Efficient one-pot trans-dihydroxylation of 2H-pyrans using dimethyldioxirane (DMD): synthesis of trans-3,4-dihydroxy-3,4-dihydro-O-methyloctandreolones, orixalone D, and trans-3,4-dihydroxy-3,4-dihydromollugin natural products

Article abstract of DOI:10.1016/j.tetlet.2007.07.022

An efficient one-pot formation of trans-diols on 2H-pyranyl rings was achieved by dimethyldioxirane in wet acetone. This new methodology was applied to the synthesis of natural products containing trans-diol on the pyranyl rings such as trans-3,4-dihydroxy-3,4-dihydro-O-methyloctandreolones, orixalone D, and trans-3,4-dihydroxy-3,4-dihydromollugin.

Full text of DOI:10.1016/j.tetlet.2007.07.022

Tetrahedron Letters 48 (2007) 6275–6280
Efficient one-pot trans-dihydroxylation of 2H-pyrans using
dimethyldioxirane (DMD): synthesis of trans-3,4-dihydroxy-
3,4-dihydro-O-methyloctandreolones, orixalone D,
and trans-3,4-dihydroxy-3,4-dihydromollugin natural products
Xue Wang and Yong Rok Lee*
School of Chemical Engineering and Technology, Yeungnam University, Gyeongsan 712-749, Republic of Korea
Received 19 June 2007; accepted 5 July 2007
Available online 30 July 2007
Abstract—An efficient one-pot formation of trans-diols on 2H-pyranyl rings was achieved by dimethyldioxirane in wet acetone. This
new methodology was applied to the synthesis of natural products containing trans-diol on the pyranyl rings such as trans-3,4-dihy-
droxy-3,4-dihydro-O-methyloctandreolones, orixalone D, and trans-3,4-dihydroxy-3,4-dihydromollugin.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
of a series of benzopyran-based potassium channel acti-
vators has generated considerable interest in the synthe-
sis of trans-diols on the 2H-pyranyl rings.3
Molecules with a cis-(1–7) or trans-dihydroxyl group (8–
14) on their 2H-pyranyl rings are distributed widely in
nature (Fig. 1).1 These compounds have a variety of
interesting biological activities and potential medical
applications.2 This range of important biological activi-
ties and properties has stimulated research into the syn-
thesis of molecules with cis- or trans-dihydroxy groups
on the 2H-pyranyl ring. In particular, the development
We recently reported that Yb(OTf)3 or ethylenediamine
diacetate-catalyzed reactions of 1,3-dicarbonyl com-
pounds or resorcinol with a,b-unsaturated aldehydes
provide a rapid route to 2H-pyrans or benzopyrans.4
These reactions involve the formal [3+3] cycloaddition
for constructing 2H-pyran rings. The synthesized
O
OH
O
O
OR4
O
O
OR3 OH
O
OH
O
N
O
OR2
O
OH
CO2Me
OH
OH
OR1
O
O
O
R5
12 R5=H orixalone D
13 R5=OMe zanthodioline
OH
OH
1 R1=H, R2= H (+)-cis-khellactone 8 R3=H
2 R1=H, R2=COCH(CH3)2
3 R1=COCH3, R2=COCH2CH3
4 R1=(z)-COC(CH3)CHCH3, R2=H
14
10 R4=H
11 R4=CH3
OH
9 R3=CH3
5 R1=COCH3, R2=COCH(CH3)2 seravshanin
6 R1=R2=COCH3 quianhucoumarin D
7 R1=COCH3, R2=COCH2CH(CH3)2 suksdorfin
Figure 1. Naturally occurring molecules with cis- and trans-diol on the pyranyl rings.
Keywords: trans-Dihydroxylation; Dimethyldioxirane; trans-3,4-Dihydroxy-3,4-dihydro-O-methyloctandreolones; Orixalone D; trans-3,4-Dihy-
droxy-3,4-dihydromollugin.
*
Corresponding author. Tel.: +82 53 810 2529; fax: +82 53 810 1496; e-mail: yrlee@yu.ac.kr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.022

