Soai reaction-Asymmetric autocatalysis withamplification of eeLiterature seminar
2017/08/19
Takashi Ishiyama(M2)1Contents

1. Introduction
2. Discovery of soai reaction
3. Application of soai reaction(Various chiral sources and origin of homochirality)
4. Mechanism of soai reaction2

Homochirality

All organism is composed of one enantiomer : Homochirality of life3

What is origin of homochirality?

4Origin of asymmetry(Circular polarized light)

Circularly polarized light is proposed
as one of the origins of chirality.

CPL

Orig. Life Evol. Biosph., 2010, 40, 335.
5https://www.nao.ac.jp/releaselist/archive/20100406/index_j.html

Origin of asymmetry(Circular polarized light)

Infrared observation resultof circularly polarized lightof Orion great nebula

Red…
Yellow…

① Solar system formed in large mass star formationarea.
② The primitive solar system was irradiated withcircularly polarized light in one direction.
③ Amino acids were biased towards L-type and later
introduced by meteorites onto the earth.

The theory that circular polarization is the origin of chirality

6Origin of asymmetry(Circular polarized light)
L form isexcessive,
butinsufficient…

Essential for associating
the origin of asymmetry
with the current homochirality
7J. R. Cronin, et al., Science, 1997, 275, 951.

Asymmetric autocatalysis with amplification of eeHigh reaction rate, theoretically infinite growth rate

Self-multiplication of chiral compounds resembles self-propagation of life.
→This reaction is related to the origin of homochirality???
(Suggested by frank in 1953)
8

F. C. Frank, Biochim. Biophys. Acta, 1953, 11, 459.

Prof. Kenso Soai

His recent research(1)Asymmetric autocatalysis (Asymmetric automultiplication,Self-replication of chiral compounds)(2) Asymmetric autocatalysis with amplification ofenantiomeric excess(3) Origins of chirality, origins of chirality of biomolecules(4) Dendritic chiral catalyst
9Contents

1. Introduction
2. Discovery of soai reaction
3. Application of soai reaction(Various chiral sources and origin of homochirality)
4. Mechanism of soai reaction

10

Asymmetric alkylation of aldehydes

Reaction rate (A)>(B) …→ Product of (A) accelerates this reaction?

K. Soai, S. Hori, S. Niwa, Heterocycles, 1989, 29, 2065.
11K. Soai, S. Yokoyama, T. Hayasaka, J. Org. Chem., 1991, 56, 4264.

First asymmetric autocatalytic reaction

12K. Soai, S. Niwa, S. Hori, J. Chem. Soc., Chem. Commun., 1990, 982.

Other substrates for asymmetric autocatalytic reaction

13K. Soai, et al. J. Fluorine Chem., 2010, 131, 525.

The most effective asymmetric autocatalyst

14K. Soai, et al. Angew. Chem., Int. Ed., 1999, 38, 659.

Asymmetric amplification• First example of Asymmetric amplificationyx

15H. B. Kagan, et al. J. Am. Chem. Soc. 1986, 108, 2353.

Asymmetric autocatalyst and Asymmetric amplification

16K. Soai, T. Shubata, H. Morioka, K. Choji, Nature, 1995, 378, 767.

Asymmetric autocatalyst and Asymmetric amplification

Amplification of ee

Relationship between catalyst and product eeyx

17

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

The most effective asymmetric autocatalyst

18

K. Soai, et al. Angew. Chem. Int. Ed., 2003, 42, 315.

Summary 1• Soai Reaction is the only example of asymmetricautocatalytic reactions with elevated enantiomeric
excess.
• Compounds with almost 100% ee can be obtained
from low ee compounds.

19

Contents

1. Introduction
2. Discovery of soai reaction
3. Application of soai reaction(Various chiral sources and origin of homochirality)
4. Mechanism of soai reaction20

Association of high ee with the origin of asymmetry• Establishing a model process where the origin ofasymmetry has led to homochirality• Finding new asymmetric origins
21

Various Chiral initiators

Various chiral compounds induce chiral amplification.
22K. Soai, et al. J. Fluorine Chem., 2010, 131, 525.

