Total synthesis of (±)-lysidicin A

Article abstract of DOI:10.1016/j.tet.2011.12.062

Lysidicin A, which has been isolated from Lisidicie rhodostegia possesses complicated structure. A total synthesis of lysidicin A has been achieved and is described herein. The key reaction is single and cascade Claisen rearrangements.

Full text of DOI:10.1016/j.tet.2011.12.062

Tetrahedron 68 (2012) 1723e1728
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of (ꢀ)-lysidicin A
Yusuke Ogura, Ken Ishigami, 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:
Received 13 October 2011
Received in revised form 19 December 2011
Accepted 21 December 2011
Available online 28 December 2011
Lysidicin A, which has been isolated from Lisidicie rhodostegia possesses complicated structure. A total
synthesis of lysidicin A has been achieved and is described herein. The key reaction is single and cascade
Claisen rearrangements.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Lysidicin A
Claisen rearrangement
Cascade reaction
Total synthesis
Acetal
1. Introduction
Lisidicie rhodostegia Hance (Fabaceae) is a Chinese medicinal
shrubbery plant, which has been used for the treatment of ache,
fractures, and hemorrhage for a long time by local folks in China.
Lysidicins AeC (1e3) have been isolated from the plant by Yu and co-
workers in 20061 and the isolation of other lysidicins DeH have also
been reported by the same group in 20072 and 2010.3 Although
lysidicin DeH showed stronger anti-oxidant activity than vitamin
E,2,3 the full details of biological activities of the other lysidicins have
not been clarified yet. Meanwhile, among the lysidicin family, lysi-
dicin A (1) has the most unique and complicated structure in which
two acetals form spiro[furan-furofuran] ring system. Moreover, any
other compounds possessing this unique structure have not been
isolated. Interest in the construction of this novel structure and the
additional contribution to bioassay prompted us to embark on the
synthetic study of lysidicin A (1). Herein, we report a full detail of the
efficient total synthesis of (ꢀ)-lysidicin A (1) (Fig. 1).
2. Results and discussion
Our synthetic strategy is shown in Scheme 1. Lysidicin A (1)
would be synthesized from spiro[furan-furofuran] 4 by three Frie-
deleCrafts acylations. Spiro[furan-furofuran] 4 would be obtained
from diene 5 by oxidative cleavage of two exo-olefins and sub-
sequent intramolecular acetalization. The key step is the single and
Fig. 1. Structures of lysidicin family: R¼isovaleryl.
cascade Claisen rearrangements (6/5), which deliver the three
aromatic rings to the correct positions, at the same time installing
the two exo-methylenes as we have already reported the pre-
liminary results recently.4 Triether 6 would be readily obtained
from phloroglucinol derivative 7 and triol 8.
* Corresponding author. Tel.: þ81 3 58415119; fax: þ81 3 5841 8019; e-mail
address: ashuten@mail.ecc.u-tokyo.ac.jp (H. Watanabe).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.062

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Y. Ogura et al. / Tetrahedron 68 (2012) 1723e1728
substrate were protected as methyl ethers, the rearrangements
were accelerated successfully only by aqueous Me3Al9 in reflux-
ing CH2Cl2 and other thermal or Lewis acidic conditions resulted
in failure. However, the same successful conditions were not fully
applicable to benzylated precursor 14 due to the decomposition
of the rearranged product, which decreased the yield to 35%.
After several investigations, it was found that Me3Al in the ab-
sence of water catalyzed the reaction more effectively even at
room temperature and the product 15 was obtained in excellent
yield (84%).
After the successful key step, the core framework of lysidicin
A
(1), spiro[furan-furofuran] ring system, was constructed
(Scheme 3). Three phenolic hydroxy groups of 7 were temporarily
acetylated, and the product 17 was submitted to ozonolysis to
give desired diketone 18 in good yield. Removal of acetyl groups
of 18 and subsequent acid treatment afforded the spiro[furan-
furofuran] 19 successfully. 1H NMR spectral data of the product
19 showed good accordance with those of our previously syn-
thesized compound 21 whose stereostructure has been clarified
unambiguously by X-ray crystallographic analysis.4 The remain-
ing phenolic hydroxy group of 19 was then protected to afford
benzyl ether 20.
Scheme 1. Retrosynthetic analysis: P¼protecting group.
The precursor 6 for the Claisen rearrangement was prepared
from known 9,5 166,7 and phlorogulcinol dibenzyl ether [7
(P¼Bn)]8 in six steps almost in the same manner described pre-
viously by us except for the protecting groups in 7 (benzyl ethers
instead of methyl ethers) as shown in Scheme 2.4 In the Mitsu-
nobu reaction (8e14), intramoleculary alkylated by-product,
which was similar to the methyl protected compound described
in our previous paper,4 was also obtained (23%). The key step,
single and cascade Claisen rearrangements, was then examined.
As reported previously,4 when the phenolic hydroxy groups of the
Scheme 3. Preparation of spiro[furan-furofuran] 20: reagents and conditions; (a)
Ac2O, NaH, THF, 0 ꢂC, 92%. (b) O3, CH2Cl2, ꢁ78 ꢂC, then PPh3, 83%. (c) K2CO3, MeOH,
0
ꢂC. (d) TsOH, CH2Cl2, 0 ꢂC to rt, 81% in two steps. (e) BnBr, NaH, DMF, 0 ꢂC, 97%.
