Total synthesis of scutellarin and apigenin 7-O-β-d-glucuronide

Article abstract of DOI:10.1016/j.carres.2019.02.005

A general protocol for direct glucuronic linkages formation featuring Au(I)-catalyzed appropriately protected glucuronyl o-alkynylbenzoate-involved glycosylation reaction, as well as a concise approach for easy access of scutellarein prominent for the mild and efficient hydroxyl group installation via borylation-oxidation sequence from flavanone derivative, has been established, based on which a novel route for scutellarin derivatives preparation has been devised. The developed strategies, among which the stepwise deprotection process was also included, guarantee the high whole synthetic efficiency, and definitely will find broad application in diversity-oriented synthesis of bioactive flavonoid glycosides.

Full text of DOI:10.1016/j.carres.2019.02.005

Accepted Manuscript
Total synthesis of scutellarin and apigenin 7-O-β-d-glucuronide
Xin Liu, Guo-En Wen, Jian-Chao Liu, Jin-Xi Liao, Jian-Song Sun
PII:
S0008-6215(19)30046-1
https://doi.org/10.1016/j.carres.2019.02.005
CAR 7678
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 24 January 2019
Revised Date: 13 February 2019
Accepted Date: 14 February 2019
Please cite this article as: X. Liu, G.-E. Wen, J.-C. Liu, J.-X. Liao, J.-S. Sun, Total synthesis of scutellarin
and apigenin 7-O-β-d-glucuronide, Carbohydrate Research (2019), doi: https://doi.org/10.1016/
j.carres.2019.02.005.
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Abstract
A general protocol for direct glucuronic linkages formation featuring Au(I)-catalyzed
appropriately protected glucuronyl o-alkynylbenzoate-involved glycosylation reaction,
as well as a concise approach for easy access of scutellarein prominent for the mild
and efficient hydroxyl group installation via borylation-oxidation sequence from
flavanone derivative, has been established, based on which a novel route for
scutellarin derivatives preparation has been devised. The developed strategies,
among which the stepwise deprotection process was also included, guarantee the
high whole synthetic efficiency, and definitely will find broad application in
diversity-oriented synthesis of bioactive flavonoid glycosides.

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Total Synthesis of Scutellarin and Apigenin 7-O-β-D-glucuronide
Xin Liu,1 Guo-En Wen,1 Jian-Chao Liu,1 Jin-Xi Liao,1 and Jian-Song Sun1*
1The National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, 99 Ziyang
Avenue, Nanchang 330022, China.
jssun@jxnu.edu.cn
Abstract
A general protocol for direct glucuronic linkages formation featuring Au(I)-catalyzed
appropriately protected glucuronyl o-alkynylbenzoate-involved glycosylation reaction,
as well as a concise approach for easy access of scutellarein prominent for the mild
and efficient hydroxyl group installation via borylation-oxidation sequence from
flavanone derivative, has been established, based on which a novel route for
scutellarin derivatives preparation has been devised. The developed strategies,
among which the stepwise deprotection process was also included, guarantee the
high whole synthetic efficiency, and definitely will find broad application in
diversity-oriented synthesis of bioactive flavonoid glycosides.
1. Introduction
As a well-known traditional Chinese medicine herb, Erigeron breviscapus has been
widely prescribed for the treatment of cerebrovascular diseases, such as cerebral
hemorrhage, stroke, cerebral thrombosis, as well as myocardial infarction. The
principle ingredients responsible for the broad pharmaceutical usages of E.
breviscapus have been proven to scutellarin 1 as well as analogues such as apigenin
7-O-β-D-glucuronide 2,[1] which indeed have been demonstrated to show numerous
pharmaceutical activities, including antitumoral activity,[2] neuroprotection,[3]
angiogenesis promotion,[4] as well as anti-HIV effects,[5] and presently are widely
clinically used in China under different dosage forms. At present, scutellarin is solely
acquired from E. breviscapus by direct extraction, thus with the demand increasing,
on the one hand resulting in exhausted natural E. breviscapus source, on the other
hand bringing about serious problems for concise quality control of products from
different batches. In addition, the access of pure scutellarin directly from natural
sources is by no means a simple problem due to the microheterogeneity. Thus,
alternative approaches to get pure scutellarin are highly desired.
Figure 1. The chemical structures of scutellarin and its analogue.
In comparison to enzymatic method,[6] limited by enzyme accessibility, production

