A Practical Synthesis of (-)-Oseltamivirccc.chem.pitt.edu/wipf/Current Literature/Filip_1.pdf · A Practical Synthesis of (-)-Oseltamivir NabuhiroSatoh, Takahiro Akiba, Satoshi Yokoshima,

A Practical Synthesis of (-)-Oseltamivir

Nabuhiro Satoh, Takahiro Akiba, Satoshi Yokoshima, Thoru Fukuyama

Current literature

July, 28th 2007

Filip Petronijevic

Angew. Chem. Int. Ed. 2007, 46, 5734.

Filip Petronijevic @ Wipf Group 1 7/30/2007

Against Influenza

1 zanamivir (Relenza)

2 oseltamivir phosphate (Tamiflu)

3 shikimic acid

4 quinic acid

• The avian H5N1 influenza shows a lethality rate of over 50%

• Three types of influenza viruses (A, B and C) have different proteins

• Inhibitors of the M2 protein (amantadine and rimantadine) show side effects

• Zanamivir causes respiratory problems in some cases

• Oseltamivir is a prodrug and acts on NA


The First Generation Approach to Tamiflu

Angew. Chem. Int. Ed. 2006, 45, 7330.

“The dependence on using azide chemistry to convert epoxide 6 into oseltamivir

phosphate was considered a weakness in the first-generation manufacturing process”


The Second Generation Approach to Tamiflu

Angew. Chem. Int. Ed. 2006, 45, 7330.

J. Org. Chem. 2001, 66, 2044.

The Third Generation Approach to Tamiflu

• several steps require high dillution

• low yield (20%) of the enzymatic

resolution step

• “… it still uses sodium azide.. “


Corey’s Approach: The approach features a highly enantioselective and high-yielding

cycloaddition promoted by a catalytic amount of oxazaborolidine

J. Amer. Chem. Soc. 2006, 128, 6310.Filip Petronijevic @ Wipf Group 5 7/30/2007

N

O

NO2

Me3SiN3

Y(OiPr)3 (2 mol %)

catalyst 2 (4 mol %)

TMSN3 (1.5 equiv)

EtCN

96% (91% ee)

N3

HN

O

NO2

NO2

NO2

N3

NHBoc

1. Boc2O, DMAP MeCN, rt, 3h

2. 4 M NaOH, rt, 2h 98% (two steps)

1. Ph3P, MeCN, 50 °C, 3h then H2O, 40 °C, 2h

2. Boc2O, Et3N, CH2Cl2 rt, 2h 90% (two steps)

NHBoc

NHBoc

NHBoc

NHBoc

O SeO2 (1 equiv) DMP (1.5 equiv) dioxane 80 °C, 12h

NHBoc

NHBoc

O

NC

1. Ni(COD)2 (10 mol %) COD (10 mol %) TMSCN, THF 60 °C, 60h

2. NBS, THF Et3N, 4 °C, 40 min

1. LiAlH(OtBu)3, THF

4 °C, 30 min (2.1 dr)

2. DEAD, Ph3P, THF

3. 3-pentanol, BF3.OEt2

30% (three steps)

NHBoc

NHBocNC

O

1. TFA, CH2Cl2, 4 °C to rt, 3h2. Boc2O, Et3N, CH2Cl2, 4 °C3. Ac2O, DMAP, pyr, rt, 1h

4. 4.2 M HCl-EtOH, 60 °C, 4h then H2O, 4 °C, 3h5. H3PO4, EtOH, cryst.

NHAc

NH3+H2PO4

-EtO2C

O

Shibasaki’s First Approach

J. Amer. Chem. Soc. 2006, 128, 6312.

EtO2C NH3+H2PO4

-

NHAc

O

NR

1R

2R

TMSN3

O

O

PPhPh

OHO

HO F

F

2


N3

NHBoc 1. I2, K2CO3

2. DBU85% (two steps)

NHO

O

N3

1. Boc2O, Et3N, 99%

2. AcSH, 2,6-lutidine 83%

NBocO

O

NHAc

O NHBoc

NHAc

1. Cs2CO3 nBuOH, 86%

2. DMP, 90%

(EtO)2P(O)CN (1 eqiv)

LiCN (1.25 eqiv) (30:1 dr)

NHAc

NC

(EtO)2PONHBoc

O

OH

NHAc

NHBocNC

1. toluene 140 °C

2. NH4Cl (aq)

Ph3P, DEADp-NO2-C6H4CO2H

1M LiOH (aq) 80%

OH

NHAc

NHBocNC

Ph3PDEAD

66% NC

NAc

NHBoc

3-pentanol

BF3.OEt2

56%

NHAc

NHBocNC

O

1. HCl, EtOH NaOH (aq) 60%

2. H3PO4, cryst

NHAc

NH3+H2PO4

-EtO2C

O

Shibasaki’s Second Approach

Org. Lett. 2007, 9(2), 259.


