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The Quest for Quinine
N
N
OMe
H
OH
Literature SeminarMarch 7, 2005
3
4
8
9
References:
Kaufman, T.; Ruvedo, E. Angew. Chem. Int. Ed. 2005, 44, 854-885.Nicolaou, K. Synder, S. Classics in Total Synthesis II; Wiley-VCH: Germany, 2003.Raheem, I.; Goodman, S.; Jacobsen, E. J. Am. Chem. Soc. 2004, 126, 706-707.Igarashi, J.; Katsukawa, M.; Wang, Y.; Acharya, H.; Kobayashi, Y. Tetrahedron Lett. 2004, 45, 3783-3786.
N
N
OMe
H
OH
Quinine: The Facts
· Properties and Uses:
· Anti-malarial · Analgesic · Anaesthetic · Antibacterial · Anti-microbial · Anti-parasitic · Antiseptic · Astringent · Febrifuge · Muscle-relaxant · Bactericide · Contraceptive · Insecticide · Insect-repellant · Stomachic · Tonic
1g/$3.61
Synthetic Uses:
· Chiral Ligand · Chiral Auxiliaries · Phase Transfer Catalysis · Asymmetric Catalyst · Chiral Resolving Agent · Enantioselective Transformations · Sharpless Asymmetric Dihydroxylation · Diels-Alder · Hydrocyanations · [2+2] Cycloadditions · Michael Additions · SmI2 Mediated Reductions · Dehydrohalogenations
· Isolated from the bark of cinchona trees
· A cinchona alkaloid
Cinchona Tree Bark used Treat Fevers by Natives
A really really long time ago. . .
1640: Cinchona Bark introduced to European Medicine: Countess of Chinchon
cured from Malaria.
1820: Authentic Sample of Quinine Isolated:Pelletier and Caventou
1681: Universally acceptedas an Antimalarial Substance
1854: Molecular Formula of Quinine Determined:Strecker
Quinine: The History
Quinine: Key Points in Synthetic History
1st attempted Synthesis: Perkin
Correct Molecular Connectivities Reported: Rabe
1908
Rabe's Reconstruction of Quinine from Quinotoxine
1918
Woodward/Doering Formal Total Synthesis
1944
Hoffmann-La Roche Total Synthesis, Gates Total Synthesis
1970
Stork Total Synthesis
2001
Jacobsen and Kobayashi Total Syntheses
20041856
Taylor Total Synthesis
1972
Quinine: Key Points in Synthetic History
1912: X-Ray Crystallography
1903: Chromatography
1945: NMR
1897: Mass Spectrometry
N
N
R
Me
H2N NH
Me
Mauvine
First Attempted Synthesis of Quinine
N
N
OMe
H
OH
C20H24N2O2
HN
Me HN
Me
+
C10H13N C10H13N
+ 3O—[H2O]
1856: Perkin's "mathematical approach"
Quinine: Determination of Structure
N
N
OMe
H
OH
HN
N
OMe
O
Acid
Quinotoxine
N
MeO
Me
H2O, !
