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Pot-Economy in Total Synthesis
Tohoku University Yujiro Hayashi
O CO2Et
AcHNNH2
(-)-oseltamivir
NH
OTMS
Prostaglandin E1 (PGE1)
HO OH
OCO2H
NH OH
F3C CF3
CF3
CF3
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
OTMSPh
NH OH
O
NH OH
O
TBDPSO
NH OH
F3C CF3
CF3
CF3
NH
O
O
8
OH
O
Jorgensen-Hayashi Catalyst
PhNO2
MeH
O
+
10 mol%
hexane, 23 °C, 1 hH
O2NOPh
Me85%, 99% ee, syn : anti = 5.7 : 1
NH
PhPh
OTMS
NH OTMS
+
1)
2) NaBH4 60%, 95% eeK. A. Jorgensen, et al., Angew. Chem. Int. Ed., 44, 794 (2005).
NH OTMS
F3C CF3CF3
CF3
MeH
O
BnS OH
Y. Hayashi, et al., Angew. Chem. Int. Ed., 44, 4112 (2005).
TMS = Me3Si-
NN
NBnS
Jorgensen-Hayashi Catalyst
R
O
H
R
NOSiMe
MeMe
+
NH OTMS
E+
R
O
HE
R
H
ON
OSiMe
MeMe
+
R
NH OTMS
Nu−
R
H
O
Nu
NH
N
HN NNN
H HN
ONH HN
ONH
HO CO2Et
CO2EtHN S
O
OCF3
NHSO2CF3
NH2 NX NH
MeNO
BntBuNHNHS
O
OO
OH NH
CO2H
Me
Conformation of Enamine
Y. Hayashi, D. Seebach, T. Uchimaru; Chem. Eur. J., ASAP.
NOSi
Conformation of Iminium ion
Y. Hayashi, D. Seebach, T. Uchimaru; Chem. Eur. J., ASAP.
NOSi
Reactions developed by our group
O2NPh O
HO
H
PhO2N
NO2OH
OHC
Ph
Ph
Ph
OHC
OPh
O MeH
O
OH
Ph
NBoc
PhPh O
OMeO
O
OMe
H
O
MeMe
O
NPh
O
O
Ph
OH
NO2
N
Ph Ph
Me
NO2
NsO
Ph Ph
Me
NO2
O
HC7H15
O
NH
ArAr
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
HPh
H
O
NO2
Michael
95% ee
There is a large effect of the substituent of silyl group on the enantioselectivity.
Type A: Iminium ion as an intermediate/ Michael type reaction
SO2PhPhO2S
Me
H
O
+Me
H
O
SO2Ph
SO2Phtoluene, rt, 20 h
10 mol%catalyst
NH OR
PhPh
1: R = Me3Si2: R = Ph2MeSi
1 90 712 88 83
2323
2 94 900
Ph H
O
MeO OMe
OO O
OMe
O
O
OMeO
Ph+
10mol% catalyst20 mol% PhCO2H
CH2Cl2, rt
NaBH4
MeOH, 0 °C
OMe
O
OH
OMeO
Ph
1 79 912 76 95
5080
Catalyst Yield/% ee/%Temperature/ °C
Catalyst Time/min Yield/% ee/%
N
Phα β
Nu-
Type A
There is small effect of the substituent of silyl group on the enantioselectivity.
Type B: Iminium ion intermediate/ Diels-Alder reaction
NH OR
PhPh
1: R = Me3Si2: R = Ph2MeSi
1 14 832 16 83
Ph H
O+
10mol% catalyst20 mol% CF3CO2H
toluene, rt, 20 h Ph
OHC
CHO
Ph+
exo endo
80:2077:23
NH OR
F3C CF3
CF3
CF3
3 86 9584:16
3: R = Me3Si4: R = Et3Si
4 80 9785:15
Catalyst Yield/% exo:endo ee/%
N
Phα β
Type B
There is no effect of the substituent of silyl group on the enantioselectivity.
