Merit of organocatalysis
Product is free from the contamination of metal.
Exclusion of water and air is not necessary.
Most of the ligands are non-toxic.
Organocatalyst in Total Synthesis
O
TBDPSO
Tohoku University
Yujiro Hayashi
8 O
O
O
N
H
N
H
OH
O
N
H
OH
O
O
Ph
N
H
CO2Et
N
F
Ph
OTMS
AcHN
N
F
NH2
F
NH2
F3 C
N
N
Background: Enamine intermediate
+
H
N
H
OH
CF3
Background: Iminium ion intermediate
CO2H
N
H
O
OH O
10 mol %
O
N
DMSO, rt
97%, 96% ee
O
B. List, R. A. Lerner, C. F. Barbas, J. Am. Chem. Soc., 2000, 122, 2395.
O
OTMS
Diels-Alder reaction
30 mol%
O
CF3
Ph
N
H
ABT-341 (Abbott laboratory)
(-)-oseltamivir
CF3
Ph
CF3
OH
O
H
Ph
+
O
N
H ·HCl
Ph
CHO
MeOH - H2O
Ph
R
1.3
OH
N
H
N
O
LUMO-lowering activation
O
OH
OH
N
R
R
H
O
O H
H
R
O
O
N
O
R
CHO
Ph
93% ee
:
1
D. W. C. MacMillan, et al., J. Am. Chem. Soc., 122, 4243 (2000).
H2O
O
+
93% ee
99%
H2O
OH
H
Ph
+
R
R
N
H ·HCl
N
R
H
Ph
Jorgensen-Hayashi Catalyst
Effective for the both enamine and iminium ion intermediate
Enamine: functionalization at the -position of aldehyde
O
N
H
OTMS
TMS = Me3Si-
H
10 mol%
N
H
NO2 +
Ph
Ph
Ph
OTMS
Ph
N
H
Iminium ion: functionalization at the -position of aldehyde
H
Y. Hayashi, et al., Angew. Chem. Int. Ed., 44, 4112 (2005).
F3C
CF3
O
1)
+
N
OTMS CF3
H
BnS
N
H
Ph
O
O2N
Ph
H
Mannich
Bz
O
O2N
H
99% ee
96% ee
Diels-Alder
Aza [3+3]
Ph
O
NH O
H
98% ee
Ph
OHC
H
NO2
O
Ph
Ph
OH
99% ee
92% ee
Michael
Carbo [3+3]
O
OH
OHC
Ar
NBoc
Ph
Ph
N
H
Ph
97% ee
94% ee
Oxidation
Michael
Domino
Ar
OTMS
Me
O
Ph
O
Epoxidation
10 mL
OMe
H
Me
N
Ph
O
O
O
CHO
Ph
2.64 g
O
O
O
O
O
H
Me
C7H15
Ph
Ph
O
Me
97% ee
95% ee
5 mol%
Domino
Domino
TESO
H
NO2
92% ee
95% ee
95% ee
94% ee
N
Ph
Ns
Me
Ph
Ph
OHC
4.7 mL
OMe
OH
Ph
decantation then
distillation
water
H
NO2
95% ee
Me
Michael
Domino
Michael
Nu
X-ray and ab initio calculation D. Seebach, Y. Hayashi, Uchimaru, et al.,
Helv. Chim. Acta, 2009, 92, 1225.
Reactions developed by our group
Michael
R
Me Si Me
OTMS
R
Me
60%, 95% ee
K. A. Jorgensen, et al., Angew. Chem. Int. Ed., 44, 794 (2005).
Michael
O
OH
2) NaBH4
H
N
H +
R
N
H
O
Nu
O
CF3
N N
Me
hexane, 23 °C, 1 h
Me
85%, 99% ee, syn : anti = 5.7 : 1
Me
BnS
R
H
R
Me Si Me
OTMS
O
O2N
H
E
O
R
O
O
E+
N
+
Ph
CF3
exo:endo 82:18
CF3
O
NH2
Ph
NO2
NO2
99% ee
99% ee
Angew. Chem. Int. Ed., 44, 4212 (2005). Angew. Chem., Int. Ed., 45, 6853 (2006). Angew. Chem., Int. Ed.,
46, 4922 (2007). Org. Lett., 9, 5307 (2007). Angew. Chem., Int. Ed., 47, 4012 (2008). Angew. Chem., Int.
Ed., 47, 4722 (2008). Angew. Chem., Int. Ed., 47, 9053 (2008). Chem. Commun,, 3083 (2009). Chem.
Asian. J., 4, 246 (2009). Org. Lett., 11, 45 (2009). Org. Lett., 11, 4056 (2009). Tetrahedron, 66, 4894
(2010). Org.Lett., 12, 4588 (2010). Org.Lett.,12, 5434 (2010).
ClO4
F3C
3.2 g, 81%
97% ee
CF3
water
RT, 8 h
Angew. Chem. Int. Ed., 47, 6634 (2008).
Synthesis of (-)--Santalol by Firmenich
CF3
1.5 mol%
2 mol%
TESO
O
H + CH3NO2
N
H2
H
1) NaH2PO32H2O
NaClO2
2-methyl-2-butene
O
OH
NH2
80%
71%, 93% ee
OHC
H2O
O
H
NO2 2) Pd/C, H2
MeOH, RT
CF3
F3C
O
Ph
OTMS
N
H
CF3
ClO4
Ph
Pregabalin: anticonvulsant
CHO
61%
exo : endo = 70 : 30
exo 95% ee, endo 78% ee
2 mol%
Ph
O
Ph
OTMS
N
H
4 mol%
H
+ CH3NO2
2 steps
H
NO2
PhCOOH
MeOH, RT
p-Cl-Ph
O
O
p-Cl-Ph
p-Cl-Ph
80%, 92% ee
OH
OH
NH2
87%
Baclofen: GABAB receptor agonist
()--Santalol
Org. Lett., 9, 5307 (2007).
