A concise and diastereoselective total synthesis of cis and trans-pterocarpans

Article abstract of DOI:10.1039/b500919g

A new strategy for the diastereoselective and convergent synthesis of pterocarpans which is able to control the relative stereochemistry of the molecule through allylation of aromatic aldehydes with cyclic allylsiloxanes is described. The Royal Society of

Full text of DOI:10.1039/b500919g

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A concise and diastereoselective total synthesis of cis and
trans-pterocarpans{
´
Leticia Jime´nez-Gonza´lez, M´ıriam Alvarez-Corral, Manuel Mun˜oz-Dorado and Ignacio Rodr´ıguez-Garc´ıa*
Received (in Cambridge, UK) 20th January 2005, Accepted 21st March 2005
First published as an Advance Article on the web 12th April 2005
DOI: 10.1039/b500919g
Mitsunobu reaction from a dihydroxylated intermediate derived
from deprotection and degradation of the olefin 2. This can be
obtained by condensation of the benzoxasilepin 3 with aromatic
aldehydes in the presence of a Lewis acid (a Sakurai–Hosomi
modified reaction). In this stage a dihydrobenzofuran ring is
formed and so are the two chiral centres of the molecule.
Therefore, the diastereoselectivity of the whole route will be
governed in this condensation. 3 can be prepared by ring closing
metathesis of allyldimethylsilyl ethers of o-propenylphenols (4).
The preparation of compounds like 4 can be achieved from
commercial starting materials in few steps through conventional
chemistry.
A new strategy for the diastereoselective and convergent
synthesis of pterocarpans which is able to control the relative
stereochemistry of the molecule through allylation of aromatic
aldehydes with cyclic allylsiloxanes is described.
Pterocarpans, the second largest group of natural isoflavonoids,
incorporate a cis fused benzofuran–benzopyran system in their
skeleton.1 They are produced by plants in response to phyto-
pathogenous fungi infections2 and their interest is due to their wide
range of biological activities, which include antitumoural,3 anti-
HIV,4 antimalarial,5 and against snake venoms.6 This range of
activities and their unique structure have attracted the interest of
synthetic organic chemists, and several syntheses, most of them in
racemic form, have been described.4b,6,7 However, these methods
usually require numerous steps and provide poor yields. The most
common strategy starts with the formation of the dihydrobenzo-
pyran ring, and in a latter stage the dihydrobenzofuran ring
closure. This pathway only allows the formation of the cis-fused
system, which is the most stable.8
Here we describe our first results. Compound 8 was prepared in
four steps from p-methoxyphenol (5) (Scheme 2). Allylation of 5
with allylbromide gave 6 (95%) which was transformed into 7
through a Claisen rearrangement (93%). Treatment with base
promoted the migration of the double bond,9 and final silylation
gave the desired diolefin 8 in 87% overall yield as a mixture of
geometric isomers (Z/E 1/12). Ring closing metathesis of 8 in the
presence of the commercial Ru-based 1st generation Grubbs
catalyst10 gave 9 in moderate yield (76%), while its imidazolidinyl-
idene analogue (2nd generation Grubbs catalyst)11 shortened
reaction times (from 24 to 1 h) and increased the yield (up to
90%)12 with a molar ratio substrate/catalyst 200/1.
We have developed a new strategy for the diastereoselective and
convergent synthesis of pterocarpans (1) which is able to control
the relative stereochemistry of the molecule in both stereogenic
carbons 6a and 11a. In addition, this synthesis ought to be easily
adaptable to an asymmetric version. Our retrosynthetic analysis
(Scheme 1) is based on the following key disconnections: the
dihydrobenzopyran ring could be easily closed through a
At this point the second aromatic ring of the pterocapan was
introduced through a modified Sakurai–Hosomi condensation of 9
with aldehyde 1013 in the presence of BF3?Et2O. High levels of
diastereoselectivity have been previously reported for the synthesis
of trisubstituted tetrahydrofurans.14,15 This is the first time that
this reaction has been described on
a benzo-fused cyclic
Scheme 1
{ Electronic supplementary information (ESI) available: experimental
details for the synthesis of all compounds, NMR data and copies of
spectra and crystallographic data for 14cis and 14trans. See http://
www.rsc.org/suppdata/cc/b5/b500919g/
Scheme 2 a) N,N-dimethylaniline, reflux; b) t-BuONa, DMSO; c)
allylchlorodimethylsilane, NEt3, DCM.
