Synthesis of (±)-kuwanon v and (±)-dorsterone methyl ethers via Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2011.02.023

The mulberry Diels-Alder adducts, the pentamethyl ethers of kuwanon V 1a and dorsterone 2a were synthesised via a biomimetic intermolecular [4+2] cycloaddition reaction between a highly electron-rich dienophile and a Lewis acid sensitive diene derived fro

Full text of DOI:10.1016/j.tetlet.2011.02.023

Tetrahedron Letters 52 (2011) 1797–1799
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of ( )-kuwanon V and ( )-dorsterone methyl ethers via Diels–Alder
reaction
Chin Fei Chee a, Yean Kee Lee a, Michael J. C. Buckle b, Noorsaadah Abd Rahman a,
⇑
a Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
b Department of Pharmacy, University of Malaya, 50603 Kuala Lumpur, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
The mulberry Diels–Alder adducts, the pentamethyl ethers of kuwanon V 1a and dorsterone 2a were syn-
thesised via a biomimetic intermolecular [4+2] cycloaddition reaction between a highly electron-rich die-
nophile and a Lewis acid sensitive diene derived from chalcone. Cycloaddition under thermal conditions
afforded 1a and 2a (in 3:2 ratio). Cycloaddition catalysed by AgOTf/Bu4NBH4 gave higher yields of the
adducts.
Received 22 November 2010
Revised 23 January 2011
Accepted 4 February 2011
Available online 24 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Diels–Alder, Kuwanon V
Dorsterone
Chalcone
Chalcones are important precursors for the biosynthesis of fla-
vonoid natural products and are often found to have a wide spec-
The syntheses of kuwanon V (1a) and dorsterone (2a) were car-
ried out via a [4+2] cycloaddition reaction between the diene 3 and
dienophile 4, as shown in Scheme 1.8 The synthesis of diene 3 was
accomplished in five steps (Scheme 2) from commercially available
trum of biological activity. For example, panduratin
A and
isopanduratin A (Fig. 1), isolated from Boesenbergia rotunda (L.)
and Boesenbergia pandurata, have been reported to show in vitro
anti-HIV protease activity1 and anti-cancer activity.2 In another
example, kuwanon V, isolated from Morus bombycis and Morus alba
L. (mulberry tree), has been reported to inhibit cyclic AMP phos-
phodiesterase and hypoxia-induced factor-1 accumulation
(Fig. 1).3
OH
HO
OH
O
O
Me
We have recently reported the syntheses of ( )-panduratin A
and ( )-isopanduratin A.4 Panduratin A showed competitive inhib-
itory activity towards dengue 2 virus NS2 protease with a Ki value
OH
O
MeO
Me
OH
OH
of 25 l
M.5 Further insight into the protein–ligand interaction
Me Me
Me
Me
study revealed that these cyclohexenyl chalcones are bound to
the catalytic triad of DEN2 NS2B/NS3 in the homology model.6 In
our efforts to carry out structure–activity relationship (SAR)
studies on the influence of the steric and lipophilicity effects of
the ligand on the protein, we came across kuwanon V and dorster-
one,7 which have larger substituents on the cyclohexyl ring than
panduratin A and isopanduratin A. However, there has been no
report, thus far, on the syntheses of these cyclohexenyl chalcones.
We report here a practical synthesis of ( )-kuwanon V and ( )-
dorsterone, via a biomimetic intermolecular [4+2] cycloaddition
reaction, for further biological testing.
HO
OH
panduratin A
Me Me
OH
1
HO
O
Me
Me
OH
O
O
HO
OH
OH
Me
Me
HO
OMe
OH
isopanduratin A
2
Figure 1. Naturally occurring prenylchalcones: panduratin A from Boesenbergia
rotunda (L.); isopanduratin A from Boesenbergia pandurata; kuwanon V (1) from
Morus alba L. and Morus bombycis; dorsterone (2) from Dorstenia barteri.
⇑
Corresponding author. Tel.: +60 3 79674643; fax: +60 3 79674193.
E-mail address: noorsaadah@um.edu.my (N.A. Rahman).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.023

