First total syntheses of four natural bioactive glucosides

Article abstract of DOI:10.1080/00397911.2021.1879151

The efficient total syntheses of four biologically interesting natural glucosides Ethylconiferin, Butylconiferin, 2’-Butoxyethylconiferin and Balajaponin B, have been achieved for the first time starting from commercially available Vanilline via concise reaction sequence of 8–10 steps with the overall yield of 26–41%. This work definitely laid the foundation for the further pharmacological study of this kind of natural compounds. Meanwhile, currently developed approach could be used as a general synthetic strategy for the syntheses of other monolignol glucosides and their derivatives, and provides an opportunity for further study of the structure-activity relationship of this kind of glucosides.

Full text of DOI:10.1080/00397911.2021.1879151

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
First total syntheses of four natural bioactive
glucosides
Guangya Xu, Min Wu, Zhongquan Yao, Hongbin Lou, Weihong Du, Mingwei
Song, Yujiao He & Hongbo Dong
To cite this article: Guangya Xu, Min Wu, Zhongquan Yao, Hongbin Lou, Weihong Du, Mingwei
Song, Yujiao He & Hongbo Dong (2021) First total syntheses of four natural bioactive glucosides,
Synthetic Communications, 51:8, 1266-1271, DOI: 10.1080/00397911.2021.1879151
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021, VOL. 51, NO. 8, 1266–1271
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https://doi.org/10.1080/00397911.2021.1879151
First total syntheses of four natural bioactive glucosides
a
b,c
b
b
b
ꢀ
ꢀ
Guangya Xu , Min Wu , Zhongquan Yao , Hongbin Lou , Weihong Du ,
b
b
b
Mingwei Song , Yujiao He , and Hongbo Dong
a
School of Basic Medicine and Clinical Medical College and Affiliated Hospital, Chengdu University,
b
Chengdu, China; Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, School of
pharmacy, Chengdu University, Chengdu, China; School of Food and Biological Engineering, Chengdu
c
University, Chengdu, China
ABSTRACT
ARTICLE HISTORY
The efficient total syntheses of four biologically interesting natural
glucosides Ethylconiferin, Butylconiferin, 2’-Butoxyethylconiferin and
Balajaponin B, have been achieved for the first time starting from
commercially available Vanilline via concise reaction sequence of
Received 19 October 2020
KEYWORDS
Balajaponin B; 2’-
Butoxyethylconiferin; butyl-
coniferin; Ethylconiferin;
total synthesis
8–10 steps with the overall yield of 26–41%. This work definitely laid
the foundation for the further pharmacological study of this kind of
natural compounds. Meanwhile, currently developed approach could
be used as a general synthetic strategy for the syntheses of other
monolignol glucosides and their derivatives, and provides an oppor-
tunity for further study of the structure-activity relationship of this
kind of glucosides.
GRAPHICAL ABSTRACT
Introduction
Monolignol glucosides (Coniferin, p-Glucocoumaryl alcohol, Syringin, Fig. 1) are con-
sidered to be the storage or excretion form of monolignols which are widely distributed
[
1–5]
plant metabolites associated with wide range of biological activities.
Over the past
several decades, significant research attention has been directed to the investigation of
these compounds. Recently, various bioactivities and pharmaceutical activities of
[
6]
Coniferin have been reported, including antioxidative activity,
antinociceptive
CONTACT Yujiao He
heyujiao@cdu.edu.cn; Hongbo Dong
donghongbo@cdu.edu.cn
Antibiotics Research and
Re-evaluation Key Laboratory of Sichuan Province, School of pharmacy, Chengdu University, Chengdu 610106, China.
ꢀ
These authors contributed equally to this work.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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Figure 1. Structures of some typical monolignol glucosides.
0
Figure 2. Structures of Ethylconiferin (1), Butylconiferin (2), 2 -Butoxyethylconiferin (3) and
Balajaponin B (4).
[
7]
[8]
activity, anti-inflammatory activity, a-Glucosidase inhibitory activity and antihyper-
[
9]
glycemic activity.
0
As shown in Figure 2, Ethylconiferin (1), Butylconiferin (2), 2 -Butoxyethylconiferin
3) and Balajaponin B (4) could be considered to be the structural relatives of Coniferin
(
and also exhibited diverse biological activities. Ethylconiferin (1) was first isolated from
[
10]
the root of Jasminum giraldii Diels (Oleaceae).
Butylconiferin (2) was isolated from a
[
11]
Chinese traditional herbal drugs Balanophora simaoensis as well as the branches of
Lawsonia inermis L. and showed accelerative effects on neurite outgrowth in PC12
[
12]
[
13]
0
cells.
annual herbaceous plant Bidens frondosa (L.)
Balanophora japonica Makino (Balanophoraceae) and showed in vitro glucosidase
2 -Butoxyethylconiferin (3) was one of main anti-inflammatory constituents of
[
14]
Balajaponin B (4) was obtained from
[
15]
inhibitory activity.
To date, these compounds have attracted scientific attention as
the result of their diverse biological activities. However, the low content of them has
limited the further investigation of these activities. Although the total syntheses of
[
16,17]
Coniferin have been reported for several times,
an appropriate synthetic method-
ology to obtain natural products 1–4 and diverse analogues of Coniferin is still required.
0
Herein we reported the first total syntheses of Ethylconiferin (1), Butylconiferin (2), 2 -
Butoxyethylconiferin (3) and Balajaponin B (4).
Results and discussion
The syntheses of natural products 1–3 shown in Scheme 1 began with readily available
Vanillin (5). We started with the conversion of 5 to Ferulic acid (6) by the Knoevenagel
condensation in 94% yield. Compound 6 was refluxed in absolute alcohol in the pres-
ence of concentrated H SO to get ester 7, in which the phenolic hydroxyl group was
2
4