As described in the retrosynthetic analysis part, we planned to
introduce the isovaleryl groups at the final stage of the synthesis.
It should be noted that the acylation at the earlier stage gave the
unsuccessful results as summarized in Scheme 4. When the
model compound 22 with the isovaleryl group was subjected to
Claisen rearrangement, the ketone reacted with Me3Al and
dehydrated products 23 and 24 were obtained. FriedeleCrafts
acylation of 25 also caused an undesired benzofuran formation as
well as the acylation to give 26 or 27 (regiochemistry was not
determined). On the other hand, 28 with a partial substructure of
30 afforded the acylated product in good yield. However, 30
itself could not be triacylated probably due to the structural
complexity.
Scheme 2. Preparation of 15: reagents and conditions; (a) TBSCl, NaH, THF, ꢁ10 ꢂC,
43%. (b) I2, Imid., PPh3, THF, rt. (c) PPh3, CH3CN, reflux. (d) n-BuLi, DME, then 16, ꢁ78 to
0
ꢂC, 83% in three steps. (e) AcOH/H2O/THF¼1:1:1, rt, 84%. (f) 7 (P¼Bn), DEAD, PPh3,
THF, 0 ꢂC to rt, 50%. (g) Me3Al, CH2Cl2, 0 ꢂC to rt, 84%.

Y. Ogura et al. / Tetrahedron 68 (2012) 1723e1728
1725
Scheme 5. Synthesis of lysidicin A: reagents and conditions; (a) isovaleryl chloride,
AgOTf, CH2Cl2, ꢁ78 ꢂC. (b) H2, Pd(OH)2, EtOH/AcOEt¼2:1, 27% of 31, 35% of 32. (c) TsOH,
CH2Cl2/ether¼5:1, 73% of lysidicin A (1), 11% of 31, 13% of 32.
CD3CN: dH¼1.93, dC¼1.39, CD3NO2: dC¼60.5). Refractive indexes
were measured with an Atago 1T refractometer. Mass spectra were
recorded on JEOL JMS SX102. Column chromatography was per-
formed using Kanto silica gel 60N (0.060e0.200 mm). TLC was
carried out on Merck glass plates precoated with silica gel 60 F254
(0.25 mm).
Scheme 4. Summary unsuccessful results: reagents and conditions; (a) Me3Al, H2O,
CH2Cl2, reflux, 42%, (23/24¼1:1), (b) isovaleryl chloride, AgOTf, CH2Cl2, ꢁ78 ꢂC to rt,
38% for 26 or 27, 90% for 29.
For the completion of the total synthesis of lysidicin A, Frie-
deleCrafts acylation of 20 was examined (Scheme 5). To our de-
light, when isovaleryl chloride was activated with AgOTf,10 the
reaction proceeded smoothly to give a mixture of regioisomers,
which were difficult to be isolated. The mixture was therefore
subjected to hydrogenolysis and the product was separated to af-
ford 31 and 32 in 27% and 35% yields (in two steps), respectively,
whose regiochemistries were confirmed by HMBC measurement.
Both 31 and 32 were regioisomeric compounds of lysidicin A, they
were separately subjected to acid catalyzed isomerization of the
acetalic spiro[furan-furofuran] ring system and total synthesis of
(ꢀ)-lysidicin A (1) have been accomplished.
3.2. Synthetic studies
3.2.1. 4-(tert-Butyldimethylsilyloxy)-3-methylenebutan-1-ol (10). To
a suspension of sodium hydride (60% in mineral oil, 2.17 g,
54.3 mmol) in THF (70 ml) was added diol 9 (5.04 g, 49.4 mmol) in
THF (20 ml) at ꢁ78 ꢂC under argon atmosphere. After the reaction
mixture was warmed up to ꢁ40 ꢂC over 1 h with stirring, TBSCl
(7.81 g, 51.8 mmol) was added. After stirring for 45 min, the re-
action mixture was poured into 10% aqueous solution of K2CO3, and
extracted three times with ether. The organic layer was washed
with water and brine and dried over anhydrous magnesium sulfate.
After concentration in vacuo, the residue was chromatographed
over silica gel. Elution with hexanes/EtOAc (8:1) gave silyloxy al-
In conclusion, we have achieved the first total synthesis of
(ꢀ)-lysidicin A effectively via single and cascade Claisen rear-
rangements and FriedeleCrafts acylation using AgOTf. The overall
yield was 3.5% in 15 steps from known diol 9. This approach would
provide an efficient synthetic way for analogous compounds.
cohol 10 (4.68 g, 44%) as colorless oil. nD¼1.4505. IR (film):
n
¼3352,
2931, 2857, 1471, 1254, 1082, 836, 776 cmꢁ1 1H NMR (300 MHz,
.
CDCl3):
d
¼0.08 (6H, s), 0.90 (9H, s), 2.32 (2H, t, J¼6.0 Hz), 2.39 (1H,
3. Experimental
3.1. General
br s), 3.70 (2H, t, J¼6.0 Hz), 4.09 (2H, s), 4.93 (1H, s), 5.10 (1H, s). 13C
NMR (125 MHz, CDCl3):
d¼ꢁ5.21, 18.51, 26.06, 37.12, 61.61, 66.66,
113.01, 145.76. ESI-TOFMS m/z calcd for C11H24NaO2Si [MþNa]þ
239.1438, found 239.1414.
