クロスカップリング（リチャード・ヘック，根岸英一，鈴木章）

196 ◇ ヘック反応
98
ヘック反応
（Heck Reaction）
196
196
HECK REACTION
HECK REACTION
(References
are on page 596)
1 4
5 39
40 47
(References
page 596)
（重要論文
，総説
，改良と展開
，反応機 are on
Importance:
体的にすいているアルケン炭素上で置換反応が起こる．6）
ア
【発見の経緯と特徴】
Importance:
48 54
構研究
リールおよびビニル部の脱離基
（X）
の性質が反応速度に大きな
）
5-39
40-47
48-54
[Seminal Publications1-4
1-4; Reviews5-39; Modifications & Improvements40-47; Theoretical Studies48-54]
[Seminal
Publications
;
Reviews
;
Modifications
&
Improvements
;
Theoretical
Studies
]
1970 年代の初め，それぞれ別々に溝呂木および R. F. Heck
影響を与え，反応速度は I＞Br～OTf≫Cl の順になる．7）
ほと
In the early
T. Mizoroki and R.F. Heck independently んどの反応例では，下図の
discovered that aryl, benzylR1and
styryl halides react with
により，0
価の 1970s,
Pd 触媒および嵩高いアミンの存在下に，ア
はアリール，芳香族ヘテロ環，
(0)
In
the early
1970s, T.
R.F. Heck in
independently
thatamine
aryl, benzyl
andcatalytic
styryl halides
react
with
olefinic
compounds
at Mizoroki
elevatedand
temperatures
the presencediscovered
of a hindered
base and
amount
of Pd
to form aryl-, benzyl-, and styryl-substituted olefins.1-3 Today, the palladium-catalyzed arylation or alkenylation of
1 3
Today,
theHeck
palladium-catalyzed
arylation
or the
alkenylation
of
to formisaryl-,
benzyl-,
styryl-substituted
olefins.
反応してカップリング体を与えることが見いだされた
．今日
いアルキル基の場合も反応が進行する．またこれらの基は電子
olefins
referred
to as and
the Heck
reaction. Since
its
discovery,
the
reaction has become
one of
most widely
olefins
is
referred
to
as
the
Heck
reaction.
Since
itsorganic
discovery,
the Heck
reaction
has
become
onereaction
of the most
widely
used
catalytic
carbon-carbon
bond
forming
tools
in
synthesis.
The
general
features
of
the
are:
1)
it
is
では，この Pd 触媒によるオレフィンのアリール化またはアル
供与性でも求引性でもかまわない．8）触媒活性種は適当な前
used applied
catalyticfor
carbon-carbon
bond
tools inolefins
organic
synthesis.
The general
features
the reaction
are: 1)
is
best
the preparation
offorming
disubstituted
from
monosubstituted
ones;
2) theofelectronic
nature
of itthe
ケニル化反応を
反応
と呼ぶ．発見以来，この
反応
駆体
〔たとえば
Pd
（OAc）
（
PPh
から反応系内で調
Heck
best
applied Heck
forthe
the
preparation
disubstituted
olefins
from
monosubstituted
ones;
2)Pdthe
electronic
nature of the
3）
4 など〕
substituents
on
olefin
only hasoflimited
influence
on the
outcome
of the reaction;
it2 や
can
be
either
electron-donating
substituents
on the olefinbut
only
has limited
influence
onolefins
the outcome
of theyields;
reaction;
it can
be either
electron-donating
は有機合成において触媒的に炭素⊖炭素結合を形成させる手段
製され，反応は単座または二座のホスフィン配位子と塩基の存
or electron-withdrawing
usually
the electron
poor
give higher
3) the
reaction
conditions
tolerate a
or
electron-withdrawing
but
usually
the
electron
poor olefins
give higher
yields;
3) the
reaction
conditions
tolerate
a
wide
range
of
functional
groups
on
the
olefin
component:
esters,
ethers,
carboxylic
acids,
nitriles,
phenols,
dienes,
として広く用いられている．この反応の一般的な特徴は以下の
在下で行われる．9）
水や酸素が存在しても反応はそれほど影
wide
range
functional for
groups
the olefin
esters,
ethers,
carboxylic4)acids,
nitriles, phenols,
dienes,
etc., are
allofwell-suited
the on
coupling,
butcomponent:
allylic alcohols
tend
to rearrange;
the reaction
rate is strongly
etc.,
are all
well-suited
the coupling,
butolefin
allylic
alcohols
tend
to rearrange;
the undergoes
reaction rate
is strongly
通りである．1）
一置換オレフィンから二置換オレフィンを合
響を受けないので，溶媒などを厳密に無水・無酸素状態にする
influenced
by
the degree for
of substitution
of the
and
usually
the more
substituted4)olefin
a slower
Heck
influenced5)by
the degree ofolefins
substitution
the olefin
and usually
the moreundergo
substituted
olefin undergoes
a slower
Heck
reaction;
unsymmetrical
(e.g., of
terminal
alkenes)
predominantly
substitution
at the least
substituted
b ⊖水素脱離の
成するのに最も利用される．2）
オレフィン上の置換基の電子
必要はない．10）
オレフィン挿入反応，および
reaction;
5)
unsymmetrical
olefins
(e.g.,
terminal
alkenes)
predominantly
undergo
substitution
at
the
least
substituted
olefinic carbon; 6) the nature of the X group on the aryl or vinyl component is very important and the reaction rates
的性質は反応にあまり影響を与えない．すなわち，電子供与基
1 過程はシン選択的に進行するため立体選択性が高い．一方，
olefinic carbon;
6) the nature
the7)aryl
component
is veryis important
and thealkenyl,
reaction
rates
group
in most cases
aryl, heteroaryl,
benzyl,
change
in the following
order:ofI >the
Br X~ group
OTf >>onCl;
theorR1vinyl
group
in には以下に示すいくつかの欠点もある．1）
most cases
aryl, heteroaryl,
alkenyl,
benzyl,
change
in
the
following
order:
I
>
Br
~
OTf
>>
Cl;
7)
the
R
b ⊖水素を
および求引基を置換基としてもつオレフィンのいずれも反応に
反応
Heck
and rarely alkyl (provided that the alkyl group possesses no hydrogen
atoms
in theisβ-position),
and these
groups
can
and
rarelyelectron-donating
alkyl (provided that
alkyl group possesses
hydrogen
atomscatalyst
in the β-position),
and
groups
can
be either
or the
electron-withdrawing;
8) thenoactive
palladium
is generated
in these
situ from
suitable
b ⊖水素脱離を
適用できるが，一般に電子求引基をもつもののほうがよい結果
もつ基質は
Pd 触媒への酸化的付加後速やかに
be
either electron-donating
electron-withdrawing;
8)
the
active
palladium
catalyst
is
generated
in
situ
from
suitable
, Pd(PPh
)
)
and
the
reaction
is
usually
conducted
in
the
presence
of
monodentate
or
precatalysts
(e.g., Pd(OAc)2or
3 4
を与える．3）
基質のオレフィン部にさまざまな官能基が存在
起こす傾向があるため，カップリング基質として適していない．
Pd(PPh
the reaction
conducted
in theand
presence
of monodentate
or
precatalysts
(e.g., Pd(OAc)
2, and
3)4) and
bidentate
phosphine
ligands
a base;
9) the
reaction is
is usually
not sensitive
to water,
the solvents
need not be
bidentate
ligands
and
base;
9) the
reaction
is2）
not
sensitive
and insertion
the solvents
need
not be
しても反応は進行する．エステル，エーテル，カルボン酸，ニ
塩化アリール化合物は反応性が低く，一般に基質としては
thoroughlyphosphine
deoxygenated;
and
10)a the
Heck
reaction
is stereospecific
as to
thewater,
migratory
of the
palladium
thoroughly
deoxygenated;
the Heck
reactionboth
is stereospecific
migratory insertion
thea palladium
complex into
the olefin andand
the 10)
β-hydride
elimination
proceed
with as
synthe
stereochemistry.
Thereofare
couple
トリル，フェノール，ジエンなどはカップリング反応により適
適していない．また最近では，1）
触媒的不斉
反応ofの開
Heck
complex
into
the
olefin
and
the
β-hydride
elimination
both
proceed
with
syn
stereochemistry.
There
are
a couple of
drawbacks of the Heck reaction: 1) the substrates cannot have
23，26hydrogen atoms on their β-carbons, because their
17，
55，34
した官能基であるが，アリルアルコールは転位反応を起こす傾
発 hydrogen
，2）分子内 Heck 反応
による四級炭素中心の構築
，
drawbacks
of the
Heck reaction:derivatives
1) the substrates
on their
because
their
corresponding
organopalladium
tend to cannot
undergohave
rapid β-hydrideatoms
elimination
toβ-carbons,
give olefins;
and
2)
aryl
56，57，47
corresponding
organopalladium
derivatives
tend
to
undergo
rapid
β-hydride
elimination
to
give
olefins;
and
2)
aryl
向にある．4）
3）親水性触媒を用いた水中での反応の開発
，および 4）
chlorides オレフィン上の置換形式は反応速度に大きく影
are not always good substrates because they react
very slowly. Several modifications were introduced
23,36 they react very slowly. Several modifications were introduced
chlorides
always1)good
substrates
because
2)
generation
of
quaternary
stereocenters
in
the
intramolecular
during theare
pastnot
decade:
asymmetric
versions;
響し，一般的には多置換オレフィンほど反応速度は遅い．5）
Pd⊘C
などの不均一系
Pd
触媒を用いた反応の開発などの改良
23,36
56,57,47
2) generation of quaternary
stereocenters in the intramolecular
duringreaction;
the past17,55,34
decade: 1) asymmetric versions;
Heck
17,55,34 3) using water as the solvent with water-soluble catalysts;40
56,57,47 and 4) heterogeneous palladium
末端アルケンのような非対称オレフィンとの反応では，より立
が加えられている
．
403) using water as the solvent with water-soluble
Heck
reaction;
catalysts;
and 4) heterogeneous palladium
on carbon catalysis.40
on carbon catalysis.
