A total synthesis of (+)-brazilin

Article abstract of DOI:10.1016/j.tetlet.2020.152052

Described herein is a concise total synthesis of (+)-brazilin from readily available 4-bromo-1,2-dimethoxybenzene. In this synthetic route, a Sharpless asymmetric dihydroxylation was employed to introduce the chiral hydroxyl group, and trifluoroacetic acid (TFA) catalyzed one-pot intramolecular tandem Prins/Friedel-Crafts reaction was also involved as the key transformation in the construction of the hybrid chromane and indane framework.

Full text of DOI:10.1016/j.tetlet.2020.152052

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A total synthesis of (+)-brazilin
Shuangping Huang a,1, Wentao Ou c,1, Wang Li c, Hesheng Xiao c, Yiying Pang c, Yi Zhou c, Xiaoji Wang c,
,
⇑
c,
Xihua Yang b, , Liping Wang
⇑
⇑
a College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan 030024, China
b Laboratory Animal Center, Shanxi Cancer Institute, Taiyuan 030013, China
c School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Described herein is a concise total synthesis of (+)-brazilin from readily available 4-bromo-1,2-
dimethoxybenzene. In this synthetic route, a Sharpless asymmetric dihydroxylation was employed to
introduce the chiral hydroxyl group, and trifluoroacetic acid (TFA) catalyzed one-pot intramolecular tan-
dem Prins/Friedel-Crafts reaction was also involved as the key transformation in the construction of the
hybrid chromane and indane framework.
Received 9 March 2020
Revised 13 May 2020
Accepted 15 May 2020
Available online xxxx
Ó 2020 Published by Elsevier Ltd.
Keywords:
Synthesis
Brazilin
Natural product
Sharpless asymmetric dihydroxylation
Tandem Prins/Friedel-Crafts reaction
Introduction
related family natural products. In recent years, several synthetic
studies have been realized to afford brazilin (Scheme 1a). Dann
Homoisoflavones skeleton structures are widely existed in bio-
logically active natural products, which exhibit intriguing biologi-
cal properties [1]. In recent years, studies on the construction of
homoisoflavones framework have attracted extensive attention in
structure modification of pharmaceutical molecules and develop-
ment of new drugs.
Brazilin and its family natural products, including brazilane,
brazilein, brazilide A, haematoxylin, and haematoxylane (Figure 1),
representing important tetracyclic homoisoflavanoid fundamental
units, are isolated from the alcoholic extracts of the heartwood of
Caesalpinia sappan L. (Leguminosae) [2]. Among them, brazilin is
structurally composed of a chroman skeleton cis-fused with a
2,3-dihydro-1H-indene moiety. Early literatures have indicated
that brazilin possesses a series of outstanding bioactivities, includ-
ing anti-inflammatory [3], hepatoprotective [4], vasorelaxant [5],
antibacterial [2e], anticancer [6] and antitumor [7] activities. Addi-
tionally, brazilin also exhibits other biological properties, such as
hypoglycemic [8] and DNA nicking activity [9].
in 1963 reported the first synthesis of brasilin from 7-methoxy-
chroman-4-one in 8 steps [10a]. Then, Pettus et al. in 2005 accom-
plished
a synthetic route to ( )-brazilin by employing a
regioselective dirhodium-catalyzed aryl CAH insertion approach
[10b]. After that, Zhang and co-workers achieved an
enantioselective total synthesis of (+)-brazilin as well as (+)-
brazilide A and (À)-brazilein through a Lewis acid mediated
lactonization to establish the bis-lactone core [10c].
Subsequently, Yadav and co-workers disclosed a formal synthesis
of ( )-brazilin and total synthesis of ( )-brazilane via palladium
(II)-catalyzed intramolecular Friedel-Crafts reaction [10d]. In the
same time, Jahng et al. realized a synthetic route to (+)- and (À)-
brazilin
through
AD-mix-
a
and
AD-mix-b
directed
enantioselective dihydroxylation [10e]. In 2015, Kim and co-
workers described a total synthetic approach to brazilin utilizing
Mitsunobu coupling followed by indium(III)-catalyzed alkyne-
aldehyde metathesis allowed for rapid construction of brazilin
core skeleton [10f]. Then, Kim and co-workers continuously
accomplished a concise synthesis of brazilin through palladium
(II)-catalyzed allylic arylation [10g]. Recently, Vranken’s group
completed a racemic total synthetic route to ( )-brazilin via
palladium-catalyzed [4+1] annulation [10h]. Although notable
methodologies have been achieved in the synthesis of brazilin,
most of the synthetic routes were over 7 steps, and some of the
aforementioned synthetic strategies were proceeded in a pitiful
Such unique structure and its variety biological properties have
drawn considerable attention in the synthesis of brazilin and its
⇑
Corresponding authors.
E-mail addresses: 2012207455@tju.edu.cn (X. Wang), yangxihua@126.com
(X. Yang), wlping92@163.com (L. Wang).
1
These two authors contributed equally to this work.
https://doi.org/10.1016/j.tetlet.2020.152052
0040-4039/Ó 2020 Published by Elsevier Ltd.
Please cite this article as: S. Huang, W. Ou, W. Li et al., A total synthesis of (+)-brazilin, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152052