Dry THF and DME were freshly prepared by distillation from
benzophenone ketyl and dry CH2Cl2 was freshly prepared by dis-
tillation from P2O5 before use. Melting points were measured with
a Yanaco micro-melting point apparatus and are uncorrected
values. IR spectra were measured with a JASCO FT/IR-230 spectro-
photometer. 1H and 13C NMR were recorded on JEOL JNM AL300 or
3.2.2. 2-[(tert-Butyldimethylsilyloxy)methyl]-4-iodo-but-1-ene
(11). To a solution of alcohol 10 (5.00 g, 23.1 mmol) in THF (200 ml)
were added imidazole (3.93 g, 57.8 mmol), triphenylphosphine
(7.27 g, 27.7 mmol), and iodine (7.62 g, 30.0 mmol) at 0 ꢂC under
argon atmosphere. After the reaction mixture was warmed up to
room temperature over 30 min with stirring, hexanes (200 ml) was
added to the reaction mixture and filtered through a pad of Celite.
The filtrate was concentrated in vacuo and the residue was filtered
JEOL JNM GSX500. Chemical shifts (d) were referenced to the re-
sidual solvent peaks as the internal standard (CDCl3: dH¼7.26,
dC¼77.23; DMSO-d6: dH¼2.49, dC¼39.5, benzene-d6: dH¼7.15,

1726
Y. Ogura et al. / Tetrahedron 68 (2012) 1723e1728
through a short pad of silica gel (hexanes/EtOAc¼10:1). Crude io-
dide 11 was used for the next reaction without further purification.
132.98, 137.00, 142.70, 160.62, 160.68, 160.79. ESI-TOFMS m/z calcd
for C68H62NaO9 [MþNa]þ 1045.4286, found 1045.4283.
1H NMR (300 MHz, CDCl3):
d
¼0.07 (6H, s), 0.91 (9H, s), 2.61 (2H, t,
J¼7.8 Hz), 3.26 (2H, t, J¼7.8 Hz), 4.09 (2H, s), 4.89 (1H, s), 5.12 (1H,
3.2.6. 3,5-Dibenzyloxy-2-[3-(4,6-dibenzyloxy-2-hydroxyphenyl)-5-
{(4,6-dibenzyloxy-2-hydroxyphenyl)methyl}-2-methylenehex-5-enyl]
phenol (15). To a solution of trimethylaluminium (1.08 M in hex-
ane, 40.7 ml, 44 mmol) in dry CH2Cl2 (270 ml) was added triether
14 (5.45 g, 5.33 mmol) in dry CH2Cl2 (20 ml) by cannula at 0 ꢂC
under argon atmosphere. After stirring for 3 h, MeOH (50 ml) was
added slowly at the same temperature and the reaction mixture
was warmed up to room temperature. Saturated aqueous Rochelle
salt (500 ml) was added and the reaction mixture was stirred
overnight. After extraction three times with CH2Cl2, the organic
layer was washed with water and brine and dried over anhydrous
magnesium sulfate. After concentration in vacuo, the residue was
chromatographed over silica gel. Elution with benzene/ether (20:1)
gave rearranged product 15 (4.61 g, 84%) as a colorless gum. IR
s). 13C NMR (125 MHz, CDCl3):
65.67, 111.40, 147.26.
d¼ꢁ5.17, 3.64, 18.52, 26.09, 37.50,
3.2.3. 2,2-Dimethyl-5-{3-[(tert-butyldimethylsilyloxy)methyl]but-3-
ene-1-ylidene}-1,3-dioxan (13). To a solution of iodide 11 (3.14 g,
9.62 mmol) in acetonitrile (50 ml) was added triphenylphosphine
(2.52 g, 9.62 mmol) at room temperature under argon atmosphere.
The reaction mixture was refluxed overnight and concentrated in
vacuo. After washing with benzene and ether, the residue was
pumped up overnight to give a phosphonium salt 12. Crude
phosphonium salt 12 was used for next reaction without further
purification. To a suspension of crude phosphonium salt in dry DME
(43 ml) was added n-BuLi in hexane (1.59 M, 6.1 ml, 9.30 mmol)
slowly at ꢁ78 ꢂC under argon atmosphere. After the reaction
mixture was warmed up to ꢁ40 ꢂC over 1 h with stirring, a solution
of ketone 16 (1.21 g, 9.30 mmol) in dry DME (10 ml) was added
dropwise at ꢁ78 ꢂC. The reaction mixture was warmed up to 0 ꢂC
and stirred for 1 h at the same temperature and poured into solu-
tion of saturated aqueous NaHCO3. The mixture was extracted three
times with ether and the organic layer was washed with water and
brine and dried over anhydrous magnesium sulfate. After concen-
tration in vacuo, the residue was chromatographed over silica gel.
