at 50 ˚C. The solution was
filtered and evaporated to a white residue, which was recrystallized
(m, 5H), 7.33 (d, J = 7.36 Hz, 1H), 7.25–7.22 (m, 1H), 7.19–7.13 (m,
1H), 5.77 (dd, J = 5.76, 1.91 Hz, 1H), 4.72 (d, J = 2.58 Hz, 1H), 3.84
1
13
from acetonitrile, affording compound 10 (418.5 mg, 75%). H NMR
(s, 3H). C NMR (125 MHz, CDCl
3
) δ ppm 171.3, 171.2, 164.9, 162.7,
(
500 MHz, CDCl
3
): δ ppm 8.06 (d, J = 7.43 Hz, 2H), 7.62 (t,
161.8, 159.8, 153.1, 143.3, 133.7, 132.2, 131.9, 129.8, 128.8, 128.2,
J = 7.40 Hz, 1H), 7.49 (t, J = 7.85 Hz, 2H), 5.74 (dd, J = 5.90,
127.3, 84.1, 73.9, 55.9, 47.5.
2
4
4
.40 Hz, 1H), 5.73 (d, J = 12.20 Hz, 1H), 5.24 (d, J = 12.20 Hz, 1H),
.93 (d, J = 8.85 Hz, 1H), 4.66 (br, 1H), 4.37 (d, J = 8.35 Hz, 1H),
.30 (td, J = 9.20 Hz, 3.80 Hz, 1H), 4.08 (d, J = 8.35 Hz, 1H), 2.69 (d,
4.3.3. Compound 13c
1
H NMR (500 MHz, CDCl ): δ ppm 7.80–7.76 (m, 2H), 7.45 (d,
3
J = 5.45 Hz, 1H), 2.67–2.56 (m, 2H), 2.25 (s, 3H), 2.15 (d, J = 6.70,
J = 8.0 Hz, 2H), 7.37 (t, J = 15.5 Hz, 2H), 7.31 (t, J = 15.0 Hz, 1H),
1
H), 2.08 (s, 3H), 2.00 (m, 1H), 1.88–1.82 (m, 1H), 1.75 (s, 3H), 1.71
7.08 (t, J = 18.5 Hz, 2H), 5.74 (dd, J = 2.3, 2.5 Hz, 1H), 4.64 (d,
1
3
13
(
s, 3H), 1.12 (s, 3H). C NMR (125 MHz, CDCl
3
) δ ppm: 171.8, 165.0,
J = 2.2 Hz, 1H), 4.60 (s, 1H), 3.83 (s, 3H). C NMR (125 MHz, CDCl
3
)
1
7
1
34.1, 131.8, 129.9, 129.1, 126.9, 84.1, 83.9, 81.0, 78.0, 76.8, 71.4,
δ ppm:173.4, 166.0, 165.9, 163.9, 138.6, 130.2, 130.1, 129.6, 129.5,
0.5, 69.0, 47.5, 42.6, 38.3, 36.7, 34.3, 31.7, 31.6, 26.8, 26.1, 22.3,
5.5, 13.9, 13.1.
128.8, 128.0, 126.9, 115.6, 73.3, 55.0, 53.2.
4.3.4. Compound 13d
1
4.2.3. Synthesis of compound 11
H NMR (500 MHz, CDCl ): δ ppm 7.76 (d, J = 8.5 Hz, 2H), 7.47 (d,
3
To a stirred solution of 10 (53.0 mg, 0.10 mmol) and DMAP
J = 8.3 Hz, 2H), 7.38 (t, J = 15.4 Hz, 2H), 7.32 (t, J = 15.5 Hz, 1H),
6.94 (d, J = 8.4 Hz, 3H), 5.74 (d, J = 9.5 Hz, 1H), 4.65 (s, 1H), 3.87 (s,
(
48.9 mg, 0.4 mmol) in dry THF (8 mL) was added Ac
2
O (0.08 mL,
1
3
0
.4 mmol) dropwise. After stirred at 25 °C for 4 h, the reaction mixture
3H), 3.85 (s, 3H). C NMR (125 MHz, CDCl ) δ ppm: 173.4, 166.4,
3
was quenched with saturated aq. NaHCO
3
, and then the solvent was
162.7, 138.9, 129.8, 129.7, 128.9, 128.8, 128.5, 127.9, 126.9, 126.3,
113.8, 73.3, 55.4, 54.8, 53.3.
evaporated under reduced pressure, followed by adding of EtOAc, the
organic layer was washed by H O (3 × 15 mL), dried over anhydrous
2
Na
2
SO
4
and concentrated in vacuo. The crude residue was purified by
4.3.5. Compound 13e
1
column chromatography on silica gel (eluent: EtOAc: hexane = 2: 1) to
H NMR (500 MHz, CDCl ): δ ppm 7.77 (d, J = 7.45 Hz, 2H), 7.51
3
1
afford 11 as a white solid (50.8 mg, 85%). H NMR (500 MHz, CDCl
3
): δ
(t, J = 7.05 Hz, 1H), 7.44 (t, J = 7.45 Hz, 4H), 7.36 (t, J = 7.40 Hz,
ppm 8.07 (d, J = 7.43 Hz, 2H), 7.62 (t, J = 7.40 Hz, 1H), 7.49 (t,
J = 7.85 Hz, 2H), 5.96 (d, J = 12.25 Hz, 1H), 5.70 (dd, J = 5.90,
2H), 7.31 (m, 1H), 7.03 (br, 1H), 5.75 (dd, J = 9.10, 1.70 Hz, 1H), 4.63
1
3
(br, 1H), 3.84 (s, 3H). C NMR (125 MHz, CDCl ) δ ppm: 173.4, 166.8,
3
2
4
4
2
1
.40 Hz, 1H), 5.49 (t, J = 8.81 Hz, 1H), 5.10 (d, J = 12.25 Hz, 1H),
.93 (d, J = 8.85 Hz, 1H), 4.66 (br, 1H), 4.37 (d, J = 8.35 Hz, 1H),
.08 (d, J = 8.35 Hz, 1H), 2.75 (d, J = 5.45 Hz, 1H), 2.62–2.48 (m,
H), 2.25(s, 3H), 2.16 (d, J = 6.70, 1H), 2.13 (s, 3H), 2.10 (s, 3H),
143.3, 138.2, 132.0, 129.1, 128.9, 128.4, 127.4, 127.1, 126.3, 113.8,
73.6, 54.8, 47.6.
