Asymmetric Autocatalysis and the Origin of Homochirality of Biomolecules

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ELSI 1

^st

Symposium Tokyo Tech, Tokyo March 27-29, 2013

Asymmetric Autocatalysis and the Origin of Homochirality of

Biomolecules

Kenso Soai

Department of Applied Chemistry Tokyo University of Science

[email protected]

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Molecular Asymmetry

C

a

b

c

d

a

b c

d C

L-Amino Acid D-Amino Acid

R

H₂N H COOH

R

NH₂ HOOC

H

Natural Unnatural

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Origins of Chiral Homogeneity of Biomolecules

Origins of chirality (proposed) Circularly polarized light Chiral inorganic crystal: Quartz

H₂N CO₂H

R H

L-amino acid Homochirality

Base

HO OH (H) HO O

D-sugar

Why and when did biomolecules become highly enantiomerically enriched ?

Chiral organic compound with low enantiomeric excess

Asymmetric induction

?

Asymmetric autocatalysis with amplification of ee

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Text books tell:

Without any chiral catalyst or ligand, the probability of the formation of S and R enantiomers is 1 : 1, the product is racemate containing the equal amounts of S and R enantiomers.

To synthesize enantioenriched compounds, one needs to use asymmetric (chiral) catalyst or ligand.

Asymmetric catalysis

A ⁺ B

C*

asymmetric cat. D*

% enantiomeric excess (ee)

R - S

R + S X¹⁰⁰

99 99.5 0.5

90 95 5

50 75 25

2 51 49

0 (racemate) 50 50

Ratio of enantiomers

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N N

CHO

+ N

N

OH N

N

OH

Asymmetric

autocatalysis N

N

CHO

The same structure &

configuration

R¹

R¹ N

N

R¹

OZn

Pyrimidyl alkanol

R¹= H: 93% ee

R¹= H: 63%, 90% ee

R¹= Me: 95% ee

R¹= Me: 48%, 96% ee

Asymmetric autocatalyst

+

"Initial Catalyst"

"Final Product"

N N

OH R¹

i-Pr₂Zn H⁺

Highly Enantioselective Asymmetric Autocatalysis

i-Pr₂Zn

N N

OH R¹

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N N

OH

N N

CHO

i-Pr₂Zn ^N

N

OH

Asymm. autocat.

(% ee)

Product Yield(%) ee(%)

>99.5 >99 >99.5 1

aldehyde : i-Pr₂Zn : catalyst = 1.0 : 1.7 : 0.2

+

The same structure &

configuration

>99%, >99.5% ee

2-Alkynyl-5-pyrimidyl alkanol

Molar ratio:

Practically Perfect Asymmetric Autocatalysis

Asymmetric autocatalyst

Product

Consecutive Asymmetric Autocatalysis

Factor of multiplication

ca. 6x10⁷times

>99.5 >99 >99.5

>99.5 >99 >99.5 2

3 4 5 6 7 8 9 10

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N N

CHO

R¹

i-Pr₂Zn

N N

OH R¹

N N

OZn R¹

N N

OH R¹

H⁺

i-Pr₂Zn

Run

(R¹= H) Asym. autocat.

(% ee)

Asym. autocat. & Product Yield (%) (% ee)

1 2 ⁴⁶ ¹⁰

+

low ee

R¹= H, Me

Asymmetric Autocatalysis with Amplification of Enantiomeric Excess

Amplification of ee without the need for any other chiral auxiliary

Asymmetric autocatalysis

Asymmetric automultiplication High ee

Consecutive asymmetric autocatalysis with amplification of ee

2 3 4 5

10 57 81 88

75 80 75 79

57 81

88

88% ee 2% ee

Soai, K.; Shibata, T.; Morioka, H.; Choji, K. Nature, 1995, 378, 767.

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Origins of Chiral Homogeneity of Biomolecules

Origins of chirality (proposed) Circularly polarized light Chiral inorganic crystal: Quartz

H₂N CO₂H

R H

L-amino acid Homochirality

Base

HO OH (H) HO O

D-sugar

Why and when did biomolecules become highly enantiomerically enriched ?

Chiral organic compound with low enantiomeric excess

Asymmetric induction

?

