Efficient construction of the core framework of lysidicin A via three Claisen rearrangements including a cascade reaction

Article abstract of DOI:10.1016/j.tetlet.2010.04.073

A model compound (6) with the core skeleton of lysidicin A was synthesized as a racemate. The key step (8→7) includes three Claisen rearrangements of the triether with phloroglucinols; two of which rearranged in a cascade manner and the other was a simple rearrangement. This one-pot reaction enabled the introduction of three phloroglucinol units at the correct positions and makes the synthetic approach significantly efficient.

Full text of DOI:10.1016/j.tetlet.2010.04.073

Tetrahedron Letters 51 (2010) 3294–3296
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Tetrahedron Letters
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Efficient construction of the core framework of lysidicin A via three
Claisen rearrangements including a cascade reaction
*
Yusuke Ogura, Hidenori Watanabe
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bukyo-ku, Tokyo 113-8657, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A model compound (6) with the core skeleton of lysidicin A was synthesized as a racemate. The key step
(8?7) includes three Claisen rearrangements of the triether with phloroglucinols; two of which rear-
ranged in a cascade manner and the other was a simple rearrangement. This one-pot reaction enabled
the introduction of three phloroglucinol units at the correct positions and makes the synthetic approach
significantly efficient.
Received 8 March 2010
Revised 10 April 2010
Accepted 19 April 2010
Available online 22 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Lysidicin A
Vasodilation activity
Claisen rearrangement
Cascade reaction
Lysidicins A–E (1–5) were isolated from Chinese medicinal
plant, Lysidice rhodostegia Hance (Fabaceae) which has been used
for the treatment of ache, fractures, and hemorrhage for a long
time by local folks in China (Fig. 1).1,2 Among the lysidicin family,
lysidicins A–C were reported to exhibit vasodilation activity.1
However, the full details of biological activity of lysidicins have
not been clarified yet. Lysidicin A (1) has the most unique and com-
plicated structure in which two acetals form spiro[furan–furofu-
ran] ring system. However, only the relative configuration of 1
was determined. Additionally, any other compounds possessing
this unique structure have not been isolated. That prompted us
to embark on the total synthesis of lysidicin A. Herein, we report
an efficient construction of the acetalic framework of lysidicin A.
We set up 6 as a model compound and our synthetic strategy of
6 (and lysidicin A) is shown in Scheme 1. Compound 6 would be
synthesized from diene 7 by oxidative cleavage of two exo-olefins
and subsequent intramolecular acetalization. Diene 7 would be ob-
tained from triether 8 by Claisen rearrangements including a cas-
cade reaction. Triether 8 would be obtained from phloroglucinol
derivative 9 and triol 10. Triol 10 would be obtained from dimethyl
itaconate 11 and ketone 12. The key step (8?7) enables the intro-
duction of three phloroglucinol units at the correct positions in a
single operation and makes our synthesis significantly efficient.
The precursor 8 for the Claisen rearrangements was prepared as
shown in Scheme 2. First of all, 11 was reduced to diol by DIBAL-
H,3 which was submitted to monosilylation to give a mixture of
13a and 13b (1:1). After SiO2 separation, iodination of the desired
alcohol 13a followed by treatment with triphenylphosphine affor-
ded phosphonium salt 14. Subsequent Wittig reaction with known
ketone 124,5 gave coupling product, whose protective groups were
removed under mild acidic condition to afford corresponding triol
10. Under the Mitsunobu condition, triol 10 was then converted to
the precursor of the key reaction, triether 8, in 51% yield along with
30% of intramolecularly O-alkylated product (15).
With key intermediate 8 in hand, Claisen rearrangement was
examined as summarized in Table 1. Thermal conditions resulted
in decomposition (entries 1 and 2).6,7 The reaction using diethyl-
aluminum chloride as a Lewis acid afforded only the partially rear-
ranged products and the desired 7 was not detected (entries 3 and
4).8 Triisobutylaluminum was also unsatisfactory (only a trace
amount of 7 was observed on silica gel TLC, entry 5).9 In contrast,
trimethylaluminum and water dramatically accelerated the Clais-
en rearrangement and 7 was obtained in excellent yield (entry 6).10
After the successful key step, model compound 6 was synthe-
sized via oxidation and subsequent acetalization (Scheme 3). Three
phenolic hydroxy groups of 7 were temporarily acetylated, and the
product 16 was submitted to ozonolysis to give desired diketone
17 in good yield. On the other hand, ozonolysis of 7 resulted in
decomposition due to the competitive oxidation of the aromatic
rings. Finally, removal of acetyl groups of 17 and subsequent acid
treatment afforded model compound 6 successfully as a major
product (47% in two steps) along with a small amount of diastereo-
mer 60 (5%). 1H NMR coupling patterns of
6 showed good
accordance with those of lysidicin A1,11 and the relative stereo-
chemistry of 6 was confirmed by X-ray analysis.12
In summary, by use of the three Claisen rearrangements in one-
pot, model compound 6 with a core framework of lysidicin A (1)
* Corresponding author.
E-mail address: ashuten@mail.ecc.u-tokyo.ac.jp (H. Watanabe).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.073

