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![Page 1: S y n t h e t i c S t u d i e s o n Q u i n i n e : Q u i ...ccc.chem.pitt.edu/wipf/Current Literature/Grace_4.pdf · ¥ S tim u la te s d ig e s tio n ¥ K ills g e r m s ¥ R e](https://reader031.vdocuments.net/reader031/viewer/2022011911/5f8ae3de50d46850866d026a/html5/thumbnails/1.jpg)
Grace Woo @ Wipf Group
Synthetic Studies on Quinine: Quinuclidine Construction via a Ketone Enolate Regio- and
Diastereoselective Pd-Mediated Allylic Alkylation
N
N
OH
OMe
Deidre M. Johns, Makoto Mori, and Robert M. Williams
Department of Chemistry, Colorado State University
Organic Letters 2006, ASAP
Current Literature, August 12, 2006
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Grace Woo @ Wipf Group
Timeline-Quinine
1820/Pelletier and Caventou
Two French chemists isolated
quinine from the bark of cinchona
tree which are found in the eastern
slopes of the Andes mountains from
Venezuela to Bolivia, and the natives
called the cinchona tree “quina-quina” (“bark of barks’, known as “fever stick”).
Natives
Bark was dried, ground to a fine powder and mixed into a liquid (usually wine) before being served.
Effective muscle relaxant and antipyretic agents.
1600s/Europe
Quinine was first used to treat malaria in Rome in 1631, where malaria was epidemic and caused countless deaths in Europe.
D. A. Casteel in Burgers Medicinal Chemistry and Drug Discovery, 5th Ed., Vol. 5 (Ed.: M. E. Wolff),
Wiley, NewYork, 1997, Chap. 59, p. 16.
N
N1
2
3
5
6
7
89
10
11
1'
2'
4'
5'
7'
8'
R
cinchonidine, R=Hquinine, R=OMe
OH
1820-1930s/Searching for Alternative Methods
Pelletier and Caventou, Hofmann, Rabe
Streaker (1854 Emperical formula C20H24N2O2)
Perkins, Prostenik and Prelog
1940s-present/Total Syntheses
Woodward and Doering
Uskokovic
Stork
Jacobsen
Kobayashi
Williams
1900s-present/Versatile Catalysts and
Ligands in Asymmetric Synthesis
NHO
N
Derivatization SiteStereochemical differentiation
Site of attachment to a polymer chain
Site of quaternary salt formation
N
N
OMe
OH
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Grace Woo @ Wipf Group
Treatments
Cinchona has been used for a number of medical reasons such as:
• Treats malaria
• Kills parasites
• Reduces fever
• Regulates heartbeat
• Calms nerves
• Stimulates digestion
• Kills germs
• Reduces spasms
• Kills insects
• Relieves pain
• Kills bacteria and fungi
• Dries secretions
Malaria has been designated as “the most significant disease for world civilization
over the past three millennia”.
… and the quinine, the most celebrated cinchona alkaloid that was claimed as “the
drug to have relieved more human suffering than any other in history’.
D. A. Casteel in Burgers Medicinal Chemistry and Drug Discovery, 5th Ed., Vol. 5 (Ed.: M. E. Wolff),
Wiley, NewYork, 1997, Chap. 59, p. 16.
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Grace Woo @ Wipf Group
1918/Rabe and Kindlers’ Synthetic Development of Quinine
“Uber die Partialle Synthesedes Chinins” /C8-N1 Bond Disconnection
N
OH
N
OMe
quinotoxine
NaBrON
OBr
N
OMe NaOEt, EtOH;25%, overall
N
O
N
OMe
HN
N
MeOO
H
+
quinidinone quininone
N
N
MeO
H
N
N
MeO
H
N
N
OMe
H N
N
OMe
HOHH
HOH
H OH
OHH
+ + +
epiquinidinine quinidinine quinine epiquinine
Al powderNaOEt/EtOH; 12%
8
1
N
N
OH
OMe
The first major step towards the synthesis of quinine!
