A Review of Three Total Syntheses of Quinine and Quinidine

A Review of Three Total Syntheses of
Quinine and Quinidine
Bryce A. Harrison
Organic Chemistry Supergroup Meeting
Princeton University
May 19, 2004

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Quinine and Quinidine
3
OMe
OMe
2
4
7
5
H
N
OH
H
8
1
6
9
N
OH
H
N
H
N
Quinine
Quinidine

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Quinine and Quinidine
3
OMe
OMe
2
4
7
5
H
N
OH
H
8
1
6
9
N
OH
H
N
H
N
Quinine
Quinidine
Biology1
Availability
• Antimalarial
• U.S. imported 68 tons of quinine in 19992
• Isolated from bark of trees of Cinchona spp.
• Quinine (anhydrous, 99%): 50g for $129 Acros3
• Native of Peru and Bolivia
• Quinidine (anydrous, 99%): 5g for $34 Acros3
• Cultivated mainly in Java
• Cultivated bark contains 7-10% alkaloids,
70% of which is quinine
1. The Merck Index, 12th ed.; Budavari, S., Ed.; Merck: Whitehouse Station, NJ, 1996; pp 383-384.
2. U.S. Department of Commerce, U.S. imports of organic chemicals for consumption; Chapter 29, subheading 293921.
3. Acros Organics; Catalog of Organics and Fine Chemicals, 2004-2005, pp 1837-1838.

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Quinine and Quinidine
3
OMe
OMe
2
4
7
5
H
N
OH
H
8
1
6
9
N
OH
H
N
H
N
Quinine
Quinidine
Chemistry
Synthesis
• 4 stereocenters: C3, C4, C8, C9
• First partial synthesis reported by Rabe in 19183
• Quinuclidine substructure
• Partial synthesis by Prelog and Prostenik in 19434
• Quinoline substructure
• First formal total synthesis by Woodward and Doering in 19445
• Structure of quinine reported by German
• First stereoselective synthesis of quinidine by Uskokovic and
chemist paul Rabe in 1907.1
Gutzwiller in 19786
• Privileged ligand and catalyst for
• First stereoselective synthesis of quinine by Stork et. al. in 20017
asymmetric catalysis2
• Synthesis of quinine and quinidine by Jacobsen et. al. in 20048
1. Rabe, P.; Ackerman, E.; Schneider, W. Chem. Ber. 1907, 40, 3655. 2. Kacprzak, K.; Gawronski, J.. Synthesis 2001, 961-998. 3.
Rabe, P.; Kindler, K. Chem. Ber. 1918, 51, 466. 4. Prostenik, M.; Prelog, V. Helv. Chim. Acta 1943, 26, 1965. 5. Woodward, R.
B.; Doering, W. E. J. Am. Chem. Soc. 1944, 66, 849. 6. Gutzwiller, J; Uskokovic, M. R. J. Am. Chem. Soc. 1978, 100, 576-581.
7. Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec, J. M.; Tata, J. R., Dake, G. R. J. Am. Chem. Soc. 2001, 123, 3239-3242.
8. Raheem, I. T.; Goodman, S. N., Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 706-707.

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Uskokovic Approach
2. Addition to an ester
1. Pt catalyzed hydrogenation
H
OMe
H
H
N
OH
3. Intramolecular SN2
N
(the Rabe disconnection)
1. Uskokovic, M. R.; Henderson, T.; Reese, C.; Lee, H. L.; Grethe, G.; Gutzwiller, J. J. Am. Chem. Soc. 1978, 100, 571-576.
2. Gutzwiller, J; Uskokovic, M. R. J. Am. Chem. Soc. 1978, 100, 576-581.

