Stereoselective Synthesis of Coreoside D and Determination of Its Absolute Configuration

Article abstract of DOI:10.1055/s-0039-1690876

We report the stereoselective synthesis of (3 S)- and (3 R)-coreoside D. The conjugated diyne in the C1-C14 moiety was synthesized through two types of palladium-catalyzed cross-coupling reaction. The introduction of the glucopyranose was achieved by a gl

Full text of DOI:10.1055/s-0039-1690876

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
letter
A
en
N. Ogawa, R. Imaizumi
Letter
Synlett
Stereoselective Synthesis of Coreoside D and Determination of Its
Absolute Configuration
Narihito Ogawa*
Ryoya Imaizumi
0
0
0
0-0
0
0
1-6
3
3
0-
1
1
0
8
glycosylation
OBz
O
BzO
BzO
HO
OTBDPS
I
OTBDPS
BzO
Department of Applied Chemistry, Meiji University,
1-1-1, Higashimita, Tama-ku, Kawasaki, Kanagawa
214-8571, Japan
O
CCl3
NH
H
Sonogashira
coupling reaction
narihito@meiji.ac.jp
OH
O
HO
O
OH
OH
HO
OH
coreoside D
Received: 06.03.2020
Accepted after revision: 17.03.2020
Published online: 31.03.2020
coreosides have been reported to exhibit potent cyclooxy-
genase-2 (COX-2) inhibitory activity. Zhang et al. reported
that only trace amounts of these compounds can be ob-
tained from their natural sources, and that the stereochem-
istry of the C3-position was yet to be determined. Here, we
report the first stereoselective syntheses of (3S)- and (3R)-
coreoside D in an attempt to determine the absolute confor-
mations of natural coreosides.
DOI: 10.1055/s-0039-1690876; Art ID: st-2020-u0132-l
Abstract We report the stereoselective synthesis of (3S)- and (3R)-co-
reoside D. The conjugated diyne in the C1–C14 moiety was synthesized
through two types of palladium-catalyzed cross-coupling reaction. The
introduction of the glucopyranose was achieved by a glycosylation reac-
tion using an imidate derivative in the presence of a Lewis acid. The
asymmetric center at the C3-position was constructed by the chiral-
pool method using D-malic acid. The stereochemistry at the C3-posi-
tion of the natural product was determined to be R by comparing the
[]D values of the synthetic stereoisomers with that reported for the
natural product.
OH
O
HO
HO
O
OH
R1
3
OR2
Key words asymmetric synthesis, coreoside D, polyacetylene glyco-
side, palladium catalysis, coupling reaction, glycosylation
coreoside A (1); R1 = H, R2 = arabinosyl
coreoside B (2); R1 = OH, R2 = arabinosyl
coreoside C (3); R1 = OAc, R2 = arabinosyl
coreoside D (4); R1 = OH, R2 = H
Plains coreopsis (Coreopsis tinctoria) is an annual plant
of the asteraceae family, and contains such chemical com-
ponents as polyacetylene glycosides, flavonoids, and phe-
nolic compounds.1 In China, it is consumed as ‘snow tea’ or
‘snow chrysanthemum’ as a medicinal drink for treating hy-
pertension and hyperlipidemia.1a In addition, it has been
reported that a polyacetylene glycoside component of C.
tinctoria, exhibits various physiological activities, such as
antiallergic, antiinflammatory, and anti-HIV activities.1e,2
Consequently, polyacetylene glycosides are attracting at-
tention as pharmaceuticals and health foods. However, al-
though there have been many reports on the biological ac-
tivity of C. tinctoria, the absolute stereostructure of its bio-
active compounds remained unclear.
