Catalytic Asymmetric Total Syntheses of Quinine and Quinidine
Zhensheng DingJanuary 22 2004
Chinese New Year Day
1. Jacobsen, E., N. J. Am. Chem. Soc. 2004, ASAP
2. Stork, G.; Niu, D. J. Am. Chem. Soc. 2001, 123, 3239
3. Nicolaou, K., C. Classics in Total Synthesis II: More Targets,
Strategies, Methods, Wiley-VCH: Weinheim, Germany, 2003, Ch. 15
N
OMe
OH
N
Quinine
1
23
45
6
7
8
9N
OMe
N
Quinidine
1
23
45
6
7
89
OH
1
1 2
1
Pasteur’s Degradation Reaction of Quinine
N
OMe
OHH
NH2SO4
N
OMe
OHH
NH
H2ON
OMe
OH
HN
N
OMe
O
HN
quinine quinotoxine
3 4
5
Classics in Total Synthesis II, Wiley-VCH,Germany, 2003, Ch. 15
Louis Pasteur (1822 - 1895)
Chance favors only the prepared mind. —Louis Pasteur
5 6 7
8 1
Formal Synthesis of Quinine By Woodward and Doering
HNN
N
OMe
ON
MeOCO2Et
BzNO
OEtH
HN
OMe
OHH
Condensation
OH
CHO
AcN
H
H MeOAcN
MeOHN
MeOH
quinine quinotoxine
Rabe route
+
1 5 9 10
11121314
Woodward/Doering’ Retrosynthetic Analysis and Strategy
J. Am. Chem. Soc. 1945, 67, 860J. Am. Chem. Soc. 1944, 66, 849
14 15 16 16
171312
12
11
11
18 19 20
21 22
22 23 10
95
What we can learn from Woodward’s Synthesis
1. The formation, modification, and eventual cleavage of carbonframeworks in cyclic settings to generate acyclic stereochemicalelements
2. Rapid construction of the carbon framework in the targetmolecule
3. The application of nitrite ester cleavage protocol can preventepimerization, directly afford the requisite ester side chain, andmake it easy to make double bond
AcN
H
H MeOBzN
O
OEtH
H10 11
NOH
17N
vs. BzNO
OEtH
H10
The First Stereoselective Total Synthesis of Quinine By Stork
Gilbert Stork (Emeritus)Department of ChemistryColumbia UniversityBox 3118, Havemeyer HallNew York, NY 10027 (212) [email protected]
Stork’s Retrosynthetic Analysis and Strategy
J. Am. Chem. Soc. 2001, 123, 3239
N
OMe
OHH
N O
N
OMeN
N
OMe
NOR
N
OMeN
OR
N
OMeN3
OR
O
N
OMeN3
OR
HO
Alkylation N
OMe
N
OMe
Me
N
OMe
NOR
H
H
NHOR
N3O
RO
1: quinine 24: deoxyquinine
8
+
Reduction and imine formation
Nucleophilicaddition
Selective hydridedelivery
2526
27 28 29 30
1 6
31 32 33
343530
29 30 28 26
25241
What we can learn from Stork’s Synthesis
1. Conformational analysis shows that the two pseudo-chair formsof the synthetic precursor are of similar energy, and makes the C-8non-stereoselective.
2. Follow the words of wisdom by Robert Ireland: “All too oftenthe most convenient way to draw a molecule on paper belies themost efficient synthetic approach.” This helps to construct the C-8stereocenter.
3. Install C-9 stereocenter by oxygenation which utilize the stericbulk of the bridgehead nitrogen in the quinuclidine ring.
N
OMeHN8
N
OMe
HNvs. 8
N
OMeN
OMe
NOR
H
H
NHOR
8 8
Catalytic Asymmetric Synthesis of Quinine and Quinidine By Jacobsen
Eric N. JacobsenSheldon Emery Professor of Chemistry
Harvard UniversityDepartment of Chemistry, 12 Oxford StreetCambridge, MA 02138(617) 496-3690 (Assistant)
J. Am. Chem. Soc. 2004, ASAP
Yesterday Once More: N1-C8 DisconnectionJacobsen’s Retrosynthetic Analysis and Strategy
N
OMe
OH
N
N
OMePNO
NH
CO2Me
OCOPh
CNPONH
Ph
O O
PO
N
OMe
PN
H
H
M
NP
N
OMe
X
quinine
IntramolecularSN2
Suzuki coupling
Enantioselectiveconjugate addition
Sharplessdihydroxylation
+
8 1
1 21 20
5 469
J. Am. Chem. Soc. 2004, ASAP
Jacobsen’s Total Synthesis of Quinine
J. Am. Chem. Soc. 2004, ASAP
Jacobsen’s Total Synthesis of Quinine
J. Am. Chem. Soc. 2004, ASAP
N
OMe
N
OH
2
Jacobsen’s Total Synthesis of Quinidine
What we can learn from Jacobsen’s Synthesis
1. Application of recently developed (salen)Al-Catalyzed conjugateaddition of methyl cyanoacetate to construct C4 stereocenterefficiently.
2. C8 & C9 chiral center can be formed by Sharplessdihydroxylation with high dr.
3. Yes, disconnection of N1-C8 bond provides a way to asymmetrictotal synthesis of quinine
Date Group Step Yield Reality Key Step2001 Stork 16 7% Stereoselective C8 High Stereospecific reduction set C82004 Jacobsen 16 5% Catalytic,
AsymmetricC4, C8 and C9 High, Sharpless
dihydroxylation
Comparison of the Two Steroselective Total Synthesis of Quinine
Large-Scale Synthesis of VANOL
Park, O. S, Jang, B. S. Archives of Phar.Research, 1995, 18, 277
Method IV to intermediate 20
Ph
OHO
OHPh
OEtO
OH
PhPh
O
CO2EtPh
O
Br CO2Et
2) Addition to ketone
Hydrolysis
+ + Zn
1) Reformatsky reaction
+ BnMgCl28 40
41 42
43
Ph
OMeO
Br CO2Et PhH Ph
OEtO
OHMeO
+Zn, I2,
96%
44 45
Ph
OBr CO2Et
PhH, Et2O, 4hPh
OEtO
OH+Zn, I2 ,
worked41 42 28
Ph
OHO
OH
28
Successful examples:
Synthesis of 20 from b-hydroxyester
Can this condition be used for my compound?
Large-Scale Synthesis of VANOL
Future Work: Synthesis of VANOL and Resolution
OHOHPh
Ph
OHPh
OOPh
Ph PO
OH
5 3
190oCair, 32h
1) POCl3
2) H2O1) (-)-brucine2) resolution3) reduction
(+) and (-)VANOL
33
N
O
N
O
MeO
MeO
H
H
H
H(-)-brucine
Key point: monomer 5 must be pure for oxidative coupling
Bao, J.; Wulff, W. D. et al J. Am. Chem. Soc., 1996, 118, 3392
Large-Scale Synthesis of VANOL
Conclusions
1) A new synthetic approach of VANOL was studied. This new method provides a cheap,efficient way for large scale synthesis of VANOL ligand.
2) Conditions for Michael addition, hydrolysis and Friedel-Crafts reaction wereoptimized.
3) Michael addition was scaled up successfully in high yields. More work is needed toscale up Friedel-Crafts reactions.
4) Dehydrogenation reaction was studied and optimization of the conditions is inprogress.
5) Some new methods have been briefly discussed.