Concise synthesis of the bioactive natural polyhydroxynaphthoate parvinaphthol B via Hauser-Kraus annulation

Article abstract of DOI:10.1016/j.tetlet.2017.11.024

Herein, we describe the first total synthesis of parvinaphthol B, a polyhydroxynaphthoate derived from the root of Pentas parvifolia which exhibits cytotoxic effects against the TNBC cell line. The key feature of the synthesis involves a Hauser-Kraus annulation to provide the polyhydroxynaphthoate skeleton. The synthesis requires only six linear steps and afforded the product in 26.5% overall yield, thus representing a simple method for the further preparation of analogs and biological studies.

Full text of DOI:10.1016/j.tetlet.2017.11.024

Accepted Manuscript
Concise synthesis of the bioactive natural polyhydroxynaphthoate parvinaph-
thol B via Hauser-Kraus annulation
Sungwan Ahn, Young Taek Han
PII:
S0040-4039(17)31427-2
https://doi.org/10.1016/j.tetlet.2017.11.024
TETL 49467
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
21 September 2017
3 November 2017
10 November 2017
Please cite this article as: Ahn, S., Han, Y.T., Concise synthesis of the bioactive natural polyhydroxynaphthoate
parvinaphthol B via Hauser-Kraus annulation, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.
2
017.11.024
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Tetrahedron Letters
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Concise synthesis of the bioactive natural polyhydroxynaphthoate parvinaphthol B via
Hauser-Kraus annulation
∗
Sungwan Ahn and Young Taek Han
College of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Herein, we describe the first total synthesis of parvinaphthol B, a polyhydroxynaphthoate
derived from the root of Pentas parvifolia which exhibits cytotoxic effects against the TNBC
cell line. The key feature of the synthesis involves a Hauser-Kraus annulation to provide the
polyhydroxynaphthoate skeleton. The synthesis requires only six linear steps and afforded the
product in 26.5% overall yield, thus representing a simple method for the further preparation of
analogs and biological studies.
Received in revised form
Accepted
Available online
2
017 Elsevier Ltd. All rights reserved.
Keywords:
Parvinaphthol B
Hauser-Kraus annulation
polyhydroxynaphthoate
total synthesis
Natural polyphenolic compounds have been considered as
important secondary metabolites because of their diverse and
strong biological activities. Many compounds in this class can be
Our retrosynthetic analysis for 1 is outlined in Figure 1, which
includes efficient construction of the polyhydroxynaphthoate
skeleton. Parvinaphthol B (1) was anticipated to be obtained from
dihydroxynaphthoate 2, which comprises all the hydroxyl groups
of the purposed naphthoate compound, by O-methylation and
subsequent deprotection of the catechol group in the final step.
The key naphthoquinone skeleton of 2 was expected to be
1
a
1b
used for the prevention and/or treatment of obesity, diabetes,
1d
1c
cardiovascular disease,
neurodegenerative diseases,
and
1e
various cancers. In this connection, natural polyphenolic
compounds have attracted considerable research attention as they
represent not only potential candidates for therapeutic use, but
also lead compounds for the identification of novel bioactive
synthesized from isobenzofuranone
3
by [4+2]-anionic
6
annulations such as the Hauser-Kraus reaction. The
isobenzofuranone 3, a 1,4-dipole synthon for the Hauser-Kraus
annulation, was planned to be prepared from commercially
available piperonylic acid 4 by amidation, ortho-formylation, and
subsequent cyano-isobenzofuranone formation.
2
compounds.
Parvinaphthol B (1) is a polyhydroxynaphthoate derivative
isolated from the roots of Pentas parvifolia, which was recently
3
reported by Erdélyi and co-workers. Their study also revealed
that this compound exhibits cytotoxic effects (LD50 = 96.5 µM)
against the triple-negative human breast cancer (TNBC) cell line
OH
1
OH
CO2Me
CO2Me
(
MDA-MB-231), an aggressive breast cancer subtype, for which
4
HO
6
5
4
O
there are no targeted therapy options. The 1,4,6-trihydroxy-4-
methoxy-naphthalene moiety, the core structure of 1, can be also
regarded as an O-methyl analog of naphthoquinone.
Naphthoquinones are well-known sub-structures in many
OH OMe
O
OH
Parvinaphthol B (1)
2
Hauser-Kraus
annulation
O
O
5
bioactive natural and synthetic compounds. Considering that its
OH
O
structure is embedded with the privileged polyphenol as well as
naphthoquinone structures, parvinaphthol B can be expected to
exhibit diverse therapeutically useful activities besides anticancer
activity. The promising anti-TNBC activity and interesting
structural features of 1 prompted us to establish a concise
synthetic route that can be utilized for further medicinal
chemistry research.
O
O
CN
O
O
3
4
Figure 1. Structure of parvinaphthol B (1) and its retrosynthetic
analysis
—
——
∗
Corresponding author. Tel.: +82-41-550-1431; fax: +82-41-889-7899; e-mail: hanyt@dankook.ac.kr

