A Suzuki coupling approach to bufadienolides

Article abstract of DOI:10.1016/S0040-4039(01)01980-3

A high yielding route to bufadienolide type steroids using a novel Suzuki coupling reaction between a range of steroid vinyl triflates and 2-pyrone-5-boronate 11 is presented.

Full text of DOI:10.1016/S0040-4039(01)01980-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9081–9084
A Suzuki coupling approach to bufadienolides
a
b
a,
a,†
Edward C. Gravett, Philip J. Hilton, Keith Jones * and Fernando Romero
a
School of Chemical and Pharmaceutical Sciences, Kingston University, Kingston-upon-Thames, Surrey, KT1 2EE, UK
b
St Thomas’ Hospital, London SE1 7EH, UK
Received 12 September 2001; revised 9 October 2001; accepted 19 October 2001
Abstract—A high yielding route to bufadienolide type steroids using a novel Suzuki coupling reaction between a range of steroid
vinyl triflates and 2-pyrone-5-boronate 11 is presented. © 2001 Elsevier Science Ltd. All rights reserved.
Synthetic routes to the bufadienolide group of steroids
are important due to the powerful biological activity of
Current work in our group requires various bufadieno-
lides derived from androsterone and its stereoisomers.
We have followed the methodology of Meinwald and
1
these compounds and their proposed role in con-
2
4
trolling the mammalian sodium pump. Bufadienolides
Liu, extending it to androsterone derived vinyl trifl-
are characterised by a 2-pyrone unit connected at the
ates, and shown it to work in these cases. However, the
use of highly toxic tin reagents was a serious concern to
us, especially when the possibility of in vivo testing was
taken into account. Even though the desired steroids
are subjected to several purification steps after the Stille
coupling, organotin residues are particularly difficult to
remove completely. The use of aryl boronic acids in
similar Pd(0)-catalysed cross couplings has been exten-
5
-position to the C-17 position of a steroid nucleus and
exemplified by the toad venom bufalin 1 (Fig. 1).
Initial synthetic routes to bufadienolides were based on
linear strategies, building up a suitable five carbon
chain at the C-17 position of a steroid prior to cyclisa3-
tion and subsequent modification of the pyrone ring.
4
Meinwald and Liu recently disclosed a convergent
6
sively studied by Suzuki and many others, and there
synthesis whereby 5-(trimethylstannyl)-2-pyrone 3 was
coupled to a suitably modified estrone nucleus 2 using
the Pd(0)-catalysed cross coupling methodology studied
have been recent reports of the coupling of 5-bromo-2-
7
pyrone 9 to various aryl boronic acids. We felt that a
5
-boron substituted 2-pyrone reagent would give more
5
by Stille. The coupled product 4 was then deprotected
synthetic flexibility and so we decided to investigate the
preparation of a suitable 2-pyrone boronic acid or
boronate ester and to study the coupling reaction of
this compound to steroid vinyl triflates.
prior to catalytic hydrogenation of the C16ꢀC17 double
bond to give the bufadienolide 6 (Scheme 1).
O
O
5
-Bromo-2-pyrone 9 is a convenient source of the 2-
pyrone sub-unit and its synthesis has been reported by
two different routes. In our experience free radical
8
dibromination of 2-pyrone 7 followed by base elimina-
tion of HBr proved the best way to obtain 5-bromo-2-
pyrone 9 in good yield and purity (Scheme 2). A recent
9
report by Masuda and co-workers reported the cou-
OH
pling of pinacolborane 10 to various aryl halides in the
presence of catalytic PdCl (dppf) and NEt in dioxane
HO
2
3
H
at 80°C to give the corresponding aryl boronates in
high yields. When we repeated these reaction conditions
with 5-bromo-2-pyrone there was little apparent evi-
dence of reaction, although GCMS analysis indicated a
very small amount of the required product had been
formed. Modifying the conditions by changing the cata-
lyst to PdCl (PPh ) and carrying out the reaction in
Bufalin 1
Figure 1.
*
Corresponding author.
Exchange student from Department of Chemistry, University of
Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland.
†
2
3 2
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01980-3

