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Organocatalyst in Total Synthesis - IASOC · Organocatalyst in Total Synthesis Tohoku University...
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Organocatalyst in Total Synthesis Tohoku University Yujiro Hayashi O CO 2 Et AcHN NH 2 (-)-oseltamivir ABT-341 (Abbott laboratory) F F F NH 2 N N N N CF 3 O N H Ph OTMS Ph 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. N H Ph OTMS Ph N H OH O N H OH O TBDPSO N H OH F 3 C CF 3 CF 3 CF 3 N H O O 8 OH O O OH N H O OH N N O H R O O H O O N R OH O H 2 O H 2 O O R OH O H R N H CO 2 H H O + O DMSO, rt OH O 30 mol% 97%, 96% ee B. List, R. A. Lerner, C. F. Barbas, J. Am. Chem. Soc., 2000, 122, 2395. Background: Enamine intermediate Background: Iminium ion intermediate + 10 mol % + D. W. C. MacMillan, et al., J. Am. Chem. Soc., 122, 4243 (2000). 99% 93% ee 93% ee Diels-Alder reaction N H N O ·HCl Ph MeOH - H 2 O CHO Ph Ph CHO R N H R ·HCl Ph N H R R + LUMO-lowering activation Ph H O Ph H O 1.3 : 1
Transcript of Organocatalyst in Total Synthesis - IASOC · Organocatalyst in Total Synthesis Tohoku University...
Organocatalyst in Total Synthesis
Tohoku University
Yujiro Hayashi
O CO2Et
AcHNNH2
(-)-oseltamivirABT-341 (Abbott laboratory)
F
F F NH2
NN N
N
CF3
O
NH
Ph
OTMS
Ph
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.
NH
Ph
OTMS
Ph
NH OH
O
NH OH
O
TBDPSO
NH OH
F3C CF3
CF3
CF3
NH
O
O
8
OH
O
O
OHNH
O
OHN
NO
HR
O
O
H
O
ON
R
OH
O
H2OH2O
O
R
OH
O
HR
NH
CO2H
H
O+
O
DMSO, rt
OH O
30 mol%
97%, 96% eeB. List, R. A. Lerner, C. F. Barbas, J. Am. Chem. Soc., 2000, 122, 2395.
Background: Enamine intermediate Background: Iminium ion intermediate
+
10 mol %
+
D. W. C. MacMillan, et al., J. Am. Chem. Soc., 122, 4243 (2000).
99%93% ee 93% ee
Diels-Alder reaction
NH
NO
·HClPh
MeOH - H2O CHOPh
PhCHO
RNH
R
·HCl
Ph
N
H
R R
+
LUMO-lowering activation
Ph
H
O
Ph
H
O
1.3 : 1
Jorgensen-Hayashi Catalyst
PhNO2
Me
H
O
+
10 mol%
hexane, 23 °C, 1 h
HO2N
OPh
Me85%, 99% ee, syn : anti = 5.7 : 1
NH
Ph
Ph
OTMS
NH OTMS
+
1)
2) NaBH460%, 95% ee
K. A. Jorgensen, et al., Angew. Chem. Int. Ed., 44, 794 (2005).
NH OTMS
F3C CF3
CF3
CF3
Me
H
O
BnSOH
Y. Hayashi, et al., Angew. Chem. Int. Ed., 44, 4112 (2005).
TMS = Me3Si-
N
N
NBnS
Enamine: functionalization at the �-position of aldehyde
Iminium ion: functionalization at the �-position of aldehyde
R
O
H
R
NO
Si
Me
MeMe
+
NH OTMS
E+
R
O
HE
R
H
O
NO
Si
Me
MeMe
+
R
NH OTMS
Nu�
R
H
O
Nu
Effective for the both enamine and iminium ion intermediate
X-ray and ab initio calculation D. Seebach, Y. Hayashi, Uchimaru, et al.,
Helv. Chim. Acta, 2009, 92, 1225.
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).
Reactions developed by our group
O2N
Ph O
H
O
H
Ph
O2N
NO2
OH
OHC
Ph
Ph
Ph
OHC
OPh
O Me
H
O
OH
Ph
NBoc
PhPh O
OMeO
O
OMe
H
O
Me
Me
O
NPh
O
O
Ph
OH
NO2
N
Ph Ph
Me
NO2
NsO
Ph Ph
Me
NO2
O
HC7H15
O
NH
Ar
Ar
OTMS
Ph
NHBz
O
H
99% ee 96% ee 92% ee99% ee
97% ee 94% ee 97% ee 95% ee
92% ee 95% ee 95% ee 94% ee 99% ee 99% ee
98% ee
Michael Michael Michael
Michael
Michael
Mannich Domino
Domino Domino Domino
Diels-Alder Aza [3+3] Carbo [3+3]
Oxidation Epoxidation
Ph O
H
Ph
H
O
NO2
Michael
95% ee
N
PhCHO
OHC
Ph
TESO
CF3
CF3
CF3
F3C
H2
ClO4
water
decantation then
distillationwater
2.64 g 4.7 mL
10 mL
5 mol%
exo:endo 82:18
97% ee3.2 g, 81%
RT, 8 h
Angew. Chem. Int. Ed., 47, 6634 (2008).
C. Fehr et al.,(Firmenich), Angew. Chem., Int. Ed., 2009, 48, 7221.
Synthesis of (-)-�-Santalol by Firmenich
H
O
1.5 mol%
H2O
ClO4
NH2
TESO
F3CCF3
CF3
CF3
OHC
CHO
exo : endo = 70 : 30
exo 95% ee, endo 78% ee
61%
OH
(�)-�-Santalol
MeOH, RT
71%, 93% ee
+
2 mol%
H
O
CH3NO2
1) NaH2PO3�2H2O
NaClO2
2-methyl-2-butene
2) Pd/C, H2
80%
H
O
NO2
OH
O
NH2
Pregabalin: anticonvulsant
NH
Ph
OTMS
Ph
p-Cl-Ph
OH
O
NH2
Baclofen: GABAB receptor agonist
+
2 mol%
4 mol%
p-Cl-Ph
80%, 92% ee
H
O
NO2CH3NO2
PhCOOH
MeOH, RTp-Cl-Ph
O
H 2 steps
87%
NH
Ph
OTMS
Ph
Org. Lett., 9, 5307 (2007).