C. Fehr et al.,(Firmenich), Angew. Chem., Int. Ed., 2009, 48, 7221.
Synthesis of Telcagepant by Merck
Total synthesis of biologically active compounds
O
N
H
F
F
H
CH3NO2
O
OH
HO
O
Ph
O
O
F
NO2
F
O
CHO
H
Me
O
H
Me
O
H
Me
O Me
OH
HO
O
OH
Me
OH
Me
HO
OMe
Me
O
Me
O
73%, 95% ee
CF3
O
N
F
F
N
N
Me
MeO
O
Me
HO
O
OO H
N
Et
N
Me
O
O
O NH
OH
MeO
O
Me
O
OH OH
O
OH
OO H
N
Ph
Et HO
Me
O
O
O
Ph
OH OMe
pseurotin A
OH
Et
H
N
O
OO
Me
O
O
O
H
N
OH
Et
Ph
OMe
O
H
O
OMe
H
OH
OH
O
O
OH
H
N
OO
OH
O
Me
nBu
OMe
O
O
OH
NH2
Me
OH
O
F
N
N
O
CO2Et
CF3 AcHN
NH2
F
baclofen
N
N
NH2
F
Cl
pregabalin
+NH3 OH
nikkomycin B
OH
NH2
O
(+) - cytotrienin A
O
FD-838
O
O
N
H
N
CO2- O
O
HO
ent-convolutamydine E
OH
O
HN
N
H
Br
CPC-1
HO
OH
O
N H
Me
O
Ph
OMe
HO
NMe
Me
O
madindoline A
O
Br
MeO
N H
NH
Me
synerazol
HO
NH
Me
HO
Me OH
fostriecin
O
H
Me
O
lucilactaene
OH
O
OH MeO
Me
Me
NaHO3PO
Me
O
O NH
Me
epolactaene
azaspirene
F. Xu et al.,(Merck), J. Org. Chem., 75, 7829 (2010).
O
C14H29
O
ovalicin 5-demethylovalicin panepophenanthrin (R)-Methyl Palmoxirate
FR-65814
NG-391
NH
Telcagepant
CGRP receptors antagonist for treatment of Migraine
O
HO
>100 kg
O
O O
HO
EI-1941-3
OH
H
O
O
fumagillol
RK-805
O
Me OH
Me
Me
OH
O
HO
EI-1941-2
Me
O
nPr
O
EI-1941-1
Me
O
OH
O
nPr
O
O
O
Me
O
nPr
O
epoxytwinol A
OMe
OH
O
O
Me
O
Me
O
OMe
O
Me
OO
Me
epoxyquinol C
Me
O
OMe
THF-H2O
Me
O
Me
O
H
Me
epoxyquinol B
Me
O
O
O
Me
O
H
Me
epoxyquinol A
O
O
O
Me
O
H
Me
OTMS
O
O
OH
OH
OH
HO
O
O
5 mol% tBuCO2H
50 mol% B(OH)3
O
O
OH
HO
Ph
5 mol%
ABT-341
(-)-oseltamivir
First retro-synthetic analysis
O
O
O
CO2Et
CO2Et
CO2Et
tBuO
AcHN
oseltamivir
NH2
AcHN
O
NO2
NH2 ·H3PO4
O
(–)-oseltamivir phosphate (Tamiflu)
O
H
tBuO
CO2Et
+
tBuO
Tamiflu: Orally administrated anti-Influenza drug developed by
Gilead Sciences, Inc. and Roche
Total Synthesis: Corey (2006), Shibasaki (2006),Yao (2006), Wong (2007)
Fukuyama (2007), Fang (2007), Kann (2007), Trost (2008)
Banwell (2008), Mandai (2009), Hudlicky (2009) et al.,
53 total syntheses
Synthetic Challenge: Control of three continuous chiral center
Selectivity (enantio- and diastereo-)
t-BuO2C
NO2 +
H
N
H
NO2
O
+
rt
O
+
t-BuO2C
NO2
syn (desired)
yield
syn : anti
hexane
60
26%
2.5 : 1
CH2Cl2
60
quant.
1.7 : 1
Ph
OTMS
H
Me
85%, 99% ee
syn : anti = 5.7 : 1
Y. Hayashi, et al., Angew. Chem. Int. Ed., 44, 4212 (2005).
H+
Acid promote
H
H
N
H
t-BuO2C
NO2
anti (undesired)
O
Ph
Ph
OTMS
H
O
H+
Acid promote
NO2
HO
Ph
Ph
OTMS
N
O
H2O
H
t-BuO2C
NO2
Ph
NO2
+
N
H
H
Me
Ph
Ph
OTMS
N
H
10 mol%
O
O
O2N
hexane, 23 °C, 1 h
Me
O
t-BuO2C
time / h
N
H
H
O
O
H
solvent
H
Proposed Reaction Mechanism
O
O
Ph
Ph
10 mol%
O
20 mol%
O
O
NO2
Ph
Ph
OTMS
O
+
O
O
Ph
NO2
O
Ph
Ph
OTMS
hexane
rt, 1 h
O
Me
O
H
Ph
85%
Me
H
+
O
Ph
NO2
syn
H2O
NO2
anti
syn : anti = 5.7 (99% ee) : 1
Y. Hayashi, et al., Angew. Chem., Int. Ed. 2005, 44, 4212.
H
Ph
Ph
OTMS
N
H
t-BuO2C
NO2
Ph
Ph
OTMS
O
NN
O
t-BuO
NO2
O
H
t-BuO
O O
H+
Acid promote
Revised reaction mechanism
O
Ph
N
H
O
NO2
t-BuO2C
H
+
O
OTMS
O
additive
O
R1
Ph
CH2Cl2, rt
O
O
H
t-BuO2C
R2
O
H
H
R
N
H
R2
NO2
H
+
O
R1
H
R1
NO2
H2O
t-BuO2C
NO2
NO2
syn
(desired)
anti
(undesired)
catalyst
/ mol%
additive (mol%)
pKa in H2O
time / h
yield
syn : anti
ee / %
syn / anti
20
none
–
60
quant.
1.7 : 1
nd
20
CF3CH2OH (40)
12.5
24
50% (brsm 95%)
2.3 : 1
nd
20
p-nitrophenol (40)
7.1
24
quant.
1.7 : 1
nd
20
PhCO2H (40)
4.2
14
quant.
2.0 : 1
nd
5
HCO2H (20)
3.77
2
quant.
4.8 : 1
nd
5
ClCH2CO2H (20)
2.86
1
quant.
6.3 : 1
96 / 87
5
Cl3CCO2H (20)
0.65
28
No Reaction
–
R
N
R1
R
N
H
H
H
R2
R2
R
N
X
R1
R1
NO2
NO2
HX
R
N
R
N
R1
NO2
R1
NO2
H
R2
R2
R2
O
N
O
D. Seebach, Y. Hayashi, et al., Helv. Chim. Acta, 2011, 94, 719.
Cf, D. Blackmond et al., J. Am. Chem. Soc., 2011, 133, 8822.
Domino Michael / Intramolecular Aldol reaction
O
O
H
+
CO2Et
NaH, DBU, Et3N, TBAF, CsF
K2CO3, Cs2CO3, DABCO, Bu3P
Tandem Michael/HWE reaction
CO2Et
t-BuO2C
t-BuO2C
O
EtO
P
EtO
O
O
1.5 equiv.
NO2
Cs2CO3, CH2Cl2
–10 °C ~ 0 °C
~ 30%
O
TBAF
CsF
Cs2CO3
O
O
O
O
t-BuO2C
CO2t-Bu
CO2t-Bu
NO2 O
NO2
O
H
t-BuO2C
NO2
5R : 5S = 4.6 : 1
Retro Aldol/HWE reaction
Cs2CO3, EtOH
23 °C, 15 min
90%
Byproducts
Base
O
O
O OEt
P OEt
CO2Et
O
Intramolecular
HWE
reaction
O
CO2Et
NO2
NO2
H
CO2Et
O
t-BuO2C
O2N
EtO2C
OEt
Base
H
~30%
P
O
OEt
O
P
O
t-BuO2C
t-BuO2C
NO2
5R
t-BuO2C
Cs2CO3, EtOH
23 °C, 15 min
quant.