4.3.6. Compound 13f
1
3
1
.99–1.93 (m, 2H), 1.79 (s, 3H), 1.67 (s, 3H), 1.10 (s, 3H). C NMR
H NMR (500 MHz, CDCl ): δ ppm 7.69 (d, J = 8.5 Hz, 2H), 7.47 (d,
3
(
125 MHz, CDCl
3
): δ ppm 171.8, 171.1, 165.0, 134.1, 131.8, 129.9,
J = 7 0.7 Hz, 2H), 7.39 (d, J = 15.5 Hz, 2H), 7.32 (t, J = 15.4 Hz, 1H),
1
3
29.0, 126.8, 84.1, 83.9, 81.0, 78.0, 76.8, 71.4, 70.5, 69.0, 47.5, 42.6,
8.3, 36.7, 34.3, 31.7, 31.6, 26.8, 26.1, 22.3, 21.4, 15.5, 13.9, 13.1.
7.25 (d, J = 7.5 Hz, 2H), 6.96 (br, 1H), 5.76 (dd, J = 5.8, 2.4 Hz, 1H),
1
3
4.66 (d, J = 5.2 Hz, 1H), 3.86 (s, 3H), 2.42 (s, 3H). C NMR (125 MHz,
CDCl ) δ ppm:173.5, 167.0, 142.3, 138.8, 131.2, 130.2, 129.3, 129.2,
3
4.3. General procedure for synthesis of compounds 13a-h
128.7, 127.9, 127.2, 127.0, 73.3, 54.9, 53.2, 21.5.
To a solution of (2R,3S)-3-Phenylisoserine 12 (100 mg, 0.52 mmol)
4.3.7. Compound 13g
1
in anhydrous MeOH (3 mL), thionyl chloride (SOCl
2
, 0.05 mL,
H NMR (500 MHz, CDCl ): δ ppm 7.57 (d, J = 8.8 Hz, 2H), 7.46 (d,
3
0
.79 mmol) was added drop-wise at 0 °C. The reaction mixture was
J = 7.7 Hz, 2H), 7.39 (t, J = 15.5 Hz, 1H), 7.34–7.30 (m, 1H), 7.04 (d,
stirred overnight at room temperature and the reactionwas monitored
by TLC. After the completion of the reaction, the reaction was quenched
J = 9.5 Hz, 1H), 5.72 (m, 1H), 4.65 (d, J = 2.2 Hz, 1H), 3.86 (s, 3H).
1
3
C NMR (125 MHz, CDCl ) δ ppm: 173.3, 157.6, 147.4, 144.2, 138.6,
3
with NaHCO
3
. The solution was evaporated under reduced pressure and
131.9, 130.4, 129.0, 128.9, 128.8, 128.0, 127.0, 114.9, 112.2, 55.1,
53.3.
diluted with H
2
O. The water phasewas extracted with EtOAc three
times, the combined organic solution was dried over Na
2
SO and the
4
solvent was removed under reduced pressure, resulting in an oil. To a
solution of the resulting oil in a mixture of THF (10 mL) and saturated
4.3.8. Compound 13h
1
H NMR (500 MHz, CDCl ) δ ppm: 7.57 (m, 1H), 7.44 (s, 1H), 7.38
3
NaHCO
3
(10 mL), one of a series of different carbonyl chlorides
(d, J = 7.3 Hz, 2H), 7.32 (t, J = 7.4 Hz, 2H), 7.26 (d, J = 7.1 Hz, 1H),
7.18–7.13 (m, 1H), 5.64 (d, J = 8.7 Hz, 1H), 4.57 (d, J = 2.0 Hz, 1H),
(
3 mmol) was added dropwise at 0 °C, respectively. The whole mixture
1
3
was stirred vigorously at room temperature for 3 h. The desired com-
pound was extracted with EtOAc. The organic solution was dried over
3.84 (s, 3H). C NMR (125 MHz, CDCl ) δ ppm: 173.2, 165.4, 161.0,
3
145.6, 140.9, 138.3, 133.2, 131.8, 131.3, 129.0, 128.7, 127.9, 127.0,
4

C. Xie, et al.
Bioorganic & Medicinal Chemistry 28 (2020) 115736
1
16.5, 109.3, 73.5, 55.7.
129.3, 129.2, 128.7, 127.9, 127.2, 127.0, 74.5, 73.3, 54.9, 53.2, 21.5.
4
.4. General procedure for synthesis of compounds 14a-h
4.4.7. Compound 14 g
1
H NMR (500 MHz, CDCl ): δ ppm 7.57 (d, J = 8.8 Hz, 2H), 7.46 (d,
3
The resulting solid 13a-h (1.0 mmol) and pyridinium p-toluene-
J = 7.7 Hz, 2H), 7.39 (t, J = 15.5 Hz, 1H), 7.34–7.30 (m, 5H), 7.04 (d,
J = 9.5 Hz, 1H), 5.89 (br, 1H), 5.72 (dd, J = 2.1, 2.1 Hz, 1H), 4.65 (d,
sulfonate (PPTS) (0.1 mmol) were dissolved in anhydrous toluene
1
3
(
8 mL), and 4-methoxybenzaldehyde dimethyl acetal (1.5 mmol) was
subsequently added drop-wise under an argon atmosphere. Following
0 min of heating at reflux, the reaction mixture was allowed to cool to
ambient temperature and was diluted with Et O. The organic layer was
washed successively with water, saturated NaHCO , water and brine;
J = 2.2 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H). C NMR (125 MHz, CDCl )
3
δ ppm: 173.3, 157.6, 147.4, 144.2, 138.6, 129.4, 129.2, 129.0, 128.9,
4
128.8, 128.0, 127.2, 127.1, 127.0, 114.9, 112.2, 74.4, 55.1, 53.3.
2
3
4.4.8. Compound 14 h
1
the solution was dried over Na
2
SO
4
; and solvents were removed under
H NMR (500 MHz, CDCl ) δ ppm: 7.57 (m, 3H), 7.44 (s, 1H), 7.38
3
reduced pressure. The resulting oil was purified by silica gel column
(d, J = 7.3 Hz, 2H), 7.32 (t, J = 7.4 Hz, 2H), 7.26 (d, J = 7.1 Hz, 1H),
7.18–7.13 (m, 3H), 5.94 (br, 1H). 5.64 (d, J = 8.7 Hz, 1H), 4.57 (d,
chromatography (EtOAc: hexane = 1: 4), yielding a product 14a-h
1
3
(
80%-90%).
J = 2.0 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H). C NMR (125 MHz, CDCl )
3
δ ppm: 173.2, 165.4, 161.0, 145.6, 140.9, 138.3, 133.2, 131.8, 131.3,
129.4, 129.2, 129.0, 128.7, 128.7, 128.4, 127.9, 127.0, 116.5, 109.3,
74.5, 73.5, 55.7.
