First synthesis of (+)-rengyolone and (+)- and (-)-menisdaurilide

Article abstract of DOI:10.1016/S0957-4166(02)00119-2

The benzofuranone natural products (+)-rengyolone and (+)- and (-)-menisdaurilide have been synthesised for the first time from a common enantiopure cyclohexane building block derived from a monoketal of p-benzoquinone.

Full text of DOI:10.1016/S0957-4166(02)00119-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 455–459
First synthesis of (+)-rengyolone and (+)- and (−)-menisdaurilide
Mariona Canto´,a Pedro de March,a,* Marta Figueredo,a Josep Font,a Sonia Rodr´ıguez,a
b
b
´
Angel Alvarez-Larena and Juan F. Piniella
aDepartament de Qu´ımica, Universitat Auto`noma de Barcelona, E-08193 Bellaterra, Spain
bUnitat de Cristal·lografia, Universitat Auto`noma de Barcelona, E-08193 Bellaterra, Spain
Received 26 February 2002; accepted 6 March 2002
Abstract—The benzofuranone natural products (+)-rengyolone and (+)- and (−)-menisdaurilide have been synthesised for the first
time from a common enantiopure cyclohexane building block derived from a monoketal of p-benzoquinone. © 2002 Elsevier
Science Ltd. All rights reserved.
In 1984 the same benzofuran natural product 1
(Scheme 1) was independently isolated by two research
groups from different sources. Endo and Hikino1
named 1 rengyolone, because they isolated it from the
fruit of the plant Forsythia suspensa, known as ‘rengyo’
in oriental medicine and used for its antiinflamatory,
diuretic and antidotal properties. Simultaneously, Ital-
ian researchers2 isolated compound 1 from the leaves of
OH
O
HO
HO
3a
7a
OH
O
HO
HO
O
OH
H
OH
O
O
cornoside
O
_
+
( )-1
A
O
O
OH
NC
O
HO
HO
O
7a
OH
6
OH
OH
menisdaurin
(-)-2
HO
CO2Et
OH
O
O
HO
HO
O
O
O
OH
O
H
Ph
Ph
H
phyllanthurinolactone
3
Scheme 1.
* Corresponding author. Tel.: 34-935811258; fax: 34-935811265; e-mail: pere.demarch@uab.es
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00119-2

456
M. Canto´ et al. / Tetrahedron: Asymmetry 13 (2002) 455–459
Halleria lucida, a plant used for magical purposes and
in folk medicine in Southern Africa, and gave it the
name halleridone. Afterwards, rengyolone, the name
that first appeared in the literature and which will be
used in this paper, was also extracted from other
plants3 and three Japanese patents claim the anticancer
activity of 1 and derived esters.4
cyclohexane chiron 3, which we previously prepared
from an enantiopure p-benzoquinone monoketal.12
The first step in the transformation of 3 into (+)-1
(Scheme 2) was the reduction of the ester group with
lithium borohydride to deliver the diol 4 as a solid
([h]2D0=+14.2 (c 2.5, CHCl3)) in 94% yield. Treatment of
4 with mercuric trifluoroacetate followed by reduction
with sodium borohydride13 afforded a ca. 2:1 mixture
of two diastereoisomeric cyclic ethers 5 and 6 in 78%
yield. Repeated column chromatography allowed the
isolation of the less polar and major isomer 5 as a solid
In 1997, a Chinese group published the isolation of six
new compounds from Clerodendrum indicum, one which
had identical structure and relative stereochemistry to
rengyolone.5 The compound was named cleroindicin F
by these authors reporting a specific rotation of [h]2D0=
−2.7 (c 0.016, MeOH). The rengyolone samples previ-
ously isolated did not present a significant value of
optical activity and it is accepted that the natural
compound occurs as a racemate, consistent with a
biosynthetic pathway involving spontaneous closure of
the achiral quinol A formed by the enzymatic hydroly-
sis of the glucoside cornoside.3d,6 Moreover, since
rengyolone had only been synthesised in racemic
form,6,7 the actual specific rotation of the pure enan-
tiomers was unknown.
1
([h]2D0=+2.4 (c 1.7, CHCl3)) in 52% yield. Its H NMR
spectrum shows the two olefinic protons at l 6.05
(J=10.0 Hz) and l 5.91 (J=10.0 Hz, J%=1.5 Hz), while
that of the minor isomer displays two isocrone olefinic
protons at l 6.00. Both 5 and 6 were expected to
present a cis fused bicyclic skeleton, according to the
reported precedents in related ring closing reactions
leading to the formation of benzofurans.6,7 The
NOESY spectrum of 5 was not conclusive in determin-
ing its stereochemistry, but an X-ray crystallographic
analysis (Fig. 1)14 confirmed the cis stereochemistry of
the ring fusion and also revealed that the absolute
configuration of the generated stereocenters (3a and 7a)
is S.
Menisdaurilide, 2, is also a natural product with a
benzofuran skeleton, which was first reported in 1978
as a product of the acid hydrolysis of menisdaurin, a
nitrile glucoside isolated from Menispermum dauricum.8
Since 1984 lactone 2 has also been isolated from several
other plants.9 The absolute configuration of natural
(−)-menisdaurilide has been established as (6S,7aR) by
circular dichroism of its benzoate9c and X-ray diffrac-
tion analysis of its p-bromobenzoate.9d Menisdaurilide
is also the aglycon of phyllanthurinolactone, a bioactive
substance that folds together the leaves of the plant
Phyllanthus urinaria in the daytime, a phenomenon
called nyctinasty.10 To the best of our knowledge, there
is only one reported synthesis of 2 as the racemate.11
Herein we describe the successful synthesis of (+)-rengy-
olone and (+)- and (−)-menisdaurilide starting from the
Removal of the chiral auxiliary from 5 using montmo-
rillonite K-1015 yielded 45% of (+)-1 as a colorless oil,
whose NMR data match those reported for ( )-1.1,2,3c,7a
The e.e. of the synthesised (+)-rengyolone was 85%,
determined by CGC and NMR analysis assisted by the
perdeuterated Pirkle alcohol16 as chiral shift reagent,
and its specific rotation was [h]2D0=+48.6 (c 0.3 MeOH).
Since the value of the specific rotation determined for
our sample of (+)-1 with 85% e.e. is much higher than
that reported for cleroindicin F5 ([h]D20=−2.7) it is
clear that this compound should be identified as
racemic rengyolone.
HO
HO
CO2Et
a
HO
HO
OH
O
H
O
b
H
+
O
O
O
O
O
O
O
O
H
H
Ph
H
Ph
H
H
H
Ph
H
Ph
H
Ph
Ph
Ph
Ph
3
6
4
5
c
HO
O
H
O
(+)-1
Scheme 2. (a) LiBH4, THF, 0°C, 4 days, 94%; (b) Hg(OCOCF3)2, DME, rt, 2 h/NaBH4, 1.2 M NaOH, rt, 5 min, 78%; (c)
montmorillonite K-10, CH2Cl2, rt, 1 day, 45%.

