The First Stereoselective Total Synthesis of Quinine

Gilbert Stork, Deqiang Niu, A. Fujimoto, Emil R. Koft, James M. Balkovec, James R. Tata and Gregory R. Dake

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

OMe N

OH H N 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 OMe N

OH H N • 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 a stereoselective approach . However, only 3 of the 4 stereocenters Retrosynthesis

MeO

OMe OMe N N N

OH H X N N

classic “Rabe” N H disconnection Retrosynthesis

OMe OMe N N

OH H N N

OMe OMe NH N H OR OR N N H OMe OMe

N N OR OR N N Retrosynthesis

OMe OMe O N3 HO N3 OR OR N N

OMe RO

+ Me N3 O N Formal Total Synthesis

O 1. Et2NH/AlMe3 LDA OTBS O 2. TBS-Cl/Imidazole/DMF Et N O 2 ICH2CH2OTBDPS

(PPTS) TBDPSO O DIBAL-H OTBS Et N SO3 H N 2 Ph3P CHOMe O O TBDPSO Mechanism of Wittig

TBDPSO TBDPSO TBDPSO DIBAl-H HO H O O O O O

TBDPSO TBDPSO

Ph3P CHOMe O OH O OH H Ph3P Ph3P C OMe OMe

TBDPSO

O PPh3 OH MeO Formal Total Synthesis

TBDPSO TBDPSO HCl Ph3P/DEAD

(PhO)2P(O)N3 THF/CH2Cl2 OH N3 MeO MeO

TBDPSO

OHC N3 Formal Total Synthesis

OTBDPS OMe TBDPSO LDA Me THF OHC N3 DMSO, (ClCO)2

N OH N3 NaHCO3 NEt3 MeO

N OTBDPS OTBDPS

Ph3P O N 3 THF N MeO MeO

N N Staudinger/Aza-Wittig Mechanism

OTBDPS OTBDPS

O N N O N MeO N N PPh3 MeO N PPh3 N N

OTBDPS OTBDPS OTBDPS

O N N MeO Ph3P O N O N N PPh3 PPh MeO MeO 3 N N N Staudinger/Aza-Wittig Mechanism

OTBDPS OTBDPS

N N O O O PPh MeO PPh3 MeO P 3 Ph3

N N

OTBDPS

N MeO

N Formal Total Synthesis

OTBDPS OMe TBDPSO LDA Me THF OHC N3 DMSO, (ClCO)2

N OH N3 NaHCO3 NEt3 MeO

N OTBDPS OTBDPS

Ph3P O N3 N MeO THF MeO

N N Formal Total Synthesis

H3B H Ar OTBDPS N OTBDPS OTBDPS

NaBH4 N MeOH/THF MeO N H H MeO N N Formal Total Synthesis

OTBDPS OH

MsCl/Py N H H N MeO HF/CH3CN H H CH Cl MeO 2 2

N N

OMs

OMe OMe N N N 1. NaH/DMSO H H MeO OH 2. O2 H N N N Formal Total Synthesis

OMe OMe 1. NaH/DMSO N N 2. O2 OH H N N

H N

H Ar

Gutzwiller, J.; Uskoković, M.R. J. Am. Chem. Soc. 1978, 100, 576 Stork’s synthesis of quinine

OMe OMe N + Me O OH O H N N

• Unique retrosynthetic analysis provided first stereoselective synthesis of quinine • Completed in 19 steps • The majority of steps were high yielding (70- 95%)