2
Tetrahedron
As shown in Scheme 1, the synthesis commenced with the
preparation of known amide 5 from piperonylic acid 4 by
7
amidation. Aldehyde 6 was obtained in high yield via
Scheme 1. Synthetic procedure of parvinaphthol B
tetramethylethylenediamine (TMEDA)-promoted direct ortho-
lithiation of amide 5 using tert-BuLi, followed by reaction with
8
DMF. On the other hand, regioisomeric mixtures were obtained
In conclusion, a concise and efficient protocol (six linear steps
and 26.5% overall yield) has been developed toward the first
total synthesis of parvinaphthol
B
(1),
a
bioactive
when the bromination of 4 and 5 was performed to introduce the
ortho-formyl moiety via halogen-lithium exchange and reaction
with DMF. Cyano-isobenzofuranone 3 was readily prepared from
polyhydroxynaphthoate derived from the root of P. parvifolia.
The key feature of our synthesis involves a Hauser-Kraus
annulation, which afforded the polyhydroxynaphthoate skeleton.
Because of its efficiency, our synthetic route can potentially be
extended to structurally related naphthoates bearing phenolic
groups. Further synthesis of analogs and biological studies are
currently underway in our laboratory.
9
ortho-formyl benzamide 6 according to a literature procedure.
Hauser-Kraus annulation of isobenzofuranone 3 with methyl
acrylate using LHMDS afforded dihydroxynaphthoate 2 in
almost quantitative yield.
Generally, phenols in the ortho-position to carbonyl groups are
considered less reactive in O-alkylation reactions compared with
1
0
those in other positions. However, O-methylation of 1,4-
dihydroxynaphthoate 2 did not proceed selectively at the 4-
Acknowledgments
hydroxyl group and gave
a
mixture of 1,4-di-
This research was supported by Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Science, ICT & Future Planning
(2017R1C1B1001826).
methoxynaphthoates, although equimolar amounts of the methyl
electrophile and base were used. We supposed that the acidity of
the phenol at the 4-position may be reduced by intramolecular
hydrogen bonding with the oxygen at the 5-position, which
causes a loss of regioselectivity. For this reason, to introduce a
methyl moiety at the 4-hydroxyl group, we synthesized
References and notes
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8

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Supplementary Material
Supplementary data (experimental section and copies of
spectra for all of compounds) associated with this article can be
found, in the online version, at http://

4
Tetrahedron
Graphical Abstract
Concise synthesis of the bioactive natural
polyhydroxynaphthoate parvinaphthol B via
Leave this area blank for abstract info.
Hauser-Kraus annulation reaction
∗
Sungwan Ahn and Young Taek Han

Highlights
ꢀ
ꢀ
The first synthesis of the parvinaphthol B
was presented.
The efficient synthetic route toward
polyhydroxynaphthoate
described.
skeleton
was
ꢀ
The selective ether-bond cleavage was also
investigated.