3. 伊藤研究室(2010∼)の研究
Cu catalysis (2000−)
Ir catalysis (Ishiyama, 2002−)
Si-B/base Chemistry (2012−)
J. Am. Chem. Soc., 2012, 134, 19997.
新規ホウ素化反応の開発
Ishiyama, Miyaura, Hatrwig, et al,
J. Am. Chem. Soc. 2002, 124, 390.
Ar H Ar Bpin
Ir cat.
B2pin2
X pinB
Cu cat.
J. Am. Chem. Soc. 2008, 130, 10044.
Nature Communications 2013, 4, 2009.
Angew. Chem., Int. Ed 2013, 52, 12828, VIP.
発光性金(I)錯体の研究
5. ホウ素−銅触媒反応系の発見(2000年)
Segawa, Y.; Yamashita, M.; Nozaki, K. Science 2006, 314, 113.
NN
B
Br
iPr
iPr iPr
iPr
NN
B
Li
iPr
iPr iPr
iPr
Li, naphthalene
THF
■ホウ素アニオンは合成が困難であった。
CuCl/KOAc: Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 982.
CuX/PR3: Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron Lett. 2000, 41, 6821.
+
cat. CuX
PR3
DMI, rt
H3O+
O
O
B
B B
O
OO
O
O
O
87%
■エノンへのホウ素基の形式的求核付加
Cu
X
B
B
Cu B
L
L
ホウ素銅触媒活性種
•求核的な反応特性
•選択性のコントロールが可能
銅触媒/ジボロン
を用いた有機ホウ
素化合物の合成法
を詳しく検討
6. 過去に合成できなかった有機ホウ素化合物の新合成方法
early study:
Tetrahedron Lett. 2000
B
OO
J. Am. Chem. Soc. 2005
J. Am. Chem. Soc. 2007
B
OR
O
O
Angew. Chem., Int. Ed. 2010
BR O
O
J. Am. Chem. Soc. 2010
(rac)-
R
B
O
O
Angew. Chem., Int. Ed. 2008
J. Am. Chem. Soc. 2010
C C C
B
Bu
Me
H
O
O
J. Am. Chem. Soc. 2008
B
O
O
J. Am. Chem. Soc. 2010
B
O
O
or
B
B
O
O
O
O
J. Am. Chem. Soc. 2013
B
O
O
Org. Lett. 2012
R
B
O
O
Nature Chem. 2010
Bu
B
O
O
Angew. Chem., Int. Ed. 2011
B B
O
OO
O
LCu X
+ LCu B
O
OX B(pin)–
7. ■
Latitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006, 128, 11036.
O
H
1.0 mol % ICyCu(O-t-Bu)
(pin)B−B(pin), toluene
86%
O
B(pin)
B(pin)
Catalytic diboration
(pin)B−B(pin)
MeOH, toluene
O
H
1.5 mol %
ICyCu(O-t-Bu) OH
B(pin)
crude product
KHF2
MeOH/H2O
OH
BF3K
81%
Molander, G. A.; Wisnieski, S. R. J. Am. Chem. Soc. 2012, 134, 16856.
■ Catalytic monoborylation
N N
ICy
カルボニル化合物のホウ素化
8. Molander, G. A.; Wisnieski, S. R. J. Am. Chem. Soc. 2012, 134, 16856.
For a review of Matteson homologation chemistry: Matteson, D. S. Tetrahedron 1998, 54, 10555.
Matteson homologation chemistry
■
Stoichiometric amount of chiral auxiliary■
B
O
O
Ph
Ph
n-BuLi
CH2Cl2
ZnCl2
THF
H
B Cl
BnOLi
THF
DMSO
H
BnO B O
O
Ph
Ph
O
O
Ph
Ph
KHF2
MeCN/H2O H
BnO BF3K
>99% ee
75% (4 steps)
B(OH)2
HO OH
Ph Ph
Et2O
Multistep synthesis
不斉補助基を用いたαーアルコキシアルキルホウ素
9. H
BnO BF3K
H
BnO
N
N
+
Cl
CsOH•H2O (5.0 equiv)
CPME/H2O (0.5 M)
105 °C
NH2Pd
P
OTf
Bu
Pd catalyst
(7.5 mol %)
86%, 99% ee
(>99% es)
99% ee
(S)
(R)
Molander, G. A.; Wisnieski, S. R. J. Am. Chem. Soc. 2012, 134, 16856.
High yield and excellent stereospecificity (>99% ee)■
Various aryl halides can be used.■
Cross-coupling reaction
鈴木カップリングで立体特異的な誘導が可能
10. R H
O
R = Alkyl, Ary
B B
O
O O
O
+
cat. Cu(I) / L*
R H
B(pin)HO
Can be asymmetric catalysis?
