Total synthesis and biological activity of (±)-rocaglamide and its 2,3-di-epi analogue

Article abstract of DOI:10.1002/ejoc.200700905

By introducing the strategy of intramolecular reductive coupling to construct the cyclopenta[b]benzofuran skeleton, the shortest and most efficient synthetic method hitherto was now established to rocaglamide 1 and its 2,3-di-epi analogue 3 in racemic form by Michael addition, SmI ₂-promoted intramolecular keto-ester coupling, amination of the ester intermediate, and reduction of carbonyl with Me₄NBH(OAc) ₃. Several steps were highly stereoselective or even stereospecific. The bioassay results indicated that both 1 and 3 were much better repellents against Plutella xylostella than azadirachtin; the insecticidal activity of 1 was higher than that of azadirachtin against Pieris rapae, P. xylostella, Laphygma exigua, and Helicoverpa armigera, but that of 3 was lower. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700905

FULL PAPER
DOI: 10.1002/ejoc.200700905
Total Synthesis and Biological Activity of (؎)-Rocaglamide and Its 2,3-Di-epi
Analogue
Hongsen Li,[a] B. Fu,[a] M. A. Wang,[a] N. Li,[a] W. J. Liu,[a] Z. Q. Xie,[a] Y. Q. Ma,[a] and
Zhaohai Qin*[a]
Keywords: Rocaglamides / Michael addition / Reductive coupling / Total synthesis / Insecticidal activity
By introducing the strategy of intramolecular reductive coup-
ling to construct the cyclopenta[b]benzofuran skeleton, the
shortest and most efficient synthetic method hitherto was
now established to rocaglamide 1 and its 2,3-di-epi analogue
3 in racemic form by Michael addition, SmI2-promoted intra-
molecular keto–ester coupling, amination of the ester inter-
mediate, and reduction of carbonyl with Me4NBH(OAc)3.
Several steps were highly stereoselective or even stereospec-
ific. The bioassay results indicated that both 1 and 3 were
much better repellents against Plutella xylostella than azadi-
rachtin; the insecticidal activity of 1 was higher than that of
azadirachtin against Pieris rapae, P. xylostella, Laphygma ex-
igua, and Helicoverpa armigera, but that of 3 was lower.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
subsequent use in SmI2-promoted intramolecular cycliza-
tion strategy (Scheme 1).
In this paper we report the total synthesis of (Ϯ)-rocagl-
amide 1 and its 2,3-di-epi analogue 3, and their repellent
and insecticidal activities. The stereochemistry in the pro-
cess of synthesis is also discussed.
Rocaglamide 1, featuring a cyclopenta[b]benzofuran ring
system, was first isolated from Aglaia elliptofolia Merr. by
King[1] in 1982, and it showed high cytotoxicity towards a
group of human cancer cell lines, such as κB, p-388, A-549,
etc.[2] Moreover, it has attracted more attention in recent
years because of its insecticidal and growth inhibitory ac-
tivity.[3] Both the structural complexity of rocaglamide and
its significant activity make it an attractive synthetic target.
To date, several synthetic routes were developed for 1 and
its derivatives.[4] To the best of our knowledge, intramolecu-
lar cyclizations, which were established by Taylor and
Sy,[4a–4f] and photocycloaddition, which was achieved by
Porco,[4h–4j] might be more easily optimized for an agroch-
emical application than other methods, despite the fact that
those methods were also highly academically valuable in
terms of synthetic methodology. In the intramolecular cycli-
zation method, the establishment of the tricyclic core (the
synthesis of key intermediate 2) by intramolecular keto–cy-
ano reductive coupling or pinacol coupling followed by oxi-
dation was no doubt a creative strategy. In this method,
however, the carboxylation of 2 at the 2-position was un-
avoidable and troublesome. Although Dobler and his co-
workers[4e] considerably and elegantly improved this
method by using Stiles carboxylation, a shorter and more
convenient synthesis was still attractive to synthetic chem-
ists. Herein we focused on the introduction of a meth-
oxycarbonyl group in a Michael addition acceptor and its
Results and Discussion
We initiated our study with the Michael addition of 4
and 5a–5d under standard experimental condition. Michael
acceptor 5a–5d were facilely obtained from Knoevenagel
condensation of benzaldehyde and the corresponding car-
boxylate (3,3-dimethoxy propaneate, cyano acetate, and
malonate). Treatment of trans-5a with 4 in the presence of
Triton B (N,N,N-trimethylbenzylammonium hydroxide) at
40 °C afforded a surprising result in that expected product
6a was not achieved, whereas demethoxy product, both
trans-isomer 9 and cis-isomer 10 were obtained. Their struc-
1
tures were assigned by H NMR spectroscopic analysis.
The addition of methyl α-formylcinnaminate (5b) to 4
gave only the enol form of product 6b as a mixture of two
diastereoisomers, which was attributed to the stability
gained through the conjugated double bond and intramo-
lecular hydrogen bonding. Disappointedly, when the
Dolbler procedure was used to perform the pinacol coup-
ling for 6b, no desired product was afforded and almost
all crude material was recovered. Maybe the enol form was
unfavorable for the coupling reaction.