6276
X. Wang, Y. R. Lee / Tetrahedron Letters 48 (2007) 6275–6280
2H-pyrans or benzopyrans appear ideal for making
natural products or biologically active materials with
cis- or trans-diols on the pyranyl rings. This Letter
reports an efficient and convenient one-pot synthesis of
trans-diols on the pyranyl rings using dimethyldioxirane.
As an application of this methodology, we report
the synthesis of biologically interesting natural products
as racemates, trans-3000,4000-dihydroxy-3000,4000-dihydro-O-
methyloctandreolone (9),5 trans-300,400-dihydroxy-300,400-
dihydro-O-methyloctandreolone orixalone D (11),6 and
trans-3,4-dihydroxy-3,4-dihydromollugin (14).7
2H-Pyrans 15 and 19–28 are easily prepared by the
ethylenediamine diacetate-catalyzed condensation of
the corresponding 1,3-dicarbonyl compounds with
3-methyl-2-butenal according to a synthetic method
reported by our group.4 The reaction of compound 15
was first investigated using several oxidants (Scheme
1). The epoxidation of compound 15 using mCPBA at
room temperature for 10 h in methylene chloride gave
the hydroxyester 16 in 78% yield as a 1:1 mixture of
cis and trans-isomers. Catalytic osmium tetroxide oxida-
tion using 2 equiv of NMO in t-BuOH/THF/H2O
(10:3:1) at room temperature for 24 h gave the cis-diol
17 in 72% yield.15 Interestingly, the treatment of com-
pound 15 with 2 equiv of DMD in wet acetone at room
temperature for 3 h provided the trans-diol 18 in 80%
yield without any of the cis-diol 17.16 The stereochemi-
cal assignment of cis and trans products was easily
defined by the observation of the coupling constants
between the vicinal protons, H3–H4. The J value for this
H3–H4 vicinal coupling in the cis-isomer 17 is 4.5 Hz,
whereas it is 7.7 Hz for the trans-isomer 18.17
2. Results and discussion
The dihydroxylation of alkenes represents a unique
synthetic method for generating 1,2-diols with a
defined relative configuration.8 A number of synthetic
approaches for cis- and trans-dihydroxylation have been
reported.9–13 The most common protocol of cis-dihydr-
oxylation is the use of OsO4, KMnO4, and RuO4,9
whereas that of trans-dihydroxylation is achieved by
the treatment with a suitable peroxycarboxylic acid in
a two-step reaction.10 The reactions first produce an
epoxide (oxirane), which then undergoes ring opening
through the anti-attack of the corresponding nucleo-
philes to give trans-diols. However, in many cases,
monoesters with a hydroxy group due to ring opening
of the corresponding carboxylic acid are normally pres-
ent in the reaction medium and are produced as a mix-
ture of cis and trans-isomers.10 The hydrolysis of this
monoester provides the 1,2-diols as a mixture of cis
and trans-isomers. In an attempt to prevent this, hydro-
gen peroxide and WO3, SeO2, V2O3, VO(acac)2, and
MeReO3 as catalysts have been used as new oxidants
to give the trans-diols.11 An example of this is the reac-
tion using MMPP/H2O2, which provides mainly trans-
diols as a 9:1 mixture.12 Furthermore, Sudalai also
developed a ‘transition-metal free’ procedure for trans-
dihydroxylation using PhI(OAc)2/LiBr in a two-step
reaction.13 Only one example of dihydroxylation of
hydroquinones using dimethyldioxirane is found in the
literature.14 However, in these reactions, 2,3-dihydroxy-
cyclohexene-1,4-diones were obtained as a mixture of
cis/trans-isomers along with quinones. In particular,
there does not appear to be any efficient and general
method for preparing trans-diols on the pyranyl rings
as a one-pot procedure using dimethyldioxirane.
In order to extend the utility of this methodology, fur-
ther reactions of a variety of compounds containing
2H-pyranyl rings were investigated. The results are
shown in Table 1. A reaction between compound 19
and DMD in wet acetone at room temperature for 3 h
gave compound 29 in 83% yield (entry 1). The treatment
of biologically active dehydro-a-lapachone (20), isolated
from Zeyhera tuberculosa,18 with DMD at room temper-
ature for 3 h afforded compound 30 in 78% yield (entry
2). Similarly, a reaction with compound 21 at room tem-
perature for 3 h gave product 31 in 63% yield (entry 3).
In the cases of biologically interesting pyranocoumarins
22–23 and pyranoquinolinones 24–27, the expected
products 32–37 were produced in 66–90% yields (entries
4-9). In the case of precocene I (28), product 38 was ob-
tained in 61% yield (entry 10). These reactions provide a
rapid route for the synthesis of trans-diols on the 2H-
pyranyl rings.
An attempt was made to synthesize the naturally occur-
ring materials, trans-3000,4000-dihydroxy-3000,4000-dihydro-O-
methyloctandreolone (9), trans-300,400-dihydroxy-300,400-
dihydro-O-methyloctandreolone (11), orixalone D (12),
and trans-3,4-dihydroxy-3,4-dihydromollugin (14) as
racemates using this methodology. trans-3000,4000-Dihy-
droxy-3000,4000-dihydro-O-methyloctandreolone (9) are
O
O
OAr
O
OH
O
OH
OH
m-CPBA
OsO4
NMO
CH2Cl2
78%
O
72%
O
16
15
17
DMD (2 eqiv)
Ar=m-chlorobenzoyl
acetone
(wet)
80%
OH
O
OH
O
18
Scheme 1.