NO2
Major byproduct detected by Mass
CO2Et
Retro Michael reaction
t-BuO2C
NO2
O
O
OH
O
Michael reaction
O
EtO
P
CO2Et
EtO
CO2Et
H
t-BuO2C
NO2
NO2
O
OEt
OEt
CO2Et
t-BuO2C
NO2
~30%
Tandem Michael/HWE reaction
O
EtO
P
EtO
O
O
CO2Et
O
1.5 eq
Cs2CO3
H
t-BuO2C
t-BuO2C
rt, 15 min
CH2Cl2, 0 °C, 3 h
NO2
CO2Et
EtOH
Unsuccessful isomerization from 5R to 5S
5R
NO2
6 : 1
61%, 5R : 5S = 4.6 : 1
One-pot Reaction: purification economy, chemical waste economy, time econony
increase yield
EtO
P
O
O
+
t-BuO2C
O2N
CH2Cl2
0 °C, 3 h
t-BuO2C
CO2Et
O
Cs2CO3
H
OH O OEt
P
OEt +
CO2Et
OEt
P
OEt
O
EtO2C
~30%
NO2
t-BuO2C
O
CO2Et
5R
t-BuO2C
CO2Et
5R : 5S = 1 : 1
Et3N
CO2Et
O
EtO
O
O
5S
t-BuO2C
NO2
O
NO2
CO2Et
t-BuO2C
NO2
NO2
~30%
~30%
CsCO3, EtOH ~90%
quant.
rt, 15 min
HS
O
CO2Et
Stol
Me
Base
O
5R
EtOH
t-BuO2C
NO2
O
CO2Et
5S
t-BuO2C
t-BuO2C
NO2
A
5R : 5S = 5 : 1
Stol
CO2Et
NO2
B
(Other diastereomer mixture)
CO2Et
5S isomer
5R isomer
t-BuO2C
H
CO2t-Bu
4.0 Hz
4
10.0 Hz
H
H
R
H
H
17.0 Hz
NO2
5
4.0 Hz
H
NO2
6
3
O
10.0 Hz
3
6
5.6 Hz
O
t-BuO2C
H
8.8 Hz
6.0 Hz
C
10.0 Hz
5
4
R
H
17.6 Hz
Yield/%
Base
temp. / °C
time / h
A
B
C
K2CO3
–5
24
85
15
–
Cs2CO3
–5
13
35
–
65
Cs2CO3
–15
36
90
<5
–
H
H
R = CO2Et
5R - isomer is stable than 5S - isomer in only 0.11 Kcal/mol
by B3LYP/6-31G(d) calculation.
Calculation was performed by Dr.Uchimaru.
Application to one-pot reaction
5 mol%
EtO
Ph
O
N
H
H
+
O
EtO
P
CO2Et
Stol
O
O
20 mol% ClCH2CO2H
NO2
t-BuO2C
Ph
OTMS
O
Cs2CO3
H
CH2Cl2
0 °C ~ rt, 4 h
t-BuO2C
CH2Cl2, rt, 6 h
NO2
Stol
O
CO2Et
5S
t-BuO2C
O
O
O
H
t-BuO2C
NO2
OEt
EtO2C
CO2Et
O
+
t-BuO2C
O2N
P(OEt)2
OH O OEt
P
OEt
CO2Et
CO2Et
P
O
t-BuO2C
O
+
t-BuO2C
NO2
O
Stol
NaN3
CO2Et
CO2Et
5R
rt, 10 min
–15° C, 36 h
t-BuO2C
O
tolSH
NO2
CO2Et
NO2
O
NO2
without purification
NH2
70%
single diastereomer
R : S = 4.6 : 1
O
CO2Et
CO2Et
N3
AcHN
5S
t-BuO2C
O
O
H2O
Acetone
0 °C
Cl
O
CH2Cl2, rt;
evaporation
HO2C
Stol
NO2
STol
EtOH
(COCl)2
cat. DMF
CO2Et
CO2Et
NO2
OEt
O
CH2Cl2, rt;
evaporation
NO2
O
TFA
NO2
(–)-Oseltamivir
3 “one-pot” synthesis of (-)-oseltamivir
5 mol%
O
AcOH
Ac2O
Stol
O
CO2Et
Stol
O
RT
49 h;
evaporation
N3
NO2
O
without purification
CO2Et
Zn, TMSCl
O
EtOH, 70 °C
+
AcHN
NO2
t-BuO2C
Stol
O
CO2Et
AcHN
Cl Zn
Cl
NH2
Stol
NH3
0 °C
10 min.
Ph
Ph
N
H
OTMS
20 mol% ClCH2CO2H
H
O
CO2Et
then
K2CO3
EtOH, rt
AcHN
NH2
82%
(6 steps)
O
CO2Et
NO2
CH2Cl2, rt
O
EtO
P
EtO
O
OEt
tolSH
CH2Cl2, 0 °C;
evaporation;
EtOH, rt
–15 °C
O
t-BuO2C
(COCl)2
cat. DMF
NaN3
CH2Cl2, rt;
eveporation
CH2Cl2, rt;
evaporation
H2O, acetone
0°C
CO2Et
5S
NO2
column chromatography
Stol
TFA
O
CO2Et
AcOH
Ac2O
rt;
evaporation
N3
O
NO2
without purification
AcHN
NH2
(–)-Oseltamivir
Zn, TMSCl
id-base extraction
Stol
Cs2CO3
EtOH, 70 °C
NH3
then K2CO3
EtOH, rt
acid-base extraction
82% (6 steps)
O
CO2Et
AcHN
· 3 "one-pot operations"
· total yield 57% from nitro alkene
NH2
(–)-Oseltamivir
Angew. Chem. Int. Ed., 48, 1304 (2009).
2 “one-pot” synthesis of (-)-oseltamivir
Column free synthesis
1 mol%
O
Ph
1 mol%
O
Ph
H
Ph
N
H
OTMS
20 mol% ClCH2CO2H
O
+
toluene, rt
NO2
t-BuO2C
O
EtO
P
EtO
H
O
Ph
N
H
OTMS
20 mol% ClCH2CO2H
O
OEt
Cs2CO3
toluene, 0 °C;
evaporation;
EtOH, rt
Stol
O
tolSH
–15 °C
CO2Et
5S
t-BuO2C
+
toluene, rt
NO2
t-BuO2C
74%
TFA
(COCl)2
cat. DMF
toluene, rt;
eveporation
toluene, rt;
evaporation
toluene
O
CO2Et
AcHN
NH2
(–)-Oseltamivir
AcOH
Ac2O
rt;
evaporation
Zn, TMSCl
EtOH, 70 °C
NH3
then K2CO3
EtOH, rt
acid-base extraction
82% (6 steps)
OEt
Stol
tolSH
toluene, 0 °C;
evaporation;
EtOH, rt
–15 °C
O
Stol
TFA
O
toluene, rt;
eveporation
HO2C
NO2
acid-base extraction
(COCl)2
cat. DMF
Me3SiN3
pyridine
AcOH
Ac2O
toluene, rt;
evaporation
toluene
rt;
evaporation
NO2
71%
· 9 steps
· 2 "one-pot operations"
· one purification by column
chromatography
· total yield 60% from nitro alkene
CO2Et
Stol
acid-base extraction
Zn, TMSCl
NH3
then K2CO3
EtOH, 70 °C
EtOH, rt
CO2Et
t-BuO2C
(EtO)2P(O)OH
O
O
CO2Et
N3
CO2Et
O
(–)-Oseltamivir
AcHN
Chem. Eur. J., 16, 12616 (2010).
NO2
Differential Scanning
Calorimetry
NH2
acid-base extraction
Chem. Eur. J., 16, 12616 (2010).
Microreactor in the Curtius Rearrangement
STol
STol
O
O
CO2Et
Microtube
reactor 1
Stream 1
Cl
O
Cs2CO3
NO2
column chromatography
Me3SiN3
pyridine
O
EtO
P
EtO
O
NO2
in DMF
TMSN3,
pyridine
in DMF
CO2Et
N3
O
NO2
Micromixer 1
rt, 26 min
Microtube
reactor 2
Stream 2
STol
O
CO2Et
Micromixer 2
Ac2O,
AcOH
in DMF
110 °C, 80 min
AcHN
NO2
Stream 3
10 g scale, 84%
After washed with H2O;
recrystallization from toluene
>99% ee
Eur. J. Org. Chem., 2011, 6020.