H
OF
F CH3NO2
NH
Ph
Ph
OTMS
5 mol%
5 mol% tBuCO2H
50 mol% B(OH)3
THF-H2O
F
F CHO
NO2
73%, 95% ee >100 kg
NO
CF3
O
N NNH
N
O
F
F
Telcagepant
F. Xu et al.,(Merck), J. Org. Chem., 75, 7829 (2010).
CGRP receptors antagonist for treatment of Migraine
Synthesis of Telcagepant by Merck Total synthesis of biologically active compounds
OO
O
HO
O
O
OH
O
HMe
MeO
O
O
HO
O
O
OH
O
HMe
Me
epoxyquinol A epoxyquinol B
OO
O
HO
O
O
OH
O
HMe
Me
epoxyquinol C
OO
O
OH
OMe
OH
O
O Me
epoxytwinol A
O
O
OMe
H
O
Me
Me
Me
RK-805 FR-65814
O
O
OMe
OH
O
Me
Me
Me
ovalicin 5-demethylovalicinfumagillol
O
OH
OMe
H
O
Me
Me
Me O
OH
OMe
H
O
Me
Me
Me O
O
OH
OH
O
Me
Me
Me
OO
OHO
OH
OMe
Me
OH
H
H
Me
Me OH
panepophenanthrin
OH
OH
Me
+NH3HN
OCO2-
ON
nikkomycin B
HN
O
O
HO OH
O
O
HO
nPr
O
OH
EI-1941-1
O
O
HO
nPr
O
O
EI-1941-2
O
HO
nPr
O
O
EI-1941-3
HO
Me
OMeOMe
O
NH
O
OHMe
O
Me
OMeOMe
O
NH
O
OH
O
HO
Me
OMeOMe
O
NH
OH
O
H
OH
epolactaeneNG-391 lucilactaene
OOOH
NaHO3PO OH
Me OH
fostriecin
HN
O
MeO
OH
O
OMe
Ph
OOH
HOEt
HN
O
Me
Et
OOH
O
OH
Ph
HN
O
Me
OOH
O
Ph
O
OMeEt
O
azaspirene pseurotin A synerazol
HN
O
MeO
OH
O
Ph
O
OMe
FD-838
OEt
ent-convolutamydine E
N
O
HO
H
madindoline A
NMe
NMe
MeO
H
CPC-1
Br
Br NH
O
HO OH
MeO O
Me nBu
NH
HO
HO
Me
HOMe
O
O
OMeHN
O
O
(+) - cytotrienin A
AcHN
NH2
O CO2Et
(-)-oseltamivir
O
OMeC14H29
O
(R)-Methyl Palmoxirate
OH
O
NH2
pregabalin
OH
O
NH2
Cl
baclofen
F
F
F
NH2
O
N
NN
N
CF3
ABT-341
O
AcHN
NH2
CO2Et
(–)-oseltamivir phosphate (Tamiflu)
·H3PO4
Tamiflu: Orally administrated anti-Influenza drug developed by Gilead Sciences, Inc. and RocheTotal 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.,
Synthetic Challenge: Control of three continuous chiral center Selectivity (enantio- and diastereo-)
53 total syntheses
First retro-synthetic analysis
O
AcHN
NH2
CO2Et
oseltamivir
O
NO2
CO2Et
tBuO
O
O
NO2
H
O
tBuO
O
+CO2Et NO2
tBuO
O H
O+
O
PhNO2
Me
H
O
+
10 mol%
hexane, 23 °C, 1 h
Y. Hayashi, et al., Angew. Chem. Int. Ed., 44, 4212 (2005).
HO2N
OPh
Me
85%, 99% eesyn : anti = 5.7 : 1
NH
Ph
Ph
OTMS
���������� ����������
t-BuO2CNO2
O
H
O
+
NH
Ph
Ph
OTMS O
t-BuO2C
NO2
H
O
O
t-BuO2C
NO2
H
O
PhNO2
Me
H
O
+
10 mol%
hexanert, 1 h
Y. Hayashi, et al., Angew. Chem., Int. Ed. 2005, 44, 4212.
NH
Ph
Ph
OTMSMe
Ph
NO2
H
O
Me
Ph
NO2
H
O
rt
syn (desired) anti (undesired)
85%syn anti
syn : anti = 5.7 (99% ee) : 1
solvent time / h yield syn : anti
hexane
CH2Cl2
60
60
26%
quant.
2.5 : 1
1.7 : 1
+
+
20 mol%
Proposed Reaction Mechanism
H+
Acid promote
H+
Acid promote
H+
Acid promote
NPh
OTMS
Ph
H
NH
PhOTMS
Ph
H2O
O
O
t-BuO2C
NO2
O
HH
O
NPh
OTMS
Ph
H
O
H2O
O
NPh
OTMS
Ph
HO
N
t-BuO
O
O
O
NO2
t-BuO2C
NO2t-BuO
O
NPh
OTMS
Ph
HO
NO2
t-BuO2C
HO
H
������������������� ����������
t-BuO2CNO2
O
H
O NH
Ph
Ph
OTMS
additive O
O
NO2
t-BuO2C
O
O
NO2
t-BuO2C
H H
syn anti
catalyst / mol%
additive (mol%) time / h yield syn : anti
20
20
5
CF3CH2OH (40)
p-nitrophenol (40)
ClCH2CO2H (20)
24
24
1
50% (brsm 95%)
quant.
quant.
2.3 : 1
1.7 : 1
6.3 : 1
5 Cl3CCO2H (20) 28 No Reaction –
CH2Cl2, rt
20 none 60 quant. 1.7 : 1
(desired) (undesired)
ee / %syn / anti
nd
nd
nd
96 / 87
+ +
pKa in H2O
12.5
7.1
2.86
0.65
–
20 PhCO2H (40) 14 quant. 2.0 : 1 nd4.2
5 HCO2H (20) 2 quant. 4.8 : 1 nd3.77
NH
R
N R
R1
H
N R
HR1
R2
N
N R
HR1
R2
NO2
NR
R1 NO2
R2
O
HR1
NO2
R2
H
O
R1
NO2
R2
H2O
HX
X
OO
N R
HR1
R2
NO2
O
HR1
NO2
R2
Revised reaction mechanism
D. Seebach, Y. Hayashi, et al., Helv. Chim. Acta, 2011, 94, 719.
Cf, D. Blackmond et al., J. Am. Chem. Soc., 2011, 133, 8822.
CO2Et+
NaH, DBU, Et3N, TBAF, CsFK2CO3, Cs2CO3, DABCO, Bu3P O
t-BuO2C
NO2
CO2EtO
t-BuO2C
NO2
O
H
Major byproduct detected by Mass
O
t-BuO2C
NO2
O
H
CO2EtPEtO
OEtO
O
t-BuO2C
NO2
O
CO2Et
P
O OEt
OEt O
t-BuO2C
NO2
CO2Et
Michael reaction
IntramolecularHWE
reaction
Domino Michael / Intramolecular Aldol reaction
TBAFCsF
Cs2CO3O
t-BuO2C
NO2
OH
O
O
CO2t-Bu
NO2
O
t-BuO2C
NO2
O
O
CO2t-Bu
NO2
O
O
t-BuO2C
NO2
H
O CO2EtPO
EtOEtO
Cs2CO3, CH2Cl2–10 °C ~ 0 °C
CO2EtO
t-BuO2C
NO2
5R
5R : 5S = 4.6 : 1~ 30%
Tandem Michael/HWE reaction
1.5 equiv.
CO2EtO
t-BuO2C
O2N
PEtO2C
O
OEt
OEt
Byproducts
CO2Et
O
t-BuO2C
NO2
OP
OOEt
OEt
~30% ~30%H
H
Cs2CO3, EtOH23 °C, 15 min
quant.
