Synthesis of lupinacidins A and B via sequential cycloaddition-double elimination

Article abstract of DOI:10.1016/j.tetlet.2010.06.121

The first synthesis of lupinacidins A and B, tumor cell invasion inhibitors of microbial origin, has been achieved in four operational steps from 3-methoxy-2-methyl-2-cyclohexenone via the Diels-Alder cycloaddition of a conjugated cyclohexadiene derivative with a juglone-derived sulfinyl quinone followed by sequential elimination of a sulfenic acid and ethylene to afford protected forms of the target molecules.

Full text of DOI:10.1016/j.tetlet.2010.06.121

Tetrahedron Letters 51 (2010) 4570–4572
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of lupinacidins A and B via sequential cycloaddition–
double elimination
*
*
Kohei Sugimoto, Masaru Enomoto , Shigefumi Kuwahara
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first synthesis of lupinacidins A and B, tumor cell invasion inhibitors of microbial origin, has been
achieved in four operational steps from 3-methoxy-2-methyl-2-cyclohexenone via the Diels–Alder cyclo-
addition of a conjugated cyclohexadiene derivative with a juglone-derived sulfinyl quinone followed by
sequential elimination of a sulfenic acid and ethylene to afford protected forms of the target molecules.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 26 May 2010
Revised 24 June 2010
Accepted 25 June 2010
Available online 30 June 2010
Keywords:
Lupinacidin
Antitumor
Diels–Alder reaction
Anthraquinone
In the course of screening for tumor cell invasion inhibitors of
microbial origin, Igarashi and co-workers discovered two novel
anthraquinones, lupinacidins A and B, from the culture broth of
the endophytic actinomycete Micromonospora lupini Lupac 08 iso-
lated from the root nodules of Lupinus angustifolius and determined
their structures to be 1 and 2, respectively, on the basis of exten-
sive spectroscopic analyses (Fig. 1).1 Lupinacidins A and B exhib-
ited significant inhibitory effects on the invasion of murine colon
O
O
OH
O
O
OH
OH
OH
OH
OH
1
2
lupinacidin A
lupinacidin B
26-L5 carcinoma cells with IC50 values of 0.07
mL, respectively, while showing low cytotoxicity against the same
cells (IC50 >10 g/mL, WST-1 staining method). The selective anti-
l
g/mL and 0.3
l
g/
Figure 1. Structures of lupinacidins A (1) and B (2).
l
invasive property of 1 and 2 suggests their potential as practical
carcinostatic agents with few side effects. From a structural view-
point, 1 and 2 are characterized by the presence of a 1,3-dihy-
droxy-2,4-dialkyl benzene unit embedded in the anthraquinone
nucleus, which is unprecedented as a structural motif found in nat-
urally occurring anthraquinones excluding anthraquinone dim-
mers (bianthraquinones).2,3 The unique substitution pattern and
the medicinally important biological activity of 1 and 2 prompted
our synthetic efforts toward lupinacidins A and B. We describe
herein the first total synthesis of lupinacidins A (1) and B (2)
through a concise cycloaddition–double elimination sequence.
Our retrosynthetic analysis of 1 and 2 is shown in Scheme 1. We
envisaged that the anthraquinone derivatives 1 and 2 would be
obtainable by the Diels–Alder cycloaddition reaction between a
properly substituted naphthoquinone derivative 4 and a conju-
O
O
OH
O
OR2
OH
R
OH
O
OH
O
1: R = (CH2)2CHMe2
2: R = (CH2)3Me
6
7
O
O
OR2
O
O
OR2
X
H
X
+
OR3
OR3
OR1
R
OR1
R
* Corresponding authors. Tel./fax: +81 22 717 8783 (S.K.).
E-mail addresses: me@biochem.tohoku.ac.jp (M. Enomoto), skuwahar@biochem.
tohoku.ac.jp (S. Kuwahara).
3
4
5
Scheme 1. Retrosynthetic analysis of 1 and 2.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.121