Practical synthesis of (-)-oseltamivir
1 mol%
O
Ph
Ph
N
H OTMS
20 mol% ClCH2COOH
H
O
O
EtO
P
EtO
• t-BuO2C
• Step economy (Wender)
• Redox economy (Baran & Hoffmann)
NO2
Acid-base extraction
to remove (EtO)2P(O)OH
Stol
Stol
CO2Et
O
TFA
CO2Et
O
Me
evaporation
then EtOH
NO2
Green Reaction
Stol
HS
Cs2CO3
+
t-BuO2C
CO2Et
HO
evaporation
O
NO2
Acid-base extraction
CO2Et
O
(COCl)2
Cl
TMSN3
pyridine
AcOH
•
•
•
•
Ac2O
110 °C
DMF
O
Operational
Pot
economyEconomy
NO2
Flow System
Stol
CO2Et
O
Ac
N
H
NH3
Zn
NO2
After recrystallization
43% (from nitroalkene, >99% ee)
then, K2CO3
Acid-base
extraction
92%
O
CO2Et
AcHN
NH2
No column
Total yield: 40%
Gram scale synthesis
Efficent and safety method
One pot reaction is not a simple combination
of each optimized reaction.
()-Oseltamivir
One-Pot Reaction
• on-insulin dependant diabetes
• Restriction on the amount of the reagent
(1:1 molar ratio)
• Restriction on the solvent Solvent of high boiling point is
not suitable)
• Restriction on the reaction
Dipeptidyl peptidase-4 (DPP-4) inhibitor
O
O
A + B
C +D
AcHN
O
Ph
+
H
O
(EtO)2P
base
CO2Me
Ph
CO2Me +
CO2Et
NH2·H3PO4
Tamiflu (Roche)
O
(EtO)2P OH
F
F
N
F
NH2
CF3
N
N
F
N
N
CF3
ABT-341 (Abbott laboratory)
N
N
N
NH2 O
F
F
JanuviaTM (Merck)
Retro-synthetic analysis
Synthesis of ABT-341 by Abott (J. Med. Chem., 2006, 49, 6439)
O
TMSO
Br
O
Br
F
NO2
F
TFA
toluene, 120 oC
CH2Cl2
rt, 10 min
2 days
61%
F
F
PBr3, DMF
NO2
F
CH2Cl2
(racemic)
0 oC to rt, 24 h
34%
F
F
NO2
F
(racemic)
CH2Cl2, rt, 12 h F
F
Br
Zn, AcOH
(Boc)2O
MeOH
80 oC, 2 h
THF
OH
OH
HCO2H, nBu3N
Pd(PPh3)2Cl2
F
F
NHBoc
F
85% (2 steps)
(racemic)
H
DMP
F
F
ABT-341
CH2Cl2
NHBoc
F
81%
(racemic)
NHBoc
H
F
(racemic)
O
OH
DMSO, 0 oC, 2 h
F
F
quant.
NHBoc
F
N
F
Asymmetric Michael Reaction
F
O
F
CF3
NH3 TFA
F
F
time / h
yield / %
ee / %
10
24
74
94
2
18
92
97
EtO
O
NO2
O
OMe
2X
N
H
H
Me 10Hequiv.
bp 21 °C
+
F
Ph
Ph
OTMS
NO
O 2
F
1 equiv.
H
N
H
P
CO2tBu
F
F
+
F
F
NO2
CO2tBu
; EtOH
H
F
O
O
H
H
NO2
F
1,4-dioxane
rt, 18 h
F
Ph
Me
NONO
2 2
Me
F
F
75%
yield, 95%
ee
byproduct
Y. Hayashi et al., Angew. Chem. major
Int. Ed.
2008, 47, 4722.
0 oC to rt
15 min
87%
OEt
P OEt
F
CO2tBu
F
NO2
F
F
NO2
CO2tBu
i Pr EtN
2
5R
F
5S
EtOH, 65 °C
F
O
OH
CO2tBu
F
Ph
OTMS
H
O
Cs2CO3
H
O
Ph
O
Chiral cyclohexene formation
CH2Cl2, 0 oC, 3 h
10 mol%
Ph
O2N
OTMS
Y. Hayashi, et al., Angew. Chem. Int. Ed., 47, 4722 (2008).
EtO
F
Ph
Ph
75%, 96% ee
H
X / equiv.
Ph
H
1,4-dioxane, 23 °C, 18 h
F
1,4-dioxane
0 oC to rt, time
Previous Results
Me
F
H
O
Ph
OTMS
N
H
F
+
13 Steps
Total Yield : <8%
including HPLC
separation
10 mol%
Ph
NO2
N
H
(chiral)
+
Me
H
X equiv.
N
N
F
Yield (no data )
NO2
Ph
N
then TFA, CH2Cl2
NHBoc
F
(chiral)
+
10 mol%
O
O
CF3
TBTU, TEA, DMF
F
F
Yield (no data )
O
NO2
NO2
NHBoc
F
(chiral)
F
Yield (no data )
N
N
rt, 5 h
F
N
O
2N NaOH aq.
NHBoc
(racemic)
Yield (no data )
HN
F
CO2tBu
P
F
F
OH
F
OMe
chiral prep.
F
MeOH, CH2Cl2
(racemic)
O
OMe
TMSCHN2
EtO
O
F
O
F
EtO
+
F
NaClO2
isoprene
NaH2PO4, buffer
NO2
F
O
F
70%
F
CF3
NH2
5S
O
F
DMF, 80 oC
12 h
F
F
CF3
N
N
78%
CO2tBu
N
N
F
NaBH(OAc)3
NO2
F
(racemic)
F
N
N
H
F
N
HN
O
OH
F
NO2
quant.
F
F
NO2
Synthesis of ABT-341
Trial one-pot reaction
CO2tBu
F
CF3CO2H
5S
F
F
N
CF3
F
CH2Cl2, rt
quant.
NO2
N
CO2H
F
F
Me
TBTU
iPr EtN
2
THF, 0 °C to rt
NO2
F
O
N
HN
85%
F
N
N
F
N
F
F
AcOEt
CF3
NO2
F
98%
CO2tBu
F
F
F
CO2tBu
F
5R
F
F
NO2
10 mol%
Cs2CO3
H
F
F
F
O
CO2tBu
CH2Cl2, 0 oC
; EtOH, 0 oC to rt
15 min
NO2
Me
CO2tBu
F
TMSCl
F
0 oC , 5 min
F
N
H
H
+
NO2
F
F
2EtN
F
0 oC to rt
; rt,o48
h rt
40
C to
; rt, 48 h
F
5S
CO2tBu
CO2tBu
F
+
92% yield
2EtN
EtOH, 65 oC,
quant.
Ph
F
NO2
CO2tBu
F
5S
F
F
NO2
CsO
N
O
desired isomer
1.2 equiv.
O
EtO
P
EtO
Ph
OTMS
CO2tBu
Cs2CO3
CH2Cl2, 0 oC
; EtOH, 0 oC to rt
15 min
TMSCl
40 oC, 5 min;
iPr EtN, 15 min;
2
rt, 48 h
evaporation
F
CO2H
CF3COOH
F
CH2Cl2
rt;
evaporation
NO2
F
NO2
F
35% yield
iPr
F
F
iPr
F
oC
-40
, 5 min
>> Convert Cs2CO3 to CsCl
for Isomerization
CO2tBu
5S
F
1,4-dioxane
0 oC to rt
5R
NO2
NO2
Cs2CO3
EtOH, rt
quant.
undesired isomer
O
F
5R
F
CF3
NH2
ABT-341
O
EtO
P
EtO
CO2tBu
iPr EtN
2
N
N
F
NO2
F
N
N
Zn, AcOH
N
F
CO2tBu
CH2Cl2, 0 oC
; EtOH, 0 oC to rt
O
H
F
1,4-dioxane
0 oC to rt
F
Cs2CO3
O
O
Ph
OTMS
N
H
NO2
Ph
+
H
O
EtO
P
EtO
10 mol%
O
+
F
F
NO2
EtO P OH
EtO
from HWE reaction
71% (4 steps)
O
F
52% yield
>5% yield
N
HN
N
CsCl
; insoluble material
TBTU
iPr
O
N
CF3
2EtN, THF
0 oC to rt
O
N
N
F
F
N
F
NO2
N
CF3
+
EtO P
EtO N
N
N
Which is the major product ?
