Benzo[f][1,2]oxasilepines in the synthesis of dihydro[b]benzofuran neolignans

Article abstract of DOI:10.1055/s-2005-921913

A short synthesis of neolignans with a dihydrobenzo[b]furan skeleton is described. The strategy is based on a ring-closing metathesis to produce benzo[f][1,2]oxasilepines which are condensed with aromatic aldehydes in a modified Sakurai-Hosomi reaction. Natural dihydrodehydrodiconiferyl alcohol (1) and 3-O-demethyldihydrodehydrodiconiferyl alcohol (2) have been prepared in this way. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-921913

LETTER
3011
Benzo[f][1,2]oxasilepines in the Synthesis of Dihydro[b]benzofuran
Neolignans
B
enzo[
f
]
[1,2]o
e
xasilepine
s
r
in the
S
y
nthesis of
D
i
ihydro
o
[
b
]benzofuranNeo
G
lignans arcía-Muñoz, Leticia Jiménez-González, Míriam Álvarez-Corral, Manuel Muñoz-Dorado,
Ignacio Rodríguez-García*
Química Orgánica, Universidad de Almería, 04120 Almería, Spain
E-mail: irodrigu@ual.es
Received 6 October 2005
ed benzaldehydes with protected benzo[f][1,2]oxa-
silepines, the latter being prepared through ring-closing
metathesis (RCM). We now report an application to
prepare both cis and trans dihydrodehydrodiconiferyl
Abstract: A short synthesis of neolignans with a dihydroben-
zo[b]furan skeleton is described. The strategy is based on a ring-
closing metathesis to produce benzo[f][1,2]oxasilepines which are
condensed with aromatic aldehydes in a modified Sakurai–Hosomi
reaction. Natural dihydrodehydrodiconiferyl alcohol (1) and 3-O- alcohols (1) as well as their analogues 3-O-demethyldihy-
drodehydrodiconiferyl alcohols (2)10 in ten steps from eu-
demethyldihydrodehydrodiconiferyl alcohol (2) have been pre-
pared in this way.
genol.
Key words: neolignans, dihydrobenzofurans, allyl siloxanes, ring-
closing metathesis, Sakurai reaction
CH2OH
OH
R'
HO
Neolignans are natural products widely distributed in na-
ture which can act as plant defense substances and exhibit
O
Si
RO
O
Me
1 R = CH3
2 R = H
OMe
Me
OMe
important biological activities as antitumor agents, bacte-
ricides, enzymatic inhibitors, antioxidants, etc.1 Many of
these compounds have a structure with a benzo[b]furan or
dihydrobenzo[b]furan core, which have been the target of
most of the syntheses of this kind of lignans reported so
far.2 In this way, three main approaches have been re-
ported: biomimetic oxidative coupling of two subunits of
propylphenol,3 cycloaddition of benzoquinones with
propenylphenols4 and intramolecular insertion of car-
benoids in C–H bonds.5
4 R' = (CH2)3OPiv
Sakurai–
Hosomi
RCM
R'
HO
CHO
+
Si
3 R' = (CH2)3OPiv
O
RO
OMe
Scheme 1 Retrosynthetic analysis for dihydrobenzo[b]furan
neolignans.
The benzo[f][1,2]oxasilepine 3 can be obtained through
RCM of allylsiloxane 4 (Scheme 2). This, in turn, can be
prepared starting from eugenol (5) in six steps. Hydro-
boration–oxidation gave mainly a primary alcohol,11 and
subsequent allylation of the phenolic hydroxyl group pro-
duced 6. Claisen rearrangement and double bond isomer-
ization with NaOt-Bu generated 7. Selective protection of
the aliphatic OH in 7 with pivaloyl chloride and sub-
sequent silylation of the phenolic OH with allylchloro-
dimethylsilane gave the allylsiloxane 4.