Type C: Enamine intermediate
H
O+
10 mol% catalyst
NO2Ph
hexane, 0 °CPh NO2 H
O
cat 1 5 h syn:anti = 16:1 85% 99% eecat 2 24 h syn:anti = >20:1 89% 99% ee
H
O+
CHCl3, rtN
O
O
Ph N
O
O
PhH
O10 mol% catalyst H
cat 1 24 h anti:syn = 8:1 70% 99% eecat 2 24 h syn:anti = 5:1 38% 99% ee
NH OR
PhPh
1: R = Me3Si2: R = Ph2MeSi
E
NPh
Type C
Three types of the reaction
E
N
Phα β N Ph
N
Phα β
Nu-
Type A Type B Type C
Type A: Bulkier silyl substituent affords higher enantioselectivity.!Type B and C: Small TMS affords excellent enantioselectivity.!!In the bulky silyl substituent, the reactivity decreases because of the slow formation of iminium ion, which is accelerated by acid.
Y. Hayashi, D. Seebach, T. Uchimaru; Chem. Eur. J., ASAP.
Michael reaction ?
PhNO2
MeH
O
+
5 mol%
HO2N
OPh
Me98%, 99% ee, syn : anti = 14 : 1
NH
PhPh
OTMSadditive time
none 6 hp-NO2C6H4OH 15 min
NO
O2NPh
88%, syn:anti=99:1D. Seebach, et al., Helv. Chim. Acta., 64, 1413 (1981).
PhNO2 +
O
D. Seebach, Y. Hayashi, et al., Helv. Chim. Acta, 2013, 96, 799.
Michael reaction ?
H
O
NOTMS
PhPh
NO2
PhH
N
NPh
Ph
OTMSPh
OO
NO2
N
Ph
Ph
OTMSPh
H
N
NO2Ph
Ph
OTMSPh
H
O
NO2Ph
NH OTMS
PhPh
NOTMS
PhPh
NO
Ph O
N
NO2Ph
OTMS
PhPh
H2O
H2O
Zwitter ion
PhNO2
MeH
O
+
5 mol%
HO2N
OPh
Me98%, 99% ee, syn : anti = 14 : 1
NH
PhPh
OTMSadditive time
none 6 hp-NO2C6H4OH 15 min
Novartis’ synthesis of Aliskiren�
NH
Ph
OTMSPh
N-methyl morpholine
NaBH4
EtOH 70% ee
10 mol%
H
O
NO2
NO2BzO OHO2N
NH2MeO
O
OMe
OH HN
O
NH2
O
• [(HO2CCH)2]1/2
Aliskiren / Tektuma®Novartis / hypertention medicationWO2008119804
exo Selective Diels-Alder reaction in the presence of water�
Angew. Chem. Int. Ed., 47, 6634 (2008).
N
PhCHO
OHC
Ph
TESO
CF3
CF3
CF3
F3C
H2ClO4 water
decantation thendistillationwater
2.64 g 4.7 mL
10 mL
5 mol%
exo:endo 82:18
97% ee3.2 g, 81%
RT, 8 h
No organic solvent = Green chemistry Unusual exo-selectivity Low temperature is not necessary
C. Fehr et al.,(Firmenich), Angew. Chem., Int. Ed., 2009, 48, 7221.
Synthesis of (-)-β-Santalol by Firmenich
H
O
1.5 mol%
H2O
ClO4
NH2
TESO
F3CCF3
CF3
CF3
OHC
CHO
exo : endo = 70 : 30exo 95% ee, endo 78% ee
61%
OH
(−)-β-Santalol
MeOH, RT
71%, 93% ee
+
2 mol%
H
O
CH3NO2
1) NaH2PO3・2H2O NaClO2 2-methyl-2-butene
2) Pd/C, H280%
H
O
NO2
OH
O
NH2
Pregabalin: anticonvulsant
NH
PhOTMS
Ph
p-Cl-Ph
OH
O
NH2
Baclofen: GABAB receptor agonist
+
2 mol%
4 mol%
p-Cl-Ph
80%, 92% ee
H
O
NO2CH3NO2
PhCOOHMeOH, RTp-Cl-Ph
O
H 2 steps
87%
NH
PhOTMS
Ph
Org. Lett., 9, 5307 (2007).