Elution with hexanes/EtOAc (10:1) gave dioxan 13 (2.52 g, 83%) as
(film):
NMR (500 MHz, C6D6):
n
¼3432, 3031, 1617, 1498, 1437, 1146, 1074, 736, 696 cmꢁ1. 1H
d
¼2.80 (1H, dd, J¼6.0, 13.5 Hz), 2.92 (1H, dd,
J¼10.0, 13.5 Hz), 3.51 (1H, d, J¼17.0 Hz), 3.56 (1H, d, J¼17.0 Hz), 3.61
(1H, d, J¼17.0 Hz), 3.74 (1H, d, J¼17.0 Hz), 4.61e4.73 (11H, m), 4.79
(1H, br s), 4.80 (1H, br s), 4.83 (1H, d, J¼11.5 Hz), 5.08 (1H, br s), 5.14
(1H, br s), 5.31 (1H, br s). 5.65 (1H, br s), 6.15 (1H, br), 6.16 (1H, br d,
J¼1.5 Hz), 6.19 (1H, br d, J¼1.5 Hz), 6.27 (1H, d, J¼2.0 Hz), 6.29 (1H,
d, J¼2.0 Hz), 6.33 (1H, d, J¼2.5 Hz), 6.38 (1H, d, J¼2.5 Hz), 7.01e7.29
(30H, m). 13C NMR (125 MHz, CD3CN, at 70 ꢂC):
d¼30.64, 30.94,
39.53, 40.54, 94.25, 95.41, 97.13, 97.19, 97.81, 109.72, 109.81, 109.95,
111.06, 112.72, 128.90, 129.03, 129.21, 129.31, 129.51, 130.06, 130.18,
139.34, 139.47, 148.97, 152.52, 158.00, 158.71, 160.09, 160.29, 160.38,
160.56. ESI-TOFMS m/z calcd for C68H62NaO9 [MþNa]þ 1045.4286,
found 1045.4305.
a colorless oil. nD¼1.4658. IR (film):
n
¼2955, 2855, 1471, 1370, 1222,
1088, 835, 776 cmꢁ1. 1H NMR (300 MHz, C6D6):
d
¼0.04 (6H, s), 0.96
(9H, s), 1.38 (6H, s), 2.51 (2H, d, J¼4.5 Hz), 3.95 (2H, s), 4.12 (2H, s),
4.32 (2H, s), 4.82 (1H, br s), 5.06 (1H, m), 5.11 (1H, br s). 13C NMR
(125 MHz, C6D6):
d
¼ꢁ5.29, 18.46, 24.27, 26.03, 30.21, 59.69, 64.24,
65.94, 99.15, 109.83, 119.36, 135.27, 147.12. ESI-TOFMS m/z calcd for
3.2.7. 2-[3-(2-Acetoxy-4,6-dibenzyloxy-phenyl)-5-{(2-acetoxy-4,6-
dibenzyloxy-phenyl)methyl}-3,5-dibenzyloxy-2-methylenehex-5-
enyl]phenyl acetate (17). To a suspension of sodium hydride (55% in
mineral oil, 1.04 g, 23.9 mmol) in DMF (150 ml) was added rear-
ranged product 15 (7.40 g, 7.24 mmol) in DMF (30 ml) at 0 ꢂC under
argon atmosphere. After stirring for 5 min, Ac2O (2.33 ml,
24.6 mmol) was added slowly at the same temperature and the
reaction mixture was stirred more over 30 min. Saturated aqueous
NaHCO3 (10 ml) was added and the reaction mixture was poured
into water (1000 ml). After extraction three times with ether, the
organic layer was washed with water and brine and dried over
anhydrous magnesium sulfate. After concentration in vacuo, the
residue was chromatographed over silica gel. Elution with benzene/
ether (20:1) gave triacetate 17 (7.65 g, 92%) as a colorless gum. IR
C17H32NaO3Si [MþNa]þ 335.2013, found 335.2017.
3.2.4. 2-(Hydroxymethyl)-5-methylenehex-2-ene-1,6-diol (8). Dioxan
13 (905 mg, 2.90 mmol) was dissolved in a mixed solvent (THF/H2O/
AcOH¼1:1:1, 15 ml) at room temperature and stirred overnight at
the same temperature. After concentration in vacuo, the residue was
chromatographed over silica gel. Elution with hexanes/EtOAc (1:1) to
CHCl3/MeOH (10:1) gave triol 8 (385 mg, 84%) as a colorless oil.
nD¼1.5151. IR (film):
n
¼3319, 2873, 1652, 1429, 1223, 1011, 902 cmꢁ1
.
1H NMR (300 MHz, CD3CN):
d
¼2.46 (2H, d, J¼7.8 Hz), 2.66 (1H, t,
J¼6.0 Hz), 2.72 (1H, t, J¼6.0 Hz), 2.82 (1H, t, J¼6.0 Hz), 3.56 (2H, d,
J¼6.0 Hz), 3.64 (2H, d, J¼6.0 Hz), 3.71 (2H, d, J¼6.0 Hz), 4.44 (1H, s),
4.58 (1H, s), 5.13 (1H, t, J¼7.8 Hz). 13C NMR (125 MHz, CD3CN):
d¼31.94, 58.92, 65.67, 66.06, 110.32, 126.31, 141.60, 149.93. ESI-
(film):
n
¼3031, 1763, 1617, 1586, 1497, 1209, 1141, 1071, 735,
TOFMS m/z calcd for C8H14NaO3 [MþNa]þ 181.0835, found 181.0870.