K. Sugimoto et al. / Tetrahedron Letters 51 (2010) 4570–4572
4571
O
O
O
STol
STol
2 steps
ref. 4
MCPBA
6
CH2Cl2
93%
OAc O
OAc O
8
9
OMe
OMe
OMe
O
OMe
O
OMe
LDA
i-Bu
LDA
TESOTf
X
H
9
I
THF/HMPA
54%
THF
CH2Cl2
O
O
OTES
OTES
OTES
OAc O
OAc O
10
11
12
13: X = S(O)Tol
14
LDA, n-BuI
THF/HMPA
59%
toluene
°
90 C
OMe
O
OH
O
OMe
O
OMe
BBr3
aq. HF
2
CH3CN
81%
CH3CN
31% from 11
16%
O
OH
OH
OTES
OH
O
OAc O
16
OAc O
17
1
15
Scheme 2. Synthesis of 1 and 2.
gated cyclohexadiene 5 followed by syn-elimination of HX from the
resulting cycloadduct 3 and a subsequent retro-Diels–Alder reac-
tion of the elimination product which would release ethylene to
form the fully substituted benzene ring. The dienophile 4 in the
Diels–Alder reaction should be prepared from a commercially
available compound 6 (juglone) by regioselective installation of
an appropriate leaving group (X), while the enophile 5 would be
readily accessible from substituted cyclohexenone 7 via its alkyl-
ation followed by enol etherification.
In conclusion, the four-step syntheses of lupinacidins A and B,
featuring the Diels–Alder reaction of the suitably substituted diene
12 with the quinone dienophile 9 possessing a p-tolylsulfinyl
group as a regiochemistry-controlling auxiliary followed by the
sequential elimination of p-tolylsulfenic and ethylene, were
achieved from the readily available starting material 10 in 14%
and 9% overall yields, respectively. Synthesis of a variety of analogs
of 1 and 2 as well as their structure–activity relationship studies is
now underway.
According to the synthetic plan, a known juglone derivative 8,
prepared in two steps from 6 by acetylation and regioselective
installation of a tolylthio group,4 was oxidized with MCPBA to afford
dienophile 9. The p-toluenesulfinyl group of 9 was chosen to effect
the Diels–Alder reaction in a regioselective manner and also as a
leaving group in the following elimination step (Scheme 2).5 The
enophile (12) for the synthesis of lupinacidin A (1) was prepared
by alkylation of the known cyclohexenone derivative 10 with 1-
iodo-3-methylbutane and by subsequent TES enol etherification of
the resulting alkylation product 11.6 Due to its instability, the diene
12 was subjected in situ to the Diels–Alder reaction with 9 to give
cycloadduct 13, which spontaneously liberated p-toluenesulfenic
acid under the reaction conditions via a syn-elimination reaction,
affording tetracyclic intermediate 14 as the only detectable regio-
isomer.5d After being roughly purified by silica gel column chroma-
tography,7 14 was heated in toluene to give anthraquinone 15 with
the evolution of ethylene.5d,6 The TES group of 15 was then removed
by directly treating the reaction mixture containing 15 with a solu-
tion of aqueous hydrofluoric acid in acetonitrile to furnish 16 in a
two-pot operation and 31% overall yield from 11. Finally, the treat-
ment of 16 with BBr3 in acetonitrile and subsequent workup with
aqueous NaHCO3 brought about the deprotection of the methoxy
and acetoxy groups, giving lupinacidin A (1) (mp 235–237 °C, lit.1
mp 234–238 °C) in 81% yield. The other target molecule 2 (mp
201–203 °C, lit.1 mp 201–203 °C) was also synthesized in the same
manner as described for 1 except that the initial alkylation of 10
was conducted with 1-iodobutane instead of 1-iodo-3-methylbu-
tane. The 1H and 13C NMR spectra of 1 and 2 were identical with
those of natural lupinacidins A and B, respectively.
Acknowledgments
We are grateful to Professor Yasuhiro Igarashi (Toyama Prefec-
tural University) for providing the spectra of lupinacidins A and B.
This work was supported, in part, by a Grant-in-Aid for Scientific
Research (B) from the Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan (No. 22380064).
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data, and NMR spectra for new compounds) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.06.121.
References and notes
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3702–3705.
2. For synthetic anthraquinones with
a benzene ring unit having the same
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55B, 267–269; (b) Wang, J.; Pettus, L. H.; Pettus, T. R. R. Tetrahedron Lett. 2004,
45, 1793–1796; (c) Rezanka, T.; Dembitsky, V. M. Nat. Prod. Res. 2006, 20, 969–
980.
3. For examples of naturally occurring bianthraquinones having analogous
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Andrade Chiappeta, A.; De Mello, J. F. Phytochemistry 1992, 31, 259–261; (b)
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