Synthesis of Telcagepant by Merck
H
OFF CH3NO2
NH
PhPh
OTMS
5 mol%
5 mol% tBuCO2H50 mol% B(OH)3
THF-H2O
FF CHO
NO2
73%, 95% ee >100 kg
NO
CF3
ON N
NH
N
O
FF
Telcagepant
F. Xu et al.,(Merck), J. Org. Chem., 75, 7829 (2010).
CGRP receptors antagonist for treatment of Migraine
Generation of quaternary stereocenters
NH
PhOTMS
Ph
neatR
H
O
+R
NO2
H
O
10~20 mol%
NO2
H
O
O NO2
H
O
EtO
EtO NO2
H
O
NO2
H
O
TsO
88%, 89% eeE : Z = 90 : 10 (SM)
76%, 91% eeE : Z = 68 : 32 (SM)
63%, 87% eeE : Z = 89 : 11 (SM)
89%, 90% eeE : Z = > 99 : 1 (SM)
MeNO2
SM : Starting Material
NO2
H
O
Br81%, 88% ee
E : Z = > 99 : 1 (SM)
NO2
H
O
Ph
74%, 72% eeE : Z = 80 : 20 (SM)
NO2
H
O
EtO
O
67%, 80% eeE : Z = > 99 : 1 (SM)
NO2
H
O
49%, 88% eeE : Z = > 99 : 1 (SM)
Chem. Eur. J., 2014, 20, 12072.
Total synthesis of (R)-Horsfiline
NBn
O
H
O
MeNO2, H2O
NH
O
N
NBn
O
OO2N
HMeO MeO
MeO
(R)-Horsfiline
95% ee
NH
Ar
OTMSAr
iPrOH
20 mol %
E/Z = 1/2
Ar = 3,5-CF3-C6H3-
NBn
O
N
NBn
O
HN
4 reactions in "one-pot"
MeO
MeO
46% (4 steps yield)
ZnAcOH
H2O
aq. H2CO Na, NH3
THF, –78 oC80%
Total yield, 33%Isolation from Horsfieldia superba:B. Bode et al., J. Org. Chem., 1991, 56, 6527.
Chem. Eur. J., 2014, 20, 13583.
Total synthesis of biologically active compounds
OO
O
HO
O
OOH
O
HMe
MeO
O
O
HO
O
OOH
O
HMe
Me
epoxyquinol A epoxyquinol B
OO
O
HO
O
OOH
O
HMe
Me
epoxyquinol C
O O
O
OH
OMe
OH
O
O Me
epoxytwinol A
O
OOMe
H
O
Me
Me
Me
RK-805 FR-65814
O
OOMe
OH
O
Me
Me
Me
ovalicin 5-demethylovalicinfumagillol
O
OHOMe
H
O
Me
Me
Me O
OHOMe
H
O
Me
Me
Me O
OOH
OH
O
Me
Me
Me
OO
OHO
OH
OMeMe
OH
H
H
MeMe OH
panepophenanthrin
OH
OH
Me
+NH3HN
OCO2-ON
nikkomycin B
HN
O
OHO 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
OMeO Me
O
NH
O
OHMe
O
Me
OMeOMe
O
NH
O
OH
OHO
Me
OMeOMe
O
NH
OH
O
HOH
epolactaeneNG-391 lucilactaene
OOOH
NaHO3PO OH
Me OHfostriecin
HNO
MeO
OH
O
OMePh
OOH
HOEt
HNO
Me
Et
OOH
O
OHPh
HNO
MeO OH
OPh
O
OMeEt
O
azaspirene pseurotin A synerazol
HNO
MeO OH
OPh
O
OMe
FD-838
OEt
ent-convolutamydine E
NO
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
OO
(+) - cytotrienin A
AcHNNH2
O CO2Et
(-)-oseltamivir
O
OMeC14H29
O
(R)-Methyl Palmoxirate
OH
O
NH2
pregabalin
OH
O
NH2
Cl
baclofen
F
FF
NH2
O
NN
NN
CF3
ABT-341
CO2Me
HO
O
OHProstaglandin E1 methyl ester
O
AcHNNH2
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), Ma (2010) et al.,
Synthetic Challenge: Control of three continuous chiral center Selectivity (enantio- and diastereo-)
62 total syntheses
Angew. Chem. Int. Ed., 2009, 48, 1304; Chem. Eur. J., 2010, 16, 12616.
