Effective total synthesis of schaftoside

Article abstract of DOI:10.1016/j.tet.2021.132216

A short and scalable approach toward the total synthesis of schaftoside, a naturally occurring bioactive C-glycosylflavone, has been developed from readily available (±)-naringenin. The highlights of this work are double Lewis acid promoted O→C rearrangement to form C-glycoside, oxidative dehydrogenation to construct flavone ring, and easy operational process to make the target product in multigram-scale.

Full text of DOI:10.1016/j.tet.2021.132216

Tetrahedron 91 (2021) 132216
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Tetrahedron
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Effective total synthesis of schaftoside
,
,
,
, b, *
Chengxiang Shang a b, Chuanfang Zhao a b, Pengpeng Nie a b, Jun Liu a
,
, b, c, **
Yuguo Du a
a State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Science,
Beijing, 100085, China
b School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
c National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang, 330022, Jiangxi, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and scalable approach toward the total synthesis of schaftoside, a naturally occurring bioactive C-
glycosylflavone, has been developed from readily available ( )-naringenin. The highlights of this work
are double Lewis acid promoted O/C rearrangement to form C-glycoside, oxidative dehydrogenation to
construct flavone ring, and easy operational process to make the target product in multigram-scale.
© 2021 Elsevier Ltd. All rights reserved.
Received 19 March 2021
Received in revised form
29 April 2021
Accepted 5 May 2021
Available online 24 May 2021
Keywords:
Schaftoside
Total synthesis
C-glycosylflavones
C-glycosylation
1. Introduction
Based on our previous work [4], we were expecting to investigate
the anti-obesity and anti-diabetic potentials of this synthetic
C-glycosylflavones are a class of important natural products
with promising druggability due to their potent bioactivities and
high stability against gastrointestinal hydrolysis metabolism
(Fig. 1). Some of them are major components of well-known folk
medicines for treating acute and chronicle hepatitis, and chole-
cystitis diseases in China [1]. Herbs containing flavonyl C-glycosides
have long been applied in cooking soup and herbal tea in Guangxi
and Guangdong provinces of China [2]. In a joint-project with
Guangxi local research institute, we were assigned to investigate
schaftoside through inhibition of pancreatic lipase and promotion
of glucose-induced insulin secretion [5], as well as its hep-
atoprotective and antiallergenic properties [6].
2. Results and discussion
According to our previous synthetic experiences [4], direct C-
glycosylation between an aromatic ring and two glycosyl donors
seems to be the most straightforward approach to the synthesis of
the target C-glycosyl flavonoid. Initially we envisaged that ther-
the potential bioactivities of schaftoside (apigenin 6-C-
b-D-gluco-
pyranosyl-8-C- -L-arabino pyranoside) possessing in sugarcane
a
modynamically favored
b-C-glycosylflavone could be prepared
(saccharum) leafs. Since there was no well-established method in
our hand to get pure di-C-glycosyl flavonoids from nature sources
[3], we thus launched an alternative and effective organic synthesis
to obtain sufficient quantities of schaftoside for the in vivo and
in vitro bioactivity screening and pharmacological exploration.
through glycosylation of 2,4,6-trihydroxyacetophenone with
armed perbenzylated sugar donor, followed by Sc(OTf)3-catalyzed
O/C rearrangement (Fries rearrangement) [7]. However, the low
overall yield and the tedious global debenzylation and purification
turned this strategy into a cost-ineffective process. Attempted
direct C-glycosylation on dihydroxyacetonphenone of apigenin (I)
never got success, and the direct C-glycosylation on unprotected
naringenin (II) in the presence of lewis acid Sc(OTf)3 was also
problematic. Results from both Sato's [8] and our preliminary
synthetic efforts revealed that Sc(OTf)3-promoted C-glycosylation
of naringenin only led to the formation of an inseparable mixture of
6-C and 8-C-glucosylnaringenin in very low yield (<20%), along
* Corresponding author. State Key Laboratory of Environmental Chemistry and
Eco-toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy
of Science, Beijing, 100085, China.
** Corresponding author. School of Chemical Sciences, University of Chinese
Academy of Sciences, Beijing, 100049, China.
E-mail address: junliu@rcees.ac.cn (J. Liu).
https://doi.org/10.1016/j.tet.2021.132216
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

C. Shang, C. Zhao, P. Nie et al.
Tetrahedron 91 (2021) 132216
available natural flavone ( )-naringenin was chosen as the starting
material which allowed an expeditious entry to the flavan precur-
sor (7) on 100 g scale.
D
-Glucose and -arabinose were elaborated to
L
the corresponding peracetylglycosyl trichloroacetimidates (8, 9) to
act as the glycosyl donors (Scheme 1). The synthetic details are thus
undertaken as described below.