O
H
1.5 mol % ICyCuCl
B2pin2 (1.0 equiv)
3 mol % Na(O-t-Bu)
MeOH (2.0 equiv)
toluene, rt, 1 h
1a
protection
H
B(pin)PO
H
B(pin)BnO
BnBr, NaH, THF
H
B(pin)PhOCO
PhCOOH, EDC, DMAP
H
B(pin)BnMe2SiO
BnMe2SiCl, imidazole
isolated yield (%)
rac-3
conditions: conditions:
33% 8% 72%
conditions:
K. Kubota
Kubota, K.; Yamamoto, E.; Ito, H. J. Am. Chem. Soc. 2015, 137, 1, 420.
不斉反応開発の は単離方法の開発
11. Ph
O
1. CuCl / L* (5 mol %)
K(O-t-Bu) (10 mol %)
MeOH (2.0 equiv)
THF, 30 °C, 6 h
2. BnMe2SiCl, imidazole
CH2Cl2, 3 h
Ph HH
BnMe2SiO B
(S)
NMR yield (%)
B B
O
O O
O
+
1.0 equiv
O
O
O
O
O
O
P
P
tBu
OMe
tBu
tBu
OMe
tBu
2
2
(R)-DTBM-SEGPHOS
72%, 96% ee
O
O
O
O
P
P
Me
Me
Me
Me
2
2
(R)-DM-SEGPHOS
71%, 32% ee
(R)-SEGPHOS
74%, 24% ee
O
O
O
O
P
P
2
2
steric hinderance
enantioselectivity
■ This is the first enantioselective nucleophilic borylation of a C=O double bond
配位子の探索:DTBMーSEGPHOSがベスト
12. R
O
1. 5 mol % CuCl/
(R)-DTBM-SEGPHOS
K(O-t-Bu) (10 mol %)
MeOH (2.0 equiv)
THF, 30 °C, 6 h
2. R3SiCl, imidazole
CH2Cl2, 3 h
H
B B
O
O O
O
+
1.0 equiv
R H
R3SiO B
(S)
isolated yield (%)
O
O
Ph
B(pin)BnMe2SiO
H
B(pin)Me3SiO
H
B(pin)Me3SiO
H
B(pin)Me3SiO
H
70%, 96% ee 51%, 96% ee 61%, 95% ee 84%, 95% ee
B(pin)HO
H
61%, 96% ee
B(pin)HO
H
61%, 92% ee
B(pin)HO
H
B(pin)HO
H
Ph
Ph
trace trace
基質適用範囲の確認:フリーで単離できるものもあり
13. R
O
1. 5 mol % CuCl/
(R)-DTBM-SEGPHOS
K(O-t-Bu) (10 mol %)
MeOH (2.0 equiv)
THF, 30 °C, 6 h
2. R3SiCl, imidazole
CH2Cl2, 3 h
H
B B
O
O O
O
+
1.0 equiv
R H
R3SiO B
(S)
isolated yield (%)
O
O
B(pin)BnMe2SiO
H
N
B(pin)Me3SiO
H
N
Boc Ts
81%, 95% ee 52%, 91% ee
B(pin)BnMe2SiO
HO
O
66%, 85% ee
B(pin)BnMe2SiO
H
69%, 90% ee
BzO
B(pin)BnMe2SiO
H
69%, 95% ee
BnO
良好な官能基許容性
14. H
O
H
B(pin)HO
CuCl / L* (5 mol %)
(pin)B−B(pin) (1.0 equiv)
K(O-t-Bu) (10 mol %)
MeOH (2.0 equiv)
THF (0.5 M), 30 °C, 6 h
Ph2MeSiCl
imidazole
CH2Cl2, 3 h
>99% conversion
L* = (R)-DTBM-SEGPHOS
H
B(pin)Ph2MeSiO
22% yield
99% ee
H
BF3KHO
KHF2 (4.0 equiv)
MeOH/H2O, 30 min
71% yield
■ Poor stability of the product toward silica gel column
Good isolated yield (71%) by converting into trifluoroborate■
芳香族アルデヒドの生成物は不安定
15. CuCl / ligand (5 mol %)
(pin)B−B(pin) (1.0 equiv)
K(O-t-Bu) (10 mol %)
MeOH (2.0 equiv)
solvent, 30 °C, 18 h
then Me3SiCl
imidazole, 3 h (R,S)
H
O
Me
TBSO
B(pin)
OSiMe3
Me
TBSO
(R,R)
B(pin)
OSiMe3
Me
TBSO
+
(R)
α-Stereocenter
ICy⋅HCl (2 mol %), toluene: 69%, (R,S):(R,R) = 30:70
(R)-DTBM-SEGPHOS, THF: 73%, (R,S):(R,R) = 89:11
(S)-DTBM-SEGPHOS, THF: 77%, (R,S):(R,R) = 5:>95
■ Strong catalyst-controlled selectivity over substrate vias
基質の不斉点との干渉少ない:Catalyst Control
16. For a review of Matteson homologation chemistry: Matteson, D. S. Tetrahedron 1998, 54, 10555.
Sadhu, K. M.; Matteson, D. S. Organometallics 1985, 4, 1687.