Y. Ogura, H. Watanabe / Tetrahedron Letters 51 (2010) 3294–3296
3295
HO
H
HO
H
HO
O
OH
O
OH
O
OH
OH
O
OH
O
OH
O
O
O
O
O
O
O
O
O
HO
HO
HO
HO
OH
OH
HO
OH
O
O
O
OH
OH
OH
Lysidicin A (1)
Lysidicin B (2)
Lysidicin C (3)
HO
OH
HO
O
HO
HO
O
O
OH
O
OH
O
OH
HO
O
OH
Lysidicin D (4)
Figure 1. Structures of lysidicin family.
Lysidicin E (5)
R'O
H
MeO
OMe
OR'
OMe
OR'
R
3 X Claisen
OH
OMe
R
O
O
O
R'O
MeO
OH
HO
rearrangement
HO
OR'
R
7
OMe
OR'
Lysidicin A (1) (R = isovaleryl, R' = H)
Model compound 6 (R = H, R' = Me)
OH
CO2Me
MeO
OMe
OMe
Me2OC
OMe
MeO
11
O
OH
9
MeO
O
HO
O
O
OMe
OH
10
O
O
8
OMe
12
Scheme 1. Retrosynthetic analysis.
a,b
c,d
e,f
CO2Me
OH
OTBS
PPh3I
MeO2C
TBSO
HO
TBSO
11
13a
1 : 1
13b
14
MeO
OMe
OMe
OMe
g
O
MeO
O
MeO
O
OH
HO
O
OMe
O
OMe
OH
10
8
15
OMe
OMe
Scheme 2. Preparation of triether 8. Reagents and conditions: (a) DIBAL-H, THF, ꢀ78 °C to rt, 95%; (b) TBSCl, NaH, THF, ꢀ10 °C, 43% (and 43% of 13b); (c) I2, Imid., PPh3,
CH3CN/ether = 1:3, rt, 96%; (d) PPh3, CH3CN, reflux; (e) n-BuLi, DME, then 12, ꢀ78 °C to 0 °C , 80% in two steps; (f) AcOH/H2O/THF = 1:1:1, rt, 84%; (g) 9, DEAD, PPh3, THF, 0 °C
to rt, 51%.