2 “one-pot” synthesis of (-)-oseltamivir
CO2EtO
t-BuO2CNO2
Stol
t-BuO2CNO2+
NH
PhPh
OTMS
1 mol%
20 mol% ClCH2CO2H
toluene, rt
PO
OEt
O
EtOEtO
Cs2CO3
toluene, 0 °C;evaporation;
EtOH, rt
tolSH
–15 °C
5S
CO2EtO
AcHNNH2
(–)-Oseltamivir70% (single diastereomer)
1) TFA; evaporation2) (COCl)2; evaporation3) TMSN3
4) AcOH, Ac2O; evaporation5) Zn, TMSCl6) NH3; K2CO3
O
t-BuO2CNO2
H
O CO2EtO
t-BuO2CNO2
5R
R : S = 4.6 : 1
H
OO
82% (6 steps)
Angew. Chem. Int. Ed., 2009, 48, 1304; Chem. Eur. J., 2010, 16, 12616.
2 “one-pot” synthesis of (-)-oseltamivir
CO2EtO
t-BuO2CNO2
Stol
t-BuO2CNO2+
NH
PhPh
OTMS
1 mol%
20 mol% ClCH2CO2H
toluene, rt
PO
OEt
O
EtOEtO
Cs2CO3
toluene, 0 °C;evaporation;
EtOH, rt
tolSH
–15 °C
5S
CO2EtO
AcHNNH2
(–)-Oseltamivir70% (single diastereomer)
1) TFA; evaporation2) (COCl)2; evaporation3) TMSN3
4) AcOH, Ac2O; evaporation5) Zn, TMSCl6) NH3; K2CO3
O
t-BuO2CNO2
H
O CO2EtO
t-BuO2CNO2
5R
R : S = 4.6 : 1
H
OO
82% (6 steps)
R1NO2
NH
PhPh
OTMSH
R2
OH
O
NO2R1
R2 H R3
O
O
O
R1
R2
NO2R3
O
OHR2
R1NO2
R3
TMSO
R2
R1NO2
R3
DBU
TiCl4
Highly diastereo- and enantio-selective
R1NO2
NH
PhPh
OTMSH
R2
OH R3
OTMS
OR2
R1NO2
R3DBU
5 mol%
TiCl4
up to 99% eeY. Hayashi et al., Angew. Chem. Int. Ed., 2011, 50, 3774.
One-pot and cascade synthesis of substituted chiral pyran
R1NO2
NH
PhPh
OTMSH
R2
OH R3
OTMS
OR2
R1NO2
R3DBU
5 mol%
TiCl4
up to 99% eeY. Hayashi et al., Angew. Chem. Int. Ed., 2011, 50, 3774.
One-pot and cascade synthesis of substituted chiral pyran
One-pot and cascade synthesis of substituted chiral pyperidine
R1NO2
NH
PhPh
OTMSH
R2
OH R3
NRTMS
NRR2
R1NO2
R3DBU
5 mol%
TiCl4
up to 99% eeY. Hayashi et al., Org. Lett., 2010, 12 , 4588.
One-pot reaction is powerful for the library synthesis. One-pot reaction is useful for the medicinal chemistry.