6-MethoxyepidineN
MeO
KOH
fusion
6-Methoxyquinoline
N
N
OMe
O
[O]
Quinone
N
N
OMe
OAc
Acylation
N
N
OMe
H
OH Br2
Br
Br
N
HO2C
N
OMe
H
OH
[O]
Quintenine
N
OHC
N
OMe
H
OH
O3
HO2CHN
Dilute Acid
[O]
Meroquinene
1908: Rabe suggests correctconnectivity of quinine
N
MeO
CO2H
[O] (HNO3, H2CrO4)
Quinic Acid
Rabe's Partial Synthesis of Quinine
N
N
OMe
H
OH
Reconstruction of Quinine from Quinotoxine
H2SO4
Quinotoxine
1853: Louis Pasteur observed quinineforms quinotoxine in aqueous sulfuric acid HN
N
OMe
O
1918: Paul Rabe effects partial synthesis from quinotoxine
HN
N
OMe
O
NaOBrN
N
OMe
O
Br
NaOEt, EtOH N
N
OMe
O
Br
N
N
OMe
O
HSolvent
N
N
OMe
OH
Aluminumpowder
N
N
OMe
H
OH
Determination of Stereochemistry: C8 Center1920s:Rabe solves C8 center
N
N
R
H
OH
N
N
R
H
OHH
Quinine: R=OMeCinchonidine: R=H
Chinchonine, R=HQuinidine, R=OMe
N
N
R
H
O
H
no cyclizationconclusion C8=S
8
8
Determination of Stereochemistry: C9 Center1932: C9 center solved
N
N
OMe
H
OH
N
N
OMe
OH
H
Weaker Base Stronger Base
Quinine: epi-Quinine
N
R
O
HR
Ar
H
R
H
Steric hinderence
N
R
O
HR
H
H
R
Ar
H H
Prelog proposed:
Determination of Stereochemistry: C3 and C4 Centers
NH
MeN
N
H
H
OH
OH 1. HBr2. Zn/AcOH
NH
Me
Me
Von-Braundegradation
PBr5
BrBr
Me
Me
CO2EtEtO2C
NaOHMe
Me
CO2H
1. Ag2. Br23. Raney Ni
Me
Me
Me Me
Me
MeO
OH
Me
Me
not optically active
(—)-2-methylbutanoic acid
CatalyticHydrogenation
compared with compound derivedfrom acid with know configuration
1944: Vladimir Prelog established cis configuration of C3 and C4 centers
Woodward/Doering Formal Total Synthesis
N
N
OMe
H
OH
A Synthesis of Quinotoxine
Quinotoxine
1944:Woodward and Doering synthesize quinotoxine
HN
N
OMe
O
RabeRoute
CondensationN
MeO
CO2Et
BzN
O
OEtH
H
+
AcN
H
HMe
O
AcN
H
HN
O
OEt
Me
OH
BzN
O
OEtH
H
Synthesis of Ethyl Quinate
NH2
OMe
EtO
O O
H2SO4N
OMe
Me
OH
1. PCl5/POCl3
2. Al/AcOH
68% 3 stepsN
OMe
Me
PhCHOZnCl2
N
OMe
Ph
1. CaMnO4
2. EtOH/H+
80% over 3 stepsN
OMe
CO2Et
Rabe. Chem. Ber. 1931, 64, 2487.
O
H
OH
EtO
OEt
NH2
N
H
OH
OEtOEt
H2SO4
NOH
CH2O, MeOHpiperidine
NOH
N
100% 64%
62%
NO
NaOMeMeOH 220 °C[H]
NOH
Me
64%
AcNOH
Me
1. PtO2, H2, HOAc2. Ac2O, py
95%
AcN
H
HMe
OAcN
H
HMe
O
1. Raney Ni, H2
(3000 psi), 150 °C
2. CrO3, HOAc
+
20%
Woodward/Doering Formal Total SynthesisA Synthesis of Quinotoxine
1944:Woodward and Doering synthesize quinotoxine
All carbon atoms installed in just 3 steps
Racemic Mixture ofcis-fused
Woodward/Doering Formal Total SynthesisA Synthesis of Quinotoxine
1944:Woodward and Doering synthesize quinotoxine
AcN
H
HMe
O
NaOEtEtOH
EtON
OAcN
H
HMe
O
EtON
O
AcN
H
HMe
ON OEt
O
AcN
H
HMe
ON
O
EtO
AcN
H
HMe
O
OEt
N
O
AcN
H
HN
O
OEt
Me
OH
Woodward/Doering Formal Total SynthesisA Synthesis of Quinotoxine
1944:Woodward and Doering synthesize quinotoxine
AcN
H
HN
O
OEt
Me
OH
NAc
EtO O
N
Me
HO
PtO2, H2
HOAcN
Ac
EtO O
NH2
Me
NBz
EtO O
N
MeO
CO2Et
1. NaOEt
2. 6 N HCl, !
Quinotoxine
HN
N
OMe
O
The First Total Synthesis Complete?
N
N
OMe
H
OH
Quinotoxine
HN
N
OMe
O
Rabe
Route
N
MeO
CO2Et
BzN
O
OEtH
H
+
Woodward and Doering did not actually carry out these steps.