Accordingly, the synthesis of the key C-glycosyl flavan 6 started
from naringenin and is outlined in Scheme 2. Regioselective silyl-
protection of the commercially available ( )-naringenin (10) with
tert-butyldimethylsilyl chloride (TBSCl) in the presence of trie-
thylamine occurred selectively at the most acidic 7-OH group at A-
ring. Acetylation of the remaining free 5-OH at A-ring and 4'0-OH at
B-ring with acetic chloride in one-pot sequence afforded diacetate
flavanone derivative 11 from ( )-naringenin with 70% yield. To our
delight, these reactions gave repeatable results over 180 g scale and
the crude product could be used directly in the next step without
chromatographic separation. Subsequently, in order to eliminate
the electron-withdrawing effect of the carbonyl group at C-4,
electron-deficient flavanone 11 was transformed into electron-rich
glycosyl acceptor 7. Removal of the carbonyl group at C-4 along
with deacetylation at 5-OH was carried out by reduction of 11 with
excess sodium borohydride in a THF/H2O (1:1) solution at 0 ꢁC to
give flavan 7 as a racemate (67e82% isolated yield from tens’ to over
one hundred gram reaction scale) [11]. Gratifyingly, C-glycosylation
of flavan 7 with glycosyl donor 8 in the presence of catalytic
Fig. 1. Structures of representative natural flavonoid C-glycosides.
with di-C-glucosylnaringenin as by-product.
NBO (Natural Bond Orbital) charge population analysis indi-
cated that the total atomic charges on phenol part (A-ring) of I, II,
and III are ꢀ0.200, ꢀ0.298, and ꢀ0.438, respectively, suggesting
that A-ring of flavan (III) is more electron rich than that of I and II
[9]. (Fig. 2) This might be due to the electron withdrawing effect of
the carbonyl group (C-4) on the C-ring of apigenin (I) and nar-
ingenin (II), as well as the strong hydrogen bonding between 5-OH
and C-4 carbonyl group. This information suggested that trans-
formation of electron-deficient naringenin (II) into an electron-rich
flavan structure (III) should be necessary for the effective C-
glycosylation. Accordingly, we designed and actually practiced the
following approach towards the total synthesis of schaftoside in
tens’ gram scale using flavan (III) as the starting material.
amounts of TMSOTf [12] gave the desired 6-C-b-D-glucopyranosyl
flavan 12 as a major product, along with a small amount of 13
generated by the loss of the TBS at the 7-OH group. It was note-
worthy that the desired 6-C-b-D-glucopyranosyl flavan 12 was ob-
tained as a single
b
-anomer (5.10 ppm, d, J ¼ 10.0 Hz, H-1'0). The
positional selectivity for this glycosylation on the aromatic ring was
evident by the absence of C-6 aromatic signal around at 6.04 ppm
(s, H-6). Selective removal of the TBS group of 12 with hydrogen
fluoride-pyridine (HFꢂPy) complex afforded phenolic compound 13
in 60% yield over two steps. Similarly, the second C-glycosylation
with another glycosyl donor 9 proceeded smoothly at C-8 to give
Retrosynthetically, the synthetic plan for schaftoside makes the
obvious disconnection at the 6-C-b-D-glucopyranoside and 8-C-a-L-
arabinopyranoside linkage to A-ring of apigenin (Scheme 1). The
conjugated system of C-ring in the flavone 5 would be recon-
structed in a two-step process involving oxidative dehydrogenation
of C-glycosylflavan 6 followed by halogenation and elimination
with the corresponding C-glycosylflavanone at a late stage. Thus,
we envisioned that the regio- and stereoselective C-glycosylations
between flavan (7) and the corresponding peracetylglycosyl tri-
chloroacetimidates (8, 9) could be fashioned via a Lewis acid pro-
moted O/C rearrangement glycosylation (in which the O-
glycoside were formed initially and then followed by Fries-type
rearrangement to give the ortho C-glycoside) [7]. In general, O/C
rearrangement type C-glycosylation depends on the electron den-
sity and steric hindrance on the aromatic ring [10]. The C-glyco-
sylation of aromatic ring with electron donating groups proceeds
smoothly, while it is suppressed by the electron withdrawing
substituted groups and steric hindrance on the aromatic ring. Based
on our previous experiences and NBO-supported charge population
analysis, the electron-rich flavan derivative 7 emerged as the best
glycosyl acceptor for this rearrangement. Therefore, readily
the desired 6-C-b-D-glucopyranosyl-8-C-a-L-arabinopyranosyl fla-
van 6 in a moderate yield of 51% over 40 g scale. The excellent
stereo- and regioselectivity for C-glycosylation was rationalized by
free 5-OH or 7-OH group directed ortho-C-glycosylation and
anchimeric assistance of the C-2 acetyl group of the glycosyl donors
[7a]. The appearance of several sets of peaks in the 1H and 13C NMR
spectra suggests that all the C-glycosides intermediates exist as
rotational isomers at ambient temperature on the NMR time-scale
[13].