1798
C. F. Chee et al. / Tetrahedron Letters 52 (2011) 1797–1799
OMe
OMe
OMe
3
α
1
2
MeO 4'
1''
3''
β
MeO
MeO
Me
7'M' e
2'
3
4
O
Me
O
O
OMe
O
3''
4''
OMe
[4+2]
OMe
OH
4''
5''
O
+
5''
8''
Me
Me
O
OH
OH
10''
Me25''
22''
Me
MeO18''
12''
21''
MeO
OMe
OMe Me24''
MeO
OMe Me
1a
2a
(endo)
(exo)
Scheme 1. Postulated biosynthesis of kuwanon V (1a) and dorsterone (2a) via a Diels–Alder reaction.
MeO
HO
HO
I
MeO
OMe
OMe
i
ii, iii
iv
v
Me
HO
Me
Me
3
I
Me
MeO
OH O
5
OH O
6
MeO
O
8
O
7
Scheme 2. Synthesis of diene 3. Reagents and conditions: (i) ICl, CH2Cl2, rt, 24 h, 40%; (ii) Me2SO4, K2CO3, acetone, rt, 8 h; (iii) 4-methoxybenzaldehyde, 50% aq KOH, EtOH,
24 h, 85% over two steps; (iv) 2-methylbut-3-en-2-ol, Pd(OAc)2, (o-tolyl)3P, Et3N, DMF, 90 °C, 18 h, 75%; (v) AcCl, pyridine, benzene, 60 °C, 8 h, 95%.
MeO
Me
OMe
MeO
OMe
MeO
MeO
OMe
iii
ii
i
4
O
O
OH O
10
O
Me
11
9
Scheme 3. Synthesis of dienophile 4. Reagents and conditions: (i) BCl3, CH2Cl2, 0 °C, 24 h, 70%; (ii) prenyl bromide, K2CO3, acetone, reflux, 8 h, 85%; (iii) Montmorillonite K10,
CH2Cl2, 0 °C, 2 h, 45%.
1-(2,4-dihydroxyphenyl)ethanone (5). First, the acetophenone 5
was iodinated with ICl/CH2Cl2 to give the C-3 iodinated acetophe-
none 6 in 40% yield. Methylation of aryl iodide 6 followed by Cla-
isen–Schmidt condensation with 4-methoxybenzaldehyde led to
the formation of chalcone 7 in 85% isolated yield. Subjecting chal-
cone 7 to Heck coupling [Pd(OAc)2, (o-tolyl)3-P, Et3N, DMF]9 with
2-methylbut-3-en-2-ol gave 8 in 75% yield which was easily dehy-
drated to afford diene 3 on treatment with acetyl chloride/
pyridine.10
NMR data with those reported for related natural products
00 00
(Fig. 2). The coupling constant J3 ,4 is of the order of 6.8 Hz (cis)
in endo 1a, while in exo 2a it is 10 Hz (trans). The coupling constant
00 00
J4 ,5 is ca. 10 Hz (trans) in both endo 1a and exo 2a. The configura-
tion of 1a was further confirmed by NOE and NOESY experi-
ments.13 In the NOESY experiment, correlations were observed
between H500 and H600b, and between H300, H400, and H600a. It was
observed from the NMR spectra that 2a undergoes epimerization
in solution to yield an equilibrium mixture of 1a and 2a.7 The
NMR signals of 2a were resolved by measurement in DMSO-d6 at
80 °C.13
The dienophile 4 was synthesised from chalcone 911 as shown
in Scheme 3. Selective demethylation of the 2-methoxy group of
9 followed by prenylation led to the formation of prenyl ether
11. The prenyl ether 11 then was subjected to a Montmorillonite
K10 promoted [1,3]-sigmatropic rearrangement to give the C-3
prenylated dienophile 4 in 45% yield.12
Table 1
Screening of the reaction conditions
The chalcones 3 and 4 were then subjected to the [4+2] cycload-
dition reaction (Scheme 1). Heating these two compounds in tolu-
ene in a pressure tube at 160 °C for 18 h afforded the endo and exo
adducts cis, trans-1a and trans, trans-2a, respectively, in a 3:2 ratio
and 55% yield. A longer reaction duration led to polymerisation due
to the sensitive diene terminal. The stereochemistries of endo 1a
and exo 2a were assigned based on comparison of the key proton
Entry Catalyst systema,b
Yieldc
(%)
endo:exod
1
ZnI2/Bu4NBH4/CoI2/1,10-phenanthroline (60/
48
63:37
10/10/10 mol %)
2
3
4
5
6
7
8
9
ZnI2/Bu4NBH4 (60/10 mol %)
AgOTf/Bu4NBH4 (60/10 mol %)
CoI/Bu4NBH4 (60/10 mol %)
CuOTf/Bu4NBH4 (60/10 mol %)
Cu(OTf)2 (100 mol %)
CuI (100 mol %)
CoCl2/PPh3(50/50 mol %)
CoCl2/PPh3/Zn (10/40/100 mol %)
45
65
—
—
—
—
—
—
58:42
60:40
a
Conditions: 0.1 mmol of 3 and 4 in 5 mL of CH2Cl2 in a pressure tube (25 mL),
60 °C, 18 h.
b
c
Formulations of mol % are based on the best result obtained from a model study.
Figure 2. 1H NMR chemical shifts (ppm) and coupling constants (Hz) of the
cyclohexene ring of 1a and 2a.
Isolated yield.
Based on 1H NMR spectroscopic integrations.
d

C. F. Chee et al. / Tetrahedron Letters 52 (2011) 1797–1799
1799
Further studies were undertaken to optimise the yield of the
Supplementary data
cycloaddition reaction. Based on the recent reports on the Diels–
Alder cycloadditon of 20-hydroxychalcone, the use of ZnI2/
Bu4NBH4/CoI2/1,10-phenanthroline (Porco’s catalyst) as a catalyst
for this reaction was evaluated.14 Initial studies revealed that a
mixture of ZnI2/Bu4NBH4/CoI2/1,10-phenanthroline in 60/10/10/
10 mol % ratio (Table 1, entry 1) produced a comparable yield of
cycloadducts as that obtained under thermal conditions. The use
of CoI2 and 1,10-phenanthroline had no significant effect on the
cycloaddition reaction (Table 1, entry 2): the yield of cycloadducts
was 45% compared to 48% using the ZnI2/Bu4NBH4/CoI2/1,10-phe-
nanthroline catalyst system (Table 1, entry 1). However, when CoI,
CoCl2, CuOTf or CuI were used as the catalyst, none of the desired
cycloadducts were obtained (Table 1, entries 4–9). Employing
AgOTf/Bu4NBH4 gave the best result, producing the desired cyc-
loadducts 1a and 2a in 65% yield (3:2 endo:exo ratio). However, at-
tempts to remove the methoxy ethers of 1a and 2a with BCl3 to
give kuwanon V (1) and dorsterone (2) resulted in decomposition.
In conclusion, we have reported the first successful synthesis of
the methyl ether derivatives 1a and 2a of kuwanon V (1) and
dorsterone (2), respectively, via a [4+2] Diels–Alder cycloaddition
reaction. Efforts towards the synthesis of other compounds in this
class are underway.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.02.023.
References and notes
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Acknowledgement
This work was supported by grants from the Ministry of Sci-
ence, Technology and Innovation (Science Fund) and the Ministry
of Higher Education under the Fundamental Research Grant
Scheme.