Scalable total synthesis of horsfiequinone A

Article abstract of DOI:10.1016/j.tetlet.2018.02.082

Starting from two commercially available substrates, methoxyhydroquinone and piperonyl alcohol, a scalable four-step total synthesis of horsfiequinone A was developed. The notable feature of the synthesis is the application of two continuous sequential transformations. Namely, the key aldehyde 9 and horsfiequinone A were prepared via scalable Wittig/hydrolysis and Wittig/catalytic hydrogenation/oxidation sequences, respectively. Importantly, the synthetic route required only three recrystallizations and one column chromatography purification step.

Full text of DOI:10.1016/j.tetlet.2018.02.082

Tetrahedron Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Scalable total synthesis of horsfiequinone A
⇑
⇑
Rui Zhan , Shou-Zhen Du, Fang Kuang, Ye-Gao Chen
School of Chemistry and Chemical Engineering, Yunnan Normal University, Kunming 650500, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from two commercially available substrates, methoxyhydroquinone and piperonyl alcohol, a
scalable four-step total synthesis of horsfiequinone A was developed. The notable feature of the synthesis
is the application of two continuous sequential transformations. Namely, the key aldehyde 9 and hors-
fiequinone A were prepared via scalable Wittig/hydrolysis and Wittig/catalytic hydrogenation/oxidation
sequences, respectively. Importantly, the synthetic route required only three recrystallizations and one
column chromatography purification step.
Received 13 January 2018
Revised 22 February 2018
Accepted 27 February 2018
Available online xxxx
Keywords:
Diarylpropane
Ó 2018 Elsevier Ltd. All rights reserved.
Horsfiequinone A
1,4-p-Benzoquinone
Scalable synthesis
Diarylpropane dimer
Diarylpropanes and their dimers containing a 1,4-p-benzo-
quinone fragment are rare natural products (<30 members) which
have been isolated only in some species of Combretum,1 Horsfiel-
dia,2 and Euonymus.3 Despite the small collection, these com-
significance of horsfiequinone A for the biosynthesis of dimeric
horsfiequinones, it is desirable to develop a scalable and facile
route towards this compound. Herein, we report a scalable four-
step total synthesis of horsfiequinone A from two commercially
pounds
exhibit
intriguing
bioactivities,
for
example,
available
compounds,
piperonyl
alcohol
and
horsfiequinone B (Fig. 1 2) shows specific inhibition (IC50 = 4.28
methoxyhydroquinone.
l
M) against HL-60 in five tested cancer cell lines (HL-60, SMMC-
Intermolecular aldol reactions of benzaldehydes with acetophe-
nones have been used to prepare diarylpropanes.7 However, syn-
theses of diarylpropanes with a 1,4-p-benzoquinone framework
are barely studied. Retrosynthetic analysis indicated that hors-
fiequinone A could be produced by the oxidation of compound 6
which could be prepared from olefin 7 by catalytic hydrogenation
(Scheme 2). Compound 7 could be synthesized from phosphonium
salt 8 and aldehyde 9 via a Wittig reaction. Compounds 8 and 9
were easily derived from two commercially available compounds,
piperonyl alcohol and methoxyhydroquinone.
Our synthesis started with the preparation of phosphonium salt
8; piperonyl alcohol was treated with N-bromosuccinimide (NBS)
and PPh3 in CH2Cl2 at room temperature to give the desired phos-
phonium salt 8 in quantitative yield (see, ESI for details).8 The phe-
nol groups of methoxyhydroquinone were benzyl protected using
BnBr/K2CO3 to give dibenzyl protected product S1 in quantitative
yield after recrystallization from petroleum ether/ethyl acetate
(PE/EA). Next, Friedel-Crafts formylation (trimethyl orthoformate/
AlCl3)9 was carried out to give aldehyde 10 which was purified
by recrystallization from PE/EA in 55% yield. Compound 10 was
further converted into aldehyde 9 via a continuous Wittig/hydrol-
ysis sequence in 91% yield after recrystallization from PE/EA. Sub-
sequently, compound 8 and 9 were combined using the Wittig
reaction to give olefin 7 as a ꢀ2:1 mixture of Z/E isomers
7721, A-549, MCF-7, and SW480),2 while euonyquinone A (4)
and combrequinone B (5) show potent inhibitory activity against
human DOPA decarboxylase (hDDC) with IC50 values of 11.5
and 21.6 M, respectively, thus representing promising treatments
for Parkinson’s (PK) disease.3
lM
l
The unique structure and important bioactivities of the hors-
fiequinones encouraged us to systematically research Horsfieldia
tetratepala4,5 and to propose their biogenetic pathway as well as
their chemical synthesis. Biogenetically, an aromatic radical cou-
pling pathway for euonyquinone A (4) was proposed by Zhang
and co-workers.3 Due to the different linkage types of the dimeric
horsfiequinones, an intramolecular vinylogous aldol pathway was
predicted (Scheme 1).6 The crucial monomer horsfiequinone A
(1) could be enolized to form its enolate, which could be further
coupled with another monomer through a vinylogous aldol reac-
tion to give intermediate A. This intermediate is converted to hors-
fiequinone B (2) by reduction and enolization. Compound 2 could
be further derivatized to form horsfiequinones C-F. Given the
⇑
Corresponding author.
E-mail addresses: sunnyzhanrui@126.com (R. Zhan), ygchen48@126.com
(Y.-G. Chen).
https://doi.org/10.1016/j.tetlet.2018.02.082
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Zhan R., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.02.082