Stereospecific Csp3-Csp3 bond formation;
One-carbon homologation
Larouche-Gauthier, R.; Elfold, T. G.; Aggarval, V. K. J. Am. Chem. Soc. 2011, 133, 16794.
Ph H
B(pin)BnMe2SiO
96% ee
ClCH2Br
n-BuLi
THF
−78 °C→rt
3 h
Ph H
BnMe2SiO B(pin)
92%, 96% ee
H2O2
NaOH Ph H
HO OH
77%, 96% ee
chiral 1,2-diol
chiral 1,2-haloalcohol
Ph H
R3SiO Br
80%, 96% ee
3,5-(CF3)2C6H3Li
then NBS, −78 °C
誘導1:Matteson ホモロゲーション
17. H
(pin)B OSiMe3
95% ee
(S)
Benzofuran (1.2 equiv)
n-BuLi (1.2 equiv)
THF, −78 °C, 1 h
NBS (1.2 equiv)
−78 °C, 1 h
then TBAF, 2 hH
Li
H
52%, 95% ee
(pin)B OSiMe3
O
OH
O
(R)
Bonet, A.; Odachowski, M.; Leonori, D.; Essafi, S.; Aggarwal, V. K. Nature. Chem. 2014, 6, 584.
Stereospecific Csp3-Csp2 bond formation;
Cross-coupling with a heteroaromatic compound
誘導2:Aggarwal アリレーション
20. Cu
B
P P
O
H
H
H
Cu
B
P P
O
H
H
H
Ph Ph
Ph Ph
Ph
Ph Ph
Ph
Si-face (favored) Re-face (disfavored)
0 kcal/mol +1.04 kcal/mol
<
TS3 ((R)-SEGPHOS) TS4 ((R)-SEGPHOS)
Observed result
24%ee Relative G value
(kcal/mol) at 298 K
1.0 atm, gas phase.
B3PW91/cc-PVDZ
DFT計算による遷移状態の構造、比較
M. Jing
K. Kubota
Kubota, K.: Jing, M.; Ito, H. manuscript preparation
21. Cu
B
P P
O
H
H
H
Cu
B
P P
O
H
H
H
Ar
Ar
Ar Ar
Ar
Ar Ar
Ar
Si-face TS (favored) Re-face TS (disfavored)
Relative G value (kcal/mol) at 298 K, 1.0 atm, gas phase.
0 kcal/mol +1.97 kcal/mol
<
observed result
96% ee
B3PW91/cc-PVDZ
DTBMーSEGPHOS: t-Buが効果的
22. Ph
O
Ph H
H
BnMe2SiO B O
O
R H
CuCl / L* (5 mol %)
K(O-t-Bu) (10 mol %)
(pin)B−B(pin) (1.0 equiv)
THF, 30 °C
BHO O
O
BnMe2SiCl
imidazole
CH2Cl2, 3 h
unstable
with MeOH: 72%, 96% ee
without MeOH: 34%, 22% ee
L* = (R)-DTBM-SEGPHOS
Mechanism
slow
isomerization
opposite
enantiomer
fast protonation
O C
Cu
R
B(pin)
P
P
O C
(pin)B
R
B(pin)
H
H
(pin)B B(pin)
LCu−B(pin)
O C
R
H
Cu
B
P P
O C
R
H(pin)B
Cu
P
P
(pin)B B(pin)
O C
R
H(pin)B
B(pin)
(S)
(R)
MeOH
Cu OR
P
P
+ O C
H
R
B(pin)
H
(S)
+
(S)
cf. Zhao, H.; Dang, L.; Marder, T. B.; Lin, Z. J. Am. Chem. Soc. 2008, 130, 5586.
プロトンソースがない場合は ee低下
23. 0
I
II
Cu B(eg)
P
P
OC
+
H
H
P
P
=
P
P
Cu
P
P
O C
B(eg)
H
H
III
Cu
P
P
O C
B(eg)
H
H
TSA
Cu
P
P
O C
B(eg)
H
H
P1
+1.4
+6.7
-19.9
B(eg) = B
O
O
FreeEnergy(kcal/mol)
B3PW91/cc-PVDZ
Relative G value (kcal/mol) at 298 K, 1.0 atm, gas phase.
