Cinchona Alkaloids : Efficient Tunable Organocatalyts in

Asymmetric Synthesis

Antonin Clemenceau04.06.15

Plan :

I- Organocatalysis: Concepts and PrincipleII- Cinchona Alkaloids

A- PresentationB- HistoryC- Other Potential Examples

III- Conclusion

3

Introduction

• Concept borns in the late 1990s

• Before only enzymes and metal-catalyst were used for asymmetric catalysis

• Another powerful tool for the Modern Organic Chemistry

• Explosion of this field during this century

Organocatalysis

Organometallic Catalysis

Biological Catalysis

Asymmetric Transformation

Organocatalysis

4

Organocatalysis: Concepts and principle

*

*organocatalyst

organocatalyst*

chiral compound

Principle

• Definition : The use of small organic molecules to catalyse asymmetric transformation

• First example of asymmetric organic synthesis was reported with proline catalyst in 1971 by two industrial research groups

Advantage:- Non-toxic, environmentally friendly- Low cost- Robust - Metal-free reaction

Creation of a new C-C or C-heteroatom bond controlled by the organocatalyst===> Induction of chirality 5

Organocalysts

N

N

R

OH

NH

CO2H

O

OP

O

OH

HN

O

NH

t-Bu

NH

S

NR2

N

NH

t-Bu

O

Ph

Ar

Ar

N

NN

Ph

Phosphoric acid

Cinchona Alkaloid

L-Proline

Thioruea

N-Carbene

Imidazolidinone

Famous organocatalysts with different reactivities and

activation modes used all around the world

6

N

R

OH

NH

N

N

OH

R

H

Quinidine (QD)Cinchonine (CN)Cupreidine (CPD)

R = OMeR = HR = OH

Quinine (QN)Cinchonidine (CD)Cupreine (CPN)

R = OMeR = HR = OH

pseudo-enantiomers8

89

911

3

44

3

5'

6'

5'

6'

101111

10Nomenclature

Cinchona Alkaloids• Quinine isolated by Pelletier in 1820

• Quinine and derivatives were recognized as antimalarial agent

• First Total Synthesis in 1944 by Woodward and Doering

• A dimer derivative ((DHQD)2-PHAL) is used as chiral ligand in the Sharpless asymmetric dihydroxylation.

Considered as pseudo-enantiomers because- The stereogenic centers (C8, C9) have the opposite absolute configuration - The centers in the quinuclidine fragment (C3, C4) are identical

Ref: R. B. Woodward and W. E. Doering J. Am. Chem. Soc., 1944, 66, 849 - 849T. Marcelli, J. H. van Maarseveen, H. Hiemstra Angew. Chem. Int. Ed. 2006, 45, 7496 – 7504B. Sharpless et al. J. Org. Chem. 1992, 57, 2771-2773

Quinquina Tree

7

N

OMe

OH

N

Hydrogen bond donating groupActivate Electrophile

Lewis / Brønsted baseActivate Nucleophile

N

OMe

OH

N

N

OMe

NH

N

S NH

CF3

CF3

N

N

OBn

NH

NH

S

CF3

CF3

Wynberg, 1981Conjugate Addition

Deng, 2004Conjugate Addition

Connon, Dixon, Soós 2005Conjugate Addition

Hiemstra, 2006Henry Reaction

Rawal, 2008Conjugate Addition

N

N

NHO

OHN

CF3

CF3

N

OMe

NH2

N

Chen 2007Michael Addition

N

OHO

N

Et

Hatakeyama, 1999Baylis-Hilman Reaction

N

OH

OR

N

N

NH

N

O

PPh2

Dixon 2011Mannich Reaction

Cinchona AlkaloidsBifunctional Catalyst

Ref: A. G. Doyle, E. N. Jacobsen Chem. Rev. 2007, 107, 5713 – 5743 J. Alemán, A. Parra, H. Jiang, K. A. Jørgensen Chem. Eur. J. 2011, 17, 6890 – 6899 J. -W. Xie, W. Chem, R. Li, M. Zeng, W. Du, L. Yue, Y. -C. Chen, Y. Wu, J. Zhu, J. -G. Deng Angew. Chem. Int. Ed. 2007, 46, 389 –392

Easily tunable moiety

8

1981: Quinine

Ref: H. Hiemstra, H. Wynberg J. Am. Chem. Soc. 1981, 103, 417.

