A Suzuki–Miyaura Coupling of ortho-Hydroxyaryl Bromide with Isopropenylboronic Pinacol Ester: Synthesis of the Potassium-Channel Opener (+)-Callitrisic Acid

Article abstract of DOI:10.1002/ejoc.201800070

A Suzuki–Miyaura coupling reaction of ortho-hydroxyaromatic bromide 8 with isopropenylboronic acid pinacol ester has been investigated. It was found that the catalyst of Pd₂(dba)₃/PCy₃ in dioxan-water gave good yield by suppressing the formation of isomeric side product 14. (+)-Callitrisic acid was synthesized from (+)-podocarpic acid using this condition with an overall yield of 54 % in about five steps. (+)-Callitrisic acid was found to be almost three times more potent than dehydroabietic acid to open a voltage-gated potassium channel.

Full text of DOI:10.1002/ejoc.201800070

A Journal of
Accepted Article
Title: A Suzuki-Miyaura Coupling of Ortho Hydroxy Aryl Bromide with
Isopropenylboronic Pinacol Ester and its Application: Synthesis of
the Potassium-Channel Opener (+)-Callitrisic Acid
Authors: Xiongyu Wu, Malin Silverå Ejneby, Nina Ottosson, Fredrik
Elinder, and Peter Konradsson
This manuscript has been accepted after peer review and appears as an
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the VoR from the journal website shown below when it is published
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800070
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800070
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10.1002/ejoc.201800070
European Journal of Organic Chemistry
COMMUNICATION
A Suzuki-Miyaura Coupling of Ortho Hydroxy Aryl Bromide with
Isopropenylboronic Pinacol Ester and its Application: Synthesis
of the Potassium-Channel Opener (+)-Callitrisic Acid
Xiongyu Wu,*[a] Malin Silverå Ejneby,[b] Nina E Ottosson,[b] Fredrik Elinder,[b] Peter Konradsson[a]
Abstract: A Suzuki-Miyaura coupling reaction of ortho hydroxy
aromatic bromide 8 with isopropenylboronic acid pinacol ester has
derivatives because it is found that some of them have the
been investigated. It was found that the catalyst of Pd2(dba)3/PCy3 in
Recently we have special interest in resin acid
potential to be developed to pharmaceutical drugs to
improve the condition for patients suffering from
hyperexcitability diseases such as epilepsy and pain related
dioxan-water gave good yield by suppressing the formation of
isomeric side product 14. (+)-Callitrisic acid was synthesized from
(+)-podocarpic acid using this condition with an overall yield of 54%
in about five steps. (+)-Callitrisic acid was found to be almost three
times more potent than dehydroabietic acid to open a voltage-gated
potassium channel.
disorders.[5] Compound
bromination of podocarpic acid
used as the starting material for reaction investigation
Table 1).
8
, which was synthesized from
(a resin acid), was then
7
T
here are more than five thousand bioactive small
(
molecules containing ortho-hydroxy-isopropyl or ortho-
hydroxy-isopropenyl phenyl moiety, including natural
products ferruginol (1), carnosol (
2
), lambertic acid (
and synthetic
) (Figure 1).[1] Several methods have been
3),
nepetaefolin
H
(
4
), teydeadione
(5)
eprotirome (
6
developed for the synthesis of isopropyl/alkyl arenes.[2]
However, some of the ligands are not commercially
available and none of those investigated starting materials
contains an ortho-hydroxyl group. To the best of our
knowledge, all the ortho hydroxy group are protected. An
ortho-hydroxy group could be problematic because of its
participation to the cross-coupling reaction. From the
literature, we find there are just a few reports on the Suzuki-
Miyaura
coupling
conditions
using
ortho-
hydroxybromobezene analogues as starting materials to
synthesize isopropenyl phenyl moiety. One of them give low
Figure 1: Structures of some natural products containing hydroxyl
isopropyl/isopropenyl phenyl ring.
yield (31%) using Dppf ‧ PdCl2 ‧ CH2Cl2 complex as the
Bromination of podocarpic acid using NBS under
catalyst. Others give high yields after ortho-phenolic
hydroxy group(s) is/are protective.[3] The free phenolic
hydroxy group at ortho position of bromo group seems to be
one of the reasons to give a low yield in Suzuki-Miyaura
coupling reaction. Now we want to investigate the Suzuki-
Miyaura coupling reaction of ortho hydroxy aryl bromide
with isopropenylboronic acid pinacol ester for further
applications, since isopropenyl group of the products is
easily reduced to isopropyl group, and they can also be
used as starting materials to synthesize other derivatives.[4]
microwave irradiation (MW) at 90 °C gave
Reaction was very slow at rt. Unlike the bromination,
Suzuki-Miyaura coupling of with 2-isopropenylboronic
8 in 97% yield.
