Synthetic Studies on Quinine: Quinuclidine

Construction via a Ketone Enolate Regio- and

Diastereoselective Pd-Mediated Allylic Alkylation

OMe
N

OH
N

Deidre M. Johns, Makoto Mori, and Robert M. Williams

Department of Chemistry, Colorado State University
Organic Letters 2006, ASAP

Current Literature, August 12, 2006

Grace Woo @ Wipf Group

 1600s/Europe 1900s-present/Versatile Catalysts and
Timeline-Quinine Quinine was first used to Ligands in Asymmetric Synthesis
treat malaria in Rome in
Site of attachment to a polymer
1631, where malaria was chain
epidemic and caused
countless deaths in Europe.
Derivatization Site
Stereochemical HO N
differentiation

10
Site of quaternary salt
11 3 formation

2
N
7 5
2' N
8 1 6
1' N
9 1940s-present/Total Syntheses
4'
1820/Pelletier and Caventou OH Woodward and Doering
Two French chemists isolated 8' 5'
cinchonidine, R=H Uskokovic
quinine from the bark of cinchona 7' quinine, R=OMe
Stork
R
tree which are found in the eastern
Jacobsen
slopes of the Andes mountains from OMe

Kobayashi N

Venezuela to Bolivia, and the natives OH

called the cinchona tree “quina-quina” (“bark of barks’, Williams N

known as “fever stick”).

Natives 1820-1930s/Searching for Alternative Methods
Bark was dried, ground to a fine powder and mixed into Pelletier and Caventou, Hofmann, Rabe
a liquid (usually wine) before being served. Streaker (1854 Emperical formula C20H24N2O2)
Effective muscle relaxant and antipyretic agents. Perkins, Prostenik and Prelog
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.
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.
Grace Woo @ Wipf Group
 1918/Rabe and Kindlers’ Synthetic Development of Quinine
“Uber die Partialle Synthesedes Chinins” /C8-N1 Bond Disconnection
OMe
N

OH
N

OMe OMe NaOEt, EtOH; MeO OMe

1 NaBrO 25%, overall O H
8 N N + N
N
H Br
O O H O
N N N N

quinotoxine quinidinone quininone

Al powder
NaOEt/EtOH; 12%

MeO MeO OMe OMe

OH OH
H H
N N
+ +
H H
N N
H H
N N
+
OH OH
H H
N N

epiquinidinine quinidinine quinine epiquinine

The first major step towards the synthesis of quinine!

P. Rabe, K. Kindler, Ber. Dtsch. Chem. Ges. 1918, 51, 466.

Grace Woo @ Wipf Group
 April 11, 1944/Woodward’s Formal Total Synthesis of Quinine
C8-N1 Bond Disconnection
1. H2NCH(OEt)2; 94% 1. NaOMe, MeOH,
N 220 oC; 65%
HO N
HO CHO 2. 80% H2SO4; NaOH, 2. H2, Pt, AcOH HO Ac
crystallization, H+; 64% N 3. Ac2O; 95% Me
2 3. Piperidine, HCHO, EtOH; 61% 3 4

1. H2, Ra/Ni, EtOH, 150 oC CH2CO2Et

H
205 bar; 1:1 cis(cryst)/trans(oil) 1. EtO-N=O, NaOEt, EtOH; 68% H Me

2. H2Cr2O7, AcOH, Et2O, H2O 2. H2, Pt, AcOH NMe3I

N H
diastereomer separation; 28% O Ac 3. MeI, K2CO3; 91%
H N
Me 5 6
Ac
CO2Et
H
CH2CO2Et OMe
o
1. 60% KOH, 180 C;
KCNO; 40% H
1. , NaOEt N
N
2. dilute HCl, EtOH, reflux; 100% H N Bz
3. PhCOCl, K2CO3; 96% N 2. 6 N HCl,reflux; 50% O
3. resolution w/
Bz D-dibenzoyl tartrate; 11% 8, quinotoxine
7, Homomeroquinene
OMe

H 8
Rabe's 1918 protocol N
1
N OH
H
1, quinine R. B.Woodward,W. E. Doering, JACS 1944,
30 mg
OMe
66, 849; R. B. Woodward, W. E. Doering,
JACS 1945, 67, 860.
Grace Woo @ Wipf Group
57 Years Later…2001/Stork’s First Stereoselective Total Synthesis
of Quinine-C6-N1 Bond Disconnection
OTBDPS
Me
MeO i. LDA, THF, -78 oC 1. DMSO, (ClCO)2, TEA; 85%
ii. TBDPSO ; 70% 2. PPh3, THF; 81%
N
OH N3 3. NaBH4, MeOH/THF; 91%
MeO
15 OHC N3 16
14 N