Although most of these methods are not too long, the
choice of suitable substituents on the aromatic rings is
limited. In addition, by-products appear quite often, main-
ly in the case of cycloadditions and oxidative couplings.
On the other hand, although the substituents on the dihy-
drofuran ring of most of the natural neolignans are in a
‘trans’ relative configuration, a small group have a ‘cis’
configuration,6 and for this group of natural products only
the carbenoid C–H insertion method is appropriate. More-
over, the literature shows some degree of confusion for
the unambiguous characterization of the cis/trans geo-
metry of these natural products, which becomes more
difficult if both stereoisomers are not available for com-
parison.7
Ring-closing metathesis with second generation Grubbs
catalyst12 gave the benzo[f][1,2]oxasilepine 3 in a clean
reaction with quantitative conversion.13 Poor results were
obtained with other systems, like first generation Grubbs
catalyst,14 or the ‘in situ’ prepared complexes described
by Grubbs15 or Dixneuf.16
We have recently reported a new total synthesis of
pterocarpans8 which uses a synthetic methodology that we
apply here to the preparation of dihydrobenzo[b]furan
neolignans (Scheme 1). The key step is a modified
Sakurai–Hosomi reaction,9 the condensation of substitut-
With the benzo[f][1,2]oxasilepine 3 in hand we next
searched for the optimal conditions for the condensation
with benzaldehydes (the modified Sakurai–Hosomi reac-
tion), testing several Lewis acids, solvents and tempera-
tures. The best results were obtained with BF3·OEt2 in
refluxing dichloromethane. Under these conditions
(Scheme 3), condensation of 3 with both aldehydes 8 or 9
SYNLETT 2005, No. 19, pp 3011–3013
0
1
.1
2
.2
0
0
5
Advanced online publication: 04.11.2005
DOI: 10.1055/s-2005-921913; Art ID: G32505ST
© Georg Thieme Verlag Stuttgart · New York

3012
S. García-Muñoz et al.
LETTER
The last stage is the oxidative degradation of the double
bond. When 10 or 11 were reacted with OsO4/KIO4, the
corresponding aldehydes were formed.20 Treatment with
a, b
c, d
HO
O
OH
21
OMe
OMe
6
LiAlH4 allowed reduction and deprotection in one step
5
to yield both neolignans 1 or 2, which could be purified by
preparative HPLC. The main spectroscopic differences
between both diasteroisomers in each case are due to H-2.
Thus, for the neolignans 1, the 1H NMR signal due to H-2
appears as a doublet at d = 5.54 ppm (J = 6.5 Hz) in the
trans isomer and at d = 5.80 ppm (J = 4.9 Hz) in the cis.
Again, this shielding for the trans isomer can be due to the
influence of the anisotropy cone of the aromatic ring.
g
Si
R'
OPiv
O
R
O
OMe
OMe
7 R, R' = OH
3
e,f
Si
4 R = OPiv, R' =
Scheme 2 (a) i. BH3·SMe2, THF; ii. H2O2, NaOH, 84%; (b)
CH2=CHCH2Br, K2CO3, Me2CO, 83%; c) N,N¢-dimethylaniline, D,
quant.; (d) NaOt-Bu, DMSO, D, 69%; (e) PivCl, DMAP, pyridine,
CH2Cl2, 83%; (f) CH2=CHCH2SiMe2Cl, Et3N, CH2Cl2, 86%; (g)
(IMesH2)(PCy3)(Cl)2Ru=CHPh, CH2Cl2, D, 75%.
yielded mixtures of cis and trans diastereoisomers of di-
hydrobenzofurans 10 or 11, in approximate 1:1 ratios17
(70–78% yields).