696 cmꢁ1. 1H NMR (300 MHz, CD3CN, at 70 ꢂC):
d¼1.98 (3H, s), 2.06
(3H, s), 2.07 (3H, s), 2.66 (1H, br dd, J¼7.2, 15.0 Hz), 2.72 (1H, br dd,
J¼6.9, 15.0 Hz), 3.05 (1H, br d, J¼16.5 Hz), 3.09 (1H, br d, J¼16.5 Hz),
3.14 (1H, br d, J¼15.9 Hz), 3.17 (1H, br d, J¼15.9 Hz), 4.22 (1H, br),
4.36 (1H, br s), 4.38 (1H, br s), 4.61 (1H, br s), 4.77 (1H, br s),
4.90e5.03 (12H, m), 6.32 (1H, d, J¼2.4 Hz), 6.34 (1H, d, J¼2.4 Hz),
6.35 (1H, d, J¼2.4 Hz), 6.49 (1H, d, J¼2.4 Hz), 6.50 (1H, d, J¼2.4 Hz),
6.51 (1H, d, J¼2.4 Hz), 7.21e7.42 (30H, m). 13C NMR (125 MHz,
3.2.5. 6-(3,5-Dibenzyloxyphenoxy)-2,5-bis[(3,5-dibenzyloxyphenoxy)
methyl]hexa-1,4-diene (14). To a solution of triol 8 (500 mg,
3.16 mmol), triphenylphosphine (4.15 g, 15.8 mmol), and phlor-
ogulcinol dibenzyl ether (7) (4.84 g, 15.8 mmol) in dry THF (15 ml)
was added diethyl azodicarboxylate in toluene (2.2 M, 7.20 ml,
15.8 mmol) at 0 ꢂC under argon atmosphere and stirred overnight at
room temperature. The reaction mixture was poured into water and
extracted three times with ether. The organic layer was washed with
water and brine and dried over anhydrous magnesium sulfate. After
concentration in vacuo, the residue was chromatographed over
silica gel. Elution with benzene/hexanes (1:1) to benzene gave
CD3NO2, at 90 ꢂC):
d
¼18.82, 18.91, 19.15, 28.97, 29.72, 37.34, 38.59,
69.59, 69.71, 69.81, 69.99, 97.85, 97.94, 97.94, 100.91, 101.08, 101.71,
107.65, 108.93, 113.99, 114.11, 116.44, 126.49, 126.64, 126.91, 127.18,
127.66, 127.74, 136.71, 136.77, 146.00, 147.80, 150.27, 150.37, 150.43,
157.50, 157.59, 157.65, 157.70, 157.81, 158.22, 168.31, 168.50, 168.58.
ESI-TOFMS m/z calcd for C74H68NaO12 [MþNa]þ 1171.4603, found
1171.4645.
triether 14 (1.62 g, 50%) as a colorless gum. IR (film):
1452, 1375, 1151, 1058, 736, 696 cmꢁ1. 1H NMR (300 MHz, CDCl3):
¼3.04 (2H, d, J¼7.5 Hz), 4.41 (2H, s), 4.60 (4H, s), 4.85e5.00 (12H,
m), 5.04 (1H, s), 5.17 (1H, s), 5.93 (1H, t, J¼7.5 Hz), 6.18e6.28 (9H, m),
7.22e7.46 (30H, m). 13C NMR (125 MHz, CDCl3):
¼31.66, 63.67,
70.24, 70.86, 94.92, 95.14, 114.23, 127.76, 128.16, 128.75, 130.57,
n¼3031, 1597,
d
3.2.8. 1,4,6-Tris(2-acetoxy-4,6-dibenzyloxyphenyl)hexan-2,5-dione
(18). Into a solution of triacetate 17 (7.64 g, 6.51 mmol) in CH2Cl2
(300 ml) was bubbled O3 gas at ꢁ78 ꢂC until starting material
d

Y. Ogura et al. / Tetrahedron 68 (2012) 1723e1728
1727
disappeared on TLC analysis. Triphenylphosphine (4.75 g,
18.1 mmol) was added to the reaction mixture at same temperature
and was warmed up to room temperature overnight. After con-
centration in vacuo, the residue was chromatographed over silica
gel. Elution with benzene/ether (20:1) gave diketone 18 (6.35 g,
organic layer was washed with water and brine and dried over
anhydrous magnesium sulfate. After concentration in vacuo, the
residue was chromatographed over silica gel. Elution with benzene/
hexanes (5:1) gave 20 (633 mg, 97%) as a colorless amorphous solid.
IR (KBr):
n
¼3031, 1607, 1504, 1437, 1375, 1150, 736, 696 cmꢁ1
.
1H
83%) as a pale yellow amorphous solid. IR (KBr):
1617,1498,1371,1206,1144,1072, 737, 697 cmꢁ1. 1H NMR (300 MHz,
CD3CN, at 70 ꢂC):
n
¼3031, 1768, 1716,
NMR (300 MHz, CDCl3):
d
¼1.95 (1H, dd, J¼8.7, 13.5 Hz), 2.61 (1H, d,
J¼13.5 Hz), 2.90 (1H, d, J¼16.5 Hz), 3.08 (1H, d, J¼16.5 Hz), 3.43 (1H,
d, J¼13.5 Hz), 3.52 (1H, d, J¼13.5 Hz), 4.22 (1H, d, J¼8.7 Hz),
4.82e5.06 (14H, m), 5.96 (1H, d, J¼2.1 Hz), 6.08 (1H, d, J¼2.1 Hz),
6.18 (2H, s), 6.26 (2H, s), 7.19e7.46 (35H, m). 13C NMR (125 MHz,
d
¼2.04 (3H, s), 2.05 (3H, s), 2.12 (3H, s), 2.22 (1H,
dd, J¼4.2, 17.4 Hz), 3.30 (1H, d, J¼17.4 Hz), 3.36 (1H, dd, J¼5.7,
17.4 Hz), 3.49 (1H, d, J¼17.4 Hz), 3.51 (1H, d, J¼18.0 Hz), 3.58 (1H, d,
J¼18.0 Hz), 4.54 (1H, br), 4.89e5.08 (12H, m), 6.34 (1H, d, J¼2.1 Hz),
6.36 (1H, d, J¼2.1 Hz), 6.40 (1H, d, J¼2.7 Hz), 6.43 (1H, d, J¼2.7 Hz),
6.49 (1H, d, J¼2.4 Hz), 6.54 (1H, d, J¼2.4 Hz), 7.26e7.42 (30H, m). 13C
CDCl3):
d
¼30.79, 37.20, 41.91, 45.81, 69.86, 70.02, 70.39, 70.51,
70.60, 90.03, 90.17, 90.55, 93.13, 93.26, 93.58, 105.32, 105.79, 109.57,
119.97, 124.46, 127.35, 127.50, 127.56, 127.81, 128.00, 128.09, 128.28,
128.69, 136.98, 137.20, 137.26, 155.37, 155.51, 159.12, 159.37, 160.17,
160.57, 160.85. ESI-TOFMS m/z calcd for C73H62NaO10 [MþNa]þ
1121.4235, found 1121.4282.
