Wonders and questions about chiral discrimination in...

Wonders and questions about chiral discrimination in

organic crystalsGuillaume Levilain, Guillaume Descamps, Guillaume Tauvel, Morgane Sanselme,

Gérard CoquerelUnité

de Croissance Cristalline et de Modélisation Moléculaire

UPRES EA 3233F-76821 Mont-Saint-Aignan Cedex FRANCE

Oleron

Cristech

October

07th

2008

Contents

Introduction: a twofold

motivation……

Heterogeneous equilibria interpreted in terms of spontaneous recognition of the handedness.

Case studies…..

Take-home

message …

A twofold

motivation

•

Fundamental science: Conservation -

breaking of

parity. Fundamental

aspects of

the

evolution

of

the

universe

and

life. Amplification of

a minute enantiomeric

excess; symmetry

breaking.

•

Applied science: resolution, enantiomeric purification, design of

resolving

agent, etc.

Pharmaceutical

drugs, agro-chemicals, etc.

Chirality in Natural and Applied Science Ed. W.J. Lough & I.W. Wainer

Blackwell Publishing CRC Press 2002

Possible R-S heterogeneous systemsUnary system if racemizable

enantiomers.

Symmetrical binary system if non racemizable

enantiomers.

Review : G. Coquerel, Enantiomer, 2000, 5, 481-498

T T T

A B C

T

D T

E F GT T

S R S R S R

S R S R S R S R

RS

<S>+<RS> <RS>+<R> <S>+<R>

<ssS>+<ssR>

<ssS>+<ssR>

<ssS> <ssR>

liq liq liq

liq liq liq liq

RSRS

<S>+<RS> <RS>+<R>

<S>+<RS> <RS>+<R>

<S>+<R>

<S>+<R>

<ssRS>

<S> + <ssRS>

<R> + <ssRS>

RS

Benefits of a stable conglomerate

Recovering of the whole e.e.

(by means of simple recrystallization)

Recovering of the whole amount of each enantiomer

(if the preferential crystallization is applicable)

Induction of the preferential primary nucleation

(initiated by addition of a pure enantiomer chemically related to the (±) solute)

Coupling Preferential Crystallization and Racemization: 100% of a given

enantiomer. Amplification of a small initial enantiomeric excess by means of attrition

statistics (≈ 5 %) (homogeneity of the distribution ?)Coquerel G.; Preferential Crystallization; Top. Curr. Chem. 2007; 269: 1-51.

V

S R

L

K

Exemple

of Chiral Discrimination induced by formation of hydrates

Triethanolamonium

Modafinate

Monohydrate

Structure

Chiral Discrimination

Triethanolamonium

Modafinate

Monohydrate

N. WERMESTER, O. LAMBERT and G. COQUEREL; CrystEngComm, 2008, 10, 724–733

Chiral discrimination via hydrate

Triethanolamonium

Modafinate

Monohydrate

•

B

C

D

E

AS R

H2O

T

I

R, H2O S, H2O

Solid solution + S, 1H2O A

A’

D’ B

Solid solution + R, 1H2O

Solid solution J + S, 1H2O + R, 1H2O

S, 1H2O + R, 1H2O + liquid I

S, 1H2O + saturated solution

A’

J

C

D D’ R, 1H2O + saturated solution

E Unsaturated solution

Liquid

<ssSR>

Chiral discrimination in the solid state with (±)-trans-1,2-diaminocyclohexane (DACH)

R

R

S*

*

NH2

NH2

*

*

NH2

NH2

S

S enantiomer R enantiomer

Conglomerate screening by using SHG effect led to spot the

citrate of DACH as a possible candidate

DACH is a useful synthon

and is a key component in the synthesis of oxaliplatin

an anticancer drug with the R enantiomer.