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Preparation of the cis-Disubstituted Piperidine
1. Pd/C (10%), AcOH,
O
CO
benzene, reflux
2Me
O
i. MeOH
LDA, MeOCO2Me
2. H
ii. HCl, i-PrOH, 60 oC
2 (200 p.s.i.), Pd/C (10%)
THF, hexanes
BnNH2
HCl, EtOH, 60 oC
31%
N
88%
55%
N
N
Bn
CO
CO
2Me
1. NCS, Et
2Me
PtO
2O
2 (0.9%), H2 (70 atm),
CO2Me
2. TFA, 200-W Hg lamp
5% HCl (aq), 60 oC
recrystalization with
Cl
l-tartaric acid
3. BzCl, K2CO3 (aq), benzene
88%, 100% cis
N
N
77%
H
N
H
racemic
O
Ph
1. Gutzwiller, J; Uskokovic, M. R. U.S. Patent 3,663,554 1972.
2. Uskokovic, M. R.; Henderson, T.; Reese, C.; Lee, H. L.; Grethe, G.; Gutzwiller, J. J. Am. Chem. Soc. 1978, 100, 571-576.

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Problem #1
Provide a mechanism for the following transformation, including a 3-D structure that accounts for the selectivity of the chlorination.
CO2Me
CO2Me
1. NCS, Et2O
CO
Me
2Me
2. TFA, 200-W Hanovia Hg lamp
Cl
O
O
N
N
Me
H
77%
Cl
N
H
N
H Cl
CO2Me
CO2Me
Me
N
Cl
CO
CO
N
2Me
2Me
H2
TFA
CO2Me
H
hν
Me
Me
=
N
H
Me
N
N
CO2Me
H
H
N
Cl
H
1. Uskokovic, M. R.; Henderson, T.; Reese, C.; Lee, H. L.; Grethe, G.; Gutzwiller, J. J. Am. Chem. Soc. 1978, 100, 571-576.

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Fragment Coupling and Quinuclidine Synthesis
O
MeO
CO2Me
1. NaOH, MeOH, H
CO
N
Ph
2O
2Me
Cl
2. KOt-Bu, benzene, DMSO
N
3. CH2N2, MeOH
LDA, THF
O
N
80 %
N
78%
MeO
O
Ph
O
Ph
N
NH
OMe
OMe
1. DIBAL-H, toluene
.
AcOH, NaOAc, benzene, reflux
H
2. BF3 Et2O, AcOH, 50 oC
N
OAc
N
82%
79%, d.r. 1: 1.3
MeO
N
H
N
N
deoxyquinine
deoxyquinidine
1. Uskokovic, M. R.; Henderson, T.; Reese, C.; Lee, H. L.; Grethe, G.; Gutzwiller, J. J. Am. Chem. Soc. 1978, 100, 571-576.
2. Gutzwiller, J; Uskokovic, M. R. J. Am. Chem. Soc. 1978, 100, 576-581.

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Stereoselective Oxidations of Deoxyquinine and Deoxyquinidine
OMe
OMe
OMe
H
OMe
N
KOt-Bu, t-BuOH, DMSO, O2
H
OH
N
N
H
72%, 100% stereoselective
N
N
H
N
OH
H
N
H
N
1 : 1.3
quinine
quinidine
17 steps, 0.64% yield
17 steps, 0.84% yield
O O
OMe
OMe
OMe
H
N
H
H
base, O2
N
N
H
OH
H
N
N
N
1. Gutzwiller, J; Uskokovic, M. R. J. Am. Chem. Soc. 1978, 100, 576-581.

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Nonselective Epoxide Approach
O
O
O
N
Ph
N
Ph
N
Ph
O
NBS, CCl4, BzO2, reflux
NaBH
Br
4, MeOH
MeO
O
40% (2 steps), 4 stereoisomers
O
MeO
MeO
N
N
N
O
N
Ph
OMe
OMe
1. DIBAL-H, toluene, -78 oC
H
N
OH
2. toluene, EtOH, reflux
N
O
MeO
OH
N
H
46%, 1:1.8:1.4:1.4 d.r.
N
N
1 : 1.4 : 1.8 : 1.4
1. Gutzwiller, J; Uskokovic, M. R. J. Am. Chem. Soc. 1978, 100, 576-581.

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