N

OMe

OH

N

O

SH

toluene, R.T.

O

15 examplesup to 75 % ee

Ar

SAr

n = 1, 2

Wynberg work:

Enantioselective conjugate addition of aromatic thiols to conjugated cycloalkenones

First example of Cinchona Alkaloid as Organocatalyst

9

1981: Suggested Mechanism

Ref: H. Hiemstra, H. Wynberg J. Am. Chem. Soc. 1981, 103, 417.

N

OMe

OH

N

N

N

OH

OMe

N

N

O

OMe

H

HO

S N

N

OH

OMe

H

O-

S

Quinine Quinidine

If the other pseudo-enantiomer catalyst is used,the other enantiomer can be formed

N

OMe

OH

N

N

OMe

OH

N

N

OMe

O

N

N

OMe

O

N

SH

-SH

O

-SH

O

O

S

H

H

H

chiral information isintroduce at this step

O

S

N

OMe

OH

NH

O-

S

10

1999 : b-Isocupreine

Ref: Y. Iwabuchi, M. Nakatani, N. Yokoyama, S. Hatakeyama J. Am. Chem. Soc. 1999, 121, 10219-10220

O

O

R1CHO

N

OHO

N

Et

R1

OH

O

O

O O

R1

OR1DMF, - 55 °C

R1 = Ar, alky, (E) PhCH=CH 21-82% yield91-99% ee

0-29% yield4-76% ee

CF3

CF3

CF3

CF3

Hatakeyama work:

b-Isocupreine• Cagelike structure • Conformationally rigid• No pseudoenantiomer of the b-isocupreine easily accessible

Asymmetric Baylis−Hillman Reaction

11

1999 : Proposed Reaction Mechanism

Ref: Y. Iwabuchi, M. Nakatani, N. Yokoyama, S. Hatakeyama J. Am. Chem. Soc. 1999, 121, 10219-10220See also: G. Masson, J. Zhu, C. Housseman Angew. Chem. Int. Ed. 2007, 46, 4614 – 4628

N

OH

O

N

Et

O-

OR2

N

O

O

N

Et

O

OR2

H OR1

HN

O

O

N

Et

O

OR2

HO R1

H

R1CHO

R1CHOR1CHO

O O

OR1

R1

R1

OH

O

O

N

OHO

N

Et

OR2

O

A

A

B

N

OH

O

N

Et

O

OR2

OR1

H

C

R1O-

CF3

CF3

elimination condensation

syn (2R, 3S)syn (2S, 3R)

Aldol reaction Aldol reaction

Conjugate Addition

HH

• Syn diastereomers are produced from the aldol reaction• Steric constraints of C unfavoured the b elimination

12

2004 : Cupreine and cupreidine

Ref: H. Li, Y. Wang, L. Tang, L. Deng J. Am. Chem. Soc. 2004, 126, 9906-9907

Enantioselective Conjugate Addition of Malonate and b-Ketoester to Nitroalkane

13

R1 NO2 R2O2C CO2R2

R1 NO2

R2O2C CO2R2

*

R1 = Ar, alkyl

R2 = Me, Et

THF, -20 °C

catalyst (10 mol%)

CP: 71-99% yield; 91-98% eeCPD: 73-99% yield; 91-96% ee

Deng work:

NO2

PhNO2*

O

OEt

O

H

O

OEt

O CP (10 mol%)

THF, R.T.

