Synthesis of 5-deoxypterocarpens, pterocarpens, and coumestans by intramolecular Heck reaction

Article abstract of DOI:10.1016/j.tetlet.2009.01.004

Two 5-deoxypterocarpens, one pterocarpen, and one coumestan were prepared from deoxychromenes, chromenes, and ortho-iodophenols. The key step in the described synthetic approach is an intramolecular Heck reaction leading to the formation of the C-ring pre

Full text of DOI:10.1016/j.tetlet.2009.01.004

Tetrahedron Letters 50 (2009) 3753–3755
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Synthesis of 5-deoxypterocarpens, pterocarpens, and coumestans
by intramolecular Heck reaction
*
Danilo P. Sant’Ana, Vagner D. Pinho, Marta C. L. S. Maior, Paulo R. R. Costa
Laboratório de Química Bioorgânica (LQB), Núcleo de Pesquisa de Produtos Naturais, Centro de Ciências da Saúde, Bl H, Ilha da Cidade Universitária, Universidade Federal do Rio
de Janeiro 21941-590, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Two 5-deoxypterocarpens, one pterocarpen, and one coumestan were prepared from deoxychromenes,
chromenes, and ortho-iodophenols. The key step in the described synthetic approach is an intramolecular
Heck reaction leading to the formation of the C-ring present in the structure of these compounds.
Ó 2009 Published by Elsevier Ltd.
Received 21 October 2008
Revised 19 December 2008
Accepted 6 January 2009
Available online 10 January 2009
1. Introduction
NMe2
O
Since the report of Lerner and co-workers1,2 describing the first
nonsteroidal compound with antiestrogen activity (MER25), atten-
tion has been focused on the development of new antihormone
analogues to control breast, prostate, and uterine cancers. These ef-
forts led to the discovery of Tamoxifen (1, Fig. 1), which was used
for the treatment of breast cancer and, in some countries, to induce
ovulation.3 Recently, 5-deoxypterocarpen 2 and pterocarpen 3,
along with a series of structurally related tetracyclic compounds,
were patented as bioligands of estrogenic receptors, and several
potential benefits for the health were claimed for this group of
compounds.4 A number of bioactive pterocarpen have also been
isolated from plants.5 Moreover, some coumestans, such as
coumestrol, also have estrogenic action6 and other interesting
pharmacological properties.7
HO
O
HO
O
O
OH
2
3
1
OH
O
O
O
O
O
O
O
O
O
O
5
4
6
OMe
R
OMe
a, R=H; b, R=OMe
Figure 1. Estrogenic compounds (1–3) and new derivatives prepared in this work.
Despite the important biological properties shown by these
compounds, few approaches are available in the literature to syn-
thesize them.4,8–10,4,11,12 In this letter, we describe the preparation
of 5-desxipterocarpen 4a,b, pterocarpen 5, and the corresponding
coumestan 6 through a new intramolecular Heck reaction.
I
OH
I
HO
R
i
iii
9
ii
O
95%
O
O
76-84%
8
2. Results
65%-75%
7
(
10
+/-)-
In Scheme 1, the synthesis of 4a and 4b is shown. Commercially
available 1,2-dihydronaphthalene 7 was allowed to react with
meta-chloroperbenzoic acid under buffered conditions, leading to
epoxide 8.13 The epoxide ring was regioselectively opened14 by
reaction with commercially available ortho-iodophenol (9a) and
9b, which was easily prepared from resorcinol.15 The resulting
alcohols 10a and 10b were tosylated under standard conditions,
leading to 11a and 11b, respectively. Reaction of these tosylates
R
OTs
iv
v
I
I
78-90%
73-86%
O
O
4
12
11
R
a,R=H
R
R
b
, R=OMe
Scheme 1. Synthesis of 4a,b through intramolecular Heck reaction in 12a,b.
Reagents and conditions: (i) MCPBA, NaHCO3 0.5 M, CH2Cl2, 0 °C to rt, 1.5 h; (ii) 11
(1.5 equiv, NaOH 100 °C, 2 h; (iii) TsCl, pyridine, CHCl3 1:3, rt, 12 h; (iv) tBuOK, THF
0 °C to rt, 1 h; (v) Pd(AcO)2 (5 mol %); TBACl, NaHCO3, DMF, 100 °C, 5–12 h.
* Corresponding author. Tel.: +55 21 256 26791; fax: +55 21 2562 6512.
E-mail address: lqb@nppn.ufrj.br (P.R.R. Costa).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.01.004