N
N
OMe
O
H Solvent N
N
OMe
OH
Aluminumpowder
N
N
OMe
H
OH
?
There is a current debate about the last step in Rabe's synthesis.
· Although successful, synthesis lacked stereocontrol.
Hoffmann-La Roche Total Synthesis
N
N
OMe
H
OH
N
N
OMe
N
MeO
Me
BzN
1970: Milan Uskokovic and his group at the Hoffmann-La Roche Pharmaceutical Company developed an improved route.
SET anddisproportionation
HN
N
OMe
RO
Coupling
CO2MeH
H
+
Use of steric bulk of the brigehead Nitrogen to govern oxygen addition
Hoffmann-La Roche Total Synthesis
BzN
1970: Milan Uskokovic and his group at the Hoffmann-La Roche Pharmaceutical Company developed an improved route.
CO2MeH
H
NBz
O
H
NaN3, PPA, 120 °C, 30 min
63%
NBz
NH
O
H
H2, Rh/Al2O3
98%
NBz
NH
O
H
H
N2O4
100%
NBz
N
O
H
H
N
O
neat125 °C, 1h
NBz
O
O
H
H
N
N
—N2
Schmidt
Hydrogenation set by existingstereocenter
98%
CH2N2
Hoffmann-La Roche Total SynthesisSchmidt Rearrangement
R R
O HN3, H+
R NH
O
R+ N2
R1 R
OH
H+
R1 R
O HN3
R1 R
H2ON
NN
R1
RN
NNR N R1
OH2
HO
N
R
R1
O
HN
R
R1
Hoffmann-La Roche Total Synthesis
N
N
OMe
H
OH
N
N
OMe
N
MeO
Me
BzN
CO2MeH
H
+O
Bz
LDA, THF
78%
1. DIBAL-H—78 °C
2. AcOHBF3OEt2
50 °C, 18 h
82%
HN
N
OMe
AcO
Cat. AcOHNaOAcC6H6, !, 14 h
HN
N
OMe
H
N
N
OMe
Deoxyquinine
t-BuOK, O2
DMSO/t-BuOH4:1
N
N
OMe
O O
N
N
OMe
SET
O O
N
N
OMe
HO O
72%32% of (-)-1
C8 Center not Set
Hoffman-La Roche Total Synthesis
N
N
OMe
H
OH
N
N
OMe
COPh
1970: Uskokovic amino epoxide ring closing approach
ONBS N
N
OMe
COPh
O
Br
NaBH4
HN
N
OMe
O
40%
Mixture of 4 epoxides
Toluene, EtOH
Reflux
Quinine: 13%Quinidine: 24%epi-Quinie: 18%epi-Quinidine: 18%
Gates Partial Synthesis
N
N
OMe
H
OH
N
N
OMe
N
MeO
CHO
AcN
H
H
+
Ac
N
N
OMe
Deoxyquinine
t-BuOK, O2
DMSO/t-BuOH4:1
SET
1970: Gates uses Wittig and Uskokovic Hydroxylation
PPh3
Acid or Base
Deprotectionfollowed by
conjugate addition26%
Wittig
BzN
CO2MeH
H
Taylor Partial Synthesis
N
N
OMe
H
OH
N
N
OMe
N
MeO
CHO
AcN
H
H
+
Ac
N
N
OMe
Deoxyquinine
t-BuOK, O2
DMSO/t-BuOH4:1
SET
1972: Taylor uses Wittig and Uskokovic Hydroxylation
PPh3
Acid or Base
Deprotectionfollowed by
conjugate addition26%
N
MeO
Cl
+BzN
H
H
OH
H2C=PPh3
N
MeO
HC PPh3
+
Wittig
Wittig
BzN
CO2MeH
H
Remember: C8 Center is not set withthese conditions
Stork's Retrosynthetic Analysis of Quinine
N
N
OMe
H
OH
Hoffmann-La RocheOxygenation N
N
OMe
NH
N
OMe
OR
N
OMe
HN
H
OR
N
OMe
NOR
N
N
OMe
OR
N3
N
OMe
OR
N3
N
OMe
OR
HOMe
N
OMe
O
N3
RO
+
Nucleophilic Addition