Cs2CO3, EtOH23 °C, 15 min
90%
Retro Michael reactionRetro Aldol/HWE reaction
Base
Base
O
t-BuO2C
NO2
H
O CO2EtP
OEtOEtO
CH2Cl2, 0 °C, 3 h
CO2EtO
t-BuO2C
NO2
5R
61%, 5R : 5S = 4.6 : 1
Tandem Michael/HWE reaction
1.5 eq
�����������6 : 1
Cs2CO3 EtOH
rt, 15 min
CO2EtO
t-BuO2C
NO2
CO2EtO
t-BuO2C
O2N
PEtO2C
O
OEt
OEt
CO2Et
O
t-BuO2C
NO2
OHP
OOEt
OEt ++
CsCO3, EtOH
rt, 15 min
O
t-BuO2C
NO2
H
O
CO2EtPEtO
OEtO
Cs2CO3
CH2Cl20 °C, 3 h
~30% ~30% ~30%
quant. ~90%
One-pot Reaction: purification economy, chemical waste economy, time econonyincrease yield CO2EtO
t-BuO2C
NO2
5R
5R : 5S = 1 : 1Et3N CO2EtO
t-BuO2C
NO2
5S
Unsuccessful isomerization from 5R to 5S
5R isomer 5S isomer
Calculation was performed by Dr.Uchimaru.
CO2t-Bu
H
O
H
H
NO2H
H17.0 Hz
6.0 Hz
10.0 Hz
4.0 Hz
4.0 Hz
3
4
5
6R
R = CO2Et
H
NO2
H
H
H
t-BuO2CO
H
8.8 Hz
10.0 Hz
10.0 Hz5.6 Hz
17.6 Hz3
4
5
6
R
5R - isomer is stable than 5S - isomer in only 0.11 Kcal/mol by B3LYP/6-31G(d) calculation.
� ���������������������� �������������������������
CO2EtO
t-BuO2C
NO2
5R
HS Me
EtOH
CO2EtO
t-BuO2C
NO2
Stol
A
Base temp. / °C time / h
K2CO3 –5 24 85 15
5S
CO2EtO
t-BuO2C
NO2
Stol
B (Other diastereomer mixture)
Base
5R : 5S = 5 : 1
Cs2CO3 –5 13 35 –
Yield/%
A B
Cs2CO3 –15 36 90 <5 –
CO2Et
t-BuO2CC
C
–
65
Application to one-pot reaction
CO2EtO
t-BuO2C
NO2
CO2EtO
t-BuO2C
O2N
PEtO2C
O
OEt
OEt
CO2Et
O
t-BuO2C
NO2
OHP
OOEt
OEt ++O
t-BuO2C
NO2
H
O
P(OEt)2
CO2Et
O
CO2EtO
t-BuO2C
NO2
5R
R : S = 4.6 : 1
EtOH
rt, 10 min
t-BuO2CNO2+
O
H
O NH
Ph
Ph
OTMS20 mol% ClCH2CO2H
CH2Cl2, rt, 6 h
5 mol%
O
t-BuO2C
NO2
H
O
CO2EtPEtO
OEtO
Cs2CO3
CH2Cl20 °C ~ rt, 4 h
tolSH
–15° C, 36 h
CO2EtO
t-BuO2C
NO2
STol
5S
70% single diastereomer
CO2EtO
AcHN
NH2
(–)-Oseltamivir
CO2EtO
t-BuO2CNO2
Stol
5S
TFA
CH2Cl2, rt;evaporation
CO2EtO
HO2CNO2
Stol (COCl)2cat. DMF
CH2Cl2, rt;evaporation
CO2EtO
NO2
Stol
Cl
O
NaN3
H2OAcetone
0 °C
CO2EtO
NO2
Stol
N3
O
without purification
CO2EtO
NO2
Stol
N3
Owithout purification
AcOHAc2O
RT49 h;
evaporation
CO2EtO
AcHNNO2
StolZn, TMSCl
EtOH, 70 °C
CO2EtO
AcHNNH2
Stol
ZnCl
Cl
NH3
0 °C10 min.
CO2EtO
AcHNNH2
StolCO2EtO
AcHNNH2
(–)-Oseltamivir
thenK2CO3
EtOH, rt
82% (6 steps)
��id-base extraction
Angew. Chem. Int. Ed., 48, 1304 (2009).
3 “one-pot” synthesis of (-)-oseltamivir
CO2EtO
t-BuO2CNO2
StolOH
O
t-BuO2CNO2
+
NH
Ph
Ph
OTMS
5 mol%
20 mol% ClCH2CO2H
CH2Cl2, rt
PO
OEt
O
EtOEtO
Cs2CO3
CH2Cl2, 0 °C;evaporation;
EtOH, rt
tolSH
–15 °C5S
TFA
CH2Cl2, rt;eveporation
(COCl)2cat. DMF
CH2Cl2, rt;evaporation
NaN3
H2O, acetone0°C
CO2EtO
NO2
Stol
O
N3
without purification
AcOHAc2O
rt;evaporation
Zn, TMSCl
EtOH, 70 °C
NH3then K2CO3
EtOH, rt
CO2EtO
AcHNNH2
(–)-Oseltamivir
· 3 "one-pot operations"· total yield 57% from nitro alkene
acid-base extraction82% (6 steps)
������� �����������������column chromatography
Chem. Eur. J., 16, 12616 (2010).
2 “one-pot” synthesis of (-)-oseltamivir
CO2EtO
t-BuO2CNO2
StolOH
O
t-BuO2CNO2
+
NH
Ph
Ph
OTMS
1 mol%
20 mol% ClCH2CO2H
toluene, rt
PO
OEt
O
EtOEtO
Cs2CO3
toluene, 0 °C;evaporation;
EtOH, rt
tolSH
–15 °C5S
74%
TFA
toluene, rt;eveporation
(COCl)2cat. DMF
toluene, rt;evaporation
Me3SiN3pyridine
toluene
AcOHAc2O
rt;evaporation
Zn, TMSCl
EtOH, 70 °C
NH3then K2CO3
EtOH, rt
CO2EtO
AcHNNH2
(–)-Oseltamivir
· 9 steps· 2 "one-pot operations"· one purification by column chromatography· total yield 60% from nitro alkene
acid-base extraction82% (6 steps)
column chromatography
CO2EtO
t-BuO2CNO2
StolOH
O
t-BuO2CNO2
+
NH
Ph
Ph
OTMS
1 mol%
20 mol% ClCH2CO2H
toluene, rt
PO
OEt
O
EtOEtO
Cs2CO3
toluene, 0 °C;evaporation;
EtOH, rt
tolSH
–15 °C
TFA
toluene, rt;eveporation
(COCl)2cat. DMF
toluene, rt;evaporation
Me3SiN3pyridine
toluene
AcOHAc2O
rt;evaporation
CO2EtO
AcHNNH2
(–)-Oseltamivir
Zn, TMSCl
EtOH, 70 °C
NH3then K2CO3
EtOH, rt
CO2EtO
HO2CNO2
Stol
acid-base extraction
acid-base extraction
(EtO)2P(O)OH acid-base extraction
71%
Column free synthesis
Chem. Eur. J., 16, 12616 (2010).
CO2EtO
NO2
Stol
O
N3
Differential ScanningCalorimetry
������
��������
��������������������� �����������������
�����������
Microreactor in the Curtius Rearrangement
Eur. J. Org. Chem., 2011, 6020.