Angew. Chem. Int. Ed., 2009, 48, 1304; Chem. Eur. J., 2010, 16, 12616.
2 “one-pot” synthesis of (-)-oseltamivir
CO2EtO
t-BuO2CNO2
Stol
t-BuO2CNO2+
NH
PhPh
OTMS
1 mol%
20 mol% ClCH2CO2H
toluene, rt
PO
OEt
O
EtOEtO
Cs2CO3
toluene, 0 °C;evaporation;
EtOH, rt
tolSH
–15 °C
5S
CO2EtO
AcHNNH2
(–)-Oseltamivir70% (single diastereomer)
1) TFA; evaporation2) (COCl)2; evaporation3) TMSN3
4) AcOH, Ac2O; evaporation5) Zn, TMSCl6) NH3; K2CO3
O
t-BuO2CNO2
H
O CO2EtO
t-BuO2CNO2
5R
R : S = 4.6 : 1
H
OO
82% (6 steps)Total Yield 60%
Tandem Michael/HWE reaction
CO2EtO
t-BuO2CNO2
CO2EtO
t-BuO2CO2N
PEtO2CO
OEtOEt
CO2EtO
t-BuO2CNO2
OHPO
OEtOEt ++O
t-BuO2CNO2
H
O
CO2EtPEtO
OEtO
Cs2CO3CH2Cl2
0 °C, 3 h
~30% ~30% ~30%
CsCO3, EtOHCsCO3, EtOH, quant.~90%
O
t-BuO2CNO2
H
O CO2EtPO
EtOEtO
CH2Cl2, 0 °C, 3 h
CO2EtO
t-BuO2CNO2
5R
~80%, 5R : 5S = 4.6 : 1
1.5 eqCs2CO3 EtOH
rt, 15 min
One-pot Reaction: purification economy, chemical waste economy, time econony, increase yield
“one-pot” synthesis of (-)-oseltamivir
One-pot operation
AcHN
+
OH
O
NH
PhPh
OSiPh2Me30 mol% HCOOH
ClC6H5, rt, 1.5 h
CO2EtPO
EtOEtO
Cs2CO3ClC6H5, 0 °C, 3 h
; EtOH, 0 °C, 30 min
MeHS
–15 °C, 36 h
CO2EtO
NH2AcHN
S
10 mol%
NO2
TMSCl , –15 °C; Zn, 70 °C, 2 h
NH3 bubbling0 °C, 10 min
; K2CO3, rt, 14 h
O
AcHNNO2
O
H
CO2EtO
NO2AcHN
Stol
S
CO2EtO
NO2
AcHNR
CO2EtO
NH2AcHN
Stol
S
No evaporationNo solvent exchangeGram-scale synthesis
(–)-Oseltamivir34% (34 mg)28% (1.02 g)
D. Ma, Angew. Chem. Int. Ed., 2010, 49, 4656. R. Sebesta, Synthesis, 2012, 44, 2424. G. Lu, ChemCatChem, 2012, 4, 1007.
Chem. Eur. J., 2013, 19 , 17789.
Pot economy
• Atom economy (Trost)�• Step economy (Wender) • Redox economy (Baran & Hoffmann)
• Purification step economy�• Chemical waste economy�• Time economy�• Solvent economy
Green Reaction
Operational Economy
CO2EtO
AcHNNH2·H3PO4
Tamiflu (Roche) ABT-341 (Abbott laboratory)
F
F F NH2
NN N
N
CF3
O
NN
NN
O
CF3
NH2
F
FF JanuviaTM (Merck)
Dipeptidyl peptidase-4 (DPP-4) inhibitor
Non-insulin dependant diabetes
NO2F
F F
TMSO
toluene, 120 oC2 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
MeOH80 oC, 2 h
(Boc)2O
THF NHBoc
F
F F(racemic)
Br OH
85% (2 steps)
NHBoc
F
F F(racemic)
OHHCO2H, nBu3NPd(PPh3)2Cl2
DMF, 80 oC12 h
70%
NHBoc
F
F F(racemic)
O
HDMP
CH2Cl2
81%
NaClO2isoprene
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
HNN
NN
CF3TBTU, TEA, DMF
then TFA, CH2Cl2
NN
NN
CF3
Yield (no data )
13 StepsTotal Yield :
Angew. Chem. Int. Ed. 2011, 50, 2824.