With the key C-glycosylflavan 6 (>40 g) in hand, we then
focused our attention on the construction of the conjugated system
of C-ring in the flavone 5 (Scheme 3). However, the envisaged
oxidative dehydrogenation of C-glycosylflavan 6 turned out to be
more difficult than we expected. Initially, the attempted direct
oxidation of C-glycosylflavan 6 without protective groups on phe-
nols failed to give any desired products and led to undesired ben-
zoquinone product along with unidentified decomposition
products. We reasoned that the oxidation of phenol A-ring
Fig. 2. Structures and NBO charge population analysis of I-III
2

C. Shang, C. Zhao, P. Nie et al.
Tetrahedron 91 (2021) 132216
Scheme 1. Retrosynthetic analysis of schaftoside (1).
Scheme 2. Synthesis of C-glycosyl flavan 6.
Scheme 3. Gram-scale synthesis of schaftoside (1).
3

C. Shang, C. Zhao, P. Nie et al.
Tetrahedron 91 (2021) 132216
probably preceded to the oxidative dehydrogenation of the C-4
position [14]. Thus, to tackle this problem, blocking of the phenolic
hydroxyl groups in 6 with benzyl groups in the presence of po-
tassium carbonate in DMF gave the bis-benzylation product 14 in
almost quantitative yield. Subsequently, oxidative dehydrogenation
of C-glycosylflavan 14 was carried out successfully by a two-step
procedure following a modified procedure from Wong [15a] and
Suzuki [15b], while the other reported one-pot methods (for
example, cerium (IV) ammonium nitrate (CAN) in AcOH/H2O/
CH3CN 10b) were fruitless in our efforts. The bis-benzylation de-
rivative 14a was smoothly oxidized by cerium (IV) ammonium ni-
trate to give the corresponding C-glycosylflavanols, which was
further oxidized by pyridinium dichromate (PDC) to give the di-C-
glycosylflavanone 15 in 83% yield over three steps. The same
oxidation conditions were also subjected to the peracetylated C-
glycosylflavan 14b, generating complicated results in our hands
(<30% yield). The low yield for bis-acetylation derivative was due to
the electron-withdrawing acyl groups in the phenolic hydroxyl
group, which decreased the oxidative reactivity of C-4 position.
Hydrogenolysis of 15 with 10% Pd/C catalyst under H2 atmosphere
obtained the corresponding phenol and subsequent treatment with
acetic anhydride in pyridine delivered the flavanone acetates 16 in a
yield of 96% over two steps. The halogenation and elimination of C-
glycosylflavanone 16 proceeded smoothly in the presence of cata-
lytic amounts of iodine following a heating in dimethyl sulfoxide
(DMSO) at 140 ꢁC for 4 h to give the desired 6-C-glucosylflavone 5 in
a good yield (84%) [16]. Global deacetylation of 5 with sodium
methoxide in dry methanol successfully achieved the desired
schaftoside (1) in 89% yield on a 10.2 g scale. The spectroscopic data
(1H, 13C NMR, and HRMS) of the synthetic schaftoside (1) were in
good agreement with those of the natural products [17].
5. Experimental procedures for the synthesis of compounds
5.1. Synthesis of compound 11
TBSCl (112.93 g, 0.749 mol) in dry THF (500 mL) was added
dropwise to the solution of ( ) naringenin (170.00 g, 0.624 mol) and
Et3N (104.15 mL, 0.749 mol) in dry THF (1200 mL) at 0 ꢁC. The
cooling bath was removed and the mixture was stirred for 2 h. After
consumption of the starting materials, Et3N (260 mL, 1.87 mol) was
added to the solution. The reaction mixture was cooled to 0 ꢁC and
acetic chloride (110.8 mL, 1.56 mol) in THF (300 mL) was added
dropwise to the mixture. After the intermediate was consumed, the
mixure was quenched with saturated solution of NaHCO3 (1200 mL,
Caution!) at 0 ꢁC. The aqueous layer was separated and extracted
with EtOAc (3 ꢃ 1200 mL), and the combined organic phase were
washed with brine, dried over Na2SO4, filtered and concentrated
under vacuum. The residue was purified by flash column chroma-
tography (Petroleum -EtOAc, 2:1) to give compound 11 as racemate
mixture (205.7 g, 70%, colorless oil). 1H NMR (400 MHz, CDCl3)
d
7.47e7.45 (m, 2H), 7.16e7.14 (d, J ¼ 8.7 Hz, 2H), 6.37e6.36 (d,
J ¼ 2.4 Hz, 1H), 6.22e6.21 (d, J ¼ 2.3 Hz, 1H), 5.46e5.42 (dd, J ¼ 13.5,
2.7 Hz, 1H), 3.02e2.95 (dd, J ¼ 16.7, 13.6 Hz, 1H), 2.73e2.68 (dd,
J ¼ 16.7, 2.8 Hz, 1H), 2.37 (s, 3H), 2.30 (s, 3H), 0.97 (s, 9H), 0.25 (s,
6H)$13C NMR (100 MHz, CDCl3)
d 188.74, 169.47, 169.34, 163.83,
162.45, 151.84, 150.91, 136.04, 127.42, 122.06, 109.70, 108.54, 106.12,
78.89, 45.14, 25.48, 21.16, 21.14, 18.18, ꢀ4.37. HRMS (Maldi) for
C25H30O7SiNa [MþNa]þ: calcd. 493.1653; found 493.1666.