In 2013, Zhang et al. isolated coreosides A–D (1–4, re-
spectively) from the capitula of plains coreopsis (Figure
1).1a Coreosides E (5) and F (6) were subsequently isolated
from the plains coreopsis by Guo et al. in 2017.1b These co-
reosides are polyacetylene glycosides that combine an agly-
cone containing a diyne skeleton with glucopyranose. The
OH
O
HO
O
3
OH
HO
OR3
coreoside E (5); R3 = H
coreoside F (6); R3 = arabinosyl
Figure 1 The structures of coreosides A–F
Scheme 1 outlines our proposed synthesis of (3S)-co-
reoside D (4a). We surmised that (3S)-coreoside D (4a)
might be obtainable by glycosylation by imidate 7 of the
C1–C14 aglycone 8, synthesized by a Sonogashira coupling
reaction between iodoolefin 9 and acetylene 10. Iodoolefin
9, in turn, might be synthesized from D-malic acid by a
Takai reaction to give the trans-iodoalkene moiety. On the
other hand, diyne 10 might be prepared from propargyl al-
cohol by two types of palladium-catalyzed coupling reac-
tion.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
N. Ogawa, R. Imaizumi
Letter
Synlett
Diethyl ester 12 was prepared from D-malic acid (11) by
esterification with AcCl/EtOH (Scheme 2). Reduction of 12
with BH3·SMe2/NaBH4 gave diol 13 as the major product in a
93:7 mixture, as observed by 1H NMR spectroscopy; the mi-
nor product was formed by reduction of the other ester
moiety (the structure of the minor product is not shown).3
After protection of alcohol 13 using TBDPSCl, reduction of
the ester group afforded 14.4 Diol 14 was protected by
treatment with cyclohexanone in the presence of PPTS to
give acetal 15. At this stage, the desired acetal 15 was clean-
ly isolated as the sole isomer by silica gel column chroma-
tography. Subsequently, deprotection of acetal 15 with
TBAF afforded alcohol 16 in a good yield. Parikh–Doering
oxidation of 16 followed by a Horner–Wadsworth–Emmons
reaction gave the ,-unsaturated ester 17 in 90% yield. Es-
ter 17 was converted into alcohol 18 upon reduction of the
C=C double bond and ester moiety. Parikh–Doering oxida-
tion of 18 gave aldehyde 19, which was subjected to a Takai
reaction in 1,4-dioxane–THF by a modified version of the
reported procedure.5 The resulting iodoolefin was treated
with TsOH·H2O to afford diol 20 (E/Z = 91:9). The E- and Z-
olefins could not be separated by purification, and were
used as a mixture in the next reaction. Finally, the hydroxy
group in 20 was protected by using TBDPSCl to give iodo-
alkene 9 in 87% yield.
OH
O
HO
HO
O
OH
OH
3
OH
(3S)-coreoside D (4a)
glycosylation
OBz
O
HO
OTBDPS
OTBDPS
3
BzO
BzO
BzO
O
CCl3
NH
7
8
Sonogashira
coupling reaction
from D-malic acid
OTBDPS
HO
OTBDPS
I
H
10
palladium-catalyzed
9
Takai reaction
C(sp)–C(sp) coupling reaction
Scheme 1 Proposed synthesis of (3S)-coreoside D (4a)
AcCl
EtOH
95%
COOH
OH
COOEt
HOOC
EtOOC
OH
12
D-malic acid (11)
The results of the two types of palladium-catalyzed cou-
pling reaction used to prepare diyne 10 are summarized in
Scheme 3. Propargyl alcohol (21) was converted into io-
doolefin 22 in 82% yield.6 Sonogashira coupling of iodoole-
fin 22 with (trimethylsilyl)acetylene afforded enyne 23,
which was then subjected to a deprotection step to remove
the trimethylsilyl group to produce 24 in good yield. A pal-
ladium-catalyzed C(sp)–C(sp) cross-coupling reaction was
BH3•SMe2
NaBH4
1) TBDPSCl
imidazole, 93%
EtOOC
OH
OH
13
THF
69%
2) NaBH4, LiCl, 97%
cyclohexanone
PPTS
OTBDPS
O
O
OTBDPS
OH OH
then separation
69%
14
15
1) TBDPSCl, imidazole
quant.