OW1N2

N1

O3

O4

O1

O2

O6

O5

O7

OW1

OW1

O3 O1

O2

O7

O5

O4

O6

N1

N2

OW1N2

N1

O3

O4

O1

O2

O6O6

O5O5

O7O7

OW1

OW1

O3 O1

O2

O7O7

O5O5

O4

O6O6

N1

N2

5 10 15 20 25 305 10 15 20 25 305 10 15 20 25 30

The crystal is representative of the bulk, the calculated XRPD pattern

obtained from the crystal structure and the experimental XRPD pattern fit perfectly.

Projection along a axis of the two dimensional H-bonds framework (In

green dashed line).In pink, H-bonds involving the -N(1)H3+

moiety

Oxygen atoms O5 & O7 do not participate to any H-bond

Experimental XRPD

Projection along c axis : H-bonded molecules propagated in (200) slices

Crystal Structure of the DACH citrate monohydrate

1.80Ǻ

1.96Ǻ1.92Ǻ

1.80Ǻ

1.96Ǻ1.92Ǻ

Details of the Crystal Structure of DACH citrate monohydrate

DACH Water Citric acid

Asymmetric unit

Hydrogen bonds

Conglomerate

with

DiBenzyl-DACH

•

2-3Dichlorophenyl acetate

is

a conglomerate

with

a : 4 –

1 stoichiometry!!!

NH

NH

FP7 Intenant

Project ; to be

published

Crystal structure of : DiBenzyl-DACH 2-3Dichlorophenyl acetate

2 deprotonated

acids

and two

protonated

acids

: salt

–

cocrystal

hybrid

phase!!!

Sodium hydrates with non congruent solubilities: an example of ‘anticonglomerate’

Na2O

(+)

(-)

H2O

N

NHS

O O

*

Recrystallization

leads

to <RS-Na2

-4H2

O> + mother

liquor

(e.e. >99%)

Preparative resolution of (±) Tenatoprazole

Non congruent solubility

salts with

a strong

propensity

to

hydrolyse in presence

of water.

No direct bond between

K+

and the imidazolate

group.

Ra

V

b

Sa

RaV

b

b

CR

CS

Sa

CR

CS

CR

CS

Ra

V

b

Sa

CS

CR

Stable conglomerate

in a quaternary

system

High performance at

2 liter scale

Crops (g) Entrainments Crude crops

(g) %ee salt-K+,2EtOH Acid H

1 140 89,42 125,2 90,9

2 130 -97,23 126,4 91,8

3 180 87,60 157,7 114,5

4 170 -94,57 160,8 116,8

5 230 96,81 222,7 161,7

WO 2008/081104 A3 Tauvel

G., Petit M-N., G. Coquerel, F. Schultze, S. Bernad, A. Cohen, S. Charbit

α-methylbenzylamine modafinic acid salts

Operations: X Offset 0.091 | X Offset 0.170 | X Offset 0.109 | ImportY + 20.0 mm - File: nw1bea1.raw - Start: 3.000 ° - End: 30.000 ° - Step: 0.040 ° - Step time: 4. s - Temp.: 25 °C (Room) - WL1: 1.54056 - Creation: 08/10/2004 17:12:37Operations: ImportY + 10.0 mm - File: nw1cha1.raw - Start: 3.000 ° - End: 30.000 ° - Step: 0.040 ° - Step time: 4. s - Temp.: 25 °C (Room) - WL1: 1.54056 - Creation: 08/10/2004 17:58:11Operations: ImportFile: nw1isa1.raw - Start: 3.000 ° - End: 30.000 ° - Step: 0.040 ° - Step time: 4. s - Temp.: 25 °C (Room) - WL1: 1.54056 - Creation: 08/10/2004 18:43:46

Lin

(Cou

nts)

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000

19000

2-Theta - Scale3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 3

XRPD of

(+) AMBA (+) MA, (±) AMBA (±) MA and (+) AMBA (-) MA

salts

(+) AMBA (-) MA(±) AMBA (±) MA(+) AMBA (+) MA

XRPD Patterns of (+) AMBA (+) MA

and (±) AMBA (±) MA salts

are identical

⇒ Conglomerate (confirmed by preferential crystallization)