The addition of ethyl α-cyanocinnaminate (5c) to 4 af-
forded two diastereoisomers 6c-1(β isomer, cis-phenyl,
38.8% yield) and 6c-2(α isomer, trans-phenyl, 18.7% yield).
Quite surprisingly, intramolecular reductive coupling of 6c-
[a] College of Science, China Agricultural University,
100094 Beijing, China
Fax: +86-10-950507-710419
E-mail: qinzhaohai@263.net
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 1753–1758
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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H. S. Li, B. Fu, M. A. Wang, N. Li, W. J. Liu, Z. Q. Xie, Y. Q. Ma, Z. H. Qin
FULL PAPER
Scheme 1. Reagents and conditions: (i) Triton B, THF or tBuOH, N2, 40 °C; (ii) 1. SmC2H4I2, C6H6/THF, sonication, N2, room temp.;
2. Py·SO3/CH2Cl2 for R = CHO; (iii) LiNMe2, THF, –78 °C, N2; (iv) Me4NBH(OAc)3, HOAc/MeCN, N2, room temp.
and keto–cyano reductive couplings have been disclosed be-
fore,[5,6] this is the first report concerning the intramolecular
reductive coupling of α-cyano-δ-oxocarboxylates. This re-
sult also implied that intramolecular keto–ester coupling
was much easier than keto–cyano coupling. An attempt to
hydrolyze 11 into 1-oxorocagloic acid 12 failed, but decar-
boxylic product 2 was isolated.
Furthermore the Michael addition of methyl α-meth-
oxycarbonylcinnaminate (5d) to 4 also gave two diastereo-
isomers, 6d-1 (β isomer, cis-phenyl, 36.1% yield) and 6d-2
(α isomer, trans-phenyl, 16.5% yield). In the following keto–
ester coupling reaction, the stereoselectivity was very inter-
esting: whether it be 6d-1 and 6d-2, the hydroxy group at
C-8b always had a cis orientation with respect to the 3a-
phenyl group. The enol form of 7 (keto/enol, 0.7:1 accord-
1
ing to H NMR spectroscopy Ϫ this was also described by
Taylor and Sy[4b,4d]) led to the disappearance of the chiral
center at the 2-position; thus, this was a stereospecific reac-
tion. Actually, we only obtained 7a (3β isomer) from 6d-1
and 7b (3α isomer) from 6d-2.
With the key intermediate 7 in hand, the next work was
1 promoted by SmI2 did not give 7; spectral analysis indi- the amination of 7 according to Taylor’s method. 1H NMR
cated that keto–ester coupling had taken place, and com- analysis indicated that the product 8 only existed as a single
pound 11 was obtained. Despite the fact that keto–ester keto form.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1753–1758

(Ϯ)-Rocaglamide and Its 2,3-Di-epi Analogue
obtained from 8b. Their analytical data were identical to
the data in the literature.[4b,4d]
We evaluated the repellent and insecticidal activity of
both title compounds, and compared them with aza-dirach-
tin. As shown in Tables 1 and 2, both 1 and 3 demonstrated
good repellent activity against Plutella xylostella, but the
insecticidal activities were quite different. Under the con-
centration of 200 µgmL–1, the repellent ratio of 1 was
71.9% and that of 3 was 70.9%; at a concentration of
100 µgmL–1 the repellent ratios were 63.7 and 60.0%,
respectively. Apparently they are much higher than that of
azadirachtin (33.3 and 40.0%, respectively, under the same
concentrations). The insecticidal activity of 1 was higher
than that of azadirachtin, whereas that of 3 was lower. The
results implied the difference of configuration had little ef-
fect on repellent activity, but it was a very important factor
to insecticidal activity.
Table 1. Repellency of (Ϯ)-1 and (Ϯ)-3 against P. xylostella.
Compound
Concentration
Repellency
[%]
[µgmL–1]
(Ϯ)-1
200
100
200
100
200
100
71.9
63.7
70.9
60.0
33.3
40.0
(Ϯ)-3
Azadirachtin
Table 2. Insecticidal activities of (Ϯ)-1 and (Ϯ)-3 (% mortality).
Compound
Conc.
Pieris
rapae xylostella
Plutella Laphygma Helicoverpa
[µgmL–1
]
exigua
armigera
(Ϯ)-1
200
100
200
100
200
100
86.7
60.0
66.7
13.3
60.0
46.6
0
90.0
46.7
80.0
33.3
83.3
66.7
0
100
100
88.1
74.1
69.3
14.8
48.1
37.0
10.0
(Ϯ)-3
50.1
11.5
96.2
96.2
13.3
Azadirachtin
CK[a]
[a] Treated only with distilled water.
Fortunately in the conversion of enol form to keto form,
i.e. the formation of 2-position new chiral center was not
only stereospecific, but also as the desired configuration.
Thus we obtained 8a (2α, 3β) from 7a, and 8b (2β, 3α) from
7b.