*irodrigu@ual.es
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allylsiloxane, and complete diastereoselection was observed, as
only the cis diastereomer (11) was obtained in 68% yield.
In the 1H NMR spectrum of 11 the hydrogen of the oxygenated
methine (H2) appears at 5.89 ppm (d, J 8.8 Hz) while H-3 gives a
dd (J 8.8, 7.8 Hz) at 4.22 ppm. The vinyl group originates three
signals at 5.37, 5.00 and 4.93 (H-10 and both H-20). A relative cis
stereochemistry was initially proposed in agreement with the
intense NOE effect observed between H-2 and H-3. Extensive
experimentation on this reaction gave always the same diaster-
eomer. Even on prolonged reaction times in refluxing dichloro-
methane and excess of BF3?Et2O, we could not detect any amount
of the trans isomer, and the only by-product that could be isolated
was 2-allyl-4-methoxyphenol (produced by protodesilylation of 9).
A possible mechanistic pathway leading to both diastereomeric
tetrahydrofurans has been described,16,17 but the isomerization of
the less stable cis isomer into the trans derivative proposed for
tetrahydrofurans was not observed in our system.
Fig. 1 Crystal structure of 14cis (ORTEP 50%). Selected bond lengths
˚
(A) and bond angles (u): O(3)–C(24) 1.469(3), C(22)–C(24) 1.540(4),
C(21)–C(22) 1.504(4), O(2)–C(21) 1.430(3), C(24)–C(22)–H(22) 108.9,
C(5)–C(24)–O(3) 108.7(2), O(2)–C(21)–C(22) 113.0(2).
The synthesis was completed by the ring closure of the
dihydrobenzopyran portion (Scheme 3) through the double bond
degradation and Mitsunobu cyclization of the dihydroxy deriva-
tive. All attempts of ozonolysis of 11 only gave aromatic ring
degradation products. Catalytic osmium tetroxide in excess of
NaIO4 gave an aldehyde (12cis) with retention of the relative
stereochemistry. However, column chromatography on SiO2
promoted partial isomerization to the thermodynamically
favoured trans diastereomer (12cis:12trans 6:1). To avoid this,
the crude mixture of the oxidation was reduced with LiAlH4 in
Et2O, which allowed the formation of 13cis in 68% yield without
epimerization. We also took advantage of this easy isomerization
of the cis aldehyde to prepare a trans pterocarpan. Thus, 11 could
be transformed into alcohol 13trans (70%) when the oxidation
crude was treated with NaBH4 in MeOH, a reagent that reduced
the aldehyde and at the same time promoted complete epimeriza-
tion of C-3. On the other hand, both reductant systems completely
removed the pivaloyl protecting group of the phenol, which was
needed for the benzopyran ring formation.
Fig. 2 Crystal structure of 14trans (ORTEP 50%). Selected bond lengths
˚
(A) and bond angles (u): O(3)–C(23) 1.435(3), C(22)–C(23) 1.463(4),
C(21)–C(22) 1.476(4), O(2)–C(21) 1.447(3), C(23)–C(22)–H(22) 106.3,
C(1)–C(23)–O(3) 118.8(2), O(2)–C(21)–C(22) 111.0(2).
Both pterocarpans 14cis and 14trans were prepared by
treatment with PPh3 and DIAD (diisopropyl azodicarboxylate)
of the corresponding alcohols, in yields higher than 70%. The
spectroscopic properties of these substances confirm their struc-
tural features (see Electronic Supplementary Information{).