5.2. Synthesis of compound 7
Sodium borohydride (30.3 g, 0.80 mol) was added by portions to
the solution of 11 (189 g, 0.40 mol) in THF/H2O (1:1, 2 L) at ꢀ5 ꢁC.
The temperature of the reaction should be controlled rigorously
below 0 ꢁC. After completion, the mixture was quenched by the
addition of saturated aq. NH4Cl (200 mL). The aqueous layer was
separated and extracted with EtOAc (3 ꢃ 1000 mL) and the com-
bined organic phase were washed with brine, dried over Na2SO4,
filtered and concentrated under vacuum. The residue was purified
by column chromatography (Petroleum -EtOAc, 3:1) to give com-
pound 7 as a white amorphous powder (111.4 g, 67%, racemate
3. Conclusion
In summary, we have accomplished the first and a scalable total
synthesis of schaftoside (1) in 11 linear steps and in 8.83% overall
yield. Taking advantages of the relatively electron-rich flavan
significantly facilitated the synthesis of C-glycosylflavone, and also
make the scale-up preparation possible. With tens’ grams of syn-
thetic schaftoside (1) in hand, we are now undergoing the inves-
tigation of biological activities, such as in-depth assessment of the
anti-obesity, anti-diabetic activity, as well as its hepatoprotective
and antiallergenic properties both in vitro and in vivo. The related
results will be disclosed in due course.
mixture). 1H NMR (400 MHz, CDCl3)
d
7.43e7.40 (dd, J ¼ 8.6, 2.8 Hz,
2H), 7.10e7.08 (dd, J ¼ 8.6, 2.4 Hz, 2H), 6.05 (s, 1H), 5.93 (s, 1H),
4.98e4.95 (dd, J ¼ 10.3, 2.2 Hz, 1H), 2.73e2.60 (m, 1H), 2.30 (s, 1H),
2.27e2.16 (dtd, J ¼ 11.5, 3.5, 1.3 Hz, 1H), 2.05e1.95 (ddt, J ¼ 9.9, 6.6,
3.6 Hz, 0H), 0.96e0.90 (s, 9H), 0.18 (s, 6H). 13C NMR (100 MHz,
CDCl3) d 169.73, 156.36, 155.03, 154.30, 150.17, 139.19, 127.21, 121.61,
4. Experimental
102.54, 101.12, 100.04, 29.45, 25.69, 21.19, 19.01, 18.19. HRMS
(Maldi) for C23H30O5SiNa [MþNa]þ: calcd. 437.1755; found
437.1766.
4.1. General Experimental
Unless noted otherwise, commercially available materials were
used without further purification. All solvents were dried according
to the established procedures ahead of use. Flash chromatography
(FC) was performed using silica gel (100e200 meshes) according to
the standard protocol. All reactions under standard conditions were
monitored by thin-layer chromatography (TLC) on gel F254 plates.
High-resolution mass spectrometry data (HRMS) were acquired
using a Q-TOF analyzer in methanol as solvent. 1H NMR, 13C NMR
were measured on 400 or 600 MHz, 100 or 150 MHz spectrometers.
5.3. Synthesis of compound 12 and 13
To a mixture of compound 7 (72.84 g, 0.176 mol), 2, 3, 4, 6-tetra-
O-acetyl-D-glucopyranosyl trichloroacetimidate (104 g, 0.21 mmol)
and molecular sieves (4 Å, 20 g) in anhydrous CH2Cl2 (2000 mL)
was added TMSOTf (5.3 mL, in 20 mL anhydrous CH2Cl2, 29 mmol)
via syringe at - 20 ꢁC under N2 protection. The solution was stirred
for 30 min at - 20 ꢁC and then warmed to room temperature for
another 2 h. After completion, hydrogen fluoride-pyridine (HF.Py,
120 mL) was added to the mixture at 0 ꢁC. The mixture was
quenched with saturated solution of NaHCO3 (1200 mL). The
aqueous layer was separated and extracted with CH2Cl2
(3 ꢃ 1000 mL) and the combined organic layers were washed with
brine, dried over Na2SO4, filtered and concentrated. The residue
was purified by flash column chromatography (Petroleum -EtOAc,
Chemicals shifts (d) were expressed in ppm relative to residual
CDCl3, MeOD or DMSO‑d6. Multiplicity is tabulated as s for singlet,
d for doublet, t for triplet, q for quadruplet, and m for multiplet and
br when the signal in question is broadened. Yields refer to chro-
matographically and spectroscopically (1H NMR) homogeneous
materials.
4

C. Shang, C. Zhao, P. Nie et al.
Tetrahedron 91 (2021) 132216
2:1) to afford compound 13 (68.7 g, 62%, white foam) as mixtures of
The crude bis-benzylation product could be used for next step
without further purification.