Monohydrate salt

a = 5.5875 Å b = 11.425 Å c = 33.895 Å V = 2163.7 Å3

orthorhombic P21

21

21

Z = 4

Crystallographic data

Crystal structure determination


Projection of the

unit cell

along

the

a axis

Crystal

structure


Molecular chain of MA-

and AMBA+

molecules linked by ionic bondsIonic chains linked by strong hydrogen bonds via water molecules

The

connectivity

between

ionic

chains

is

ensured

by H-bonds

involving

H2

O

Reciprocal

quaternary

system: α-methylbenzylamine modafinic acid salts

ARBR

_1H2

O

ASBRASBs_1H2

O

ARBS

e1

m

e4 e3

E2E1

TfASBS

e2

TfARBR

TfARBS

TfASBR

T T (+)A(+)B_1H2

O →

p salt

(–)A(–)B _1H2O

→

p’

salt

The stable pair of salts

(+)A(–)B →

n salt

(–)A(+)B →

n’

salt

No racemic

double salt (stable or metastable phase)

has been

observed

Ethanolamine mandelate

H10A

H9A

H10BH4

H1B

C10

C9

C4

H5

N1

H3

H1C

C5

C3

H9B

O4

H1A

H1O4O2

C6

C2

H6

H2

C1

C8

O3

C7

H7

O1H1

a

bc

Evidence of the solid solution of ethanolamine mandelate at room temp.

00-005-0628 (*) - Halite, syn - NaCl - Y: 50.00 % - d x by: 1. - WL: 1.54056 - Cubic - a 5.64020 - b 5.64020 - c 5.64020 - alpha 90.000 - beta 90.000 - gamma 90.000 - Face-centered - Fm-3m (225) - 4 - 179.42Y + 20.0 mm - File: R+NaCl.RAW - Temp.: 25 °C (Room) - Creation: 25/02/2004 09:11:59 - R mandélate éthanolamine + NaCl - Start: 3.000 ° - End: 40.000 ° - Step: 0.020 ° - Step time: 30. s - WL1: 1.54056File: rac-mand-ethanolamine-NaCl-2.R AW - Temp.: 25 °C (R oom) - Creation: 21/02/2004 08:21:00 - Rac mandelate ethanolamine+Nacl - Start: 3.000 ° - End: 40.000 ° - Step: 0.020 ° - Step time: 30. s - W L1: 1

Lin

(Cou

nts)

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000

19000

20000

21000

22000

23000

24000

25000

26000

27000

28000

29000

30000

2-Theta - Scale5 10 20 30

Evidence of the solid solution of ethanolamine mandelate at room temp.

1 5 2 02 5

N. WERMESTER et al.Tetrahedron: Asymmetry, 18, 2007, pp. 821-831

System

and

space

group Orthorhombique, P21

21

21

Number

of

molecule

per

asymmetric

unit Z' = 1 ; Z = 4

a = 6,058 Å

b = 8,093 Å

c = 21,915 Å

R factor

for I>2sigma(I) R1 = 2,80 %

Strong bonds: H, ionic ou iono-H

A priori not favorable to the formation of solid solution

Strong bonds: H, ionic ou iono-H

A priori not favorable to the formation of solid solution

Structure of ethanolamine mandelate

Chiral anionic sliceAchiral cationic

sliceChiral anionic slice

Achiral cationic

sliceChiral anionic slice

Projection long b axis :Molecular modeling study :

Simulation of the presence of the counter enantiomer by means of inversion(s) of: –OH et –H :

- for an isolated molecule,

- for a half a ribbon,

- for a slice.