Reduction and imine formation
Selective HydrideDelivery
Avoids previous C8-N disconnection
Synthesis of Starting Azido Aldehyde
O
N3
RO
OO
1. Et2NH, AlMe3
DCM, 0 °C
2. TBSCl, imid, DMF79%
Et2N
O
OTBS
LDA, —78 °CTHF; then
IOTBDPS
Et2N
O
OTBS
OTBDPS
cat. PPTSEtOH, 25 °C, 12 h
then xylenes!, 12h
OO
TBDPSO
MeO
OH
TBDPSO
1. DIBAL-H, THF —78 °C, 5 h
2. THF, 0 °CPh3P OMe
75%
1. Ph3P, DEAD (PhO)2P(O)N3
2. 5 N HCl, THF/ DCM (1:4)
74%
93%
Stork's Total Synthesis of Quinine
Stork's Total Synthesis of Quinine
O
N3
RO
Me
N
OMe
LDA, THF
—78 °C
N
OMe
+THF
—78 °C70%
N3
N
OMe
OTBDPS
HO
DMSO(COCl)2Et3N
85%
N3
N
OMe
OTBDPS
OPh3P, THF, !
81%
N
N
OMe
OTBDPS
NH
N
OMe
OTBDPS
H NaBH4
MeOH/THF
91%
1. HF, MeCN2. MsCl, py, DCM
NH
N
OMe
OMs
HMeCN, !, 3 h
65%
N
N
OMe
deoxyquinine
N
N
OMe
H
OH
(—)-quinine
NaH, DMSO70 °C, 1 h
O2, 45 min
78% 14:1 ds
Jacobsen's Retrosynthetic Analysis of Quinine
N
N
OMe
OH
X
N
OMe
Suzuki Cross CouplingEnantioselective
Conjugate Addition
Intramolecular SN2
PN
N
OMe
H
H
NPMe
+NH
O
COPh
CN
CO2Me
PO
Raheem, I.; Goodman, S.; Jacobsen, E. J. Am. Chem. Soc. 2004, 126, 706-707.
OMe
NH2
O
O Me
1. MeOH, RT, 12 h
63%
NH
O
MeO
2. Dowtherm A, 250 °C 30 min
Ph3PBr2
MeCNMicrowave
170 °C, 15 min
86%
N
Br
MeO
Jacobsen's Total Synthesis of Quinine
PEtO
O
OEtNH
O
Ph
O
TBSO H
O
+n-BuLi, THF
—78 to 0 °C>50:1 E/Z
84%TBSO
O
NH
Ph
O
N
N
tBu
tBu
tBu
tBu
O
O
Al O
2
(salen)Al complex
methyl cyanoacetate5 mol% (salen)Al complext-BuOH, C6H12, RT
91%92% ee
TBSO
O
NH
Ph
O
CO2Me
CN
Raney Ni, H2
tol/MeOH (3:1)650psi, 80 °C, 12 h
89%
NH
O
CO2MeTBSO
cis=1:1.7
cis=3:1
1. LDA THF —78 °C
2. H2O/THF—78 °C
N
TBSO
CBz
1. LAH, THF2. CBzO, TEA, DCM3. TPAP, NMO, DCM4. KOtBu, THF, 0 °C
37% Overall
100% cis
Me P
Ph
Ph
Ph
Br
NCBz
BO O
1. TBAF, THF2. TPAP, NMO, DCM
3. CrCl2, LiI, THF
>20:1 E/Z
68% Overall
Jacobsen's Total Synthesis of Quinine
NCBz
BO O
N
OMe
+
NCBz
N
Br
MeOPCy2
OMeMeO
Pd(OAc)2, 2.5 mol% Ligand
K3PO4·H2O
THF, 16h, RT>20:1 E/Z, 89%
N
OMe
NCBz
O
ADmix-! CH3SO2NH2
tBuOH, H2O, 0 °C, >96:4 dr
Me C
OMe
OMe
OMe
2. Acetyl Bromide, DCM3. K2CO3, MeOH
1. PPTS(cat), DCM
N
OMe
NCBz
HOOH
Et2AlClThioanisole0 °C to RT
then Microwave, 200 °C, 20min
N
N
OMe
OH
68%
Standard Suzuki conditions unsuccessful:used Buchwald protocol
Kobayashi's Retrosynthetic Analysis of Quinine
N
N
OMe
OH
N
OMe
Intramolecular SN2
PN
N
OMe
NBz
O+
O
H
AcO
OH
POEt
O
OEt
Igarashi, J; Katsukawa, M.; Wang, Y.; Acharya, H.; Kobayashi, Y. Tet. Let. 2004, 45, 3783-3786.