8
acid pinacol ester was more problematic.
Table 1. Optimization of coupling of bromide 8 to give compound 9
[a]
[b]
Dr. X. Wu and Prof. Dr. P. Konradsson
Department of Physics, Chemistry and Biology, Linköping
Catalyst
Solvent
T. and
time
9[a]
Side
Ratio of
9:14[b]
University, Linköping, Sweden
E-mail: Xiongyu.wu@liu.se
M. S. Ejneby, Dr. N.E. Ottosson, Prof. Dr. F. Elinder
Department of Clinical and Experimental Medicine, Linköping
University, Linköping, Sweden,
product
1
Pd(PPh3)4
DME/
H2O
140⁰C,
30 min
trace
7, 10-
13[c]
Supporting information for this article is given via a link at the end of
the document
2
3
Pd(PPh3)4
Pd(PPh3)4
Tol/EtOH
/H2O
Dioxane/
H2O
Dioxane/
H2O
140⁰C,
30 min
135⁰C,
30 min
135⁰C,
30 min
trace
50%
7, 12[d]
7, 10，
13-14[e]
14
3.3:1
1.7:1
4
Pd-Peppsi-iPr
70%
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10.1002/ejoc.201800070
European Journal of Organic Chemistry
COMMUNICATION
5
Pd2(dba)3/PCy3
Pd2(dba)3/PCy3
Pd-Peppsi-iPent
Dioxane/
H2O
135⁰C,
30 min
135⁰C,
7 min
135⁰C,
7 min
81%
91%
94%
10, 14
10, 14
14
10:1
Another major side product was compound 13, a palladium
complex with diphenylphosphinylated podocarpic acid, which
was probably formed after the Oxidative insertion step of
palladium catalytic cycle due to the ortho-group participation of
free phenol. Since triphenylphosphine ligand was problematic
here, another type of catalysts, Peppsi-iPr, was then tested. It
was found that no palladium complex like 13 was formed and
the yield of Suzuki-Miyaura coupling product was improved to
about 70%. But the product was a mixture with a ratio of
compounds 9/14 at about 1.7:1, which was worse than that
acheived from catalyst of Pd(PPh3)4. Bulky ligands in coupling
reactions are found to reduce the isomerization problem of
isopropyl group in the Suzuki-Miyaura and Negishi coupling
reactions.[2b,2g] Peppsi-iPent, which is more bulky, was also
tested for this reason, although the mechanisms were probably
different. Unfortunately, the reaction was worse and gave a ratio
of 9/14 at about 1:1.3 according to 1H NMR, with the n-propenyl
side product as major under our condition. For other coupling
conditions (entries 1-3) that gave low yields, it was found that
some side products contained phenylphosphine moiety. Other
non-phenylphosphine ligands could be helpful for the coupling
reaction. Another catalytic system of Pd2(dba)3/PCy3 was then
tried and finally good yield (91%) was achieved for this step with
6[f]
7
Dioxane/
H2O
Dioxane/
H2O
11:1
1:1.3
[a] isolated yield; [b] 1H-NMR ratio; [c] LC ratio of 7/11/12/13: 2:1:1.8:5; [d] LC
ratio of 7/12: 1:1.3; [e] LC ratio of 7/9(14)/10/13: 6:39:1:24; [f] Reaction
condition: The mixture of bromide
isopropenylboronic acid pinacol ester, 3 mol% Pd2(dba)3, 6 mol% PCy3, 4
equiv of Na2CO3, 3.5 mL dioxane/water (4:1), was irradiated under MW at 135
⁰C for 7 min.
8
(0.284 mmol),
3
equiv of
Figure 2: Different side products from Suzuki-Miyaura coupling reaction step
under different conditions.
1
a ratio of 9/14 at about 11:1 according to H NMR. Compound
10 was formed as a minor side product in most of the coupling
conditions (trace, entries 4 and 7). It was probably formed from
compound 9. The isopropenyl group of
9 was possibly
protonated by the ortho phenolic group to form a benzylic cation,
followed by the attack from water and deprotonation to give 10.