F
F F
NO2
Me H
O
NH
Ph
OTMSPh
10 mol% CO2tBuPO
EtOEtO
HNN
NN
CF3
ABT-341
iPr2EtN
EtOH−40 oC to rt
; evaporation
F
F FNH2
NN
NN
CF3
O
One-Pot Total Synthesis of ABT-341
Cs2CO3
CF3CO2H
1.4-dioxane0 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
ZnAcOH
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
HO OH
O
PGE1
CO2H
HO OH
O
PGE2
CO2H
HO OH
HO
PGF2α
CO2H
OH
O
PGA1
CO2H
OH
O
PGB1
CO2H
OH
HO
PGF3α
CO2H
HO
O
HO
CO2H
OHPGI2
OOH
PGG2
CO2HOO
latanoprost
HO OH
PhCO2iPr
HO
Prostaglandins
Total syntheses: Corey, Stork, Woodward, Noyori, Danishefsky etc.beraprost
HO OH
O
OH
PGH2
CO2HOO
O OH
HO
PGD2
CO2H
OHO
OH
CO2H
OHTXB2
O
CO2H
OH
O
TXA2
HO
CO2H
OHCarbacyclin
HO OH
O
limaprost
CO2H
HO
CO2H
OH
iloprost
HO OH
O
ornoprost
CO2MeO
CO2Na
cloprostenol
HO OH
CO2H
HO
O
Cl
bimatoprost
HO OH
PhCONHEt
HO
Corey’s Total Synthesis
E. J. Corey et al., J. Am. Chem. Soc., 91, 5675 (1969).!E. J. Corey et al., J. Am. Chem. Soc., 92, 2586 (1970).!Cf. V. K. Aggarwal et al., Nature, 489, 278 (2012).
MeO
CN
Cl
2 steps 3 steps HO
O
HO
KI3NaHCO3
OO
HO
2 stepsO
O
AcOCorey lactone
OMe OMe
OMe
PGE1
HO OH
OCO2H
PGE2
HO OH
CO2H
O
PGF2α
HO OH
CO2H
HO
Total 19 steps
I
8 steps
11 steps
NH OTMS
PhPh10 mol%
THF, rt
OHO OH
66%, 99% eeY. Hayashi et al., Angew. Chem. Int. Ed., 46, 4922 (2007).
NO2HO R
H
O
O2N R
Our background: Formal 4+2 cycloaddition reaction
N OTMSPh
Ph
N OTMSPh
Ph
NO2R
H
O
HNH OTMS
PhPh
H2OH2O
Michael type reaction
Henry reaction
H
O
CHO
H
O
NO2O R
H
N OTMSPh
Ph
NO2HO R
H
OH2O
-H2O
OHO OH
O2N R
Retrosynthetic analysis 1
OH
CO2MeO
HO O
O2NR
H
O2N
HO
O
RO2N
ON
R'H
H
O
O
O2NCO2Me
Formal 3+2 cycloaddition
CO2Me
OMeO OMe Amberlyst 15
H2O, 90 °C
H
OH
O
TCI: 22 euro (25 g)75%
10 mol% p-nitrophenol
MeCN, rt
(MeO)2PO O
iPr2NEt
0 oC
LiCl, iPr2NEt
THF, rt
2 steps 87%
NH
PhOTMS
Ph10 mol%
H
OH
O
O
O2NCO2Me
HO
H
O2NCO2Me
HO
O
O2N CO2Me
dr = 76:17:7
Al2O3
(ClCH2)2, 60 oC
75%, 94% eecis : trans = 91 : 9
-20 oC, 8 h
68%, dr = 96:4 OH
O2NCO2Me
HO
OH
O2NCO2Me
OH
OCO2Me
BCl2
HO
PGE1 methyl ester
OH
O2NCO2Me
OH
OCO2Me
HO
R2
R1O
HOR2
R1O
O R2
R1O
R2
R1O
R2
R1O2N
Retrosynthetic analysis 2
OH
O2NCO2Me
OH
OCO2Me
OH
O2NCO2Me
OH
OCO2Me
DABCO (X eq.)