1
268
G. XU ET AL.
ꢂ
Scheme 1. Reagents and conditions: (a) CH (COOH) , piperidine, p-methylaniline, PhCH , 80 C, 94%;
(
2
2
3
ꢂ
b) H SO , CH CH OH, reflux, 94%; (c) Dihydropyran, PPTS, 65 C, 75%; (d) BnCl, LiAlH , THF, r.t., 90%;
2 4 3 2 4
(
(
e) NaH, DMF, r.t., 10a:CH CH I, 93%, 10 b: CH CH CH CH I, 90%, 10c: CH CH OCH CH CH CH Cl, 78%;
3 2 3 2 2 2 3 2 3 2 2 2
ꢂ
f) PPTS, CH OH, r.t.; (g) Compound 13, TBAB, K CO , H O/CHCl , 65 C, 12a: 77%, 12 b: 73%, 12c:
3 2 3 2 3
8
2% for two steps; (h) CH ONa, CH OH, 1: 95%, 2: 97%, 3: 96%.
3 3
protected as tetrahydropyranyl ether (ꢁOTHP) to obtain cinnamate 8. Subsequently the
ester group of 8 was reduced by LiAlH to obtain key intermediate 9. Then ethers 10a-
4
c were formed by coupling corresponding alkyl halides to compounds 9 in the presence
of NaH, respectively. Deprotection of the THP groups of compounds 10a-c with PPTS
in CH OH resulted in formation of compounds 11a, 11 b and 11c smoothly.
3
Glycosylation of aglycones 11a-c with 2,3,4,6-tetra-O-acetyl-a- -glucopyranosyl bromide
D
(
13) under basic conditions, in the presence of the phase transfer catalyst tetra-butylam-
[
18]
monium bromide (TBAB), afforded compound 12a-c in good yields (77%–82%).
The
target natural products 1–3 were obtained from 12a-c by direct deacetylation with
CH ONa/CH OH in excellent yields (over 95% to almost in quantitative).
3
3
As shown in Scheme 2, our strategy for the total synthesis of Balajaponin B (4)
involved a key intermediate aglycone 15. Initially we wanted to convert cinnamyl alco-
hol 10 to cinnamyl bromide 14, which could be coupled with 10 to afford aglycone 15.
However, the attempts to obtain 14 via Appel-Lee reaction (in the presence of CBr and
4
PPh ) or PBr brominated reaction were unsuccessful due to the high instability of 14.
3
3
As shown in Scheme 3, the synthetic route was then modified. In the modified route,
phenolic hydroxyl group of 8 was protected by triisopropylsilyl ether (-OTIPS), which
was more stable than tetrahydropyranyl ether (-OTHP) under brominated conditions to
get cinnamic acid ethyl ester 16. Compound 16 was reduced, brominated and coupled
with compound 10 to form protected aglycone 19 successfully. The TIPS group of 19
was removed by treatment with tetra-n-butylammonium fluoride (TBAF) followed by
deprotection in the presence of PPTS\CH OH to afford aglycone 15. Glycosylation of
3
compound 15 with 3 equiv. of 2,3,4,6-tetra-O-acetyl-a- -glucopyranosyl bromide (13)
D
under similar conditions above, yielded compound 21 in 60%. Compound 21 was

