Tetrahedron Letters
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.
1
These two authors contributed equally to this work.
0040-4039/Ó 2020 Published by Elsevier Ltd.