リール，ベンジル，およびハロゲン化スチリルとオレフィンが
アルケニル，ベンジル基であり，まれに
位に水素をもたな
1-3
olefinic compounds at elevated temperatures in the presence
of a hindered amine base and catalyticbamount
of Pd(0)
R11 X
R X
+
+
H
H
R44
R22
R
R33
R
R11
R
Pd(0)
(catalytic)
Pd(0) (catalytic)
ligand, base, solvent
ligand, base,
heat solvent
heat
R
R44
R
R22
R33
R
R
Arylated or alkenylated
Arylated olefin
or alkenylated
olefin
R11 = aryl, benzyl, vinyl (alkenyl), alkyl (no β hydrogen); R22, R33, R44 = alkyl, aryl, alkenyl; X = Cl, Br, I, OTf, OTs, N2++;
R = aryl, benzyl, vinyl (alkenyl), alkyl (no β hydrogen); R , R , R = alkyl, aryl, alkenyl; X = Cl, Br, I, OTf, OTs, N2 ;
ligand = trialkylphosphines, triarylphosphines, chiral phosphines; base = 2° or 3° amine, KOAc, NaOAc, NaHCO3
ligand = trialkylphosphines, triarylphosphines, chiral phosphines; base = 2° or 3° amine, KOAc, NaOAc, NaHCO3
Mechanism: 58,59,21,22,51,53
58,59,21,22,51,53
Mechanism:
58，59，21，
23，51，53
Heck 反応の機構は完全には解明され
媒に対する酸化付加の段階である．このほかにも，アニオン性
【反応機構】
The mechanism of the Heck reaction is not fully understood and the exact mechanistic pathway appears to vary
The mechanism
of the
Heck reaction
is not
understood
and
the exactsequence
mechanistic
pathway
appearswith
to vary
ておらず，また反応条件によっても反応経路が若干異なる．下
またはカチオン性反応中間体を経由する機構がさまざまな実験
subtly
with changing
reaction
conditions.
Thefully
scheme
shows
a simplified
of events
beginning
the
(0)21，
subtly with of
changing
reaction
conditions.
The
scheme shows
a issimplified
sequence
of of
events
beginning
with
the
36
the active
Pd(0)
catalyst.
The
rate-determining
step
the
oxidative
addition
Pd
into
the
C-X
bond.
図はgeneration
0 価の Pd 触媒によって進行する反応の一般的な機構を示
結果を説明するために提唱されている
．
(0)
(0)
generation
of
the
active
Pd
catalyst.
The
rate-determining
step
is
the
oxidative
addition
of
Pd
into
the
C-X
bond.
To account for various experimental observations, refined and more detailed catalytic cycles passing through anionic,
している．この反応の律速段階は，基質の
C ⊖ X 結合の refined
Pd 触
To
account
for various
experimental
observations,
cationic
or neutral
active
species have
been proposed.21,36and more detailed catalytic cycles passing through anionic,
cationic or neutral active species have been proposed.21,36
Pd(0)
or Pd(II) complexes (precatalysts)
Pd(0) or Pd(II) complexes (precatalysts)
- HX
- HX
R11 X
R X
LnPd(0)
base
oxidative
reductive base
LnPd(0)
oxidative
addition
addition
reductive
eliminaton
eliminaton X
R11
R
R44
R
R22
R
R33
R
X
LnPd(II)
LnPd(II)
H
H
X
X
LnPd(II)
LnPd(II)
R11
R
syn β -hydride
syn
β -hydride
elimination
H
elimination H
Pd(II)
L nX
Pd(II)LnX
R22 1 3 R44
R R1 R3 R
R R
C-C bond rotation
C-C bond rotation
H
H
R44
R
R22
R33
R
R
migratory
migratory
insertion
(syn)
insertion (syn)
R11
Pd(II)
L nX
R
Pd(II)LnX
4
H 2 3 R4
H R2 R3 R
R R
197
197
197
HECK REACTION
HECK REACTION
HECK REACTION
Heck Reaction ◇ 197
Synthetic Applications:
Synthetic Applications:
Synthetic Applications:
Ecteinascidin　エクティナサイジン
743 is a potent antitumor
agent that was
isolated
from a marine
T. Fukuyama
et al. applied the
743（ecteinascidin
743）
つ基質を
5 mol％ tunicate.
Pd 触媒および
20 mol％のホスフィン配位子
【合成への展開】
Ecteinascidin
743
is areaction
potent antitumor
was
isolated
from
marine
tunicate.
T. Fukuyama
et 60
al.Toward
applied this
the
intramolecular
Heck
as the keyagent
step that
in the
assembly
of
thea
central
bicyclo[3.3.1]
ring system.
Ecteinascidin
743
is
a
potent
antitumor
agent
that
was
isolated
from
a
marine
tunicate.
T.
Fukuyama
et 60
al.Toward
applied this
the
は海洋産の被嚢類から単離された抗腫瘍活性化合物である．福
とアセトニトリル中，還流条件下で反応させると，望みの三環
intramolecular
Heck
reaction
as
the
key
step
in
the
assembly
of
the
central
bicyclo[3.3.1]
ring
system.
60
end, the cyclic Heck
enamide
precursor
was
exposed
to 5assembly
mol% of palladium
catalyst
and 20 mol%
of a phosphine
ligand
intramolecular
reaction
as
the
key
step
in
the
of
the
central
bicyclo[3.3.1]
ring
system.
Toward
this
end,
the cyclic
enamidetoprecursor
was
exposed
to 5分子
mol% of性構造をもつ化合物が
palladium
catalyst yield.
and
20 mol% of a phosphine ligand
山らはこの化合物がもつビシクロ
［3．
3．
1］
環を構築する際に
83％の収率で得られた．
in refluxing
acetonitrile
afford
the
desired
tricyclic
in 83% isolated
end,
the cyclic
enamidetoprecursor
exposed
to 5intermediate
mol% of palladium
catalyst yield.
and
20 mol% of a phosphine ligand
in refluxing
acetonitrile
afford thewas
desired
tricyclic
intermediate
in 83% isolated
60
in refluxing
acetonitrile
to afford the desired tricyclic intermediate in 83% isolated yield.
内 Heck
反応を利用した
．すなわち，環状エナミド構造をも
BnO
BnO
BnO
RO
RO
RO
Me
Me
Me
I
I
I Boc
Boc
Boc
N
N
N
N
N
Me
N
Me
Me
Me
Me
Me
Boc
Pd2(dba)3
Boc
Pd
(dba)3 RO
Boc
2mol%)
(5
Pd2(dba)3 RO
N
(5
mol%)
RO
o
-tol)
P(
O
3
N
(5 mol%)
BnO
O
-tol)3
P(omol%)
N
O
P(o-tol)3
BnO
O
O OAc (20
(20 mol%)
N
BnO
O OAc
OAc (20 mol%)
N
CN
TEA,
CH
OAc
3
OAc
H 2C
N
CN
TEA,
CH
OAc
H
reflux3
H 2C
H
TEA,
CH3CN
H
reflux
H
C
83%
2
H
HO
MsO
reflux
83%
HO
MsO
MsO
O
83%
MsO
MsO
O
O
MsO
O
O
Me
O
Me
O
Me
O
Me
R = Me O
Me
O
Me
R = Me
R = Me
RO
RO
RO
steps
steps
steps
Me
Me
Me
Me
Me
Me
N
N
N
OH O
OH O
O HN
OH
O
HN
O
HN
HO
H
H
AcO
O
AcO
O
AcO
O
O
MeO
Me
O
MeO
Me
O
MeO
Me
Ecteinascidin
743
Ecteinascidin 743
Ecteinascidin 743
HO
HO
HO
H
H
H
N
N
SN
S
S
OH
OH
OH
The introduction of the C3 quaternary center was the major challenge during the total synthesis of asperazine by L.E.
The introduction
of the C361quaternary
center
was the major
challenge
during the total
synthesis of asperazine
by L.E.
address
this synthetic
problem,
a diastereoselective
intramolecular
Heckmoiety
reaction
Overman
co-workers.
61 To
used.
Theand
α,β-unsaturated
amide
precursor
was efficiently
coupled
with the tethered
aryl iodide
in was
the
おいては，C3
位の第四級炭素の導入が大きな課題であったが，
ド部と側鎖のヨウ化アリール部との反応がジアステレオ選択的
address
this synthetic
problem,
a diastereoselective
intramolecular
Heck reaction
was
Overman
and
co-workers. To
used.
The
α,β-unsaturated
amide
precursor
was
efficiently
coupled
with
the
tethered
aryl
iodide
moiety
in was
the
(dba)
⋅CHCl
and
one
equivalent
of
(2-furyl)
P
ligand.
The
desired
hexacyclic
product
presence
of
20
mol%
Pd
2
3
3
3
used. The α,β-unsaturated 分子内
amide Heck
precursor
was efficientlyに進行し，目的とする中間体が単一ジアステレオマーとして
coupled with the tethered aryl iodide moiety in the
この問題はジアステレオ選択的な
反応one
によって解
(dba)
⋅CHCl
and
equivalent
of
(2-furyl)
P
ligand.
The
desired
hexacyclic
product
was
presence
of
20
mol%
Pd
2
3
3
3
obtained
as
single
in 66%
yield.
presence
of a
mol%diastereomer
Pd2(dba)3⋅CHCl
3 and one equivalent of (2-furyl)3P ligand. The desired hexacyclic product was
61
obtained
as
a20single
diastereomer
in366%
yield.