3296
Y. Ogura, H. Watanabe / Tetrahedron Letters 51 (2010) 3294–3296
Table 1
Examination of Claisen rearrangement
MeO
OMe
MeO
O
OMe
OMe
OMe
see
OH
OMe
O
MeO
OH
MeO
O
HO
OMe
Table 1
8
7
OMe
OMe
Entry
Catalyst
Solvent
Temperature
Time (h)
Result
1
2
3
4
5
6
—
—
DecalinÒ
N,N-Dimethylaniline
CH2Cl2
CH2Cl2
CH2Cl2
Reflux
160 °C
ꢀ78 °C
0 °C
0 °C to rt
Reflux
17
24
3
3
2.5
4
Decomposition
Decomposition
Incompletion
Incompletion
Incompletion
83%
Et2AlCl
Et2AlCl
(i-Bu)3Al
Me3Al/H2Oa
CH2Cl2
a
Me3Al (16 equiv), H2O (4 equiv).
MeO
OMe
MeO
OMe
MeO
OMe
OMe
OMe
OMe
OH
OMe
OAc
O
OAc
OMe
a
b
MeO
OH
MeO
OAc
AcO
MeO
OAc O
AcO
HO
OMe
7
16
17
OMe
OMe
OMe
MeO
H
MeO
H
OMe
OMe
OMe
OMe
c,d
O
O
O
O
O
O
MeO
MeO
HO
OMe
HO
OMe
6
6'
OMe
47%
OMe
5%
Scheme 3. Synthesis of model compound 6. Reagents and conditions: (a) Ac2O, NaH, THF, 0 °C, 92%; (b) O3, CH2Cl2, ꢀ78 °C, then PPh3, 69%; (c) K2CO3, MeOH, 0 °C; (d) TsOH,
CH2Cl2, 0 °C to rt, 47% in two steps.
6. Hiratani, K.; Kasuga, K.; Goto, M.; Uzawa, H. J. Am. Chem. Soc. 1997, 119, 12677–
12678.
proach would provide an efficient synthetic way for analogous
7. Yoshida, H.; Hiratani, K.; Ogihara, T.; Kobayashi, Y.; Kinbara, K.; Saigo, K. J. Org.
was synthesized in 12 steps from dimethyl itaconate (11). This ap-
compounds as well as lysidicin A itself. Total synthesis of lysidicin
Chem. 2003, 68, 5812–5818.
8. Marcune, B. F.; Hiller, M. C.; Marcoux, J.-F.; Humphrey, G. R. Tetrahedron Lett.
2005, 46, 7823–7826.
A (1) is now in progress and will be reported in due course.
9. Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1981, 22, 3985–3988.
10. Wipf, P.; Ribe, S. Org. Lett. 2001, 3, 1503–1505.
Acknowledgment
11. Physical and spectral data of model compound
6 : mp 194–196 °C
(recrystallized from hex/EtOAc = 10:1), 1H NMR (500 MHz CDCl3) d 7.16 (1H,
s), 6.18 (1H, d, J = 2.4 Hz), 6.15 (1H, d, J = 2.1 Hz), 6.08 (1H, d, J = 2.4 Hz), 6.07
(1H, d, J = 2.1 Hz), 5.98 (1H, d, J = 1.8 Hz), 5.81 (1H, d, J = 1.8 Hz), 3.94 (1H, d,
J = 8.7 Hz), 3.81 (3H, s), 3.77 (9H, s), 3.76 (3H, s), 3.68 (3H, s), 3.40 (1H, d,
J = 15.0 Hz), 3.27 (1H, d, J = 15.0 Hz), 3.26 (1H, d, J = 16.8 Hz), 3.07 (1H, d,
J = 16.8 Hz), 2.63 (1H, d, J = 13.2 Hz), 2.07 (1H, dd, J = 8.7 Hz, 13.2 Hz). 13C NMR
(125 MHz, CDCl3) d 162.09, 161.45, 160.67, 159.73, 159.39, 159.38, 157.60,
156.42, 156.31, 124.22, 120.06, 108.47, 103.89, 102.33, 94.91, 92.05, 91.95,
We thank Mr. M. Bando of Otsuka Pharmaceutical Co., Ltd for X-
ray analysis.
References and notes
1. Hu, Y.-C.; Wu, X.-F.; Gao, S.; Yu, S.-S.; Liu, Y.; Qu, J.; Liu, J.; Liu, Y.-B. Org. Lett.
2006, 8, 2269–2272.
2. Wu, X.-F.; Hu, Y.-C.; Gao, S.; Yu, S.-S.; Pei, Y.-H.; Tang, W.-Z.; Huang, X.-Z. J.
Asian Nat. Prod. Res. 2007, 9, 471–477.
3. Ferraboschi, P.; Grisenti, P.; Manzicchi, A.; Santaniello, E. Tetrahedron:
Asymmetry 1994, 5, 691–698.
4. Hoppe, D.; Schmincke, H.; Kleemann, H. Tetrahedron 1989, 45, 687–694.
5. Forbes, D. C.; ENe, D. G.; Doyle, M. P. Synthesis 1998, 45, 687–694.
91.83, 89.00, 88.63, 55.85, 55.48, 45.35, 42.02, 36.77, 30.52. IR (KBr)
m = 3676–
3153 (br), 2941, 2841, 2081, 1740, 1613, 1453 cmꢀ1. ESI-HRMS m/z calcd for
C30H32NaO10 [M+Na]+ 575.1888, found 575.1876.
12. Crystallographic data (excluding structure factors) for the structures of 6 have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication CCDC 768120. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.Uk).