First synthesis of naturally occurring (±)-epi-conocarpan

Article abstract of DOI:10.1016/S0040-4039(02)02860-5

(±)-epi-Conocarpan 1 was synthesized via the key intermediate 5-bromo-cis-2-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzofuran 6 which was synthesized by a ruthenium(II) porphyrin-catalyzed intramolecular C-H insertion reaction using aryl tosylhydrazone salt 5 as the carbene source, starting from the commercially available 5-bromo-2-hydroxyacetophenone.

Full text of DOI:10.1016/S0040-4039(02)02860-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1445–1447
First synthesis of naturally occurring ( )-epi-conocarpan
Shi-Long Zheng,a,* Wing-Yiu Yu,b Ming-Xia Xua and Chi-Ming Cheb,*
aWest China School of Pharmacy, Sichuan University, Chengdu 610041, PR China
bDepartment of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong
Received 22 October 2002; revised 5 December 2002; accepted 13 December 2002
Abstract—( )-epi-Conocarpan 1 was synthesized via the key intermediate 5-bromo-cis-2-(4-methoxyphenyl)-3-methyl-2,3-dihy-
drobenzofuran 6 which was synthesized by a ruthenium(II) porphyrin-catalyzed intramolecular C–H insertion reaction using aryl
tosylhydrazone salt 5 as the carbene source, starting from the commercially available 5-bromo-2-hydroxyacetophenone. © 2003
Elsevier Science Ltd. All rights reserved.
Piperaceae species are pioneer shrubs with economic
and medicinal importance. (−)-epi-Conocarpan was iso-
lated from the roots of Piper regnellii (Piperaceae).1
epi-Conocarpan 1 is the epimer of conocarpan 2,2
epi-conocarpan and epi-conocarpan have the 3-methyl-
2,3-dihydrobenzofuran skeleton, the basic structure of a
sub-class of neolignan natural products which possess a
wide variety of antibacterial, cytotoxic, antiprolifera-
tive, immunosuppressive, antioxidant, antiangiogenic
and insecticidal activities.3 Conocarpan is toxic to the
larvae of the European corn borer at 10 mg/mL.4 How-
ever, due to the limited amounts of (−)-epi-conocarpan,
its biological activity has not yet been established. Here
we report the first synthesis of ( )-epi-conocarpan 1.
imidoruthenium porphyrins are known to effect alkane
hydroxylations and amidations via CꢀH bond activa-
tion.7 However, our earlier studies revealed that the
reaction of [RuII(TTP)(CO)] (H2TTP=meso-tetrakis(p-
tolyl) porphyrin) with g-alkoxy-a-diazo-b-ketoesters
afforded ruthenium–carbene porphyrin complexes,
which then underwent subsequent intramolecular
cyclization to furnish 1,3-dioxolanes exclusively.8 For-
tunately, we recently found the first ruthenium por-
phyrin-catalyzed intramolecular carbenoid C–H
insertion to afford selectively cis-2,3-disubstituted-2,3-
dihydrobenzofurans using aryl tosylhydrazone salts as
the carbene sources.
The reaction conditions of the ruthenium(II) por-
phyrin-catalyzed intramolecular C–H insertion reac-
tions using aryl tosylhydrazone salt 5 as carbene source
to provide 5-bromo-cis-2-(4-methoxyphenyl)-3-methyl-
2,3-dihydrobenzofuran 6 was investigated. As shown in
Table 1, when the [RuII(TTP)(CO)]-catalyzed C–H
insertion reaction of 5 was performed in refluxing tolu-
ene, the reaction was finished in only 2 h affording 6 in
82% yield, albeit with slightly compromised cis-selectiv-
ity (entry 3). Phase transfer catalysts (PTC) n-Bu4N+
Br− and BnEt3N+Cl− gave similar ratios under identical
conditions (entries 1 and 2). Contrary to expectation,
Rh2(OAc)4 was a less effective catalyst giving low yields
and stereoselectivity (entry 5). In the absence of a
Although there are several approaches available for the
formation of the 3-methyl-2,3-dihydrobenzofuran skele-
ton,5 all methods yield only the trans-3-methyl-2,3-
dihydrobenzofurans as the major product. So, the
synthesis of the intermediate cis-2,3-dihydrobenzofuran
derivative 6 is the key step (see Scheme 1). Intra- and
intermolecular metal carbene C–H insertion has
emerged as a general strategy for the formation of
carbocycles and heterocycles.6 High-valent oxo- and
1
catalyst, no product was found according to H NMR
analysis of the reaction mixture (entry 4).
The benzylation of 5-bromo-2-hydroxyacetophenone
with p-methoxybenzyl chloride afforded 5-bromo-2-(4-
methoxy benzyloxy)acetophenone 39 under microwave
irradiation in only a few minutes, which was then
Keywords:
( )-epi-conocarpan;
cis-2,3-dihydrobenzofuran;
intramolecular C–H insertion; ruthenium(II) porphyrin.
* Corresponding authors. Tel.: 86-28-85501382; fax: 86-28-85437960;
e-mail: zshilong1@163.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02860-5