Conclusions
The shortest and most efficient route to racemic rocagl-
amide and its 2,3-di-epi analogue has been described. In
our research, SmI2-promoted intramolecular keto–ester re-
ductive coupling, amination of the ester group, and re-
duction of the carbonyl functionality with Me4NBH-
(OAc)3 are highly stereoselective, and in some instances
even stereospecific. Apparently, if a highly diastereoselective
and enantioselective Michael addition method is estab-
lished, we will conveniently synthesize natural rocaglamides
by this method, as this is quite important to both rocagl-
Finally, the reduction of 8 by Me4NBH(OAc)3 was amides and their derivatives. Further studies are in progress
highly stereoselective to give target rocaglamides, because in our laboratory.
reduction could be accomplished only from the β face by
Our research also indicates that the configurations of ro-
templating the reducing agent with the neighboring hydroxy caglamides are significantly correlated to their insecticidal
group.[4k] Thus, (Ϯ)-rocaglamide 1 was generated from 8a, activities, but it seems to have little effect on repellency ac-
whereas the (Ϯ)-2,3-di-epi analogue of rocaglamide 3 was tivity.
Eur. J. Org. Chem. 2008, 1753–1758
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1755

H. S. Li, B. Fu, M. A. Wang, N. Li, W. J. Liu, Z. Q. Xie, Y. Q. Ma, Z. H. Qin
FULL PAPER
by a similar procedure to that used for 6a except THF was used to
afford 6b (1.20 g, 36.7%) as a white crystalline solid. M.p. 124–
Experimental Section
125 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.65 (s, 3 H,
Melting points were measured with a XT-4 melting point apparatus
and are uncorrected. NMR spectra were recorded with a Bruker
Avance DPX300 spectrometer with tetramethylsilane as the in-
ternal standard. Mass spectra were obtained with a VG-ZAB-HS
mass spectrometer. Solvents used were purified and dried by stan-
dard procedures. Compounds 4, 5c, and 5d were synthesized ac-
cording to literature procedures.[4c,7,8]
CH3O), 3.70 (s, 3 H, CH3O), 3.76 (s, 3 H, CH3O), 3.86 (s, 3 H,
4
CH3O), 4.99 (s, 1 H, 3-H), 5.81 (d, JH,H = 1.8 Hz, 1 H, C6H1),
4
3
6.20 (d, JH,H = 1.8 Hz, 1 H, C6H1), 6.83 (d, JH,H = 9.0 Hz, 2 H,
C6H2), 7.05–7.15 (m, 3 H, C6H3), 7.29–7.34 (m, 2 H, C6H2), 7.45
3
3
(d, JH,H = 9.0 Hz, 2 H, C6H2), 7.81 (d, JH,H = 12.6 Hz, 1 H,
CH=), 11.80 (d, 3JH,H = 12.6 Hz, 1 H, OH, disappeared after D2O
exchange) ppm.
Methyl α-Dimethoxymethyl Cinnamate (5a) and Methyl α-Formyl
Cinnamate (5b):[9,10] To a solution of methyl 3,3-dimethoxypropi-
onate (3.05 g, 20.6 mmol) and benzaldehyde (2.24 g, 21 mmol) in
dry THF (20 mL) was added NaH (70% in mineral oil, 0.8 g,
23 mmol) in portions, and the mixture was stirred for 5 h at room
temperature. H2O (20 mL) was then slowly added, and the aqueous
phase was extracted with diethyl ether (3ϫ30 mL). The combined
organic phase was washed with brine (2ϫ10 mL), dried with anhy-
drous Na2SO4, and concentrated under reduced pressure. The
crude product was purified by silica-gel column chromatography
(petroleum ether/EtOAc, 9:1) to give two isomers of 5a. trans Iso-
mer: pale-yellow oil. Yield: 0.91 g, 19.3%. 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 3.39 (s, 6 H, CH3O), 3.84 (s, 3 H, CH3O), 5.14
(s, 1 H, 1Ј-H), 7.37–7.55 (m, 5 H, C6H5), 7.80 (s, 1 H, 3-H) ppm. cis
Isomer: pale-yellow oil. Yield: 1.02 g, 21.6%. 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 3.41 (s, 6 H, CH3O), 3.84 (s, 3 H, CH3O), 5.22
(s, 1 H, 1Ј-H), 7.13–7.35 (m, 6 H, C6H5, 3-H) ppm.
Ethyl 2-Cyano-3-[4,6-dimethoxy-2-(4-methoxyphenyl)-3-oxo-2,3-di-
hydrobenzofuran-2-yl]-3-phenylpropionate (6c): Prepared from 5c by
a similar procedure to that used for 6a except THF was used to
afford 6c-1 (1.27 g, 38.8%) and 6c-2 (0.61 g, 18.7%) as white solids.