N
CF3
One-Pot Total Synthesis of ABT-341
N
HN
N
CO2H
F
F
CF3
(1.1 equiv.)
TBTU (2.0 equiv.)
O
EtO P OH
EtO
+
NO2
F
1.0 equiv.
O
iPr
2EtN, THF
oC to rt, 12 h
N N
N
F
NO2
+
O
EtO P
EtO O
N N
N
iPr
N
F
N
NO2
O
87%
2EtN
+
EtO P
EtO N
N
N
EtOH
40 oC to rt
; evaporation
N
CF3
N
CF3 <5%
TBTU : N
F
F
CO2tBu
F
CH2Cl2, 0 oC
; EtOH, 0 oC to rt
F
; TMSCl, 40 oC
F
CO2tBu
NO2
N Me BF4
N
N Me
O
N Me
Me
CO2H
CF3CO2H
5S
F
N
F
F
1.0 equiv.
1.2 equiv.
Cs2CO3
H
NO2 1.4-dioxane
0 oC to rt
; evaporation
CO2tBu
5R
F
NO2
N
HN
N
O
F
F
O
Ph
OTMS
N
H
H
Me
2.0 equiv.
F
O
EtO
P
EtO
10 mol%
Ph
O
F
F
0
1.0 equiv.
O
N
F
F
CH2Cl2
40 oC to rt
; evaporation
NO2
Zn
AcOH
TBTU
F
F
NO2
2EtN, THF
0 oC to rt
N
N
N
F
iPr
; nPrNH2, rt
F
F
1.1 equiv. CF3
F
O
EtOAc, 0 oC
; NH4OH
N
NH2
6 steps
One-Pot Operation
CF3 Total yield : 63%
N
ABT-341
Angew. Chem. Int. Ed. 2011, 50, 2824.
fumagillins, ovalicins, panepophenanthrin
Hayashi Laboratory ( Tokyo University of Science, TUS)
HayashiLab.Homepage:http://www.ci.kagu.tus.ac.jp/lab/orgchem1/
Total Synthesis of Bioactive Compounds
O
CO2H
O
O
O
O
Me
Me MnO2
O
O
Cl
O
O
O
CH2Cl2
0 °C
OH
CO2Me
OH
toluene
rt
oxidative dimerization
HO
O
syn
OH
OH
O
O
O
Me
anti
O
O
O
Me
syn Me
Me
O
endo-hetero
O
syn
OH
OH
O
O
O
O
Me
anti Me
O
OH
anti
OH
O
O
O
O O
O
O
angiogenesis inhibitor
HO
CHO
O
ClCH2CO2H
N
R
R
Ar=3,5-(CF3)2-C6H3
HO
Me Me
O
OTIPS
R=H, 73%, 85% ee
R=Br, 86%, 82% ee
O
ONHPh
N
R
DMF
OTIPS
O
Me
O
10 mol%
key intermediate
O
>99% ee
O
O
O
O
OH
OH
HO
O
O
O
O
H Me
O
Me
epoxyquinol A
O
OH
OH
HO
O
O
O
O
O
O
O
H Me
O
Me
H Me
O
Me
epoxyquinol B
epoxyquinol C
OO
panepophenanthrin
ubiquitin-activating
enzyme inhibitor
O
MeO
O
N H
O
Me
Me
O
O
epoxytwinol A
NMe
N H
Me
O
Bu
Org. Lett. 2009, 11, 3854.
BuO2C
Pr
Pr
OH
OTBS
O
n
O
O
TBSO
Me
OTBS
THF-HMPA
78 oC
O
O
H +
O
+
TBSO
TBSO
OTBS
t
BuO
OH
Me
O
Me
t
BuO
O
O
H
O
1
NH O
NH O
NMP
20 oC
Me
NH2
O
TBSO
CO2H
N
H
H
O
Me
Me
Me
O
MeO
O
O
HO
O
O
HO
O
HO
HO
TBSO
O
NH OH
THF, 78 oC
ICE (interleukin 1- converting enzyme) inhibitor
Org. Lett. 2004, 6, 4535.
J. Org. Chem. 2005, 70, 9905.
N
HN
O
O
NG-391
MeO
OH
CO2 O
O
NH
OH
lucilactaene
cell cycle inhibitor
in p53-transfected cancer cells
Angew. Chem. Int. Ed. 2005, 44, 3110.
1,4-asymmetric induction
Me
O
OH
nikkomycin B
OMe
H O
H
Me
O
formal total synthesis of fostriecin
H +NH3 OH
N
O
O
Me
OH
Me
O
O NH
Me
HO
neuronal cell-protecting molecule
OH
O
LiAlH(OtBu)3
EI-1941-3
EI-1941-2
epolactaene
Me
O
Pr
O
OH
O
O NH
Me
neurtie outgrowth in SH-SY5Y cells
n
Pr
EI-1941-1
MeO
1
Tetrahedron, 2002, 58, 9839.
n
Pr
HO
Me
O
MeO
TBDPSO
OMe
O
n
O
O
Me
CN
O
OH
syn : anti = 14 : 1, 96%ee
O
O
Me
HO
Chem. Lett. 1998, 313
J. Org. Chem. 2002, 67, 9443.
three-component cross-Mannich reaction
10 mol%
O
Me
LDA
CH3CHO
t
Me
O
cat. Pd(II)
benzoquinone
n
N
H
Br
formal total synthesis of nikkomycin B
EI-1941-1, EI-1941-2, EI-1941-3
O
epolactaene, NG-391, lucilactaene
ent-convolutamydine E
CPC-1
n
Me
OH
O
madindoline A
angiogenesis inhibitor
Angew. Chem., Int. Ed., 41, 3192 (2002); T etrahedron Lett., 43, 9155 (2002);
Tetrahedron Lett., 44, 7205 (2003);J. Org. Chem., 69, 1548 (2004);
70,
J. Org. Chem.,
79 (2005) ; Org. Lett., 8, 1041 (2006).
Review; Eur. J. Org. Chem., 23, 3783 (2007).
Chem. Asian J., 1, 845 (2006).
Br
HO
HO
OH
Me
O
H
OH
OH
O
OH
OH
O
OH
H
O
O
dimerization
HO
O
OHO
O
Me OH
Me
Me
Me
Me
H2O
O
OH
CO2H
O
Me
Me
OH
Me
exo-homo
exo-homo
5-demethylovalicin
ovalicin
Angew. Chem., Int. Ed., 45, 789 (2006),
ReView; Chem. Eur. J. 2010, 16, 3884.
