Asymmetric Autocatalysis with Amplification of Enantiomeric Excess

1
Asymmetric Autocatalysis with Amplification of
Enantiomeric Excess

• Sophie Rousseaux
• October 30, 2008

2
Asymmetric Synthesis
Strecker Reaction
Corey, E. J. Grogan, M. J. Org. Lett. 1999, 1,
157.
3
Absolute Asymmetric Synthesis
Formation of optically active materials from
achiral starting materials in the absence of
optically active reagents or catalysts.
For a review on absolute asymmetric synthesis
Feringa, B. L. van Delden, R. A. Angew. Chem.
Int. Ed. 1999, 38, 3418.
4
Biomolecular Homochirality and the Origins of Life
The backbone of DNA (and RNA) is strictly made up
of D-sugars
L-amino acids are encoded into proteins to
generate their primary structure
When and how did this biomolecular chirality
originate?
5
Origins of Biomolecular Chirality
Bada, J. L. Nature 1995, 374, 594.
6
Spontaneous Asymmetric Synthesis - A Theoretical
Possibility
RARE EVENT
A simple and sufficient life model for the
present purpose is a chemical substance which is
a catalyst for its own production and an
anti-catalyst for the production of its optical
antimer.
Frank, F. C. Biochim. Biophys. Acta 1953, 11, 459.
7
Mechanistic Proposals for the Origin of Chirality
in Organic Compounds

• Extraterrestrial Origin - Murchison Meteorite
• Murchison Meteorite - Most recently
  observed/studied meteorite to have fallen to
  earth (Australia, 1969)
• Type of meteorite that is rich in organic
  molecules

Circular-polarized light has been observed in
areas of star formation.
An excess of unnatural L-amino acids has been
discovered in the Murchison meteorite.
Circular polarization might have been important
in inducing chiral asymmetry in interstellar
organic molecules that could be subsequently
delivered to the early Earth by comets,
interplanetary dust particles, or meteors.
For a review on absolute asymmetric synthesis
Feringa, B. L. van Delden, R. A. Angew. Chem.
Int. Ed. 1999, 38, 3418. Cronin, J. R.
Pizzarello, S. Science 1997, 275, 951. Engel, M.
H. Macko, S. A. Nature 1997, 389, 265. Bailey,
J. Chrysostomou, A. Hough, J. H. Gledhill, T.
M. McCall, A. Clark, S. Ménard, F. Tamura, M.
Science 1998, 281, 672.
8
Mechanistic Proposals for the Origin of Chirality
in Organic Compounds
Absolute Asymmetric Synthesis via Preferential
Photosynthesis
Circular polarized light (CPL) - chiral
electromagnetic radiation Irradiation of a
prochiral molecule with CPL might preferentially
convert the ground state of molecules into an
excited state with a certain chirality.
For a review on absolute asymmetric synthesis
Feringa, B. L. van Delden, R. A. Angew. Chem.
Int. Ed. 1999, 38, 3418. Moradpou, A. Nicoud, J.
F. Balavoine, G. Kagan, H. Tsoucaris, G. J.
Am. Chem. Soc. 1971, 93, 2353.
9
Mechanistic Proposals for the Origin of Chirality
in Organic Compounds
Absolute Asymmetric Synthesis via Preferential
Photodestruction
Circular polarized light (CPL) - chiral
electromagnetic radiation Right- and
left-handed CPL should preferentially interact
with one enantiomer of substances.
For a review on absolute asymmetric synthesis
Feringa, B. L. van Delden, R. A. Angew. Chem.
Int. Ed. 1999, 38, 3418. Flores, J. J. Bonner,
W. A. Massey, G. A. J. Am. Chem. Soc. 1977, 99,
3622.
10
Outline
RARE EVENT

• Nonlinear Effects
• ML2 model
• Reservoir model
• Asymmetric Autocatalysis
• Mechanistic Understanding of Asymmetric
  Autocatalysis with Amplification of ee
• Absolute Asymmetric Autocatalysis
• Conclusion

