The First Stereoselective TotalSynthesis of Quinine

Gilbert Stork, Deqiang Niu, A. Fujimoto, EmilR. Koft, James M. Balkovec, James R. Tata

and Gregory R. Dake

J. Am. Chem. Soc. 2001, 123, 3239 - 3242

N

OMeN

HOH

Presented by Jennifer Eddy

Gilbert Stork

• Born in Brussels, Belgium on Dec. 31, 1921• 1939: Moved to U.S.• 1945: Ph.D. Univ. of Wisconsin

Advisor: S.M. McElvain• 1945-1946: Senior Research Chemist, Lakeside Laboratories• 1946- 1948: Instructor, Harvard University• 1948- 1953: Associate Professor, Harvard University• 1953-1955: Associate Professor, Columbia University• 1955- 1993: Professor, Columbia University• 1993- Present: Professor Emeritus, Columbia University

Previous work

• 1907: The correct connectivity is “unraveled” by Rabe• 1918: Rabe and Kindler synthesize quinine from

quinotoxine• 1944: Woodward and Doering synthesize quinotoxine• 1978: Uskoković, Gutzwiller and collaborators at

Hoffmann- La Roche synthesize quinine using astereoselective approach However, only 3 of the 4 stereocenters

N

OMeN

HOH

Retrosynthesis

N

OMeN

N

OMeN

HOH

N

MeO

NH

X

classic “Rabe”disconnection

Retrosynthesis

N

OMeN

N

OMeNH

ORN

OMe

NH

HOR

N

OMeN

HOH

N

OMe

NOR

N

OMeN

OR

Retrosynthesis

N

OMeN3

OR

O

N

OMeN3

OR

HO

N

OMe

Me + N3

RO

O

Formal Total Synthesis

OO1. Et2NH/AlMe3

2. TBS-Cl/Imidazole/DMF Et2N OTBSO

LDAICH2CH2OTBDPS

O

TBDPSO

O

DIBAL-H

Ph3P CHOMeEt2NOTBS

O

TBDPSO

(PPTS)

SO3 NH

Mechanism of Wittig

O

TBDPSO

O

DIBAl-H

O

TBDPSO

HO O

TBDPSO

OH

Ph3P CHOMe

TBDPSO

OHPh3P C

H

OMe

O

TBDPSO

OHOPh3P OMe

TBDPSO

OHMeO

PPh3O

Formal Total Synthesis

TBDPSO

OHMeO

Ph3P/DEAD(PhO)2P(O)N3

TBDPSO

N3MeO

HCl

THF/CH2Cl2

TBDPSO

N3OHC

Formal Total Synthesis

N

OMe

MeLDATHF

TBDPSO

N3OHC

NaHCO3

N

MeOOH N3

OTBDPS

DMSO, (ClCO)2

NEt3

N

MeON3

OTBDPS

OPh3P

THF

N

MeO

OTBDPS

N

Staudinger/Aza-WittigMechanism

N

MeON

OTBDPS

O N NPPh3

N

MeON

OTBDPS

O N N PPh3

N

MeON

OTBDPS

O NPh3P N

N

MeON

OTBDPS

O PPh3

N

MeON

OTBDPS

O PPh3

Staudinger/Aza-WittigMechanism

N

MeO

OTBDPS

NPPh3

O

N

MeO

OTBDPS

NO PPh3

PPh3O

N

MeO

OTBDPS

N

Formal Total Synthesis

N

OMe

MeLDATHF

TBDPSO

N3OHC

NaHCO3

N

MeOOH N3

OTBDPS

DMSO, (ClCO)2

NEt3

N

MeON3

OTBDPS

OPh3P

THF

N

MeO

OTBDPS

N

Formal Total Synthesis

N

MeO

OTBDPS

NNaBH4

MeOH/THF

N

MeO

OTBDPS

NHH

NOTBDPSAr

HH3B

Formal Total Synthesis

N

MeO

OTBDPS

NHH HF/CH3CN

N

MeO

OH

NHH

MsCl/Py

CH2Cl2

N

MeO

OMs

NHH

N

OMeN

1. NaH/DMSO

2. O2 N

OMeN

HOH

Formal Total Synthesis

N

OMeN

1. NaH/DMSO

2. O2

N

OMeN

HOH

Gutzwiller, J.; Uskoković, M.R. J. Am. Chem. Soc. 1978, 100, 576

NH

HAr

Stork’s synthesis of quinine

• Unique retrosynthetic analysis provided firststereoselective synthesis of quinine

• Completed in 19 steps• The majority of steps were high yielding (70-

95%)

OO+

N

OMeN

HOH

N

OMe

Me