A concise synthetic approach to β,γ-dehydrocurvularin: Synthesis of (±)-di-O-methyl-β,γ-dehydrocurvularin

Article abstract of DOI:10.1271/bbb.70094

A concise synthesis of di-O-methyl-β,γ-dehydrocurvularin, the di-O-methylated derivative of the naturally occurring nematicidal macrolide, β,γ-dehydrocurvuralin, was accomplished by starting from a commercially available aromatic carboxylic acid in a thre

Full text of DOI:10.1271/bbb.70094

Biosci. Biotechnol. Biochem., 71 (6), 1592–1594, 2007
Note
A Concise Synthetic Approach to ꢀ,ꢁ-Dehydrocurvularin:
Synthesis of (Æ)-Di-O-Methyl-ꢀ,ꢁ-dehydrocurvularin
y
Takuho MIYAGI and Shigefumi KUWAHARA
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science,
Tohoku University, Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
Received February 16, 2007; Accepted February 28, 2007; Online Publication, June 7, 2007
[doi:10.1271/bbb.70094]
A concise synthesis of di-O-methyl-ꢀ,ꢁ-dehydrocur-
vularin, the di-O-methylated derivative of the naturally
occurring nematicidal macrolide, ꢀ,ꢁ-dehydrocurvura-
lin, was accomplished by starting from a commercially
available aromatic carboxylic acid in a three-step se-
quence consisting of esterification, Friedel-Crafts acy-
lation, and microwave-promoted ring-closing metathe-
sis.
O
O
O
O
RO
HO
γ
α
β
OR
O
OH
O
1: R = H
2: R = Me
3
Fig. 1. ꢀ,ꢁ-Dehydrocurvularin (1) and Related Compounds.
Key words: curvuralin; nematicide; macrolide; ring-
closing metathesis; microwave-promoted
reaction
O
O
HO
CO2H
ꢀ,ꢁ-Dehydrocurvularin (1), which belongs to the
curvularin family of polyketides represented by curuvu-
larin (3), has recently been isolated from the culture
broth of a species of Aspergillus collected in Tottori,
Japan, and its structure was determined by spectroscopic
methods (Fig. 1).1) The octaketidic macrolide exhibited
considerable nematicidal activity against the root-lesion
nematode, Pratylenchus penetrans, without any inhib-
itory effects on the growth of lettuce seedlings, and is
therefore expected to be a promising lead for practical
nematicides. This agriculturally intriguing biological
activity as well as the substantially unstable ꢀ,ꢁ-unsat-
urated ketone structural unit incorporated in 1 stimulated
our interest in its total synthesis.2,3) In this note, we
describe part of our synthetic efforts toward 1, which
successfully resulted in a short-step synthesis of its di-O-
methylated derivative [(ꢀ)-2] possessing the same
carbon framework as that of 1.
Commercially available aromatic carboxylic acid 4
and 5-hexen-2-ol were condensed under conventional
conditions (DCC/DMAP/toluene) to give ester 5 in a
76% yield (Scheme 1). The Friedel-Crafts acylation of
5 with 3-butenoyl chloride in the presence of MeAlCl2
as a Lewis acid catalyst proceeded regioselectively to
afford desired C2-acylation product 6 in a 60% yield;
fortunately, this unstable ꢀ,ꢁ-unsaturated ketone (6)
survived the acidic reaction conditions, and no detect-
able degree of double-bond migration to generate the
MeO
MeO
DCC
DMAP
76%
OMe
OMe
5
4
O
O
Cl
O
MeO
Grubbs-II
( )-2
α
MeAlCl2
60%
µW
4
2
β
γ
61%
OMe O
6: β,γ-double bond
7: α,β-double bond
Scheme 1. Synthesis of Di-O-Methyl-ꢀ,ꢁ-dehydrocurvularin.
more stable conjugated enone(s) (7) took place. The next
ring-closing metathesis step was first attempted by using
the first-generation Grubbs catalyst.4–6) Despite exten-
sive examination of various reaction conditions [amount
of the catalyst (5–50 mol %), solvent (CH2Cl2 or tol-
uene), concentration (5 mM–150 mM), reaction temper-
ature (room temperature to reflux), and reaction time
(up to 1 week)], no desired product [(ꢀ)-2] could be ob-
tained, resulting in the recovery of the starting material
(6), generation of 7, or the formation of a complex
mixture. Similar attempts with the second-generation
Grubbs catalyst (Grubbs-II) were also unsuccessful in
y
To whom correspondence should be addressed. Fax: +81-22-717-8783; E-mail: skuwahar@biochem.tohoku.ac.jp