4
.4.1. Compound 14a
1
H NMR (500 MHz, CDCl ): δ ppm 7.53 (d, J = 7.85 Hz, 2H), 7.48
3
(
d, J = 5.90 Hz, 2H), 7.43–7.31 (m, 5H), 7.30–7.21 (m, 4H), 7.03 (br,
1
H), 5.89 (br, 1H), 5.77 (dd, J = 5.80, 2.00 Hz, 1H), 4.77 (d,
4.5. General procedure for synthesis of compounds 15a-h
1
3
J = 2.61 Hz, 1H), 3.85 (s, 3H), 3.85 (s, 3H). C NMR (125 MHz,
CDCl
3
): δ ppm 171.7, 171.3, 165.5, 165.5, 164.9, 163.8, 158.8, 153.1,
A solution of KOH (1.1 mmol) in water (4 mL) was added slowly at
room temperature to a stirred solution of 14a-h in MeOH (30 mL). The
reaction mixturewas stirred for 2 h. After the completion of the reac-
tion, MeOH was evaporated under reduced pressure. The residual
1
1
43.1, 136.0, 131.9, 130.4, 129.2, 129.2, 128.8, 128.6, 128.3, 128.2,
27.3, 118.9, 73.5, 73.2, 54.8, 47.5.
4.4.2. Compound 14b
mixture successively was diluted with water, washed with Et O, acid-
2
1
H NMR (500 MHz, CDCl
3
): δ ppm 7.96–7.90 (m, 1H), 7.52–7.46
ified with 1 N HCl, and extracted with EtOAc successively. The organic
(
m, 5H), 7.33 (d, J = 7.36 Hz, 1H), 7.25–7.22 (m, 3H), 7.19–7.13 (m,
phase was dried over Na
2
SO and evaporated under reduced pressure.
4
3
H), 5.89 (br, 1H), 5.77 (dd, J = 5.76, 1.91 Hz, 1H), 4.72 (d,
The resulting solid (2.0 mmol), compound 11 (1.0 mmol), EDC
(2.0 mmol) and DMAP (1.0 mmol) were dissolved in an hydrous toluene
(6.0 mL), and the reaction mixture was stirred for 2 h at room tem-
perature. The reaction mixture was diluted with EtOAc and washed
1
3
J = 2.58 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H). C NMR (125 MHz,
CDCl
3
) δ ppm: 171.3, 171.2, 164.9, 162.7, 161.8, 159.8, 153.1, 143.3,
1
1
33.7, 132.2, 131.9, 129.8, 129.4, 129.2, 128.8, 128.6, 128.2, 128.1,
27.3, 84.1, 73.9, 73.4, 55.9, 47.5.
with saturated NH
4
Cl, water, saturated NaHCO
3
, and brine. The organic
layer was dried over Na
2
SO and the solvent was removed under re-
4
4.4.3. Compound 14c
duced pressure. The resulting oil was purified by silica gel column
chromatography (EtOAc: hexane = 1: 3), yielding 15a-h as a white
solid (85%-90%).
1
H NMR (500 MHz, CDCl ): δ ppm 7.80–7.76 (m, 2H), 7.45 (d,
3
J = 8.0 Hz, 2H), 7.37 (t, J = 15.5 Hz, 2H), 7.31 (t, J = 15.0 Hz, 1H),
7
,21–7.08 (m, 6H), 5.87(br, 1H), 5.74 (dd, J = 2.3, 2.5 Hz, 1H), 4.64
13
(
d, J = 2.2 Hz, 1H), 4.60 (s, 1H), 3.83 (s, 3H), 3.81 (s, 3H). C NMR
4.5.1. Compound 15a
1
(
125 MHz, CDCl
3
) δ ppm: 173.4, 171.2, 166.0, 165.9, 163.9, 159.8,
H NMR (500 MHz, CDCl ): δ ppmδ ppm 8.04 (d, J = 8.05 Hz, 2H),
3
1
1
53.1,138.6, 130.2, 130.1, 129.6, 129.5, 129.4, 129.3, 128.8, 128.0,
7.61 (t, J = 7.51 Hz, 1H), 7.47 (t, J = 7.85 Hz, 4H), 7.41–7.28 (m, 7H),
26.9, 115.6, 74.2, 73.3, 55.0, 53.2.
7.24–7.19 (m, 2H), 6.92–6.80 (br, 2H), 5.93 (t, J = 7.60 Hz, 1H), 5.87
(
d, J = 12.25 Hz, 1H), 5.78 (dd, J = 6.05, 2.25 Hz, 1H), 5.45 (br, 1H),
4.4.4. Compound 14d
5.39 (t, J = 8.90 Hz, 1H), 5.09 (d, J = 12.25 Hz, 1H), 4.91 (d,
J = 8.60 Hz, 1H), 4.77 (d, J = 2.61 Hz, 1H), 4.36 (d, J = 8.45 Hz, 1H),
4.10 (d, J = 8.45 Hz, 1H), 3.83 (s, 3H), 2.66 (d, J = 6.00 Hz, 1H),
2.71–2.48 (m, 2H), 2.29 (s, 3H), 2.09 (s, 3H), 2.05 (d, J = 9.45, 1H),
2.01–1.94 (m, 1H), 1.80 (s, 3H), 1.73 (s, 3H), 1.71(s, 3H), 1.58–1.51
1
H NMR (500 MHz, CDCl ): δ ppm 7.76 (d, J = 8.5 Hz, 2H), 7.47 (d,
3
J = 8.3 Hz, 2H), 7.38 (t, J = 15.4 Hz, 2H), 7.31–7.21 (m, 5H), 6.94 (d,
J = 8.4 Hz, 3H), 5.94 (br, 1H), 5.74 (d, J = 9.5 Hz, 1H), 4.65 (s, 1H),
1
3
3
.87 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H). C NMR (125 MHz, CDCl ) δ
3
1
3
ppm: 173.4, 166.4, 162.7, 138.9, 129.8, 129.7, 129.6, 129.5, 128.9,
(m, 1H), 1.20 (s, 3H). C NMR (125 MHz, CDCl ): δ ppm 171.7, 171.3,
3
1
5
28.8, 128.5, 128.7, 128.6, 127.9, 126.9, 126.3, 113.8, 74.3, 74.2,
5.4, 54.8, 53.3.
171.0, 165.5, 164.9, 143.1, 137.9, 136.0, 136.0, 134.0, 131.9, 130.4,
130.4, 129.8, 129.0, 128.8, 128.3, 127.3, 122.4, 122.4, 119.1, 118.9,
8
4.1, 83.8, 81.1, 78.0, 76.2, 73.5, 71.2, 70.4, 70.3, 47.5, 43.2, 42.6,
4
.4.5. Compound 14e
38.2, 34.3, 31.6, 26.7, 26.0, 22.6, 21.4, 15.6, 13.0.
