The Origin of Chirality Anne-Catherine BédardCharette Group MeetingJan 25th 2012

“Any man who, upon looking down at his bare feet, doesn't laugh, has either no

sense of symmetry or no sense of humour”

(Descartes, cf. Walker 1979)

About Me !Québec Ottawa

Biopharmaceuticals Sciences - COOP

ParisHonours Project

JCEMolChem

Montréal

2

Outline

Terrestrial vs Extraterrestrial Theories1.Stereochemistry in Life2.Minority report : opposite handedness3.Difference in energy of enantiomers4.Chirality form polarized light5.Chiral field : Magnetism6.Amplification and transfert of chirality7.Crystallization8.Unidirectional rotation of Earth

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Louis Pasteur

•1848 : Pasteur 1st to draw attention to the homochirality in nature

•Optical purity is inherent to life▫Failure of other planets to yield

optically active material = evidence for the absence of life of complexity comparable to earth’s

•1874 : Van’t Hoff = assymmetry on carbon atom.

•Dextrogyre (+)-D•Levogyre (-)-L

1822-1895 France

Tartaric AcidCO2HHO

CO2HHO

4

Enantiotopic TS

5

R1 H

O 1. MeMgBr

2. H2O

R1

HO

Me MgBrMe MgBr

SiRe

HR1

O

MeH

R1

O

Me

E

Me

OH

R1

HMe

OH

R1

H

EnantiotopicSAME ENERGY

Me

OH

R1

HMe

OH

R1

H

Diastereotopic TS

6

H

O1. MeMgBr

2. H2O

HO

Me MgBrMe MgBr

SiRe

E

DiastereotopicDIFFERENT ENERGY

RS

RL

H

RLRSH

RS

RL

H

O H

Me

H

RL

RS

O H

Me

Me

HO

RS

RL

H

H

Me

H

RS

RL

H

OH

Me

HO

RS

RL

H

H

Me

H

RS

RL

H

OH

Biomolecular Homochirality

• Basic elements of biochemistry▫20 (L)-amino acids ▫5 bases (A, G, C, U, T)▫ (D)-Ribose▫ (D)-Glucose▫Fats▫Phosphatides

• Formation of proteins, enzymes, DNA, RNA, sources and storages of metabolic energy !

OHO

HOOH

OH

-D-glucopyranoseOH

CHO

OHH

HHO

OHH

OHH

CH2OH

CHO

OHH

OHH

OHH

OHH

CH2OH

D-glucose D-ribose

H2NOH

O

R(L)-amino acid

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Chirality and Physical Property

R-Carvone : caraway odourS-Carvone : spearmint odour

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Thalidomide (1957-1961)Morning sickness

treatmentCause congenital

abnormalities

NNH

O

O O

O

O

(R)

O

(S)

D-Amino Acids

• Ingestion of D-A.A. in food▫Racemization with vinegar, yogurt, potatoes…

•Enzyme : D-A.A. oxidase•Babies : 60% of D-aspartic acid in prefrontal

cortex at 14th week of gestation▫Decreased by birth to traces amount

•Alzheimer’s : accelerated racemisation of aspartic acid residue

•Racemisation is linked to the process of ageing…•A. A. clock : complementary to 14C-dating method

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H2NOH

O

(L)-aspartic acid

CO2HH

NH2HO

O

(D)-aspartic acid

HO2CH

Racemisation

•Thermodynamically favored process•Gain of entropy (in the solid state)

•Room temperature racemisation of alanine ▫Thousand of years!

H2NOH

O

Me(L)-alanine

H2NOH

O

Me(rac)-alanine

H2NOH

O

Me(R)-alanine

10

11

The Weak (Nuclear) Force – Parity Violation• 4th fundamental force of physics• Influence electrons inside atoms causing them to

travel helical paths that gives all atoms a handedness

• 1013 time weaker than the strong force that holds protons and neutrons in the nucleus

• Discovery in 1956 by • Tsung Dao Lee (Columbia U.) • Chen Ning Yang (Princeton)• Nobel prize of Physics in 1957!• Lee (30) and Yang (34)

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Lee, T. D.; Yang, C. N. Phys Rev 1956, 104, 254

The Weak (Nuclear) Force – Parity Violation• Most familiar effect : β-decay (60Co, 14C)• Inherently left-handed!