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scale, as well as high production cost, the chemical synthesis holds the promise to
solve the problem of scutellarin acquirement completely. Thus, the synthetic
investigation towards scutellarin has been undertaken in as early as 1958 by Zemplén
and coworkers,[7] and finally culminated in the first total synthesis in 1974.[8]
Afterwards, with the new pharmaceutical effects of scutellarin being disclosed
continuously, the interest, both from chemists and from pharmacologists, in synthetic
investigation were refuelled, as exemplified by the appearance of quite a few
approaches for scutellarin synthesis.[9] As all existing synthetic methods are heavily
depend
on
expensive
starting
materials,
including
2-hydroxy-4,5,6-trimethoxyacetophenone or scutellarein, and conventional
glycosylation protocols, such as glycosyl bromide involved glycosylation under the
effect of stoichiometric amounts of silver salts or phase transfer catalyst (PTC)
conditions, they suffer from not only tedious synthetic sequence and accordingly
compromised overall synthetic efficiency but also harsh reaction conditions,
unacceptable synthetic cost, as well as restricted synthetic flexibility.[10] In line with
our continuous interest in bioactive flavonoid glycosides synthesis,[11] we decided to
launch a program to establish a practical approach for scutellarin derivatives
synthesis.
The scarce scutellarein aglycon and, in particular, the glycuronyl phenolic linkage
which is notorious for unsatisfactory formation efficiency due to the diminished
reactivity not only for glycosylation donor but also for acceptor, [12] poses
considerable challenge for scutellarin derivatives synthesis, and also constitutes the
underlying factors responsible for the sluggish development of the synthetic field.
Thus, as prerequisites for efficient synthetic approach establishment, two pivotal
problems, that is efficient glycosidic linkages construction with appropriate glucuronic
donors and easy accessibility of scutellarein aglycon, should be solved first. The
developed solutions should enjoy broad application scope, thus based on which the
pining diversity-oriented synthesis of scutellarin derivatives could be expected.
2. Results and discussion
Glycuronyl residues are widely spread in nature, and, in particular, they are also
comprised in drug derivatives used for drug metabolism study as reference
compounds.[13] Nevertheless, the construction of glycuronic linkages in a highly
efficient manner represents one of the most challenging problems in synthetic
carbohydrate chemistry. The main difficulties associated with glycuronylation lie in
the lowered reactivity of the glycosylation donors, originating from the strongly
electron-withdrawing 5-CO2R group, which frequently leads to orthoester or
transacylating byproducts formations. To avoid the deleterious effect of the ester
group in glycosylation reactions, a detour postglycosylation oxidation strategy has
been devised.[14] However, the additional steps required for C-6-OH oxidation state
adjustment after glycosidic linkage construction compromises the convergent extent
of the synthesis and accordingly the synthetic efficiency. On the contrary, from a
synthetic perspective, the alternative preglycosylation oxidation strategy featuring
C-6-OH oxidation level manipulation prior to glycosidic linkages construction is more