STol
CO2Et
NO2
O
AcHN
in DMF
TMSN3,
pyridine
in DMF
Microtubereactor 1
Ac2O,
AcOH
in DMF
Microtubereactor 2
Micromixer 1
Micromixer 2
Stream 1
Stream 2
Stream 3
STol
CO2Et
NO2
O
O
Cl
rt, 26 min
110 °C, 80 min
STol
CO2Et
NO2
O
O
N3
After washed with H2O;recrystallization from toluene
>99% ee
10 g scale, 84%
Practical synthesis of (-)-oseltamivir
t-BuO2CNO2
+
O
H
O
NH
Ph
Ph
OTMS
1 mol%
20 mol% ClCH2COOH
CO2EtP
O
EtO
EtO
Cs2CO3
evaporationthen EtOH
MeHSCO2EtO
NO2
t-BuO2C
Stol
TFAAcOH
Ac2O110 °C
NH3
then, K2CO3
TMSN3
pyridine
DMF
(COCl)2
evaporation
Zn
(�)-Oseltamivir92%
CO2EtO
NO2
Stol
O
HO
CO2EtO
NH2
AcHN
Acid-base extractionto remove (EtO)2P(O)OH
Acid-base extraction
CO2EtO
NO2
Stol
O
Cl
CO2EtO
NO2
NH
Stol
Ac
Flow System
After recrystallization43% (from nitroalkene, >99% ee)
Acid-baseextraction
No columnTotal yield: 40%Gram scale synthesisEfficent and safety method
Pot economy
•
• Step economy (Wender)
• Redox economy (Baran & Hoffmann)
•
•
•
•
Green Reaction
One pot reaction is not a simple combination
of each optimized reaction.
Operational Economy
One-Pot Reaction
•
• 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
A + B C + D
Ph H
O
(EtO)2P
O
CO2Me+
basePh
CO2Me +(EtO)2P
O
OH
CO2EtO
AcHNNH2·H3PO4
Tamiflu (Roche) ABT-341 (Abbott laboratory)
F
F FNH2
NN
NN
CF3
O
NN
NN
O
CF3
NH2
F
FF
JanuviaTM (Merck)
Dipeptidyl peptidase-4 (DPP-4) inhibitor
�on-insulin dependant diabetes
NO2F
F F
TMSO
toluene, 120 oC
2 days
TFA
CH2Cl2rt, 10 min
O
NO2
F
F F
(racemic)
61%
NO2
F
F F
(racemic)
Br
H
O
PBr3, DMF
CH2Cl20 oC to rt, 24 h
34%
NO2
F
F F
(racemic)
Br OH
NaBH(OAc)3
CH2Cl2, rt, 12 h
78%
Zn, AcOH
MeOH
80 oC, 2 h
(Boc)2O
THFNHBoc
F
F F
(racemic)
Br OH
85% (2 steps)
NHBoc
F
F F
(racemic)
OH
HCO2H, nBu3N
Pd(PPh3)2Cl2
DMF, 80 oC
12 h
70%
NHBoc
F
F F(racemic)
O
HDMP
CH2Cl2
81%
NaClO2
isoprene
NaH2PO4, buffer
DMSO, 0 oC, 2 h
quant.
NHBoc
F
F F
(racemic)
O
OH
NHBoc
F
F F
(racemic)
O
OMeTMSCHN2
MeOH, CH2Cl2NHBoc
F
F F
(chiral)
O
OMechiral prep.
Yield (no data ) Yield (no data )
NHBoc
F
F F(chiral)
O
OH2N NaOH aq.
rt, 5 h
Yield (no data )
NH3 TFA
F
F F(chiral)
O
HN
NN
N
CF3
TBTU, TEA, DMF
then TFA, CH2Cl2
N
NN
N
CF3
Yield (no data )
13 StepsTotal Yield : <8%including HPLC separation
Synthesis of ABT-341 by Abott (J. Med. Chem., 2006, 49, 6439) Retro-synthetic analysis
F
F FNH2
O
N
NN
N
CF3
ABT-341
HN
NN
N
CF3 F
F FNO2
CO2tBu
5S
F
F FNO2
O
HCO2
tBuPEtO
OEtO
+Me
O
H
NO2F
F F
+
PhNO2
H
O
+
10 mol%
1,4-dioxane, 23 °C, 18 h
Y. Hayashi, et al., Angew. Chem. Int. Ed., 47, 4722 (2008).
HO2N
OPh
75%, 96% ee
NH
Ph
Ph
OTMS
F
F F
NO2
Me H
ONH
Ph
OTMS
Ph
10 mol%
1,4-dioxane
0 oC to rt, time
F
F F
O
H
NO2
X / equiv. time / h
24
yield / % ee / %
74 94
Asymmetric Michael Reaction
+
X equiv.
10
NH OTMS
Ph
Ph
10 mol%
1,4-dioxanert, 18 h
75% yield, 95% eeY. Hayashi et al., Angew. Chem. Int. Ed. 2008, 47, 4722.
PhNO2
Me H
O
O
Ph
H
NO2
Previous Results
+
10 equiv. 1 equiv.
bp 21 °C
2 X
NH OTMS
Ph
Ph
Me
O
H
F
F FNO2
O
H
O
NO2
Me
H
major byproduct
Me H
O F
F F
18 92 972
F
F F
O
NO2
H
CO2tBuP
OEtO
EtO
Cs2CO3
CH2Cl2, 0 oC, 3 h
F
F FNO2
CO2tBu
OHP
OOEt
OEt
+F
F FNO2
CO2tBu
F
F FNO2
CO2tBu
5R; EtOH
0 oC to rt
15 min
87%
FNO2
F
F
CO2tBu
i Pr2EtN5S
EtOH, 65 °C
quant.
Chiral cyclohexene formation
FNO2
F
F
CO2tBu
5S
CF3CO2H
CH2Cl2, rt quant.
F
F FNO2
CO2H
HN
NN
N
CF3
TBTUiPr2EtN
F
F FNO2
O
N
NN
N
CF3
85%THF, 0 °C to rt
Zn, AcOH
AcOEtF
F FNH2
O
N
NN
N
CF398%
ABT-341
Synthesis of ABT-341 Trial one-pot reaction
F
F F
H
O
NO2
Me H
O F
F F
NO2
+
NH
Ph
Ph
OTMS
10 mol%
1,4-dioxane
0 oC to rt
CO2tBuP
EtO
EtOO
CH2Cl2, 0 oC
; EtOH, 0 oC to rt
Cs2CO3
F
F FNO2
CO2tBu iPr2EtN
5R F
F FNO2
CO2tBu
5S
FNO2
F
F
CO2tBu
undesired isomer
FNO2
F
F
CO2tBu
desired isomer
iPr2EtN
EtOH, 65 oC,
quant.
Cs2CO3
EtOH, rt
quant.