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60Coe- () e

60Co 60Ni + e- + e

Conservationof momentum

60Co Beta-Decay – Wu’s Experiment

•If parity is conserved, then the probability of electron emission at θ is equal to that at 180o - θ.

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60Co

Magnetic Field

Parity Conserved

60Co

Magnetic Field

Parity Violated

60Co

spin spin spin

Nuclei polarised through spin alignment in a large magnetic field at 0.01oK

Wu, C. S. and al. Phys Rev 1957, 105, 1413Bonner, W. A. Chirality 2000, 12, 114

Difference in Energy of Enantiomers

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•Femtojoule (10-15) to picojoule (10-12) scale•L-A.A. and D-sugars are more stable !•No experiment has been successful in

confirming the effect.

H F

Me

BrHF

Me

Br

Diastereomers ???

MacDermott, A. J. Orig Life Evol Biosphere, 1995, 25, 191Quack, M. Angew. Chem. Int. Ed. 2002, 41, 4618 Salam, A. J Mol Evol 1991, 33, 105

Chemical effect of polarized radiationPhotochemical asymmetric synthesisPhotochemical decomposition of racemates

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Kagan’s Decomposition of Camphor

20% ee99% decomp

Balavoine, G.; Moradpour, A.; Kagan, H. B. J. Am. Chem. Soc. 1974, 96, 16.

290-370 nm CPL (UV)

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Bonner’s Polarised Light Exp.

•Selective destruction of D enantiomer of A.A. with right circularly polarized light (UV)

•Exact and opposite effect of RCPL and LCPL▫Leucine has the highest molecular absoption

coefficient▫Predicted = 2% ee at 80% photolyzed

Flores, J. J.; Bonner, W. A.; Massey, G. A.; J. Am. Chem. Soc. 1977, 99, 11

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Leucine’s Photolysis

•212.8 m, CPL

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H2NOH

O

H2NOH

OH2N

OH

O

LCPL RCPL

(D) (L)

Photodecomposition vs photosynthesis

Light polarization

% Decomposition

Enantiomeric Excess

RCPL 59 1,98 ± 0,31

LCPL 75 2,50 ± 0,35

Unpolarized 54 0,30 ± 0,33

Flores, J. J.; Bonner, W. A.; Massey, G. A.; J. Am. Chem. Soc. 1977, 99, 3622

Assymmetric Photosynthesis

•Photocyclisation of alkenes in solution

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400nm (CPL)

I2, O2 about 20% ymax 2% ee

(UV light)

R

R

R

R

R

R

Bernstein, W. J.; Calvin, M.; Bechardt, O. J. Am. Chem. Soc. 1973, 95, 527

Circularly Polarized Light (CPL)

• Sunlight is polarized linearly (LPL) and non-assymmetric

• Right or left CPL is a result of natural (LPL) sunlight reflexion at the earth’s surface and earth’s magnetic field (0,1%)

• Sunlight is considered insufficient for enantioselective photochemistry.

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Circular Polarization in Space

• Strong IR circular polarisation resulting from dust scattering in Orion OMC-1 star-formation region

Baileys, J. and al. Science 1998, 281, 672

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Extraterestrial A.A. Meteorite

•Meteorite : Murchinson Autralia in 1970•Issue of terrestrial contamination…•5 α-Me A.A. (extremely rare or

unreported)CO2

-+H3N

Me Et

e.e. 15.2% S

CO2-

+H3N

Me Pr

e.e. 2.8% S

CO2-

+H3N

Me iPr

e.e. 2.8% S

CO2-

+H3N

Me

e.e. 7% S (3S)

CO2-

+H3N

Me

e.e. 9.1% S (3R)Et

MeMeEt

Cronin, J. R. ; Pizzarello, S. Science 1997, 275, 951.

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Strecker Synthesis in Space

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Silicate grains of sub-micrometer diameter coated with ice layer

Contains H2O, CO2, CO, CH3OH, NH3

Subsequent aggregation = formation of comets !