P. Rabe, K. Kindler, Ber. Dtsch. Chem. Ges. 1918, 51, 466.
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Grace Woo @ Wipf Group
April 11, 1944/Woodward’s Formal Total Synthesis of Quinine
C8-N1 Bond Disconnection
R. B.Woodward,W. E. Doering, JACS 1944,
66, 849; R. B. Woodward, W. E. Doering,
JACS 1945, 67, 860.
NH
H
OHN
H
OMe
HO CHO
1. H2NCH(OEt)2; 94%
2. 80% H2SO4; NaOH,
crystallization, H+; 64%
3. Piperidine, HCHO, EtOH; 61%
HON
N
1. NaOMe, MeOH,
220 oC; 65%
2. H2, Pt, AcOH3. Ac2O; 95%
HON
Me
Ac
1. H2, Ra/Ni, EtOH, 150 oC
205 bar; 1:1 cis(cryst)/trans(oil)
2. H2Cr2O7, AcOH, Et2O, H2Odiastereomer separation; 28% O
N
Me
Ac
H
H
1. EtO-N=O, NaOEt, EtOH; 68%
2. H2, Pt, AcOH3. MeI, K2CO3; 91%
N
Ac
Me
NMe3I
H
H
CH2CO2Et
1. 60% KOH, 180 oC;
KCNO; 40%
2. dilute HCl, EtOH, reflux; 100%3. PhCOCl, K2CO3; 96% N
Bz
H
H
CH2CO2Et
1. , NaOEtN
OMe
CO2Et
2. 6 N HCl,reflux; 50%3. resolution w/D-dibenzoyl tartrate; 11%
N
ON
H
OMe
Bz
Rabe's 1918 protocol
1, quinine30 mg
2 3 4
5 6
8, quinotoxine
1
8
7, Homomeroquinene
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Grace Woo @ Wipf Group
57 Years Later…2001/Stork’s First Stereoselective Total Synthesis
of Quinine-C6-N1 Bond Disconnection
G. Stork, et al JACS 2001, 123, 3239.
NH
H
OHN
H
OMe
N
1, quinine
Me
MeO i. LDA, THF, -78 oC
TBDPSO
OHC N3
ii.
N
MeO
N3
OTBDPS
OH; 70%
1. DMSO, (ClCO)2, TEA; 85%
2. PPh3, THF; 81%3. NaBH4, MeOH/THF; 91%
N
MeO
OTBDPS
NHH
HF, ACN; 95%
N
MeO
OH
NHH
MsCl, py, DCM
ACN, reflux; 68%
N
N
H
OMe
1. NaH, DMSO
2. O2; 78%
15
14
16
17 18 19
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Grace Woo @ Wipf Group
2004/Jacobsen’s First Catalytic Asymmetric Total Syntheses of
Quinine and Quinidine
C8-N1 Bond Disconnection
I. T. Raheem, S. N. Goodman, E. N. Jacobsen, JACS 2004, 126, 706.
O
NH
O
Ph
TBSO
CN
CO2Me
P
O
NH
O
Ph
O
EtO
EtO
+
TBSO
O
H
O
NH
O
Ph
TBSO
n-BuLi, THF
>50:1 E/Z; 84%
methylcyanoacetate,
20
21
22
(S,S)-23, t-BuOH, C6H12; 91%, 92%ee
Ra/Ni, H2, 650 psi; 89%
NH
O
CO2MeTBSO
cis/trans=1:1.7 3:1 ]LDA
1. LAH, THF; CBz2O,
TEA; 51%
2. TPAP, NMO, DCM3. methyltriphenylphosphoniumbromide, KOtBu; 73%
N
TBSO
Cbz
NCbz
BO O
1. TBAF, THF2. TPAP, NMO, DCM; 86%
3. Cl2CHB(pinacolate), CrCl2, LiI, THF; >20:1 E/Z, 79%
24
25
26
27
tBu
tBu
tBu
Al
tBu
O
2
(S,S)-23
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Grace Woo @ Wipf Group
2004/Jacobsen’s Catalytic Asymmetric Total Syntheses of
Quinine and Quinidine
C8-N1 Bond Disconnection
NH
H
OHN
H
OMe
1, quinine
N
Br
MeO
28
NCbz
BO O
27
+
1. Pd(OAc)2, 28, K3PO4, THF;>20:1 E/Z, 89%
N
MeO
NCbz
O
PCy2
OMeMeO
28
30
1. ADmix-!, CH3SO2NH2, tBuOH, H2O; >96:4 dr, 88%
N
MeO
NCbz
29
2. 1. Trimethylorthoacetate,PPTS (cat), DCMii. acetyl bromide, DCMiii. K2CO3, MeOH; 81%