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S. Huang et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. Pharmaceutical molecules containing tetracyclic homoisoflavonoids
skeleton.
Scheme 2. Retrosynthetic approach to (+)-brazilin (1).
3, which in turn could be generated from 4 by employing a classic
Sharpless asymmetric dihydroxylation. We envisaged that the
intermediate 4 could be obtained through Mitsunobu etherifica-
tion reaction from terminal hydroxyl compound 5 and commer-
cially available 3-methoxyphenol (10). Synthesis of the
intermediate 5 could be realized from another commercially avail-
able 4-bromo-1,2-dimethoxybenzene (6) via three sequential pro-
cedures, including preparation of the Grignard reagent, lithium and
copper co-catalyzed coupling reaction and diisobutylaluminium
hydride (DIBAL-H) reduction.
Our synthesis commenced with the preparation of the Grignard
reagent 7 from readily available 6 in the presence of magnesium
ribbon and iodine (Scheme 3). With fresh Grignard reagent 7 in
hand,
a,b-unsaturated keto ester 9 could be easily achieved from
methyl 2-(bromomethyl)acrylate (8) through lithium chloride
and copper iodide co-catalyzed coupling reaction [11]. In the pres-
ence of DIBAL-H, compound 9 was converted into the correspond-
ing terminal hydroxyl compound 5 in an excellent yield. Under the
promotion of diisopropyl azodicarboxylate (DIAD) and triph-
enylphosphine [12], the benzyl ether bond in the intermediate 4
was smoothly constructed in 98% yield from compound 5.
To establish the dihydroxyl groups, a classic Sharpless asym-
metric dihydroxylation conditions [13], including potassium
osmate(VI) dihydrate, red prussiate (K3Fe(CN)6) and (DHQD)2PHAL
(Hydroquinidine 1,4-phthalazinediyl diether), were introduced
into those reaction system, and the desired product 3 was provided
in 86% yield with 98% ee value. However, when 4-methylmorpho-
line N-oxide (NMO) instead of K3Fe(CN)6 was adopted as the pro-
Scheme 1. Different strategies for the synthesis of brazilin.
overall yield. Thus, a short and efficient synthetic approach is still
of great interest. Herein, we disclose a concise total synthesis of
(+)-brazilin from commercially available material within 7 steps
(Scheme 1b).
Results and discussion
As outlined in Scheme 2 of our retrosynthetic approach, the key
synthetic challenge associated with (+)-brazilin (1) was the con-
struction of cis-fused chromane and indane framework of the B
and C rings, which could be achieved from precursor 2 through
an intramolecular tandem Prins/Friedel-Crafts reaction. The inter-
mediate 2 would be obtained via Parikh-Doering oxidation from
oxidant, the enantioselectivity of dihydroxyl product
3 was
dropped to 90% ee value. In the process of Parikh-Doering oxida-
tion, the hydroxyl-aldehyde 2 was generated in 85% yield when
sulfur trioxide-pyridine was employed [14]. It should be noticed
that, when N,N-diisopropylethylamine (DIPEA) was replaced with
Please cite this article as: S. Huang, W. Ou, W. Li et al., A total synthesis of (+)-brazilin, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152052

S. Huang et al. / Tetrahedron Letters xxx (xxxx) xxx
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Scheme 3. Preparation of the intermediate 4.
triethylamine, compound 2 was obtained in only 31% yield under
Parikh-Doering oxidation condition. Besides, the yield of
2
decreased to 60% when Swern oxidation condition was introduced
into this transformation. Furthermore, the oxidation reaction was
failed to proceed in the presence of Dess-Martin periodinane
(DMP) or 2-iodoxybenzoic acid (IBX). These above-mentioned
comparison results indicated that sulfur trioxide-pyridine com-
bined with DIPEA were the optimal oxidation condition. With the
key intermediate 2 in hand, we subsequently focused our attention
on the construction of cis-fused chromane and indane framework
of the B and C rings. In the presence of TFA, the desired product
13 was smoothly obtained in 80% yield in one-step via an
intramolecular tandem Prins/Friedel-Crafts reaction [15], in which
the C ring may be first formed (11) [10c,16]. Subsequently, under
the control of the quaternary carbon center, the B ring was then
constructed with the desired cis-fused rings. Finally, the methoxy
groups were successfully removed to deliver the desired natural
product (+)-brazilin (1). Under the treatment of boron tribromide
[17], precursor 13 was transformed into the target molecular 1 in
79% yield (Scheme 4). Additionally, the NMR data of compound 1
was consistent with previous report [10b], which helps us to
further confirm the absolute configuration of (+)-brazilin (1) in
our synthetic works.
Scheme 4. Synthesis of the target molecular (+)-brazilin (1).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152052.
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Please cite this article as: S. Huang, W. Ou, W. Li et al., A total synthesis of (+)-brazilin, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152052