Ar
OH
N
H
O
O
OH
Me
H
Me
O
O
Ar
+
Me
O
OH
O
OTBS
immunosuppressive effect
OOHMe
Me
O
OMe
HO
Me
R
O
O
O
O
O
+ PhN=O
O
OH
Me
OOHMe
O
OH
FR-65814
angiogenesis inhibitor
O
CPC-1, ent-convolutamydine E, and
half segment of madindoline A
OH
fumagillol
RK-805
Me
O
OMe
OH
ONHPh
Me
OH Me
Me
O
OMe
O
O
Me
OH Me
Me
O
OMe
>99% ee
epoxyquinols
Me
OH Me
OTBS
OH
-aminoxylation
10 mol%
H
antifungal activity
(CO)3
(CO)3
Co Co OBOM
H
Co2(CO)8
OBOM
CH2Cl2
OPMB
(CO)3 (CO)3
Co Co OBOM
OH
NMO
OBOM
OPMB
CH2Cl2
OPMB
OH Me OH
Me OH
O
Me OH
allylSnPh3
TiCl2(Oi Pr)2
OPMB
Tetrahedron, 2005, 48, 11393.
Me OH
60%, syn : anti = 92 : 8
azaspirene, pseurotin A, synerazol, FD-838
Me
Me
O
O
O
Et
OMe
OHC
Ph
MgBr2兟OEt2
Et
TBSO
Me O
O OMe Ph
Me
Et
O
OMe
HO
O
Et H H OH
O
1,3-asymmetric induction
NH
Me
Me O
Ph
OTIPS
O
OTBDPS
Me
Me O
O
O
ZnBr2, nBuLi
H
Me O
O
NaHO3PO
OTBDPS
OH
O
OH
Me OH
fostriecin
Me O
PP2A inhibtor
single diastereomer
OH
OO H
N
Et
O
Org. Lett. 2008, 10, 1405.
Chem. Eur. J. 2010, 16, 10150.
O
OO H
N
Ph
O
Ph
OH OMe
Et HO
Me
OH OH
Me
O
Et
OO H
N
Me
O
OH
O
azaspirene
pseurotin A
synerazol
neurite outgrowth in PC12 cells
antifungal antibiotic
Org. Lett. 2003, 5, 2287.
Et
Ph
OMe
angiogenesis inhibitor
J. Am. Chem. Soc. 2002, 124, 12078.
OO H
N
O
Me
O
OH
O
R
( )- oseltamivir (Tamiflu )
Ph
OMe
5 mol%
FD-838
O
diffrenttiation of leukamia
antifungal antibiotic
J. Org. Chem. 2005, 70, 5643.
(+) - cytotrienin A
O
H
H
BuO2C
Asymmetric cross
( ) 8 O aldol reaction
10 mol%
OH
O
H
N
H
CO2H
neat, 4 °C, 48 h
HO
MeOH
HO
Me
O
Me
Me
Me
O
O
O
PMP
; EtOH, rt
O
O
CO2Et
BuO2C
6 steps
CO2Et
BuO2C
NO2
NO2
O
6-reaction
''one-pot''
sequence 81%
t
t
BuO2C
t
S
Me
HO
CO2Et
AcHN
NH2
NH
Me
TESO
O
H
N
O
O
TESO
H
N
O
O
HO
Me
O
OMe
O
10 mol%
O
NH
Me
HO
2) Amberlyst 15
OMe
O
ABT-341
HO
Me
Me
neuraminidase inhibtor
Angew. Chem. Int. Ed. 2009, 48, 1304.
Chem. Eur. J. 2010, 16, 12616.
OTr
1) Grubbs 1st cat.
OH
Total yield : 60%
5-reaction ''one-pot'' sequence : 74%
Me
TIPSO
64% (3 steps)
After Recrystallization
> 99% ee, > 99% de
No column chromatography
NH2
O
HS
Cs2CO3
H
OTIPS
TESO
H
N
O
ClCH2CO2H
Me
CO2Et
( )-oseltamivir
NaBH4
Me
O
EtO
P
EtO
O
NO2
OMe
TESO
Ph
Ph
OTMS
NO2
t
Me
N
H
+
Bioorg. Med. Chem. Lett. 2009, 19, 3863.
O
O
OH
O
O
O
(+) - cytotrienin A
apotosis indcing activity in HL-60 cell
O
Angew. Chem. Int. Ed. 2008, 47, 6657.
F
F
Ph
H
N
H
NO2
F
Ph
OTMS
O
EtO
P
EtO
Cs2CO3
N
HN
CO2tBu
N
i
Pr2EtN
CF3CO2H
6-reaction "one-pot" sequence : 61%
TBTU
N
CF3
O
Zn
N
N
F
F
N
N
F
NH2
CF3
ABT-341
DPP4 selective Inhibtor
Angew. Chem. Int. Ed. in press
Reaction using diarylprolinol silyl ether derivatives as catalyst
Mannich reaction
Ar
Hayashi Lab. Homepage http://www.ykbsc.chem.tohoku.ac.jp/
O
NHTs
Development of new reactions
R1
Asymmetric reaction using amino acid or their derivatives as a catalyst,
environmental conscious asymmetric reaction using water as a solvent, and research about origin of chirality
O
OH
N
H
1) ClCO2Et
K2CO3, MeOH
Ar
2) ArMgBr, THF
N
CO2Et
Michael reaction
TMSCl
imidazole
Ar
KOH
OH
MeOH
OH
N
H
NO2
H
Ar
R = alkyl
or aryl
DMF
This catalyst is synthesized in short steps from
proline.
Substituents on aryl and silyl moiety are easily
modified.
Excellent enantioselectivity is obtained
Ar
OTMS
N
H
Michael reaction
Ph
O
hexane, 0 oC
MeNO2
H
85%, 99% ee
Angew. Chem., Int. Ed., 44, 4212 (2005).
Michael reaction
Ph Ph
O
OTBS
N
10 mol%
H
p-NO2C6H4OH
H
H
H
NO2
Ph
Ph
HO
O
OH
N
H2
H
O
NHBoc
Ph
OHC
H
CHO
N
H
R2
N
R2
O
O
O
O
Ph
OTBS
10 mol%
MeO
O
Ph
O
O
OMe
O
Me
R2
NO2
0
H
H
OTMS
10 mol%
N
H
N
R
toluene, RT
H
Concerted Mechanism
N
R
H
H
up to 99% ee
J. Am. Chem. Soc., 133, 20175 (2011).
Direct catalytic enantioselective -aminoxylation
Me
MeOH, RT
O2N
R
COOH
N
H 30 mol%
O
PhN=O
H
OMe
H
CH3CN, -20 oC
Me
slow addition
O
O
O
COOH
N
H
PhN=O
ONHPh
O
ONHPh
10 mol%
DMF, 0 oC
Me
CuSO4兟5H2O (cat)
OH
MeOH, 0 oC
slow addition
79%, >99% ee
87%
Angew. Chem., Int. Ed., 43, 1112 (2004).
J. Org. Chem., 69, 1548 (2004).
quant, 98% ee
Tetrahedron Lett., 44, 8293 (2003).
The direct and enantioselective, One-Pot, Three-Component,
Cross-Mannich reaction of aldehydes
OTMS
N
10 mol%
H
PhCO2H
OH
OH
NaHCO3
OH
R
OMe
O
H
R
N
H
H
10 mol%
HN
NMP, -20 oC
Me
NO2
OMe
COOH
O
O
O
MeOH, RT
NO2
CHO
NH2
a
b
up to 99% ee, a : b = 9 : 1
Org. Lett., 11, 4056 (2009).
Me
Angew. Chem., Int. Ed., 42, 3677 (2003).
Adv. Synth. Catal., 347, 1604 (2005).
Nature Protocols, 2, 113 (2007).