MeO
NH
N
MeO
N
MeO
MeO
MeO
HO
N
MeO
X
1. H2SO4
2. POCl3
3. Zn, AcOH
72%
1. m-CPBA2. Ac2O
3. K2CO3
43%
SOCl2
X=Cl
X=P(=O)(OEt)2
H-P(=O)(OEt)2
Kobayashi's Total Synthesis of Quinine
AcO
OH
1. CH2(CO2Me)2
t-BuOK, Pd(PPh3)4
2. KI, DMF, 125 °C
70% OH
CO2Me
1. LAH
2. TBDPSCl
OH
OTBDPS
63%
1. Hg(OAc)2, 190 °C
OEt
2. NaBH4
3. t-BuCOCl, Et3N
OTBDPS
OPiv
66%
X
OPivTBDPSO
X
O3
n-PrOH—78 °Cthen, NaBH4
X = OHX = I
I2, PPh3
Imidazole
81%
88%
BnNH2
Dioxane98%
OPivTBDPSO
NR
R = BnR = CO2Et
ClCO2Et, tol
99%
1. NaOEt, EtOH
2. o-(NO2)C6H4SeCN PBu3, THF then 35% H2O2
77%
TBDPSO
NRR = CO2EtR = Bz
1. MeLi, 0 °C2. BzCl
61%
CHO
NBz
1. TBAF2. PCC
80%
+
N
OMe
POEt
O
OEt
PN
N
OMe
NaH, THF
82%
Grieco Procedure
Se CN
NO2
Bu P
Bu
Bu
Se
NO2
PBu3
OH
Se
NO2
O PBu3
Se
NO2
H2O2
Se
NO2
R
R
R
RO
H
RSe
NO2
HO
+
Grieco, Gilman, Nishizawa JOC, 1979, 41, 1485.
Kobayashi's Total Synthesis of Quinine
N
N
OMe
N
N
OMe
HO
OH
AD-mix-!
0 °C to RT
MeC(OMe)3
PPTS
DCM, TMSClK2CO3, MeOH
N
N
OMe
O
96%
BzBz
Bz
R = BzR = H
DIBAL-H, tol
N
N
OMe
OH
DMF, 160 °C
66%
N
N
OMe
HOH
Comparison of Syntheses
1944: Woodward/Doering:Condensation
1970: Hoffman-La Roche: Coupling
1970/1972: Gates and Taylor: Wittig
2001: Stork: Nucleophilic Addition
2004: Jacobsen: Suzuki Cross Coupling
2004: Kobayashi: Horner-Wadsworth-Emmons
N
N
OMe
HOH
1918: Rabe (Woodward/Doering): Substitution1970: Hoffmann-La Roche: Conjugate Addition and Epoxide Opening
2001: Stork: Substitution
2004: Jacobsen and Kobayashi: Intramolecular SN2
Stereocontrolled Total Synthesis
Stork:
Jacobsen:
Kobayashi:
13
16
17
Longest Linear Steps Overall Yield
15%
5%
3.9%
![Phytochemical Investigations of the Medicinal Plant ... · PDF fileIsolation of any compound from any plants is un- ... Quinine [6], an anti-malarial alkaloid, was isolated from cinchona](https://img.pdfslide.us/doc/110x75/5ab577a97f8b9ab7638cca99/phytochemical-investigations-of-the-medicinal-plant-of-any-compound-from-any.jpg)