5R 5S
NCsO O
CsCl; insoluble material
F
F F
H
O
NO2
CO2tBuP
EtO
EtOO
CH2Cl2, 0 oC
; EtOH, 0 oC to rt
15 min
Cs2CO3
F
F FNO2
CO2tBu
TMSCl
0 oC , 5 min
5R
F
F FNO2
CO2tBu
5S
>> Convert Cs2CO3 to CsCl for Isomerization
iPr2EtN
0 oC to rt
; rt, 48 h
35% yield
F
F FO
CO2tBu
52% yield
+
92% yield >5% yield
-40 oC , 5 min
�40 oC to rt
; rt, 48 h
CO2tBuP
EtO
EtOO
CH2Cl2, 0 oC
; EtOH, 0 oC to rt
15 min
Cs2CO3Me H
O
F
F F
NO2+
NH
Ph
Ph
OTMS
10 mol%
1,4-dioxane
0 oC to rt
TMSCl
�40 oC, 5 min; iPr2EtN, 15 min;
rt, 48 h
evaporation
F
F FNO2
CO2H
CF3COOH
CH2Cl2rt;
evaporation
+EtO
PEtO
O
OH
from HWE reaction
HN
NN
N
CF3TBTU
iPr2EtN, THF
0 oC to rt
F
F FNO2
+ EtO
PEtO
OO
N
NN
N
CF3
N
NN
N
CF3
Which is the major product ?
71% (4 steps)
1.2 equiv.
F
F FNO2
CO2tBu
F
F FNO2
CO2H
+EtO
PEtO
O
OH
HN
NN
N
CF3
TBTU (2.0 equiv.)
iPr2EtN, THF
0 oC to rt, 12 h1.0 equiv. 1.0 equiv.
(1.1 equiv.)
EtO
PEtO
O
O
N
NN
O
N
N
Me
Me
Me
Me
BF4
TBTU :
NN
N
F
F FNO2
O
O
N
NN
+
F
F FNO2
EtO
PEtO
O
O
N
NN
N
CF3
N
NN
N
CF3
87%
<5%
+
Angew. Chem. Int. Ed. 2011, 50, 2824.
F
F F
NO2
Me H
O
NH
Ph
OTMS
Ph
10 mol% CO2tBuP
OEtO
EtO
HN
NN
N
CF3
ABT-341
iPr2EtN
EtOH
�40 oC to rt
; evaporation
F
F FNH2
N
NN
N
CF3
O
One-Pot Total Synthesis of ABT-341
Cs2CO3
CF3CO2H
1.4-dioxane
0 oC to rt
; evaporation
CH2Cl2, 0 oC
; EtOH, 0 oC to rt
; TMSCl, �40 oC
CH2Cl2�40 oC to rt
; evaporation
TBTUiPr2EtN, THF
0 oC to rt
; nPrNH2, rt
Zn
AcOH
EtOAc, 0 oC
; NH4OH
F
F FNO2
H
O
F
F FNO2
CO2tBu
F
F FNO2
CO2tBu
F
F FNO2
CO2H
6 stepsOne-Pot OperationTotal yield : 63%
1.0 equiv.
2.0 equiv.
1.2 equiv.
1.1 equiv.
5R
5S
OO
O
HOO
OOH
OHMe
MeO
O
O
HOO
OOH
OHMe
Me
O O
O
OHO
Me
OH
O
O Me
epoxyquinol A epoxyquinol B
Angew. Chem., Int. Ed., 41, 3192 (2002); Tetrahedron Lett., 43, 9155 (2002);Tetrahedron Lett., 44, 7205 (2003);J. Org. Chem., 69, 1548 (2004);
J. Org. Chem., 70, 79 (2005) ; Org. Lett., 8, 1041 (2006).Review; Eur. J. Org. Chem., 23, 3783 (2007).
angiogenesis inhibitor
OCl
OO
CO2Me
OH
O
OH
O
OHMe MnO2
CH2Cl20 °C
O
OH
O
OMe
O
OHO
O
Me
OMe
O
OH
O
syn
antiendo-hetero
O
O OH
O
Me
OMe
O
OH
O
syn
synexo-homo
O
O OH
O
Me
OMe
O
OH
O
anti
antiexo-homo
toluenert
OO
O
HOO
OOH
OHMe
Me
epoxyquinol C
epoxyquinols
oxidative dimerization
O O
O
OHO
Me
OH
O
O Me
epoxytwinol A
H
OOTBS
NH2
NH
Me
+ + H
O
MeO
O
TBSO
H
O NH
MeO
TBSO
O
OMe
NH
MeO
TBSO
OH
OMe
NMP20 oC
THF, 78 oC OH
OH
Me
+NH3HN
OCO2
ON
nikkomycin Bantifungal activity
HN
O
O
Tetrahedron, 2005, 48, 11393.
formal total synthesis of nikkomycin B
LiAlH(OtBu)3
HO OH
NH
CO2H
10 mol%
syn : anti = 14 : 1, 96%ee
three-component cross-Mannich reactionEI-1941-1, EI-1941-2, EI-1941-3
O
O
TBSO
nPr
O
OH
cat. Pd(II)benzoquinone
O
O
TBSO
nPr
O
O
O
O
HO
nPr
O
OHEI-1941-1
O
O
HO
nPr
O
OEI-1941-2
O
HO
nPr
O
OEI-1941-3
HO
ICE (interleukin 1- converting enzyme) inhibitorOrg. Lett. 2004, 6, 4535.
J. Org. Chem. 2005, 70, 9905.
(+) - cytotrienin A
H
OMe
neat, 4 °C, 48 h
10 mol%
NaBH4
HOH
OHHO MeN
HCO2H
OO
O
MeO
PMP O Me
HO
TIPSO
Me OTIPS
OTrMeOH
64% (3 steps)After Recrystallization
> 99% ee, > 99% deNo column chromatography
O
O
8
OHN
OO
Me
TESOMe
OMe
OHNH2
NH
TESO
TESO
Me
TESO Me
O
O
OMe
1) Grubbs 1st cat.
2) Amberlyst 15
HN
OO
NH
HO
HO
Me
HOMe
O
O
OMeHN
OO
Asymmetric crossaldol reaction
Angew. Chem. Int. Ed. 2008, 47, 6657.
(+) - cytotrienin Aapotosis indcing activity in HL-60 cell
EtHO NHO
Ph
OTIPSO
HNO
MeO OH
O
OMePh
OOH
HOEt
Org. Lett. 2003, 5, 2287.J. Am. Chem. Soc. 2002, 124, 12078.
HNO
Me
Et
O OH
O
OHPh
J. Org. Chem. 2005, 70, 5643.
HNO
MeO OH
OPh
O
OMeEt
O
azaspirene, pseurotin A, synerazol, FD-838
OO
Et OMeTBSO
Me Me
Et OMe
OPhOHC
PhO
O
HHEt OH
MeMe OMe
OMgBr2�OEt2
azaspireneangiogenesis inhibitor
pseurotin Aneurite outgrowth in PC12 cells
synerazolantifungal antibiotic
Bioorg. Med. Chem. Lett. 2009, 19, 3863.
HNO
MeO OH
OPh
O
OMe
FD-838diffrenttiation of leukamia
antifungal antibiotic
OEt
N
R
R
O
O
+Me H
O
NO
R
R
HOCHO
key intermediate
NH
HOAr
ArOH
Ar=3,5-(CF3)2-C6H3
DMFOTIPS
OTIPSR=H, 73%, 85% eeR=Br, 86%, 82% ee
ent-convolutamydine E
NO
HO
H
madindoline A
NMe
NMeMeO
H
CPC-1
Br
Br NH
O
HO OH
MeO O
Me nBu Org. Lett. 2009, 11, 3854.