MeCNtemp., time
A
C
PGA1 methyl ester (B)
+
+
time / hyield / %
X eq.
121
temp. / oC
23
161 0
301.5 0
A B C
0 42 19
60 11 trace
0 73 trace
NO2
18O2 (1 atm)DABCO
MeCN, rt, 8 h
18O
70%, 90% incorporation of 18O
R'
RNO
O
R'
RODABCO
CH3CN, 0 °C, 30 h73%
RN
R'
OO
RN
R'
OO base acid
R
N
R'
OHHO
R
N
R'
OHHO
OH
H
R R'O
Nef Reaction
H2O
N16O2 MeCN-H218Ort, 20 h
16O
71%
DABCO
N18O2
DABCO
MeCN, rt, 20 h
16O
74%
R'
RNO
O
R'
RODABCO
CH3CN, 0 °C, 30 h73%
RN
R'
OO
RN
R'
OO base acid
R
N
R'
OHHO
R
N
R'
OHHO
OH
H
R R'O
Nef Reaction
H2O
R1 N
R2O
O
NN
R1 N
R2O
ONR3
HNR3
R1 O
R2R1 N
R2
O
OO2
SET mechanism
Chem. Eur. J. ASAP.
R1 R2
NO2 base
R1 R2
NO O
O O
R1 R2
NO O
R1 R2
NO O
O O O O
NO O
R2R1 O O
NO O
R2R1 O
ONO2R1 R2
OOR1 R2
NO O
R1OOR2
R1 R2
NO O
NO2
R1 R2
O2
SET
Chem. Eur. J. ASAP.
H2O2 aq.NaOH aq.
MeOH, -45 oC
MeOH-Et2O, rt
NH4Cl aq.Zn
2 steps 74%PGE1 methyl ester
OH
OCO2Me
OH
OCO2Me
O
HO OH
OCO2Me
1) E. J. Corey et al., J. Org. Chem., 38, 3187 (1973).
1)
OH
O2NCO2Me
OH
OCO2MeDABCO
MeCN0 °C, 30 h
PGA1 methyl ester73%
H2O2 aq.NaOH aq.
MeOH, -45 oC
MeOH-Et2O, rt
NH4Cl aq.Zn
2 steps 74% PGE1 methyl esterOH
OCO2Me
O HO OH
OCO2Me
1) E. J. Corey et al., J. Org. Chem., 38, 3187 (1973).
1)
10 mol% p-nitrophenol
MeCN, rt
(MeO)2PO O
iPr2NEt
0 oC
LiCl, iPr2NEt
THF, rt2 steps 87%
NH
PhOTMS
Ph10 mol%
H
OH
O
O
O2NCO2Me
HO
O2N CO2Me
dr = 76:17:7
Al2O3
(ClCH2)2, 60 oC-20 oC, 8 h
BCl2
68%
Y. Hayashi, S. Umemiya, Angew. Chem. Int. Ed., 2013, 52, 3450.3 pot, Total yield 14%
3 “One-pot” synthesis of PGE1 methyl ester
2013, July
Angew. Chem. Int. Ed., 2013, 52, 3450.
Summary
O CO2Et
AcHNNH2
(-)-oseltamivir Prostaglandin E1 (PGE1)
HO OH
OCO2H
ABT-341 (Abbott laboratory)
F
F F NH2
NN N
N
CF3
O
One catalyst can change the synthesis.
NH
OTMS
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