Data for 6c-1: M.p. 193–194 °C. 1H NMR (300 MHz, CDCl3,
3
3
25 °C): δ = 0.98 (t, JH,H = 7.2 Hz, 3 H, CH3), 3.69 (d, JH,H
=
4.5 Hz, 1 H, 3-H), 3.70 (s, 3 H, CH3O), 3.81 (s, 3 H, CH3O), 3.88
(s, 3 H, CH3O), 3.95 (q, 3JH,H = 7.2 Hz, 2 H, CH2O), 4.30 (d, 3JH,H
4
= 4.5 Hz, 1 H, 2-H), 5.83 (d, JH,H = 1.8 Hz, 1 H, C6H1), 6.38 (d,
3
4JH,H = 1.8 Hz, 1 H, C6H1), 6.95 (d, JH,H = 9.0 Hz, 2 H, C6H2),
7.16–7.18 (m, 3 H, C6H3), 7.55–7.57 (m, 2 H, C6H2), 7.82 (d, 3JH,H
= 9.0 Hz, 2 H, C6H2) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ
= 194.0, 174.5, 170.1, 164.9, 160.1, 159.0, 132.8, 130.2, 128.4, 127.4,
126.4, 116.0, 114.5, 103.4, 93.4, 92.4, 88.7, 62.8, 56.1, 55.9, 55.3,
52.1, 39.5 ppm. Data for 6c-2: M.p. 254–255 °C. 1H NMR
3
(300 MHz, CDCl3, 25 °C): δ = 1.09 (t, JH,H = 7.2 Hz, 3 H, CH3),
The mixture of trans-5a (0.50 g, 2.11 mmol) and sulfuric acid (15%,
5 mL) was stirred at 80 °C for 5 h and then cooled. The reaction
mixture was extracted with diethyl ether (3ϫ30 mL), and the com-
bined organic phase was washed to neutral pH with brine and dried
with anhydrous Na2SO4. The crude product was purified by silica-
gel column chromatography (petroleum ether/EtOAc, 9:1) to give
trans-5b. Pale-yellow oil. Yield: 0.26 g, 65.0%. 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 3.84 (s, 3 H, CH3O), 7.14 (s, 1 H, 3-H), 7.30–
7.53 (m, 5 H, C6H5), 9.61 (s, 1 H, CHO) ppm.
3
3.66 (s, 3 H, CH3O), 3.88 (s, 3 H, CH3O), 3.90 (d, JH,H = 3.7 Hz,
3
1 H, 3-H), 3.94 (s, 3 H, CH3O), 4.06 (q, JH,H = 7.2 Hz, 2 H,
CH2O), 4.34 (d, 1 H, 3JH,H = 3.7 Hz, 2-H), 6.05 (d, 4JH,H = 1.8 Hz,
4
3
1 H, C6H1), 6.50 (d, JH,H = 1.8 Hz, 1 H, C6H1), 6.65 (d, JH,H
=
=
3
9.0 Hz, 2 H, C6H2), 7.16–7.19 (m, 3 H, C6H3), 7.37 (d, JH,H
9.0 Hz, 2 H, C6H2), 7.42–7.46 (m, 2 H, C6H2) ppm.
Methyl 2-Methoxycarbonyl-3-[4,6-dimethoxy-2-(4-methoxyphenyl)-
3-oxo-2,3-dihydrobenzofuran-2-yl]-3-phenylpropionate (6d): Pre-
pared from 5d by a similar procedure to that used for 6a except
THF was used to afford 6d-1 (1.25 g, 36.1%) and 6d-2 (0.57 g,
16.5%) as white crystalline solids. Data for 6d-1: M.p. 173–174 °C.
1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.17 (s, 3 H, CH3O), 3.27
(s, 3 H, CH3O), 3.65 (s, 3 H, CH3O), 3.77 (s, 3 H, CH3O), 3.86 (s,
Methyl 2-Methoxymethylen-3-[4,6-dimethoxy-2-(4-methoxyphenyl)-
3-oxo-2,3-dihydrobenzofuran-2-yl]-3-phenylpropionate (6a): Under a
N2 atmosphere, to a solution of 4 (2.0 g, 6.67 mmol) in tert-butyl
alcohol (100 mL) was added a solution of Triton B (40% in
CH3OH, 0.23 mL) and a solution of trans-5a (1.91 g, 8.10 mmol)
in tert-butyl alcohol (40 mL) by syringe. After stirring at 60 °C for
3 h, the solvent was removed in vacuo. To the residue was added a
solution of HCl (1 , 25 mL), and this solution was extracted with
CH2Cl2 (3ϫ40 mL). The combined organic phase was washed with
brine (2ϫ20 mL), dried with Na2SO4, and concentrated. The crude
product was separated by silica-gel column chromatography (petro-
leum ether/EtOAc, 1:1) to afford 9 (0.63 g, 18.5%) and 10 (0.44 g,
13.2%). Compound 9: white solid, m.p. 167–168 °C. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 3.60 (s, 3 H, CH3O), 3.73 (s, 3 H,
CH3O), 3.74 (s, 3 H, CH3O), 3.75 (s, 3 H, CH3O), 3.82 (s, 3 H,
3
3
3 H, CH3O), 4.33 (d, JH,H = 10.8 Hz, 1 H, 3-H), 4.53 (d, JH,H
=
4
10.8 Hz, 1 H, 2-H), 5.78 (d, JH,H = 1.8 Hz, 1 H, C6H1), 6.27(d,
4JH,H = 1.8 Hz, 1 H, C6H1), 6.82–6.85 (m, 2 H, C6H2), 7.05–7.13
(m, 3 H, C6H3), 7.31–7.34 (m, 2 H, C6H2), 7.69–7.76 (m, 2 H,
C6H2) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 194.4, 174.1,
169.6, 167.7, 167.6, 159.7, 159.2, 135.5, 130.0, 127.8, 127.6, 127.4,
127.0, 113.4, 103.8, 92.9, 92.4, 88.5, 55.9, 55.8, 55.3, 54.2, 52.3,
52.2, 51.5 ppm. MS (EI): m/z (%) = 520 (3.3) [M]+, 300 (25.0), 299
(100), 191 (3.3), 163 (3.3), 135 (13.0), 121 (3.0). HRMS: calcd. for
C29H28O9 [M]+ 520.1739; found 520.1739. Data for 6d-2: M.p. 169–
170 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.29 (s, 3 H,
CH3O), 3.54 (s, 3 H, CH3O), 3.67 (s, 3 H, CH3O), 3.84 (s, 3 H,
4
CH3O), 5.27 (s, 1 H, 3-H), 5.80 (d, JH,H = 1.8 Hz, 1 H, C6H1),
4
3
6.21 (d, JH,H = 1.8 Hz, 1 H, C6H1), 6.77 (d, JH,H = 9.0 Hz, 2 H,
C6H2), 7.04–7.12 (m, 3 H, C6H2, C6H1), 7.16 (s, 1 H, CH=), 7.33–
3
CH3O), 3.88 (s, 3 H, CH3O), 4.21 (d, JH,H = 9.3 Hz, 1 H, 3-H),
3
3
4
7.38 (m, 2 H, C6H2), 7.47 (d, JH,H = 9.0 Hz, 2 H, C6H2) ppm.