93% yield91% ee

N

OH

OH

N

N

N

OH

OH

Cupreine (CP) Cupreidine (CPD)

2 H-bond donors

2005 : Thiourea Cinchona Alkaloids

Ref: J. Ye, D. J. Dixon, P. S. Hynes Chem. Commun. 2005,4481 S. H. McCooey, S. J. Connon Angew. Chem. Int. Ed. 2005, 44, 6367 B. Vakulya, S. Varga, A. Csámpai, T. Soós Org. Lett., 2005, 7, 1967-1969 M. S. Taylor, E. N. Jacobsen Angew. Chem. Int. Ed. 2006, 45, 1520 – 1543

N

R

N

N

H Nu

NS H

H X R2

R1

Ar

• Simultaneous donation of two hydrogens• Electrophile activation as enzymes system• Strong and directional H-bonds formation

14

2005 : Thiourea Cinchona Alkaloids

Ref: J. Ye, D. J. Dixon, P. S. Hynes Chem. Commun. 2005, 4481-4483 S. H. McCooey, S. J. Connon Angew. Chem. Int. Ed. 2005, 44, 6367 B. Vakulya, S. Varga, A. Csámpai, T. Soós Org. Lett., 2005, 7, 1967-1969

Enantioselective Conjugate Addition

15

O

R1O

O

OR1

O

R2 NO2R1O

O

OR1

O

R2 NO2

R1

R2

O

R1

R2

NO2

MeNO2

9-epi-DHQT (0.5 - 10 mol %)

toluene, R.T.

5 examples

80-97% yield89-98% ee

Soós work:

R1O

O

OR1

O

R2 NO2R1O

O

OR1

O

R2 NO2

Conon work:

Dixon work:

13 examples

63-95% yield75-99% ee

9-epi-CT (10 mol %)

DCM, -20 °C

16 examples

81-99% yield82-97% ee

*

9-epi-DHQT or9-epi-DHQDT (2-5 mol %)

toluene, -20 °C - R.T.

N

OMe

NH

N

S NH

CF3

CF3 N

N

NH

OMe

NH

S

CF3

F3C

Connon, Soós catalysts

N

N

NH

NH

S

CF3

F3C

9-epi-DHQT 9-epi-DHQDT

Dixon catalyst

9-epi-CT

2006 : C6’-Thiourea Cinchona Alkaloids

N

N

OBn

NH

NH

S

CF3

CF3

R H

OMeNO2

RNO2

OH

(10 mol%)

THF, -20 °C

C6'

8 examples90-99% yield85-92% ee

R H

OMeNO2

RNO2

OH(10 mol%)

THF, -20 °C

C6'-thiourea quinine

3 examples87-97% yield87-93% ee

Hiemstra work:

Ref: T. Marcelli, R. N. S. van der Haas, J. H. van Maarseveen, H. Hiemstra Angew. Chem. Int. Ed. 2006, 45, 929 –931

Asymmetric Henry reaction

Switch of the H-bond donor C9 to C6’ N

N

OR

NH

NH

S

CF3

CF3

C6'

N

OR

NH

N

S NH

CF3

CF3

C9

16

2007 : Amino Cinchona Alkaloids

Ref: P. Melchiorre Angew. Chem. Int. Ed. 2012, 51, 9748 – 9770 L. Jiang, Y. -C. Chen Catal. Sci. Technol. 2011,1, 354-365 S. Bertelsen, K. A. Jørgensen Chem. Soc. Rev., 2009, 38, 2178–2189

Activation mode

17

O

R N

R1

H+

Iminium activation mode: ( -functionalisation)

R

R2

Nu-

N

R1

R2

X

H

N

-OR3

-OHR3CO2-

Nu-

Secondary Amine is sensitive to hinderance

H+

Primary Amine need acid as a cocatalyst

Choose the good catalyst in f unction of thesubstrate to activate

N

OMe

NH2

NNH2

N

2007 : Amino Cinchona Alkaloids

Ref: P. Melchiorre Angew. Chem. Int. Ed. 2012, 51, 9748 – 9770 L. Jiang, Y. -C. Chen Catal. Sci. Technol. 2011,1, 354-365 S. Bertelsen, K. A. Jørgensen Chem. Soc. Rev., 2009, 38, 2178–2189

Activation mode: Secondary amine vs Primary amine

18

Enamine activation mode (-functionalisation)

R1

O

R2

R1

N

R2 E+

N

OMe

NH2

NNH2

H

H

H

R1

N

R2 HR1

N

R2 H

XHH

R1

N

R2

XHH

E+ Primary Amine- Unfavorable imine-enamine equilibrium

Secondary Amine- More nucleophilic- Better stabilization of the iminium ion by hyperconjugation