決された
．すなわち，20
mol％ Pd（dba）
・CHCl
66％の収率で得られた．
2
3 と 20 mol％
obtained as a single diastereomer
in 66% yield.
The
introduction
of the C361quaternary
center
was
the major
challenge
during
the total
synthesis of asperazine
by L.E.
a，b ⊖不飽和アミ
L.Overman
E. Overman
らによるアスペラジン
（asperazine）
の全合成に
（2 a
⊖ フリル）
3P 存在下に反応を行うと，基質の
To address
this synthetic
problem,
diastereoselective
intramolecular
Heck reaction
was
and
co-workers.
H
H
H
NR RN
NR RN
NR RN
H
H
H
O
O
O
NBoc
NBoc
NBoc
O
O
O
N
Boc
N
N
Boc
Boc
O
O
OI
I
I
Pd2(dba)3·CHCl3
Pd2(20
(dba)
3·CHCl3
mol%)
Pd2(dba)
3·CHCl3
(20
mol%)
P(2-furyl)
(20 mol%)3
P(2-furyl)
(20
mol%)3
P(2-furyl)
(20 mol%)3
(20
mol%)
PMP,
DMA
PMP,
DMA
90 °C
PMP,
DMA
90
°C
66%
90
°C
66%
66%
R = SEM
R = SEM
R = SEM
BocN
BocN
BocN
NR
NR
NR
H
H
H
O
O
O
3
3
3
O
O
HO
H
H
O
O
O
O
O
O
NR
NR
NR
steps
steps
steps
NH
NH
NH
3
3
3
NH
NH
NH
N
H
N
H
O
H
N
H
H O
NH
H O
NH
NH
Ph
Ph
Ph
NH
H
NH
H
OH
NH O
O
O
HO
O HN
HN
H
HN
H Ph
Ph
Asperazine
Ph
Asperazine
Asperazine
NBoc
NBoc
NBoc
The total
synthesis
of the potent anticancer macrocyclic natural
product Heck
lasiodiplodin
was achieved in the laboratory
また，A.
Fürstner
らにより抗腫瘍活性をもつラシオジプロ
体の合成に
反応が用いられている．アリールトリフラー
62
TheA.total
synthesis
of key
the potent
anticancer step
macrocyclic
natural
was achieved
in the derivative,
laboratory
of
Fürstner.
The
macrocyclization
was carried
outproduct
by thelasiodiplodin
alkene metathesis
of a styrene
which
was
prepared
in
excellent
yield
via
an
intermolecular
Heck
reaction
between
an
aryl
triflate
and
high-pressure
of
A. Fürstner.
Theinkey
macrocyclization
was carried
out reaction
by the alkene
metathesis
of a styrene
derivative,
which
was
prepared
excellent
yield via anstep
intermolecular
Heck
between
an aryl triflate
and high-pressure
鍵段階である大員環構築の段階では
アルケンメタセシス
が用い
率でスチレン誘導体が合成された．
ethylene
gas.
which
was
prepared
in
excellent
yield
via
an
intermolecular
Heck
reaction
between
an
aryl
triflate
and
high-pressure
ethylene gas.
ethylene gas.
られているが，そのメタセシス反応の基質であるスチレン誘導
62
62
TheA.total
synthesis
of the potent anticancer
macrocyclic
natural
was achieved
in the
laboratory
ジン（lasiodiplodin）
の合成が達成されている
．この合成では，
トと高圧下のエチレンガスとの
分子間
反応derivative,
により，高収
of
Fürstner.
step
was carried
outproduct
by thelasiodiplodin
alkene metathesis
of a Heck
styrene
62 The key macrocyclization
OMe O
OMe O
OMe O
MeO
MeO
MeO
O
O
O
OTf
OTf
OTf
H2C CH2
H(40
2C CH2
H2C bar)
CH
(40 bar) 2
(40
bar) 3)2
PdCl
2(PPh
PdCl
2(PPh3)2
(5 mol%)
PdCl
2(PPh3)2
(5 mol%)
LiCl,
Et3N
(5 mol%)
LiCl, Et
DMF,
903N
°C
LiCl,
Et
DMF,
903N
°C
20h; 92%
DMF,
90
°C
20h; 92%
20h; 92%
OMe O
OMe O
OMe O
MeO
MeO
MeO
O
O
O
styrene derivative
styrene derivative
styrene derivative
OMe O
OMe O
OMe O
steps
steps
steps
MeO
MeO
MeO
O
O
O
Lasiodiplodin
Lasiodiplodin
Lasiodiplodin
310 ◇ ①根岸クロスカップリング
155
根岸クロスカップリング
（Negishi Cross−Coupling）
【発見の経緯と特徴】（重要論文1 6，総説7 24，改良と展開25 32）
310
1972 年のニッケル触媒を用いるハロゲン化アルケニルおよ
は活性化された亜鉛との直接反応，あるいは有機リチウムまた
はマグネシウム反応剤と亜鉛ハロゲン化物（ZnX2）
とのトラン
NEGISHI CROSS-COUPLING
33，34
びアリールと Grignard 反応剤のカップリング反応
（
熊田クロス are on
スメタル化によって調製できる
．6）有機亜鉛反応剤を用い
(References
page 637)
310
Importance:
カップリング
）の発見以来，リチウムやマグネシウムよりも陽
るこの反応は，有機リチウム化合物あるいは Grignard 反応剤
NEGISHI CROSS-COUPLING
性度が低い金属からなる有機金属化合物を用いて，カップリン
を用いる
熊田クロスカップリング
に比べて，求核剤と求電子剤
1-6
are; Modifications
on
page 637)
[Seminal Publications(References
; Reviews7-24
& Improvements25-32]
Importance:
グ反応の官能基選択性を向上させるという努力が見られた．
のいずれに関してもはるかに優れた官能基選択性を示す．7）
In 1972, after the discovery of Ni-catalyzed1-6coupling of
alkenyl
and aryl halides with Grignard
reagents (Kumada
7-24
25-32
1976 年に根岸らは，ニッケル触媒を用いるアルケニルアラン
有機亜鉛化合物を用いる他の利点として，高い反応性・高い位
[Seminal
Publications
Reviews
; Modifications
& Improvements
] of the process, the
cross-coupling), it became
apparent
that in ;order
to improve
the functional
group tolerance
（有機アルミニウム反応剤）
のクロスカップリング反応として，
置選択性・高い立体選択性・幅広い適用範囲・幅広い応用性・
organometallic coupling
partners should contain less electropositive
metals than lithium and magnesium. In 1976, E.
In
1972,and
afterco-workers
the discovery
of Ni-catalyzed
coupling ofNi-catalyzed
alkenyl and alkenyl-alkenyl
aryl halides with
reagents
(Kumada
Negishi
reported
the
first
stereospecific
andGrignard
alkenyl-aryl
cross-coupling
ハロゲン化アルケニルおよびアリールとの立体特異的なアルケ
副反応の少なさ・毒性がほとんどないことがあげられる．8）
1,2 functional group tolerance of the process, the
cross-coupling),
it
became
apparent
that
in
order
to
improve
the
of alkenylalanes (organoaluminums) with alkenyl- or aryl halides. 2 Extensive research by Negishi showed that2 the
ニル⊖アルケニルおよびアルケニル⊖アリールカップリングを報
C
（sp ）
同士の反応が最もよく用いられるが，C
C
（sp）
カ
organometallic
coupling
partners
should
contain less electropositive
metals
than lithiumare
and
magnesium.
In （sp
1976,）⊖E.
best results (reaction
rate,
yield, and
stereoselectivity)
are obtained
when
organozincs
coupled
in the presence
of
3,4,7
Negishi
and
co-workers
reported
the
first
stereospecific
Ni-catalyzed
alkenyl-alkenyl
and
1，2 (0)
2
3 alkenyl-aryl cross-coupling
-catalysts.
The Pd- or Ni-catalyzed（stereoselective
cross-coupling
of organozincs
and aryl-, alkenyl-, or
告したPd．根岸らによるより詳細な検討の結果，Pd
0）
触媒を
ップリングや
C
（sp
）
⊖C
（sp ）カップリングも知られている．9）
1,2
by Negishi
showed
that Pdthe
of
alkenylalanes
with
alkenyl- or aryl
halides.
alkynyl
halides is (organoaluminums)
known as the Negishi
cross-coupling.
The
general Extensive
features ofresearch
the reaction
are: 1) both
Ni- and
用いる有機亜鉛化合物のカップリング反応が，反応速度・収
有機亜鉛化合物のほかに，有機アルミニウムおよび有機ジルコ
best
results
(reaction
rate,
yield,
and
stereoselectivity)
are
obtained
when
organozincs
are
coupled
in
the
presence
of
phosphine
complexes
work well as catalysts. However, the Pd-catalysts tend to give somewhat higher yields and
(0)
3,4,7
-catalysts.
The and
Pd- their
or Ni-catalyzed
stereoselective
organozincs
aryl-,有機アルミニウムあ
alkenyl-,
or
Pd
better
stereoselectivity,
functional group
tolerance ニウム化合物も用いることができる．10）
iscross-coupling
better; 2) the of
active
catalysts and
are relatively
unstable
率・立体選択性の観点から最も良好な結果を与えることがわか
(0)
(II)
alkynyl
halides
is known as but
the these
Negishi
cross-coupling.
general
of theNi
reaction
both Ni- and
Pd- and
Pd(0)-complexes
can
be generatedThe
in situ
fromfeatures
more stable
- and are:
Pd(II)1)
-complexes
with
a
Ni
7
った3，4，phosphine
．パラジウムあるいはニッケル触媒による有機亜鉛化
るいは有機ジルコニウム化合物の反応性が十分でない場合には，
complexes
work
well
as
catalysts.