This result was at first surprising, as we expected the ex-
clusive formation of cis isomers, according to our previ-
ous results,8,18 although a mechanistic explanation for this
lack of diastereoselectivity has been proposed.19 Fortu-
nately, the separation of both diastereoisomers could be
achieved by careful column chromatography in each case,
and therefore the study of cis and trans systems could be
done separately. The relative stereochemistry of both of
them was assigned from their NMR properties. Specially
relevant is the deshielding of the signal of H-2 in the cis
isomer when compared to the trans isomer (Dd = 0.48
ppm). This behavior can be explained in terms of the in-
fluence on this hydrogen of the anisotropy cones of the vi-
nyl group and aromatic ring, as it has been previously
observed.8,19 Also significant is the NOE effect observed
in the trans isomer between H-2 and H1¢¢, which is not
shown by the cis isomer (Figure 1).
CHO
8 R = Me
9 R = Piv
OR
Figure 1 Diagnostic nuclear Overhauser enhancements in trans and
cis isomers of 10.
OPiv
PivO
a
O
PivO
OMe
PivO
OMe
Si
O
In summary, we have developed a new synthetic method,
concise and of high versatility, to prepare benzodihydro-
furan neolignans in ten steps. One of the main advantages
of this strategy is that it broadens the choice of products
that can be prepared, as it can tolerate a variety of sub-
stituents in both aromatic rings, when adequate starting
materials are used. Although mixtures of cis and trans in-
termediates are formed, they can be separated, allowing
the comparison of the spectral properties of isomeric neo-
lignans in order to clarify misleading assignments of these
natural products.
RO
10 R = Me
11 R = Piv
3
b
CH2OH
O
OH
HO
RO
1 R = Me
2 R = H
OMe
Scheme 3 (a) BF3·OEt2, CH2Cl2; (b) i. OsO4, KIO4, THF–H2O, 95%
for 10 and 91% for 11; ii. LiAlH4, THF, –60 °C, 90% for 1 and 84%
for 2.
Synlett 2005, No. 19, 3011–3013 © Thieme Stuttgart · New York

LETTER
Benzo[f][1,2]oxasilepines in the Synthesis of Dihydro[b]benzofuran Neolignans
3013
(8) Jiménez-González, L.; Álvarez-Corral, M.; Muñoz-Dorado,
M.; Rodríguez-García, I. Chem. Commun. 2005, 2689.
(9) (a) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 17,
1295. (b) Meyer, C.; Cossy, J. Tetrahedron Lett. 1997, 38,
7861. (c) Cassidy, J. H.; Marsden, S. P.; Stemp, G. Synlett
1997, 1411.
Acknowledgment
We wish to acknowledge the spanish Ministerio de Educación y
Ciencia for financial support (Project BQU2002-03254) and for
scholarships to L. Jiménez-González and S. García-Muñoz.
(10) Yang, S.; Fang, J.; Cheng, Y. J. Chin. Chem. Soc. 1999, 46,
811.
References
(11) Use of BH3·SMe2, H2O2, NaOH produced a mixture of
primary (91%) and secondary (9%) alcohols, which were
easily separated by column chromatography. Use of bulkier
hydroborating agents, like 9-BBN, did not increase the
selectivity.
(1) (a) Ward, R. S. Nat. Prod. Rep. 1993, 10, 1. (b) Ward, R. S.
Nat. Prod. Rep. 1995, 12, 183. (c) Ward, R. S. Nat. Prod.
Rep. 1997, 14, 43. (d) Ward, R. S. Nat. Prod. Rep. 1999, 16,
75. (e) MacRae, W. D.; Towers, G. H. N. Phytochemistry
1984, 23, 1207.
(12) For (IMesH2)(PCy3)(Cl)2Ru=CHPh (IMesH2 = 1,3-
dimesityl-4,5-dihydroimidazol-2-ylidene) see: Scholl, M.;
Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
(13) Careful column chromatography of compound 3 was needed
to avoid silica gel promoted protodesilylation.
(14) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100.
(15) Louie, J.; Grubbs, R. H. Angew. Chem. Int. Ed. 2001, 40,
247.