C-2 epimers (Rotamers observed by 1H NMR and 13C NMR). 1H NMR
(400 MHz, CDCl3)
d
7.40e7.38 (d, J ¼ 5.8 Hz, 1H), 7.10e7.07 (m, 1H),
Cerium ammonium nitrate (225.3 g, 0.368 mol) was added by
portions to the solution of crude 14 in CH3CN/H2O (5:1, 800 mL) at
room temperature. After completion, the mixture was diluted with
H2O (300 mL) and the aqueous layer was separated and extracted
with EtOAc (3 ꢃ 400 mL). The combined organic layers were
washed with brine, dried over Na2SO4, filtered and concentrated to
afford crude C-glycosylflavanol as a brown syrup. The crude C-
glycosylflavanol could be used for next step without further puri-
fication. Pyridinium dichromate (PDC) (69.6 g, 0.184 mol) was
added by portions to the solution of the above residue in CH2Cl2
(500 mL) and the mixture was heated to reflux for 4 h. After
completion, the mixture was filtered with Celite and the filter cake
was washed with CH2Cl2 (200 mL). The combined organic layers
were concentrated and purified by flash column chromatography
(Petroleum -EtOAc, 1:1) to afford compound 15 (33.29 g, 83%, white
amorphous solid) as mixtures of C-2 epimers (Rotamers observed
5.89e5.89 (s, 1H), 5.41e5.27 (m, 3H), 5.14e5.12 (d, J ¼ 3.3 Hz,1H),
4.95e4.87 (m, 1H), 4.34e4.29 (m, 1H), 4.18e4.14 (m, 1H), 3.91e3.87
(m, 1H), 2.77e2.72 (m, 1H), 2.67e2.58 (tt, J ¼ 10.7, 5.4 Hz, 1H), 2.31
(s, 2H), 2.34e1.86 (m, 18H). 13C NMR (100 MHz, CDCl3)
d 170.80,
170.51, 169.71, 169.48, 156.66, 139.10, 127.29, 127.24, 121.59, 77.24,
77.16, 76.17, 76.11, 74.27, 73.84, 73.78, 70.83, 70.77, 67.88, 61.48,
61.45, 29.46, 29.30, 21.17, 20.69, 20.59, 20.39, 20.36,19.11,19.01.
HRMS (Maldi) for C31H34O14Na [MþNa]þ: calcd. 653.1841; found
653.1855. In our original procedure, the crude intermediate 12 was
purified on a silica gel column to get the physical spectra data.
(Rotamers observed by 1H NMR and 13C NMR): 1H NMR (400 MHz,
CDCl3)
d
7.44e7.42 (d, 2H), 7.38 (s, 1H),7.12e7.09 (dd, J ¼ 8.6, 2.4 Hz,
2H), 5.92e5.91 (d, 1H), 5.45e5.39 (d, J ¼ 9.1 Hz, 1H), 5.33e5.26 (m,
2H), 5.10e5.07 (d, J ¼ 10.0 Hz, 1H), 4.99e4.89 (m, 1H), 4.36e4.32
(m, 1H), 4.19e4.16 (d, J ¼ 10.3 Hz, 1H), 3.85e3.77 (dt, J ¼ 9.4, 2.9 Hz,
1H), 2.84e2.79 (m, 1H), 2.71e2.61 (m, 1H), 2.39e1.84 (m, 19H), 1.06
by 1H NMR and 13C NMR). 1H NMR (400 MHz, CDCl3)
d 7.72e7.39
(s, 9H), 0.30e0.18 (m, 6H). 13C NMR (100 MHz, CDCl3)
d
170.63,
(m, 9H), 7.20e7.16 (m, 2H), 6.15e5.99 (m, J ¼ 42.6, 9.8 Hz, 1H),
5.62e5.40 (m,1H), 5.27e4.66 (m, 3H), 4.16e4.10 (m, J ¼ 12.4, 4.5 Hz,
3H), 3.54e3.47 (dq, J ¼ 8.1, 2.4 Hz, 1H), 2.31 (s, 1H), 2.02e1.53 (m,
170.29,169.45, 169.40, 169.05, 169.02, 156.62, 156.60, 155.04, 155.01,
152.00, 151.90, 150.28, 150.26, 139.12, 139.08, 127.33, 121.62, 104.54,
104.50, 103.89, 103.76, 98.63, 98.52, 77.56, 77.42, 77.31, 76.43, 76.35,
74.87, 74.05, 74.00, 70.22, 70.18, 68.02, 61.45, 29.63, 29.33, 25.75,
25.71, 21.14, 20.68, 20.66, 20.58, 20.41, 20.39, 19.23, 19.15,
18.22, ꢀ4.09, ꢀ4.14, ꢀ4.79, ꢀ4.85.