1
H NMR (500 MHz, CDCl ): δ ppm 7.35 (t, J = 7.30 Hz, 1H),
3
7
5
.32–7.25 (m, 7H), 7.25–7.19 (m, 5H), 6.85 (br, 1H), 5.87 (br, 1H),
4.5.2. Compound 15b
1
3
1
.43 (br, 1H), 4.88 (s, 1H), 3.81 (s, 3H), 3.79 (s, 3H). C NMR
H NMR (500 MHz, CDCl ): δ ppm 8.04 (d, J = 8.05 Hz, 2H), 7.62
3
(
125 MHz, CDCl
3
) δ ppm: 171.0, 166.4, 153.2, 143.3, 138.9, 132.1,
(t, J = 7.97 Hz,1H), 7.55–7.45 (m, 5H), 7.41–7.34 (t, J = 7.03 Hz ,7H),
7.35–7.30 (m, 1H), 7.25–7.22 (m, 1H), 7.19–7.13 (m, 1H), 5.92 (t,
J = 8.10 Hz, 1H), 5.91–5.87 (m, 1H), 5.86 (d, J = 12.20 Hz, 1H), 5.77
1
5
29.9, 128.9, 128.8, 128.4 128.0, 127.2, 127.1, 126.3, 113.5, 74.3,
5.5, 54.8, 52.7.
(
dd, J = 5.76, 1.91 Hz, 1H), 5.45 (br, 1H), 5.39 (t, J = 9.08 Hz, 1H),
4.4.6. Compound 14f
5.08 (d, J = 12.20 Hz, 1H), 4.90 (d, J = 8.60 Hz, 1H), 4.72 (d,
J = 2.58 Hz, 1H), 4.36 (d, J = 8.45 Hz, 1H), 4.10 (d, J = 8.45 Hz, 1H),
3.85 (s, 3H), 2.72–2.65 (m, 1H), 2.67 (d, J = 5.98 Hz, 1H), 2.61–2.49
(m, 1H), 2.28 (s, 3H), 2.10 (s, 3H), 2.05 (d, J = 8.93, 1H), 2.01–1.94
(m, 2H), 1.80 (s, 3H), 1.73 (s, 3H), 1.71 (s, 3H), 1.55–1.49 (m, 1H),
1
H NMR (500 MHz, CDCl ): δ ppm 7.69 (d, J = 8.5 Hz, 2H), 7.47 (d,
3
J = 7 0.7 Hz, 2H), 7.39 (d, J = 15.5 Hz, 2H), 7.32 (t, J = 15.4 Hz, 1H),
7
4
.25 (d, J = 7.5 Hz, 2H), 6.96 (br, 1H), 5.76 (dd, J = 2.4, 2.4 Hz, 1H),
13
.66 (d, J = 5.2 Hz, 1H), 3.86 (s, 3H), 2.42 (s, 3H). C NMR (125 MHz,
) δ ppm: 173.5, 167.0, 142.3, 138.8, 131.2, 130.2, 129.8, 129.7,
CDCl
3
1.18 (s, 3H).13C NMR (125 MHz, CDCl
): δ ppm 171.3, 171.2, 171.0,
3
5

C. Xie, et al.
Bioorganic & Medicinal Chemistry 28 (2020) 115736
1
1
7
2
62.7, 161.8, 153.1, 143.3, 138.2, 134.0, 133.8, 133.7, 132.2, 130.9,
29.8, 129.0, 128.8, 128.2, 127.3, 84.1, 83.8, 81.2, 78.0, 76.2, 73.9,
1.3, 71.0, 70.5, 47.5, 43.2, 42.5, 38.2, 34.3, 31.9, 31.9, 31.6, 30.3,
6.8, 22.7, 22.5, 21.4, 15.6, 14.1, 13.0.
34.4, 31.7, 26.8, 26.1, 22.8, 22.6, 21.6, 21.5, 15.7, 14.3, 13.1.
4.5.7. Compound 15g
1
H NMR (500 MHz, CDCl ): δ ppm 8.04 (d, J = 7.50 Hz, 2H),
3
7
.92–7.68 (m, 3H), 7.65–7.60 (m, 2H), 7.51–7.45 (m, 4H), 7.38 (t,
4.5.3. Compound 15c
J = 7.10 Hz, 2H), 7.35–7.27 (m, 5H), 5.93 (t, J = 8.10 Hz, 1H), 5.87
(d, J = 12.20 Hz,1H), 5.81–5.75 (m, 2H), 5.45 (br, 1H), 5.39 (t,
J = 8.50 Hz, 1H), 5.08 (d, J = 12.20 Hz, 1H), 4.90 (d, J = 8.60 Hz,
1H), 4.75 (s, 1H), 4.36 (d, J = 8.40 Hz, 1H), 4.10 (d, J = 8.40 Hz, 1H),
3.83 (s, 3H), 2.68 (d, J = 5.65 Hz, 1H), 2.70–2.62 (m, 1H), 2.55–2.47
(m, 1H), 2.28 (s, 3H), 2.08 (s, 3H), 2.05 (d, J = 9.45 Hz, 1H), 2.00–1.93
(m, 1H), 1.83 (s, 3H), 1.80 (s, 3H), 1.71 (s, 3H), 1.58–1.51 (m, 1H),
1
H NMR (500 MHz, CDCl ) d (ppm): 8.05 (d, J = 8.0 Hz, 2H); 7.60
3
(
t, J = 14.5 Hz, 1H), 7.47 (t, J = 16.5 Hz, 3H), 7.28–7.38 (m, 8H),
6
2
1
3
.93–6.87 (m, 4H), 5.58 (br, 1H), 5.45 (br, 1H), 5.07 (d, J = 12.5 Hz,
H), 5.04 (dd, J = 3.5, 2.4 Hz, 1H), 4.94 (br, 1H), 4.90 (d, J = 10.3 Hz,
H), 4.61 (d, J = 11.5 Hz, 1H), 4.37–4.32 (m, 2H), 4.15–4.09 (m, 3H),
.83 (s, 3H), 2.76 (d, J = 6.5 Hz, 1H), 2.66–2.59 (m, 1H), 2.53–2.45
1
3
(
m, 1H), 2.01 (s, 3H), 1.99 (s, 3H), 1.85–1.88 (m, 1H), 1.84 (s, 3H),
1.19 (s, 3H). C NMR (125 MHz, CDCl ): δ ppm 171.8, 171.3, 171.0,
3
1
3
1
1
7
2
.71 (s, 3H), 1.66–1.70 (m, 1H), 1.56 (s, 3H), 1.55 (s, 3H), 1.28 (s,
165.4, 165.0, 143.2, 137.6, 135.8, 132.1, 130.5, 130.4, 129.9, 129.0,
128.9, 127.4, 125.6, 81.2, 83.9, 81.2, 78.1, 76.3, 73.5, 71.4, 70.5, 70.4,
60.5, 47.6, 43.3, 42.7, 38.3, 34.4, 31.8, 26.8, 26.1, 22.7, 21.5, 15.7,
14.3, 13.1.
1
3
H). C NMR (125 MHz, CDCl ) d (ppm): 171.7, 171.3, 171.0, 165.7,
3
64.9, 153.1, 143.2, 138.1, 134.0, 131.9, 129.9, 129.8, 129.5, 129.4,
29.0, 128.8, 128.8, 128.3, 127.3, 115.9, 115.7, 84.1, 83.8, 81.1, 78.0,
6.2, 73.5, 71.2, 70.4, 70.3, 47.5, 43.2, 42.6, 38.2, 34.3, 31.6, 30.3,
6.7, 26.0, 22.6, 21.4, 15.6, 13.0.