Minimisation E

In every case :

ΔE < 4kJ/mol

Within the margin of uncertainty

In every case :

ΔE < 4kJ/mol

Within the margin of uncertainty

Probable

Statistic desorder between –OH et -H

Probable

Statistic desorder between –OH et -H

Refinement of the lattice parameters from XRPD patterns : Δ

(a;b;c) < 0,1 Å

Structure of ethanolamine mandelate

Maximum composition of the solid solutions at 25°C :86.8 % e.e.

86.8% e.e.

Ethanol / Waterazeotropic mixture

(+) E.M. (-) E.M.

‘SS’ stands for solid solution(s) 25°C

25 °

C75

°C

125

°C

•

: DITA experimental

points,

: Stable liquidus

curve,

: Tie line limit between triphasic

and biphasic domain,

•••••

: Metastable

liquidus

curve

Liq.

<SS(-)>

<SS(-)> + <SS(+)>

<SS(+)>

Ethanol / Water Azeotropic mixture

90 10

(+) E.M. (-) E.M.

8020

<SS(-)

> + <SS(+)

> + poly-saturated

solution

<SS(-)

> + liq.

<SS(+)

> + liq.

↑

Isothermal section of the ternary phase diagram [(+)E.M. -

(-)E.M. -

(ethanol-water azeotropic

mixture)] at 25°C, stable and metastable equilibria. ↓

Binary diagram of [(+)E.M. -

(-)E.M.]

▼

: Experimental points by DSC measurements,

……. : Extrapoled

solvus.

Heterogeneous equilibria in case of ethanolamine mandelate

SO

R

OS

R

O O

Chirality in the

‘modafinil’

series

* *

Mirror

S enantiomer R enantiomer

R = NH2

: 7 polymorphic

racemic compounds

R = OH : Stable conglomerate

P31 – P32

R = OCH3

: conglomerate with partial solid solutions

Ethanolic saturated solution of DMSAM at room

temperature

Ethanolic saturated solution of DMSAM at room

temperature

•Molecular

Structure from

single crystal

X-ray diffraction

Formula C16

H16

SO3

Space goup P21

21

21

a / Å 5.693(1)b / Å 16.139(2)c / Å 16.131(2)

α= β

= γ

/° 90.00V / Å3 1482(1)

Flack parameter -0.02(6)

R(-)DMSAM

Single crystalsSupersaturated

solution

Drilled Parafilm

Single crystalsSupersaturated

solution

Drilled Parafilm

0.1 mm

•Molecular

Structure from

single crystal

X-ray

diffraction

Obtained

from

(±)DMSAM

Presence of R and S enantiomers in the structure

Formula C16

H16

SO3

Space Group P21

21

21 (P21

21

21

)a / Å 5.711(1) (5.688(1))

b / Å 15.989(2) (16.148(2))

c / Å 16.101(2) (16.130(2))

α= β

= γ

/° 90.00 (90.00)

V / Å3 1470(1) (1481(1))Flack parameter 0.10(10)

Volume of the

unit cell

decreases

a

R

S

•Growth

of single crystals

in solutions with intermediate

compositions

Composition of solutions

ee

= 0%(±)DMSAM

ee

= 60% ee

= 75% ee

= 100%R(-)DMSAM

Space group P21

21

21

a / Åb / Åc / ÅV / Å3

Flack parameter

5.711(1)15.989(2)16.101(2)1470(1)0.10(10)

5.689(1)16.074(2)16.107(2)1473(1)0.01(6)

5.694(1)16.117(2)16.125(2)1480(1)0.01(6)

5.693(1)16.139(2)16.131(2)1482(1)-0.02(6)

Composition of single crystals using structure refinement

ee= 50(±1)% ee= 80(±1)% ee= 85(±1)% ee= 100%

Composition of single crystals using HPLC

ee= 52(±1)% ee= 82(±1)% ee= 90(±1)% ee= 98(±1)%

Conclusion: ⇒ good

accuracy

of the measurements⇒ DMSAM forms partial solid solutions at room temperature

Ternary phase diagram at 20°CMethanol

S DMSAM R DMSAM

Solubility measurements

DITA measurements [4]