X. Wang, Y. R. Lee / Tetrahedron Letters 48 (2007) 6275–6280
Table 1. Reactions of a variety of 2H-pyrans with DMD to give trans-diols
6277
Entrya
Starting material
Time (h)
Product
Yieldb (%)
O
O
OH
O
OH
1
3
83
78
O
29
19
O
O
O
OH
OH
2
3
4
5
3
3
3
3
O
20
O
30
O
OH
OH
O
O
63
90
71
O
31
O
O
O
21
OH
OH
O
O
O
O
O
O
32
22
OH
OH
O
O
O
O
O
O
33
23
OH
OH
O
O
6
2
66
N
H
O
24
N
H
O
34
OH
OH
O
N
O
N
7
2
81
O
O
35
25
OH
OH
O
N
O
N
8
2
72
O
O
36
26
OH
OH
O
N
O
N
9
2
76
O
O
37
27
(continued on next page)

6278
X. Wang, Y. R. Lee / Tetrahedron Letters 48 (2007) 6275–6280
Table 1 (continued)
Entrya
Starting material
Time (h)
Product
Yieldb (%)
OH
O
OH
10
3
61
MeO
O
28
MeO
38
a 2 equiv of DMD was used in wet acetone.
b Only trans-diols were isolated.
isolated primarily from the roots of Melicope erromang-
ensis.5 Orixalone D (12) is isolated from Orixa japonica
(Rutaceae), and is considered to be one of the constitu-
ents of the crude drug ‘Johzan’.6 The leaves of this plant
are used in Japan as an insecticide for livestock.19 In
China and other Asian countries, the root of this plant
has been used in traditional medicine as febrifuges and
analgesics.20 Orixalone D derivatives were also found
to inhibit the production of nitric oxide in murine
macrophage-like RAW 264.7 cells stimulated with
interferon-c and lipopolysaccharide.6 trans-3,4-Di-
hydroxy-3,4-dihydromollugin (14) was isolated from
Pentas longiflora, which is an important medicinal plant
in Tropical East Africa.7 In Kenya, it is known as
‘Nekilango’ or ‘Segimbe’, and the roots of this plant
are widely used as traditional medicines for treating
tapeworm, itchy rashes, and pimples.21 A decoction of
the roots is also used as a cure for malaria. In Rwanda,
this plant is known as ‘Isagara’, and the powder of the
roots is used as an ointment to cure scabies and the skin
disease, pityriasis versicolor.22
the synthetic materials 9 and 11 were clearly assigned
1
by a comparison with the reported H NMR data in
the literature for the natural products.5
Compound 42, which was used for the synthesis of the
orixalone D (12), was prepared using commercially
available compound 41 in 57% yield in a one-step reac-
tion using an earlier reported method (Scheme 3).4a The
treatment of compound 42 with 2 equiv of DMD in wet
acetone gave compound 12 in 77% yield. The spectro-
scopic data of the synthetic material 12 was same as
the data reported in the literature for the natural
product.6
The synthesis of the natural product 14 was accom-
plished from mollugin (45), which is also a natural prod-
uct. Mollugin (45) was synthesized in three-steps starting
