Negishi cross-coupling reaction as a route to isocombretastatins

Article abstract of DOI:10.1055/s-0033-1339334

A series of isocombretastatins A has been synthesized by a new method based on the Negishi cross-coupling reaction in 19-84% yields. Five of the synthesized compounds exhibit high cytotoxic activity in nanomolar concentrations (IC₅₀ = 1-100 n) towards Jurkat, K562, Colo357, and A549 cell lines. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1339334

1772▌
LETTER
lNetteergishi Cross-Coupling Reaction as a Route to Isocombretastatins
Synthesis of Isocombretastatins
Yulia B. Malysheva,a Svetlana Y. Buchvalova,a Elena V. Svirshchevskaya,b Valery V. Fokin,c Alexey Y. Fedorov*a
a
Department of Organic Chemistry, Lobachevsky State University of Nizhni Novgorod, 23 Gagarin avenue, Nizhni Novgorod 603950, Russian
Federation
Fax +7(831)4623085; E-mail: afnn@rambler.ru
b
М.М. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, 16/1 Miklucho-Maklaya str.,
В-437, Moscow 117997, Russian Federation
Fax +7(495)3306601; E-mail: esvir@mx.ibch.ru
c
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Fax +1(858)7847515; E-mail: fokin@scripps.edu
Received: 26.04.2013; Accepted after revision: 10.06.2013
Abstract: A series of isocombretastatins A has been synthesized by
a new method based on the Negishi cross-coupling reaction in 19–
84% yields. Five of the synthesized compounds exhibit high cyto-
toxic activity in nanomolar concentrations (IC50 = 1–100 nМ) to-
wards Jurkat, K562, Colo357, and A549 cell lines.
MeO
MeO
X
OMe
OMe
CA-4 X = OH
CA4P X = OP(O)(ONa)2
AVE8062 X = NH-Ser
Key words: isocombretastatins, antitubulin agents, turbo Grignard
reagent, Negishi cross-coupling, cytotoxicity
O
MeO
MeO
Y
MeO
MeO
R
Microtubules are dynamic proteins composed of tubulin
and are an attractive pharmacological target for anticancer
drugs.1 Combretastatins (Figure 1) belong to the family of
the most potent antitubulin agents whose phosphate and
ammonium salts are currently undergoing clinical trials.2
Despite the remarkable therapeutic activity, (Z)-stilbenes
are characterized by high tendency to double-bond isom-
erization during handling and storage leading to E-iso-
mers, that dramatically reduces their activity.3,4 The
phenstatins (bisarylketones) exhibit high potency as tubu-
lin polymerization inhibitors which are not prone to isom-
erization (Figure 1).5 The high antitumor activity of their
1,1-diarylethene analogues (Figure 1) was found during
the past several years.6 In contrast to their natural parent
combretastatins, isocombretastatins A (isoCA) can be
synthesized without the necessity of the double-bond ge-
ometry control. They do not suffer from the potential E/Z
isomerization and, in terms of structure–activity relation-
ship, they show that the optimal bridge length between
two aromatic pharmacophores is not necessarily two at-
oms like in natural combretastatins.6 Notably, isocombre-
tastatins A display the similar order of tubulin
polymerization inhibitory activity in comparison with the
best representatives of the combretastatin family.6,7
OMe
OMe
phenstatin Y = OH
phenstatin phosphate Y = P(O)(ONa)2
OMe
isocombretastatins A
Figure 1 Structure of combretastatins and their analogues
acetophenone derivatives12 or to Weinreb amides13 and
subsequent transformation of obtained tertiary alcohols,
the regioselective hydrostannation of terminal arylalkynes
and further Stille reaction or sequential iodolysis–Negishi
coupling.14
Previously, we developed a mild and stereoselective
method for synthesizing CA-4 analogues using Negishi
cross-coupling.15 This approach has been extended in the
current report for the preparation of isoCA via the se-
quence of a three-step, one-pot reaction, using palladium-
mediated cross-coupling of alkenylzinc reagents with dif-
ferent aryl halides (Scheme 1). The proposed method pro-
vides access to various 1,1-diarylethenes bearing different
substitution patterns.