1
The main difference between them in their H NMR spectra is
the coupling constant between H-6a and H-11a, which is 6.6 Hz
for the cis isomer (in the range of the average values of
natural pterocarpans) and 13.4 Hz for the trans isomer. The
other significant difference is the lower field shift of both
hydrogens on C-6 [3.68, 4.29 (cis) and 4.47, 4.88 (trans)].
Appropriate crystals for X-ray diffraction could be prepared
from both final products, thus confirming the proposed relative
stereochemistry. This is the first time that an X-ray crystal-
lographic analysis of
a
trans pterocarpan has been
described.{
In conclusion, we have achieved a diastereoselective total
synthesis of pterocarpans in eight steps from commercial aldehydes
or phenols. We are now applying the strategy to the preparation of
a series of natural and unnatural pterocarpans in order to evaluate
their biological activities. Looking ahead, we foresee that if the
Sakurai reaction could be carried out with a chiral acid, there
would be an extraordinarily simple way to make the route
enantioselective.
We wish to acknowledge the spanish Ministerio de Educacio´n
y
Ciencia for financial support (Project PB98-1006 and
Scheme 3
BQU2002-03254) and for a scholarship to L. Jime´nez-Gonza´lez.
2690 | Chem. Commun., 2005, 2689–2691
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´
Leticia Jime´nez-Gonza´lez, M´ıriam Alvarez-Corral,
6 A. J. M. Da Silva, A. L. Coelho, A. B. C. Simas, R. A. M. Moraes,
D. A. Pinheiro, F. F. A. Ferna´ndez, E. Z. Arruda, P. R. R. Costa and
P. A. Melo, Bioorg. Med. Chem. Lett., 2004, 14, 2, 431.
7 T. G. van Aardt, H. van Rensburg and D. Ferreira, Tetrahedron, 2001,
57, 33, 7113 and references therein.
Manuel Mun˜oz-Dorado and Ignacio Rodr´ıguez-Garc´ıa*
Dept. Organic Chemistry, University of Almer´ıa, 04120-Almer´ıa, Spain.
E-mail: irodrigu@ual.es; Fax: +34-950-015081; Tel: +34-950-015610
8 A. Scho¨ning and W. Friedrichsen, Z. Naturforsch., B: Chem. Sci., 1989,
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Notes and references
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10 P. Schwab, R. H. Grubbs and J. W. Ziller, J. Am. Chem. Soc., 1996,
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11 M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett., 1999, 1,
953.
12 Quantitative conversions were usually observed by 1H-NMR of the
reaction crudes. Careful column chromatography was needed to avoid
silica promoted protodesilylation
{ Crystal data for 14cis. C17H16O4, M 5 284.30, triclinic, space group P1,
˚
a 5 4.7090(7), b 5 8.2955(12), c 5 9.1628(13) A, a 5 92.006(2)u,
3
˚
b 5 94.865(2)u, c 5 104.989(3)u, V 5 343.9(9) A , T 5 273 K, Z 5 1,
m(Mo–Ka) 5 0.098 mm21. A total of 1568 reflections were collected, 1200
unique reflections (Rint 5 2.23) which were used in all calculations. The
final wR (F2) was 0.0697 (all data). Crystal data for 14trans. C17H16O4,
¯
M 5 284.30, triclinic, space group P1, a 5 8.0941(8), b 5 8.7487(8),
˚
c 5 10.2094(10) A, a 5 78.617(2)u, b 5 82.940(2)u, c 5 77.161(2)u,
3
V 5 688.65(11) A , T 5 273 K, Z 5 2, m(Mo–Ka) 5 0.097 mm21. A total
˚
of 3775 reflections were collected, 2407 unique reflections (Rint 5 2.37)
which were used in all calculations. The final wR (F2) was 0.1901 (all data).
CCDC 260556 & 260557. See http://www.rsc.org/suppdata/cc/b5/b500919g/
for crystallographic data in CIF or other electronic format.
.
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Chem. Commun., 2005, 2689–2691 | 2691