1) SO3•py, NEt3
CH2Cl2/DMSO
OH
TBAF
O
OH
O
I
OTBDPS
22
THF
94%
2) Cp2ZrCl2, DIBAL
then I2
82%
2) (EtO)2P(O)CH2CO2Et
NaH, THF
propargyl alcohol
16
(21)
90%
TMS
COOEt
OH
1) H2, Pd/C
2) LiAlH4
94%
Pd(PPh3)4, dppb, CuI
O
O
OTBDPS
O
O
R
NEt3
82%
23, R = TMS
24, R = H
17
18
K2CO3
MeOH
99%
CHO
1) CrCl2, CHI3
SO3•py, NEt3
1,4-dioxane/THF
O
O
TMS
I
OTBDPS
2) p-TsOH•H2O
CH2Cl2/DMSO
Pd(PPh3)4, CuBr, t-BuNH2
19
48% from 18
E/Z = 91:9
25
TMS
THF
I
K2CO3
OTBDPS
OR OH
TBDPSCl
imidazole
20, R = H
9, R = TBDPS
MeOH
H
10
87%
53% from 24
Scheme 2 Synthesis of iodoolefin 9
Scheme 3 Synthesis of diyne 10
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
N. Ogawa, R. Imaizumi
Letter
Synlett
then carried out to afford diyne 25.7 Finally, the trimethylsi-
lyl group in 25 was removed by using K2CO3/MeOH to give
the desired diyne 10.
Scheme 4. The 1H NMR, 13C NMR, and UV spectral data ob-
tained for (3R)-coreoside D (4b) were in good agreement
with those reported for the natural product. The optical ro-
22
In the last stage, we completed the synthesis and char-
acterization of (3S)-coreoside D (4a), as shown in Scheme 4.
Construction of the C1–C14 moiety of (3S)-coreoside D (4a)
was achieved by Sonogashira coupling of 9 (E/Z = 91:9) and
10 to give alcohol 8.8 In this coupling reaction, up to 5% of
the the E-olefin at the C12–C13 position isomerized to the
Z-isomer upon conducting the reaction for more than two
hours. In addition, (Z)-9 did not react in the coupling reac-
tion. Subsequently, the glycosylation reaction with imidate
79 in the presence of TMSOTf and 4Å MS proceeded
smoothly to afford acetal 26.10 Finally, deprotection and hy-
drolysis of 26 afforded (3S)-coreoside D (4a) in 71% yield
from 8. The 1H NMR, 13C NMR, and UV spectral data for the
synthetic (3S)-coreoside D (4a) were in good agreement
with those reported for the natural product. However, the
optical rotation of the synthetic compound was inconsis-
tent with the literature data: []D21 –31 (c 0.06, MeOH); Lit.1
tation was also in agreement with the literature data: []D
–13 (c 0.05, MeOH); Lit.1 []D22 –13 (c 0.04, MeOH).
1) PPh3, AcOH, DIAD
2) K2CO3, MeOH
68%
TBDPSO
I
OH
9
10, Pd2(dba)3•CHCl3
PPh3, CuBr, t-BuNH2
TBDPSO
I
OH
ent-9
THF
93%
7
12
TMSOTf
MS4Å
HO
OTBDPS
OTBDPS
CH2Cl2
ent-8
OR2
21
[]D –13 (c 0.04, MeOH). This result suggested that the
R2O
R2O
O
O
OR1
OR1
stereochemistry at the C3-position was incorrect, and
prompted us to synthesize the corresponding (3R)-isomer 4b.