However,
the
Pd-catalysts
tend
to
give
somewhat
highercatalyst,
yields and
reducing agent (e.g., 2 equivalents of DIBAL-H or n-BuLi); 3) in the absence of the transition metal
the
better stereoselectivity,
their with
functional
grouphalides
tolerance
is better;
2) theextent;
active 4)
catalysts
relatively
合物とハロゲン化アリール，アルケニル，アルキニルの立体選
亜鉛の塩を加えてトランスメタル化すればよい．この方法を
複
organozinc
reagents
do and
not react
the alkenyl
to any
appreciable
the mostare
widely
used unstable
ligand is
(0)
(0)
Pd
-complexes
butchiral
thesephosphine
can be generated
in situbeen
fromsuccessfully
more stable
Ni(II)- and
Pd(II)various
-complexes
with a
Ni -3,and
35 used;
but
other
achiral
and
ligands
have
5)
the
organozinc
PPh
択的なクロスカップリング反応は
根岸クロスカップリング
と呼
合金属触媒
と呼ぶ．11）
を含む有機
reducing
agent
2 equivalents
of DIBAL-H
3) inhalide
the absence
the Al，Zr，B，Sn，Cu，Zn
transition
metal
reagents can
be(e.g.,
prepared
by either direct
reactionorofn-BuLi);
the organic
with zincofmetal
or activated
zinccatalyst,
metal orthe
by
33,34 used ligand is
organozinc
reagents
do
not
react
with
the
alkenyl
halides
to
any
appreciable
extent;
4)
the
most
widely
ばれている．この反応の一般的な特徴は以下の通りである．1）
金属化合物のうち，通常有機亜鉛化合物がパラジウム触媒クロ
6) the use of
transmetallation of the corresponding organolithium or Grignard reagent with a zinc halide (ZnX2);
achiral
and for
chiral
phosphine
havegroup
been tolerance
successfully
used;coupling
5) thepartners
various than
organozinc
PPh
3, but other
organozinc
reagents
allows
a much
greaterligands
functional
in both
in the （たと
ニッケルおよびパラジウムのホスフィン錯体が触媒として働く
スカップリング反応において最も反応性が高く，添加物
reagents
can
be
prepared
by
either
direct
reaction
of
the
organic
halide
with
zinc
metal
or
activated
zinc
metal
by
Kumada cross-coupling where organolithiums and Grignard reagents are utilized as coupling partners;
7) or
other
33,34
が，パラジウム触媒を用いたほうが収率および立体選択性が若
えば，
鈴木クロスカップリング
における塩基）
6) scope
theを必要としな
useand
of
transmetallation
of the
Grignard
reagent
with and
a zinc
halide (ZnX
2); wide
advantages
of the
usecorresponding
of organozincsorganolithium
include: highorreactivity,
high
regio-,
stereoselectivity,
2
20
organozinc
reagents
allows
for
a
much
greater
functional
group
tolerance
in
both
coupling
partners
than
in
the
applicability, few side reactions and almost
no toxicity; 8) theいreaction
is mostly used for the
coupling of two C(sp )
干高く，官能基選択性でも優れている．2）
触媒活性種は比較
．根岸クロスカップリング
の制約は以下の通りである．1）
3
Kumada
cross-coupling
Grignardare
reagents
are utilized
as coupling
partners;
7) other
carbons but
C(sp2)-C(sp)where
as wellorganolithiums
as C(sp2)-C(spand
) couplings
well-known;
9) besides
organozincs,
compounds
of
的不安定な
Ni
（0）
および
Pd
（0）
錯体であるが，これらはより安
ホモプロパルギル亜鉛は反応するがプロパルギル亜鉛はカップ
advantages
of the
organozincs
high reactivity,
high
regio-, and stereoselectivity,
and
Al and Zr can
alsouse
be ofutilized;
10) if include:
the organoaluminum
and
organozirconium
derivatives arewide
not scope
sufficiently
2
)
applicability,
few
side
reactions
and
almost
no
toxicity;
8)
the
reaction
is mostly
used
for the coupling
of
two C(sp
定な Ni
（II）およthey
び Pd
（II）
錯
体
に
還
元
剤
（た
と
え
ば，2
当
量
の
リングしない．2）
第二級および第三級のアルキル亜鉛は異性
reactive,
can
be
transmetallated
by
the
addition
of
zinc
salts,
and
this
protocol
is
referred
to
as
the
double
metal
2
2
3
35
carbons
butand
C(sp
)-C(sp)
as well
as C(sp
)-C(sp ) couplings
are
well-known;
9) besidesare
organozincs,
compounds
of
11)
of
all
the
various
organometals
(Al,
Zr,
B,
Sn,
Cu,
Zn),
organozincs
usually
the
most
reactive
catalysis;
DIBALAl
⊖ Hand
や nZr
⊖ BuLi）
化を起こしてしまうが，第一級アルキル亜鉛およびベンジル亜
can を作用させることで系中で容易に発生さ
also
be utilized;reactions
10) if the
anduse
organozirconium
derivatives
areinnot
sufficiently
in Pd-catalyzed
cross-coupling
andorganoaluminum
do not require the
of additives (e.g.,
bases as
Suzuki
cross20
reactive,
can遷移金属触媒非存在下では，有機亜鉛
be
transmetallated
by the
addition
of zincofsalts,
and thiscross-coupling
protocol is referred
topropargylzincs
as有機亜鉛化合物の高い反
the doubledo
metal
せることができる．3）
鉛は問題なくカップリングする．3）
Some
of
the
limitations
the
Negishi
are:
1)
not
couplings)they
to
boost
the
reactivity;
35
and
11)
of all the various do;
organometals
(Al,and
Zr, B,
Sn, Cu,
Zn), organozincs
are usually
the most
reactive
catalysis;
couple
well
but
homopropargylzincs
2)
secondary
tertiary
alkylzincs
may
undergo
isomerization,
but
cross反応剤はハロゲン化アルケニルとまったく反応しない．4）
応性のために，より反応性が低い有機スズ化合物の反応
in Pd-catalyzed
cross-coupling
reactions and
not 最
requireresults;
the use
of 3)
additives
(e.g.,
as inorSuzuki
cross- （カル
couplings
of primary
alkyl- and benzylzincs
givedosatisfactory
and
due to the
highbases
reactivity
organozincs,
20
couplings)
to
boost
the
reactivity;
Some
of
the
limitations
of
the
Negishi
cross-coupling
are:
1)
propargylzincs
do
not
もよく用いられる配位子は
PPh
であるが，他のアキラルある
ボニル化を伴う
カップリング
の項，p.
436
参照）
とは異な
Stille
3
CO insertion usually does not happen unlike in the case of less reactive organotins (see carbonylative Stille crosscouple
well but homopropargylzincs do; 2) secondary and tertiary alkylzincs may undergo isomerization, but crosscoupling).
いはキラルなホスフィン配位子も問題なく利用できる．5）さ
り，通常，一酸化炭素の挿入を伴うカップリングは困難である．
couplings of primary alkyl- and benzylzincs give satisfactory results; and 3) due to the high reactivity or organozincs,
NiLn or PdLn
まざまな有機亜鉛反応剤が，有機ハロゲン化物と金属亜鉛また
CO insertion
usually
does
not
happen
unlike
in
the
case
of
less
reactive organotins
(see carbonylative Stille
R1 crossR2
R2 Zn X
(catalytic)
R1 X
+
coupling).
R1 = aryl, alkenyl,
R1 Xacyl
alkynyl,
X = 1Cl, Br, I, OTf, OAc
R = aryl, alkenyl,
alkynyl, acyl
X = Cl, Br, I, OTf, OAc
Mechanism:
+
Coupled
product
R1 R 2
solvent
(ligand)
NiLn /orL PdL
n
L = PPh
(catalytic)
3, P(o-tolyl)3,
dppe, dppp, dppb, dppf,
solvent
/ L (ligand)
BINAP,
diop,
chiraphos
L = PPh3, P(o-tolyl)3,
dppe, dppp, dppb, dppf,
BINAP, diop, chiraphos
R2 = aryl, alkenyl, allyl, benzyl
R2 homopropargyl
Zn X
homoallyl,
X
=
Cl,
Br, I
R2 = aryl, alkenyl, allyl, benzyl
homoallyl, homopropargyl
X = Cl, Br, I
Coupled
product
10
【反応機構】
10
10
Mechanism:
Ni-catalyzed
process:
Pd-catalyzed process:
L2Ni(II)X2
Pd(0) or Pd(II) complexes (precatalysts)
Pd-catalyzed process:
RZnX
Ni-catalyzed2process:
transmetallation
L2Ni(II)X2
2 RZnX
L2Ni(II)R2
transmetallation
R' X
R'
R'
R
R
L2Ni(II)
oxidative
addition
oxidative
addition
reductive
elimination
R'
oxidative
L2Ni(II)R2
addition
'
X
R'
reductive
elimination L
X
2Ni
(II)
L2Ni(II)
oxidative
R'addition
X R
R'
L2Ni(II)
R
R
X
R'
2 XZnX
2 XZnX
R R
reductive
elimination
RZnX
reductive
transmetallation
R R elimination
RZnX
X
R'
coordination
R'coordination
X
Pd(0) or Pd(II) complexes
(precatalysts)
LnPd(0)
L2Ni(II)
L2Ni(II)
XZnX
R'
R
R'
R
LnPd(0)
R
R'
X
X
oxidative
addition
R'
LnPd(II)
X
R'
LnPd(II)
X
reductive
elimination
transmetallation
R'
XZnX
R
R'
R'
oxidative
addition
reductive
elimination
RZnX
R'
LnPd(II)
R
R'
LnPd(II)
R
XZnX RZnX
transmetallation
XZnX
transmetallation
311
NEGISHI CROSS-COUPLING
NEGISHI CROSS-COUPLING
NEGISHI CROSS-COUPLING
Synthetic Applications:
311◇ 311
① Negishi Cross − Coupling
311
根岸クロスカップリングは，T. Sammakia
【合成への展開】
ジンと ZnCl2 のトランスメタル化によって調製した有機亜鉛反
Synthetic Applications:
The Negishi
cross-coupling
was utilized
during the final stages
of the total synthesis of caerulomycin C⊖トリブチルス
for the
応剤とカップリングする．興味深いことに，2
らによってカエルロマイシン
C
（caerulomycin
C）の全合成の最
Synthetic
Applications:
preparation
the bipyridyl system
by T. 36Sammakia
et
al.36stages
The highly
substituted
6-bromopyridine
was coupled,
in
The Negishiofcross-coupling
was utilized
during
the
final
of
the
total
synthesis
of
caerulomycin
C
forでは，目的
the
タニルピリジンを用いる
クロスカップリング
終段階で，ビピリジル構造の構築に用いられた
．Pd（dba）
⊘
Stille
2
3
36
system,
with
2-lithiopyridine,
which
was
transmetallated
by
ZnCl
in
situ
to
the
presence
of
Pd
The
Negishi
cross-coupling
was
utilized
during
the
final
stages
of
the
total
synthesis
of
caerulomycin
for
the
2(dba)3/PPh
3 catalyst
2C
preparation of the bipyridyl system by T. Sammakia et al.36 The highly substituted 6-bromopyridine was coupled, in
PPh3 触媒存在下，多置換
6organozinc
⊖ブロモピリジンを，2
⊖リチオピリ
物は低収率でしか得られない．
the presence
corresponding
reagent.