Supplementary experiments

Composition by HPLC of thesingle crystal with the maximum of enantiomer miscibility

ee (%)= 100 52 52 10081 81

Undersaturated Liquid

Saturated solution+

Solid Solution (S DMSAM)Doubly

saturated solution (0% ee)

+ Solid Solution (S DMSAM)

+ Solid Solution (R DMSAM)

Saturated solution

+Solid Solution (R DMSAM)

Experimental

ternary

phase diagram

at

20°C

System:

S(+)/R(-)DMSAM/MeOH

Domains of stable solid solution at 20°C ee

[100%-52%]

ee

= 0

Renou, L. et al. Crystal Growth & Design 2007, 7, (9), 1599-1607

HPLC on single crystals

grown

at

various

temperatures

No change in the

crystal

structures

T (°C)

40°C

20°C

5°C

40°C

20°C

5°C

T (°C)

40°C

20°C

5°C

40°C

20°C

5°C

Temperature Composition

40°C ee=52(+/-1)%

20°C ee=52(+/-1)%

5°C ee=50(+/-1)%

S DMSAM R DMSAM

EtOH

Quasi-ideal

behavior

which

fulfills Meyerhoffer

“double solubility

rule”

Single crystal of solid solution immersed in a large excess of

saturated solution

0.75(± 0.02)1.58(± 0.02)Molar solubiliy(%) in EtOH

4.48(± 0.02)9.20(± 0.02)Mass solubiliy (%) in EtOH

R(-)DMSAM(±)DMSAMCompounds

0.75(± 0.02)1.58(± 0.02)Molar solubiliy(%) in EtOH

4.48(± 0.02)9.20(± 0.02)Mass solubiliy (%) in EtOH

R(-)DMSAM(±)DMSAMCompounds

Single crystal of solid solution

•

Experimental

conditions: at

20°C, in a thermostated vial

Partial dissolution in a saturated solution of R enantiomer

XX

??????

t = 2h

a

100 μm

Partial dissolution in a saturated solution of R enantiomer

S DMSAM R DMSAM

EtOH

X


S DMSAM R DMSAM

EtOH

X


t = 0h

a

t = 0h

a

30 μm

t = 2h

10 μm

•Single crystal partially dissolved•Hypothesis: dissolution of a single enantiomer of the

solid solution and single crystal reshaping

t = 4h

a

100 μm

1 mm a

t >

20h

HPLC: ee

= 98(±1)

%Slow evaporation

of the

solvent

•Regrowth

of the

crystal

Take-home

messageA H-bond network is supposed to enhance the chiral discrimination at

the solid state. This might not be sufficient to ensure the recognition of the molecular handedness.

Most of the time water and other solvent molecules inside crystallized organic solids do not act as a simple space filler but rather as

active

partners in the H-bond networks. These solvent molecules can also be involved in the ionic bonds.

Therefore, screening of conglomerates needs differnts

counter ions, solvents and other co-crystal formers.

More than 150 years after the seminal Pasteur’s work almost no progress has been done on the predictability of the chiral discrimination in the solid state!!!!!!!!!!!!!!!!

Acknowledgements

Cephalon

Inc. Sanofi-AventisServier

Group

DSMRhodiaSyncom

Merck KGaAInnate PharmaSteba

France

Former PhD students of the lab.

Dr Pierric

Marchand

Dr Franck MalletDr Loïc Lefebvre

Dr Morgan Pauchet

Dr Arnault Grandeury

Dr Nicolas WermesterDr Laurent Ferron

Dr Laurent Courvoisier

Dr Elias Ndzié

Dr Éric AubinDr Fabrice Dufour

Dr Stéphane Beilles

Dr Guillaume Tauvel

Dr Saoussen

Wacharine

Wonders and questions about chiral discrimination in...

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