Rapid continuous photoflow synthesis of naturally occurring arylnaphthalene lignans and their analogs

Article abstract of DOI:10.1080/14786419.2021.1920019

Naturally occurring arylnaphthalene lignans (ANLs) are subclass of lignans in many dietary or medicinal plants. The progressing interest of ANLs is due to their diversified biological activities. Herein, we developed a convenient method for the preparation of naturally occurring ANLs and their analogs through the continuous photoflow intramolecular Diels–Alder reaction in several minutes under mild conditions with good yields and regioselectivities.

Full text of DOI:10.1080/14786419.2021.1920019

Natural Product Research
Formerly Natural Product Letters
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Rapid continuous photoflow synthesis of naturally
occurring arylnaphthalene lignans and their
analogs
Xiang Ge, Haowen Jiang & Jinlong Li
To cite this article: Xiang Ge, Haowen Jiang & Jinlong Li (2021): Rapid continuous photoflow
synthesis of naturally occurring arylnaphthalene lignans and their analogs, Natural Product
Research, DOI: 10.1080/14786419.2021.1920019
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2021.1920019
SHORT COMMUNICATION
Rapid continuous photoflow synthesis of naturally
occurring arylnaphthalene lignans and their analogs
a
b
a
Ã
Ã
Xiang Ge , Haowen Jiang and Jinlong Li
b
aSchool of Pharmacy, Nantong University, Nantong, People’s Republic of China; Shanghai Institute
of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China
ABSTRACT
ARTICLE HISTORY
Received 2 March 2021
Accepted 14 April 2021
Naturally occurring arylnaphthalene lignans (ANLs) are subclass of
lignans in many dietary or medicinal plants. The progressing inter-
est of ANLs is due to their diversified biological activities. Herein,
we developed a convenient method for the preparation of natur-
ally occurring ANLs and their analogs through the continuous
photoflow intramolecular Diels–Alder reaction in several minutes
under mild conditions with good yields and regioselectivities.
KEYWORDS
Arylnaphthalene lignans;
continuous photoflow
synthesis; intramolecular
Diels–Alder reaction
1. Introduction
Arylnaphthalene lignans (ANLs) are widely distributed in dietary or medicinal
plants, which serve as sources of diversified structures due to good biological
activities, such as tumour or cancer cell line inhibition activities, antioxidant, anti-
inflammatory, antimicrobial, antiviral, etc. (Li et al. 2020). Structurally, these natur-
ally occurring ANLs can be divided into type I and type II ANLs based on the
position of lactones and phenyl groups (Figure S1). The desire to access ANLs for
further investigation has led to the development of many successful synthetic
methods for them. They can be roughly classified into two approaches: transition
metal-mediated annulations and pericyclic reactions (Zhao et al. 2018; Park et al.
CONTACT Jinlong Li
These authors contributed equally to this work.
jinlongli@ntu.edu.cn
Ã
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14786419.2021.1920019.
ß 2021 Informa UK Limited, trading as Taylor & Francis Group

2
X. GE ET AL.
Table 1. Continuous photoflow synthesis of naturally occurring ANLs and their analogs.
Reactanta
Ring A
Ring B
Productsb
1a
2a (63.1%)
3a (15.3%)
1b
1c
2b (47.1%)
3b (13.1%)
2c (52.2%)
3c (17.3%)
1d
1e
2d (41.8%)
3d (14.5%)
2e (38.2%)
3e (23.6%)
aConcentration: 0.005 M.
bIsolated yields.
2020). Among them, the utilisation of 3-phenylprop-2-yn-1-yl 3-phenylpropiolates
to form the ANLs via intramolecular Diels–Alder (D–A) reaction is an atom-eco-
nomic method. However, the poor regioselectivity and the high temperature condi-
tions limit its application (Stevenson and Weber 1991). Photochemistry reactions
use light as the energy source to initiate chemical transformations, which contrib-
ute in a significant way to the existing repertoire of carbon–carbon bond-forming
reactions, especially in the key cyclisation steps in the total synthesis of some com-
plex natural products (Bach and Hehn 2011). In recent years, the continuous photo-
flow synthesis approaches have received widespread attentions in the field of
photocatalysis. The large surface area to volume ratio of a microreactor maximises
the illumination, and at the same time allows for efficient cooling, which may
€
shorten reaction times and provides higher selectivity (Oelgemoller and Shvydkiv
ꢀ
2011; Cambie et al. 2016).
The progressing interest of ANLs is due to their significant biological activities. In
order to meet the needs of structural diversity for further studies on their biological
activities and structure–activity relationships, we carried out the continuous photoflow
intramolecular D–A reaction method for the synthesis of naturally occurring ANLs and
their analogs in several minutes under mild conditions with good yields and
regioselectivities.

