Total synthesis of quinine Historical Perspective

Malaria, Quinine, Total Synthesis, R B Woodward, Gilbert Stork, Synthesis of Natural Product, the 150-year long quest for synthesis and structure determination of Quinine.

1. Quinine Synthesis
Perkin (1856) to Jacobsen (2004)
1
Division of Organic chemistry
=N
=O
=H

2. 2
There are some researchers who
think of synthesis as a
manifestation of human
arrogance, thou they usually call
it aspiration or endeavor
We need no more demonstrations that the
molecules of the life are same, and have the same
biological activity however they have made
Sir J. W. Cornforth in Aust. J. Chem.1993, 46, 157

3. 3
The Quest for Quinine: Those Who Won the Battles and Those Who Won
the War
T .S.Kaufman, E.A. Rfflveda Angew. Chem. Int. Ed. 2005, 44, 854 –885
The Woodward–Doering/Rabe–Kindler Total Synthesis of Quinine: Setting
the Record Straight
Jeffrey I. Seeman Angew. Chem. Int. Ed. 2007, 46, 1378 –1413
Rabe Rest in Peace: Confirmation of the Rabe–Kindler Conversion of
d-QuinotoxineInto Quinine: Experimental Affirmation of the
Woodward–DoeringFormal Total Synthesis of Quinine
Robert M. Williams et al Angew. Chem. Int. Ed. 2008, 47, 1736 –1740

4. 4
Paul RabeWilliam Henry Perkin
Vladimir Prelog Woodward/ Doering
Gilbert Stork Uskokovic
Eric Jacobsen
Gilbert Stork

5. 5

6. A. Strecker, Liebigs Ann. Chem. 1854, 91, 155
6

7. W. H. Perkin, J.Chem. Soc. 1896, 69, 596
7

8. French designers referred aniline purple as mauve (Bright
pink) before becoming known as mauveine.
O. Meth-Cohn, M. Smith, J. Chem. Soc. Perkin Trans. 1, 1994, 5
8

9. N
H
OH
N
OMe
H
N
OHC
O
3
N
HO
2
C
HCO
2
H
N
HO
2
CHN
meroquinene
quintenine
Br
2
HN
O
N
OMe
[O]
[O]
Br
Br
acylation
hydrolysis
H
OAc
HN
H
H
O
HN
[O]
quininone
(epimerizesto
quinidinone)
KOH
fusion
N
MeO
N
MeO
Me
N
MeO
CO
2
H
6-methoxyquinoline6-methozylepidinequinicacid
Someofthereactionsthatprovidedcluestothestrutctureofquinine
quinotoxine
[O](HNO
3
,H
2
CrO
4
)
H
2
OorH
+
,
Pasteur
1853
Rabe
Konig
Konig
Baeyer
9

10. 10
P. Rabe, K. Kindler, Ber. Deutsch. Chem. Ges. 1918, 51, 466–467

11. 11
Its Tough to be first

12. HO
H
N
HO
H
O
OEt
OEt
N
HO
N
HO
N
N
HO
NH
HO
NAc
HO
NAc
HO NAc
O
H
H
H
2
NCH(OEt)
2
94%
1.80%H
2
SO
4
2.NaOH,
crystalization
H
+
(64%)
N
H
HCHO,EtOH
(61%)
NaOMe,MeOH
220°C,16h(65%)H
2
,Pt,AcOH
Ac
2
O
1:1
cis(crystalline)/trans(oil)
H2,Raneynickel,EtOH,
150°C,205bar,16h
H
2
Cr
2
O
7
,AcOH;
Et
2
O/H
2
O,
diastereomerseparation
(28%)
(95%)
N
OH
12

13. 13

14. 14
Quinine
Shortage

15. 15
N
CO
2
Me
Me
PtO
2
(0.9%),H
2
(70atm),
5%HCl(aq),60°C
(88%)
N
H
CO
2
Me
Me
N
H
CO
2
Me
MeS
R
resolutionwith
L-tartaricacid(25%)
N
H
H
H
H
CO
2
Me
1.NCS,Et
2
O
2.TFA,200-W
Hglamp,
N
Bz
Cl
H
H
CO
2
Me
1.NaOH,MeOH,H
2
O
2.KOtBu,benzene/
DMSO,70°C,
7h.
N
CO
2
Me
H
H
O Ph
O
BnNH
2
i)MeOH
ii)HCl,i-PrOH60°C
31%
racemic
N
H
O
Me
1.Pd/C(10%),AcOH
benzene,reflux
2.H
2
(200p.s.i),Pd/C(10%)
HCl,EtOH,60°C
55%
N
Me
LDA,MeOCO
2
Me
THF,hexanes
88%
3.BzCl,K
2
CO
3
(aq),benzene
77%
3.CH
2
N
2
,MeOH
(80%)