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direct and appealing. Unsurprisingly, a variety of glycosylation protocols have been
adopted to this strategy in attempts to set up an efficient approach for direct
glycuronic linkage construction, however, only limited successes have been
achieved.[15] Considering that the recently introduced Yu glycosylation[16] has
shown impressive performances in challenging glycosidic linkages construction[17]
and has not been tried in direct glycuronide synthesis,[18] we decided to check the
feasibility of glucuronyl o-alkynylbenzoate donor in glucuronides synthesis with the
hope to establish a general protocol for highly efficient and direct glucuronic linkages
construction to facilitate not only the synthesis of scutellarin derivatives but also the
synthesis of other bioactive compounds containing glucuronic acid residues. Inspired
by the instructive work of Huang, wherein an extremely important statement in
carbohydrate chemistry, that is the higher reactivity one donor has the more
potential glycosylation capability it possesses, has been put forward and testified,[19]
the glucuronyl o-alkynylbenzote donor 4 equipped with electron-donating benzyl
groups on 3,4-di-OH was designed and synthesized. As a comparison, the donor 6
with all its 2,3,4-tri-OH blocked by electron-withdrawing benzoyl groups was also
made (Scheme 1). On the 2-OH of both donors, an benzoyl group was selected so as
to control the 1,2-trans-chirality of newly formed glycosidic linkages via the
neighboring-group participating effect. Thus, with 3 [20] as starting material, ceric
ammonium nitrate (CAN) mediated anomeric OH liberation and sequential
dehydrative esterification with o-alkynylbenzoic acid afforded donor 4 (71%, for 2
steps); while the reference donor 6 was prepared under standard acylation conditions
from lactol 5 (76%).[21]
Scheme 1. Synthesis of glucuronyl o-alkynylbenzoate donors 4 and 6.
With both donors 4 and 6 in hand, they were put to condense with a variety of
acceptors to evaluate their glycosylation potential (Table 1). Under the effect of
catalytic amounts of Au(I) complex, all primary acceptors 7-9 were smoothly
glycosylated with 4, to deliver the desired disaccharides 17-19 with excellent yields
(above 89%). Simple as well as complex sugar secondary alcohols 10-14 were proved
to be vital substrates for donor 4 as well, providing glycosylation products 20-24 with
good to excellent yields upon treated with standard glycosylation conditions (above
86% yields). It is worth noting that the glycosylation potential of 4 is so impressive
that even the bulky and inert tertiary 1-adamantanol 15 could be efficiently
glycosylated to afford the glycosylation product 25 in a good 82% yield. Furthermore,

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Table 1. Direct glucuronic linkages construction with donors 4 and 6.
the coupling of 4 with phenolic acceptor 16 proceeded smoothly in spite of the
decreased reactivity of the phenolic acceptor, and good yield of phenolic glycoside 3
[20] was obtained (76%), which boded well for the ensuing application of 4 in the
synthesis of scutellarin and analogues thereof. As comparisons, donor 6 was
evaluated subsequently to react with different acceptors. Although 6 could also
condense with primary acceptor 7, the glycosylation yield was diminished to 75%;
while in terms of the secondary acceptor 11, only low yield of product 27 was
recorded (25%). With the assistance of 2-OBz, all glycosylation proceeded
stereoselectively to afford only β-glycosides, as verified by the diagnostic anomeric
protons of all glycosylation products, which all appear in doublet forms with J values
ranging from 7.6 to 8.0 Hz. The conspicuous glycosylation capability difference
between 4 and 6 highlights the profound effect of electron-donating protecting
groups at 3,4-di-OH on the glycosylation potential of glucuronyl donors via offsetting
the deactivating effect of C-6 ester group. Furthermore, in comparison to the widely
adopted PTC glycosylation protocol in scutallerin derivative synthesis, the present Yu
protocol shows evident advantages as to the substrate scope as well as the flexibility.
Inspired by the promising result of coupling between 4 and 16, the application of 4 in
the synthesis of scutellarin derivative apigenin 7-O-β-D-glucuronide 2 was
subsequently investigated (Scheme 2). Effected by the low reactivity of acceptor 28
[22], presumably originating from the electron-withdrawing acyl protecting groups,
the condensation between 4 and 28 proceeded inefficiently; under conventional
conditions (0.3 equivalents of Au(I) complex, overnight) only 50% yield of 29 was
obtained. Modification of the conventional glycosylation procedure by changing the
addition manner of catalyst from one portion to two portions at an interval of 8 h and
prolonging the reaction time to 16 h brought about an upsoar in yield, leading to an
82% yield for 29. The two benzyl groups in 29 were removed by hydrogenolysis to