90%, 98% ee
anti : syn = 1 : >95
i
Bu2NH
p-NO2C6H4OH
MeOH, RT
MeOH, RT
O
R
HOOH
H
N
H
N
H
N
OTMS
10 mol%
toluene, RT
Ns
Ph
1,4-dioxane
; evapo
OSiMePh2
20 mol%
H
N
O
R
hexane, RT
O
Ph
O
H
Michael / Henry / acetal formation / additional reaction
TMS
TiCl4
CH2Cl2
Me
N
Ph
R1
Ph
NO2
up to 99% ee
Single diastereomer
Org.Lett., 12, 4588 (2010).
N
H
O
Ns
NO2
H
2
R
OTMS
10 mol%
toluene, RT
; evapo
N
H
O
H
up to 95% ee
Org. Lett., 12, 5434 (2010).
Ph Ph
Reaction by siloxyproline catalyst
Reaction by proline-derived catalyst
Ph Ph
OTBS
N
10 mol%
H
p-NO2C6H4OH
Ph Ph
H
R1
:
100
up to 95% ee
ChemCatChem, 4, 959 (2012).
O
Ph Ph
H
H
Michael / aza Henry / aminal formation / additional reaction
Ph
R2
O
R
O
63%, 95% ee
Tetrahedron, 66, 4894 (2010).
O
R1
epoxidation
Ph
NO2
H
R3
Reaction catalyzed by proline
OTBS
O
Ph Ph
H
O
H
NO2
R3
Ph
10 mol%
78%, 92% ee
Chem. Commun,, 3083 (2009).
Michael / cyclization reaction
O
OH
R
up to 99% ee
Chem. Eur. J., 17, 8273 (2011).
O
10 mol%
R1
up to 99% ee
Org. Lett., 11, 45 (2009).
O
Ph
THF, RT
N
Ph Ph
Ph Ph
Ph
R2
R
Michael reaction / isomerization
N
H
MeNO2
NBoc
Ph
CH2Cl2, RT
O
R
H
MeOH
MeOH, RT
PhCO2H
H
3
-Benzoyloxylation
H
NaBH4
H
OSiPh2Me
N
H
H
R3
Ph Ph
N
H
OMe
H
O
75%, 96% ee
Angew. Chem., Int. Ed., 47, 4722 (2008).
R
O
N
R1
Ph
O2N
Ts
NH O
R
OH
Ph
O
10 mol%
OTMS
10 mol%
1,4-dioxane, RT
H
90%, 94% ee, : = 34 : 66
Angew. Chem., Int. Ed., 47, 4012 (2008).
O
O
up to 99% ee
up to >90% de
Chem. Asian. J., 4, 246 (2009).
O
Ts
Cl
1,4-dioxane, RT
H
Ph
O
toluene, 0 oC
R3
O
NO2
H
Ph Ph
NBoc
Formal carbo [3+3] cycloaddition
OTBS
N
H
Ar = 3,5-(CF3)2C6H3-
Ar
O
OH
OH
Ph Ph
O
SO2Ph
OHC
Ph
(CH2Cl)2, 70 oC
Ph
Michael reaction
R1
NH O
Ph
NaHCO3
H
H
up to 95% ee
Angew. Chem., Int. Ed., 50, 3920 (2011).
Ph
OTMS
10 mol%
N
H
O
O
[6+2] cycloaddition reaction
OTBS
10 mol%
N
H
exo : endo = 80 : 20, 97% ee (exo)
Org. Lett, 9, 2859 (2007).
Angew. Chem., Int. Ed., 47, 6634 (2008).
O
Ar
NHTs
Ph Ph
ClO45 mol%
Ph
+
Bz
Formal aza [3+3] cycloaddition
OTMS
Ar
Ph Ph
THF, 4 oC
H
Cl
66%, 99% ee
Angew. Chem., Int. Ed., 46, 4922 (2007).
Ar = 3,5-(CF3)2C6H3-
Ar
Ph
H
H
NO2
H2O, RT
O
O
2 mol%
THF, RT
Ph
O2N
MeOH
Michael reaction (1,4-Addition versus 1,6-Addition)
OTMS
N
H
84%, 92% ee
Angew. Chem., Int. Ed., 45, 6853 (2006).
O
O2N
Ph Ph
Ph
Ar
Bz
O
90%, 95% ee
Org. Lett., 9, 5307 (2007).
O
MeNO2
NaOAc
THF
H
Michael reaction
Tandem Michael / Henry reaction
O
MeOH, RT
Diels-Alder reaction
Ar
Ar = 3,5-(CF3)2C6H3-
Ar
OTMS
N
10 mol%
H
p-NO2C6H4CO2H
Mannich reaction
Ph
MeOH, RT
H
Ph
H
DDQ
87%, 98% ee
Angew. Chem., Int. Ed., 47, 9053 (2008).
OTMS
N
H
10 mol%
PhCO2H
O
O2N
Ar
H
Ph
R1
O
up to 99% ee
Chem. Eur. J., 17, 8273 (2011).
Ph Ph
OTMS
10 mol%
N
NH O
R2
Mannich reaction
Ar
Ph Ph
N
H
O
Ph
Ar
1,4-dioxane or brine, 10 C
OTMS
20 mol%
N
H
H
R2
1
Reaction using diarylprolinol silyl ether derivatives as catalyst
Ph Ph
Ts
o
H
SO2Ph
Formal C-H insertion
Ar = 3,5-(CF3)2C6H3-
Ar
OTMS
N
10 mol%
H
NaHCO3
TBSO
NMP, 0 oC
O
CO2H
CHO
N
H
CF3CO2
30 mol%
兟 -aminoxylation
O
O
J. Org. Chem., 72, 6493 (2007).
O
H
Reaction by cystein-derived catalyst
+
MeCN
TMS
TiCl4
CH2Cl2
S
R2
O
R1
R3
NO2
up to 99% ee
Single diastereomer
Angew. Chem., Int. Ed., 50, 3774 (2011).
Ph
CHO
O
PhHNO
PhN=O
Ph
O
兟Mannich reaction
N
HN
H2
10 mol%
CF3CO2
CHO
Ph
O
quant, 99% ee
cis : tr ans = 8.3 : 1
J. Am. Chem. Soc., 127, 16028 (2005).
acetone, 0 oC
O
Ph
H
Ph
O
H
R3
DBU
This catalyst is more
reactive than proline.
L-proline
Siloxy proline
OMe
+
24 h, <5%
2 h, 50%, 99% ee
MeO
+
O
NH O
H
NH2
Ph
L-proline
20 h, <5%
Siloxy proline 20 h, 63%, 96% ee
Adv. Synth. Catal., 346, 1435 (2004).
䞉Organic solvent free Dry and Wet condition asymmetric aldol reaction with proline catalyst
Organic solvent free reaction
䞉aldehyde-aldehyde
䞉Organic solvent free asymmetric aldol reaction between ketone and aldehyde
CO2 H
O
O
O
Aldol reaction by diarylprolinol as a catalyst
O
OH
N
H
F3C
O
ClCO2Et
K2CO3
N
MeOH
O
F3C
OMe
O
OH
H
CF3
OEt
N
OH
H
Diarylprolinol CF3
Ar
Cl
NaBH4
O
OH
MeOH
Filtration
(60 ml AcOEt)
O
R1
water (3 eq.)
R2
R3
R2
anti : syn = >20 :1
up to >99% ee
Chem. Commun. , 2007, 957.
NaBH4
O
OH
MeOH
NMP, 4 C
OH
OH
Cl
10 g (70%)
ant i:syn=10:1
>99%ee
56%, 82% ee
Org. Lett., 10, 5581 (2008).