OTMS

Cl

Cl

O

O

1. THF, rt (endo:exo=2:1)

CON3

CON3

2. TMSN3 DMAP

OH

55%

tBuOH, reflux

ONH

O

NHBoc

1. LiOH2. Ac2O, Et3N

OH

NHAc

NHBoc

(iPrCO)2O

DMSO

53% (4 steps)

O

NHAc

NHBoc

NHAc

NH3+H2PO4

-EtO2C

O

Shibasaki’s Third Synthesis

Tet. Lett. 2007, 48, 1403.


CHO

NHBoc

O

NHBoc

O

NPMB Z

TBDPSO

HN

BocN

OCbz

OTBDPS

BocHN

MOMO

NHCbz

Tamiflu

O

1. OsO4, NMO, acetone/H2O

2. Pd(OH)2, H2, MeOH, 35 °C

3. CbzCl, NaHCO3, H2O/EtOAc

4. TBDPSCl, imid., DCM

5. (COCl)2, DMSO, Et3N, -78 °C

6. Ph3PCH3Br, nBuLi, THF

BiBr3, MeCN rt, 89%

HO

OTBDPSHN

NHBoc

CbzOTBDPS

HN

NHBoc

Cbz

1. Swern oxidation

2. vinyl MgBr, ZnBr2

HO

1. MOMCl DIPEA CH2Cl2, rt

2. Grubbs II (10 mol %) CH2Cl2, rt

Cong and Yao’s Approach: The synthesis is based on a ring-closing

metathesis reaction, catalyzed by second-generation Ru carbene catalyst

J. Org. Chem. 2006, 71, 5365.

J. Org. Chem. 2004, 69, 5314.


Fukuyama’s Synthesis: Retrosynthetic Analysis

Angew. Chem. Int. Ed. 2007, 46, 5734.


N

CbzCl NaBH4

MeOH-50 °C to -35 °C 1h

N

Cbz

NH2

+Cl-

NMe

MeMeBn

O

(10 mol %)

acroleinMeCN-H2O rt, 12h

NCbz

CHO

NaClO2 NaH2PO4

.2H2O

2-methyl-2-butene

tBuOH-H2O

0 °C to rt, 1h

NCbz

CO2H

Br2 NaHCO3 (aq)

CH2Cl2, rt

26% (4 steps)

N

O

O

Br

Cbz H2, Pd/C Boc2O

EtOH-THF rt, 2h 92%

N

O

O

Br

Boc RuO2.nH2O

NaIO4

ClCH2CH2Cl

H2O

80 °C, 1.5h

86%

N

O

O

Br

Boc

O

NH3

tBuOH

THF, 0 °C

95%

NBr

Boc

O

OH CONH2

MsCl Et3N

CH2Cl2 rt, 1h

NBr

Boc

O

OMs CONH2

Fukuyama’s Synthesis: The Asymmetric Diels-Alder Reaction in Action

Angew. Chem. Int. Ed. 2007, 46, 5734.


NBr

Boc

O

OMs CONH2

allyl alcohol PhI(OAc)2 M.S. (4A)

toluene 60 °C, 10h 88%

NBr

Boc

O

OMs NHAlloc

NaOEt

EtOH 0 °C 87%

BocN

CO2Et

NHAlloc

BF3.OEt2

3-pentanol

-20 °C

62%

CO2Et

NHAlloc

O

BocHN

CO2Et

NHAlloc

O

AcHN

1. TFA CH2Cl2 0 °C to rt

2. Ac2O pyridine 88% (2 steps)

Pd/C, Ph3P1,3-dimethyl-barbituric acid

EtOHreflux, 40 min 76%

CO2Et

NH3+H2PO4

-

O

AcHN

Fukuyama’s synthesis: The End

Angew. Chem. Int. Ed. 2007, 46, 5734.


Conclusions

• inexpensive and commonly used reagents are employed

• the overall yield of lactone from benzyl chloroformate is rather low (26%)

this intermediate can be obtained easily with no tedious purification

• the other reactions proceed in high yields

• oseltamivir phosphate is obtained in 5.6% yield from benzyl chloroformate

by using an asymmetric DA reaction and a Hoffman rearrangement as key

transformations

• this synthesis uses an easily available starting material compared to the

current industrial Roche synthesis in which shikimic acid is employed as

precursor

• this route is has great potential for tamiflu analogues syntheses


Documents

A Practical Synthesis of (-)-Oseltamivirccc.chem.pitt.edu/wipf/Current Literature/Filip_1.pdf · A Practical Synthesis of (-)-Oseltamivir NabuhiroSatoh, Takahiro Akiba, Satoshi Yokoshima,