17H), 1.31 (s, 1H)$13C NMR (100 MHz, CDCl3)
d 189.54, 188.81,
170.69, 170.63, 170.61, 170.59, 170.39, 170.34, 170.07, 169.98, 169.34,
169.08, 169.03, 168.89, 168.61, 166.32, 166.27, 164.47, 164.36, 160.46,
160.38, 151.18, 151.10, 137.31, 137.18, 136.72, 136.56, 136.33, 135.87,
129.23, 129.02, 128.93, 128.88, 128.81, 128.72, 128.66, 128.57,
128.49, 128.42, 128.14, 128.07, 128.01, 127.87, 127.54, 125.93, 125.91,
122.11, 121.99, 121.95, 118.21, 117.52, 115.41, 114.94, 112.67, 111.49,
79.48, 79.30, 79.14, 78.91, 77.59, 77.30, 75.69, 74.95, 74.71, 73.51,
73.08, 72.65, 72.49, 70.42, 70.31, 68.36, 68.23, 68.18, 68.14, 67.93,
67.10, 66.59, 61.91, 61.78, 46.32, 45.16, 21.12, 20.74, 20.71, 20.66,
20.58, 20.56, 20.51, 20.43, 20.34, 20.31, 20.17, 20.08, 19.79. HRMS
(Maldi) for C56H58O22Na [MþNa]þ: calcd. 1105.3312; found
1105.3325.
5.4. Synthesis of compound 6
To a mixture of compound 13 (57.25 g, 0.09 mol), 2, 3, 4-tri-O-
acetyl-L-Arabinopyranosyl trichloroacetimidate (41.9 g, 0.1 mol)
and molecular sieves (4 Å, 10 g) in anhydrous CH2Cl2 (1000 mL) was
added TMSOTf (1.65 mL, in 8 mL anhydrous CH2Cl2, 9 mmol) via
syringe at - 20 ꢁC under N2 protection. The solution was stirred for
30 min at - 20 ꢁC and then warmed to room temperature for
another 4 h. After completion, the mixture was quenched with
saturated solution of NaHCO3 (1200 mL). The aqueous layer was
separated and extracted with CH2Cl2 (3 ꢃ 600 mL) and the com-
bined organic layers were washed with brine, dried over Na2SO4,
filtered and concentrated. The residue was purified by flash column
chromatography (Petroleum -EtOAc, 1:1) to afford compound 6
(41.15 g, 51%, white amorphous foam) as mixtures of C-2 epimers
(Rotamers observed by 1H NMR and 13C NMR). 1H NMR (400 MHz,
5.6. Synthesis of compound 16
A solution of 15 (33.28 g, 30.8 mmol) in THF (500 mL) was hy-
drogenated over palladium-loaded activated carbon (Pd/C, 10%,
3.0 g) under hydrogen atmosphere. After completion, the Pd/C
catalyst was filtered and the filtrate was concentrated to afford
crude phenol as colorless syrup. The crude phenol could be used for
next step without further purification. Acetic anhydride (25 mL)
was added to the solution of crude phenol in pyridine (200 mL) at
room temperature. The solution was warmed to 50 ꢁC for 2 h. After
completion, the mixture was concentrated and purified by flash
column chromatography (Petroleum -EtOAc, 1:1) to afford com-
pound 16 (29.1 g, 96% white amorphous solid) as mixtures of C-2
epimers (Rotamers observed by 1H NMR and 13C NMR). 1H NMR
CDCl3)
d 7.70e7.68 (s, 1H), 7.46e7.38 (m, 3H), 7.16e7.13 (m, 2H),
5.53e5.24 (m, 6H), 5.13e5.02 (m, 2H), 4.89e4.86 (d, J ¼ 7.5 Hz, 1H),
4.33e4.28 (m, 1H), 4.16e4.07 (m, 2H), 3.89e3.78 (m, 2H),
2.85e2.58 (m, 2H), 2.32e1.68 (m, 26H)$13C NMR (100 MHz, CDCl3)
d
170.66, 170.37, 170.33, 170.22, 170.02, 169.79, 169.60, 169.46,
168.58, 155.25, 155.18, 153.40, 153.10, 153.04, 150.25, 150.06, 139.36,
138.73, 127.26, 127.00, 126.41, 121.77, 121.75, 121.61, 103.08, 102.22,
101.55, 76.19, 76.09, 74.30, 73.71, 72.04, 71.96, 70.27, 68.66, 68.37,
68.06, 67.89, 61.55, 30.85, 28.72, 21.17, 21.14, 20.94, 20.79, 20.73,
20.71, 20.62, 20.55, 20.50, 19.82, 18.89. HRMS (Maldi) for
C42H48O21Na [MþNa]þ: calcd. 911.2580; found 911.2597.
