Tetrahedron Letters
NbCl5 mediated biomimetic cascade reaction: efficient and scalable
one-pot synthesis of dunnione and nor-b-lapachone
Jinlei Bian a,c, Xue Qian a,c, Jun Fan a,c, Xiang Li a,c, Haopeng Sun a,c, Qidong You a,b,c, Xiaojin Zhang a,d,
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a Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
b State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
c Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
d Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A regioselective biomimetic synthesis of bioactive natural products dunnione and nor-b-lapachone is
described. This cascade provides a new strategy of a one-pot process mediated by Lewis acid NbCl5
involving a tandem Claisen rearrangement–cyclization reaction. This procedure was efficient, mild, and
easily scalable that avoided using highly hazardous concd H2SO4.
Received 15 October 2014
Revised 17 November 2014
Accepted 23 November 2014
Available online 4 December 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Dunnione
Nor-b-lapachone
One-pot
Biomimetic cascade reaction
Natural products
1,2-Naphthoquinones have attracted a great deal of attention
due to their pharmacological activities.1 Among reported 1,2-naph-
thoquinones, natural products dunnione (1) and nor-b-lapachone
(2) have been found to show important biological activities, includ-
ing anti-inflammatory, antitumor, and antimicrobial activities
(Fig. 1).1 Studies have also shown that compounds containing the
dihydrofuran-fused ortho-naphthoquinone core scaffold were
promising antitumor agents.2 Therefore, it is not surprising that
the synthesis of the two pharmaceutically important natural prod-
ucts has attracted great interest in recent decades.
A substantial body of research describes the synthesis of 1 and
2.3 Most of these methods were efficient to obtain the desired
product. However, one disadvantage of some reported cyclization
reactions was the employment of large amounts of concd H2SO4
as both catalyst and solvent. For example, Cook’s group reported
the concd H2SO4 mediated cyclization of 1 derived from dunniol
(3) (Scheme 1A).3a Fieser and co-workers described the method
for the preparation of 2 with the acid mediated cyclization of
nor-lapachol (5) which was obtained from lapachol (4) via Hooker
oxidation (Scheme 1B).3b The significant excess of concd H2SO4
used in these methods was highly hazardous and hard to handle,
making them not suitable for industrial-scale production. More-
over, we found that when the amount of concentrated H2SO4
O
O
O
O
O
O
nor- -lapachone (2)
β
dunnione (1)
Figure 1. Structures of natural products 1 and 2.
was reduced to 5 equiv, the cyclization was shown to be 81% in
producing 1, but together with 12% yield of its
a-isomer
(Scheme 1A). Recently, Ferreira’s group described the synthesis of
2 starting from lawsone (6) in a one-pot procedure.3c However, this
method also led to a mixture of 2 and its
a-isomer (Scheme 1C).
Therefore, the search for an adaptable synthesis protocol that is
simple to implement and results in the efficient and regioselective
synthesis of the two natural products 1 and 2 currently represents
an enormous challenge.
Interestingly, 2 and its related quinone derivatives including 6,
lawsone 2-prenyl ether (7) and 3, are all natural products isolated
from the fungus Streptocarpus dunnii (Scheme 1).4 It is worth
noting that the prenylated naphthoquinones 3 and 7 have been
reported to be the key biosynthetic intermediates for all the
dihydrofuran naphthoquinones in S. dunnii.4 In fact, one of the dis-
tinct chemical features of prenylated naphthoquinones is their
ability to undergo pericyclic reactions. It has been proposed that
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0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.