H+- H+H+

R1

N

R2

H

Secondary Amine wins

Example 1: non-hindered carbonyl compound

- H+

R1

O

R2

R1

N

R2

E+

R3

R3

H

R1

N

R2 R3

R1

N

R2R3

XHH

R1

N

R2

XHH

H+- H+H+

R1

N

R2

H

Example 2: hindered carbonyl compound

Primary Amine- Easy acess to a planar conformation enamine

Secondary Amine- Steric factors affect condensation rate- Steric inhibition of enamine resonance

Primary Amine wins

R3

R1

N

R2

XHH

R3-

-

R3

R1

N

R2

H

R3

- H+

Ref: J.-W. Xie, W. Chen, R. Li, M. Zeng, W. Du, L. Yue, Y. –C. Chen, Y. Wu, J. Zhu, J. –G. Deng Angew. Chem. Int. Ed. 2007, 46, 389 –392 W. Chen, W. Du, Y. –Z. Duan, Y. Wu, S.-Y. Yang, Y.- C. Chen Angew. Chem. Int. Ed. 2007, 46, 7667 –7670The same year, 2 other groups published organocatalytic reaction with Amino Cinchona Alkaloids: S. H. McCooey, S. J. Connon Org. Lett. 2007, 9, 599 – 602. G. Bartoli, M. Bosco, A. Carlone, F. Pesciaioli, L. Sambri, P. Melchiorre Org. Lett. 2007, 9, 1403 – 1405.

(10 mol %)

N

N

NH2

OMeO

n

NN-

O

H R

TIPBA (20 mol%)

NN

O

R

H

HO

nTHF, 4 Å M.S., 40 °C

22 examples

86-95% ee67-99% yield

n = 0, 1, 2 R = Aryl

(20 mol %)

N

TFA (40 mol%)

THF, 0 °C

NH2

N

OMe

X

NC CN

X

NC CN

R1

O

H

R1 R2

O13 examples

87-99% ee51-98% yield

Chen work:

Iminium activation mode Iminium activation mode

2007 : Amino Cinchona Alkaloids

19

(20 mol %)

N

N

NH2

OMe(10-20 mol %)

N

PhCO2H (10-20 mol %)

NH2

N

OMe

R4 NO2

up to 98% yieldup to 99% eeup to 99:1 dr

Connon work:

R1

O

R3

R2R1

O

R2 R3

R4

NO2**

Melchiorre work:

NH

XO

R2

R1

(40 mol %) 56-99% yield70-96% ee

BocHN CO2H

PhO

R2R1NH

X

Enamine activation mode Iminium activation mode

Ref: J. P. Malerich, K. Hagihara, V. H. Rawal, J. Am. Chem. Soc. 2008, 130, 14416. J. Alemán, A. Parra, H. Jiang, K. A. Jørgensen Chem. Eur. J. 2011, 17, 6890 – 6899.

2008 : Squaramide Cinchona Alkaloids

R1

O

R1

O

ArNO2 R1O

O

OR1

O

ArNO2

(0.1-2 mol %)

DCM, R.T.

N

N

NHO

OHN

CF3

CF3

21 examples

65-98% yield77-99% ee1:1-50:1 dr

R3

R3

Rawal work:

Difference with thiourea:

Asymmetric conjugate addition of dicarbonyle to nitroalkene

20

Ref: F. Sladojevich, A. Trabocchi, A. Guarna, D. J. Dixon J. Am. Chem. Soc. 2011, 133,1710 –1713.P. Shao, J. Liao, Y. A. Ho, Y. Zhao Angew.Chem. Int. Ed. 2014, 53,5435 –5439.I. Ortín, D. J. Dixon Angew.Chem. Int. Ed. 2014, 53 ,3462 –3465.R. De la Campa, I. Ortín, D. J. Dixon Angew.Chem. Int.Ed. 2015, 54,4895 –4898.