(400 MHz, CDCl3) d 7.72e7.64 (m, 2H), 7.43e7.36 (m, 1H), 7.19e7.14
(m, 2H), 6.02e5.91 (m, 1H), 5.74e5.61 (m, 2H), 5.29e4.93 (m, 5H),
4.49e3.70 (m, 5H), 3.68e3.38 (m, 3H), 3.20e2.51 (m, 3H),2.49e1.12
(m, 43H)$13C NMR (100 MHz, CDCl3)
d 188.95, 170.71, 170.44,
170.29, 170.24, 169.54, 169.09, 169.03, 168.22, 168.07, 167.38, 167.27,
163.10, 155.28, 151.17, 150.04, 150.01, 135.96, 128.01, 128.01, 127.79,
126.80, 122.47, 122.17, 122.03, 116.95, 115.41, 112.27, 79.42, 74.75,
74.50, 74.01, 72.52, 72.40, 72.01, 69.40, 68.93, 68.48, 68.34, 68.18,
66.17, 61.85, 45.26, 21.38, 21.23, 21.12, 20.76, 20.70, 20.67, 20.64,
20.60, 20.37, 20.28, 20.25, 19.83. HRMS (Maldi) for C46H50O24Na
[MþNa]þ: calcd. 1009.2584; found 1009.2606.
5.5. Synthesis of compound 15
To a mixture of 6 (32.92 g, 37.1 mmol) and K2CO3 (25.6 g,
0.184 mol) in dry DMF (500 mL) was added BnBr (11 mL, 92 mmol)
via syringe at room temperature. The solution was warmed to 50 ꢁC
for another 5 h. After completion, the mixture was cooled to room
temperature and diluted with H2O (600 mL). The aqueous layer was
extracted with EtOAc (3 ꢃ 600 mL) and the combined organic phase
were washed with brine, dried over Na2SO4, filtered and concen-
trated under reduced pressure to afford crude 14 as a reddish syrup.
5.7. Synthesis of compound 5
A solution of 16 (18.0 g, 18.26 mmol) in dry DMSO (400 mL) was
5

C. Shang, C. Zhao, P. Nie et al.
Tetrahedron 91 (2021) 132216
heated to 140 ꢁC with iodine (465 mg, 1.8 mmol). After completion,
the mixture was quenched with solution of Na2S2O3 (400 mL) at
0
(3 ꢃ 300 mL). The combined organic layers were washed with
brine, dried over Na2SO4, filtered and concentrated. The residue
was purified by flash column chromatography (Petroleum -EtOAc,
2:3) to afford compound 5 (15.09 g, 84%) as a white amorphous
Appendix A. Supplementary data
ꢁC. The aqueous layer was separated and extracted with EtOAc
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132216.
solid. (Rotamers observed by 1H NMR and 13C NMR). [
a]
20 ꢀ 12.01 (c
References
D
1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.03e8.01 (d, J ¼ 8.3 Hz,
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2H), 7.86e7.84 (d, J ¼ 8.3 Hz, 1H), 7.34e7.32 (d, J ¼ 8.4 Hz, 1H),
7.25e7.23 (s,1H), 6.58e6.50 (d,1H), 6.07e6.02 (s, 1H), 5.76e5.67 (d,
J ¼ 13.1 Hz, 2H), 5.54e5.45 (m, 1H), 5.35e5.14 (m, 5H), 4.46e4.33
(dd, 10.0 Hz, 2H), 4.26e4.11 (m, 2H), 3.98e3.64 (ddd, J ¼ 86.4, 31.7,
11.4 Hz, 4H), 2.56e1.58 (m, 46H)$13C NMR (100 MHz, CDCl3)
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169.86, 169.67, 169.59, 169.46, 168.99, 168.78, 168.55, 168.21, 167.68,
167.58, 163.02, 161.14, 157.22, 154.90, 153.48, 153.13, 150.81, 149.36,
129.59, 128.59, 127.52, 122.95, 122.39, 121.55, 118.89, 117.29, 115.83,
115.66, 115.36, 110.54, 109.03, 74.93, 74.67, 74.44, 73.45, 72.62,
72.30, 72.09, 70.32, 70.10, 69.71, 69.35, 68.70, 68.62, 68.13, 67.95,
67.03, 61.84, 21.39, 21.30, 21.23, 21.15, 21.05, 20.96, 20.77, 20.71,
20.69, 20.65, 20.62, 20.50, 20.30, 20.20, 20.13. HRMS (Maldi) for
C46H50O22Na [MþNa]þ: calcd. 1007.2428; found 1007.2451.
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5.8. Synthesis of schaftoside (1)
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To a solution of 5 (14.58 g, 14.8 mmol) in dry CH3OH (300 mL,
freshly distilled) was added sodium methoxide (1 M, freshly made)
at room temperature. The pH of the solution was controlled around
9e10 with sodium methoxide. After completion, the mixture was
neutralized with Dowex 50W ꢃ 8 (Hþ) resin. The mixture was
filtered and the organic layers were concentrated to afford Schaf-
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[9] The Geometry Structures of Apigenin (I), Naringenin (II) and Flavan (III) Were
Optimized with M062X/6-31þG(d,p) Methods and SMD Solvation Model in
Dichloromethane Solution, and Frequency Analysis Was Carried Out at the
Same Level, to Make Sure These Structures Are Local Minimum on the Po-
tential Energy Surface. To Explain Their Reactivity, NBO Charge Population
Analysis Were Performed. All the Computations Were Carried Out with
Gaussian09 Software. Full Details of NBO Charge Analysis Can Be Found in the
Supporting Information (Table 1).