16. 16

17. 17

18. 18

19. N
OMe
O
1.DIBAL-H;
2.PhCOCl;
3.Cl
2
HCLi
Bz
N
Bz
CHCl
2
OH
KOH,benzene
N
H
Cl
H
O
N
H
OHC
1.AgNO
2
;2.EtOH/H
+
1.Et
2
O,-78°C(30–40%);
2.DIBAL-H(59%);
N
H
H
N
OMe
H
OH
N
H
H
N
OMe
OH
H
Quinine epi-quinine
13% 5%
N
H
N
OMe
H
OHH
N
H
N
OMe
H
OHH
epi-quinidine quinidine
15%5%
N
H
EtOOC
Et
2
O,-78°C(30–40%);
N
MeO
Li
N
MeO
Li
N
H
H
N
OMe
H
OH
Quinine
33%
N
H
N
OMe
H
OHH
quinidine
36%
19

20. N
H
H
OH
N
OMe
H
N
H
H
N
OMe
N
H
H
N
OMe
N
H
H
X
N
OMe
N
MeO
N
H
X
HN
N
OMe
X
N
N
OMe
X
H
H
H
a
HN
N
MeO
X
b
H
H
H
20
Rabe, Woodward,
Uskokovic,Taylor,gates
Stork

21. O
O
1)Et
2
NH/AlMe
3
Et
2
N
OTBS
O
OTBDPS
Et
2
N
OTBS
O
O
O
TBDPSO
TBDPSO
N
3
MeO
TBDPSO
OH
MeO
OHC
TBDPSO
N
3
2)TBS-Cl/
lmidazole/DMF
LDA,-78°C,
ICH
2
CH
2
OTBDPS
PPTS(0.3equiv),EtOH,12h,
thenxylenes,reflux8-10h.
1)DIBAL-H,-78°C,
2)Ph
3
PhCHOMe
PH
3
P/DEAD,
(PhO)
2
P(O)N
3
5NHCl,THF/
CH
2
Cl
2
21

22. N
MeO
Me
6-methoXylepidine
LDA,THF,-78
o
C
THF,-78
o
C
aq.NaHCO
3
N
MeO
OTBDPS
N
MeO
N
H
OTBDPS
N
MeO
N
OTBDPS
N
3
OH
N
MeO
OTBDPS
N
3
O
H
DMSO,(ClCO)
2
,NEt
3
85%
Ph3P,
THF,reflux
NaBH4
MeOH/THF
70%
81%
91%
CHO
OTBDPS
N
3
HF/CH
3
CN
95%
N
MeO
N
H
OH
H 95%
22

23. 23

24. 24
Stairs made by
fathers (20
th
)and
forefathers (19
th
)
of organic
chemistry and
chemistry
In 21
st
Century

25. 25

26. 26

27. NH
2
OMe
MeO
N
H
O
MeO
N
Br
N
CBz
B
O
O
MeO
N
N
CBz
MeO
N
N
CBz
O
MeO
N
N
CBz
OH
HO
Pd(OAc)
2
,(2.5mol%),
K
3
PO
4
.
H
2
O,THF,16h,
rt,>20:1E/Z,89%;
MeO OMe
PCy
2
i.ethylpropiolate,MeOH,rt,12h
ii.DowthermA,250°C,30min
Ph
3
PBr
2
,CH
3
CN,microwave,
170°C,15min.
ADmix-,CH
3
SO
2
NH
2
,
tBuOH,H
2
O,0°C,>96:4
dr,88%
ii.acetylbromide,CH
2
Cl
2
iii.K
2
CO
3
,MeOH,81%
i.trimethylorthoacetate,
PPTS(cat),
CH
2
Cl
2microwave,200°C,20min,68%
Et
2
AlCl,thioanisole,0°Ctort, N
H
H
N
OMe
OH
27

28. 28

29. RoadofNaturalproductsynthesisalthoughtough,testing
humanpatience,totalsynthesisofnaturalproductsgive
pleasureofachievement,satisfactionandperfectionto
individualandworthinformationtosociety,classicexample
isQuinine(keptengagedlegendsofchemistryoftheirerafor
150years).
Quininehadbeenthesourceofinspirationforbirthof
chemicalindustry(dye),alsotodevelopchemistryofN-
heterocycles(quinoline,piperidine).
29