4.5.8. Compound 15h
1
H NMR (500 MHz, CDCl ): δ ppm 8.04 (d, J = 7.50 Hz, 2H),
3
4.5.4. Compound 15d
7.69–7.62 (m, 3H), 7.65–7.60 (m, 2H), 7.50–7.45 (m, 5H), 7.38 (t,
J = 7.06 Hz, 2H), 7.35–7.30 (m, 2H), 7.24–7.18 (m, 1H), 5.93 (t,
J = 8.10 Hz, 1H), 5.86 (d, J = 12.20 Hz,1H), 5.81–5.75 (m, 2H), 5.45
(br, 1H), 5.38 (t, J = 8.85 Hz, 1H), 5.08 (d, J = 12.20 Hz, 1H), 4.90 (d,
J = 8.60 Hz, 1H), 4.75 (s, 1H), 4.36 (d, J = 8.40 Hz, 1H), 4.21 (s, 1H),
4.10 (d, J = 8.40 Hz, 1H), 3.83 (s, 3H), 2.66 (d, J = 5.65 Hz, 1H),
2.70–2.61 (m, 1H), 2.55–2.47 (m, 1H), 2.28 (s, 3H), 2.09 (s, 3H), 2.05
(d, J = 9.45 Hz, 1H), 2.02–1.94 (m, 1H), 1.83 (s, 3H), 1.80 (s, 3H),
1
H NMR (500 MHz, CDCl ): δ ppm 8.03 (d, J = 8.12 Hz, 2H),
3
7
.64–7.60 (m, 1H), 7.50–7.46 (m, 4H), 7.40–7.28 (m, 8H), 7.06–7.02
(
(
m, 1H), 5.93 (t, J = 7.60 Hz, 1H), 5.87 (d, J = 12.10 Hz, 1H), 5.80
dd, J = 5.59, 2.20 Hz, 1H), 5.76 (dd, J = 5.86, 1.95 Hz, 1H), 5.45 (br,
1
H), 5.39 (t, J = 8.58 Hz, 1H), 5.09 (d, J = 12.10 Hz, 1H), 4.90 (d,
J = 8.60 Hz, 1H), 4.77 (d, J = 2.61 Hz, 1H), 4.35 (d, J = 8.45 Hz, 1H),
4
2
.12 (d, J = 8.45 Hz, 1H), 3.85 (s, 3H), 2.67 (d, J = 6.00 Hz, 1H),
1
3
.70–2.63 (m, 1H), 2.56–2.48 (m, 1H), 2.29 (s, 3H), 2.09 (s, 3H), 2.05
1.71(s, 6H), 1.58–1.51 (m, 1H), 1.19 (s, 3H). C NMR (125 MHz,
(
(
d, J = 9.40 Hz, 1H), 2.00–1.94 (m, 1H), 1.80 (s, 3H), 1.75 (s, 3H), 1.70
CDCl ): δ ppm 171.7, 171.4, 171.1, 165.0, 164.7, 164.7, 153.8, 153.2,
3
1
3
s, 3H), 1.58–1.51 (m, 1H), 1.19 (s, 3H). C NMR (125 MHz, CDCl
3
): δ
143.1, 137.9, 134.1, 132.1, 130.9, 130.8, 129.9, 129.1, 129.0, 128.9,
128.5, 127.4, 123.5, 123.5, 117.8, 117.7, 117.2, 117.1, 84.2, 83.9,
81.3, 78.1, 76.3, 75.5, 71.3, 70.5, 70.4, 47.6, 43.3, 42.7, 38.3, 34.4,
31.7, 26.8, 26.1, 22.7, 21.1, 15.7, 14.2, 13.1.
ppm 171.7, 171.3, 170.9, 166.6, 164.9, 153.1, 138.1, 135.2, 134.0,
1
8
3
31.9, 129.8, 129.0, 128.8, 128.3, 127.3, 118.6, 118.0, 112.7, 84.1,
3.8, 81.1, 78.0, 76.2, 73.6, 71.2, 70.4, 70.3, 54.7, 47.5, 43.2, 42.6,
8.2, 34.3, 31.6, 26.7, 26.0, 22.6, 21.4, 15.6, 13.0.
4.6. General procedure for synthesis of compounds 16a-h
4.5.5. Compound 15e
1
H NMR (500 MHz, CDCl
3
): δ ppm 8.02 (d, J = 8.05 Hz, 2H), 7.61
The resulting solid 15a-h (1.0 mmol) was dissolved in MeOH (5 mL)
(
t, J = 7.51 Hz, 1H), 7.47 (t, J = 7.85 Hz, 4H), 7.41–7.30 (m, 8H),
.24–7.19 (m, 2H), 6.92–6.81 (br, 2H), 6.18 (t, J = 7.60 Hz,1H), 6.03
d, J = 12.30 Hz,1H), 5.78 (dd, J = 6.05, 2.25 Hz, 1H), 5.58 (br, 1H),
.50 (t, J = 8.90 Hz,1H), 5.15 (d, J = 12.30 Hz, 1H), 4.93 (s, 1H), 4.88
and p-toluenesulfonic acid (1.5 mmol) was added. After stirring for 2 h
at 50 °C, the reaction mixture was diluted with EtOAc and washed three
7
(
times with saturated NaHCO and brine. The organic layer was dried
3
5
over Na
2
SO and the solvent was removed under reduced pressure. The
4
(
d, J = 8.50 Hz, 1H), 4.77 (d, J = 2.61 Hz, 1H), 4.32 (d, J = 8.40 Hz,
resulting oil was purified by silica gel column chromatography (EtOAc:
hexane = 2: 3), and the unreacted minor diastereomer was discarded,
yielding 16a-h as a white powder (80%-85%).
1
2
2
H), 4.08 (d, J = 8.40 Hz, 1H), 3.83 (s, 3H), 2.72 (d, J = 6.00 Hz, 1H),
.58–2.47 (m, 2H), 2.11 (s, 3H), 2.09 (s, 3H), 2.05 (d, J = 9.45 Hz, 1H),
.00–1.94 (m, 2H), 1.80 (s, 3H), 1.76 (s, 3H), 1.51–1.58 (m, 5H), 1.43
1
3
(
s, 3H), 1.19 (s, 3H). C NMR (125 MHz, CDCl
3
): δ ppm 171.8, 171.4,
4.6.1. Compound 16a
1
1
1
7
2
71.0, 166.8, 165.0, 153.1, 143.3, 138.2, 134.1, 132.1, 132.0, 129.9,
H NMR (500 MHz, CDCl ): δ ppm 8.04 (d, J = 8.05 Hz, 2H), 7.61
3
28.9, 128.8, 127.4, 127.1, 118.6, 84.2, 83.9, 81.2, 78.1, 76.3, 73.6,
1.4, 70.5, 70.4, 47.6, 43.3, 42.7, 38.3, 34.4, 31.8, 26.8, 26.1, 22.7,
1.5, 15.7, 13.1.