1446
S.-L. Zheng et al. / Tetrahedron Letters 44 (2003) 1445–1447
Scheme 1. Reagents and conditions: (a) p-methoxybenzyl chloride, K2CO3, microwave irradiation, 99%; (b) TsNHNH2, ethanol,
reflux, 86%; (c) sodium, methanol; (d) Bn(Et)3N+Cl−, [RuII(TTP)(CO)], toluene, 60–70°C, 48 h, 77% (two steps including c and
d); (e) n-BuLi, THF, 0.5 h; then DMF, −78–25°C, 1.5 h, 48%; (f) n-BuLi, THF, (Ph)3P+EtBr−, 79%; (g) PdCl2·2CH3CN, CH2Cl2,
93%; (h) n-BuLi, (Ph)2PH, THF, 85%.
Table 1. Ru- or Rh-catalyzed intramolecular C–H insertion reaction to form 6 using aryl tosylhydrazone salt 5 as carbene
source
Entry
Catalyst
PTC
Temp. (°C)
Time (h)
Yield (%)
cis:transa
1
2
3
4
5
[RuII(TTP)(CO)]
[RuII(TTP)(CO)]
[RuII(TTP)(CO)]
None
n-Bu4N+Br−
BnEt3N+Cl−
n-Bu4N+Br−
n-Bu4N+Br−
n-Bu4N+Br−
60–70
60–70
110b
60–70
60–70
48
48
2
48
48
77
75
82
0
\98
\98
84:16
–
[Rh2(OAc)4]
29
76:24
a The ratio of cis to trans was determined by 1H NMR.
b The reaction was performed in refluxing toluene.
treated with p-toluenesulfonohydrazide to afford 2-(4-
methoxybenzyloxy)-5-bromo-acetophenone tosylhydra-
zone 49 in 86% yield. The compound 4 was transformed
to the salt 5 with sodium methoxide, which was formed
in situ by the reaction of sodium with methanol. 5-
Bromo-cis-2-(4-methoxyphenyl)-3-methyl-2,3-dihydro-
benzofuran 69 was formed by [RuII(TTP)(CO)]-cata-
lyzed intramolecular C–H insertion using the salt 5 as
carbene source with high stereoselectivity (>98%, cis).
The replacement10 of the bromine substituent in 6 with
an aldehyde group using n-butyllithium as the metalla-
tion reagent and DMF as the formyl source afforded 2-
(4 - methoxyphenyl) - 3 - methyl - cis - 2,3 - dihydrobenzo-
furan-5-carbaldehyde 7.9 The Wittig reaction11 of com-
pound 7 with ethyltriphenylphosphonium bromide
using potassium carbonate in moist dioxane led to the
formation of an oily mixture of stereoisomers of 2-(4-
methoxyphenyl)-3-methyl-5-(1-propenyl)-cis-2,3-dihydro-
benzofuran. The isomerization reaction11b of the stereo-
isomers using bis-(acetonitrile)dichloropalladium(II) in
dichloromethane produced the (E)-isomer 8.9
Demethylation5b of 8 with LiPPh2 in anhydrous tetra-
hydrofuran gave an 85% yield of ( )-epi-conocarpan 1
as a crystalline solid with identical spectral data to
those of the natural product.1
In conclusion, a total synthesis of ( )-epi-conocarpan
was achieved in eight steps with a 20% overall yield
from 5-bromo-2-hydroxyacetophenone. Ruthenium(II)
porphyrin-catalyzed intramolecular C–H insertion
using aryl tosylhydrazone salt 5 as the carbene source
provided a general route to the key intermediate 5-
bromo-cis-2-(4-methoxyphenyl)-3-methyl-2,3-dihydro-
benzofuran 6 with high stereoselectivity (>98% cis) for
the synthesis of 1. It is our belief that this strategy will
be versatile and practical for the synthesis of a variety
of other natural products with cis-2,3-dihydrobenzo-
furan skeleton.

S.-L. Zheng et al. / Tetrahedron Letters 44 (2003) 1445–1447
1447
References
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128.0, 114.2, 114.0, 113.1, 70.6, 55.5, 21.7, 16.7. IR (KBr,
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