CPC-1, ent-convolutamydine E, andhalf segment of madindoline A
ClCH2CO2H
( )
Hayashi�Lab.�Homepage:�http://www.ci.kagu.tus.ac.jp/lab/org�chem1/
Hayashi Laboratory Hayashi Laboratory ( Tokyo University of Science, TUS)( Tokyo University of Science, TUS)
Total Synthesis of Bioactive CompoundsTotal Synthesis of Bioactive Compounds
O
O O
O
O O
ONHPh
O
OHOMe
H
O
MeMe
MeOH
OTBS
O
O
OOMe
H
O
MeMe
Me
RK-805
O
OHOMe
H
O
MeMe
Me
FR-65814
O
O
O
OTBS
O
OOMe
OH
O
MeMe
Me
ovalicin
O
OOH
OH
O
MeMe
Me
5-demethylovalicinangiogenesis inhibitor
angiogenesis inhibitor immunosuppressive effect
Angew. Chem., Int. Ed., 45, 789 (2006),
O
OH
O Me
MeOH
O O
OHOOH
OMe MeOH
HH
MeMe OH
O O
OOH
OHMe Me
MeMeHO
O
OHubiquitin-activating
enzyme inhibitor
Chem. Asian J., 1, 845 (2006).
fumagillins, ovalicins, panepophenanthrin
>99% ee
dimerization
+ PhN=O
CO2H
10 mol%-aminoxylation
O
O O
ONHPh
>99% eeCO2H
10 mol%
fumagillol
panepophenanthrin
tBuO2C
MeOTBS
MeOTBS
LDACH3CHO
THF-HMPA78 oC
Me
MeOH
Me
OMeO Me
O
NH
O
OHMe
O
Chem. Lett. 1998, 313J. Org. Chem. 2002, 67, 9443.
Me
OMeO Me
O
NH
O
OH
OHO
Me
OMeO Me
O
NH
OH
O
HOH
Tetrahedron, 2002, 58, 9839.Angew. Chem. Int. Ed. 2005, 44, 3110.
Me
MeO Me
O
OCN
TBDPSO
OH
epolactaene, NG-391, lucilactaene
epolactaeneneurtie outgrowth in SH-SY5Y cells
NG-391neuronal cell-protecting molecule
lucilactaenecell cycle inhibitor
in p53-transfected cancer cells
OtBuO
HO
Me
OtBuO
(CO)3H
O
OPMBMe OH
OBOM Co2(CO)8OPMB
Me OH
OBOMH
O
Co CoallylSnPh3TiCl2(OiPr)2
CH2Cl2
(CO)3
OPMBMe OH
OBOM
OH
Co Co
CH2Cl2
60%, syn : anti = 92 : 8
(CO)3 (CO)3
OO OHNaHO3PO OH
formal total synthesis of fostriecin1,4-asymmetric induction
Me OH
OPMBMe OH
OBOMOH
NMO
fostriecinPP2A inhibtor
Org. Lett. 2008, 10, 1405.Chem. Eur. J. 2010, 16, 10150.
OO H
O
Me O
OMeMe
OO
O
Me O
MeMe OTBDPS
OHZnBr2, nBuLi
OTBDPS1,3-asymmetric induction
single diastereomer
tBuO2CNO2
+H
OO
NH OTMS
PhPh
5 mol%
ClCH2CO2H
tBuO2CNO2
H
OO
EtOPO
EtOCO2Et
Cs2CO3
; EtOH, rttBuO2C
NO2
O CO2Et
tBuO2CNO2
O CO2EtS
6 steps
AcHNNH2
O CO2Et
Angew. Chem. Int. Ed. 2009, 48, 1304.Chem. Eur. J. 2010, 16, 12616.
( )-oseltamivirneuraminidase inhibtor
( )- oseltamivir (Tamiflu )R
MeHS
Me
F
F F
NO2
Me H
O
NH
Ph
OTMSPh
10 mol%CO2
tBuPO
EtOEtO
HNN
NN
CF3
ABT-341DPP4 selective Inhibtor
iPr2EtN F
F FNH2
NN
NN
CF3
O
ABT-341
Cs2CO3 CF3CO2H TBTU Zn
ReView; Chem. Eur. J. 2010, 16, 3884.
Angew. Chem. Int. Ed. in press
H2O
1
1O
5-reaction ''one-pot'' sequence : 74%
6-reaction''one-pot''
sequence 81%
Total yield : 60%
6-reaction "one-pot" sequence : 61%
Ph
O
HMeOH, RT
p-NO2C6H4OHiBu2NH
p-NO2C6H4OH
MeOH, RT Ph
O
H MeOH, RTPhMeNO2
NH
Ph Ph
OTMS
10 mol%
Michael reaction
Org. Lett., 9, 5307 (2007).
hexane, 0 oC
NH
Ph Ph
OTMS10 mol%
Michael reaction
Angew. Chem., Int. Ed., 44, 4212 (2005).
PhNO2
H
OO2N
Ph
THF, RT
NH
Ph Ph
OTMS2 mol%
Tandem Michael / Henry reaction
Angew. Chem., Int. Ed., 46, 4922 (2007).
PhNO2
OHO OH
NO2
OH
OHC
Ph
Ph
O
HH2O, RT
Ph
OHC
CHO
Ph
exo : endo = 80 : 20, 97% ee (exo)
Angew. Chem., Int. Ed., 47, 6634 (2008).
NH
Ph Ph
OTBS10 mol%
Michael / cyclization reaction
Tetrahedron, 66, 4894 (2010).
O
H THF, RT
NH
Ph Ph
OTBS10 mol%
Chem. Commun,, 3083 (2009).
Ph O
OO Ph
O
OPh
O MeH
O
-Benzoyloxylation
Ph
O
HMeOH, RT
p-NO2C6H4OH
NH
Ph Ph
OTBS10 mol%
Ph
O
H
Ph
O
H
84%, 92% eeAngew. Chem., Int. Ed., 45, 6853 (2006).
Michael reaction
Ph
O
H
OH
PhPh
NHBocNBoc
Ph(CH2Cl)2, 70 oC
OH
Ph
NBoc
Ph
NH
Ph Ph
OTBS10 mol%
90%, 94% ee, : = 34 : 66Angew. Chem., Int. Ed., 47, 4012 (2008).
Formal aza [3+3] cycloaddition
O
HCH2Cl2, RT R
Formal carbo [3+3] cycloaddition
O
OMeO
O
OMe
R
PhCO2H
NH
Ph Ph
OTBS
10 mol%
OMeO
O
O
OMe
Org. Lett., 11, 45 (2009).up to 99% ee
R1
H
O
O
Ntoluene, 0 oC
H
O
R1R2
O
NR3
O
+R3O
R2 NH
Ph Ph
OTBS
10 mol%
up to 99% eeup to >90% de
Chem. Asian. J., 4, 246 (2009).