-30.5
P2
Cu
P
P
C O
B(eg)
H
H
TSB
TSC
O
C
H H
B(eg)Cu
P
P
O C
B(eg)
H
H
Cu
P
P
-15.7
-1.4
isomerization step
addition step
cf. Zhao, H.; Dang, L.; Marder, T. B.; Lin, Z. J. Am. Chem. Soc. 2008, 130, 5586.
プロトンソースなしでは異性化(ラセミ化)が進行する
24. B(eg) = B
O
O P
P
=
P
P
P1 major
0 (0)
-5.4 (-14.2)
Cu
P
P
O C
B(eg)
H
HH
O
Me
IV
-2.9 (-15.0)
TSC
+1.76 (+2.9)
P2
Cu
O C
B(eg)
H
HH
O
Me
P P
Cu OMe
P
P
O C
B(eg)
H
HH
+
Cu
P
P
O C
B(eg)
H
H
MeOH
+
MeOH
CuOMe
FreeEnergy(kcal/mol)
V
O
Cu
Me
P P
H
O
C
H
B(eg)
H
-4.1 (-14.4)
Relative G value (kcal/mol) at 298 K, 1.0 atm, gas phase.
Electronic energies are shown in parentheses.
B3PW91/cc-PVDZ
プロトン化の活性化エネルギーは小さい
27. Liu, D.; Zhao, G.; Xiang, L. Eur. J. Org. Chem. 2010, 3975.
chiral indolineindole
Enantioselective dearomatization strategy
chiral
catalyst
Zhuo, C.-X.; Zhang, W.; You, S.-L. Angew. Chem. Int. Ed. 2012, 51, 12662.
N
PG
R2
R3
R1
N
PG
R4R2
R5
R3
R1
N
CO2H
O
CH3
CH3
CO2Et
strychnine (+)-aspidospermidine pentopril
N O
N
O
H
H
N
N
CH3
H3C
H
CH3
O
(−)-physostigmine
N
H
N H
H
H
ON
CH3
H3C
光学活性インドリン誘導体
28. Hydrogenation
Electrophilic allylic substitution
Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem. Soc. 2000, 122, 7614.
Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314.
Trost ligand
(S,S)-(R,R)-PhTRAP
Fe
Fe
PPh2PPh2
O
N
H
HN O
Ph2P
PPh2
2.5 mol % Pd2(dba)3CHCl3
7.5 mol % chiral ligand
9-BBN-C6H13 (1.05 equiv)
CH2Cl2, 4 °C
N
H
N
+
HO
MeO
MeO
3 equiv
92%, 85% ee
1.0 mol % [Rh(nbd)2]SbF6
1.05 mol % PhTRAP
10 mol % Cs2CO3
i-PrOH, H2 (5.0 MPa)
60 °C, 2 h
N
Ac
N
Ac
91%, 91% ee
芳香族のインドールから合成するのは有力な方法
29. N OR
O
PG
R OH
Nucleophilic borylative
dearomatization
Electron deficient
indole
Consecutive
stereogenic centers
*LCu B
N OR
O
PG
B
*
*
H
K. Kubota K. Hayama Kubota, K.; Hayama, K. Ito, H. Angew. Chem., Int. Ed. 2015, accepted.
世界初の方法:インドールの不斉ホウ素化
30. N OR
O
PG
R OH
*LCu B
N OR
O
PG
B
*
*
H
N OR
O
PG
OH
*
*
H
N OR
O
PG
NH2
*
*
H
Nucleophilic borylative
dearomatization
Stereospecific
functionalizations
N OR
O
PG
C
*
*
H
Kubota, K.; Hayama, K. Ito, H. Angew. Chem., Int. Ed. 2015, accepted.K. Kubota K. Hayama
世界初の方法:光学活性インドリン誘導体
31. 10 mol % Cu(O-t-Bu)
10 mol % chiral ligand
10 mol % Na(O-t-Bu)
N
O
OMe
Cbz
N
O
OMe
Cbz
B(pin)
0.5 mmol
+
O
B
O
B
O
O
2.0 equiv
t-BuOH (2.0 equiv)
THF, 30 °C, 18−48 h
NMR yield (%)
PP
Me
Me
Me
Me
Me
Me
Me
Me PP
P
P
Me
Me
Me
Me
(R,R)-BenzP*
77%, d.r. 91:9
61% ee
(R,R)-Me-Duphos
71%, d.r. 97:3
37% ee
P
P
Me
tBu
tBu
Me
N
N P
P
Me
tBu
tBu
Me
(R,R)-3,5-xyl-BDPP
98%, d.r. 97:3
93% ee
(R,R)-BDPP
98%, d.r. 89:11
74% ee
(R,R)-QuinoxP*
93%, d.r. 90:10
27% ee
Kubota, K.; Hayama, K. Ito, H. Angew. Chem., Int. Ed. 2015, accepted.