from compound 43 using the known procedure (Scheme
4).24 The esterification of compound 43 with diazome-
thane followed by condensation with 2-methyl-3-
buten-2-ol in the presence of boron trifluoride diethyl
etherate gave compound 44 in 46% overall yield (two
steps). The oxidation of compound 44 with DDQ in
refluxing toluene afforded natural compound 45 in
56% yield. The treatment of compound 45 with 2 equiv
of DMD at room temperature for 3 h afforded com-
pound 14 in 62% yield. The spectral data of the synthetic
material 14 were identical with that described in the
literature.25
As shown in Scheme 2, compound 39, which was used
for the synthesis of the natural product 9, was prepared
using a known method.23 The condensation of 2,4,6-tri-
hydroxyacetophenone (39) with 3-chloro-3-methyl-1-
butyne in the presence of copper(I) iodide followed by
methylation of the phenol group with methyl iodide in
acetone gave 40 in 34% overall yield (two steps).23
A
reaction of compound 40 with 1.1 equiv of DMD in
wet acetone at room temperature for 3 h afforded com-
pound 9 in 53% yield, whereas that with 2 equiv of
DMD at room temperature gave compounds 9 and 11
in 52% and 27% yields, respectively. The structures of
In conclusion, a new and general procedure for the
synthesis of trans-diols on the 2H-pyranyl rings was
developed using DMD in wet acetone. This new method-
ology was applied to the synthesis of naturally occurring
Cl
O
O
OMe
O
O
OMe OH
O
i)
O
OH
OH
CuI
DMD
acetone
acetone
(wet)
O
ii) CH3I
HO
OH
K2CO3
9
39
acetone
40
+
OMe
34% (2-steps)
O
O
O
OH
11
OH
Scheme 2.

X. Wang, Y. R. Lee / Tetrahedron Letters 48 (2007) 6275–6280
6279
OH
OH
OH
N
O
O
N
O
N
H
DMD
acetone(wet)
77%
Yb(OTf)3
CH3CN
reflux 12 h
57%
O
O
O
41
42
12
Scheme 3.
OH
O
O
OH
O
O
OH
O
i) CH2N2
ether
DDQ
OMe
OMe
OH
toluene
reflux
OH
ii)
45
44
43
56%
OH
.
BF3 OEt2
dioxane
46%
acetone
wet
62%
O
DMD
OH
OMe
OH
14
O
OH
Scheme 4.
trans-3000,4000-dihydroxy-3000,4000-dihydro-O-methyloctand-
2005, 3026; (e) Lee, Y. R.; Lee, W. K.; Noh, S. K.; Lyoo,
W. S. Synthesis 2006, 853.
reolone (9), trans-300,400-dihydroxy-300,400-dihydro-O-
methyloctandreolone (11), orixalone D (12), and trans-
3,4-dihydroxy-3,4-dihydromollugin (14).
5. Muyard, F.; Bissoue, A. N.; Bevalot, F.; Tillequin, F.;
Cabalion, P.; Vaquette, J. Phytochemistry 1996, 42, 1175.
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T.; Kaneda, N.; Hisada, Y.; Okuda, K.; Furukawa, H. J.
Nat. Prod. 2004, 67, 1800.
Acknowledgment
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This research was supported by the Yeungnam Univer-
sity research Grants in 207-A-235-032.
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