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Scheme 2. Desigh of initial attempt to prepare 15.
Scheme 3. Reagents and conditions: (a) TIPSCl, imidazole, DMF, r.t., 93%; (b) BnCl, LiAlH , THF, r.t.,
4
ꢂ
ꢂ
7
0
7%; (c) PBr , THF, 0 C; (d) Compound 10, NaH, DMF, r.t. to ꢁ20 C, 66% for 2 steps; (e) TBAF, THF,
3
ꢂ
ꢂ
C, 97%; (f) PPTS, CH OH, 99%; (g) Compound 13, TBAB, K CO , H O/CHCl , 65 C, 60%; (h) CH ONa,
3
2
3
2
3
3
CH OH, 85%.
3
treated subsequently with CH ONa in CH OH to generate the desired natural products
3
3
4
in 85% yield.
Based on the above synthetic routes, the key steps of the present processes are TBAB
promoted glycosylations between aglycones (11a-c, 15) with 2,3,4,6-tetra-O-acetyl-a-D-
glucopyranosyl bromide (13) in CH Cl -water solvent system. The glycosylations led to
2
2
the desired b-O-glucosides in good yields (60%–82%) and the coupling constant of H -
1
’
H of compound 1–3 and 4 indicated high stereoselective formation of beta-glycosidic
2
’
3
1
bond ( J
0
¼ 7.2–7.4 Hz in the H NMR spectra).
1
’2
Conclusions
In summary, the first total syntheses of the naturally occurring and biologically interest-
0
ing Ethylconiferin (1), Butylconiferin (2), 2 -Butoxyethylconiferin (3) and Balajaponin B
(4) via a same strategy have been achieved. Syntheses of 1–3 utilized eight-step synthe-
ses from the commercially available Vanillin (5) and gave compound 1–3 in overall
yields of 37%–41%. However, 10 steps were required to produce 4 in an overall yield of

1
270
G. XU ET AL.
2
6% from the same starting material. The total syntheses of these compounds thus pro-
vides an efficient synthetic route to diverse coniferin derivatives that can be used in fur-
ther investigations.
Experimental
Synthesis of ethylconiferin (1)
Under N atmosphere, the acetyl-protected glycoside 12a (0.43g, 0.8 mmol) was dissolved in
2
6
0ml of CH OH. After that, CH ONa (130mg, 2.4 mmol) was added. Then the mixture
3 3
stirred at room temperature for 1 h. When the deprotection was completed, the solution was
neutralized by ion-exchange resin (Amberlite IR120). The agitation was maintained for
1
0min, and then filtered. The CH OH was eliminated by vacuum evaporation to afford
3
1
compounds 1 (0.28g, 95%) as a white solid: [A]D ꢁ19.5 (CH OH, c ¼ 0.11); H NMR
3
(
6
CD OD) d 7.08 (d, J ¼ 8.3 Hz, 1H), 7.05 (d, J ¼ 1.9 Hz, 1H), 6.93 (dd, J ¼ 8.4, 1.9 Hz, 1H),
3
.54 (d, J ¼ 15.9 Hz, 1H), 6.21 (dt, J ¼ 15.9, 6.2 Hz, 1H), 4.87 (d, J ¼ 7.4 Hz, 1H), 4.09 (dd,
J ¼ 6.2, 1.4 Hz, 2H), 3.86 (m, 1H), 3.85 (s, 3H), 3.72–3.62 (m, 1H), 3.57–3.50 (m, 2H),
3
.49–3.41 (m, 2H), 3.40–3.35 (m, 1H), 3.28 (dt, J ¼ 3.2, 1.6 Hz, 1H), 1.19 (t, J ¼ 7.0 Hz, 3H);
13
C NMR (CD OD) d 149.5, 146.5, 132.0, 131.9, 124.6, 119.5, 116.5, 110.0, 101.4, 76.9, 76.5,
3
þ
7
3
3.5, 70.9, 70.0, 65.3, 61.2, 55.4, 14.1; HRMS(ESI) calcd for C H O Na [Mþ Na]
18 26 8
93.1520, found 393.1515. The spectral and physical characteristic of the compound is agree-
[
10]
ment with that reported in the literature by Yue et al.
Funding
This work was supported by the National Natural Science Foundation of China [82003619,
1803561, 21702022] and Sichuan Science and Technology Program [2018JY0222, 2020YJ0487].
8
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