Strecker Synthesis in Space

Interstellar conditions in the lab :•Vaccum (10-7 mbar)•Low temperature (12K)•Mixture : H2O, NH3, CH3OH, CO, CO2•Irradiation with UV light for 24h•Warmed slowly up to room temperature. •Photochemically formed radicals are assumed to recombine in order to form oligomers and polymers

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Caro, M. and co. Chem Eur J 2005, 11, 4895

GC-MS Analysis• 16 amino acids were formed• 5/20 protein-constituent• Glycine = most abundant

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R H

O1. NH3, HCN H2N

R

OH

O

2. H+, H2O

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Magnetochiral Photochemistry•0.2M aq. solution Cr(III)tris-oxalato complex •Dissociation and reassociation of the ligands•Laser (unpolarized) around 696 nm (vis

rouge)•Magnetic field (B) at 7,5T

CrO

O O

O

O

O

OO

OO

O

O

33K

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Rikken, G. L. J. A.; E. Raupach E. Nature, 2000, 405, 932

Magnetochiral Photochemistry

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Enantioselectivity as a fct. of the magnetic field (B)

Enantioselectivity as a fct. of the wavelenght (λ)

CrO

O O

O

O

O

OO

OO

O

O

33K

Rikken, G. L. J. A.; E. Raupach E. Nature, 2000, 405, 932

Magnetochiral Photochemistry

• Does the magnetic field convert unpolarized light in CPL ?

• Earth’s magnetic field : 10-4 T … (vs 7.5 T)

Photoresolution time : 6minRacemization : 70min

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CrO

O O

O

O

O

OO

OO

O

O

33K

Rikken, G. L. J. A.; E. Raupach E. Nature, 2000, 405, 932

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Adsorption of Chiral Organic Molecules on Enantiomorphous Crystals•Quartz = most abondant mineral on Earth•Can be helically chiral in the solid form•1974 (Bonner) : preferential adsorption of

one a.a. enantiomer out of a racemate on the crystal▫Leads to enrichement of the solution in one enantiomer !

•Drawback : anhydrous conditions…

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Bonner, W. A. and al. Science 1974, 186, 143

Amplification Reaction - Saoi

•Discovered in 1995•Autocatalytic reaction

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N

N

H

O

iPr2Zn, PhMe0oC, 40h

N

N

OH

0,2 eq (99% ee)

N

N

OZn(iPr)HCl/H2O

N

N

OH

93% ee

in solution

Saoi on Crystals

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N

N

H

O

N

N

OZn(iPr)

N

N

OH

tBu

tBu

tBu

Zn

N

N

OZn(iPr)

tBu

N

N

OH

tBu

small ee small ee

N

N

H

O

tBu

N

N

H

O

tBu

Zn Zn

high eehigh ee

CD(+) CD(-)

Saoi, K. and al. Orig Life Evol Biosph, 2010, 40, 65

Snail Shells

•Right-helical shells are stereoselectively preferred and dominant

•1 ‘racemic’ snail (Cuban tree)•Helically chiral CaCO3 ! •

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Prebiotic synthesis : Formose Reaction•Ribose (C5H10O5) is a formal pentamer of

formaldehyde (CH2O)

Northrup, A. B.; MacMillan, D. W. C., J.A.C.S. 2002, 124, 6798Breslow, R. Tetrahedron Letters 52 (2011) 2028–2032Breslow, R. Tetrahedron Lett. 1959, 21, 22.

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H H

O2 slow CHO

OHH

H

H H

O

Aldol

CHO

OHH

CH2OH

Glyceraldehyde

higher carbohydrates

(D)-Glyceraldehyde

NH

CO2H

(L)-Proline

H

O

Me

NH

CO2H

10 mol%

DMF, 4oCH

O

Me

OH

Me80% y4:1 syn/anti99% ee

A.A. as Asymmetric Catalysts• Alanine : most common in protein• Isovaline : most common in meteorite• Aldol condensation of glycoaldehyde in water

H2NOH

O

Me

(L)-Alanine

H2NOH

O

Et

(L)-isovaline

Me

Pizzarello, S.; Weber, A. L. Science 2004, 303, 1151

H

O

HO

H2N

Me

OH

O

pH 5.4, 50oC, H2O HOH

HN

Me

OH

O

H

O

HO

H2N

Me

OH

O

CHO

HHO

OHH

CH2OH

D-theose7% ee

100% ee

L-A.A. gives D-sugars !