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Origins of Homochirality of Organic Compounds

Circularly polarized light

Chiral organic crystals formed from achiral compounds

Chiral inorganic crystals: Quartz, Sodium chlorate Spontaneous absolute asymmetric synthesis

Examination in Conjunction with Asymmetric Autocatalysis

Achiral organic crystal formed from achiral compound

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N N R

OZn

i-Pr₂Zn N

N R

CHO

S

Asymmetric Autocatalysis of Pyrimidyl Alkanol

without Adding Chiral Substance

N N R

OZn

N N R

OH N

N R

OH

Asymmetric

autocatalysis with amplification of ee

Not adding

chiral substance +

S

Low ee

K. Soai, T. Shibata, Y. Kowata, Japanese Patent, (1997) 9268179.

R R

Spontaneous Absolute Asymmetric Synthesis

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N N

OH

t-Bu

N N t-Bu

OH S i-Pr₂Zn/toluene i-Pr₂Zn/toluene

HCl

0 ℃

R +

Et₂O Et₂O

+ +

Asymmetric synthesis of Pyrimidyl Alkanol without Adding Chiral Substance in Conjuction with Asymmetric Autocatalysis in a Mixed Solvent of Diethyl Ether and Toluene

N N

CHO

t-Bu

N N

CHO

t-Bu

0.1 mmol

0.2 mmol

0.4 mmol

0.8 mmol

0.7 ml 3.0 ml

stirred for 1h stirred for 1h

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0 2 4 6 8 10 12 14 16 18

100 80 60 40 20 5 0.5 0.5 5 20 40 60 80 100 Ee of the produced pyrimidyl alkanol

Distribution of ( S )-and ( R )-pyrimidyl alkanol is almost stochastic

Frequency

S:R = 51:49

S R

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Direct Irradiation of

Circularly Polarized Light

to Asymmeric Autocatalysis

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N N t-Bu

OH

N N t-Bu

OH

N N t-Bu

OH

N N t-Bu

OH

N N t-Bu

OH

i-Pr₂Zn ⁺ N

t-Bu N

CHO

i-Pr₂Zn

+ N

t-Bu N

CHO 500 W Hg lamp

313 nm EtOH 40 ºC, 96 h

cumene, 0 ºC

S

R R

S

racemate

low ee

high ee

Asymmetric Autocatalysis of Pyrimidyl Alkanol Irradiated with l- or r-CPL (313 nm)

*

Asymmetric autocatalysis photoreaction

decomposition <10%

l-CPL

r-CPL

Entry 5-pyrimidyl alkanol Yield/ % ee/ %

1 2 3 4

l r l r

95 97 97 98

85 82 60 65

CPL config.

S R S R

Entry 5-pyrimidyl alkanol Yield/ % ee/ %

5 6 7 8

l r l r

92 90 95 94

65 56 62 70

CPL config.

S R S R

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N N t-Bu

OH

N N t-Bu

OH

N N t-Bu

OH

i-Pr₂Zn ⁺ N

t-Bu N

CHO

i-Pr₂Zn ⁺ N

t-Bu N

CHO

500 W Hg lamp 313 nm (290-390 nm)

cumene, 0 ºC

S

racemate

>99.5% ee

Direct Relationship Between CPL and Organic Compound with High ee

Asymmetric Autocatalysis

>99.5% ee

l-CPL

r-CPL ^R

Asymmetric Photoreaction

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Enantioselective Synthesis of Pyrimidyl Alkanol in the Presence of d- or l-Quartz

Pyrimidyl alkanol

Run Quartz

Yield (%) ee(%)(config.) Series A

A1 d (4.4 m) 90 89 (S)

A2 l (7.6 m) 97 85 (R)

A3 d 88 86 (S)

A4 l 96 84 (R)

Series B

B1 l 97 95 (R)

B2 l 97 93 (R)

B3 d 96 95 (S)

B4 d 97 95 (S)

Series C

C1 d 93 97 (S)

C2 l 97 97 (R)

C3 l 95 97 (R)

Series D

D1 l (3.4 m) 95 93 (R)

D2 d (2.9 m) 95 94 (S)

For Series B-D, quartz (SiO2) : aldehyde :i-Pr2Zn = 1.9 : 1.0 : 2.0. Added in three portions.

For Series A, quartz (SiO2) : aldehyde :i-Pr2Zn = 8.0 : 1.0 : 2.5. Added in two portions.

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The Deuterium Enrichment of Amino acids in Carbonaceous Meteorites

Amino acid Murchison Murray

Pizzarello S.; Huang Y. Geochim. Cosmochim. Acta 2005, 69, 599.

δ D of terrestrial compound is about 50 Glycine

D -Alanine

-Methylalanine

DL -Isovaline

399 ± 17 614 ± 61 3097 ± 86 3181 ± 108 3419 ± 118

429 ± 127 3058 ± 186

δ D ‰  δ D ‰ 

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Glycine--d 0.05 mmol

HO O

 NH₂ D

+ i-Pr₂Zn in

m.c.h.

0.15 mmol

over 12 h, r.t. toluene, 0 °C

0.05 mmol in m.c.h.(2.0 ml)

N N t-Bu

CHO

i-Pr₂Zn in m.c.h.