Various Chiral initiators(origin of chiral?)[Circularly polarized light][Quartz][Chiral organic crystal]Candidate for origin of chiral↓>99.5% ee products

Indicating thatthey can be the origin of chiral
23K. Soai, et al. Chem. Rec., 2014, 14, 70.

Spontaneous absolute asymmetric synthesis

But…

(%)

30
25
20
15
10

Coin toss (×10)

500123456789

Enantiomeric excess by statistical fluctuation (undetectable)

1024

Spontaneous absolute asymmetric synthesis

× 3725

K. Soai, et al. Atetrahedron: Asymmetry., 2003, 14, 185.

Result (table)(S)-product × 19, (R)-product × 18
26

K. Soai, et al. Atetrahedron: Asymmetry., 2003, 14, 185.

Result (graph)(R)-product(S)-product

The only example that achieved spontaneous asymmetric synthesis
27

K. Soai, et al. Tetrahedron: Asymmetry., 2003, 14, 185.

Chirality by isotope replacement

28

Asymmetric Autocatalysis triggered by C12/C13 Chirality

29

K. Soai, et al. Science, 2009, 324, 109.

Asymmetric Autocatalysis triggered by H/D Chirality

K. Soai, et al. Chem. Commun., 2009, 4396.
30
K. Soai, et al. Chem. Lett., 2011, 40, 324.

Asymmetric Autocatalysis triggered by H/D Chirality

meteorite

Amino acids in the meteorite contain a lot of deuterium.
A new theory that the origin of homochirality is chirality bydeuterium substitution?
31

S. Pizzarello, et al. GeoChim. Cosmochim. Acta, 2005, 69, 599.

Summary 2• From very small asymmetric bias induced byasymmetric environment, almost chiral molecules
can be obtained.
• Association between asymmetric origin andhomochirality• Presentation of new asymmetric origin candidates

32

Contents

1. Introduction
2. Discovery of soai reaction
3. Application of soai reaction(Various chiral sources and origin of homochirality)
4. Mechanism of soai reaction

33

Autocatalysis Alone

catalyst is only a tiny fraction less than perfect(ee0 < 1).

< eecat,0

Autocatalysis alone is not enough.
Need something to amplify ee of products.
34

D. G. Blackmond, Proc. Nat. Acad. Sci. USA 2004, 101, 5732.

Autocatalysis Plus Inhibition

F. C. Frank, Biochim. Biophys. Acta, 1953,3511, 459.
D. G. Blackmond, Proc. Nat. Acad. Sci. USA 2004, 101, 5732.

Autocatalysis Plus Inhibition

Asymmetric amplification is achieved when theequilibria governing dimer formation areF. C. Frank, Biochim. Biophys. Acta, 1953,3611, 459.
biased toward formation of SR.
D. G. Blackmond, Proc. Nat. Acad. Sci. USA 2004, 101, 5732.

A Paradox Emerges

Initial rate for a racemic catalyst wasobserved to be approximately onehalf that of an enantiopure catalyst.

How to describe compatibility between nonselective formationof the heterochiral and homochiral dimers and ee amplification in a compatible manner?
37

D. G. Blackmond, Proc. Nat. Acad. Sci. USA 2004, 101, 5732.

Catalyst is not monomer

If the homochiral catalyst is more active than the heterochiralcatalyst, we can explain the amplification of ee
38

D. G. Blackmond, Proc. Nat. Acad. Sci. USA 2004, 101, 5732.

reaction rate analysis
Broken curve…
simulation assuming the first-order autocatalytic reaction

Start : 1 mol%

The active species of the reaction is not a monomer.
39

K. Soai, et al. Tetrahedron: Asymmetry, 2001, 12, 1965.

Tetrameric transition state?

This result showed that Dimer of alkoxide reacts with two aldehyde.
40

F. G. Buono, D. G. Blackmond, J. Am. Chem. Soc., 2003, 125, 8978.

NMR study of dimer catalyst

Dimer of the product was observed by NMR.
41

J. M Brown, et al. Angew. Chem. Int. Ed., 2004, 43, 4884.

DFT study of soai reaction

L. Schiaffino, G. Ercolani, Angew. Chem. Int. Ed., 2008, 47, 6832.
42
L. Schiaffino, G. Ercolani, Chem. Eur. J., 2010, 16, 3156.