反応条件、不斉配位子の検討
32. N
O
OR3
Cbz
N
O
OR3
Cbz
B(pin)
+
O
B
O
B
O
O
2.0 equiv
10 mol % Cu(O-t-Bu)
10 mol % (R,R)-3,5-xyl-BDPP
10 mol % Na(O-t-Bu)
t-BuOH (2.0 equiv)
THF, 30 °C, 4−18 h
0.5 mmol
R1
R2
R1
R2
isolated yield
(NMR yield)
74% (93%)
d.r. 97:3, 95% ee
64% (93%)
d.r. 97:3, 95% ee
74% (96%)
d.r. 93:7, 92% ee
74% (99%)
d.r. 97:3, 97% ee
N
O
OMe
Cbz
B(pin)
N
O
OMe
Cbz
B(pin)
N
O
OMe
Cbz
B(pin)
N
O
OMe
Cbz
B(pin)
F Cl Br MeO
76% (88%)
d.r. 94:6, 93% ee
N
O
OMe
Cbz
B(pin)
62% (99%)
d.r. 93:7, 86% ee
N
O
OMe
Cbz
B(pin)
Br MeO
52% (55%)
d.r. 86:14, 95% ee
N
O
OEt
Cbz
B(pin)
71% (82%)
d.r. 83:17, 89% ee
N
O
OMe
Cbz
B(pin)
Ph
基質の適用範囲
33. 10 mol % Cu(O-t-Bu)
10 mol % (R,R)-3,5-xyl-BDPP
10 mol % Na(O-t-Bu)
N
Me
Cbz
N
Me
Cbz
B(pin)
0.5 mmol
+
O
B
O
B
O
O
2.0 equiv
t-BuOH (2.0 equiv)
THF, 30 °C, 24 h
not detected
LUMO
-1.51 eV
LUMO+1
-0.68 eV
N
O
O
Ph
O
O Me
N
Me
O
O
Ph
DFT analysis (B3PW91/ccpVDZ)
電子吸引基が必要:LUMOの比較
34. Optically active alcohol was obtained with high stereospecificity.✓
N
O
OMe
Cbz
B
TBSCl (2.0 equiv)
imidazole (3.0 equiv)
N
O
OMe
Cbz
OH
NaBO3•4H2O (4.0 equiv)
d.r. 97:3, 95% ee
N
O
OMe
Cbz
OTBS
THF/H2O, rt, air, 2 h
CH2Cl2, rt, 4 h
O
O
64% yield
d.r. >99:1, 94% ee
F
F
F
誘導反応:酸化
36. 10 mol %
Cu(O-t-Bu) / L*
(pin)B−B(pin)
Na(O-t-Bu)
t-BuOH, THF
N
O
OR3
Cbz
N
O
OR3
Cbz
B O
O
R1
R2
R1
R2
up to 97:3 d.r.up to 99%
up to 97% ee
N
O
OMe
Boc
N
O
OMe
Boc
B(pin)
0.5 mmol 45%, d.r. 54:46
10 mol % Cu(O-t-Bu)
10 mol % Xantphos
(pin)B−B(pin) (2.0 equiv)
20 mol % K(O-t-Bu)
t-BuOH (2.0 equiv)
THF, 30 °C, 11 h
N
O
OMe
Boc
54%, d.r. 57:43
2 stereoisomers
OH
Ph
toluene
60 °C, 16 h
Ph
O
H
(3.0 equiv)
The first enantioselective borylative dearomatization
of heteroaromatic compounds has been achieved.
L* = (R,R)-xyl-BDPP
PP
Me
Me
Me
Me
Me
Me
Me
Me
Current study
インドールの脱芳香族ホウ素化
Kubota, K.; Hayama, K. Ito, H. Angew. Chem., Int. Ed. 2015, accepted.
37. ■ シリルボラン/塩基法 遷移金属フリーのホウ素化
92% yield
(1.5 equiv)
KOMe (1.2 equiv)
DME, 30 °C, 1 h
Si B
O
O
Br B
O
O
Ph
Yamamoto, E.; Izumi, K.; Horita, Y.; Ito, H. J. Am. Chem. Soc. 2012, 134, 19997.
Dr. E. Yamamoto
Y. Horita K. Izumi
■ 有機リチウムやGrignard試薬利用
B
X Li
BuLi
BX
官能基許容性に問題あり
■ 宮浦パラジウム触媒法
X
Pd cat.