Interestingly,
the analogous
Stille cross-coupling
using was
2-tributylstannyl
preparation
ofofthe
system
by T. Sammakia
et al.
The
highly substituted
6-bromopyridine
coupled, in
the
Pdbipyridyl
2(dba)3/PPh3 catalyst system, with 2-lithiopyridine, which was transmetallated by ZnCl2 in situ to
pyridine
was
far
less
efficient
and
gave
a
low
yield
of
the
desired
product.
(dba)
/PPh
catalyst
system,
with
2-lithiopyridine,
which
was
transmetallated
by
ZnCl
the
presence
of
Pd
2
3
3
2 in situ to
the corresponding organozinc reagent. Interestingly, the analogous Stille cross-coupling using 2-tributylstannyl
the
corresponding
Interestingly,
analogous
pyridine
was far lessorganozinc
efficient andreagent.
gave a low
yield of the the
desired
product.Stille cross-coupling using 2-tributylstannyl
OMe
pyridine was
product.
OMe
OMefar less efficient and gave a low yield of the desired
MeO
MeO
MeO
Br
Br
Br
OMe
OMe
N
N
N
N
O
MeO
Li
MeO
MeO
ZnCl2, N
Pd2(dba)
Li 3
Li
PPh3,NTHF, r.t.
ZnCl2,80%
Pd2(dba)3
ZnCl
2(dba)
PPh23,,Pd
THF,
r.t. 3
PPh380%
, THF, r.t.
80%
O
N(i-Pr)
O 2
N(i-Pr)2
N(i-Pr)2
N
N
N
MeO
OMe
OMe
N
N
N
O
O
N(i-Pr)
O 2
OMe
OMe
MeO
MeO
steps
steps
steps
H
N
H
N H
N
OH
N
N
N
Caerulomycin
C OH
N
N
OH
Caerulomycin C
Caerulomycin C
N
N(i-Pr)2
N(i-Pr)2
有機亜鉛化合物である左側のサブユニットと
（E）
キンを
（E）⊖体の三置換ジルコニウムに変換したのち，無水
The modified Negishi protocol was used
in ⊖体のヨウ
J.S. Panek’s total
synthesis
of (–)-motuporin to couple the left-hand
37
left-hand subunit
was the
prepared
by
subunit
organozinc
compound
with
the
right-hand
subunit
(E)-vinyl
化ビニルである右側のサブユニットをカップリングさせる
根岸
ZnCl
とトランスメタル化して調製した．得られたビニル亜鉛
2 iodide. ofThe
The modified Negishi protocol was used in J.S. Panek’s total synthesis
(–)-motuporin
to couple
left-hand
37
the
Schwartz
hydrozirconation
of
a
disubstituted
alkyne
to
give
an
(E)-trisubstituted
zirconate,
which
was
The
modified
Negishi
protocol
was
used
in
J.S.
Panek’s
total
synthesis
of
(–)-motuporin
to
couple
the
left-hand
The left-hand subunit5 mol％の
was prepared
by3）4 存在
subunit organozinc
compound
the （－）
right-hand
subunit (E)-vinyl
iodide.
カップリングの改良法
が，J.
S. Panek with
らによる
⊖ モツポリ
に 1 当量の
（E）
Pd
（PPh
37⊖体のヨウ化ビニルを
subsequently
transmetalated
anhydrous
ZnCl2.subunit
The resulting
vinylzinc
was immediately
treated
with one
The left-hand
subunit was
prepared
by
subunit
organozinc
compoundwith
with
the
right-hand
(E)-vinyl
iodide. species
the
Schwartz
hydrozirconation
of
37a disubstituted alkyne to give an (E)-trisubstituted zirconate, which was
ン〔（－）
⊖
motuporin〕
の全合成に用いられた
．有機亜鉛化合物
下で直ちに作用させると，
（E，
⊖ジエンのカップリング生成
E）
equivalent
of
the
(E)-vinyl
iodide
in
the
presence
of
5
mol%
Pd(PPh
afford
the
(E,E)-diene
coupled
product
with
the
Schwartz
hydrozirconation
of
a
disubstituted
alkyne
to
give
an
(E)-trisubstituted
zirconate,
which
was
3)4 to
subsequently transmetalated with anhydrous ZnCl2. The resulting vinylzinc species was immediately treated with one
complete
stereoselectivity.
subsequently
transmetalated
withinanhydrous
ZnClof
The
resulting
vinylzinc
species was immediately treated with one
2. 5
は，まず
によって内部アル
物が完全な立体選択性で得られた．
Schwartz
equivalent
ofのヒドロジルコニウム化
the
(E)-vinyl iodide
the
presence
mol%
Pd(PPh
3)4 to afford the (E,E)-diene coupled product with
equivalent
of
the
(E)-vinyl
iodide
in
the
presence
of
5
mol%
Pd(PPh
)
to
afford
the (E,E)-diene coupled product with
3
4
complete stereoselectivity.
OTBDPS
complete stereoselectivity.
I
(E)
OTBDPS
OTBDPS
CH3
(E)
I (E)
HN
I
O
CH3
CH3
HN
O
HN
O
i-Pr
NHBoc
Right-Hand
Subunit
i-Pr
NHBoc
i-Pr
NHBoc
Right-Hand Subunit
Right-Hand Subunit
Me
Me Me
Me (E)Me ZnCl
OMe (E) ZnCl
(E) ZnCl
OMe
Left-Hand
Subunit
OMe
+
+
+
Me
1. Cp2Zr(H)Cl, THF
50 °C, 1h
1.
Cp2Zr(H)Cl, THF
)
(hydrozirconation
1.
Cp50
2Zr(H)Cl,
°C, 1h THF
50 2°C,
(3 1h
equiv))
ZnCl
hydrozirconation
(2.
)
(hydrozirconation
2 min, r.t
2.
ZnCl2 (3 equiv))
(transmetallation
(3
equiv)
2.
ZnCl
2
2 min, r.t
2 min, r.t
)
(transmetallation
(transmetallation)
Me
Left-Hand Subunit
Left-Hand Subunit
Me
Me
Me
OMe
Me
OMe
OMe
Me
Me
Me(E)
Me Me(E)
Me (E)
Me(E)
HN
OMe
Pd(PPh3)4 (5 mol%)
THF, r.t., 20 min
Pd(PPh3)4 (5 mol%)
Pd(PPh
3)4 (5
THF, 81%
r.t.,
20mol%)
min
THF, r.t., 20 min
81%
81%
(E)
(E)
OMe
OMe
HN
Me HN
OTBDPS
OTBDPS
OTBDPS
CH3
O
CH3
CH3
O
O
NHBoc
Me
Me Me NHBoc
NHBoc
Fragment in the total synthesis of (−)-motuporin
Me
Me
Fragment in the total synthesis of (−)-motuporin
Fragment in the total synthesis of (−)-motuporin
The convergent and stereocontrolled synthesis of (+)-amphidinolide J was achieved in the laboratory of D.R.
38
To installJ〔（＋）
the (E)C7-C8 doubleJ〕
bond
stereoselectively,
a homoallylic
alkylzinc
was coupled with
Williams.
（＋）
⊖アンフィジノリド
⊖ amphidinolide
の収束的か
ウ化ホモアリルに
当量の
BuLi
ZnCl2 と
t ⊖inreagent
The
convergent and
stereocontrolled
synthesis
of (+)-amphidinolide
J was 2achieved
theを作用させたのち
laboratory of D.R.
38 iodideand
an
(E)-vinyl
using
the
Negishi
reaction.
The
very
stable
homoallylic
alkylzinc
species
was
prepared
in of
oneD.R.
pot
The
convergent
stereocontrolled
synthesis
of
(+)-amphidinolide
J
was
achieved
in
the
laboratory
(E)C7-C8
double bond stereoselectively,
a homoallylic alkylzinc reagent was coupled
with
Williams.38 To installD.the
つ高立体選択的な合成が
R.
Williams
らによって達成され
トランスメタル化させることで調製している．これに，触媒量
from
the corresponding
by
treatment
with two
equivalents
of t-BuLi
followed
bywas
transmetallation
To
install
the homoallylic
(E)-Negishi
C7-C8 iodide
double
bond
stereoselectively,
a homoallylic
alkylzinc
reagent
coupled
Williams.
an (E)-vinyl
iodide
using
the
reaction.