Et2AlCl, thioanisole
"W, 200 oC, 20 min; 68%
16 longest linear steps with
overall yields of ca. 5%
I. T. Raheem, S. N. Goodman, E. N. Jacobsen, JACS 2004, 126, 706.
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Grace Woo @ Wipf Group
2004-5/Kobayashi’s Stereocontrolled Synthesis of Quinine and
Quinidine C8-N1 Bond Disconnection
AcO
OH NBn
PivO
TBDPSO
9 steps1. TeocCl, K2CO3, THF; 92%
2. NaH, EtOH; 82%NTeoc
HO
TBDPSO
o-NO2C6H4SeCN, PBu3 then H2O2; 83%
NTeocTBDPSO
1. 3% HCl MeOH2. PCC; 77%
NTeoc
OHC N
P(=O)(OEt)2
MeO
NaH, THF; 95% N
MeO
NTeoc
AD-mix-!; 72%
N
MeO
NTeoc
HO
OH
i. MeC(OMe)3, PPTS
ii. TMSCliii. K2CO3, MeOH; 86%
N
MeO
NTeoc
O
CsF
DMF-tBuOH
N
MeO
NTeoc
O78%
NH
H
OHN
H
OMe
1, quinine
30 3132
33 34
35
36
37 38
39
9 steps from intermediate
31, with overall yields of
ca. 22.1%
J. Igarashi, M. Katsukawa, Y.-G. Wang, H. P. Acharya, Y. Kobayashi, TL 2004, 45, 3783; J. Igarashi, Y.
Kobayashi, TL 2005, 46, 6381
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Grace Woo @ Wipf Group
2006/Williams’ Synthetic Studies on Quinine
C3-C4 Bond Disconnection
D. M. Johns, M. Mori, R. M. Williams, OL 2006, asap.
N
N
OMe1, quinine
40, 7-hydroxyquinine
Williams Disconnection
Stork Disconnection
Rabe JacobsenKobayashi
Disconnection
OH
1
2
5
6
7
8
9
3
4
N
N
OMe
OH
OHPd(0)-mediated
cyclization
N
OMe
OR1
NOX1
H
8
3
4
N
MeO
X2
OAc
NHR3
R1O
N
MeO
CO2R2
NHR3
R1O
68 4
8
N
MeO
CHO
NCbz
O OPh
Ph
+
asymmetricaldol
3
4
41
42
43
44, Willliam's lactone
45
(C3-C4 ring closure)
(setting stereo-chemistries at C8/C9)
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Grace Woo @ Wipf Group
2006/Williams’ Synthetic Studies on Quinine
Asymmetric Aldol Reaction
Preparation of Piperidine Derivative
N
MeO
CHO
CbzN O
O
PhPh
CbzN O
OTBS
PhPh
44 46
45
N
MeO
O
NCbz
Ph
Ph
O
OTESNaHMDS
TBSCl; 97%
1. TBAF, -78 oC to rt; 76%
2. TESOTf, DMAP; 99%
1. H2, Pd/C2. ZnCl2, MeOH3. Pb(OAc)4
4. H2, Pd/C, (Boc)2O;79%, 4 steps
47, >30:1 dr
N
MeO
CO2Me
NHBoc
TESO
48
N
MeO
CO2Me
NHBoc
TESO
48
N
MeO
OMs
BocHN
AcO
OTES
N
MeO
OMs
BocHN
AcO
OTES
1. DIBALH; 81%2. BnO(CH2)3MgBr; 87%3. Ac2O
4. H2, Pd/C5. MsCl
N
MeO
BocN
TESO
OAc
49 50
1. DIBALH; 81%2. BnO(CH2)3MgBr; 87%
N
MeO
OBn
BocHN
HO
OTES
1. DMP; 85%
2. DIBALH;67%, >20:1 dr3. Ac2O4. H2, Pd/C5. MsCl; 77%, 3 steps
51 52
NaH. THF; 99%
N
MeO
BocN
TESO
OAc
53
OAc
H
H
NHBocQ
H
AcO
H
NHBocQ
C8-C7 conformation requiredfor cyclization of C7-(R)
C8-C7 conformation requiredfor cyclization of C7-(S)