M. Canto´ et al. / Tetrahedron: Asymmetry 13 (2002) 455–459
457
the g-lactone was achieved by intramolecular addition
of the carboxylic acid to the olefin promoted either by
trifluoroacetic acid or mercury trifluoroacetate.17 In
both cases, crystalline lactones 8 (IR 1774 cm−1) and 9
(IR 1785 cm−1) were exclusively produced (60 and 28 or
30 and 45% yields, respectively), both of them with a cis
ring fusion (vide infra). Lactone 8 could be isolated in
pure form ([h]2D0=+15.6 (c 1.0, CHCl3)), while 9 ([h]2D0=
+18.0 (c 1.0, CHCl3)) was contaminated with ca. 7% of
8, according to NMR analysis. The synthesis of menis-
daurilide was continued from each diastereoisomer
independently. Dehydration of the tertiary alcohol of 8
with thionyl chloride afforded 10 in 84% yield ([h]2D0=
1
−96.6 (c 4.7, CHCl3)). In the H NMR spectrum of 10,
the olefin protons H-3, H-4 and H-5 absorb at l 5.92,
6.31 and 6.74 as two double doublets and a doublet,
respectively, and the IR spectrum shows the character-
istic absorptions of a butenolide at 1785 and 1758 cm−1.
Removal of the acetal was again performed by treat-
ment of 10 with montmorillonite K-10. This reaction
furnished 49% yield of the benzofuranone 11 ([h]2D0=
−207.4 (c 1.2, acetone)), which spectroscopic data are
identical to those reported for racemic 11.11b Finally,
(+)-menisdaurilide ([h]2D0=+27.6 (c 0.6, MeOH)) was
Figure 1. Molecular structure of 5 (ellipsoids at the 50%
level).
The first step for the synthesis of 2 was the potassium
hydroxide-mediated saponification of 3 (Scheme 3),
providing acid 7 as a white solid (IR 1709 cm−1, [h]D20=
+14.8 (c 1.2, CHCl3)) in 84% yield. The formation of
O
O
HO
CO2Et
a
HO
COOH
HO
HO
O
H
O
H
b
+
O
O
O
O
O
O
O
O
H
H
Ph
H
Ph
H
H
Ph
H
H
Ph
H
Ph
Ph
Ph
Ph
9
8
3
7
O
O
O
O
O
O
3
HO
O
O
4
5
e
d
c
H
H
O
O
O
O
O
OH
H
Ph
H
Ph
Ph
H
Ph
H
(-)-11
(+)-2
8
10
O
O
O
O
O
HO
O
H
O
H
O
h
g
f
O
O
O
O
O
OH
H
Ph
H
Ph
Ph
H
Ph
H
(+)-11
(-)-2
9
12
Scheme 3. (a) KOH, H2O:EtOH, rt, 5 h, 84%; (b) CF3COOH, CHCl3, rt, 2 days, 60% of 8 and 28% of 9 or Hg(OCOCF3)2,
CH2Cl2, rt, 1 day, 30% of 8 and 45% of 9; (c) SOCl2, py, rt, 30 min, 84%; (d) montmorillonite K-10, CH2Cl2, reflux, 6 days, 49%;
(e) NaBH4, CeCl3·7H2O, EtOH, 0°C, 30 min, 74%; (f) SOCl2, py, rt, 15 min, 89%; (g) montmorillonite K-10, CH2Cl2, reflux, 1
day, 65%; (h) NaBH4, CeCl3·7H2O, EtOH, 0°C, 30 min, 63%.