9
082
E. C. Gra6ett et al. / Tetrahedron Letters 42 (2001) 9081–9084
O
O
OTf
O
O
Pd(PPh3)4
LiCl
+
SnMe3
TBDMSO
TBDMSO
2
3
4
O
TBAF
O
O
O
H Pd/CaCO3
2
HO
HO
5
6
Scheme 1.
toluene at reflux temperature led to a good yield (70%)
of the desired 2-pyrone-5-boronate 11 (Scheme 2).
boronates and triflates have been reported in the
11
literature using the PdCl (dppf) catalyst and this
2
proved to be successful in our examples. Use of an
organic base (entries 2 and 3) gave low yields of cou-
pled product but switching to an inorganic base showed
an immediate improvement with K PO being superior
The palladium-catalysed cross coupling reaction of 11
with a range of steroidal vinyl triflates could now be
investigated (Scheme 3). Four commercially available
androsterones, one dehydroandrosterone and estrone
were modified in the same way as described by Mein-
3
4
to KF (entries 4–6). It proved essential to finely crush
the K PO4 to achieve successful coupling. Optimum
3
conditions for the coupling gave yields in the range
4
wald and Liu, i.e. TBDMS protection of the secondary
7
5–91% for the five androsterone derivatives 12a–d, 14
alcohol at C-3 followed by formation of the vinyl
triflate, both reactions proceeding in >90% yield for all
our examples.
12
(
entries 7–11). These conditions were less effective for
coupling to the estrone derived vinyl triflate 2 and there
was a tendency for the coupled product to be depro-
tected in situ (entry 12). As our interest lay in the
androsterone-derived products, coupling of 11 to 2 was
not optimised. Hydrogenation of the C16ꢀC17 double
bond in 13a–d, 15 to give bufadienolides was achieved
straightforwardly using the conditions reported by
We investigated various combinations of solvent, cata-
lyst and base for the coupling reaction and these are
10
summarised in Table 1. Initially standard Suzuki cou-
pling conditions were tried (entry 1) but no coupling
was observed. Coupling reactions between aryl
4
Meinwald and Liu.
O
O
O
O
O
O
H
B
O
O
O
Br hν
2
NEt3
+
O
O
PdCl (PPh )
NEt3
2
3 2
B
Br
O
Br
Br
7
8
9
10
11
Scheme 2.