NMR (125 MHz, CD3CN, at 70 ꢂC):
d
¼21.63, 37.36, 39.67, 42.86,
44.94, 71.93, 71.98, 72.16, 72.28, 99.85, 100.22, 100.32, 103.04,
103.38, 103.65, 111.82, 111.94, 115.32, 128.91, 128.97, 129.03, 129.44,
129.68, 129.76, 130.22, 138.74, 138.78, 138.88, 152.38, 152.71, 159.60,
159.78, 159.88, 160.49, 160.59, 160.93, 170.32, 170.49, 170.63,
206.86, 207.02. ESI-TOFMS m/z calcd for C72H64NaO14 [MþNa]þ
1175.4188, found 1175.4206.
3.2.11. (2R*,3aR*,8aR*)-8a0-[{2,4,6-Trihyroxy-3-(30-methyl)butanoyl-
phenyl}methyl]-5,50-di-(30-methyl)butanoyl-3a0,8a0-dihydro-3H,30H-
spiro[1-benzofuran-2,20-furo[2,3-b][1]benzofuran]-4,40,6,60-tetraol
(31), (2R*,3aR*,8aR*)-8a0-{[2,4,6-trihyroxy-3-(30-methyl)butanoyl-
phenyl]methyl}-7,50-di-(30-methyl)butanoyl-3a0,8a0-dihydro-3H,30H-
spiro[1-benzofuran-2,20-furo[2,3-b][1]benzofuran]-4,40,6,60-tetraol
(32). To a solution of furofuran 20 (116 mg, 0.10 mmol) and AgOTf
(147 mg, 0.57 mmol) in dry CH2Cl2 (5.8 ml) was added isovaleryl
chloride (39.9 ml, 0.31 mmol) at ꢁ78 ꢂC under argon atmosphere.
After stirring for 2 h, isovaleryl chloride (26.6 ml, 0.21 mmol) at the
same temperature and reaction mixture was stirred further 2 h.
After addition of AgOTf (26 mg, 0.10 mmol) and isovaleryl chloride
(13.3 ml, 0.10 mmol), the reaction mixture was stirred further 1 h at
same temperature and poured into saturated aqueous NaHCO3
(30 ml). After extraction three times with CH2Cl2, the organic layer
was washed with water and brine and dried over anhydrous
magnesium sulfate. Organic layer was concentrated in vacuo and
the residue was short chromatographed over silica gel. Elution with
benzene/ether (20:1) gave mixture of triacylated compounds
(156 mg). The mixture was used for next reaction without further
purification. To a solution of mixture of triacylated compounds
(156 mg) in mixed solvent (EtOH/AcOEt¼2:1, 15 ml) was added
Pd(OH)2/C (50 mg) at room temperature under hydrogen atmo-
sphere. After stirring for 5 h at same temperature, the reaction
mixture was filtered through a pad of Celite. After concentration in
vacuo, the residue was chromatographed over silica gel. Elution
with hexanes/EtOAc (1:1) gave 31 (18 mg, 27%) and the regioisomer
3.2.9. (2R*,3aR*,8aR*)-8a0-{(4,6-Dibenzyloxy-2-hydroxy-phenyl)
methyl}-4,40,6,60-tetrabenzyloxy-3a0, 8a0-dihydro-3H,30H-spiro[1-
benzofuran-2,20-furo[2,3-b][1]benzofuran] (19). To
a solution of
diketone 18 (1.45 g, 1.26 mmol) in a mixed solvent (MeOH/
CH2Cl2¼1:1, 140 ml) was added anhydrous K2CO3 (1.74 g,
12.6 mmol) at 0 ꢂC under argon atmosphere. After stirring for
45 min, the reaction mixture was poured into saturated aqueous
NH4Cl (300 ml) and small amount of 3 N HCl was added to adjust
the pH at 7. After extraction three times with CH2Cl2, the organic
layer was washed with water and brine and dried over anhydrous
magnesium sulfate. Organic layer was concentrated in vacuo and
crude triphenol was used for next reaction without further purifi-
cation. To a solution of crude triphenol (1.26 g, 1.23 mmol) in dry
CH2Cl2 (300 ml) was added p-touenesulfonic acid monohydrate
(235 mg, 1.23 mmol) at 0 ꢂC under argon atmosphere. After stirring
for 3 h at same temperature, the reaction mixture was poured into
saturated aqueous NaHCO3 (300 ml). After extraction three times
with CH2Cl2, the organic layer was washed with water and brine
and dried over anhydrous magnesium sulfate. Organic layer was
concentrated in vacuo, the residue was chromatographed over sil-
ica gel. Elution with benzene/hexanes (5:1) gave furofuran 19
(1.03 g, 81%) as colorless amorphous solid. IR (KBr):
1624, 1500, 1454, 1149, 1098, 1027, 736, 696 cmꢁ1
(300 MHz, CDCl3):
n
¼3420, 3030,
1H NMR
¼1.98 (1H, dd, 9.0, J¼13.5 Hz), 2.57 (1H, d,
.