Synthesis of Di-O-Methyl-ꢀ,ꢁ-dehydrocurvularin
1593
most cases, but we noticed that a small amount of (ꢀ)-2
was produced together with 7 (main product) when the
reaction mixture was refluxed in toluene for 4 hours in
the presence of 20 mol % of the Grubbs-II catalyst.
Encouraged by this result, we next tried the application
of microwave irradiation which has recently been shown
to dramatically promote a variety of reactions including
cross-metathesis and has been successfully applied to
the syntheses of many natural products.7,8) To our
delight, microwave irradiation of the mixture of 6 and
the Grubbs-II catalyst (35 mol %) in toluene at 90 ꢁC
greatly facilitated the intramolecular metathesis reac-
tion, furnishing a 61% yield of the desired product (ꢀ)-2
in only 15 min. Furthermore the newly formed double
bond of the cyclization product was installed exclusively
99.2, 107.3, 115.0, 136.4, 137.8, 160.9, 171.1; HRMS
m=z (Mþ): calcd. for C16H22O4, 278.1518; found,
278.1519.
1-Methyl-4-pentenyl [2-(3-butenoyl)-3,5-dimethoxy-
phenyl)]acetate (6). To a stirred solution of 5 (300 mg,
1.08 mmol) in CH2Cl2 (100 ml) were successively added
3-butenoyl chloride (345 mg, 3.30 mmol) and MeAlCl2
(1.0 M in hexane, 4.3 ml, 4.3 mmol) at 0 ꢁC under a
nitrogen atmosphere. After being stirred for 1 h at 0 ꢁC,
the mixture was quenched with water and extracted with
CH2Cl2. The extract was successively washed with
water and brine, dried (MgSO4), and concentrated in
vacuo. The residue was chromatographed over SiO2
(hexane/EtOAc, 5:1) to give 6 (228 mg, 60%) as a
colorless oil. IR ꢂmax cmꢂ1: 3080 (w), 1732 (s), 1685
1
1
in the E-form, as assigned from the H-NMR coupling
(m), 1640 (w), 1604 (s), 1318 (s), 1156 (s); H-NMR
constant (15.3 Hz) between the two olefinic protons.
In conclusion, an efficient synthesis of di-O-methyl-
ꢀ,ꢁ-dehydrocurvularin [(ꢀ)-2)] was achieved by starting
from commercially available carboxylic acid 4 in only
three steps. Unfortunately, removal of the methyl pro-
tecting groups of the two phenolic hydroxyls with
several Lewis acids to deliver naturally occurring 1 was
not successful. Synthetic efforts toward 1 are now under-
way by using other protecting groups and (S)-5-hexen-2-
ol, and the results will be reported in due course.
(300 MHz) ꢃ: 1.22 (3H, d, J ¼ 6:3 Hz), 1.52–1.62 (1H,
m), 1.62–1.74 (1H, m), 2.00–2.11 (2H, m), 3.630 (2H,
dt, J ¼ 6:9, 1.6 Hz), 3.631 (2H, s), 3.82 (3H, s), 3.83
(3H, s), 4.84–4.96 (1H, m), 4.95 (1H, dm, J ¼ 10:3 Hz),
5.00 (1H, dq, J ¼ 17:2, 1.6 Hz), 5.13 (1H, dq, J ¼ 17:2,
1.6 Hz), 5.14 (1H, dm, J ¼ 10:3 Hz), 5.78 (1H, ddt, J ¼
17:2, 10.3, 6.6 Hz), 6.00 (1H, ddt, J ¼ 17:2, 10.3, 6.9
Hz), 6.38 (1H, d, J ¼ 2:3 Hz), 6.40 (1H, d, J ¼ 2:3 Hz);
13C-NMR (75 MHz) ꢃ: 19.8, 29.5, 34.9, 39.1, 49.0, 55.3,
55.5, 71.0, 97.4, 107.9, 115.0, 118.0, 119.1, 131.8,
135.2, 137.9, 159.1, 161.7, 171.1, 204.3; HRMS m=z
(Mþ): calcd. for C20H26O5, 346.1780; found, 346.1784.
Di-O-Methyl-ꢀ,ꢁ-dehydrocurvularin [(ꢀ)-2]. A test
tube containing a solution of 6 (50.0 mg, 0.144 mmol)