Problem of the simple dimer model
1. The homochiral dimers are the only catalytically activespecies.
2. The reaction rate is first-order in the homochiral dimers.
3. The homochiral dimers reproduce themselves with 100 %enantioselectivity.
4. There is a fast metathesis equilibrium between homoand heterodimer which is only dictated by statistics.

43

L. Schiaffino, G. Ercolani, ChemPhysChem, 2009, 10, 2508.

Problem of the simple dimer modelThis simple dimer model is unsuitable to explain the amplification ofchirality observed in the case of 1a at 0 ℃.
44

L. Schiaffino, G. Ercolani, ChemPhysChem, 2009, 10, 2508.

Inverce temperature dependence on reaction rate

in situ formation of an active
oligomeric catalyst−substratecomplex?
It becomes increasingly stabilized
as the temperature decreases.

45

D. G. Blackmond, et al. J. Am. Chem. Soc., 2010, 132, 15104.

Detailed analysis by 2D-NMR
Rotationally restrictedpyrimidine rings

Proposed Structure for Homochiral Tetramer (3c)4Formation of tetramers at low temperature was observed by NMR studies.
Aggregation is maintained at ambient temperature.
46D. G. Blackmond, et al. J. Am. Chem. Soc., 2010, 132, 15104.

Problem of Schiaffino and Ercolani’s model?

Large energy is required for the dissociation of
the tetrameric product into two molecules ofthe dimeric catalyst.
Recovery of the catalyst from the product isvirtually impossible?
L. Schiaffino, G. Ercolani, Chem. Eur. J., 2010, 16, 3156.
47
I. D. Gridnev, A. K. Vorobiev, ACS. Catal., 2012, 2, 2137.

Computation of the catalytic cycle with the Homochiral tetramer

48

I. D. Gridnev, A. K. Vorobiev, ACS. Catal., 2012, 2, 2137.

Transition state of this model• Substrate molecule has a suitable shapecomplementarity to the cavity of 3·ZnPr2i .
• But–C≡C– substituent of the pyrimidyl ring serves asa structural anchor leading to a well-defined
substrate orientation.
• Formation of the product with the same
handedness as the tetrameric catalyst49

X-ray analysis of asymmetric autocatalyst

Obtained four kinds of single crystals
50

K. Soai, et al. Angew. Chem. Int. Ed., 2015, 54, 15218.

Tetramer structures(crystal A/B)

two dimers coordinate to eachother to form a 12-memberedmacrocycle

51

K. Soai, et al. Angew. Chem. Int. Ed., 2015, 54, 15218.

Tetramer structures(crystal A/B)

• Difference of conformation around the 12-membered macrocycles seems to be important.
• Unsaturated Zn should have higher catalytic activity.
52

K. Soai, et al. Angew. Chem. Int. Ed., 2015, 54, 15218.

Oligomeric structures(crystal C/D)

• No coordinative diisopropylzinc→N in the pyrimidine ring forms anoter
12-membered macrocycles.
→oligomeric structure• Both oligomer structure have similarconformation.

53K. Soai, et al. Angew. Chem. Int. Ed., 2015, 54, 15218.

Change of crystal structure due to THF• Two THF in the tetramer structure• No coordinatively unsaturated Zn atoms

54Summary 3• Several groups examined mechanism of soai
reaction based on kinetic experiments, reaction
modeling, NMR, and DFT calculations.
• Asymmetric amplification of this reaction occurs
because the alkoxide of the product forms a
multimer and the homochiral catalyst is more
active than the heterochiral catalyst.
• In particular, the tetramer has a structure that issignificantly different between chiral and racemic.
→key to asymmetric amplification?

55

Today’s summary• Prof. Soai showed that molecules of nearly purechirality can be obtained from various asymmetricsources and gave great insight to unresolved
problems of homochirality and the origin of life.
• Although the mechanism of the asymmetric self
reaction reaction has not yet been elucidated,
useful clues are being obtained.

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