Chia-Wei Yang2020/02/15

Introduction

• Quinine was first isolated in 1820 from the bark of a cinchona tree• It is a medication used to treat malaria and babesiosis• It is also the ingredient in tonic water that gives it its bitter taste

Quinine

Quinidine

From Wikipedia, Cinchona

• Quinidine is a stereoisomer of quinine.• It was originally derived from the bark

of the cinchona tree.• It is a medication that acts as a class I

antiarrhythmic agent in the heart.

Introduction

Introduction

Precursor synthesis

AcO

H Ts

AcO

Ts+toluene, 130 oC, 12 h

83%

O

OZn, NH4Cl

THF/H2O (1:0.8), 115 oC, 6 h

AcOmethyl acrylate

69%

AcO

NaBH4

MeOH, 0 to 25 oC, 2 h

HOH

HOTs

TsCl, DMAP, Et3N

CH2Cl2, 25 oC, 2 h

94% over two steps

HCN

NaCN

DMSO, 35 oC, 12 h

91%

p-TsCl + Me3Si SiMe3

AlCl3

CH2Cl2, rt, 12 hp-Ts SiMe3

p-Ts SiMe3

80%

K2CO3, KHCO3

MeOH, H2O, 30 oC, 10 minp-Ts H

Na, EtOH

cyclohexane, 5 oC, 45 min

O

O

50 oC, 25 min

OH

OAcAc2O

10 oC, 30 min

Precursor synthesis

AcO

H Ts

AcO

Ts+toluene, 130 oC, 12 h

83%

O

OZn, NH4Cl

THF/H2O (1:0.8), 115 oC, 6 h

AcOmethyl acrylate

69%

AcO

NaBH4

MeOH, 0 to 25 oC, 2 h

HOH

HOTs

TsCl, DMAP, Et3N

CH2Cl2, 25 oC, 2 h

94% over two steps

HCN

NaCN

DMSO, 35 oC, 12 h

91%

Precursor synthesis

HCN

HCN

OHOH

CHOCHO

HCN

HCN

NPMB

OsO4, NMO

acetone/H2O (1:1),25 oC, 12 h

Pb(OAc)4

CH2Cl2, 25 oC, 10 min

NaBH3CN, PMBNH2, AcOH

MeOH, 25 oC, 2 h

67% no purification

78% over two steps

TeocCl

CH2Cl2, 25 oC, 2 h

HCN

NTeoc

76%

TFA/CH2Cl2 (1:4)

25 oC, 2 h

HCN

NH2+

TFA-

HCN

NBoc

Boc2O, NaHCO3

CH2Cl2/H2O (3:2), 25 oC, 2 h

92% over two steps

TMSOH

TMSO Cl

O(TeocCl)

triphosgene, pyridine

Et2O, _30 oC, 10 h

triphosgene

Cl O O Cl

OClCl

ClCl

49%cooxidant

N-Methylmorpholine N-oxide

N+

O

-ONMO

O O O

O O

Boc2O

Precursor synthesis

H

NBoc

NC H

NBoc

NMeO

Me

O

H

NBoc

HO2CNaOH

MeOH/H2O (2:1)120 oC, 9 h

91% over two steps

EDC, HOBt, Et3N,N,O-dimethylhydroxylamine

hydrochloride

CH2Cl2, 25 oC, 12 h

N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC)

N,O-dimethylhydroxylaminehydrochloride

HN

O

HCl

NN

NOH

HOBtHydroxybenzotriazole

Mechanism:

Precursor synthesis

H

NBoc

NMeO

Me

OLDA, THF

_78 °C, 4 h

N

MeO+

H

NBoc

ON

OMe

92%OMe

NH2

O

N

MeOFeCl3, ZnCl2

EtOH, 80 oC to rt, 15 h+

Ac2O, DMAP, Et3N

THF, rt, 2d

59%

Mechanism:

Precursor synthesis

Quinoline

Doebner-Millerreaction

H

NBoc

ON

OMe

H

NBoc

OHN

OMe

NaBH4, MeOH

0 oC to 25 oC, 2 h

93%

H

NBoc

OHN

OMe

Et3N, DMAP, CH2Cl2, 25 oC, 2 h

separate isomers

H

NBoc

ORN

OMe

*

O

Me MeCOCl

Me O

+

R= O

Me MeC(O)

Me OK2CO3

acetone/MeOH (4:1), rt, 12 h

H

NBoc

OHN

OMe

Precursor synthesis

(1S)-(-)-camphanic chloride

(Separate isomers)

Quinine synthesisH

NBoc

OHN

OMe

NN

O OH

HOMe

OBoc

Hdioxane/H2O (3:1), 25 oC, 3 h

OsO4, 2,6-lutidine, NaIO4

N2,6-lutidine

no purification

NN

O O

HOMe

Boc

HNN

O O

HOMe

OBoc

HCH2Cl2, 0 oC to 25 oC, 1 h

DMP

THF, _78 oC to 25 oC, 1 h

MeSO2PT, KHMDS

no purification 42% over three steps

Dess-Martin periodinaneKHMDS

Potassium(K) HexaMethylDiSilazide

N

NNN

SO2Me

MeSO2PT

Julia olefination

Quinine synthesis

NN

O O

HOMe

Boc

H

LiAlH4

THF,0 oC, 2 h

N

NOHBoc

OMe

HO

N

NOTBSBoc

OMeHO

82%

TBSOTf, 2,6-lutidine

THF, _78 oC, 10 min

Et3N, MsCl

CH2Cl2, 0 oC to 25 oC, 1 h

N

NOTBSBoc

OMeMsO

90% 84%

MsClMethanesulfonyl chloride

TBSOTf

Si O SO

OCF3

SO

OCl

Quinine synthesis

N

NOTBSBoc

OMeMsO TFA/CH2Cl2

(1:9)

25 oC, 1 h

NaHCO3

MeCN, 85 oC, 12 h

N

N

OMeMsO

H HO

N

N

OMe

HO

no purification no purification

(COCl)2, DMSO, Et3N_78 oC, h

N

N

OMe

H

N

N

OMe

O [Rh(COD)Cl]2, dppp

diglyme, 140 oC, 18 h

74% 41%

N

N

OMe

NaH/DMSO, O2

70 oC, 45 min

N

N

OMe

OH

quinine

Quinine synthesis

H

NBoc

OHN

OMe

Et3N, MsCl

CH2Cl2, 0 oC to 25 oC, 1 h

H

NBoc

OMsN

OMe

94%

dioxane/H2O (4:1), 25 oC, 3 h

OsO4, 2,6-lutidine, NaIO4

NN

MeO

OO

OMsH

BocN

N

MeO OMsH

BocTHF, _78 oC to 25 oC, 1 h

MeSO2PT, KHMDS

N

N

OMe

N

N

OMe

H

MsOTFA/CH2Cl2

(1:10)

25 oC, 1 h

NaHCO3

MeCN, 85 oC, 12 h

Quinidine synthesis

43% over two steps

90% over two steps

N

N

OMeKOtBu, O2

DMSO/t-BuOH (4:1)

0 oC to 25 oC, 2 h

NIS, K2CO3

MeCN, 25 oC, 12 h

N

N

OMe

OH

N

N

OMe

O I

K2OsO4.2H2O, K3Fe(CN)6K2CO3

t-BuOH/H2O (1:1), rt, 12 hN

N

OMe

O I

OHHO

Quinidine synthesis

56% over two steps 85%

N

N

OMe

O I

OHHO

N

N

OMe

OH

OHHO

t-BuLi

THF, _78 oC, 5 min

MeOH/H2O (2:1), rt, 12 h

NaIO4

N

N

OOMe

OH

[Rh(COD)Cl]2, dppp

diglyme, 140 oC, 12 h

N

N

OMe

OH

quinidine

Quinidine synthesis

46% over two steps 62%

Thanks for your listening!!