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