4.47 (d, JH,H = 9.3 Hz, 1 H, 2-H), 5.97 (d, JH,H = 1.8 Hz, 1 H,
Compound 10: white solid, m.p. 182–184 °C. 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 3.59 (s, 3 H, CH3O), 3.71 (s, 3 H, CH3O), 3.75
(s, 3 H, CH3O), 3.77 (s, 3 H, CH3O), 3.85 (s, 3 H, CH3O), 5.20 (s,
4
C6H1), 6.27 (d, 1 H, JH,H = 1.8 Hz, C6H1), 6.63–6.67 (m, 2 H,
C6H2), 7.04–7.11 (m, 3 H, C6H3), 7.17–7.21 (m, 2 H, C6H2), 7.36–
7.42 (m, 2 H, C6H2) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ
= 194.6, 174.0, 169.8, 167.8, 167.6, 159.2, 159.1, 136.2, 130.2, 128.4,
127.4, 127.0, 126.9, 113.2, 104.3, 93.2, 92.7, 88.8, 55.9, 55.1, 53.4,
52.5, 52.1, 52.0 ppm. MS (EI): m/z (%) = 520 (3.3) [M]+, 300 (33.3),
299 (100), 271 (3.3), 241 (2.0), 192 (4.0), 163 (4.0), 135 (13.3), 121
4
4
1 H, 3-H), 5.80 (d, JH,H = 1.8 Hz, 1 H, C6H1), 6.20 (d, JH,H
=
1.8 Hz, 1 H, C6H1), 6.83 (d, 3JH,H = 9.0 Hz, 2 H, C6H2), 7.04–7.13
3
(m, 4 H, C6H3, CH=), 7.34–7.36 (m, 2 H, C6H2), 7.47 (d, JH,H
9.0 Hz, 2 H, C6H2) ppm.
=
Methyl 2-Formyl-3-[4,6-dimethoxy-2-(4-methoxyphenyl)-3-oxo-2,3- (3.3), 106 (3.0), 77 (2.0). HRMS: calcd. for C29H28O9 [M]+
dihydrobenzofuran-2-yl]-3-phenylpropionate (6b): Prepared from 5b 520.1739; found 520.1739.
1756
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Eur. J. Org. Chem. 2008, 1753–1758

(Ϯ)-Rocaglamide and Its 2,3-Di-epi Analogue
8b-Hydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-1-oxo-3-phenyl-
2,3,3a,8a-tetrahydrocyclopenta[b]benzofuran-2-nitrile (11): To the
reactant of metal Sm (1.50 g, 10 mmol) in a flame-dried, 100-mL,
three-necked round-bottom flask equipped with a stir bar, septum,
and nitrogen inlet was added a solution of C2H4I2 (1.41 g,
5.0 mmol) in THF (7 mL). After stirring for 1 h, the solution
changed to blue, and the reaction was continued for 3 h under ul-
trasound irradiation. Anhydrous benzene (20 mL) was then added,
and the reaction was continued for an additional 2 h. A solution
of 6c-1 (1.30 g, 2.6 mmol) in benzene (100 mL) was added, and the
reaction was allowed to proceed for 10 h under ultrasound irradia-
tion. The reaction was quenched with the addition of HCl (1 ,
20 mL), and the solution was extracted with CH2Cl2 (2ϫ30 mL).