3754
D. P. Sant’Ana et al. / Tetrahedron Letters 50 (2009) 3753–3755
O
a nitrogen atmosphere until starting material disappeared (12a:
O
i
O
O
O
O
O
O
O
ii
12h; 12b: 5h; and 19: 2h). The cooled solution was partitioned be-
tween dichloromethane and water. The organic layer was washed
with water (3 times), dried, filtered, and evaporated. The material
obtained was purified by silica gel chromatography, except for 5,
which was purified by basic alumina.
80%
OH
77%
Br
OH
OBz
O
(+/-)-15
iii
(+/-)-14
13
iv
O
O
O
60% for the
two steps
O
4. 5-Deoxypterocarpen 4a
OH
O
O
I
OMe
vi
(+/-)-17
1H NMR (CDCl3), d (ppm): 7.64 (1H, d, J = 7.4 Hz); 7.48 (2H, m);
7.28–7.16 (5H, m); 3.07 (2H, t, J = 7.8 Hz); 2.92 (2H, t, J = 7.6)—13C
NMR (CDCl3), d (ppm): 155.2(C); 151.6(C); 135.8(C); 128.3(C);
128.9(CH), 127.6(C); 127.5(CH); 126.7(CH); 123.9(CH); 122.6(CH);
120.4(CH); 119.0(CH); 113.9(C); 111.3(CH); 28.56(CH2);
19.20(CH2)—MS: m/z = 220.
O
(+/-)-16
v
82%
O
O
O
O
O
vii
81%
O
I
O
89%
OMe
OTs
O
19
(+/-)-18
5. 9-Methox-5-deoxypterocarpen 4b
I
OMe
1H NMR (CDCl3), d (ppm): 7.59 (1H, d, 3J = 7.4 Hz); 7.35 (1H, d,
J = 8.6 Hz); 7.29–7.14 (3H, m); 7.07 (1H, d, 4J = 2.4 Hz); 6.88 (1H,
dd, 3J = 8.6 Hz, J = 2.4 Hz); 3.87 (3H, s); 3.08 (2H, t, J = 8.0 Hz);
O
O
O
O
O
viii
O
2.92 (2H, t, J = 7.8)—13C NMR (CDCl3),
d (ppm): 157.9(C);
O
100%
O
O
156.2(C); 150.9(C); 135.2(C); 127.9(CH), 127.8(C); 126.9(CH);
126.7(CH); 121.8(C); 119.2(CH); 119.8(CH); 114.1(C); 111.4(CH);
96.35(CH); 55.69(CH3); 26.6(CH2); 19.34(CH2)—MS: m/z = 250.
5
6
OMe
OMe
Scheme 2. Synthesis of 5 and 6 through intramolecular Heck reaction of 19. (i)
MCPBA, NaHCO3 0.5 M, CH2Cl2, 0 °C to rt, 1.5 h; (ii) NBS, H2O, DMSO, 0 °C to rt,
15 min; (iii) NaH (2 equiv) THF, rt, 20 min; (iv) 11b, rt, 12 h; (v) TsCl, pyridine,
CHCl3 1:3, rt, 12 h; (vi) tBuOK, THF 0 °C to rt, 1 h; (vii) Pd(AcO)2 (5 mol %) TBACl,
NaHCO3, DMF, 100 °C, 2 h; (viii) DDQ, THF, t.a., 2 h.
6. 1,3-Dioxolo-9-methoxypterocarpen 5
1H NMR (CDCl3), d (ppm): 7.21 (1H, d, J = 8.6 Hz); 7.05 (1H, d,
J = 2.0 Hz); 6.97 (1H, s); 6.87 (1H, dd, J = 8.6 Hz, J = 2.0 Hz); 6.51
(1H, s); 5.93 (2H, s); 5.48 (2H, s); 3.86 (3H)—13C NMR (CDCl3), d
(ppm): 157.7(C); 156.3(C); 149.2(C); 147.9(C), 147.6(C); 142.2(C);
119.2(C); 118.6(CH); 111.8(CH); 109.6(C); 106.0(C); 101.3(CH2);
100.3(CH); 99.3(CH); 99,6(CH); 66.4(CH2); 55.8(CH3)—MS: m/
z = 296.
with tBuOK furnished the corresponding key intermediates, olefins
12a and 12b. These compounds cyclized to the corresponding 5-
desoxipterocarpens 4a and 4b in the presence of 5 mol % of
Pd(OAc)2.16 A similar strategy was described by Santosh and co-
workers for the synthesis of pterocarpans through radical cycliza-
tion promoted by nBu3SnH.17
Our next goal was the synthesis of pterocarpen 5 and coume-
stan 6 (Scheme 2). Chromene 13, required for this synthesis, was
prepared from sesamol, as described in the literature.18 Under
the same conditions used for epoxidation of 7, 13 led exclusively
to benzoate 14. Alternatively, chromene 13 led to bromohydrin
15 regioselectively by reaction with NBS in DMSO/H2O.
This compound was transformed, in one pot, to alcohol 17 as a
mixture of epimers (3:1) at the benzylic carbon by reacting with
sodium hydride in THF in the presence of phenol 9b.19 It seems
reasonable to accept that epoxide 16 is an intermediate in this
transformation.
7. 1,3-Dioxolo-9-methoxycoumestan 6
1H NMR (CDCl3), d (ppm): 8.03 (1H, d, J = 2.2 Hz); 7.32 (1H, s);
7.21 (1H, d, 4J = 0.6); 7.12 (1H, dd, J = 2.2 Hz, J = 0.6 Hz); 7.03
(1H,s); 6.15 (2H,s); 3.89 (3H)—13C NMR (CDCl3),
d (ppm):
159.3(C); 156.4(C); 151.1(C); 150.4(C); 145.2(C), 132.5(C);
121.7(CH); 120.2(C); 116.6(C); 113.3(CH); 106.3(C); 102.4(CH2);
100.0(C); 99.2(CH); 99.1(CH); 99.6(CH); 55.9(CH3)—MS: m/z = 310.
Acknowledgments
We thank CAPES, FAPERJ, FINEP, and CNPq for financial support
and CNPq for fellowships to the authors. We also thank Professor
Alcides J. M. da Silva for the sample of chromene 13.
Alcohol 17 (mixture of epimers) was tosylated leading to 18
(mixture of epimers).
The desired key intermediate, olefin 19, was formed when 18
reacted with tBuOK in THF at rt. Pterocarpen 5 was obtained from
19 through an intramolecular Heck reaction in the presence of
5 mol % of Pd(OAc)2.16 Finally, coumestan 6 was prepared in quan-
titative yield by oxidation of 5 with DDQ in THF.
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