(16) Sémeril, D.; Cléran, M.; Perez, A. J.; Bruneau, C.; Dixneuf,
P. H. J. Mol. Catal. A: Chem. 2002, 190, 9.
(17) The aldehyde present in the crude reaction mixture shows
the same chromatographic properties as the reaction
products. Complete separation could only be achieved
through transformation into its carboxylic acid by mild
oxidation of the crude reaction mixture with NaClO2 and
extraction with base.
(18) The cis/trans ratio proved to be independent of the
temperature, concentration, and the number of equivalents
of Lewis acid used.
(2) Sefkow, M. Synthesis 2003, 17, 2595.
(3) (a) Kuo, Y.; Wu, C. J. Nat. Prod. 1996, 59, 625. (b) Shiba,
T.; Xiao, L.; Miyakoshi, T.; Chen, C. J. Mol. Catal. B:
Enzym. 2000, 10, 605. (c) Juhász, L.; Kürti, L.; Antus, S. J.
Nat. Prod. 2000, 63, 866.
(4) (a) Angle, S. R.; Turnbull, K. D. J. Org. Chem. 1993, 58,
5360. (b) Gates, B. D.; Dalidowicz, P.; Tebben, A.; Wang,
S.; Swenton, J. S. J. Org. Chem. 1992, 57, 2135. (c)Engler,
T. A.; Combrink, K. D.; Letavic, M. A.; Lynch, K. O. Jr.;
Ray, J. E. J. Org. Chem. 1994, 59, 6567. (d) Engler, T. A.;
Wei, D.; Letavic, M. A.; Combrink, K. D.; Reddy, J. P. J.
Org. Chem. 1994, 59, 6588. (e) Engler, T. A.; Gfesser, G.
A.; Draney, B. W. J. Org. Chem. 1995, 60, 3700.
(f) Engler, T. A.; Chai, W.; LaTessa, K. O. J. Org. Chem.
1996, 61, 9297. (g) Engler, T. A.; Chai, W. Tetrahedron
Lett. 1996, 37, 6969. (h) Akai, S.; Morita, N.; Iio, K.;
Nakamura, Y.; Kita, Y. Org. Lett. 2000, 2, 2279.
(5) (a) Zheng, S.; Yu, W.; Xu, M.; Che, C. Tetrahedron Lett.
2003, 44, 1445. (b) Cheung, W.; Zheng, S.; Yu, W.; Zhou,
G.; Che, C. Org. Lett. 2003, 5, 2535.
(6) (a) Aiba, C. J.; De Alvarenga, M. A.; Castro, O.; Giesbrecht,
A. M.; Gottlieb, O. R.; Pagliosa, F. M. Phytochemistry 1977,
16, 741. (b) Su, W.; Fang, J.; Cheng, Y. Phytochemistry
1995, 40, 563. (c) Li, J. X.; Shi, Q.; Xiong, Q. B.; Prasain, J.
K.; Tezuka, Y.; Hareyama, T.; Wang, Z. T.; Tanaka, K.;
Namba, T.; Kadota, S. Planta Med. 1998, 64, 628.
(7) Li, S.; Iliefski, T.; Lundquist, K.; Wallis, A. F. A.
Phytochemistry 1997, 46, 929.
(19) Miles, S. M.; Marsden, S. P.; Leatherbarrow, R. J.; Coates,
W. J. J. Org. Chem. 2004, 69, 6874.
(20) The OsO4 oxidation of 10cis or 11cis yielded mixtures of cis/
trans aldehydes, which could not be separated due to the fast
isomerization of the cis isomers in contact with silica gel.
(21) Epimerization was observed during reduction of the cis
aldehyde with NaBH4 in MeOH. LiAlH4 in THF at –60 °C
allowed fast and complete reduction and deprotection of
pivaloyl group. No epimerization was observed in these
conditions.
Synlett 2005, No. 19, 3011–3013 © Thieme Stuttgart · New York