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toside (1) (7.44 g, 89%) as a yellowish solid. (Rotamers observed by
20
1H NMR and 13C NMR). [
a]
þ77.8 (c 1.0, MeOH), 1H NMR
D
(400 MHz, DMSO‑d6, 100 ꢁC)
d 13.77 (1H, brs, OH-5), 10.13 (1H, brs,
OH-7), 9.24 (1H, brs, OH-40), 8.08 (2H, br d, H-20,60), 6.94e6.92 (2H,
d, J ¼ 8 Hz, H-30,50), 6.76 (1H, s, H-3); 6-C-ß -Glc: 4.74 (1H, d,
J ¼ 9.8 Hz, H-100), 3.92 (1H, m, H-200), 3.28 (1H, m, H-300), 3.28 (1H, m,
H-400), 3.28 (1H,m, H-500), 3.70, 3.54 (2 ꢃ 1H, 2 ꢃ m, 600-CH2); 8-C-
a-
(b) J.G. Sweeny, G.A. Iacobucci, Tetrahedron 33 (1977) 2927e2932. It was
noteworthy that flavan 7 could be obtained in a good yield of 82% on ten-
gram scale, but the yields will be decreased at higher reaction scales. It
seemed that the yield was extremely sensitive to the reaction temperature
and addition rate of sodium borohydride.
Ara: 4.81 (1H, d, J ¼ 9.6 Hz, H-1000), 4.09 (1H, br m, H-2000), 3.53 (1H,
m, H-3000), 3.88 (1H, m, H-4000), 3.93, 3.69 (2 ꢃ 1H, 2 ꢃ m, 5000-CH2);
13C NMR (125 MHz, DMSO‑d6, 60 ꢁC)
d101.9 (C-2),102.0 (C-3), 181.8
(C-4), 160.7 (C-5), 108.0 (C-6), 159.0 (C-7), 104.0 (C-8), 153.9 (C-9),
103.0 (C-10), 120.9 (C-10), 161.0 (C-40), 128.6 (C-20,60), 115.6 (C-30,50);
6-C-ß-Glc: 73.1 (C-100),70.6(C-200), 78.2 (C-300), 69.7(C-400), 80.9 (C-
[12] E. El Telbani, S. El Desoly, M.A. Hammad, A.R. Hassan, A.R.H.A. Rahman,
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gram Scale and Key Intermediates Were Separated Chromatographically in
Order to Be Fully Characterized. Due to the Restricted Rotation of C-Glycosidic
Bond Linkage to C-6 and C-8 on the Aromatic Ring, the Rotational Isomers of
Our Synthetic C-Glycosides Were Observed Both in the 1H NMR and 13C NMR
Spectra.
500), 60.5 (C-600); 8-C- -Ara: 74.6(C-1000), 68.7 (C-2000), 74.1 (C-3000),
a
68.3 (C-4000), 70.3 (C-5000). HRMS (ESI) for C26H28O14Na [MþNa]þ:
calcd. 587.1371; found 587.1362.
[14] L. He, Z. Zhang, M. Tanoh, G. Chen, J. Praly, E.D. Chrysina, C. Tiraidis,
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(2007) 596e606.
Declaration of competing interest
[15] (a) K. Ohmori, H. Ohrui, K. Suzuki, Tetrahedron Lett. 41 (2000) 5537e5541;
(b) J.J. Shie, C.A. Chen, C.C. Lin, A.F. Ku, T.J. Cheng, J.M. Fang, C.H. Wong, Org.
Biomol. Chem. 8 (2010) 4451e4462.
[16] (a) H. Tanaka, M.M. Stohlmeyer, T.J. Wandless, L.P. Taylor, Tetrahedron Lett. 41
(2000) 9735e9739;
The authors declare the following financial interests/personal
relationships which may be considered as potential competing
interests: Jun Liu reports financial support and administrative
support were provided by Chinese Academy of Science.
(b) J.A. Smith, D.J. Maloney, S.M. Hecht, D.A. Lannigan, Bioorg. Med. Chem. 15
(2007) 5018e5034.
[17] See Supplementary Information for the detailed comparisons of 1H and 13C
NMR of natural and synthetic schaftoside. The observed optical rotation
20
Acknowledgements
values for our synthetic schaftoside was [
a
]
þ77.8 (c 1.0, MeOH). However,
D
the optical rotation for natural schaftoside was not recorded in literature.3 the
rotational isomerism of synthetic schaftoside was confirmed by variable-
temperature 1H NMR in DMSO-d6 from 60ꢁC to 100 ꢁC. The full character-
ized details (1H, 13C NMR, COSY, HSQC, HSBC, HPLC, and HRMS) of synthetic
schaftoside can be found in the Supporting Information.
This work was supported by the STS Project of Chinese Academy
of Sciences (KFJ-STS-QYZD-201-5-1) and the National Key Research
and Development Program of China (2016YFA0203102).
6