E. C. Gra6ett et al. / Tetrahedron Letters 42 (2001) 9081–9084
9083
O
O
O
OTf
O
Pd(0)
+
B
R
O
O
R1
R2
R
R1
R2
1
2
1
2a R = H R = OTBDMS R = α-H
1
2
1
3a R = H R = OTBDMS R = α-H
1
2
b R = OTBDMS R = H R = α-H
1
2
b R = OTBDMS R = H R = α-H
11
1
2
c R = H R = OTBDMS R = β-H
1
2
c R = H R = OTBDMS R = β-H
1
2
d R = OTBDMS R = H R = β-H
1
2
d R = OTBDMS R = H R = β-H
O
O
O
OTf
O
Pd(0)
+
B
O
O
TBDMSO
TBDMSO
14
11
15
Scheme 3.
Table 1. Coupling reaction of 11 with steroidal vinyl triflates, Scheme 3
Entry
Steroid
11 (equiv.)
Solvent
Catalyst (equiv.)
Base (equiv.)
K PO (1.5)
NEt3 (2.0)
NEt3 (2.0)
KF (1.0)
Time (h)
T (°C)
Product (yield)
1
2
3
4
5
6
7
8
9
12d
12b
2
12b
14
1.1
1.0
1.0
1.0
1.5
1.0
1.3
1.3
1.3
1.3
1.3
1.3
Dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Pd(PPh3)4 (0.03)
6
6
6
18
18
6
6
6
6
6
6
6
90
60
60
60
60
60
60
60
60
60
60
60
None
13b (27%)
4 (5%)
3
4
PdCl (dppf) (0.03)
2
PdCl (dppf) (0.03)
2
PdCl (dppf) (0.03)
13b (41%)
15 (42%)
4 (52%)
13a (75%)
13b (76%)
13c (85%)
13d (91%)
15 (84%)
5 (35%)
2
PdCl (dppf) (0.03)
KF (1.0)
2
2
PdCl (dppf) (0.03)
K PO (1.5)
2
3
4
12a
12b
12c
12d
14
PdCl (dppf) (0.1)
K PO (3.5)
2
3
4
PdCl (dppf) (0.1)
K PO (3.5)
2
3
4
PdCl (dppf) (0.1)
K PO (3.5)
2
3
4
1
1
1
0
1
2
PdCl (dppf) (0.1)
K PO (3.5)
2
3
4
PdCl (dppf) (0.1)
K PO (3.5)
2
3
4
2
PdCl (dppf) (0.1)
K PO (3.5)
2
3
4
In summary, we have shown that the Pd(0)-mediated
coupling of 2-pyrone-5-boronate 11 to a range of
steroid vinyl triflates is an efficient method of preparing
bufadienolide type steroids without the use of toxic tin
reagents and hence avoids the risk of contamination of
products with tin residues.
References
1. Steyn, P. S.; van Heerden, F. R. Nat. Prod. Rep. 1998, 16,
397–413.
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Gordon, D. B.; Hilton, M. J.; Forni, L. G.; McKinnon,
W.; Ismail, F. M. D.; Keenan, M.; Jones, K.; Morden,
W. E. Lancet 1996, 348, 303–305.
Acknowledgements
3
. For example: Bauer, P. E.; Kyler, K. S.; Watt, D. S. J.
We should like to acknowledge financial support from
the Special Trustees for St Thomas’ Hospital.
Org. Chem. 1983, 48, 34–39 and references cited therein.
4. Liu, Z.; Meinwald, J. J. Org. Chem. 1996, 61, 6693–6699.

9
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E. C. Gra6ett et al. / Tetrahedron Letters 42 (2001) 9081–9084
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solved in dry DMF (5 ml) under a N atmosphere. Some
2
5
08–524.
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6
7
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3
4
solution and this slurry was heated to 60°C for 6 h. The
DMF was removed under reduced pressure to give a dark
solid which was initially purified by dissolving in DCM
and filtering through a plug of silica, followed by a
further elution of DCM (100 ml). The solvent was
removed under reduced pressure to give a brown crys-
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1
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8
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1
1
0. Oh-e, T.; Miyaura, N.; Suzuki, A. Synlett 1990, 221–223.
1. (a) Coudret, C.; Mazenc, V. Tetrahedron Lett. 1997, 38,
lH (CDCl , 300 MHz) 0.00 (6H, s), 0.87 (9H, s), 0.89
(3H, s), 0.96 (3H, s), 1.05–1.95 (19H), 2.18 (1H, m), 4.02
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3
5
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(1H, dd, J 9.6, 2.4) and 7.48 (1H, br. s); lC (CDCl , 75
3
1
2. Typical procedure for the Suzuki couplings: The vinyl
MHz) −4.8, 16.4, 18.1, 21.1, 23.9, 25.9, 26.4, 26.8, 28.6,
29.9, 31.5, 34.2, 34.5, 35.2, 35.8, 36.6, 40.3, 47.4, 57.5,
67.3, 116.2, 116.4, 128.7, 144.3, 146.6, 147.1 and 161.5;
triflate of TBDMS protected 3b-etiocholanolone 12d
(0.24 g, 0.45 mmol), 2-pyrone-5-boronate 11 (0.14 g, 0.6
+
mmol), and PdCl (dppf) (40 mg, 0.045 mmol) were dis-
m/z (electrospray) 483 (MH ).
2