Michael reaction
63%, 95% ee
78%, 92% ee
66%, 99% ee
85%, 99% ee
Diels-Alder reaction
90%, 95% ee
O
HMeOH, RT
O
R
PhCO2H
NH
Ph Ph
OTMS10 mol%
Org. Lett., 11, 4056 (2009).up to 99% ee, a : b = 9 : 1
O2N
OH
R
OH
NO2
O
R
OH
NO2
NaHCO3
MeOH, RT
a b
Ar = 3,5-(CF3)2C6H3-
O
H
NH
Ar Ar
OTMSNH
Ar Ar
OHN
Ar Ar
OH
CO2EtNH
OH
O 1) ClCO2EtK2CO3, MeOH
2) ArMgBr, THFKOH
MeOH
TMSClimidazole
DMF
Michael reaction / isomerization
This catalyst is synthesized in short steps fromproline.Substituents on aryl and silyl moiety are easilymodified.Excellent enantioselectivity is obtained
Reaction using diarylprolinol silyl ether derivatives as catalyst
O
H
PhO2N
PhCO2H
NO2PhMe
H
O NH
Ph Ph
OTMS10 mol% Ph
NNs
TMS
NNs
PhPhNO2
Me
toluene, RT 1,4-dioxane; evapo
CH2Cl2
Michael / aza Henry / aminal formation / additional reaction
RO
H HOOHhexane, RT
NH
Ph Ph
OSiMePh220 mol%
RO
HO
up to 95% ee
epoxidation
Org. Lett., 12, 5434 (2010).
up to 99% eeSingle diastereomer
Org.Lett., 12, 4588 (2010).
NO2R1
R2H
O NH
Ph Ph
OTMS10 mol%
TMS
O
R3R1
NO2
R2
toluene, RT; evapo
CH2Cl2
Michael / Henry / acetal formation / additional reaction
up to 99% eeSingle diastereomer
Angew. Chem., Int. Ed., 50, 3774 (2011).
H
O
R3
MeCN
DBU TiCl4TiCl4
NH2
Ar Ar
OTMS
5 mol%ClO4
-
Development of new reactionsAsymmetric 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
Org. Lett, 9, 2859 (2007).
Hayashi Lab. Homepage http://www.ykbsc.chem.tohoku.ac.jp/
1,4-dioxane, RT
NH
Ph Ph
OTMS10 mol%
Angew. Chem., Int. Ed., 47, 4722 (2008).
PhNO2
H
OO2N
Ph
75%, 96% ee
O
HPh
NBz
H
O
H
Michael reaction
NH
Ar Ar
OTMS10 mol%
p-NO2C6H4CO2H
THF, 4 oC Ph
NHBz
O
H87%, 98% ee
Angew. Chem., Int. Ed., 47, 9053 (2008).
Ar = 3,5-(CF3)2C6H3-Mannich reaction
R1
NHTs
SO2Ph
O
H
NH
Ar Ar
OTMS10 mol%
NaHCO3
1,4-dioxane or brine, 10 oC R1
NHTs
O
H
up to 99% eeChem. Eur. J., 17, 8273 (2011).
Ar = 3,5-(CF3)2C6H3-Mannich reaction
R2R2
O
H
NH
Ph Ph
OTMS20 mol%
DDQ
Ar
O
H
Angew. Chem., Int. Ed., 50, 3920 (2011).
THF
H
Ar
MeNO2NaOAc
MeOH
O2N
R1 = alkylor aryl up to 95% ee
Formal C-H insertion
Reaction using diarylprolinol silyl ether derivatives as catalyst
H
O
H
Htoluene, RT
NH
Ph Ph
OTMS10 mol%
J. Am. Chem. Soc., 133, 20175 (2011).up to 99% ee
[6+2] cycloaddition reaction
O
H
R2 R1
R3
MeOH, RT
NH
Ph Ph
OSiPh2Me10 mol%
ChemCatChem, 4, 959 (2012).up to 95% ee
Michael reaction (1,4-Addition versus 1,6-Addition)
MeNO2
O
H
R2 R1
R3 NO2
O
HR3
R2R1
NO2
100 0:
Concerted Mechanism
NHTs
SO2Ph
O
H
NH
Ar Ar
OTMS10 mol%
NaHCO3
1,4-dioxane, RT
NTs
OH
up to 99% eeChem. Eur. J., 17, 8273 (2011).
Ar = 3,5-(CF3)2C6H3-
R R
ClNaBH4
MeOH
Mannich reaction
ClNH
H
O
R
Ts
N NR
H
HR
O
PhN=ONH 10 mol%
DMF, 0 oCslow addition
OONHPh CuSO4�5H2O (cat)
MeOH, 0 oC
OOH
79%, >99% ee 87%Angew. Chem., Int. Ed., 43, 1112 (2004).
J. Org. Chem., 69, 1548 (2004).
Direct catalytic enantioselective -aminoxylation
H
OOMe
NH2
H
O
Me
NH 10 mol%
NMP, -20 oCHN
Me
CHO
OMe
90%, 98% eeanti : syn = 1 : >95
Angew. Chem., Int. Ed., 42, 3677 (2003).Adv. Synth. Catal., 347, 1604 (2005).
Nature Protocols, 2, 113 (2007).
The direct and enantioselective, One-Pot, Three-Component,Cross-Mannich reaction of aldehydes
Reaction catalyzed by proline
Tetrahedron Lett., 44, 8293 (2003).
H
O
PhN=ONH 30 mol%
CH3CN, -20 oCslow addition
H
OONHPh
quant, 98% ee
Me Me
COOH
COOH COOH
H
HPh
OPhHNO
PhH
O+ PhN=O
L-proline 24 h, <5%Siloxy proline 2 h, 50%, 99% ee
Ph H
O
OMe
NH2
O
Ph
ONH
MeO
+ +
L-proline 20 h, <5%Siloxy proline 20 h, 63%, 96% ee
NH
TBSOCO2H
Adv. Synth. Catal., 346, 1435 (2004).
� -aminoxylation
�Mannich reaction
Reaction by siloxyproline catalyst
This catalyst is morereactive than proline.
H
OO
O O
CHONH
NMP, 0 oC
J. Org. Chem., 72, 6493 (2007).
NH
Reaction by proline-derived catalyst
CF3CO230 mol%
Ph
O
CHO Ph
O
CHO
S
NH2
O
HN
acetone, 0 oC
CF3CO2 10 mol%
quant, 99% eecis : trans = 8.3 : 1
J. Am. Chem. Soc., 127, 16028 (2005).
Reaction by cystein-derived catalyst
H
ONH
Ar Ar
OH10 mol%
DMF, 4 oC
NaBH4
MeOHOH
OH
82%, 98% eeAngew. Chem., Int. Ed., 47, 2082 (2008).
H
ONH
Ar Ar
OH10 mol%
NMP, 4 oC3
OH
OO NaBH4
MeOH OH
OH
56%, 82% eeOrg. Lett., 10, 5581 (2008).
Cl
H
O Cl
toluene, RT
NH
Ar Ar
OH10 mol% Ph3P=CHCO2Et
RH
O
F3C
OH
OEtIn 10% EtOH
F3CCO2Et
Rup to 96% ee
OH
Synlett, 485, (2011).