In terms of structure–activity relationship, the 3,4,5-tri-
methoxyphenyl fragment of antitubulin ligands appears to
be critical for efficient colchicine-site binding.16 There-
fore the proposed methodology is based on the prepara-
There is a number of reported synthetic routes to isocom-
bretastatins using the Wittig reaction,6a,8 cross-coupling of
Grignard reagents9 and arylboronic acids10 with alkenyl
halides or phosphates, the palladium-catalyzed coupling
of N-tosylhydrazone with aryl halides11 or triflates,6b nu-
cleophilic addition of aryllitium or magnesium reagents to
tion of an organometallic reagent bearing
a
trimethoxyphenyl fragment. Such an approach afforded
the desired cross-coupling products using different types
of aryl halides without the synthesis of a number of or-
ganometallic compounds. The corresponding aryl-substi-
tuted terminal alkyne 2 was prepared from commercially
available 3,4,5-trimethoxybenzaldehyde (1) via Corey–
Fuchs alkyne synthesis.17 The reaction of arylacetylene 2
with B-Br-9-BBN afforded poor yield of the desired α-
bromostyrene, because of cleaving the methyl aryl ether.
SYNLETT 2013, 24, 1772–1776
Advanced online publication: 01.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339334; Art ID: ST-2013-B0387-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Isocombretastatins
1773
The regiochemical control of the hydrostannation of ter- Grignard reagent 4b give the product 5b-NHBoc in 41%
minal arylalkynes reported by Alami14 requires the para- yield in the presence of the same catalyst (Table 1, entry
π-electron-withdrawing or ortho-directing groups. The 11). The highest yield of 1,1-diarylethene 5b-NHBoc was
transformation of arylacetylene 2 to halostyrene 3 was achieved by Negishi cross-coupling reaction of alkenylz-
best achieved by α-selective Ni-catalyzed hydroalumina- inc reagent 4c with the corresponding aryl iodide cata-
tion followed by iodination reaction, according to the lyzed by SPhosPd(OAc)2 in THF at room temperature
method proposed by Hoveyda et al.18 (Scheme 1). Hy- (76%, Table 1, entry 14).
droalumination of arylacetylene 2 proceeds with a strong
Using these optimized conditions a range of isocombreta-
preference for α-vinylaluminum species in the presence of
statins 5a–k,21 containing the donor and acceptor aromatic
2 mol% Ni(dppe)Cl2 (Scheme 1). α-Iodostyrene 320 was
fragments, as well as heteroaromatic moieties, was syn-
thesized in good yields 58–84% (Table 2). Isocombreta-
statins containing the N-acetylphenyl group (5f and 5g)
were isolated in modest yields 19–26% (Table 2). In vitro
synthesized in 75% overall yield. Compound 3 was con-
verted into the corresponding alkenylmagnesium deriva-
tives 4a and 4b by the exchange reactions with i-PrMgCl
or turbo Grignard reagent (i-PrMgCl·LiCl) under mild
cytotoxicity of the synthesized compounds 5a–k was in-
conditions (–20 °C, 20 min, Scheme 1).15,19 Alkenylmag-
vestigated toward Jurkat, K562, Colo357, and A549 cell
lines. The obtained data are summarized in Table 2. Some
synthesized compounds (5a–e) manifest high antiprolifer-
ative activity in nanomolar range of concentrations
nesium derivative 4b was treated with 1 M ZnCl2 solution
in THF at –20 °C over one minute to give organozinc re-
agent 4c (Scheme 1). Organometallic reagents 4a–c were
used in Kumada or Negishi cross-coupling reactions with
(IC50 = 1–100 nМ).