(t, J = 7.40 Hz, 1H), 7.56–7.46 (m, 5H), 7.43–7.31 (m, 5H), 7.23–7.18
(m, 1H), 5.93 (t, J = 7.60 Hz, 1H), 5.87 (d, J = 12.25 Hz, 1H), 5.78
(dd, J = 6.05, 2.25 Hz, 1H), 5.39 (t, J = 8.90 Hz, 1H), 5.09 (d,
J = 12.25 Hz, 1H), 4.91 (d, J = 8.60 Hz, 1H), 4.77 (d, J = 2.61 Hz,
1H), 4.36 (d, J = 8.45 Hz, 1H), 4.10 (d, J = 8.45 Hz, 1H), 2.66 (d,
J = 6.00 Hz, 1H), 2.71–2.48 (m, 2H), 2.29 (s, 3H), 2.09 (s, 3H), 2.05 (d,
J = 9.45 Hz, 1H), 2.01–1.94 (m, 1H), 1.80 (s, 3H), 1.73 (s, 3H), 1.71 (s,
4.5.6. Compound 15f
1
H NMR (500 MHz, CDCl ): δ ppm 8.04 (d, J = 7.35 Hz, 2H), 7.68
3
(
d, J = 8.11 Hz, 2H), 7.51–7.40 (m, 6H), 7.37 (t, J = 7.21 Hz, 2H),
1
9
7
.34–7.20 (m, 6H), 5.92 (t,
J
=
8.25 Hz, 1H), 5.88 (d,
3H), 1.58–1.51 (m, 1H), 1.20 (s, 3H). F NMR (470 MHz, CDCl
3
): δ
1
3
J = 12.20 Hz,1H), 5.77 (dd, J = 6.05, 2.25 Hz, 1H), 5.56 (d,
J = 9.60 Hz, 1H), 5.45 (br, 1H), 5.40 (t, J = 8.90 Hz,1H), 5.09 (d,
J = 12.20 Hz, 1H), 4.91 (d, J = 8.65 Hz, 1H), 4.77 (s, 1H), 4.36 (d,
J = 8.50 Hz, 1H), 4.10 (d, J = 8.50 Hz, 1H), 3.83 (s, 3H), 2.68 (d,
J = 5.65 Hz, 1H), 2.73–2.64 (m, 1H), 2.56–2.46 (m, 1H), 2.38 (s, 3H),
ppm −111.3 (m, 1F). C NMR (125 MHz, CDCl
3
): δ ppm 171.7, 171.3,
171.0, 165.5, 165.5, 164.9, 163.8, 158.8, 153.1, 143.1, 137.9, 136.0,
136.0, 134.0, 131.9, 130.4, 130.4, 129.8, 129.0, 128.8, 128.3, 127.3,
122.4, 122.4, 119.1, 118.9, 84.1, 83.8, 81.1, 78.0, 76.2, 73.5, 71.2,
70.4, 70.3, 54.8, 47.5, 43.2, 42.6, 38.2, 34.3, 31.6, 26.7, 26.0, 22.6,
+
2
1
.29 (s, 3H), 2.09 (s, 3H), 2.05 (d, J = 9.45 Hz, 1H), 2.00–1.94 (m,1H),
21.4, 15.6, 13.0. HR-MS (ESI): calcd for C48
884.3288, found: 884.3282.
H
50FNO14 ([M + H] ):
.80 (s, 3H), 1.75 (s, 3H), 1.70 (s, 3H), 1.58–1.51 (m, 1H), 1.19 (s, 3H).
1
3
C NMR (125 MHz, CDCl ): δ ppm 171.8, 171.4, 171.0, 166.8, 165.0,
3
1
8
43.4, 138.4, 134.0, 131.9, 130.9, 129.5, 129.1, 128.3, 127.1, 84.2,
3.2, 78.4, 76.3, 73.7, 71.3, 70.5, 70.4, 60.5, 47.6, 43.3, 42.6, 38.3,
4.6.2. Compound 16b
1
H NMR (125 MHz, CDCl ): δ ppm 8.07–8.02 (m, 2H), 7.92 (m,1H),
3
6

C. Xie, et al.
Bioorganic & Medicinal Chemistry 28 (2020) 115736
7
.62 (t,
J
=
7.97 Hz, 1H), 7.55–7.45 (m, 5H), 7.41–7.34 (t,
(500 MHz, CDCl
3
): δ ppm 171.8, 171.4, 171.0, 166.8, 165.0, 153.2,
J = 7.03 Hz, 2H), 7.35–7.30 (m, 1H), 7.25–7.22 (m, 1H), 7.19–7.13 (m,
143.3, 138.2, 134.1, 133.8, 132.1, 132.0, 129.9, 129.1, 128.9, 128.9,
1
H), 5.92 (t, J = 8.10 Hz, 1H), 5.91–5.87 (m, 1H), 5.86 (d,
128.4, 127.4, 127.1, 84.2, 83.9, 81.2, 78.1, 76.3, 73.6, 71.4, 70.5, 70.4,
J = 12.20 Hz, 1H), 5.77 (dd, J = 5.76, 1.91 Hz, 1H), 5.39 (t,
J = 9.08 Hz, 1H), 5.08 (d, J = 12.20 Hz, 1H), 4.90 (d, J = 8.60 Hz,
54.8, 47.6, 43.3, 42.7, 38.3, 34.4, 31.8, 26.8, 26.1, 22.7, 21.5, 15.7,
+
13.1. HR-MS (ESI): calcd for C48
found: 866.3383.