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convert 29 to 30 (78%), which was then exposed to mild basic conditions (10% LiOH)
to cleave all acytyl protecting groups and simultaneously saponify the methyl ester to
provide 2 in a good 72% yield. The reaction temperature is vital for the final
deprotection step, as high reaction temperature leads to a mixture of products, which
can be ascribed to the labile property of electron-rich flavonoid residue to air under
basic conditions as well as the propensity of glucuronyl moiety to undergo
epimerization and elimination side reactions under harsh basic conditions.[23] The
spectroscopic data of synthetic 2 was proved to identical to those of authentic
sample.[1]
Scheme 2. Synthesis of scutellarin analogue 2.
OHex
Ph3PAuNTf2 (0.3 eq)
OMe
O
O
HO
O
BnO
BnO
O
+
AW-300 MS, DCM, 40 o
82%
C
OBz
O
OHexO
4
28
OMe
OMe
O
OHex
OHex
O
O
O
HO
HO
Pd/C, H2
BnO
BnO
O
O
O
O
rt, 78%
OBz
OBz
30 OHexO
29
OHexO
OH
OH
O
O
HO
HO
10% LiOH, THF
-7 oC, 72%
O
O
OH
2
OH O
With the glycosylation protocol for glucuronic linkage construction settled, our
attention was then shifted to the scutellarein access problem. To avoid the drawbacks
of existing routes for scutellarein preparation, including tedious synthetic sequence,
expensive starting materials, and harsh reaction conditions, a new approach with
flavonoid compounds as starting materials was pursued (Scheme 3). Thus, starting
from naringein derivative 31,[24] flavone 32 was generated via a sequence of
DDQ-mediated oxidation and selective 4’-OH benzylation (80%, for 2 steps). The
regioselective C-6 iodination of 32 was subsequently effected by
benzyltrimetylammonium dichloroiodate (BTMA-ICl2) under the assist of the directing
effect of the free 5-OH.[25] The directing effect of 5-OH is efficacious, so that the
inherent propensity of flavone moiety to undergo regioselective C-8 iodination is
completely overrode, and the C-6 iodinated flavone 33 was isolated as the only
product (66%). After the 5-OH was blocked with benzyl group, compound 34 ready for
C-6-OH installation was obtained. With 34 in hand, the substitution of iodide with
hydroxyl group or its surrogates was investigated extensively. Impeded by the severe
steric hindrance of the iodide atom imposed by the two flanked substituents, all
attempts in copper- or palladium-catalyzed coupling with allyl alcohol,
1-trimethylsilyethanol, benzyl alcohol, and benzaldoxime under different
conditions[26] uniformly met with failure, except for the try of coupling with sodium
methoxide under the effect of CuBr, which indeed afforded the methyl protected
scutellarein derivative.[9b] However, the methylated scutellarein can not serve as

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intermediate in the novel synthetic route, since the demethylation entails harsh
reaction conditions. Finally, the borylation-oxidation sequence was invoked. Although
the classic as well as the modified Miyaura borylation conditions failed to provide the
desired borylation intermediate (PdCl2(dpf), (PinB)2 or Pd(OAc)2, PCy2(o-biph),
PinBH),[27a-d] it was finally shown that the combination of Pd(OAc)2/P(o-Tol)/PinBH
effected the borylation efficiently to afford the boronic ester, which was directly
exposed to oxidation conditions to afford phenol 35 (NaBO3, 67% for 2 steps).[27e]
Protection of the newly formed OH with benzyl group was followed by MOM removal
with BBr3, thus affording the appropriately protected scutellarein acceptor 37 (65%,
for 2 steps).
Scheme 3. Synthesis of appropriately protected scutellarein 37 from naringenin
derivative.
As the spectroscopic data of 33 could not provide convincing proofs to support the
C-6 iodination in the above synthetic approach, to corroborate the chemical structure
of the synthetic 37, it was resynthesized with peracetylated scuteller-in 38 [28] as
starting material (Scheme 4). The one-pot regioselective 7-OAc cleavage and
simultaneous allylation afforded 39 smoothly (71%). The following replacement of
acetyl groups with benzyl groups was achieved via acid-mediated deacetylation and
ensuing benzylation to deliver the fully protected scutellarein 40 (62%, 2 steps), which
was then exposed to palladium-catalyzed deallylation conditions to give 37 (65%). The
1H NMR comparison of synthetic 37 with different origins showed that actually
identical spectra were obtained,[29] corroborating the structure of 37 as well as the
reliability of the novel scutellarein synthesis approach.
Scheme 4. Determination of the chemical structure of 37 via resynthesizing with 38 as
starting material.
OAc
OAc
AcO
AcO
O
AllO
AcO
O
AllBr, KI, K2CO3, DMF
rt, 71%
1) HCl, EtOH, reflux
2) BnBr, KI, K2CO3, DMF
50 oC, 62% (2 steps)
OAc
O
OAc
O
38
39
OBn
OBn
HO
O
O
AllO
BnO
O
Pd(PPh3)4, NaBH4
THF, rt, 65%
BnO
OBn
OBn
O
37
40