The combined organic phase was washed with brine (2ϫ20 mL),
dried with anhydrous Na2SO4, and concentrated. The crude prod-
uct was purified by silica-gel column chromatography (petroleum
ether/EtOAc, 2:3) to afford 11 (0.28 g, 23.6%) as a white crystalline
to this solution was added NHMe2 (1.07 g, 23.8 mmol) and n-bu-
tyllithium (1.2 mL, 3 mmol)by syringe. After stirring for 20 min, a
solution of 7a (0.15 g, 0.31 mmol) in THF (6 mL) was added by
syringe, and the reaction was continued at –78 °C for 30 min. The
cold bath was then removed, and the reaction mixture was allowed
to stir at room temperature for an additional 1 h. The reaction was
quenched by the addition of CH3OH (2 mL), and aqueous HCl
(1 , 15 mL) was then added dropwise slowly. The mixture was
extracted with CH2Cl2 (4 ϫ 15 mL), and the combined organic
phase was washed with brine (3ϫ10 mL), dried with Na2SO4, and
concentrated. The crude product was purified by silica-gel column
chromatography (petroleum ether/EtOAc, 2:3) to afford 8a (0.13 g,
84.4%) as a white crystalline solid. M.p. 143–144 °C. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 2.90 (s, 3 H, CH3N), 3.01 (br. s, 1
H, 8b-OH), 3.25 (s, 3 H, CH3N), 3.73 (s, 3 H, CH3O), 3.80 (s, 3
3
H, CH3O), 3.84 (s, 3 H, CH3O), 4.33 (d, JH,H = 13.2 Hz, 1 H, 3-
3
4
H), 4.51 (d, JH,H = 13.2 Hz, 1 H, 2-H), 6.08(d, JH,H = 1.8 Hz, 1
1
4
solid. M.p. 190–191 °C. H NMR (300 MHz, [D6]DMSO, 25 °C):
H, C6H1), 6.32 (d, JH,H = 1.8 Hz, 1 H, C6H1), 6.70–6.73 (m, 2 H,
δ = 3.60 (s, 3 H, CH3O), 3.74 (s, 3 H, CH3O), 3.77 (s, 3 H, CH3O),
C6H2), 6.82–6.85 (m, 2 H, C6H2), 6.98–7.01 (m, 2 H, C6H2), 7.07–
4
4.50 (s, 1 H, 3-H), 5.64 (d, JH,H = 1.8 Hz, 1 H, C6H1), 5.88 (s, 1 7.09 (m, 3 H, C6H3) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ
4
H, 8b-OH, disappeared after D2O exchange), 6.06 (d, JH,H
=
= 205.7, 165.3, 164.8, 161.1, 158.9, 158.5, 136.2, 128.0, 127.9, 126.9,
3
1.8 Hz, 1 H, C6H1), 6.73–6.76 (m, 2 H, C6H2), 6.93–6.96 (d, JH,H 126.1, 113.2, 106.2, 99.3, 93.0, 89.9, 88.6, 55.6, 55.1, 53.9, 52.0,
3
= 9.0 Hz, 2 H, C6H2), 7.12–7.15 (m, 3 H, C6H3), 7.36 (d, JH,H
=
37.7, 36.2 ppm. MS (EI): m/z (%) = 485 (25.3) [M]+, 458 (2), 414
9.0 Hz, 2 H, C6H2), 11.33 (s, 1 H, 1-OH, disappeared after D2O
exchange) ppm.
(8), 300 (100), 285 (19.3), 176 (3.3), 131 (7.3), 103 (3.3), 72 (5.0).
Following the same procedure, 8b (0.13 g, 81.8%) was prepared
from 7b (0.15 g, 0.31 mmol). M.p. 209–210 °C. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 2.96 (s, 6 H, Me2N), 3.47 (s, 1 H,
8b-OH), 3.77 (s, 3 H, CH3O), 3.78 (s, 3 H, CH3O), 3.80 (m, 3 H,
Methyl 8b-Hydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-1-oxo-3-
phenyl-2,3,3a,8a-tetrahydrocyclopenta[b]benzofuran-2-carboxylate
(7): Prepared from 6d-1 by a similar procedure to that used for 11
to afford 7a (0.68 g, 53.7%) as a white crystalline solid. M.p. 163–
164 °C (keto form) (ref.[4d] 87.5–89.5 °C as keto/enol, 65:35). 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 3.04 (s, 1 H, 8b-OH, disap-
peared after D2O exchange), 3.66 (s, 3 H, CH3O), 3.71 (s, 3 H,
3
3
CH3O), 4.54 (d, JH,H = 13.2 Hz, 1 H, 3-H), 4.75 (d, JH,H
=
4
13.2 Hz, 1 H, 2-H), 6.03 (d, JH,H = 1.8 Hz, 1 H, C6H1), 6.16 (d,
4JH,H = 1.8 Hz, 1 H, C6H1), 6.87 (d, JH,H = 9.0 Hz, 2 H, C6H2),
3
7.03–7.06 (m, 2 H, C6H2), 7.17–7.20 (m, 3 H, C6H3), 7.37 (d, 3JH,H
= 9.0 Hz, 2 H, C6H2) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ
= 204.8, 166.3, 164.5, 162.0, 159.2, 158.1, 135.2, 128.9, 128.8, 128.2,
128.0, 127.3, 113.3, 104.8, 97.5, 92.5, 88.6, 87.0, 55.7, 55.6, 55.2,
54.0, 52.3, 37.0, 35.9 ppm. MS (EI): m/z (%) = 485 (3.3) [M]+, 300
(100), 285 (20.0), 242 (2.3), 176 (5.3), 131 (12.0), 103 (8.0), 72
(12.0), 44 (6.0).