It was found that the amount of 10 was increased obviously if
the reaction mixture was placed at rt for a few hours after work
up. It was probably difficult to avoid it completely, but the
optimized condition with Pd2(dba)3/PCy3 as catalysts was ready
for further application.
Dehydroabietic acid (15) (Figure 3) and its derivatives have
been widely explored in material and pharmaceutical studies.[7a]
They could be used as anti-hyperexcitability, anti-tumor, anti-
inflammatory, and anti-allergic agents,[7] or even as starting
material for synthesis of other natural products, such as 3-
oxosapriparaquinone, (+)-pisiferic acid and pygmaeocine E.[8]
Scheme 1: Plausible mechanism of formations of compounds 9 and 14.[6]
Different conditions have been carried out to afford a good
yield of the coupling step. When Pd(PPh3)4 was used as the
catalyst, different side products were obtained in different
solvents under microwave irradiation (Table 1 and Figure 2).
Compound 11 was found to be one of the major side products
when DME and water were used as solvents. It seemed that the
methoxy group was transferred from DME to the desired product
to form a methyl ether. The solvent mixture of toluene/EtOH/H2O
was then used to suppress the formation of side product 11.
Although the presence of EtOH didn’t give any problem of
formation of ethyl ether side product like 11, unfortunately
another side product of 12 together with podocarpic acid 7 (from
debromination) were dominated. The desired product was trace
in both conditions (entries 1 and 2). Dioxane/H2O were then
used, and the reaction mixture was irradiated under MW at
135 °C for 30 min. The reaction gave moderate yield at about
50%. The yield was increased from trace to moderate with
compound 14 as one of the major side products. The
mechanism of the formation of 14 was shown in Scheme 1.[6]
Compared to dehydroabietic acid, callitrisic acid (16) and
derivatives are less investigated due to the commercial non-
availability, although callitrisic acid is also
a
bioactive
substance.[9] Synthesis of callitrisic acid and other epimers of
dehydroabietic acid have been investigated before, but the
synthetic routes are either lengthy and/or giving racemates.[10]
With the compound 9 synthesized from the Suzuki-Miyaura
coupling reaction above, further steps were exploited to
synthesize (+)-callitrisic acid (16) (Scheme 2).
Figure 3: Structures of Dehydroabietic acid and Callitrisic acid.
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10.1002/ejoc.201800070
European Journal of Organic Chemistry
COMMUNICATION
Scheme 2: a) NBS, 90 °C, MW, 30 min, 97%; b) Pd2(dba)3, PCy3, Na2CO3,
Dioxan/H2O, 135 °C, MW, 7 min. 90%, ratio of 9:14 at about 11:1; c) i) Pd/C,
H2, rt; ii) TMSCH2N2, rt; iii) triflic anhydride, Py, DCM, rt, 80%; d) Pd(OAc)2,
dppf, HCOOH, DiPEA, DMF, 110 °C, MW, 30 min, 81%; e) t-BuOK, DMSO,
150 °C, MW, 20 min, 95%.
Figure 5: Different potency of the two diasteroisomers dehydroabietic acid
(DHAA) and (+)-callitrisic acid (CTSA) to the wild type Shaker KV channel. A) K
currents at -30 mV and B) normalized G(V) curves (shift = -7,0) before (black)
and after (red) application of 100 µM CTSA. C) G(V) shifts for 100 µM DHAA
(n = 10) and CTSA (n = 6). Mean SEM.
Hydrogenation and methyl esterification using TMSCH2N2
followed by the formation of triflate of compound 17 were carried
out smoothly under the described conditions above (Scheme 2).
A good yield was also achieved. But it was problematic for the
A lipid protein drug-binding pocket of a potassium channel is
recently discovered by us.[11a] It is found that (+)-callitrisic acid is
much more potent than its epimer dehydroabietic acid in
opening the genetically modified Shaker 3R KV channel,
designed to be more sensitive to compounds acting by the
desired lipoelectric mechanism.[5a],[11] Here, we showed that (+)-
callitrisic acid act as an opener of the wild type Shaker KV
channel (that is similar to other human KV channels) by shifting
the voltage-dependence of activation (the conductance-versus-
voltage, G(V), curve) by -6.3 0.8 mV (Figure 5). The shift was
almost three times as large compared to dehydroabietic acid (-
2.4 0.4 mV).[5a] Therefore, (+)-callitrisic acid and its derivatives
have the potential to be developed to potent KV channel openers
with the potential to reduce epileptic seizures, pain, and cardiac
arrhythmia.
reduction
of
triflate
17.