the corresponding aryl iodides or bromides in the presence
In conclusion we have developed an efficient synthesis to
of palladium catalysts. A number of palladium complexes
isocombretastatins A, using palladium-mediated Negishi
cross-coupling reaction of α-alkenylzinc reagents with
different aryl halides. The proposed route permits to syn-
thesize isoCA analogues in good yield via the sequence of
three-step, one-pot reactions. Several prepared com-
pounds possess promising cytotoxic properties.
was tested during the optimization of cross-coupling reac-
tions with Boc-protected 3-amino-4-methoxyphenyl io-
dide (Table 1). Only trace amounts of the desired product
5b-NHBoc were achieved by Kumada cross-coupling
with organomagnesium reagent 4a in the presence of
SPhosPd(OAc)2 (Table 1, entry 6). The reaction using
BocHN
MeO
I
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
NHBoc
OMe
MeO
MeO
(a)
(c)
(b)
I
O
M
(d)
OMe
OMe
OMe
OMe
5b-NHBoc
OMe
4a M = MgCl
1
2 92%
3 81%
4b M = MgCl⋅LiCl
4c M = ZnCl⋅MgCl2⋅LiCl
Scheme 1 Synthetic methodology to isocombretastatins A. Reagents and conditions: (a) CBr4 (1.5 equiv), Ph3P (3 equiv), CH2Cl2, 0 °C, 2.5
h, 93%; BuLi (3.6 equiv, 2.5 M solution in hexane), THF, –78 °C, 2 h, 99%; (b) DIBAL-H (2 equiv), Ni(dppe)Cl2 (2 mol%), THF, r.t., 2 h; I2,
THF, –78 °C, 1.5 h, 81%; (c) i-PrMgCl (2 M solution in THF) or i-PrMgCl·LiCl (0.97 M solution in THF), –20 °C, 20 min; ZnCl2 (1 M solution
in THF), –20 °C, 1 min; (d) aryl iodide (1 equiv), palladium complex (4 mol%), r.t., 24 h.
Table 1 Cross-Coupling Optimization
Entry
Organometallic reagent
Solvent
THF
Catalyst
Yield (%)
1
2
3
4
5
6
(Ata-Phos)2PdCl2
Pd(Ph3P)4
DPE-PhosPd2(dba)3
SPhosPd2(dba)3
DPE-PhosPd(OAc)2
SPhosPd(OAc)2
0
0
0
0
0
4
MeO
MgCl
MeO
OMe
7
8
9
10
11
THF + NMP
DME
THF
THF
THF
Fe(acac)3
0
0
0
0
41
MeO
Fe(acac)3
MgCl⋅LiCl
(Ata-Phos)2PdCl2
Pd(Ph3P)4
MeO
SPhosPd(OAc)2
OMe
OMe
MeO
MeO
12
13
14
(Ata-Phos)2PdCl2
Pd(Ph3P)4
SPhosPd(OAc)2
0
15
76
ZnCl⋅MgCl2⋅LiCl
THF
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1772–1776

1774
Y. B. Malysheva et al.
LETTER
Table 2 Yields and Cytotoxicity of Isocombretastatinsa
MeO
MeO
MeO
MeO
R
(a)
ZnCl⋅MgCl2⋅LiCl
+
X
R
OMe
OMe
5a–k
4c
Product
Yield (%)
IC50 (μM)
Jurkat
K562
0.005
Colo357
10
A549
0.1
MeO
MeO
OH
5ab
79d
0.005
OMe
OMe
MeO
MeO
NH2
5bc
71d
81
0.005
0.1
0.005
0.005
0.001
0.01
0.01
0.1
OMe
OMe
OMe
OMe
MeO
MeO
NO2
5c
>1
OMe
MeO
MeO
NO2
5d
66
>10
>1
0.1
MeO
MeO
5e
5f
84
19
26
63
0.5
>1
>1
>1
>1
0.3
>40
>0.1
>10
10
SMe
OMe
OMe
OMe
OMe
MeO
MeO
NHAc
>10
5
MeO
MeO
5g
5h
>10
>10
10
NHAc
MeO
MeO
>10
N
MeO
MeO
5i
71
>10
>1
>10
>10
N
NHAc
OMe
Synlett 2013, 24, 1772–1776
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Isocombretastatins
1775
Table 2 Yields and Cytotoxicity of Isocombretastatinsa (continued)
MeO
MeO
MeO
MeO
R
(a)
ZnCl⋅MgCl2⋅LiCl
+
X
R
OMe
OMe
5a–k
4c
Product
Yield (%)
IC50 (μM)
Jurkat
K562
>1
Colo357
>10
A549
N
MeO
MeO
5j
60
>10
>10
>50
OMe
OMe
MeO
MeO
S
5k
58
>10
>1
>50
a Cross-coupling conditions: aryl halides (1 equiv), Pd(OAc)2 (4 mol%), SPhos (6 mol%), THF, r.t., 1–10 h.