3
CH3O), 3.81 (s, 3 H, CH3O), 3.85 (s, 3 H, CH3O), 4.06 (d, JH,H
= 13.2 Hz, 1 H, 3-H), 4.24 (d, 3JH,H = 13.2 Hz, 1 H, 2-H), 6.10 (d,
4
4JH,H = 1.8 Hz, 1 H, C6H1), 6.35 (d, JH,H = 1.8 Hz, 1 H, C6H1),
6.66–6.70 (m, 2 H, C6H2), 6.89–6.97 (m, 4 H, C6H4), 7.08–7.12 (m,
3 H, C6H3) ppm. 13C NMR (75 MHz, CDCl3 + D2O, 25 °C): δ =
203.3, 167.2, 164.9, 161.0, 158.9, 158.6, 135.4, 129.1, 128.0, 127.9,
127.7, 127.1, 125.4, 113.2, 112.2, 106.1, 99.3, 92.9, 89.9, 88.5, 56.4,
55.7, 55.6, 55.1, 55.0, 52.9, 52.0, 51.5 ppm. MS (EI): m/z (%) = 472
(6.0), 414 (4.6), 300 (100), 285 (26.6), 269 (3.0), 242 (3.0), 135
(10.0), 104 (3.0), 77 (3.0), 44 (7.3).
1,8b-Dihydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-N,N-dimeth-
yl-3-phenyl-2,3,3a,8b-tetrahydrocyclopenta[b]benzofuran-2(1H)-
carboxamide (؎)-1 and (؎)-3: Under a N2 atmosphere, a mixture of
Me4NBH(OAc)3 (0.45 g, 1.71 mmol), CH3CN (1 mL), and HOAc
(1 mL) was stirred at room temperature for 0.5 h, and then a solu-
tion of 8a (0.12 g, 0.24 mmol) in CH3CN (2.5 mL) was added by
syringe. The reaction mixture was stirred at room temperature for
an additional 24 h. The reaction was quenched with a saturated
solution of NaHCO3 (50 mL), and the solution was then extracted
with CH2Cl2 (4ϫ5 mL). The combined organic phase was washed
with brine, dried with Na2SO4, and concentrated. The crude prod-
uct was purified by silica-gel column chromatography (petroleum
ether/EtOAc, 1:4) to afford (Ϯ)-1 (0.105 g, 87.2%) as a white crys-
talline solid. M.p. 120–122 °C (ref.[4d] 119–120 °C). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 2.94 (s, 3 H, CH3N), 3.31 (s, 3 H,
CH3N), 3.70 (s, 3 H, CH3O), 3.83 (s, 3 H, CH3O), 3.85 (s, 3 H,
Following the same procedure, 7b (0.64 g, 50.2%) was obtained
1
from 6d-2. M.p. 95–96 °C. H NMR (300 MHz, CDCl3, 25 °C): δ
= 3.52 (br. s, 1 H, 8b-OH), 3.62 (d, 3JH,H = 6.3 Hz, 1 H, 3-H), 3.70
(s, 3 H, CH3O), 3.75 (s, 3 H, CH3O), 3.78 (s, 3 H, CH3O), 3.80 (s,
3
4
3 H, CH3O), 4.40 (d, JH,H = 6.3 Hz, 1 H, 2-H), 6.01 (d, JH,H
=
4
2.1 Hz, 1 H, C6H1), 6.14 (d, JH,H = 2.1 Hz, 1 H, C6H1), 6.89 (d,
3JH,H = 8.5 Hz, 2 H, C6H2), 7.03–7.06 (m, 2 H, C6H2), 7.19–7.23
(m, 3 H, C6H3), 7.34 (d, JH,H = 8.5 Hz, 2 H, C6H2) ppm. 13C
3
NMR (75 MHz, CDCl3, 25 °C): δ = 203.2, 168.3, 164.7, 163.8,
161.9, 159.4, 159.3, 158.2, 134.0, 130.4, 128.9, 128.7, 128.3, 128.2,
128.1, 127.7, 127.6, 127.4, 127.3, 126.6, 113.5, 113.4, 104.1, 97.2,
92.5, 92.3, 88.4, 88.2, 88.1, 86.8, 55.7, 55.2, 54.8, 54.3, 52.6 ppm.
MS (EI): m/z (%) = 472 (13.3), 458 (2.0), 414 (12.7), 399 (2.0), 300
(100), 285 (27.3), 269 (4.0), 242 (3.0), 181 (2.0), 135 (10.0), 121
(3.0), 103 (4.0), 77 (4.0).
3
3
CH3O), 4.05 (dd, JH,H = 13.5 Hz, JH,H = 6.5 Hz, 1 H, 2-H), 4.55
3
3
(d, JH,H = 13.5 Hz, 1 H, 3-H), 4.93 (d, JH,H = 6.5 Hz, 1 H, 1-H),
4
4
6.10 (d, JH,H = 1.8 Hz, 1 H, C6H1), 6.27 (d, JH,H = 1.8 Hz, 1 H,
C6H1), 6.65–6.70 (m, 2 H, C6H2), 6.84–6.87 (m, 2 H, C6H2), 7.01–
7.13 (m, 5 H, C6H5) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ
= 169.6, 163.9, 161.1, 158.6, 157.3, 137.6, 128.9, 127.8, 127.7, 127.1,
126.3, 112.7, 107.6, 101.7, 94.1, 92.5, 89.3, 78.6, 56.0,55.7, 55.1,
47.6, 37.0, 35.8 ppm. MS (EI): m/z (%) = 505 (12.0) [M]+, 487
(10.0), 442 (5.3), 416 (19.3), 390 (60.7), 368 (4.7), 325 (4.0), 313
8b-Hydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-1-
oxo-3-phenyl-2,3,3a,8a-tetrahydrocyclopenta[b]benzofuran-2-carbox-
amide (8): THF (8 mL) in a flame-dried, 50-mL, three-neck, round-
bottomed flask equipped with a stir bar, thermometer, septum, and
nitrogen inlet was cooled to –78 °C in a dry ice/acetone bath, and
Eur. J. Org. Chem. 2008, 1753–1758
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1757

H. S. Li, B. Fu, M. A. Wang, N. Li, W. J. Liu, Z. Q. Xie, Y. Q. Ma, Z. H. Qin
FULL PAPER
(61.3), 285 (22.0), 269 (6.0), 243 (7.3), 223 (4.7), 205 (26.7), 181
(41.3), 176 (100), 148 (5.3), 131 (16.7), 116 (18.0), 91 (3.7), 72
(27.3), 46 (6.7). HRMS: calcd. for C29H29NO7 [M]+ 505.2101;
found 505.2104.