B B
B
パラジウム触媒の残存
立体障害に弱い、反応が遅い
C(sp2)ーX へのホウ素置換反応
38. シリルボランの性質
シリルボランは塩基による活性化でケイ素求核剤となる
O
B
O
Si
Mes
Mes
OMe Si
Mes
Mes
OMeLi
BuLi
(2 equiv)
toluene
–78 °C, 1 h
Me3SiCl
(2.45 equiv)
Si
Mes
Mes
OMeMe3Si
88% yield
Kawachi, A.; Minamimoto, T.; Tamao, K. Chem. Lett. 2001, 1216.
Chiral NHC (10 mol%)
O
B
O
Si Ph R1
O
R2
1
R1
O
R2
Si
up to 98% yield
up to 98:2 er
R1 = alkyl, aryl,
OMe, H
DBU (15 mol%)
Ph
N N
Ph Ph
Ph Ph
Me Me
Chiral NHC
O'Brien, J. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 7712.
Si B
O
O
Ph + RO–M+
Si
B
O
O
Ph
OR
Si
B
O
O
Ph
OR
39. Br
base (1.2 equiv)
solvent, 30 oC , 1 h
B(pin)
MeO MeO
SiMe2Ph1
MeO
O
B
O
Si Ph
(1.5 equiv)
なぜか芳香族ハロゲン化物のホウ素化が進行!
Yamamoto, E.; Izumi, K.; Horita, Y.; Ito, H. J. Am. Chem. Soc. 2012, 134, 19997.
base
LiOMe
NaOMe
KOMe
KOtBu
K2CO3
KF
DBU
B/Si
80:20
95:5
73:27
total yield (%)
0
81
92
66
0
0
0
bSolvent: DME
tBuO では選択性・収率低下
ナトリウムでは選択性低下
アルコキシド塩基:
カリウムメトキシドがベスト
BBS法と名付けた
base promoted borylation with silylborane
山本英治博士
41. Yamamoto, E.; Izumi, K.; Horita, Y.; Ito, H. J. Am. Chem. Soc. 2012, 134, 19997–20000.
官能基や立体障害があってもスムーズに反応が進行する
B(pin)
R' = H, 64(85)%
B(pin)
50(84)%
O
S
B(pin)
63(78)%
R'
R' = Ph, 62(87)%
Yamamoto, E., Ukigai, S., Ito, H. Chem. Sci. 2015, 6, 2943 - 2951.
42. 官能基や立体障害があってもスムーズに反応が進行する
B(pin) B(pin)
Me Me
72% (isolated) 85% (isolated)
Murata, M.; Smbommatsu, T.; Watanabe, S.; Masuda, Y. Synlett. 2006, 1867.
Br B(pin)
H-B(pin) (2.0 equiv)
Pd(dba)2, t-Bu-DPEphos (5 mol%)
1,4-dioxane, Et3N (3.0 equiv)
100 ºC, 6 h
72% (isolated)
O
(t-Bu)2P P(t-Bu)2
t-Bu-DPEphos:
Br B(pin)
PMe2Si B(pin) (1.5 equiv)
KOMe (1.2 equiv)
DME, 30 ºC, 1 h
92% (NMR)
82% (isolated)
43. BBS法はヘテロ環化合物についても適用可能
Yamamoto, E., Ukigai, S., Ito, H. Chem. Sci. 2015, 6, 2943 - 2951.
(87)% 58(63)%
N
NBn
B(pin)
O
N
B(pin)
S B(pin) N
N
B(pin)
N
O
B(pin)
Ph Ph
59(68)% 67%c 51d(74)%
52%
B(pin)
S
(77)%
74(85)%
O
B(pin)N
Et
B(pin)
61(75)%
S
B(pin)
N
SEt B(pin)
N
N
B(pin)N
N
B(pin) N
N
B(pin)
MeO N
46(68)%
not detected(38)% 73%
S. Ukigai
44. BBS法はヘテロ環化合物についても適用可能
Yamamoto, E., Ukigai, S., Ito, H. Chem. Sci. 2015, 6, 2943 - 2951.
(66)%
N
B(pin)
58%
N
B(pin)
N
(1.0 equiv) 3w 20% isolated yield
KOMe (1.2 equiv)
DME, 30 oC, 1 h
PhMe2Si–B(pin) (1.5 equiv)
N SiMe2Ph
N SiMe2Ph
R
work-upborylation
conditions
■ シリル付加が収率を
下げるケースもある。
45. アルケニルハライドは立体特異的に変換される
Yamamoto, E., Ukigai, S., Ito, H. Chem. Sci. 2015, 6, 2943 - 2951.