NATURAL PRODUCT RESEARCH
3
2. Results and discussion
Inspired by the intramolecular D–A approach developed by Stevenson and the
method of photochemical reaction in the preparation of naphthalenes reported by
Wessig et al. (2005). The photochemistry reaction of 3-(4-methoxyphenyl)prop-2-yn-1-
yl 3-(4-methoxyphenyl) propiolate (1a) was exploited. As expected, under a high-pres-
sure mercury lamp (175 W) irradiation for 12 h, most of the ester was converted to the
corresponding ANLs in 70% yield and the ratio of 2a (type I) to 3a (type II) is 2.3:1
(Scheme S1).
On the basis of this experiment, we attempted a continuous photoflow method for
the reaction. The reactor consists of a simple design in which fluorinated ethylene pro-
pylene (FEP) capillary tubing (ID 1.0 mm) was coiled around the UV lamp. A solution of
ester 1a in 1,2-DCE (0.005 M) was injected into the photoreactor used for the photo-
chemical reaction by a syringe pump. Encouragingly, after exposure for 6 min (the
average time that the reactants spend in the reactor), the reaction reached a modest
conversion rate of 50.3%. Moreover, the regioselectivity was also improved (ꢀ4.8:1)
(Entry 6, Table S1). In general, the selection of a proper solvent is a crucial step in con-
tinuous photoflow as the solvent needs to be able to solubilise the chemicals and
products to prevent reactor clogging and undesired light scattering. In the following
experiments, different solvents were selected for the reaction. Protonic solvents, such
as methanol, HFIP and acetic acid exhibited lower conversion rate of 19.5%, 22.8%
and 13.3%, respectively (Entries 10–12, Table S1). In contrast, most of the aprotic sol-
vents showed moderate conversions and excellent regioselectivity. The optimal choice
are haloalkanes, represented by DCM or 1,2-DCE (Entries 1, 6 and 13–17, Table S1).
The UV exposure time is also an important factor in the photoflow reactions. In Entries
1–8 (Table S1), experiments showed that the conversion of ester 1a to products 2a
and 3a was fast at the beginning several minutes, but the situation turned in after
10 min, which suggested that the prolonged irradiation may cause degradation of the
reactants or products. The initial concentration of 1a was also discussed. The conver-
sion rates were similar at the concentrations of 0.0025 and 0.005 M, however, with the
increase of concentrations (0.01 and 0.02 M), the conversion rates were decreased
(Entries 2, 6, 9 and 18–20, Table S1). In summary, the most efficient conditions of this
reaction seem to be: 1a in haloalkanes (0.005 M) was pumped through the FEP tubing
for a total exposure time (175 W Hg lamp) of 10 min.
The conditions of continuous photoflow method provide the possibilities for the
rapid preparation of ANLs and their analogs. For the preparation of those ANLs, the
corresponding 3-phenylprop-2-yn-1-yl 3-phenylpropiolates were prepared at first.
Herein, as shown in Scheme S3, we take the preparation of 1a as an example:
Anisaldehyde was first converted to dibromoalkene 4a, which was subjꢁected to the
Corey–Fuchs alkyne synthesis condition (2.5 equiv of n-BuLi in THF, À78 C) to gener-
ate alkyne anion, followed by addition of dry ice to give the desired 3-phenylpropiolic
acid 5a; while 6a was prepared by addition of paraformaldehyde to the alkyne anion
ꢁ
solution at À78 C. Coupling reaction of 5a and 6a was performed using DCC and
DMAP in DCM to afford the ester 1a.
With a series of 3-phenylprop-2-yn-1-yl 3-phenylpropiolates (1a–1e) in hands, rapid
pipelining preparation of naturally occurring ANLs were undertaken (Conditions:

4
X. GE ET AL.
0.005 M in DCM solution, the 175 W mercury lamp as light source, exposure for
10 min). Herein, we listed the preparation of some well-known naturally occurring
ANLs as examples, they are justicidin E (2b), taiwanin C (3b), retrochinensin (2c), justi-
cidin B (3c), retrojusticidin B (2d) and chinensin (3d). The corniculin (2e1) can be easily
obtained by hydrogenolysis of compound 2e (Table 1, Scheme S4).
Taken overall, all these reactants (1a–1e) convert to the corresponding ANLs in
good yields (56.3%–79.6%) and regioselectivities (1.6:1–4.1:1) (Table 1). It is noteworthy
that except for the regioselectivities in the position of lactones, the cyclisation sites for
those of 3,4-di-substituted benzyls were mainly at C-6 (reactants 1b–1e). In general,
the good performance of continuous photoflow reactions may attributed to the homo-
geneous irradiation the enhanced mass-, heat- and photon-transport phenomena
observed in microchannels.
In summary, we provided a rapid, convenient and catalysts free synthetic method
for the preparation of naturally occurring ANLs and their analogs by 3-phenylprop-2-
yn-1-yl 3-phenylpropiolates in good yields and regioselectivities. Utilisation of the
continuous photoflow reactions may break through the limitation of natural product
separation and provide the possibilities for the preparation of numerous structurally
diversities of naturally occurring ANLs and their analogues in a short time. The further
structure activity relationships investigations of those ANLs with diversified biological
activities are ongoing.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was partial supported by the National Natural Science Foundation of China under
Grant [81803384], the Natural Science Foundation of Jiangsu Province under Grant
[BK20180947] and the Nantong Scientific Research Project under Grant [JC2019104].
ORCID
Jinlong Li
http://orcid.org/0000-0002-0915-4095
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