OTBDPS OH
H

HF, ACN; 95% MsCl, py, DCM N

N
N N ACN, reflux; 68%
H H H H
MeO MeO
17 18 19
N N OMe

H N
1. NaH, DMSO
N OH
2. O2; 78%
H
1, quinine

OMe

G. Stork, et al JACS 2001, 123, 3239.

Grace Woo @ Wipf Group
2004/Jacobsen’s First Catalytic Asymmetric Total Syntheses of
Quinine and Quinidine
C8-N1 Bond Disconnection
O O O
EtO O O
P
N Ph
EtO H n-BuLi, THF N Ph
20 H
+ >50:1 E/Z; 84%
O
TBSO 22
TBSO H
21
O O
Ra/Ni, H2, 650 psi;
methylcyanoacetate, N Ph 89%
H
(S,S)-23, t-BuOH, C6H12;
CN
91%, 92%ee 24
TBSO CO2Me

O
1. LAH, THF; CBz2O, Cbz
NH N
25 TEA; 51%
tBu 2. TPAP, NMO, DCM
TBSO CO2Me 3. methyltriphenylphosphonium TBSO
bromide, KOtBu; 73%
cis/trans=1:1.7 26
tBu 3:1 ]LDA
Cbz
N
Al O
1. TBAF, THF
2. TPAP, NMO, DCM; 86%
tBu
3. Cl2CHB(pinacolate), CrCl2,
LiI, THF; >20:1 E/Z, 79% B
O O 27
tBu 2

(S,S)-23

Grace Woo @ Wipf Group I. T. Raheem, S. N. Goodman, E. N. Jacobsen, JACS 2004, 126, 706.
2004/Jacobsen’s Catalytic Asymmetric Total Syntheses of
Quinine and Quinidine
C8-N1 Bond Disconnection

Cbz Cbz
Br N N PCy2
MeO 1. Pd(OAc)2, 28, K3PO4, THF;
MeO OMe
+ >20:1 E/Z, 89%

N
B MeO
O O 28
28 27 29
N

Cbz H
1. ADmix-!, CH3SO2NH2, N Et2AlCl, thioanisole
tBuOH, H2O; >96:4 dr, 88% "W, 200 oC, 20 min; 68% H N
2. 1. Trimethylorthoacetate, N OH
PPTS (cat), DCM O
MeO H
ii. acetyl bromide, DCM 1, quinine
iii. K2CO3, MeOH; 81% 30
N OMe

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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 2004-5/Kobayashi’s Stereocontrolled Synthesis of Quinine and
Quinidine C8-N1 Bond Disconnection
9 steps HO o-NO2C6H4SeCN,
AcO PivO
1. TeocCl, K2CO3, THF; 92% PBu3 then H2O2; 83%
2. NaH, EtOH; 82%
TBDPSO NTeoc
OH TBDPSO NBn
32
30 31
MeO
P(=O)(OEt)2
MeO

1. 3% HCl MeOH 35
2. PCC; 77% N NTeoc
OHC
TBDPSO NTeoc NTeoc NaH, THF; 95% N
33 34 36

MeO MeO
AD-mix-!; 72% HO i. MeC(OMe)3, PPTS O
NTeoc ii. TMSCl NTeoc
OH iii. K2CO3, MeOH; 86%
N N
37 38

MeO H
O
CsF 78%
DMF-tBuOH
NTeoc H N 9 steps from intermediate
N 39
N OH 31, with overall yields of
H ca. 22.1%
1, quinine

OMe

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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 2006/Williams’ Synthetic Studies on Quinine
C3-C4 Bond Disconnection

Rabe Williams Disconnection

Jacobsen 3
Kobayashi 2
Disconnection 7 4 5
8 N
1 6
9
OH Stork Disconnection

N
1, quinine
OMe

3
4
3 H
4 N NHR3 X2
1
N X O
Pd(0)-mediated 8 R1O 8 4
6
OH cyclization
OR1 MeO OAc
OH
(C3-C4 ring closure) N
N N
OMe 42
OMe
41
40, 7-hydroxyquinine Ph O O
3
NHR
1 asymmetric Ph N 44, Willliam's lactone
RO
8 CO2R 2 aldol Cbz
MeO
(setting stereo- +
chemistries at C8/C9) CHO
N
43 MeO