H
51NO14 ([M + H] ): 866.3382,
1
H), 4.72 (d, J = 2.58 Hz, 1H), 4.36 (d, J = 8.45 Hz, 1H), 4.10 (d,
J = 8.45 Hz, 1H), 2.72–2.65 (m, 1H), 2.67 (d, J = 5.98 Hz, 1H),
2
2
.61–2.49 (m, 1H), 2.28 (s, 3H), 2.10 (s, 3H), 2.05 (d, J = 8.93 Hz, 1H),
4
.6.6. Compound 16f
1
.01–1.94 (m, 2H), 1.80 (s, 3H), 1.73 (s, 3H), 1.71(s, 3H), 1.55–1.49
H NMR (500 MHz, CDCl ): δ ppm 8.04 (d, J = 7.35 Hz, 2H), 7.68
3
1
9
(
m, 1H), 1.18 (s, 3H). F NMR (470 MHz, CDCl
3
): δ ppm −113.1 (m,
(
d, J = 8.11 Hz, 2H), 7.51–7.46 (m, 3H), 7.37 (t, J = 7.21 Hz, 2H),
1
3
1
1
1
8
3
F). C NMR (125 MHz, CDCl ): δ ppm 171.3, 171.2, 171.0, 164.9,
3
7
.34–7.20 (m, 5H), 5.92 (t,
J
=
8.25 Hz,1H), 5.88 (d,
62.7, 161.8, 159.8, 153.1, 143.3, 138.2, 134.0, 133.8, 133.7, 132.2,
31.9, 130.9, 129.9, 129.8, 129.0, 128.8, 128.2, 127.3, 84.1, 83.8,
1.2, 78.0, 76.2, 73.9, 71.3, 71.0, 70.5, 55.9, 47.5, 43.2, 42.5, 38.2,
J = 12.20 Hz,1H), 5.77 (dd, J = 6.05, 2.25 Hz, 1H), 5.56 (d,
J = 9.60 Hz, 1H), 5.40 (t, J = 8.90 Hz, 1H), 5.09 (d, J = 12.20 Hz,
1
4
1
H), 4.91 (d, J = 8.65 Hz, 1H), 4.77 (s, 1H), 4.36 (d, J = 8.50 Hz, 1H),
.10 (d, J = 8.50 Hz, 1H), 2.68 (d, J = 5.65 Hz, 1H), 2.73–2.64 (m,
H), 2.56–2.46 (m, 1H), 2.38 (s, 3H), 2.29 (s, 3H), 2.09 (s, 3H), 2.05 (d,
4.3, 31.9, 31.9, 31.6, 30.3, 26.8, 22.7, 22.5, 21.4, 15.6, 14.1, 13.0. HR-
+
MS (ESI): calcd for C48
H
50FNO14 ([M + H] ): 884.3288, found:
8
84.3273.
J = 9.45, 1H), 2.00–1.94 (m, 1H), 1.80 (s, 3H), 1.75 (s, 3H), 1.70 (s,
1
3
3
H), 1.58–1.51 (m,1H), 1.19 (s, 3H). C NMR (125 MHz, CDCl ): δ
3
4.6.3. Compound 16c
ppm 171.8, 171.4, 171.0, 166.8, 165.0, 153.2, 143.4, 142.6, 138.4,
1
H NMR (500 MHz, CDCl ): δ ppm 8.06 (d, J = 8.60 Hz, 2H), 7.79
3
1
8
3
34.0, 131.9, 130.9, 129.9, 129.5, 129.1, 128.3, 127.4, 127.1, 84.2,
3.2, 78.4, 76.3, 73.7, 71.3, 70.5, 70.4, 60.5, 54.7, 47.6, 43.3, 42.6,
8.3, 34.4, 31.7, 26.8, 26.1, 22.8, 22.6, 21.6, 21.5, 15.7, 14.3, 13.1. HR-
(
m, 1H), 7.62 (t, J = 8.00 Hz ,1H), 7.50–7.45 (m, 4H), 7.41–7.39 (m,
2
5
H), 7.33–7.28 (m, 2H), 7.12–7.06 (m, 2H), 5.93 (t, J = 7.60 Hz, 1H),
.87 (d, J = 12.25 Hz, 1H), 5.78 (dd, J = 6.01, 2.24 Hz, 1H), 5.76 (dd,
MS (ESI): calcd for C49
H
53NO14 ([M + H]+): 880.3539, found:
J = 5.85, 1.99 Hz, 1H), 5.39 (t, J = 8.87 Hz, 1H), 5.08 (d,
J = 12.25 Hz, 1H), 4.90 (d, J = 8.60 Hz, 1H), 4.77 (d, J = 2.61 Hz,
8
80.3538.
1
H), 4.35 (d, J = 8.43 Hz, 1H), 4.11 (d, J = 8.43 Hz, 1H), 2.65 (d,
4
.6.7. Compound 16 g
J = 6.00 Hz, 1H), 2.70–2.61 (m, 1H), 2.53–2.46 (m, 1H), 2.28 (s, 3H),
1
H NMR (500 MHz, CDCl ): δ ppm 8.04 (d, J = 7.50 Hz, 2H), 7.92
3
2
1
.08 (s, 3H), 2.05 (d, J = 9.45 Hz, 1H), 2.01–1.94 (m, 1H), 1.80 (s, 3H),
19
(
s, 1H), 7.68 (d, J = 7.75 Hz, 1H), 7.65–7.60 (m, 2H), 7.51–7.45 (m,
.73 (s, 3H), 1.71 (s, 3H), 1.57–1.50 (m, 1H), 1.18 (s, 3H). F NMR
4
1
H), 7.38 (t, J = 7.10 Hz, 2H), 7.35–7.27 (m, 3H), 5.93 (t, J = 8.10 Hz,
H), 5.87 (d, J = 12.20 Hz, 1H), 5.81–5.75 (m, 2H), 5.39 (t,
1
3
(
470 MHz, CDCl
3
): δ ppm −107.2 (m, 1F). C NMR (125 MHz, CDCl ):
3
δ ppm 171.7, 171.3, 171.0, 166.0, 165.7, 164.9, 164.0, 153.1, 143.2,
J = 8.50 Hz, 1H), 5.08 (d, J = 12.20 Hz, 1H), 4.90 (d, J = 8.60 Hz,
1
1
7
2
38.1, 134.0, 131.9, 129.9, 129.9, 129.8, 129.5, 129.5, 129.4, 129.0,
28.8, 128.8, 128.3, 127.3, 115.9, 115.7, 84.1, 83.8, 81.1, 78.0, 76.2,
3.5, 71.2, 70.4, 70.3, 54.8, 47.5, 43.2, 42.6, 38.2, 34.3, 31.6, 30.3,
1
2
H), 4.75 (s, 1H), 4.36 (d, J = 8.40 Hz, 1H), 4.10 (d, J = 8.40 Hz, 1H),
.68 (d, J = 5.65 Hz, 1H), 2.70–2.62 (m, 1H), 2.55–2.47 (m, 1H), 2.28
(
(
s, 3H), 2.08 (s, 3H), 2.05 (d, J = 9.45 Hz, 1H), 2.00–1.93 (m, 1H), 1.83
6.7, 26.0, 22.6, 21.4, 15.6, 13.0. HR-MS (ESI): calcd for C48
H50FNO14
13
s, 3H), 1.80 (s, 3H), 1.71 (s, 3H), 1.58–1.51 (m, 1H), 1.19 (s, 3H).
C
+
(
[M + H] ): 884.3288, found: 884.3285.