Reduction
with
Peppsi-
iPr/HCOOH/DiPEA, Pd2(dba)3/HCOOH/DiPEA and Pd/C/Mg
didn’t give any desired product. When Pd(PPh3)4 was used as a
catalyst, the reaction gave a moderate yield of 53%. But side
products of 19 and 20 were also obtained, which caused the
lower yield (Figure 4). After optimization with other catalysts,
the yield was successfully increased to 81% when
dppf/Pd(OAc)2 was used. After hydrolysis of 18 with t-BuOK in
DMSO under MW at 150 °C for 20 min, the (+)-callitrisic acid 16
was got in 95% yield. The (+)-callitrisic acid was then
synthesized in an overall yield of 54% from podocarpic acid.
A Suzuki-Miyaura coupling reaction of ortho hydroxyl aryl
bromide with isopropenylboronic acid pinacol ester has
been investigated. Optimized condition has been
discovered, which was applied in the concise synthesis of
(+)-callitrisic acid from (+)-podocarpic acid. It was found that
(+)-callitrisic acid was much more potent than
dehydroabietic acid as a potassium channel opener. The
synthetic route can also be applied in the syntheses of
other analogues of dehydroabietic acid with a different
chiral center at carbon 4. Interesting side products were
also found during the optimizations, which help us to
understand Suzuki-Miyaura coupling reaction better.
Substance like 13 could probably be used as a chiral
catalyst in organometallic chemistry.
Figure 4: Different side products from reduction of trifluoromethan sulfonate
using Pd(PPh3)4/HCOOH/DiPEA.
Table 2. Optmization of reduction of triflate 17 to give compound 18.
Entry
Catalyst
T. and time
Compd.
S.P.
18[a]
1
2
Peppsi-iPr
Pd(PPh3)4
125 ⁰C, 45
min, MW
120 C, 30 min,
then 125 ⁰C,
1h
-
-
53%,
19, 20[b]
3
Pd(PPh3)4
100 ⁰C, 7.5 h
in total
21%
19, 20
4
Pd/C/Mg
Dppf/Pd(OAc)2
rt
trace
81%
-
5[c]
110 ⁰C, 30
min, MW
Acknowledgements
[a] isolated yield; [b] LC ratio of 18/19/20: 4.2:1:1.9; [c] The mixture of triflate
17 (0.204 mmol), 10 mol% Pd(OAc)2, 20 mol% dppf, HCOOH (5 equiv.) and
DiPEA (4 equiv.) in DMF was irradiated under MW at 110 °C for 30 min.
Financial support from Center for Systems Neurobiology,
Linköpings Univetsitet, is gratefully acknowledged. This
work was also supported by grants from the Swedish
Research Council, the Swedish Heart-Lung Foundation and
the Swedish Brain Foundation.
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10.1002/ejoc.201800070
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COMMUNICATION
Keywords: Suzuki-Miyaura • (+)-callitrisic acid • potassium ion
channel • channel opener • podocarpic acid
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10.1002/ejoc.201800070
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
OH
Drug discovery
OH
Br
Xiongyu Wu,* Malin Silverå Ejneby,
Nina E Ottosson, Fredrik Elinder, Peter
Konradsson
Pd2(dba)3
PCy3,
MW, 7 min
54% overall yield
Kv channel opener
H
HO
H
HO
H
HO
O
O
O
(+)-Callitrisic acid
Page No. – Page No.
Isomeric side product was supressed successfuly by the catalyst of
Pd2(dba)3/PCy3 in dioxan-water in the Suzuki-Miyaura coupling reaction of ortho
hydroxy aromatic bromide with isopropenylboronic acid pinacolester. (+)-Callitrisic
acid synthesized from (+)-podocarpic acid using this condition was found to be a
potent wild type voltage-gated potassium channel opener.
A Suzuki-Miyaura Coupling of Ortho
Hydroxy
Aryl
Bromide
with
Isopropenylboronic Pinacol Ester and
its Application:
Potassium-Channel
Callitrisic Acid
Synthesis of the
Opener (+)-
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