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With both glycosylation protocol and reliable access route to acceptor established,
now the stage was set for the completion of the synthesis of scutellarin (Scheme 5).
Benefited from the electron-donating benzyl protecting groups on acceptor 37, its
condensation with 4 proceeded without any event under standard conditions, and an
excellent yield of fully protected scutallerin 41 was obtained (82%). In the final
deprotection processes, the sequence of methyl ester saponification, benzoyl and
benzyl groups removal was systematically screened, and finally resulted in the optimal
protecting groups manipulation order of methyl ester saponification followed by
benzoyl group cleavage prior to benzyl groups hydrogenolysis. Under mild basic
o
conditions (10%, LiOH, -7 C), the methyl ester in 41 was successfully saponified, to
yield 42 (89%), which was then put to harsh basic conditions to remove the benzoyl
group (NaOMe/MeOH, rt). The resultant debenzoylated acid intermediate was
thenconverted to the target molecule 1, upon treatment with conventional
hydrogenolysis conditions (58%, for 2 steps). This deprotection sequence can exclude
the possible side reactions to a maximum extent: the exposure of carboxyl group in
the early stage of the deprotection process can prevent the possible epimerization as
well as elimination processes of glucuronyl residue under harsh basic conditions
required for benzyol group departure; while the final hydrogenolysis process can
segregate the oxidation-labile multi-hydroxy-substituted flavone residue in 1 from the
air during protecting group manipulation. Finally, the spectra comparison of the
synthetic 1 with authentic compound was made, and fortunately, excellent
accordance was observed.[1]
Scheme 5. The completion of the synthesis of 1.
3. Conclusions
In summary, a novel and flexible approach toward scutellarin and its analogue
featuring highly efficient and direct glucuronic linkage construction with glucuronyl
o-alkynylbenzoate as donor as well as easy access of scutellarein from flavanone
starting material has been established. Through the synthetic investigation, a general
protocol for direct glucuronic linkage constructions with glucuronyl o-alkynylbenzoate
donor carrying benzoyl group on its 2-OH and two benzyl groups on its 3,4-di-OH has
been devised; meanwhile, capitalizing on the borylation-oxidation sequence, a

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concise route for easy access of scutellarein has also been set up. In addition, the
optimized stepwise deprotection sequence for scutellarin synthesis supressed the
possible side reactions to a maximum extent guaranteeing the efficiency of the whole
synthesis, which can find broad application in the synthesis of scutellarin
analogues.[30]
Acknowledgements
This work was financially supported by the National Natural Science Foundation of
China (21572081, 21762024, and 21877055) and Natural Science Foundation of
Jiangxi Province (20161ACB20005, 20171BCB23036, and 20171BAB203008).
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Heterocycles 81 (2010) 1871-1879. For modified borylation conditions, see: c) O. Baudoin, D.
Guénard and F. Guéritte, J. Org. Chem. 65 (2000) 9268-9271. d) O. Baudoin, A. Décor, M.
Cesario and F. Guéritte, Synlett (2003) 2009-2012. For NaBO3 mediated oxidation, see: e) A.
Takagi, T. Ikawa, Y. Kurita, K. Saito, K. Azechi, M. Egi, Y. Itoh, H. Tokiwa, Y. Kita and S. Akai,
Tetrahedron 69 (2013) 4338-4352.
[28] Z.-H. Shi, N.-G. Li, Z.-J. Wang, Y.-P. Tang, Z.-X. Dong, W. Zhang, P.-X. Zhang, T. Gu, W.-Y. Wu,
J.-P. Yang and J.-A. Duan, Eur. J. Med. Chem. 106 (2015) 95-105.

ACCEPTED MANUSCRIPT
[29] See Supporting Information.
[30] J. Sun, S. Laval and B. Yu, Synthesis (2014) 1030-1045.

ACCEPTED MANUSCRIPT
Highlights
1, A novel route for scutellarin and analogue thereof preparation.
2, Au(I)-catalyzed glycosylation by use of glucuronyl o-alkynyl benzoate as donors.
3, A concise approach for easy access of scutellarein prominent for the mild and
efficient hydroxyl group installation via borylation- oxidation sequence from
flavanone derivative.