Si-B equiv base solvent yield of B (%) Z/E B/Si
1.5 KOMe DME 53 92:8 95:5
1.5 NaOMe DME 72 96:4 96:4
1.5 NaOEt DME 79 97:3 96:4
2.0 NaOEt DME 89 97:3 96:4
2.0 NaOEt 1,4-dioxane 81 98:2 99:1
2.0 NaOEt CH2Cl2 2
2.0 NaOEt toluene 0
PhMe2Si–B(pin)
Base (1.2 equiv)
solvent, 30 ˚C, 1 h
Cy
I
Cy
B(pin)
Cy
SiMe2Ph
Z/E = 98:2
46. アルケニルハライドは立体特異的に変換される
Yamamoto, E., Ukigai, S., Ito, H. Chem. Sci. 2015, 6, 2943 - 2951.
DME, 30 ˚C, 1 h
Alkenyl X
NaOEt (1.2 equiv)
Alkenyl B(pin)
X = Br, I
PhMe2Si–B(pin) (2 equiv)
B(pin)
Cy
B(pin)
B(pin)
Ph
B(pin)
OMOM
B(pin)
B(pin)
B(pin)
B(pin)
O 5
B(pin)
O
B(pin)
Ph
Ph
O
OBuO
B(pin)
Cy
(E)-6a, X = I, 68% (Z)-6b, X = I, 72% (Z)-6c, X = I, 64%
(Z)-6g, X = I, 51(70)% (Z)-6h, X = I, 74%
6d, X = Br, 43%
(E)-6e, X = I, 64% 6f, X = Br, (60)%
6j, X = Br, 68%6i, X = B, 58%r 6k, X = Br, 53%
OPh
O
5
47. アルケニルハライドは立体特異的に変換される
i) 1 (1.5 equiv)
KOMe (1.2 equiv)
DME, 30 ˚C, 1 h
2 4
Ar–B(pin)Ar–Br
3
Pd(PPh3)4 (5 mol %)
K2CO3 (2 equiv)
solvent, temp.
Ar'–I (2 equiv)
Ar–Ar'
ii) TBAF treatment
NO2NC
4x, 36%b
4l, 74%c
N
N
N
4t, 78%d
O
NO2
4h, 84%b
NO2
S
N
4u, 64%d
N
4v, 58%d
48. アルケニルハライドは立体特異的に変換される
1 (1.5 equiv)
KOMe (1.2 equiv)
DME, 30 ˚C, 1 h
3y, 61(51)%a
N
N
Br
NBoc
N
N
B(pin)
NBoc
2y
N
NHN
N
NH2
O
Cl
Cl F
Crizotinib
(anti-cancer drug)
N
N
NBocN Br
1 (1.5 equiv)
KOMe (1.2 equiv)
DME, 30 ˚C, 1 h
N
N
NBocN OH
2z
ii) oxidation
3z, 71%a
N
N
NBocN B(pin)
N
N
NBocN O
S
O
O
GPR119 agonist
49. ■
Key Features of Boron Element
N
N
Pt
OO
B
Wang, Suning et al. Chem. Commun. 2011.
■
Triarylboron-‐‑‒Containing Materials
N B N B
B
B
S
S
B
n
Shirota, Y et al. J. Am. Chem. Soc. 1998.
Doty, J. C.; Babb, B.; Grisdale, P. J.; Glogowski, M.; Williams, J. L. R. J. Organomet. Chem. 1972, 38, 229.
含ホウ素有機電子材料:トリアリールボラン
50. K. IzumiDr. E. Yamamoto
BBS法をトリアリールボランに適用
base solvent temp. (℃) yield (%) B/Si
KOMe DME 30 28 39:61
NaOMe 1,4-dioxane 50 76 77:23
Na(O-t-Bu) 1,4-dioxane 50 78 87:13
Na(O-t-Bu)
1,4-dioxane/
hexane (1:1)
50 80 90:10
Si B
Et Br
base (1.2 equiv), 24 h
BEt SiEt+
51. 含ホウ素有機電子材料:トリアリールボラン
manuscript under preparation
MeO B
Mes
Mes
94% yield (90% purity)
B:Si=88:12 (NMR)
61% isolated yield
B
Me
Mes
Mes
90% yield (NMR)
B:Si=92:8 (NMR)
66% isolated yield
F3C B
Mes
Mes
69% yield (NMR)
B:Si=84:16 (NMR)
53% isolated yield
B
Me
Mes
Mes
46% yield
B:Si=67:33 (NMR)
20% isolated yield
N B
Mes
Mes
77% yield (NMR)
B:Si=96:4 (NMR)
50% isolated yield
N
Me
B
Mes
Mes
89% yield (NMR)
B:Si=93:7 (NMR)
62% isolated yield
Cl B
Mes
Mes
81% yield (NMR)
B:Si=91:9 (NMR)
69% isolated yield
B
Mes
Mes
89% yield
B:Si=90:10 (NMR)
43% isolated yield
B
SS Mes
Mes
55% yield
B:Si=89:11 (NMR)
42% isolated yield
Me
Br B
Mes
Mes
78% yield
B:Si=92:8 (NMR)
57% isolated yield
Me
Br
B
Mes
Mes
49% yield
B:Si=91:9 (NMR)
29% isolated yield
60. 遷移金属の触媒作用ではない
Pd, Cu, Fe, Ni, Rh, Ag, Co, Pt, Ru, Ir
の添加による加速効果は見られず
KOMe 試薬のICP発光分析
遷移金属は検出限界以下
Yamamoto, E.; Izumi, K.; Horita, Y.; Ito, H. J. Am. Chem. Soc. 2012, 134, 19997–20000.
