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

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


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

http://en.wikipedia.org/wiki/Image:Cinchona.pubescens03.jpg


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.


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.


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


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


2004/Jacobsen’s First Catalytic Asymmetric Total Syntheses of

Quinine and Quinidine


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


2004/Jacobsen’s Catalytic Asymmetric Total Syntheses of

Quinine and Quinidine


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.


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


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)



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




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



2006/Williams’ Synthetic Studies on Quinine-Key Transformation

Pd(O)-Mediated Allylic Alkylation-C3-C4 Bond Formation


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



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



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.

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

Documents