7
7
D. M. Johns, M. Mori, R. M. Williams, OL 2006, asap.
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Grace Woo @ Wipf Group
2006/Williams’ Synthetic Studies on Quinine
Completion of Allylic Alkylation Precursor
53
1. LAH; 94%2. TMSOTf, 2,6-lut.
54
N
MeO
BocN
TESO
OAc
N
MeO
HN
TESO
OTMS
BnOI
K2CO3, TEA, DMF;93%, 2 steps
N
MeO
N
TESO
OTMS
BnO
N
N
OMe
OH
BnO
O
H
1. 1N HCl2. (COCl)2, DMSO, TEA;90%, 2 steps
55
56
D. M. Johns, M. Mori, R. M. Williams, OL 2006, asap.
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Grace Woo @ Wipf Group
2006/Williams’ Synthetic Studies on Quinine-Key Transformation
Pd(O)-Mediated Allylic Alkylation-C3-C4 Bond Formation
D. M. Johns, M. Mori, R. M. Williams, OL 2006, asap.
N
N
OMe
OTES
BnO
O
H
56
1. CNCO2MeNaHMDS; 86%
2. Bu3SnOMePd2(dba)3
P(2-furyl)3; 67%, 4 diast
N
N
OMe
OTES
OH
CO2Me
H
N
N
H
OMe
OTES
OH
CO2Me
+8
57 (5%)58 (epi-C8, 9%)
59 (11%)60 (epi-C8, 42%)
Bu3SnFPd2(dba)3
P(2-furyl)3
TMSCl, LHMDS,
-78 oC; 59%
N
N
OMe
OTES
BnO
TMSO
H
61
DIBALHN
N
OMe
OTES
O
H
H
64 (39%)
N
N
OMe
OTES
OH
N
N
OMe
OTES
H
62 63 (2%)
HO
N
N
OMe
OH
OH+
TBAF; 88%
407-hydroxyquinine
+
Allylic Alkylation of Malonic Ester Derivatives
Regio- and Diastereoselective Allylic Alkylation of Ketone-Derived TMS Enol Ether
preformed ketone enolate
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Grace Woo @ Wipf Group
2006/Williams’ Synthetic Studies on Quinine
Plausible Mechanism for the Key Pd(O)-Mediated Allylic Alkylation
N
N
OMe
OTES
BnO
TMSO
H
61
Pd-Sandwich Complex Formation
Pd-mediated etherification, Claisen
Rearrangement Sequence
D. M. Johns, M. Mori, R. M. Williams, OL 2006, asap.
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Grace Woo @ Wipf Group
Summary
N
N
OH
OMe
• While the quinine has played an important historical role in organic chemistry, the first stereoselective total synthesis was accomplished by Stork et al, only five years ago.
• Since, the Stork’s asymmetric synthesis of quinine, only a handful of alternative syntheses has been published, in which most of them following the classical Rabe’s C8-N1 disconnection strategy to build the quinuclidine ring system.
• In Williams group, the synthesis of 7-hydroxyquinine was accomplished by featuring a C3-C4 Pd-mediated SN2’-type cyclization reaction to construct the quinuclidine ring system.
• In addition, the establishment of the C8/C9 stereogenic centers were set by the asymmetric aldol reaction developed in Williams’ group,
• While 7-hydroxyquinine was successfully synthesized in Williams’ group, this quinine analogue was found to be inactive against two strains of Plasmodium falciparum, a parasite that causes malaria.
• The further application of this innovative approach to the total synthesis of the Cinchona alkaloids is currently being investigated in Williams’ group.
Relevent Readings:
T.S. Kaufmann and E. A. Ruveda ACIE 2005, 44, 854.
K.K.J. Gawronski Synthesis 2001, 7, 961.