0.05 mmol

slowly portionwise

addition 2 times ^N

N t-Bu

 OH

0 °C

Entry Glycine-α-d Pyrimidyl alkanol

Yield(%) ee(%) Config.

1 2 3 4 5 6

R

R S

S

90 94 94 95 94 94

91 96 93 93 91 94

R

R S

S

Asymmetric Autocatalysis using Chiral Deuterated Glycine as

Chiral Initiator

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3 R 89 89 85 S

4 S 93 97 94 R

5 R 89 94 92 S

6 S 93 95 96 R

Asymmetric Autocatalysis Triggered by Carbon Isotopically Chiral Alcohol

N N

CHO

N N t-Bu

OH +

t-Bu i-Pr₂Zn

S N

N t-Bu

OH R

Asymmetric autocatalysis with amplification of ee

13CH₃ H₃C

Ph OH H₃¹³C CH₃

OH Ph

R S

12C/¹³C-Chiral Alcohol Pyrimidyl alkanol Entry

Config. ee (%) Yield (%) ee (%) Config.

1 R 89 96 88 S

2 S 93 92 93 R

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(R) (S)

Ph

HO ¹⁸OH Ph

(R) (S)

Ph

H¹⁸O OH Ph meso-

Hydrobenzoin (1)

18O-Labelling

(S)-1-¹⁸O (R)-1-¹⁸O

(R) (S)

Ph

HO OH

Ph

Chiral oxygen isotopomer

Generation of chirality by the oxygen isotope substitution

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N N

R CHO

N N R

OH N

N R

OH

+ i-Pr₂Zn

(S)-3

(R) (S)

Ph

HO ¹⁸OH Ph

(R) (S)

Ph

H¹⁸O OH Ph

(S)-1-¹⁸O

(R)-1-¹⁸O Asymmetric

Autocatalysis with

Amplification of ee

(R)-3

2

R = t-Bu-CC-

Chiral trigger 5-Pyrimidyl alka nol 2 Entry

Sam ple# Yield ee config.

1 (S)-1-^{1 8}O #1 97 97 R

2 (R)-1-^{1 8}O #2 96 89 S

3 (S)-1-^{1 8}O #1 85 93 R

4 (R)-1-^{1 8}O #2 93 91 S

5 (S)-1-^{1 8}O #3 82 93 R

6 (R)-1-^{1 8}O #4 94 96 S

Asymmetric autocatalysis triggered by

chiral oxygen isotopomer

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Correlation Between Crystal Face and CD

Kawasaki, T.; Hakoda, Y, Mineki, H.; Suzuku, K.; Soai, K. J. Am. Chem. Soc. 2010, 132, 2874-2875.

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0.075 mmol in toluene Aldehyde

0.025 mmol

N N

CHO

t-Bu

+ i-Pr₂Zn

Cytosine dehydrated Crystal [CD(+)310(KBr)]

Cytosine dehydrated Crystal [CD(-)310(KBr)]

N N t-Bu

OH S

N N t-Bu

OH R

Portionwise Addition 3 Times

Portionwise Addition

1st: Aldehyde 0.1 mmol, i-Pr₂Zn in Toluene 0.3 mmol 2nd: Aldehyde 0.4 mmol, i-Pr₂Zn in Toluene 0.8 mmol 3rd: Aldehyde 0.8 mmol, i-Pr2Zn in Toluene 1.6 mmol

Additional 4 rounds of asymmetric autocatalysis.Additional 3 rounds of asymmetric autocatalysis.

a) b)

Asymmetric Autocatalysis Initiated by Chiral Dehydrated Crystal of Cytosine

1 2 3 4 5 6 7 8 9 10

CD(+)310(KBr) CD(-)310(KBr) CD(+)310(KBr)

CD(-)310(KBr) CD(+)310(KBr)

CD(-)310(KBr)

S R S R S R S R S R

Entry Chiral Initiator

Crystal of Dehydrated Cytosine

Pyrimidyl Alkanol

Yield (%) Ee(%) Config.

88 88 85 88 87 87 95 99 88 90

92 94 89 96 96 91 90 96

>99.5

a) b)

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Summary

N

OH N N

* *OH

R

N N

*OH

>99%, >99.5% ee

N

*OH

ca. 0.00005% ee >99.5% ee ^N

N

*OH R

( I )

( II )

N N

*OH R High ee

aldehyde ⁺ i-Pr₂Zn

( III )

R Practically perfect

asymmetric autocatalysis

Origin of homochirality of organic compound

Circularly polarized light Chiral compound with high ee

Inorganic chiral crystals

d- and l-Quartz

d- and l-Sodium chlorate

Spontaneous asymmetric synthesis Chiral silica