11
Linearity in Asymmetric Synthesis
eeprod eemax x eecat where eemax is the
maximum ee value that can be obtained with an
enantiopure auxiliary
eeprod ()
eeaux ()
For a review Girard, C. Kagan, H. B. Angew.
Chem. Int. Ed. 1998, 37, 2922.
12
An Odd Observation for the Sharpless Asymmetric
Epoxidation
ee epoxide ()
The product ee exceeds that of the catalyst
(R,R)-()-DET.
45 ee product 20 ee catalyst
ee DET ()
Puchot, C. Samuel, O. Duñach, E. Zhao, S.
Agami, C. Kagan, H. B. J. Am. Chem. Soc. 1986,
108, 2353.
13
Nonlinearity in Asymmetric Synthesis
eeprod ()
eeaux ()
For a review Girard, C. Kagan, H. B. Angew.
Chem. Int. Ed. 1998, 37, 2922.
14
Linearity in Asymmetric Synthesis
eeprod ()
eeaux ()
eeprod ()
eeaux ()
14
For a review Girard, C. Kagan, H. B. Angew.
Chem. Int. Ed. 1998, 37, 2922.
15
Kagans MLn model
Guillaneux, D. Zhao, S.-H. Samuel, O.
Rainford, D. Kagan, H. B. J. Am. Chem. Soc.
1994, 116, 9430.
16
Kagans ML2 model
Guillaneux, D. Zhao, S.-H. Samuel, O.
Rainford, D. Kagan, H. B. J. Am. Chem. Soc.
1994, 116, 9430.
17
Kagans ML2 model - Positive NLE
meso
? ?
fast
fast
slow
eeprod ()
eeaux ()
Guillaneux, D. Zhao, S.-H. Samuel, O.
Rainford, D. Kagan, H. B. J. Am. Chem. Soc.
1994, 116, 9430.
18
Kagans ML2 model - Negative NLE
meso
? ?
fast
slow
fast
slow
fast
slow
eeprod ()
eeaux ()
Guillaneux, D. Zhao, S.-H. Samuel, O.
Rainford, D. Kagan, H. B. J. Am. Chem. Soc.
1994, 116, 9430.
19
NLEs in Asymmetric Epoxidation
ee epoxide ()
ee DET ()
Puchot, C. Samuel, O. Duñach, E. Zhao, S.
Agami, C. Kagan, H. B. J. Am. Chem. Soc. 1986,
108, 2353.
20
Reservoir Model
Guillaneux, D. Zhao, S.-H. Samuel, O.
Rainford, D. Kagan, H. B. J. Am. Chem. Soc.
1994, 116, 9430.
21
NLEs in the Addition of Dialkylzincs to Aldehydes
eeprod ()
eeaux ()
Kitamura, M. Okada, S. Suga, S. Noyori, R. J.
Am. Chem. Soc. 1989, 111, 4028. Kitamura, M.
Suga, S. Niwa, M. Noyori, R. J. Am. Chem. Soc.
1995, 117, 4832.
22
NLEs in the Addition of Dialkylzincs to Aldehydes
52
2
4 ee
48
48
0
Kitamura, M. Okada, S. Suga, S. Noyori, R. J.
Am. Chem. Soc. 1989, 111, 4028. Kitamura, M.
Suga, S. Niwa, M. Noyori, R. J. Am. Chem. Soc.
1995, 117, 4832.
23
From Nonlinear Effects to Autocatalysis
Nonlinear effects
Asymmetric autocatalysis
RARE EVENT
24
Asymmetric Autocatalysis
catalyst

• Advantages
• No chiral auxiliary
• High reaction efficiency (increased rate over
  time)
• No deterioration or loss of chiral catalyst

For reviews (a) Soai, K. Shibata, T. Satu I.
Acc. Chem. Res. 2000, 33, 382. (b) Soai, K.
Sato, I. Shibata, T. Chem. Record 2001, 1, 321.
25
The First Experimental Observation of Asymmetric
Autocatalysis
with correction 67 yield, 35 ee
Soai, K. Niwa, S. Hori, H. J. Chem. Soc., Chem.
Commun. 1990, 982.
26
Highly Enantioselective Asymmetric Autocatalysis
Shibata, T. Morioka, H. Hayase, T. Choji, K.
Soai, K. J. Am. Chem. Soc. 1996, 118, 471.
27
Autocatalysis with Amplification of Enantiomeric
Excess
Positive NLE
Soai, K. Shibata, T. Morioka, H. Choji, K.
Nature 1995, 378, 767.
28
Autocatalysis with Amplification of Enantiomeric
Excess
Soai, K. Shibata, T. Morioka, H. Choji, K.
Nature 1995, 378, 767.
29
Autocatalysis with Amplification of Enantiomeric
Excess
Start - 3.7 mg, 2 ee Finish - 1.88 g, 88 ee
5 Reactions
Soai, K. Shibata, T. Morioka, H. Choji, K.
Nature 1995, 378, 767.
30
Evidence for the Formation of Dimers
Enantiopure mixture
(R,R) dimer
Racemic mixture
Gridnev, I. D. Serafimov, J. M. Brown, J. M.
Angew. Chem. Int. Ed. 2004, 43, 4884.
31
Reaction Calorimetry
Reaction calorimetry is a method for the direct
measurement of the heat evolved or consumed (q)
by a reaction which in turn is directly
proportional to the reaction rate.
conversion
Heat flow (Watts)
Time (min)
For a review on reaction calorimetry in kinetic
analysis Blackmond, D. G. Angew. Chem. Int. Ed.
2005, 44, 4302.
32
Reaction Progress Kinetic Analysis
Blackmond, D. G. McMillan, C. R. Ramdeehul, S.
Schorm, A. Brown, J. M. J. Am. Chem. Soc. 2001,
123, 10103.
33
Dimers Are the Catalysts
Blackmond, D. G. McMillan, C. R. Ramdeehul, S.
Schorm, A. Brown, J. M. J. Am. Chem. Soc. 2001,
123, 10103. Blackmond, D. G. Tetrahedron
Asymmetry 2006, 17, 584.
34
What We Have Learned