NMR (125 MHz, CDCl
3
): δ ppm 171.8, 171.3, 171.0, 165.4, 165.0,
1
1
7
2
53.2, 143.2, 137.6, 135.8, 134.1, 132.1, 130.5, 130.4, 129.9, 129.1,
29.0, 128.9, 128.5, 127.4, 125.6, 81.2, 83.9, 81.2, 78.1, 76.3, 73.5,
1.4, 70.5, 70.4, 60.5, 54.9, 47.6, 43.3, 42.7, 38.3, 34.4, 31.8, 26.8,
4.6.4. Compound 16d
1
H NMR (500 MHz, CDCl ): δ ppm 8.03 (d, J = 8.12 Hz, 2H),
3
7
.64–7.60 (m, 1H), 7.50–7.46 (m, 4H), 7.40–7.28 (m, 6H), 7.06–7.02
6.1, 22.7, 21.5, 15.7, 14.3, 13.1. HR-MS (ESI): calcd for C48
H
50BrNO14
(
(
m, 1H), 5.94 (t, J = 7.60 Hz, 1H), 5.87 (d, J = 12.10 Hz, 1H), 5.80
dd, J = 5.59, 2.20 Hz, 1H), 5.76 (dd, J = 5.86, 1.95 Hz, 1H), 5.39 (t,
[M + H]+): 944.2487, found: 944.2492.
(
J = 8.58 Hz, 1H), 5.09 (d, J = 12.10 Hz, 1H), 4.90 (d, J = 8.60 Hz,
4
.6.8. Compound 16 h
1
H), 4.77 (d, J = 2.61 Hz, 1H), 4.35 (d, J = 8.45 Hz, 1H), 4.12 (d,
J = 8.45 Hz, 1H), 3.81 (s, 3H), 2.67 (d, J = 6.00 Hz, 1H), 2.70–2.63
m, 1H), 2.56–2.48 (m, 1H), 2.29 (s, 3H), 2.09 (s, 3H), 2.05 (d,
J = 9.40 Hz, 1H), 2.00–1.94 (m, 1H), 1.80 (s, 3H), 1.75 (s, 3H), 1.70 (s,
1
H NMR (500 MHz, CDCl ): δ ppm 8.04 (d, J = 7.50 Hz, 2H),
3
7
.69–7.65 (m, 1H), 7.65–7.60 (m, 2H), 7.50–7.44 (m, 4H), 7.38 (t,
(
J = 7.06 Hz, 2H), 7.35–7.30 (m, 2H), 7.24–7.18 (m, 1H), 5.93 (t,
J = 8.10 Hz, 1H), 5.86 (d, J = 12.20 Hz, 1H), 5.81–5.75 (m, 2H), 5.38
1
3
3
H), 1.58–1.51 (m, 1H), 1.19 (s, 3H). C NMR (125 MHz, CDCl ): δ
3
(
t, J = 8.85 Hz, 1H), 5.08 (d, J = 12.20 Hz, 1H), 4.90 (d, J = 8.60 Hz,
ppm 171.7, 171.3, 170.9, 166.6, 164.9, 159.9, 153.1, 143.2, 138.1,
1
H), 4.75 (s, 1H), 4.36 (d, J = 8.40 Hz, 1H), 4.21 (s, 1H), 4.10 (d,
J = 8.40 Hz, 1H), 2.66 (d, J = 5.65 Hz, 1H), 2.70–2.61 (m, 1H),
.55–2.47 (m, 1H), 2.28 (s, 3H), 2.09 (s, 3H), 2.05 (d, J = 9.45 Hz, 1H),
1
1
5
1
35.2, 134.0, 131.9, 129.8, 129.7, 129.0, 128.8, 128.8, 128.3, 127.3,
18.6, 118.0, 112.7, 84.1, 83.8, 81.1, 78.0, 76.2, 73.6, 71.2, 70.4, 70.3,
2
5.5, 54.7, 47.5, 43.2, 42.6, 38.2, 34.3, 31.6, 26.7, 26.0, 22.6, 21.4,
+
2.02–1.94 (m, 1H), 1.83 (s, 3H), 1.80 (s, 3H), 1.71(s, 6H), 1.58–1.51
5.6, 13.0. HR-MS (ESI): calcd for C49
H
53NO15 ([M + H] ): 896.3488,
1
9
(
m, 1H), 1.19 (s, 3H). F NMR (470 MHz, CDCl
3
): δ ppm −131.7 (m,
): δ ppm 171.7, 171.4,
71.1, 165.0, 164.7, 164.7, 153.9, 153.8, 153.2, 143.1, 137.9, 134.1,
found: 896.3483.
1
3
1
1
F), −135.5 (m, 1F). C NMR (125 MHz, CDCl
3
4.6.5. Compound 16e
1
132.1, 130.9, 130.9, 130.9, 129.9, 129.1, 129.0, 128.9, 128.5, 127.4,
H NMR (500 MHz, CDCl ): δ ppm 8.04 (d, J = 8.05 Hz, 2H), 7.79
3
1
8
3
23.5, 123.5, 123.5, 123.5, 117.8, 117.7, 117.2, 117.1, 84.2, 83.9,
1.3, 78.1, 76.3, 75.5, 71.3, 70.5, 70.4, 54.9, 47.6, 43.3, 42.7, 38.3,
4.4, 31.7, 26.8, 26.1, 22.7, 21.1, 15.7, 14.2, 13.1. HR-MS (ESI): calcd
(
d, J = 7.10 Hz, 2H), 7.62 (t, J = 7.45 Hz, 1H), 7.51–7.47 (m, 4H),
7
5
.43 (t, J = 7.85 Hz, 2H), 7.38 (t, J = 7.11 Hz, 2H), 7.35–7.28 (m, 2H),
.93 (t, J = 7.60 Hz,1H), 5.87 (d, J = 12.30 Hz,1H), 5.82 (dd,
for C48
H
F
49 2
NO14 ([M + H]+): 902.3194, found: 902.3190.
J = 6.05, 2.25 Hz, 1H), 5.77 (m, 1H), 5.40 (t, J = 8.90 Hz, 1H), 5.09
(
d, J = 12.30 Hz, 1H), 4.91 (d, J = 8.50 Hz, 1H), 4.77 (d, J = 2.61 Hz,
H), 4.36 (d, J = 8.40 Hz, 1H), 4.10 (d, J = 8.40 Hz, 1H), 2.67 (d,
Declaration of Competing Interest
1
J = 6.00 Hz, 1H), 2.69–2.63 (m, 1H), 2.54–2.47 (m, 1H), 2.29 (s, 3H),
2
1
.09 (s, 3H), 2.05 (d, J = 9.45 Hz, 1H), 2.00–1.94 (m, 2H), 1.84 (s, 3H),
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to
.74 (s, 3H), 1.71 (s, 3H), 1.51–1.58 (m, 5H), 1.19 (s, 3H). 13C NMR
7

C. Xie, et al.
Bioorganic & Medicinal Chemistry 28 (2020) 115736
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Acknowledgements
The authors thank Drs. H.M. Deng and M. Shao, The Instrumental
Analysis& Research Center of Shanghai University, for structural ana-
lysis. This work was in part supported by National Natural Science
Foundation of China (Nos 21272154 & 81202402) and Science and
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