The
very stable
homoallylic
alkylzinc
species
was prepared
in onewith
pot
with
ZnCl
addition
of
the
(E)-vinyl
iodide
in
the
presence
of
catalytic
amounts
Pd(PPh
)
the
coupled
た38．（E）
⊖
C7
⊖
C8
二重結合を立体選択的に導入するために，
の
Pd
（
PPh
）
存在下，
（E）
⊖体のヨウ化ビニルを加えると，1，
5⊖
an
(E)-vinyl
iodide
using
the
Negishi
reaction.
The
very
stable
homoallylic
alkylzinc
species
prepared
in one1,5pot
2. The
3was
4 gave
3
4
from the corresponding homoallylic iodide by treatment with two equivalents of t-BuLi followed by transmetallation
diene
product
in high yield.
from ZnCl
the
corresponding
homoallylic
iodide
by treatment
with two
equivalents
of t-BuLi
followed
by transmetallation
with
of the (E)-vinyl
iodide
in the presence
of catalytic
amounts
Pd(PPh
ホモアリル亜鉛反応剤と
（E）
⊖体のヨウ化ビニル間に
根岸反応
ジエン構造をもつ生成物が高収率で得られる．
2. The addition
3)4 gave the coupled 1,5with ZnCl
of the (E)-vinyl iodide in the presence of catalytic amounts Pd(PPh3)4 gave the coupled 1,52. The
diene
product
in addition
high yield.
を適応している．この安定なホモアリル亜鉛種は，対応するヨ
diene product in high yield.
I
Me H
I
I
OTHP
Me H OTHP
-BuLiOTHP
(2 equiv)
Me1. tH
THF, -78 °C
1. t-BuLi (2 equiv)
1.
-BuLi2 -78
(2
(1 equiv)
2. tZnCl
THF,
°C
THF,
THF,
-78-78
°C °C
to r.t.
2. ZnCl2 (1 equiv)
2. ZnCl
2 (1
THF,
-78
°Cequiv)
to r.t.
THF, ZnCl
-78 °C to r.t.
ZnCl
ZnCl
Me H OTHP
Me H
Me H
OTHP
OTHP
SEMO
CH3
SEMO
SEMO
CH3
CH3OR
I
OR
OR
Pd(PPh
I
3)4 (5 mol%)
I
THF, 22 °C
Pd(PPh
mol%)
3)4 3(5steps
84% for
Pd(PPh
(5 °C
mol%)
3)422
THF,
R
=
TBDPS
THF,
°C
84%
for22
3 steps
84% for 3 steps
R = TBDPS
R = TBDPS
CH3
CH3
SEMO
SEMO
SEMO
7
7
7
Me H
8
CH3 OR
CH3
OR
OR
8
8
HO
steps
steps
steps
OTHP
Me coupled
H OTHP
1,5-diene
product
Me H OTHP
1,5-diene coupled product
1,5-diene coupled product
HO
HO
CH3
CH3
CH3
CH3
CH3
CH3
CH
H
3
8
CH3
7
8
O
H
7
H H
CH3
O
OO H
H CH3
Me H
CH3
O
J
Me (+)-Amphidinolide
H
O
Me H
(+)-Amphidinolide J
(+)-Amphidinolide J
7
8
448
SUZUKI CROSS-COUPLING
448 ◇ ②鈴木クロスカップリング／鈴木−宮浦クロスカップリング
(SUZUKI-MIYAURA CROSS-COUPLING)
448
(References are on page 691)
SUZUKI CROSS-COUPLING
鈴木クロスカップリング／鈴木−宮浦クロスカップリング
(SUZUKI-MIYAURA CROSS-COUPLING)
Importance:
224
; Reviews are; on
Modifications
]
[Seminal
Publications(References
page 691) & Improvements
Cross−Coupling／Suzuki−Miyaura
Cross−Coupling
（Suzuki
）
1-3
4-38
39-49
Importance:
In 1979, A. Suzuki and N. Miyaura reported the stereoselective synthesis of arylated (E)-alkenes by the reaction of 11
1-3 39 49
4-38
39-49
1 3
4 38
The palladium-catalyzed
cross-coupling
alkenylboranes with
aryl
halides
in，改良と展開
the presence
catalyst.&
（重要論文
，総説
） of a palladium
; Reviews
; Modifications
Improvements
]
[Seminal
Publications
び位置選択的
である．7）
宮浦カップリング
B アルキル鈴木
【発見の経緯と特徴】
reaction between organoboron compounds and organic halides or triflates provides
a powerful and general method
3
1979 年に，パラジウム触媒存在下における 1 アルケニルボ
法を用いると sp 混成アルキル型ボランをカップリングできる．
for1979,
the formation
carbon-carbon
bonds known
as the Suzuki synthesis
cross-coupling.
There(E)-alkenes
are severalbyadvantages
In
A. Suzukiofand
N. Miyaura reported
the stereoselective
of arylated
the reactiontoofthis
11
ランとハロゲン化アリールの反応を用いたアリール化
（E）
アpalladium
また反応の欠点は，
1）
一般にハロゲン化アリールの反応が遅い．
method:
1) mild with
reaction
availability
of many
boronic
acids;
3) the inorganic by-products
are
The
palladium-catalyzed
cross-coupling
alkenylboranes
arylconditions;
halides in 2)
thecommercial
presence
of
a
catalyst.
1
easily
removed
from
the reaction
mixture,
making
the reaction
for industrial
4) boronic
are
reaction
between
organoboron
compounds
and炭素結合
organic
halides
or triflates
provides processes;
a powerful and
generalacids
method
ルケンの合成が鈴木と宮浦により報告された
．炭素
2）suitable
溶媒に溶解している酸素により自己カップリングした副生
environmentally
and much less
toxic known
than organostannanes
(see Stille coupling);
5) starting
tolerate
a
for the formationsafer
of carbon-carbon
bonds
as the Suzuki cross-coupling.
There are
severalmaterials
advantages
to this
形成に強力かつ一般的方法である有機ホウ素化合物と有機ハロ
成物が形成する．3）ホスフィンに結合したアリール基のカッ
wide
variety
of reaction
functional
groups, 2)
and
they are availability
unaffectedofby
water;
6) the
coupling
is generally
stereo- and
method:
1) mild
conditions;
commercial
many
boronic
acids;
3) the inorganic
by-products
are
ゲン化物のパラジウム触媒クロスカップリング反応を
鈴木
プリング生成物が得られることがある．4）
反応は塩基が存在
regioselective;
7)the
sp3reaction
-hybridized
alkyl boranes
can宮
also be
coupled
B-alkylprocesses;
Suzuki-Miyaura
cross-coupling.
easily removedand
from
mixture,
making
the
reaction
suitable by
forthe
industrial
4) boronic
acids are
Some
disadvantages
are:
1)
generally
aryl
halides
react
sluggishly;
2)
by-products
such
as
self-coupling
products
are
environmentally
safer
and
much
less
toxic
than
organostannanes
(see
Stille
coupling);
5)
starting
materials
tolerate
a
浦クロスカップリングと呼ぶ．この方法には多くの利点がある．しないと進行しないため，光学活性化合物のラセミ化やアル
formedvariety
because
solvent-dissolved
oxygen;
coupling
products
phosphine-bound
arylsisare
often formed;
andand
4)
wide
of of
functional
groups, and
they3)are
unaffected
by of
water;
6) the coupling
generally
stereo3 多くのボロン酸が市販品として
1）反応条件が温和である．2）
ドール縮合などの副反応が併発することがある．
鈴木
宮浦カ
since the reaction
proceed in
theboranes
absencecan
of aalso
base,
side reactions
as Suzuki-Miyaura
racemization of cross-coupling.
optically
active
regioselective;
anddoes
7) spnot
-hybridized
alkyl
be
coupled
by thesuch
B-alkyl
compounds
or aldol condensations
occur.
Improvements
ofップリング
the Suzuki
cross-coupling
include
the development
of
入手できる．3）
副生成物である無機物は反応混合物から容易
の改良法には，反応性の乏しいハロゲン化アリール
Some
disadvantages
are: 1) generally
aryl halides
react sluggishly;
2) by-products
such as
self-coupling
products are
39,40
42,44,50
39，
40
3
the
ability
to react sp3-hybridized
alkyl
halides,
catalysts
facilitating
coupling of unreactive
aryl3)halides,
formed because
of solvent-dissolved
oxygen;
coupling products
of phosphine-bound
aryls are
often
formed;
andand
4)
に除去でき，工業的プロセスに適している．4）
ボロン酸は環
のカップリングを促進する触媒の開発
，sp
混成ハロゲン化
45-47
the
use
alkyl, alkenyl,
aryl,proceed
and alkynyl
in place
of boronic
acids.