3
OR2
HO
OTBDPS
I
(3R)-26; R1 = TBDPS, R2 = Bz
(3R)-27; R1 = H, R2 = Bz
3HF•NEt3
NaOMe
(3R)-coreoside D (4b); R1 = R2 = H
9 (E/Z = 91:9)
Pd2(dba)3•CHCl3, PPh3
Scheme 5 Synthesis of (3R)-coreoside D (4b)
CuBr, t-BuNH2
+
THF
79%
OBz
OTBDPS
In conclusion, we have accomplished stereoselective
syntheses of (3S)-coreoside D (4a) and its (3R)-isomer 4b.
The key intermediate, iodoolefin 9 was synthesized by
Horner–Wadsworth–Emmons and Takai reactions from D-
malic acid (11) as a starting material. On the other hand,
diyne 10 was derived from propargyl alcohol (21) by two
types of palladium-catalyzed coupling reaction. The C1–
C14 carbon chain was constructed by a Sonogashira cou-
pling reaction of iodoolefin 9 and diyne 10, after which the
glucose moiety was introduced to synthesize (3S)-coreoside
(4a) over 18 steps in a total yield of 7.6% from D-malic acid
(11). The chiral carbon in alcohol 9 was inverted through a
Mitsunobu reaction to afford ent-9, which was transformed
into (3R)-coreoside D (4b) in the same manner. A compari-
son of the []D values of 4a and 4b with that reported for
natural coreoside D was decisive in determining the R con-
figuration of the C3 stereocenter in coreoside D and thus,
the reported chirality was revised.
H
10
O
BzO
BzO
BzO
O
CCl3
NH
12
7
HO
OTBDPS
OTBDPS
TMSOTf, MS4Å
CH2Cl2
8
OR2
R2O
R2O
O
3
O
OR1
OR1
OR2
(3S)-26; R1 = TBDPS, R2 = Bz
(3S)-27; R1 = H, R2 = Bz
(3S)-coreoside D (4a); R1 = R2 = H
3HF•NEt3
NaOMe
71% from 8
Scheme 4 Synthesis of (3S)-coreoside D (4a)
Funding Information
The synthesis of the (3R)-isomer (4b) is summarized in
Scheme 5. Iodoolefin 9 was converted into ent-9 in 68%
yield by a Mitsunobu reaction. Thereafter, (3R)-coreoside D
(4b) was synthesized in the same manner as shown in
This work was supported by Research Project Grant B from the Insti-
tute of Science and Technology, Meiji University.()
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
N. Ogawa, R. Imaizumi
Letter
Synlett
Acknowledgment
(6) Spino, C.; Tremblay, M.-C.; Gobdout, C. Org. Lett. 2004, 6, 2801;
corrigendum: Org. Lett. 2005, 7, 1673.
We thank Dr. Yuichi Kobayashi, a researcher at Meiji university and
emeritus professor of Tokyo Institute of Technology, for helpful dis-
cussion.
(7) (a) Shi, W.; Luo, Y.; Luo, X.; Chao, L.; Zhang, H.; Wang, J.; Lei, A.
J. Am. Chem. Soc. 2008, 130, 14713. (b) Jahnke, E.; Weiss, J.;
Neuhaus, S.; Hoheisel, T. N.; Frauenrath, H. Chem. Eur. J. 2009,
15, 388. (c) Gulia, N.; Pigulski, B.; Szafert, S. Organometallics
2015, 34, 673.
(8) Nomoto, A.; Sonoda, M.; Yamaguchi, Y.; Ichikawa, T.; Hirose, K.;
Tobe, Y. J. Org. Chem. 2006, 71, 401.
(9) Ning, J.; Yi, Y.; Kong, F. Tetrahedron Lett. 2002, 43, 5545.
(10) (a) Doepner, A. M.; Aboagye, E. O.; Barrett, A. G. M. Tetrahedron
Lett. 2015, 56, 3293. (b) Ziegler, T.; Bien, F.; Jurisch, C. Tetrahe-
dron: Asymmetry 1998, 9, 765.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690876.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
References and Notes
(11) (3S)-Coreoside (4a)
A 1.02 M solution of NaOMe in MeOH (0.25 mL, 0.255 mmol)
was added to a solution of diol (3S)-27 (0.126 mmol) in 1:1
MeOH–THF (4 mL), and the mixture was stirred at r.t. for 1 h,
then neutralized with Amberlite IR-120 (hydrogen form). The
resulting mixture was filtered through paper and concentrated.