d
32 (22 mg, 35%) as yellow powder. Compound 31: IR (KBr):
2924, 1622, 1440, 1369, 1303, 1242, 1159, 1119, 817 cmꢁ1. 1H NMR
(300 MHz, DMSO-d6):
n
¼3379,
J¼13.5 Hz), 3.02 (1H, d, J¼16.5 Hz), 3.20 (1H, d, J¼16.5 Hz), 3.23 (1H,
d, J¼14.7 Hz), 3.38 (1H, d, J¼14.7 Hz), 4.02 (1H, d, J¼9.0 Hz),
4.79e4.98 (12H, m), 5.87 (1H, d, J¼2.1 Hz), 6.06 (1H, d, J¼2.1 Hz),
6.16 (3H, s), 6.20 (1H, d, J¼2.1 Hz), 7.05 (1H, br s), 7.08e7.39 (30H,
d
¼0.55 (3H, d, J¼6.6 Hz), 0.64 (3H, d,
J¼6.6 Hz), 0.88e0.92 (12H, m), 1.726 (1H, m), 1.85 (1H, dd, J¼7.5,
15 Hz), 2.09e2.20(2H, m), 2.21(1H, dd, J¼9.3, 13.8 Hz), 2.44 (1H, dd,
J¼5.4,15 Hz), 2.60 (1H, d, J¼13.8 Hz), 2.76e2.96 (5H, m), 3.01 (1H, d,
J¼16.2 Hz), 3.05 (1H, d, J¼13.8 Hz), 3.17 (1H, d, J¼13.8 Hz), 4.20 (1H,
d, J¼9.3 Hz), 5.83 (1H, s), 5.87 (1H, s), 6.01 (1H, s), 10.49 (1H, s),
10.70 (1H, s), 10.75 (1H, s), 11.32 (1H, s), 12.99 (1H, s), 13.65 (1H, s),
m). 13C NMR (125 MHz, CDCl3):
d
¼31.32, 37.01, 41.98, 45.45, 69.99,
70.23, 70.28, 70.42, 70.60, 89.98, 90.48, 93.72, 93.95, 94.08, 94.22,
96.22, 102.94, 104.79, 109.00, 120.23, 124.28, 127.41, 127.51, 127.63,
127.81, 127.89, 128.14, 128.23, 128.56,128.75, 137.10, 155.48, 155.57,
157.63, 158.37, 159.37, 159.79, 160.87, 161.16. ESI-TOFMS m/z calcd
for C66H56NaO10 [MþNa]þ 1031.3766, found 1031.3728.
14.34 (1H, s). 13C NMR (125 MHz, DMSO-d6):
d
¼21.81, 21.94, 22.63,
22.69, 24.42, 24.94, 25.21, 29.63, 35.32, 40.44, 44.50, 49.21, 52.00,
52.14, 89.22, 94.12, 95.78, 99.40, 100.98, 102.71, 103.62, 105.37,
105.73, 120.71, 124.71, 159.93, 160.15, 160.27, 160.94, 163.46, 163.76,
164.01, 164.08, 164.79, 203.76, 205.05, 205.43. ESI-TOFMS m/z calcd
for C39H44NaO13 [MþNa]þ 743.2674, found 743.2696. Compound
3.2.10. (2R*,3aR*,8aR*)-8a0-[(2,4,6-Tribenzyloxyphenyl)methyl]-
4,40,6,60-tetrabenzyloxy-3a0, 8a0-dihydro-3H,30H-spiro[1-benzofuran-
2,20-furo[2,3-b][1]benzofuran] (20). To a suspension of sodium hy-
dride (55% in mineral oil, 38 mg, 0.89 mmol) in DMF (20 ml) was
added furofuran 19 (600 mg, 0.59 mmol) in DMF (10 ml) at 0 ꢂC
under argon atmosphere. After stirring for 5 min, benzyl bromide
(105 ml, 0.89 mmol) was added at same temperature and the re-
action mixture was stirred for further 30 min. Saturated aqueous
NaHCO3 (10 ml) was added and the reaction mixture was poured
into water (300 ml). After extraction three times with ether, the
32: IR (KBr):
n
¼3353, 2925, 1622, 1436, 1303, 1241, 1211, 1157, 1117,
822 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
.
d
¼0.87e0.97 (18H, m),
2.05e2.20 (4H, m), 2.47 (1H, d, J¼9.9 Hz), 2.81e2.92 (7H, m), 3.02
(1H, d, J¼16.5 Hz), 3.05 (1H, d, J¼13.5 Hz), 3.16 (1H, d, J¼13.5 Hz),
4.16 (1H, d, J¼9.0 Hz), 5.58 (1H, s), 5.88 (1H, s), 6.01 (1H, s), 10.48
(1H, s), 10.74 (1H, s), 11.34 (1H, s), 11.36 (1H, s), 13.29 (1H, s), 13.48
(1H, s), 14.34 (1H, s). 13C NMR (125 MHz, DMSO-d6):
d¼22.64, 24.67,

1728
Y. Ogura et al. / Tetrahedron 68 (2012) 1723e1728
24.89, 24.93, 29.03, 35.15, 40.62, 44.32, 52.00, 52.14, 89.28, 89.51,
94.10, 94.44, 101.88, 103.59, 104.99, 105.05, 106.05, 120.58, 124.54,
159.17, 159.66, 160.89, 163.32, 163.45, 163.54, 163.81, 164.22, 164.78,
205.04, 205.52, 205.57. ESI-TOFMS m/z calcd for C39H44NaO13
[MþNa]þ 743.2674, found 743.2690.