since
theofreaction
does not
in thetrifluoroborates
absence of a base,
side
reactions
such
as racemization of optically active
42，
44，50
境に安全で有機スズ化合物より毒性が少ない
（Stille
クロスカッ
アルキルとの反応
，またボロン酸の代わりにアルキル，
compounds or aldol condensations occur. Improvements of the Suzuki cross-coupling
include the development of
39,40
the
ability to react sp3-hybridized alkyl halides,42,44,50 and
catalysts
facilitating
coupling
of unreactive aryl halides,
プリング
，p. 438
を参照）
．5）出発原料は多くの官能基を許容
アルケニル，アリール型トリフルオロボラートの使用があ
the use of alkyl, alkenyl, aryl, and alkynyl trifluoroborates
in (catalytic)
place
of boronic acids.45-47
Pd(0)
し，水にも影響されない．6）カップリングは一般に
立体およ
る45 47．
R1 R2
2
1
+
X B(R)2
R X
+
R B(R)2
base, ligand
Coupled product
(0)
Pd (catalytic)
R1 R2
2
+ phosphate);
X B(R)2
+
R11 = B(R)
X OH, O-alkyl; R2 = alkenyl, aryl, alkyl; X = Cl, Br,I,
R
alkyl,2 allyl, alkenyl, alkynyl,
aryl; R =Ralkyl,
OTf, OPO(OR)2 (enol
base, ligand
+ Coupled
product
base = Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, TlOH, KF, CsF, Bu4F, NaOH, M ( O-alkyl)
R1 = alkyl, allyl, alkenyl, alkynyl, aryl; R = alkyl, OH, O-alkyl; R2 = alkenyl, aryl, alkyl; X = Cl, Br,I, OTf, OPO(OR)2 (enol phosphate);
base = Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, TlOH, KF, CsF, Bu4F, NaOH, M+(-O-alkyl)
Mechanism:
51-55,24,56,57,50,58-60
51 55，24，56，57，50，58 60
The mechanism
of the 鈴木
Suzuki 宮浦カップリングの反応機
cross-coupling is analogous to 錯体にトランスメタル化しないが，相当するアート錯体は容易
the catalytic cycle for the other cross-coupling reactions
【反応機構】
51-55,24,56,57,50,58-60
and
has
four
distinct
steps:
1)
oxidative
addition
of
an
organic
halide to the Pd(0)-species to form Pd(II); 2) exchange
Mechanism:
構は他のクロスカップリング反応の触媒サイクルと同様であり
にトランスメタル化する．ホウ素化合物をアニオンで四級化す
(II)
of the anion attached to the palladium for the anion of the base (metathesis); 3) transmetallation between Pd and
(0)
四段階から構成される．1）
Pd
（
0）
に対する有機ハロゲン化物
ると，アルキル基の求核性が増加してトランスメタル化段階に
the alkylborate
and 4)cross-coupling
reductive elimination
to form
sigma
bond
of Pd . reactions
Although
The
mechanismcomplex;
of the Suzuki
is analogous
to the
the C-C
catalytic
cycle
forand
the regeneration
other cross-coupling
(II)
(0)
thetocorresponding
ate-complexes
undergo
organoboronic
acids
do
not 1)
transmetallate
to the of
Pdan -complexes,
to form Pd(II)readily
; 2) exchange
and has four distinct
steps:
oxidative
addition
organic
halide
the Pd -species
の酸化付加による
Pd
（II）の形成．2）
塩基によるパラジウムに
おけるパラジウムへの移動を促進するからである．非常に嵩高
(II)
transmetallation.
The quaternization
of for
thethe
boron
atom
withbase
an anion
increases3)the
nucleophilicitybetween
of the alkyl
and
of
the anion attached
to the palladium
anion
of the
(metathesis);
transmetallation
Pd group
結合したアニオン配位子の交換．3）Pd
（II）中間体とアルキル
く電子豊富な配位子 P
（t Bu）3 は，酸化付加段階を促進するた
(0)
and
it accelerates
its transfer
to reductive
the palladium
in the transmetallation
and electron-rich
(e.g.,
the alkylborate
complex;
and 4)
elimination
to form the C-C step.
sigmaVery
bondbulky
and regeneration
of Pdligands
. Although
(II)
ボラート錯体とのトランスメタル化．4）
め，他の方法では使えない塩化アリールの反応を触媒する．
of 還元脱離による
otherwise
aryl
chlorides
by accelerating
the rate of
the oxidative
P(t-Bu)3) increase
the corresponding
ate-complexes
readily
undergo
organoboronic
acidsthe
do reactivity
not transmetallate
to theunreactive
Pd C-complexes,
addition
step.
transmetallation.
The
quaternization
of
the
boron
atom
with
an
anion
increases
the
nucleophilicity
of
the
alkyl
group
C s 結合の形成と Pd
（0）の再生である．有機ボロン酸は Pd
（II）
and it accelerates its transfer to the palladium in the transmetallation step. Very bulky and electron-rich ligands (e.g.,
P(t-Bu)3) increase the reactivity of otherwise unreactive aryl chlorides by accelerating the rate of the oxidative
addition step.
L Pd(0)
n
R1 R 2
reductive
elimination
R1 R 2
L
reductive
elimination
L(n-1)Pd
(II)
L(n-1)Pd(II)
transmetallation
R1
R
2
L
R1 B(R)2
R1 B(R)2
transmetallation
OR
L + RO B(R)2
+
organoborane
R1
R2
+
organoborane
OR
1
R
M+(-OR)
base
M+(-OR)
base
oxidative
addition2
R
B(R)2
X
oxidative
addition
LnPd(II)
LnPd(II)
borate
OR
1
R
L + RO B(R)2
R2 X
LnPd(0)
X
R2
X
R2
M+(-OR)
metathesis
B(R)2
M+(-OR)
borate
LnPd
(II)
OR
LnPd(II)
OR
R2
OR
R2
+ metathesis
M ( X)
M+(-X)
449
SUZUKI CROSS-COUPLING
(SUZUKI-MIYAURA
CROSS-COUPLING)
② Suzuki
Cross − Coupling／Suzuki − Miyaura Cross − Coupling ◇ 449
449
Synthetic Applications:
酸エステルの鈴木宮浦カップリングが用いられ，化合物のビ
S. J. Danishefsky らによるプロテオソーム
【合成への展開】
SUZUKI CROSS-COUPLING
During the total synthesis of the proteosome inhibitor TMC-95A by S.J. Danishefsky et al., the biaryl moiety of the
61
(SUZUKI-MIYAURA CROSS-COUPLING)
阻害剤 TMC compound
95A の全合成にヨウ化アリールとアリールホウ
was assembled in good yield by the Suzuki アリール骨格が収率よく構築された
cross-coupling of an aryl iodide and ．
an arylboron
intermediate.61
Synthetic Applications:
449
O
During the total synthesis of the proteosome
inhibitor
TMC-95A byOS.J. Danishefsky et al., theOH
biaryl moiety
of the
SUZUKI
CROSS-COUPLING
449
N
R
O was assembled in good yield by the Suzuki
compound
cross-coupling
of an arylHOiodide and an arylboron
Boc
O
(SUZUKI-MIYAURA CROSS-COUPLING)
61
N
intermediate.
B
H
SUZUKI CROSS-COUPLING
O
Boc
N
O HN
O
O
OH
O
Cbz
steps HO
O biaryl
N moiety of
NHthe
N O S.J. Danishefsky et HO
During
the
total synthesis of (E)
the
proteosome
inhibitor TMC-95A
al., the
R
Synthetic
O Applications:
2
K2CO3, DME,
BocN by
O
NH
HO
Narylboron
Hcross-coupling of an aryl iodide and
compound
assembled in good yield
Suzuki
an
80 °C by the
B was
H
R
61
N O
O
N
O
HN
Boc of the proteosome
2h;2(dppf)
75% inhibitor
intermediate.
During the total synthesis
TMC-95ANHCbz
by S.J. Danishefsky et al., the biaryl
of the
O
PdCl
N moiety
2
H
O
N
H an arylboron
O
OMewas assembled
compound
in good CH
yield
of an aryl iodide
and
I
2Cl2by the Suzuki cross-coupling
OMe
O
+
H
61
Cbz
intermediate.
OOH N O
R=OBn
O steps HO
TMC-95A
(E)
NH2
K2CO3, DME,
N
O
NH
HO
O
HO
H
N
R
O
80
°
C
Boc
R
O
O
N
O
O N
62OH N
NHCbz
2h; 75%
B
H the BThey
utilized
The antitumor
product
H N epothilone A was synthesized in the laboratory of J.S. Panek.
HO
O
O natural
H
HN
N
Boc
O
OMe
3
R
O
O
I
PdCl
(dppf)
OMea (Z)-iodoalkene for the construction
2
2
Boc
-hybridized
alkylborane
and
alkyl
Suzuki
between
an sp
O A（epothilone
O N O of the
N
抗腫瘍活性
天然
物でcross-coupling
あるエポチロ
ン
A）
が
いる末端アルキンのヒドロホウ素化反応により合成され，これ
CH
Cl
2 2
R=OBn
B
+ The alkylborane
HTMC-95A
main
fragment.
was prepared
by hydroborating the terminal alkene with
9-BBN
andH the (Z)Cbz
N
O
O
62
3
steps HO
O
PdCl
O ヨードアルケンとともにパラジウム触媒と塩基を添加
O HN
2(dppf)sp
2catalyst
J. S. Panek らによって合成された
．主骨格の構築は
混成 and the
に
（Z）
(E) theK
iodoalkene was addedBoc
along
with
palladium
base.
N
O NH2
CO
,
DME,
N
O
2
3
N
O
CH2Cl2
NH
H
H
+
H 62
80
°
C
Cbz
R 宮
OAc product epothilone
steps
アルキルボランと
（Z）ヨードアルケンの
アルキル鈴木
して行われた．
B
They
utilized
the BThe antitumor
natural
A
was
synthesized
in
the
laboratory
of
J.S.
Panek.
O
HO
N
O
(E)
NH2
2h;375%
3
NN O
N NHCbz
O and a (Z)-iodoalkene for the construction
2CO
H betweenKan
-hybridized alkylborane
of the
alkyl Suzuki
sp, DME,
NH cross-coupling
H
HH
Oで達成された．アルキルボランは
OMe
I
浦カップリング
9
BBN
を用
80
°
C
OMeterminal alkene with 9-BBN and
(S)
Rby hydroborating the
O
mainS fragment. The
alkylborane
was
prepared
the
(Z)OAc
N
O
NHCbz
2
2h;Pd(dppf)Cl
75%
N
R=OBn
TMC-95A
iodoalkene
H I with the palladium catalyst and the base.