The residue was purified by chromatography [silica gel, CH2Cl2–
MeOH (4:1)] to give a white solid; yield: 35.6 mg [71% from
(1) (a) Zhang, Y.; Shi, S.; Zhao, M.; Chai, X.; Tu, P. Fitoterapia 2013,
87, 93. (b) Guo, J.; Wang, A.; Yang, K.; Ding, H.; Hu, Y.; Yang, Y.;
Huang, S.; Xu, J.; Liu, T.; Yang, H.; Xin, Z. Phytochemistry 2017,
136, 65. (c) Ma, Z.; Zheng, S.; Han, H.; Meng, J.; Yang, X.; Zeng, S.;
Zhou, H.; Jiang, H. J. Funct. Foods 2016, 20, 575. (d) Wang, W.;
Chen, W.; Yang, Y.; Liu, T.; Yang, H.; Xin, Z. J. Agric. Food Chem.
2015, 63, 200. (e) Wang, N.; Yao, X.; Ishii, R.; Kitanaka, S. Chem.
Pharm. Bull. 2001, 49, 938.
(2) (a) Pellati, F.; Calò, S.; Benvenuti, S.; Adinolfi, B.; Nieri, P.;
Melegari, M. Phytochemistry 2006, 67, 1359. (b) Zhang, H.; Lu,
Z.; Tan, G. T.; Qiu, S.; Farnsworth, N. R.; Pezzuto, J. M.; Fong, H. S.
Tetrahedron Lett. 2002, 43, 973.
(3) (a) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T. Tet-
rahedron 1992, 48, 4067. (b) Sauret-Cladière, S.; Jeminet, G. Tet-
rahedron: Asymmetry 1997, 8, 417.
(4) Lee, Y.-J.; Park, Y.; Kim, M.-h.; Jew, S.-s.; Park, H.-g. J. Org. Chem.
2011, 76, 740.
alcohol (S)-8]; mp 40 °C; Rf = 0.25 (CH2Cl2–MeOH, 4:1); []21
31 (c 0.06, MeOH).
–
D
1H NMR (400 MHz, CD3OD):  = 1.56–1.83 (m, 4 H), 2.30 (q, J =
7.1 Hz, 2 H), 3.16 (t, J = 8.3 Hz, 1 H), 3.21–3.40 (m, 3 H), 3.62–
3.72 (m, 2 H), 3.72–3.81 (m, 1 H), 3.81–3.92 (m, 2 H), 4.14 (dd,
J = 4.7, 2.0 Hz, 2 H), 4.34 (d, J = 8.3 Hz, 1 H), 5.66 (d, J = 16.0 Hz, 1
H), 5.83 (d, J = 15.6 Hz, 1 H), 6.35 (dt, J = 15.6, 7.1 Hz, 1 H), 6.37
(dt, J = 16.0, 4.7 Hz, 1 H). 13C NMR (100 MHz, CD3OD):  = 30.1,
35.4, 38.2, 59.5, 62.68, 62.75, 71.6, 73.1, 74.9, 75.3, 77.8, 77.9,
78.2, 79.7, 81.2, 103.9, 109.0, 109.7, 147.4, 150.0. HRMS (FD):
m/z [M]+ calcd for C20H28O8: 396.17842; found: 396.17676. UV
(MeOH): max 262, 276, 293, 313 nm.
(5) (a) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408. (b) Evans, D. A.; Cameron, B. J. Am. Chem. Soc. 1993, 115,
4497. (c) Evans, D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem. Soc.
1993, 115, 11446.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D