2011 : Cinchona-Derived Amino Phosphine precatalyst

R2 CO2R1

Dixon work:

N

NH

N

O

PPh2

X

R4R3

NC

Ag2O

(5 mol%)

(2.5 mol%)

NX

R3 CO2R1R2R4

Aldol (or Mannich) reaction

21

N

NH

N

O

PPh2

Bronsted base

H-bond donor

Lewis base Metal ligation

Transition state tabilisation

Proton Transfer

Metal

NNH

N

O

PPh2

M

Binary catalyst system

Other potential application

Over the years simple asymmetric reactions were performswith Cinchona Alkaloids

How has been used this organocatalyst scaffold inchallenging transformations?

22

Other Potential Application

Ref.: Y. Wang, H. Li, Y. -Q. Wang, Y. Lui, B. M. Foxman, L. Deng J. Am. Chem. Soc. 2007, 129, 6364-6365

N

N

NH

OMe

NH

S

CF3

F3C

epiQDTU-2

N

N

OR

OH

CP-1O

R4

OO

R4HOR1

OOR4

HOR1

endoexo

O

OH

R1 R2

O

R3 Et2O or EtOAc, 0 °C or R.T.R2

O

R3 R2O

R3

O

O

OH

R1

OO

CNCN

HOR1

OOCN

HOR1

endoexoCN

OOX

HOR1CN

exo

CN

CN

Et2O or TBME, R.T. or -20 °C

epiQDTU-2

Et2O or TBME, T. (°C)

O

O

OH

R1X

NC

X = H (R.T.)96-4 exo:endo ratio

91% ee94% yield

Deng work:

95:12-93-7 exo:endo ratio90-94% ee

75-99% yield

>97-3 exo:endo ratio85% ee

92% yield

X = CN (-20 °C)93-7 exo:endo ratio

81% ee97% yield

OO

XHOR1

CNendo

Asymmetric Diels−Alder Reactions

23

Other Potential ApplicationAsymmetric Diels−Alder Reactions

Ref.: Y. Wang, H. Li, Y. -Q. Wang, Y. Lui, B. M. Foxman, L. Deng J. Am. Chem. Soc. 2007, 129, 6364-6365

N

N

O

OH

O

O

OH

N

N

NH

OMe

NH

S

CF3

F3C

epiQTU-2

epiQDTU-2

CN

Cl

N

OMe

NH

N

S NH

CF3

CF3

N

OH

N

O

CP-1

CPD-1

OO

HO

CN

Cl

OO

HO

Cl

CN

OO

OHCl

NC

OO

OHCN

Cl

75% ee78:22 dr

85% ee87:13 dr

85% ee91:9 dr

89% ee93:7 dr

(S,S,R)

4 possible stereoisomers control by

the 2 pseudoenantioners couples

24

Ref: P. Kwiatkowski, T. D. Beeson, J. C. Conrad, D. W. C. MacMillan J. Am. Chem. Soc. 2011, 133, 1738–1741

O

N

F

PhO2S SO2PhO

F

1.5 eq. Na2CO3

10 mol %

-fluoro ketone17 examples

88-99% ee

N

N

NH2

OMe

ketoneNFSI THF, -20 °C

TCA

MacMillan work:

And 35 : 88 % 99 % ee with THF and TCA (as co-solvant)

Other Potential ApplicationEnantioselective α-Fluorination

• First highly enantioselective fluoration usingOrganocatalysis• Cinchona Alkaloids give the best result• Enamine activation mode

25

Other Potential Application

Ref: F. Manoni, S. J. Connon Angew. Chem. Int. Ed. 2014, 53, 2628 –2632

Asymmetric Tamura cycloadditions

TMSCHN2MeOH

(5 mol %)

N

OMe

NH

N

HN

O

O

N

R1

O

Boc

O

O

O

R2

R3

N

O

Boc

O

CO2MeR1R2

R3MTBE, 30 °C

1)

2)

Connon work:

10 examples

65-98% yield89-99% ee

N

EtO2C

O

Boc

O

O

O2) TMSCHN2 MeOH, -30 °C

1 ) catalyst (5 mol%) MTBE, -30 °C N

O

Boc

O

CO2MeCO2Et

74% yield98% ee

Syn diastereomer obtainedat low temperature

26

Other Potential Application

Ref: X. Yin, Y. Zheng, X. Feng, K. Jiang, X. -Z. Wei, N. Gao, Y. –C. Chen Angew. Chem. Int. Ed. 2014, 53, 6245-6248