N was added along
H
O
OMe
I (Z)
O OMe
Cs2CO3, DMF,
O
BnO
OTBS
(S)
S
OAc
H2O, r.t.; 60%
+
R=OBn
TMC-95A
N laboratory of J.S. Panek.62 They utilized the BThe antitumor natural product epothilone A was synthesized in the
O
OTBS
3
BnO cross-coupling
OTBS
BR
(Z)
2 S Suzuki
(S)
for the construction of the
alkyl
between an sp -hybridized alkylborane and a (Z)-iodoalkene
OAc
Pd(dppf)Cl2
62
main
fragment.
The
alkylborane
was
prepared
by
hydroborating
the
terminal
alkene
with
9-BBN
and
the
B synthesized in the laboratory of J.S. Panek. They utilized the(Z)BThe antitumor
natural product
epothilone
N
I
BR2 =A was
OTBS
3
DMF,
(Z)alongbetween
2CO
3, catalyst
iodoalkene
added
with the palladium
and
the
-hybridized
alkylborane
and a (Z)-iodoalkene
for BnO
the construction
of the
alkyl Suzukiwas
cross-coupling
anCssp
OTBS
(S)
S base.
Key fragment of Epothilone A
H2O, r.t.; 60%
+
main fragment. The alkylborane was prepared by hydroboratingN the terminal alkene with 9-BBN and the (Z)OAc
OTBS
iodoalkene
was added
BnO
OTBS along with the palladium catalyst and the base.
BR
(Z)
2
Synthetic Applications:
+
PdCl2(dppf)2
(SUZUKI-MIYAURA
CROSS-COUPLING)
CH Cl
2
O
2
N
H
The last and key(S)
step in the total synthesis of myxalamide A by C.H. Heathcock et al. was a Suzuki cross-coupling
OAc
S
B 63
BR2 Pd(dppf)Cl
=
The
(E)-vinylborane was OAc
prepared prior to the coupling by reacting
between an (E)-vinylborane
and a (Z)-iodotriene.
OTBS
2
N
I
the precursor enyne
with
2
equivalents
of
cathecholborane.
Upon completion
the hydroboration,
Keyoffragment
of Epothilone it
A was combined
Cs
CO
,
DMF,
(S) (Z)
2
3
S
BnO
OTBS
(S)
OAc
S
with the (Z)-iodotriene
and catalytic amounts
acetate.
r.t.;palladium
60%
HPd(dppf)Cl
2
+
2O, of
N
I
N
Cs2CO
DMF,
OTBS
The2 last BnO
and keyOTBS
step(Z)in the total synthesis
of3,myxalamide
A by
SuzukiOTBS
cross-coupling
(S) (Z) et al. was aBnO
BR
S C.H. Heathcock
H2O, r.t.; 60%
63
+
(E)
was prepared prior to the coupling by reacting
between an (E)-vinylborane and a (Z)-iodotriene. The (E)-vinylborane
N
B 2, TPPTS
C. H. Heathcock
らによるミキサルアミド
A（myxalamide
A）
を反応させ（E）ビニルボランが合成された．ヒドロホウ素化
=
2 Pd(OAc)
OH
OTBS
BR2 BRof
the2 precursor
withOTBS
2 equivalents
cathecholborane.
Upon completion of
BnO enyne
OTBS
BR
(Z) the hydroboration, it was combined
i-PrNEt
2
Key fragment
of Epothilone AO
with the (Z)-iodotriene and（E）
catalytic
amounts of
palladium
acetate.
の全合成における最終かつ鍵段階は
ビニルボランと
（Z）
が完結したのち，
（Z）
ヨードトリエンと触媒量の酢酸パラジ
BR2 = CHB
3CN/H2O
NH
OTBS
+
63
ヨードトリエンの
である6h,
．カッ
ウムが混合された．
I 鈴木宮浦クロスカップリング
O
r.t.,
Key fragment
of Epothilone A
(E)
(E)
The last and key step in the total synthesis
of for
myxalamide
A by C.H. Heathcock et al. was a Suzuki cross-coupling
44%
2 steps
OH
Pd(OAc)63
2, TPPTS
OH
プリングの前に，エンイン前駆体と
当量のカテコールボラン
The (E)-vinylborane was prepared prior to the coupling by reacting
between
an (E)-vinylborane
a (Z)-iodotriene.
BR
N 2 and
2
(Z)
H
2
the precursor
enyne
2 equivalents
of cathecholborane.
completion
of the
hydroboration,
itOwas
combined
The
last and key
stepwith
in the
total synthesis
ofi-PrNEt
myxalamide
AUpon
by C.H.
Heathcock
et al.
was
cross-coupling
(Z) a Suzuki
63
CN/H
O
CH
2 (E)-vinylborane
with the (Z)-iodotriene
and catalytic
amounts of3palladium
acetate.
NHreacting
The
was prepared
prior to the
between
an
and a (Z)-iodotriene.
+
Myxalamide
A coupling by
BR(E)-vinylborane
2 = BO2C6H4
6h, r.t.,
the Iprecursor enyneOwith 2 equivalents of cathecholborane.
Upon completion of the (E)
hydroboration, it was combined
44%
2 steps acetate.
with the (Z)-iodotriene and catalytic
of for
palladium
OH amounts
N (E)
(Z)
Pd(OAc)
,
H of oximidine
2 TPPTS
OH
BR2 II was achieved
A formal total synthesis
by G.A. Molander et al., using an (Z)
intramolecular Suzuki-type
2
(E)alkenyl potassiumi-PrNEt
cross-coupling
between
an
trifluoroborate
and an alkenyl bromide
to construct
highly strained,
Myxalamide
A the O
BR2 = BO2C6H4
64
CHcore
Pd(OAc)
3CN/H
2, TPPTS
OH
NH
polyunsaturated 12-membered
macrolactone
of2O
the natural product. The stability of potassium trifluoroborates
BR2
+
i-PrNEt
O to establish the best conditions
O
6h, r.t.,2 for the macrocyclization.
wasI exploited in order
(E)
CN/H
CH3for
44%
2 steps
2O
NH
OH
+
A formal
total synthesis
Molander et al., using an intramolecular Suzuki-type
BnO
I(Z)
O N of oximidine II was achieved
6h, r.t., by G.A.
OBn
(E)
cross-coupling betweenH an alkenyl potassium
trifluoroborate
and
an
alkenyl
bromide
to
construct
the
highly
strained,
H
(Z)
)4 for 2 steps
OH Pd(PPh344%
64
N trifluoroborates
The stability
of potassium
polyunsaturated
12-membered
macrolactone
core of the natural product.
Myxalamide
A
N
OMOM
(Z) O BR2 = BO
C
H
(10
mol%)
OH
OH O
2 6 4
H
was exploited in
conditions for the macrocyclization.
(Z)
(S)order to establish
Cs2the
CObest
3 (5 equiv)
O
OMOM
THF:H
O
(10:1)
OH N
stepsMyxalamide
O 2 (S)
2
OH AO
BR
= BO2C6H4
O (S) (S)
BnO
(Z)
OBn
(E)
(Z)
reflux, II20h;
42%
OMe
A
formal
total
synthesis
of
oximidine
was
achieved
by
G.A.
Molander
et
al.,
using
an
intramolecular
Suzuki-type
H
非常に歪んだ多不飽和 12 (Z)
員環マクロラクトン骨格の構築に
II
（oximidine II）の形式全合成が G.
Molander
らにより達成
ON A.
3)4 trifluoroborate and an alkenyl bromide to construct the
cross-coupling
between an alkenyl Pd(PPh
potassium
highly strained,
OMOM
(10 mol%)
OH O (E)
64
(Z)
OH O
64
Br
カリウムアルケニルトリフルオロボラート塩と臭化アルケニル
された
．カリウムトリフルオロボラート塩が安定であること
potassium trifluoroborates
polyunsaturated
12-membered
macrolactone
core of the
product.
A formal total synthesis
of oximidine
was achieved
bynatural
G.A.
Molander
etThe
al., stability
using anofintramolecular
Suzuki-type
Cs2COII
3 (5 equiv)
BF3K(S) OMOM
O
was exploited
inbetween
order to an
establish
the
best
conditions
for the macrocyclization.
cross-coupling
alkenyl
potassium
trifluoroborate
and
an(S)alkenyl bromide
THF:H
OHstrained,
N
steps to construct
O (S)
2O (10:1)
OH O the highly
O (S)
の分子内鈴木polyunsaturated
宮浦クロスカップリング
を行い，オキシミジン
が，環化反応の効率的達成に大きく寄与している．
64
Oximidine
II
trifluoroborates
12-membered
macrolactone core of the natural
product.(Z) The stability of potassium
(E)
(Z)
reflux, 20h; 42%
OMe
BnO
was exploited
to establish the best conditions for the macrocyclization.
OBnin order
OH
(Z)
(E)
(Z)
Pd(PPh3)4
N
Br
BnO
OMOM
(10 mol%)
OH O OBn
OH O
BF3K
H
(S)
Cs2Pd(PPh
CO3 (5 equiv)
OMOM
N O II
3)4
Oximidine
(S) (S)
THF:H
O (10:1)
OH N
OH O
OMOM steps
(10 2mol%)
OH O O (S)
OH O O
(Z)
(E)
(S)
Cs
CO320h;
(5 equiv)
(Z)
reflux,
42%
OMe
2
O
OMOM
THF:H2O (10:1)
OH N
steps
O (S) (Z)
OH O O
O (S) (S)
(E)
BF3K (Z)
(E)
BF3K
(Z)
Br
Br
reflux, 20h; 42%
(E)
(Z)
(Z)
(Z)
O
Oximidine II
Oximidine II
OMe

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