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Amino acid Ratio (D/L)

L-Serine 50,3/49,7

L-Alanine 50,8/49,2

L-Phenylalanine 52,2/47,8

L-Valine 52,2/47,8

L-Leucine 54,4/45,6

L-Glutamic Acid 60,7/39,3

L-Proline 28,9/71,1

Enantioselective Formose Reaction

L-A.A. catalyze the formation of D-glyceraldehyde preferentially?

Breslow, R. Tetrahedron Letters 52 (2011) 2028–2032

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CHO

OHH

HH H

O

CHO

OHH

CH2OH

R

H2N

O

OH

H2NOH

O

(L)-glutamic acidO

OH

21% ee

Enantioselective Formose Reaction

Breslow, R. Tetrahedron Letters 52 (2011) 2028–2032

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• Only small ee was obtained … amplification by selective solubilisation▫D-glyceraldehyde = complete water solubility▫DL-glyceraldehyde = limited water solubility

• 61/39 (21% ee) can become 92/8 (84% ee) after slow water evaporation

CHO

OHH

H

H H

O

CHO

OHH

CH2OH

H2NOH

O

O

OH

21% ee

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Morowithz Treatment – A. A.

•Most A.A. form racemic compound crystals are less solubles (and higher m.p.) than L or D enantiomers

•Ex : 1% ee solution of D and L-A.A (in H2O)▫As the water evaporates the less soluble

crystals would precipitates leaving increased richness in one enantiomers

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Morowitz, H. J. Theor. Biol. 1969, 25, 491

Example • 500mg of phenylalanine with 1% ee • Dissolved in water• Slow evaporation until the bulk of the material had

crystallized (>400mg)• Solution is now 40% ee … repeat• Solution is now 90,9% ee• Recovered mass is 20mg

H2NOH

O

Bn(L)-Phenylalanine

Breslow, R.; Levine, M. S. PNAS 2006, 35, 12979

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Precipitation of A.A.

•2001 (Viedma)•D-tyrosine crystallized faster

than L-tyrosine•Parity non-conserving energy

•2006 (Scolnik): repeated experiment

•Same result !• ‘undetectable impurities’…

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H2NOH

O

(L)-tyrosineOH

Viedma, C. Orig Life Evol Biosphere 2001, 31, 501Scolnik, Y. and al. Phys Chem 2006, 8, 333

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Unidirectional Rotation of Earth

•Tornado have a ‘prefered’ rotation that are opposite from Northern and Southern hemisphere.

•Due to ‘not well understood’ amplification mechanism

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Kovacs, K. L.; Keszthelyi, L. Origin of Life 1981, 11, 93

NaClO3

• 100g of NaClO3 in 120mL of H2O at 50oC• Induce precipitation = racemic

• Stirred solution • 99,7% ee in 32 differents crystallisations

▫18 (L) ; 14 (R) • Unpredicable and random

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Kondepudi, D. K. and al. Science 1990, 250, 975

Unidirectional Rotation of Earth

• 1981 : Clockwise stirring = preference for the incorporation

of D-isomers into the polymers and longer polymers• Not convincing enough to conclude unequivocally…

HN

OO

R

O

NCA

H2N

R

NH

O R

OH

O

n

CO2

*NaOMe (cat.)

Kovacs, K., L.; Keszthelyi, L.; Goldanskii, V. J.; Origin of Life 1981, 11, 93-103

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Aggregation of Disk-Shaped Porphyrins

• Stacks (electrostatic and H-bonding interactions)

• Small aggregates assemble into fiberlike structures with helical orientation▫ controlled by the direction

of the vortex motion

• Orientations detected by the absorption of circularly polarized light.

Ribo, J. M. et al. Science 2001, 292, 2063

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• How ? a particular handedness is imposed by the stirring direction

• 1st unequivocal demonstration of chiral selection induced by stirring.

• The supramolecular structure may act as a homochiral template for subsequent asymmetric reactions or may function as a chiral catalyst.

Aggregation of Disk-Shaped Porphyrins

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Ribo, J. M. et al. Science 2001, 292, 2063

Conclusion

•No hypothesis has been accepted yet•Terrestrial vs Extraterrestrial theory

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1. Difference in energy of enantiomers : Parity violation

2. Chirality form polarized light : Selective degradation

3. Chiral field : Magnetism4. Amplification and transfert of chirality5. Crystallization6. Unidirectional rotation of Earth