458
M. Canto´ et al. / Tetrahedron: Asymmetry 13 (2002) 455–459
prepared in 74% yield by reduction of the ketone
function of (−)-11 using Luche’s reagent, as previously
described for the synthesis of ( )-2.11 In a similar way,
the levorotatory natural isomer of 2 was synthesised
from lactone 9. Dehydration of 9 afforded 12 as a solid
([h]2D0=+222.8 (c 4.3, CHCl3)) in 89% yield. Removal of
the chiral auxiliary provided a 65% yield of the solid
benzofuranone (+)-11 ([h]2D0=+165.6 (c 1.3, acetone)),
which was reduced by the same procedure described for
its enantiomer, affording a sample of crystalline (−)-2 in
63% yield ([h]2D0=−20.0 (c 0.4, MeOH)). The specific
rotation values previously reported for (−)-2 were −28.9
(c 0.13, MeOH)9b and −27.3 (c 0.31, MeOH).9d
(Takasago Perfumery Co.) JP 02,200,631, 1990 [Chem.
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Phytochemistry 1993, 32, 455–457.
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Matsuura, T.; Cahnmann, H. J. J. Am. Chem. Soc. 1975,
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The spectral data of both (+)-2 and (−)-2 matched
exactly those of ( )-2.9b–d,11b The enantiomeric purity of
our samples was determined by NMR analysis in the
presence of perdeuterated Pirkle alcohol16 as chiral shift
reagent. The measured e.e. of (+)-2 was >98% and that
of (−)-2 80%.
8. Takahashi, K.; Matsuzawa, S.; Takani, M. Chem. Pharm.
Bull. 1978, 26, 1677–1681.
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In conclusion, we have accomplished the first synthesis
of (+)-rengyolone, (+)- and (−)-menisdaurilide from the
common cyclohexane building block (+)-3 in 22, 15 and
14% overall yields, respectively. The specific rotation of
synthetic (+)-1 demonstrates that the isolated com-
pound named cleroindicin F is rengyolone. Enantiose-
lective syntheses of other natural products with the
benzofuran-2-one structure from chiral building blocks
derived from p-benzoquinone monoketals are now
being pursued.
10. Ueda, M.; Shigemori-Suzuki, T.; Yamamura, S. Tetra-
hedron Lett. 1995, 36, 6267–6270.
11. (a) Mori, K.; Audran, G.; Nakahara, Y.; Bando, M.;
Kido, M. Tetrahedron Lett. 1997, 38, 575–578; (b)
Audran, G.; Mori, K. Eur. J. Org. Chem. 1998, 57–62.
12. Busque´, F.; de March, P.; Font, J.; Rodr´ıguez, S. Tetra-
hedron: Asymmetry 2001, 12, 3077–3080.
13. Kocovsky´, P.; Pour, M. J. Org. Chem. 1990, 55, 5580–
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Acknowledgements
14. X-Ray single-crystal structure determination of 5 (crystal-
lized from ethyl acetate/hexane). Crystal dimensions:
0.65×0.65×0.50 mm, colorless prisms. Empirical formula
C22H22O4. Molecular weight 350.40. Crystal system:
orthorhombic. Space group P212121 (No. 19). Lattice
We thank the Universitat Auto`noma de Barcelona for
the award of predoctoral fellowships to S.R. and M.C.
This research was supported by the DGES (project
PB97-0215) and the CIRIT (projects 1997SGR 00003
and 1999SGR 00091).
parameters:
a=9.4207(13),
b=10.4392(16),
c=
3
,
,
19.1629(18) A, V=1884.6(4) A , Z=4. Calculated den-
sity 1.235 g cm−3. F(000)=744. v(Mo Ka)=0.084 mm−1
.
Data were collected at 293(2) K on an Enraf Nonius
CAD4 diffractometer using Mo Ka radiation (u=
,
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