(1H, s), 10.73 (1H, s), 10.81 (1H, s), 13.05 (1H, s), 13.27 (1H, s), 14.39
(1H, s). 13C NMR (125 MHz, DMSO-d6):
d
¼21.82, 22.02, 22.16, 22.61,
24.83, 24.86, 25.16, 29.94, 35.45, 40.70, 44.54, 48.92, 50.42, 51.97,
94.10, 95.76, 96.09, 99.63, 100.37, 100.92, 102.70, 103.62, 106.31,
120.59, 124.10, 159.85, 160.23, 160.34, 160.50, 160.81, 163.29, 164.09,
164.81, 164.96, 203.54, 203.60, 204.99. ESI-TOFMS m/z calcd for
C39H44NaO13 [MþNa]þ 743.2674, found 743.2690.
3.2.12. (2R*,3aR*,8aR*)-8a0-{[2,4,6-Trihyroxy-3-(30-methyl)butanoyl-
phenyl]methyl}-5,70-di-(30-methyl)butanoyl-3a0,8a0-dihydro-3H,30H-
spiro[1-benzofuran-2,20-furo[2,3-b][1]benzofuran]-4,40,6,60-tetraol
(1) (lysidicin A). To a solution of 31 (8 mg, 11.1 mmol) in mixed
solvent (CH2Cl2/ether¼5:1,1.2 ml) was added p-touenesulfonic acid
monohydrate (1 mg, 5.3 mmol) at 0 ꢂC under argon atmosphere.
After stirring for 2 h at same temperature, the reaction mixture was
poured into saturated aqueous NaHCO3 (20 ml). After extraction
three times with ether, the organic layer was washed with water
and brine and dried over anhydrous magnesium sulfate. Organic
layer was concentrated in vacuo, the residue was chromatographed
over silica gel. Elution with hexanes/EtOAc (1:1) gave lysidicin A (1)
(5.8 mg, 73%), the regioisomer 31 (0.9 mg, 11%) and 32 (1.0 mg, 13%)
Ackowledgements
We thank to Dr. K. Furihata of the University of Tokyo for
2D-NMR 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, 2269e2272.
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, 5, 471e477.
3. Wu, X.-F.; Hu, Y.-C.; Yu, S.-S.; Jiang, N.; Ma, J.; Tan, R.-X.; Li, Y.; Lv, H.-N.; Liu, J.;
Ma, S.-G. Org. Lett. 2010, 12, 2390e2393.
4. Ogura, Y.; Watanabe, H. Tetrahedron Lett. 2010, 51, 3294e3296.
5. Ferraboschi, P.; Grisenti, P.; Manzicchi, A.; Santaniello, E. Tetrahedron: Asym-
metry 1994, 5, 691e698.
6. Hoppe, D.; Schmincke, H.; Kleemann, H. Tetrahedron 1989, 45, 687e694.
7. Forbes, D. C.; Ene, D. G.; Doyle, M. P. Synthesis 1998, 879e882.
8. Curtis, D. C.; Stoddart, J. F.; Jones, G. H. J. Chem. Soc., Perkin 1 1997, 7, 785e788.
9. Wipf, P.; Ribe, S. Org. Lett. 2001, 3, 1503e1505.
10. Effenberger, F.; Steegmueller, D.; Null, V.; Ziegler, T. Chem. Ber. 1988, 121,
125e130.
as yellow powder. IR (KBr):
1433,1369,1307, 1165, 1009, 976, 823, 695 cmꢁ1. 1H NMR (500 MHz,
DMSO-d6):
n
¼3262, 2925, 2853, 1707, 1621, 1509,
d
¼0.55 (3H, d, J¼7.0 Hz), 0.62 (3H, d, J¼6.0 Hz), 0.79 (3H,
d, J¼6.5 Hz), 0.80 (3H, d, J¼6.5 Hz), 0.89 (6H, d, J¼6.5 Hz), 1.68e1.76
(2H, m), 1.96e2.04 (1H, m), 2.08e2.16(1H, m), 2.35e2.48(2H, m),
2.55(1H, dd, J¼6.5, 15.5 Hz), 2.63 (1H, d, J¼13.5 Hz), 2.86 (2H, d,
J¼7.0 Hz), 2.92 (1H, dd, J¼6.5, 15.5 Hz), 2.95 (1H, d, J¼16.5 Hz), 3.12
(1H, d, J¼16.5 Hz), 3.15 (1H, d, J¼13.5 Hz), 3.21 (1H, d, J¼13.5 Hz),
4.17 (1H, d, J¼9.5 Hz), 5.84 (1H, s), 5.85 (1H, s), 6.00 (1H, s), 10.49