Acknowledgments
We would like to thank the National Natural Science Foundation
of China for financial support (No. 20772151). We are most grate-
ful to Professor Rui Changhui (Institute of Plant Protection, Chi-
nese Academy of Agriculture Science) for his kind assistance with
the bioassay study.
Following the same procedure, (Ϯ)-3 (0.10 g, 83.3%) was prepared
1
from 8b. M.p. 108–109 °C. H NMR (300 MHz, CDCl3, 25 °C): δ
3
= 2.85 (s, 3 H, CH3N), 2.99 (s, 3 H, CH3N), 3.58 (dd, JH,H
=
3
10.0 Hz, JH,H = 12.2 Hz, 1 H, 2-H), 3.78 (s, 3 H, CH3O), 3.82 (s,
3 H, CH3O), 3.83 (s, 3 H, CH3O), 4.24 (d, JH,H = 12.2 Hz, 1 H,
3-H), 4.81 (d, JH,H = 10.0 Hz, 1 H, 1-H), 6.10 (d, JH,H = 2.0 Hz,
1 H, C6H1), 6.20 (d, JH,H = 2.0 Hz, 1 H, C6H1), 6.84–6.89 (m, 2
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3
4
4
[2] a) P. Porksch, M. Giaisi, M. K. Treiber, K. Palfi, A. Merling,
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H, C6H2), 6.99–7.02 (m, 2 H, C6H2), 7.13–7.17 (m, 3 H, C6H3),
7.37–7.42 (m, 2 H, C6H2) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 171.4, 163.7, 161.9, 159.2, 157.9, 135.8, 129.3, 129.2,
128.3, 127.8, 126.9, 113.4, 105.7, 99.9, 92.4, 91.7, 88.6, 84.7, 55.7,
55.6, 55.2, 54.8, 47.3, 37.4, 36.0 ppm. MS (EI): m/z (%) = 505
(10.0), 487 (9.3), 469 (2.0), 442 (4.0), 415 (6.7), 390 (95.3), 313
(100), 285 (23.3), 271 (2.7), 243 (10.0), 222 (2.7), 205 (20.0), 181
(46.0), 176 (74.0), 148 (7.3), 135 (18.7), 116 (47.3), 91 (5.0), 72
(30.0), 46 (12.0). HRMS: calcd. for C29H29NO7 [M]+ 505.2101;
found 505.2105.
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Bioassay: Compounds 1, 3, and azadirachtin were dissolved in
chloroform (1% M/V), respectively, and then diluted with water
containing 0.02% emulsifier and 0.05% Triton X-100 to the tested
concentrations.
Insect Repellency: The leaf of Brassica chinensis Linn. was washed,
dried by airing, and cut as a Ø70 mm round disc, which was then
divided into two halves. One half of the disc was daubed with
0.2 mL tested agent prepared above on both sides. The other half
of the disc was a control, which was only daubed with water con-
taining emulsifier and Triton X-100. After being dried by airing,
the discs were put in a Ø85 mm culture dish and 10 third instar
larvae of Plutella xylostella (Linnaeus) were put on the half leaf
disc containing insecticide, covered with cling film, and kept at
(27Ϯ1) °C for 24 h. Experiments were replicated three times at ev-
ery concentration. The contents of worm at each treated or control
diet was counted and the repellency (%) was calculated by the fol-
lowing formula:
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Repellency (%) = (C – E)/Tϫ100%
where C is the insect numbers in the negative control half of the
leaf disc, E is the insect numbers in the treated half of disc, and T
is the number of total insects. C, E, and T were the mean data of
the three replicates.
Insecticidal Activity: The third instar larvae of Pieris rapae Lin-
naeus, Brassica napus Linn., and second instar larvae of Laphygma
exigua (Hubner) were treated with Potter’s method under 200 and
100 µgmL–1.
The leaf of Brassica chinensis Linn. was cut to Ø15 mm round discs.
These leaf discs were immersed in sample solution for 10 s, dried by
airing, and then put in a testing box with ten holes, which in every
hole a piece of leaf disc was needed. The third instar larva of Helico-
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Supporting Information (see footnote on the first page of this arti-
Received: September 22, 2007
cle): Spectral data for the synthesized compounds.
Published Online: February 20, 2008
1758
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1753–1758