反応機構に関する実験:遷移金属コンタミネーション?
このような反応は、どのような遷移金属の触媒反応においても、知られていない
61. 一電子移動&アニオンラジカル経由の機構
I
+
K(O-t-Bu) (3 equiv)
EtOH (cat)
DMF, 80 °C, 2 h
73%
Shirakawa, E.; Zhang, X.; Hayashi, T. Angew. Chem., Int., Ed. 2011, 50, 4671.
X+
I
O-t-Bu
I
Ph
p-Tol
Ph
RO– M+
Si B
O
O
Ph
OB
O
OR
Si
Ph
M X X
Si B
O
O
Ph OR Si B
O
O
Ph RO
? ?
67. AFIR自動反応経路探索: 北海道大学 前田・武次先生
Ref: 前田理、畑中美穂、植松遼平、
武次徹也、諸熊奎治
人工力誘起反応法による化学反応経路の自動探索:
有機合成化学への応用と展望
有機合成化学協会誌, 2014, 5, 567.
Dr. S. Maeda Pro. T. Taketsugu
RO– M+
Si B
O
O
Ph X
R. Uematsu
(天然物合成経験あり)
72. なぜ立体障害に強いのか?
Ar
Br
OB
O
RO
Si
Ph
M B O
O
O
R
M
Ar
Br
Si
Me
MePh
Ar
HBr
OB
O
RO
Si
Ph
M
ΔG‡: 18.4 kcal/mol0 kcal/mol
ΔG: -11.7 kcal/mol
B O
O
O
R
M
Ar
Br
Si
Me
MePh
B
O
O
Ar
ΔG‡: 1.0 kcal/mol
B O
O
O
R
M
Ar
Br Si Me
Me
Ph
Ar SiMe2Ph
ΔG‡: 2.4 kcal/mol
■ ハロゲンアタックが律速段階
profiles provided several points that can be beneficial for further
optimization of the BBS method.
At first, the activation energy in the halogenophilic attack on
sterically hindered 2,4,6-triisopropylbromobenzene (3e) was inves-
tigated and found to be reasonably low (ΔΔG⧧
= 1.9 kcal/mol,
Figure 4). TS(B2′/B3) was slightly lower than TS(B3/B4) for 3e
of
sol
the
Na
wh
in t
affo
alth
rea
Si−
of
me
cle
Inf
obt
cor
ana
ene
and
Figure 4. TS structures, free energies (ΔG⧧
) relative to the reactants
(1, 2a, and 3b/3e), and activation free energies (ΔΔG⧧
) for the halo-
Journal of the American Chemical Society
73. 改めてアリールアニオン種発生の確認
Then,
stance
pro-
gy of
n the
lation
ceeds
firmed
nd B7
ails of
S6-1.
ecked
d the
f silyl
elated
es the
adical
k22
at
that
state.
nergy
PhBr
reaction of 3c with silylborane 1 in the presence of potassium
methoxide proceeded as an intramolecular silyl substitution
reaction instead of a boryl substitution reaction to give TBS-
substituted product 12c in moderate yield (53% isolated yield),
without detection of borylation product 5c. This result
suggested that the corresponding aryl anion species was
generated in situ and that this species subsequently attacked
Scheme 3. Intramolecular Retro-Brook Rearrangement of a
Silylborane Species in the Presence of an Alkoxy Base
MeO
SiMe2Ph
8d', 51% GC yieldSi LiPh
p-MeOC6H4Br
(1 equiv)
THF, 30 ˚C, 1 h
Si LiPh Br OMe Si
Br
Ph
OMeLi