b At the stage of the cross-coupling reaction the phenolic group was protected as MOM ether.
c At the stage of the cross-coupling reaction free amino group was protected as Boc amide.
d Overall yield for isocombretastatin preparation including the stage of protecting-group cleavage.
41, 1688. (b) Liou, J. P.; Chang, C. W.; Song, J. S.; Yang, Y.
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P. J. Med. Chem. 2004, 47, 4247. (d) Alvarez, C.; Alvarez,
R.; Corchete, P.; Perez-Melero, C.; Pelaez, R.; Medarde, M.
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Acknowledgment
This work was supported by Russian Foundation for Basic Research
(12-03-00214-а) and Federal Targeted Programme ‘Scientific and
Scientific-Pedagogical Personnel of the Innovative Russia in 2009–
2013’ (16.740.11.0476).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
(6) (a) Alvarez, R.; Alvarez, C.; Mollinedo, F.; Sierra, B. G.;
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m
iotSrat
ungIifoop
r
t
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LETTER
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syringe, followed by dropwise addition of DIBAL-H (4.18
mL, 1 M solution in toluene, 4.18 mmol) at r.t. (gas
evolution occurs as DIBAL-H is added). The resulting
solution was cooled to 0 °C and 3,4,5-trimethoxyphenyl-
acetylene (445 mg, 2.32 mmol) in THF (4 mL) was added
slowly. The resulting black solution was allowed to warm to
r.t. and stirred for 2 h. A solution of I2 in THF (5 mL, 1.768
g, 6.96 mmol) was added into the hydroalumination reaction
mixture at –78 °C. The resulting dark brown solution was
stirred for 1.5 h. Then a sat. solution of sodium potassium
tartrate (10 mL) was added to the reaction mixture, followed
by stirring for 10 min at r.t. The organic layer was separated,
and the aqueous layer was extracted with MeOt-Bu, the
combined organic layers were washed with brine, dried over
Na2SO4, then concentrated in vacuo, and the residue was
purified by flash chromatography on silica gel (PE–EtOAc,
8:1) to give 3 (602 mg, 1.88 mmol, 81%) as light yellow oil.
1H NMR (400 MHz, CDCl3): δ = 6.72 (s, 2 H), 6.39 (d, J =
1.7 Hz, 1 H), 6.02 (d, J = 1.7 Hz, 1 H), 3.87 (s, 6 H), 3.84 (s,
3 H). 13C NMR (101 MHz, CDCl3): δ = 152.56, 138.66,
137.49, 126.95, 107.24, 105.63, 60.96, 56.25.
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(21) Preparation of 5a-OMOM (Typical Procedure)
A dry argon-flushed Schlenk flask, equipped with a
magnetic stirrer and a septum, was charged with a solution
of 1-iodo-1-(3′,4′,5′-trimethoxyphenyl)ethylene (3, 48 mg,
0.15 mmol) in dry THF (1.5 mL). The solution of
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1986, 27, 4431.
i-PrMgCl·LiCl (0.17 mL of 0.97 M solution in THF, 0.165
mmol) was added slowly at –20 °C, and the reaction mixture
was stirred at this temperature for 20 min to complete the
I–Mg exchange. A 1 M solution of ZnCl2 (0.15 mL of 1 M
solution in THF, 0.15 mmol) was added dropwise for 1 min
at –20 °C, and the reaction mixture was warmed to r.t.