N
D. M. Johns, M. Mori, R. M. Williams, OL 2006, asap.
Grace Woo @ Wipf Group
45
 2006/Williams’ Synthetic Studies on Quinine
Asymmetric Aldol Reaction CHO
MeO

Ph O O 1. H2, Pd/C NHBoc

Ph Ph Ph Ph 45 N 2. ZnCl2, MeOH TESO
NaHMDS o
1. TBAF, -78 C to rt; 76% OTES 3. Pb(OAc)4 CO2Me
CbzN O CbzN O Ph N MeO
TBSCl; 97% Cbz
2. TESOTf, DMAP; 99% 4. H2, Pd/C, (Boc)2O;
O OTBS MeO
79%, 4 steps
N
44 46 N 48
Preparation of Piperidine Derivative 47, >30:1 dr

NHBoc 1. DIBALH; 81% AcO 7

OMs H
TESO 2. BnO(CH2)3MgBr; 87% BocN
CO2Me H
3. Ac2O BocHN OTES TESO
MeO
MeO MeO
4. H2, Pd/C OAc Q NHBoc
N 5. MsCl
N OAc
48 N
49 C8-C7 conformation required
50 for cyclization of C7-(R)
1. DIBALH; 81%
2. BnO(CH2)3MgBr; 87%

7
AcO
HO OMs H
OBn NaH. THF; BocN
1. DMP; 85%
OTES 99% TESO AcO
OTES BocHN
BocHN 2. DIBALH;
MeO MeO OAc
MeO 67%, >20:1 dr
3. Ac2O Q NHBoc
4. H2, Pd/C N N H
N
5. MsCl; 77%, 3 steps C8-C7 conformation required
51 52 53 for cyclization of C7-(S)

D. M. Johns, M. Mori, R. M. Williams, OL 2006, asap.

Grace Woo @ Wipf Group
 2006/Williams’ Synthetic Studies on Quinine

Completion of Allylic Alkylation Precursor

BocN HN
TESO TESO
1. LAH; 94% BnO
I
MeO OAc 2. TMSOTf, 2,6-lut. MeO OTMS
K2CO3, TEA, DMF;
N 93%, 2 steps
N
53
54

BnO

BnO 1. 1N HCl
N 2. (COCl)2, DMSO, TEA; O
TESO 90%, 2 steps H N

MeO OTMS 56
OH

N N

55 OMe

D. M. Johns, M. Mori, R. M. Williams, OL 2006, asap.

Grace Woo @ Wipf Group
 2006/Williams’ Synthetic Studies on Quinine-Key Transformation
Pd(O)-Mediated Allylic Alkylation-C3-C4 Bond Formation
Allylic Alkylation of Malonic Ester Derivatives

BnO
H H
CO2Me CO2Me
O 1. CNCO2Me O O
H N H
H N NaHMDS; 86% N
8
+
2. Bu3SnOMe OTES OTES
OTES
Pd2(dba)3
N P(2-furyl)3; 67%, 4 diast N N
OMe OMe OMe
56 57 (5%) 59 (11%)
58 (epi-C8, 9%) 60 (epi-C8, 42%)

TMSCl, LHMDS,
-78 oC; 59%
Regio- and Diastereoselective Allylic Alkylation of Ketone-Derived TMS Enol Ether
BnO
H
preformed ketone enolate
Bu3SnF HO
TMSO O
Pd2(dba)3
H N DIBALH N N N
H N P(2-furyl)3
H + OH + OH
OTES OTES OTES OH
OTES
N N N N
N
OMe OMe OMe OMe
OMe
40
61 62 63 (2%) 64 (39%) 7-hydroxyquinine

D. M. Johns, M. Mori, R. M. Williams, OL 2006, asap. TBAF; 88%

Grace Woo @ Wipf Group
2006/Williams’ Synthetic Studies on Quinine
Plausible Mechanism for the Key Pd(O)-Mediated Allylic Alkylation

Pd-Sandwich Complex Formation

BnO

TMSO
H N

OTES

N
OMe
61

Pd-mediated etherification, Claisen

Rearrangement Sequence

D. M. Johns, M. Mori, R. M. Williams, OL 2006, asap.

Grace Woo @ Wipf Group
 Summary

• 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. OM e
N
K.K.J. Gawronski Synthesis 2001, 7, 961. OH
N

Grace Woo @ Wipf Group