Asymmetric [5+3] formal cycloadditions

N

OMe

NH2

N

CO2H

OH

NO2

O

R1

NS

O O

R2

R3

HNS

R3O

O

O

R1

R2(20 mol%), (40 mol%)

H2O (20 mol%)

CHCl3, 35 °C

R1 = alkyl, aryl

R2 = aryl 24 examples

97-99% ee63-99% yield

Cascade Dienamine-Dienamine activation mode

O

R1

E

E

'

NH

N

R1

'

N

R1

'

n n n

dienamine endo-dienamine5 carbonsm carbons

formal [5+m] cycloaddition

Chen work:

27

(-)-Nakadomarin A

Dixon work:

N

O

MeO2C

N

N

O

H

O2N

O

+

O

P

O

OMe

OMe

OTs

HNO

NO

MeO2C

O2NO

N

N

NH

NH

S

CF3

F3C

Fan work:

O

O

NH

O

NNH

O

(+)-Lunarine

C

N

Br

OO

O I

MOM

CN

O

O

Br

MOM

O

OI

COCH3+

NNH

N

S NH

CF3

CF3

Ref: P. Jakubec, D. M. Cockfield, D. J. Dixon J. Am. Chem. Soc. 2009, 131, 16632 – 16633P. Chen, X. Bao, L.-F. Zhang, M. Ding, X.-J. Han, J. Li, G.-B. Zhang, Y.-Q. Tu, C.-A. Fan Angew. Chem. Int. Ed. 2011, 50, 8161-8166

Other Potential Application …Toward Total Synthesis

28

SeO2PhAr

N

CO2Me Ar

N

CO2Me

SeO2Ph

*N

OH

On-Bu

N

Toluene, 4 Å M.S. - 40 °C

NH

N N

N OMe

Total Synthesis of the (+)-Trigonoliimine A (overall yield 7.5%)

and (-)-Trigonoliimine A (9 steps, overall yield 6.8%).

,-Disubstituted-Amino Acids

14 examples

87:13-98:2% e.r.

Zhu work:

Ar

H2N

CO2H

SeO2Ph

*

Ref: T. Buyck, Q. Wang, J. Zhu Angew. Chem. Int. Ed. 2013, 52, 12714 – 12718

Other Potential Application …Toward Total Synthesis

29

Conclusion

N

N

NHO

OHN

CF3

CF3

N

OMe

NH2

N

N

OMe

OH

N

N

OHO

N

EtN

OH

OR

N

N

OMe

NH

N

S NH

CF3

CF3

N

NH

N

O

PPh2

- Easily avalaible & tunable- Various way of substrate activation- Enantioselective control- Catalytic process- Environmentally friendly

Widely used in organocatalysis… Still lot of thing can be done

Dual and cooporatives catalysis can be an issue

Thanks for your attention

Suggested Mechanism

O

O

O

R2

R3

N

O

Boc

O

R1R2

R3O

OH

O

R2

R3

N

R1

O

Boc

O

NBoc

O

R3R2R

1OH

NH

HN

S

Ar

N

NO

O O-

stereochemistry controlby the temperature

TMSCHN2MeOH

N

O

Boc

O

R1R2

R3

O OMe

Asymmetric Tamura cycloadditions

Ref: F. Manoni, S. J. Connon Angew. Chem. Int. Ed. 2014, 53, 2628 –2632

Suggested Mechanism

N

R1

R2

NH

R1

N

R1

R2

N

R1N S

N

R1HN S

R2

R2 O

R1HN S

R2

H+

H+

hydrolysis

N

R1

- H+

H

- H2O NH

SO

O

N

R1

R2

NS

O

O

HN

R1

R2

NS

O

O

H

OOH

OO

OO

NS

O

O

R3

R3

R3R3

R3

R3

R3

- H+

Ref: X. Yin, Y. Zheng, X. Feng, K. Jiang, X. -Z. Wei, N. Gao, Y. –C. Chen Angew. Chem. Int. Ed. 2014, 53, 6245-6248

Asymmetric [5+3] formal cycloadditions