• Autocatalytic reaction
• Positive nonlinear effect (product ee is higher
  than the catalyst ee)
• ML2 model best describes the reaction kinetics
  (dimers are the catalysts!!!)
• Racemic (heterochiral) dimer is inactive

35
Effect of (i-Pr)2Zn Stoichiometry on Rate Laws
Zero-order kinetics in (i-Pr)2Zn
Buono, F. G. Blackmond, D. G. J. Am. Chem. Soc.
2003, 125, 8978. Blackmond, D. G. Tetrahedron
Asymmetry 2006, 17, 584.
36
Effect of (i-Pr)2Zn Stoichiometry on Rate Laws
Third order rate law
Zero-order kinetics in (i-Pr)2Zn
Buono, F. G. Blackmond, D. G. J. Am. Chem. Soc.
2003, 125, 8978. Blackmond, D. G. Tetrahedron
Asymmetry 2006, 17, 584.
37
Effect of (i-Pr)2Zn Stoichiometry on Rate Laws
rate k aldehyde (i-Pr)2Zn catalyst
rate k aldehyde catalyst
Third order kinetics
Second order kinetics
Buono, F. G. Blackmond, D. G. J. Am. Chem. Soc.
2003, 125, 8978. Blackmond, D. G. Tetrahedron
Asymmetry 2006, 17, 584.
38
Effect of (i-Pr)2Zn Stoichiometry on Rate Laws
rate k aldehyde (i-Pr)2Zn catalyst
rate k aldehyde catalyst
Third order kinetics
Second order kinetics
Buono, F. G. Blackmond, D. G. J. Am. Chem. Soc.
2003, 125, 8978. Blackmond, D. G. Tetrahedron
Asymmetry 2006, 17, 584.
39
Effect of (i-Pr)2Zn Stoichiometry on Rate Laws
rate k aldehyde (i-Pr)2Zn catalyst
rate k aldehyde catalyst
Third order kinetics
Second order kinetics
Buono, F. G. Blackmond, D. G. J. Am. Chem. Soc.
2003, 125, 8978. Blackmond, D. G. Tetrahedron
Asymmetry 2006, 17, 584.
40
Second-Order Dependence in Aldehyde
Second-order dependence in aldehyde
rate k aldehyde2 catalyst
Buono, F. G. Blackmond, D. G. J. Am. Chem. Soc.
2003, 125, 8978. Blackmond, D. G. Tetrahedron
Asymmetry 2006, 17, 584.
41
An Accurate Rate Expression
rate k aldehyde2 catalyst
Buono, F. G. Blackmond, D. G. J. Am. Chem. Soc.
2003, 125, 8978.
42
Association of (i-Pr)2Zn with the Starting
Material
aryl H
aldehyde H
-6.5 kcal/mol
-9.1 kcal/mol
Gridnev, I. D. Serafimov, J. M. Brown, J. M.
Angew. Chem. Int. Ed. 2004, 43, 4884. Gridnev, I.
D. Brown, J. M. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5727.
42
43
Association of (i-Pr)2Zn with the Catalyst
alkynyl 13C signals
Gridnev, I. D. Serafimov, J. M. Brown, J. M.
Angew. Chem. Int. Ed. 2004, 43, 4884.
44
A Plausible Mechanism
very fast (saturation kinetics)
Schiaffino, L. Ercolani, G. Angew. Chem. Int.
Ed. 2008, 47, 6832.
45
Origin of the Slight Enantiomeric Imbalance
Nonlinear effects
Asymmetric autocatalysis
RARE EVENT
46
Leucine as a Chiral Initiator
Flores, J. J. Bonner, W. A. Massey, G. A. J.
Am. Chem. Soc. 1977, 99, 3622. Shibata, T.
Yamamoto, J. Matsumoto, N. Yonekubo, S.
Osanai, S. Soai, K. J. Am. Chem. Soc. 1998, 120,
12157.
47
Absolute Asymmetric Synthesis A Thought
Experiment
A common misconception racemates are composed of
identical amounts of both enantiomers.
Siegel, J. S. Chirality 1998, 10, 24. Soai, K.