and the 2nd-generation Grubbs catalyst (43 mg, 51
mmol) in toluene (5 ml) under a nitrogen atmosphere was
capped with a septum, and inserted into the cavity of
Discover Microwave System apparatus (from CEM).
The mixture was irradiated at 150 W for 15 min (90 ꢁC
internal temperature, controlled and monitored with the
standard infrared temperature control system for the
Discover System) before being cooled to room temper-
ature and concentrated in vacuo. The residue was
chromatographed over SiO2 (hexane/EtOAc, 10:1) to
give (ꢀ)-2 (28.0 mg, 61%) as a colorless oil. IR
Experimental
IR spectra were recorded as films by a Jasco FT/IR-
4100 spectrometer. NMR spectra were recorded with
TMS as an internal standard in CDCl3 by a Varian
Gemini 2000 spectrometer (300 MHz for 1H and 75
MHz for 13C) or by a Varian Unity plus-600 spectrom-
eter (600 MHz for 1H and 150 MHz for 13C). Mass
spectra were obtained with a Jeol JMS-700 spectrometer
operated in the EI mode. Silica gel 60N (Kanto Kagaku;
spherical neutral, 100–210 mm particle size) was used
for column chromatography.
1-Methyl-4-pentenyl
(3,5-dimethoxyphenyl)acetate
(5). To a stirred solution of 5-hexen-2-ol (300 mg, 3.00
mmol) in toluene (40 ml) were successively added 1,3-
dicyclohexylcarbodiimide (1.24 g, 6.01 mmol), 4-(dime-
thylamino)pyridine (147 mg, 1.20 mmol) and 3,5-dime-
thoxybenzoic acid (1.18 g, 6.48 mmol) at room temper-
ature under a nitrogen atmosphere. After being stirred
for 1 h, the mixture was filtered through a pad of Celite.
The filter cake was washed with a mixture of hexane and
ether (2:1), and the combined filtrate was concentrated
in vacuo. The residue was chromatographed over SiO2
(hexane/EtOAc, 20:1) to give 5 (635 mg, 76%) as a
colorless oil. IR ꢂmax cmꢂ1: 3075 (w), 1731 (s), 1597 (s),
1205 (m), 1156 (s); 1H-NMR (300 MHz) ꢃ: 1.22 (3H, d,
J ¼ 6:3 Hz), 1.52–1.64 (1H, m), 1.65–1.76 (1H, m),
1.94–2.12 (2H, m), 3.53 (2H, s), 3.78 (6H, s), 4.87–4.97
(1H, m), 4.94 (1H, dm, J ¼ 10:2 Hz), 4.96 (1H, dq, J ¼
16:8, 1.6 Hz), 5.76 (1H, ddt, J ¼ 16:8, 10.2, 6.9 Hz),
6.37 (1H, t, J ¼ 2:3 Hz), 6.45 (2H, d, J ¼ 2:3 Hz); 13C-
NMR (75 MHz) ꢃ: 19.8, 29.5, 35.0, 42.0, 55.2, 71.0,
ꢂ
max cmꢂ1: 1729 (vs), 1690 (s), 1605 (vs), 1313 (s),
1
1203 (s), 1157 (s); H-NMR (600 MHz) ꢃ: 1.17 (3H, d,
J ¼ 5:9 Hz) 1.55–1.62 (1H, m), 1.62–1.69 (1H, m),
1.97–2.05 (1H, m), 2.22–2.30 (1H, m), 3.20–3.48 (2H,
br m), 3.54 (1H, br d, J ¼ 15:7 Hz), 3.59 (1H, br d, J ¼
15:7 Hz), 3.80 (3H, s), 3.83 (3H, s), 5.02–5.10 (1H, m),
5.24 (1H, dt, J ¼ 15:3, 7.3 Hz), 5.44–5.56 (1H, m), 6.39
(1H, d, J ¼ 2:3 Hz), 6.47 (1H, d, J ¼ 2:3 Hz); 13C-NMR
(150 MHz) ꢃ: 21.0, 30.5, 33.7, 37.9, 48.9, 55.4, 55.6,
72.4, 97.5, 108.0, 120.0 (two overlapping peaks), 133.9,
137.2, 157.5, 161.1, 170.8, 204.8; HRMS m=z (Mþ):
calcd. for C18H22O5, 318.1467; found, 318.1472.
Acknowledgment
This work was financially supported, in part, by grant-
aid for scientific research (B) from the Ministry of

1594
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