Aldol reaction by diarylprolinol as a catalyst
N
R
R
O
O
OTIPS
O
H
NH
Ar Ar
OH30 mol%
ClCH2CO2H
DMF, 4 oC N
R
RO
OTIPS
HOCHO
R = H, 73%, 85% eeR = Br, 86%, 82% ee
NH
Br
BrO
HO OH
NH
HO
OH N
Me
MeO
NMeH
ent-Convolutamydine E a half fragment ofMadindoline A and B CPC-1
HO
Org. Lett., 11, 3854 (2009).
aq MeCN
NH
Ar Ar
OH10 mol%
RH
O
EtO2C
O
H
Polymer form
EtO2C
OHCO2
tBu
R
EtO2C
OH
ROMe
OMe
up to 99% eeOrg. Lett., 12, 2966 (2010).
Ph3P=CHCO2tBu
MeOH, PPTS
THF, RT
NH
Ar Ar
OH10 mol% Ph3P=CHCO2Et
RH
OOH
OH CO2Et
Rup to 99% ee
OH
Chem. Commun., 48, 4570 (2012).
O O40 wt% in water
NH
Ar Ar
OH10 mol%
RH
OO
H
HC(OMe)3, TsOH
CO2Et
R
ROMe
OMe
up to 99% ee
ClTHF, RT
O
O40 wt% in water
Angew. Chem., Int. Ed., 50, 2804 (2011).
RH
OOHCl
Ph3P=CHCO2Et
ROMe
OMeOHCl
R
OHCl CO2Et
K2CO3
K2CO3
EtO2CR
H
OOH
CO2Et
O
n
KOHMeOH
This catalyst is synthesized in short steps fromproline.This is effective olganocatalyst of direct,enantioselective aldol reaction.Excellent enantioselectivity is obtained.
NH N
H
O
OH
CF3
F3C MgBr
OH
F3C CF3
CF3
CF3
N OH
F3C CF3
CF3
CF3OEtO
ClCO2EtK2CO3
MeOH N
O
OMe
OEtO
THF
Diarylprolinol
Organic solvent free reactionOrganic solvent free reaction
OMe
NH2
O ONH
MeO
++
MeO
H
O
MeO
NH
CO2H
cat.
1 atm, RT 0%, -% ee2000 atm, -20 oC 99%, 96% ee
J . Am. Chem. Soc., 125, 11208 (2003).
Research about of Research about of chiralitychirality
Amplification of ee from initial low ee The key to find out origin of chiralityAngew. Chem., Int. Ed. 45, 4593 (2006).
1) 24 h��, ���
10% ee��L-Proline��
99% ee (L)��2)�� N
H
CO2H
NH
CO2H
CHCl3NH
CO2H
MeO
OMeH
O+
OMe
NH2
O
MeO
OMe
NHPMP
ONH
TBDPSO
NH
NNN
+
10 mol%
water , 0 oC
93%, 95% eesyn : anti =4.6 : 1Org. Lett., 10, 21 (2008).
H
O
O2N
+
O OH O20 proteinogenicamino acid (30 mol%)
DMSO and aq DMSO
<5-89%, 0-96% eeanti : syn = 0.8-13 : 1
Gly, Ala, Val, Leu, lle, Phe, Trp, Pro, Ser, Thr, Tyr, Cys, Met, His, Lys, Arg, Asp, Asn, Glu, Gln
Synlett , 2006, 1565.
positive water effect
Application of High Pressure Application of High Pressure lnducedlnduced by Waterby Water--Freezing to Freezing to the direct catalytic asymmetric reactionthe direct catalytic asymmetric reaction
�Organic solvent free asymmetric aldol reaction between ketone and aldehyde
�Intermolecular aldol reaction between aldehydes in the presence of water
�Self aldol reaction of propanal in water – reaction in water with proline-amide catalyst
�Organic solvent free Dry and Wet condition asymmetric aldol reaction with proline catalyst
�Organic solvent free asymmetric Mannich reaction with proline catalyst
�Effect of water on aldol reaction with 20 proteinogenic amino acid
The novel method of high pressure by water-freezing:
The high pressre (cat. 200 MaPa) is easilly is essily achieved
simply by freesing water (-20 �) in a sealed autoclave.
�Mannich reaction
�Organic solvent free asymmetric Diels-Alder reaction with proline derived catalyst
�Aldol reactionTetrahedron Lett., 45, 4353 (2004).
�Michael reactionChem. Lett., 2002, 296.
�Baylis-Hillman reactionTetrahedron Lett., 43, 8683 (2004).
99% ee(L) solution
1)stirred for 240 oC
2)filtration
Angew. Chem. Int. Ed., 47, 6634 (2008).
OH
14.6 g (94%)anti / syn = 1.4 / 198% ee
H2O (3.8 mL)
RT, 72 h
H2O (40 mL)water phase
organic phase
O
2.4 g (30 mol%)
7.9 mL (70 mmol)
9.3 mL (105 mmol)
NH
CO2H
H
OCl
Cl O
Distillation
NH
CO2H
OHCl O
O
Organic solvent-free aldol reaction
Cl
H
O
+O
H
NH
CO2HO
O
Cl
OHMe
OHNaBH4
MeOHwater, 0 oC
Hydrophobic parrt
Hydrophiic part
97%, 99% eeanti : syn =19 : 1
Angew. Chem. Int. Ed., 45, 5527 (2006).
10 mol%
O
H
NH
CONH2
OH
H
O
Water
(cat.)
high enantioselectivity
Chem. Commun., 2007, 2524.
RT, 24 h
1 atm, RT 0%, -% ee200 atm, -20oC 99%, 96% ee
prepared 10% ee(L-Proline excess)
N
PhCHO
OHC
Ph
TMSO
CF3
CF3
CF3
F3C
H2
ClO4 water
decantation thendistillationwater
(2.64 g, 20 mmol) (4.7 mL, 60 mmol)
10 mL
5 mol% exo:endo 82:18
97% ee3.2 g, 81%
RT, 8 h
Helvetica Chemica Acta, 94, 719 (2011).
NH
R
N R
R1H
N R
HR1
R2
N
N R
HR1
R2
NO2
N R
R1 NO2
R2
O
HR1
NO2
R2H
O
R1
NO2
R2
H2O
X
OO
N R
HR1
R2
NO2
O
HR1
NO2
R2
HX
O
HO2NPh
R1
NH
PhPh
OTMSO2N
Ph O
HR1hexane, 0 oC
10 mol%
R1 H
O+
R2
O
H R1
OH
H
O
R2
NH
CO2H
(cat.)
neatanti : syn = up to 14 :1up to 95% ee
R1 H
O+
R2
O
R3 R1
OH
R3
O
R2
NH
CO2H
(cat.)
water (3 eq.)
anti : syn = >20 :1up to >99% ee
Chem. Commun. , 2007, 957.
�aldehyde-aldehyde
�aldehyde-ketone
H2O
Distillation
NH
CO2H
TBDPSO
10 g (70%)ant i:syn=10:1>99%ee
O
H
O
OH O
7.4 g (1 eq) 13.7 g (2 eq)
259 mg (1 mol%)
2.5 g silica gel
Filtration(60 ml AcOEt)
3.8 mL (3 equiv.)2 days
Y. Hayashi e t al., Angew. Chem., Int. Ed., 45, 958 (2006).
Y. Hayashi e t al., Chem. Eur . J., 13, 10246 (2007).
Proposed mechanistic cycleProposed mechanistic cycle
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