2
R. Zhan et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Fig. 1. Structures of selected diarylpropane monomer and dimers.
Scheme 1. Plausible biogenetic pathway of the horsfiequinones.
Please cite this article in press as: Zhan R., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.02.082

R. Zhan et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
Scheme 2. Retrosynthesis of horsfiequinone A.
Table 1
Oxidation of hydroquinone 6.
Entry
Conditions
Yield 6 (%)a
Scheme 3. Scalable synthesis of horsfiequinone A.
1
2
3
DDQ (2.0 eq.), toluene/CH2Cl2 (5:1), 0 °C, 10 min
Ag2O (2.0 eq.), Et2O, RT, 2 h
87
69
90
77
90
96
NaIO4 (5.0 eq.), MeOH, 0 °C, 1.5 h
MnO2 (2.0 eq.), CH2Cl2, RT, 4 h
Silica gelc, CH2Cl2, RT, 12 h
Acknowledgments
4
5b
6
Silica gelc, neat, air, 60 °C, 4 h
This research was supported financially by the National Natural
Science Foundation of China [grant number 31460086]; the
Science and Technology Program of Yunnan Province [grant num-
ber 2014FD013]; the Scientific Research Program of the Education
Department of Yunnan Province [grant number 2014Z047].
a
b
c
Isolated yield.
BRSM, ꢀ50% starting materials were recovered.
Silica gel was 20-fold (weight) to substrate.
(determined by 1H NMR, ESI) in 90% yield. Catalytic hydrogenation
of 7 in EtOAc/MeOH allowed removal of the two benzyl protecting
groups to provide hydroquinone 6 in 93% yield.
A. Supplementary data
Supplementary material including the procedures and 1H and
13C NMR spectra for all compounds. Supplementary data associ-
ated with this article can be found, in the online version, at
https://doi.org/10.1016/j.tetlet.2018.02.082.
Although trace amounts of the target product 1 was detected
during the work-up and purification process, the autoxidation of
6 was incomplete when it was purified on a silica column. Thus,
various oxidative conditions were examined for this transforma-
tion (Table 1). All of the tested oxidants (DDQ, Ag2O, NaIO4,
MnO2, entries 1–4) promoted this transformation, and to our
delight, the oxidation also proceeded in the presence of silica gel
in CH2Cl2 at room temperature in 90% yield BRSM (Entry 5). In
order to optimize the reaction, compound 6 was loaded onto silica
gel (excess) to form a slightly yellow powder which was heated at
60 °C under air for 4 h to give 1 in 96% yield (Entry 6).
After completion of the synthesis, the synthetic route was sim-
plified using a Wittig/catalytic hydrogenation/oxidation sequence
starting from compound 9 (13.6 g). Namely, aldehyde 9 was con-
densed with phosphonium salt 8 via a Wittig reaction, followed
by catalytic hydrogenation (Pd/C, H2) and air mediated oxidation
on silica gel to provide the target product 1 (9.6 g) as an orange
amorphous solid after purification on a silica column (Scheme 3).
In summary, a facile and scalable total synthesis route to hors-
fiequinone A (1) was achieved within four steps in 43% overall
yield. Moreover, three recrystallizations and only one purification
using column chromatography were needed in this approach.
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Please cite this article in press as: Zhan R., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.02.082