R
Br
HO
HO
CHO
O
7.9 mL
(70 mmol)
O
N
H
Br
OTIPS
R = H, 73%, 85% ee
R = Br, 86%, 82% ee
ent-Convolutamydine E
Hydr ophiic part
Cl
O
NMe
N H
N H
H
Me
a half fragment of
CPC-1
Madindoline A and B
Org. Lett., 11, 3854 (2009).
Cl
O
N
H
O
RT, 24 h
10 mol%
O
O
Cl
NaBH4
H +
OH
2.4 g
(30 mol%)
CO2H
Hydrophobi c par rt
Cl
OH
O
O
H
MeOH
o
EtO2C
H
H
aq MeCN
EtO2C
H
Me
14.6 g (94%)
anti / syn = 1.4 / 1
98% ee
EtO2C
TBDPSO
n
O
O
MeO
H
+
N
H
10 mol%
䞉Self aldol reaction of propanal in water – reaction in water with proline-amide catalyst
N N
N N
H
OMe
OMe
R
up to 99% ee
Org. Lett., 12, 2966 (2010).
+
CONH2
PMP
Ph3P=CHCO2Et
Ar
OH OMe
Cl
OH
w ater , 0 C
N
H 10 mol%
O
O
H
H
40 wt% in water
THF, RT
R
O
R
O
OH O
Cl
O Me
HC(OMe)3, TsOH
OH
Cl
K2CO3
O
+
OH
Chem. Commun., 2007, 2524.
䞉Organic solvent free asymmetric Diels-Alder reaction with proline derived catalyst
O
DMSO and aq DMSO
OMe
10 mL
<5-89%, 0-96% ee
anti : syn = 0.8-13 : 1
positive water eff ect
(2.64 g, 20 mmol)
O
OH
F3C
OEt
In 10% EtOH
N
H
H
R
Ar
Ar
OH
10 mol% Ph3P=CHCO2Et
toluene, RT
OH
OH
F3C
CO2Et
R
up to 96% ee
Synlett, 485, (2011).
OH
O
R
40 wt% in water
O
H
N
H
5 mol%
CF3
exo:endo 82:18
TMSO
3.2 g, 81%
97% ee
CF3
Ar
NH2
OH
10 mol% Ph3P=CHCO2Et
THF, RT
OHC
(4.7 mL, 60 mmol)
Ph
Gly, Ala, Val, Leu, lle, Phe, Trp, Pro, Ser, Thr, Tyr, Cys, Met, His, Lys, Arg, Asp, Asn, Glu, Gln
Sy nlett , 2006, 1565.
Ar
decantation then
distillation
CHO
Ph
O2N
OMe
R
up to 99% ee
Angew. Chem., Int. Ed., 50, 2804 (2011).
CO2Et
R
high enantioselectivi ty
water
20 proteinogenic
amino acid (30 mol%)
O
H
H
R
H
Water
䞉Effect of water on aldol reaction with 20 proteinogenic amino acid
CO2Et
OMe
OH O
(cat.)
H
93%, 95% ee
syn : anti =4.6 : 1
Org. Lett., 10, 21 (2008).
R
N
H
O
O
MeO
OMe
K2CO3
NH
o
NH2
Ar
Cl
䞉Organic solvent free asymmetric Mannich reaction with proline catalyst
R
OH OMe
O
CO2Et
Distillation
CO2tBu
EtO2C
MeOH, PPTS
R
R
Polymer form
O
Angew. Chem. Int. Ed., 45, 5527 (2006).
OH
Ph3P=CHCO2t Bu
OH O
OH
OH
water, 0 C
Ar
CO2H
N
H
organic phase
O
9.3 mL
(105 mmol)
CO2H
N
H
97%, 99% ee
anti : syn =19 : 1
Ar
O
H
H2O (40 mL)
water phase
Y. Hayashi et al., Angew. Chem., Int. Ed., 45, 958 (2006).
MeO
HO
OH
O
N
R
OTIPS
OH
N
H 10 mol%
O
H2O (3.8 mL)
RT, 72 h
DMF, 4 oC
H
N
R
OH O
(cat.)
R3
H
R1
䞉Intermolecular aldol reaction between aldehydes in the presence of water
O
N
H
+
Ar
OH
N
H 30 mol%
ClCH2CO2H
O
H
R2
anti : syn = up to 14 :1
up to 95% ee
CO 2H
O
O
Y. Hayashi et al., Chem. Eur . J., 13, 10246 (2007).
R
R2
Organic solvent-free aldol reaction
O
o
Distillation
Ar
R1
neat
OH O
82%, 98% ee
Angew. Chem., Int. Ed., 47, 2082 (2008).
HO
OH O
H
H
䞉aldehyde-ketone
CO2H
N
H
259 mg (1 mol%)
H 2O
Ar
3
H
13.7 g (2 eq)
TBDPSO
3.8 mL (3 equiv.)
2 days
OH
N
H 10 mol%
OH
7.4 g (1 eq)
This catalyst is synthesized in short steps from
proline.
This is effective olganocatalyst of direct,
enantioselective aldol reaction.
Excellent enantioselectivity is obtained.
CF3
Ar
DMF, 4 oC
R1
(cat.)
2.5 g silica gel
CF3
KOH
MeOH
N
OEt
OH
N
H 10 mol%
H
F3C
CF3
THF
Ar
O
CF3
MgBr
O
Cl
+
O
H
CF3
N
H
OH
CO2Et
O
R
up to 99% ee
Chem. Commun., 48, 4570 (2012).
Application of High Pressure lnduced by WaterWater-Freezing to
the direct catalytic asymmetric reaction
water
CF3
ClO4
F3C
RT, 8 h
Angew. Chem. Int. Ed., 47, 6634 (2008).
The novel method of high pressure by water-freezing:
Proposed mechanistic cycle
The high pressre (cat. 200 MaPa) is easilly is essily achieved
simply by freesing water (-20 䉝) in a sealed autoclave.
10 mol%
O
䞉Mannich reaction
Ph
O2N
CO2H
OMe
O
H
MeO
+
N
H
O
+
R
NH
1
O
O
R1
NH2
H
MeO
cat.
Ph
Ph
Ph
OTMS
O
O2N
H
o
hexane, 0 C
R
1
O
R1
H
R2
MeO
N
H
O
H
R2
R
N
H
NO2
H
R
NO2
1
H2 O
atm,
-% ee
11
atm,
RTRT
0%,0%,
-% ee
oo
200atm,
atm,-20
-20
2000
CC 99%,99%,
96% 96%
ee ee
J . Am. Chem. 䞉Baylis-Hillman
Soc., 125, 11208
(2003).
reaction
䞉Michael reaction
Chem. Lett., 2002, 296.
䞉Aldol reaction
Tetrahedron Lett., 45, 4353 (2004).
Tetrahedron Lett., 43, 8683 (2004).
Research about of chirality
R
R
H
2
R
N
H
H
2
R
R
1
NO2
HX
N
H
1) 1)stirred
24 hᨩᢾ
, 㻜㻌䉝
for
24
CO2H
N
H
R
X
N
1
1
NO 2
CHCl3
CO2H
R
N
R
10% ee䛻ㄪ〇
prepared 10% ee
㻔L-Proline㐣๫㻕
o
0 C
2) ℐ㐣
2)filtration
CO2H
N
H
Amplification of ee from initial low ee
R
The key to find out origin of chirality
Angew. Chem., Int. Ed. 45, 4593 (2006).
R
N
99% ee(L) solution
(L-Proline excess)
R
N
99% ee (L)⁐ᾮ
1
NO2
R
2
R
R
NO2
1
H
2
2
R
O
N
O
Helvetica Chemica Acta, 94, 719 (2011).