3-(Methoxymethoxy)-4-methoxyphenyl iodide (44 mg, 0.15
mmol) was placed in a round-bottom flask under argon.
Solution of Pd(OAc)2 (1.35 mg, 0.006 mmol) and SPhos (3.7
mg, 0.009 mmol) in THF (1 mL) was added, followed by
dropwise addition of prepared solution of organozinc
reagent (0.15 mmol) over a period of 1 min at r.t. The
reaction mixture was stirred at r.t. for 5 h, poured into sat. aq
NH4Cl solution and extracted with EtOAc. The organic layer
was washed with brine, dried over Na2SO4, concentrated in
vacuo, and the residue was purified by flash chromatography
on silica gel (PE–EtOAc, 5:1) to give 5a-OMOM (44 mg,
0.122 mmol, 81%) as brown oil. 1H NMR (400 MHz,
CDCl3): δ = 7.18 (d, J = 2.0 Hz, 1 H), 6.98 (dd, J = 8.4, 2.0
Hz, 1 H), 6.86 (d, J = 8.4 Hz, 1 H), 6.56 (s, 2 H), 5.38 (s, 1
H), 5.34 (s, 1 H), 5.21 (s, 2 H), 3.90 (s, 3 H), 3.87 (s, 3 H),
3.81 (s, 6 H), 3.50 (s, 3 H). 13C NMR (101 MHz, CDCl3):
δ = 153.00, 152.92, 149.88, 149.45, 145.97, 137.30, 134.12,
122.85, 116.87, 112.96, 111.34, 105.74, 95.68, 61.02, 56.36,
56.22, 56.02.
(20) Synthesis of 1-Iodo-1-(3′,4′,5′-trimethoxyphenyl)-
ethylene (3)
Ph3P (7.86 g, 30 mmol) was added to a solution of CBr4
(4.98 g, 15 mmol) in CH2Cl2 (60 mL) at 0 °C under argon
atmosphere. The resulting solution was stirred at 0 °C for 25
min. 3,4,5-Trimethoxybenzaldehyde (1.96 g, 10 mmol) in
CH2Cl2 (20 mL) was added dropwise. The solution was
stirred at 0 °C for 1.5 h. The solvent was removed under
reduced pressure, and the resulting oil was purified by
column chromatography on silica gel (PE–EtOAc, 4:1) to
give 1,1-dibromo-2-(3′,4′,5′-trimethoxyphenyl)ethylene
(3.27 g, 9.3 mmol, 93%) as pale yellow crystals. 1,1-
Dibromo-2-(3′,4′,5′-trimethoxyphenyl)ethylene (3 g, 8.52
mmol) was dissolved in THF (30 mL) and cooled to –78 °C.
n-BuLi (12.9 mL, 32.38 mmol, 2.5 M in hexane) was added
dropwise for 30 min. The solution was stirred at –78 °C for
2 h. Then sat. NH4Cl (20 mL) was added, and the solution
was warmed to r.t. The solution was extracted with EtOAc,
the combined organic layers were washed with brine, dried
over Na2SO4, then concentrated in vacuo, and the residue
was purified by flash chromatography on silica gel (PE–
EtOAc, 3:1) to give 2 (1.63 g, 8.43 mmol, 99%) as a white
solid. Ni(dppe)Cl2 (24 mg, 0.046 mmol) was placed in a dry
argon-flushed Schlenk flask equipped with a stir bar and
sealed with a septum. THF (5 mL) was added through a
Synlett 2013, 24, 1772–1776
© Georg Thieme Verlag Stuttgart · New York