Sato, I. Shibata, T. Komiya, S. Hayashi, M.
Matsueda, Y. Imamura, H. Hayase, T. Morioka,
H. Tabira, H. Yamamoto, J. Kowata, Y.
Tetrahedron Asymmetry 2003, 14, 185.
48
Absolute Asymmetric Synthesis A Thought
Experiment
Hypothetical Question Is the product mixture
racemic after the formation of the first 5
molecules of product?
20 ee
Siegel, J. S. Chirality 1998, 10, 24. Soai, K.
Sato, I. Shibata, T. Komiya, S. Hayashi, M.
Matsueda, Y. Imamura, H. Hayase, T. Morioka,
H. Tabira, H. Yamamoto, J. Kowata, Y.
Tetrahedron Asymmetry 2003, 14, 185.
49
Absolute Asymmetric Synthesis A Thought
Experiment
Hypothetical Question Is the product mixture
racemic after the formation of the first 5
molecules of product?
Siegel, J. S. Chirality 1998, 10, 24. Soai, K.
Sato, I. Shibata, T. Komiya, S. Hayashi, M.
Matsueda, Y. Imamura, H. Hayase, T. Morioka,
H. Tabira, H. Yamamoto, J. Kowata, Y.
Tetrahedron Asymmetry 2003, 14, 185.
50
Absolute Asymmetric Synthesis
Approximately random distribution for the
formation of the R vs. S enantiomer (18 times R
vs. 19 times S).
Soai, K. Sato, I. Shibata, T. Komiya, S.
Hayashi, M. Matsueda, Y. Imamura, H. Hayase,
T. Morioka, H. Tabira, H. Yamamoto, J.
Kowata, Y. Tetrahedron Asymmetry 2003, 14, 185.
51
Conclusion
Autocatalytic reaction Positive nonlinear effect
ML2 model (homochiral dimers are the
catalyst) rate k aldehyde2 catalyst -
second-order dependence in aldehyde - zero-order
dependence in i-Pr2Zn (saturation
kinetics) Absolute asymmetric autocatalysis
52
Acknowledgments
Prof. Keith Fagnou Benoit Liégault Dave
Stuart David Lapointe Élisia Villemure Derek
Schipper Mégan Bertrand-Laperle Laurence
Caron Dan Shore Chris Whipp Malcolm
Huestis Ho-Yan Sun Nicolas Guimond Ivan
Petrov Olivier René Pamela Alsabeh
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55
Mechanistic Proposals for the Origin of Chirality
in Organic Compounds
Terrestrial Origin - Chiral Symmetry Breaking via
Crystallization
Symmetry is broken during the crystallization of
achiral NaClO3 molecules to generate optically
active chiral crystals.
5050 mixture of dextro and levo crystals for
each crystallized solution
Exclusive formation of either dextro or levo
crystals
For a review on absolute asymmetric synthesis
Feringa, B .L. van Delden, R.A. Angew. Chem.
Int. Ed. 1999, 38, 3418. Kondepudi, D.K.
Kaufman, R.J. Singh, N. Science 1990, 250, 975.
56
Autocatalysis with Amplification of Enantiomeric
Excess
Over 942-fold increase in the (S)-enantiomer of
the initial catalyst after five successive
asymmetric autocatalytic reaction compared to
only 16-fold for the (R)-enantiomer (i.e.
significant increase in ee).
Soai, K. Shibata, T. Morioka, H. Choji, K.
Nature 1995, 378, 767.
57
Evidence for the Formation of Dimers
Enantiopure mixture
Racemic mixture
Gridnev, I. D. Serafimov, J. M. Brown, J. M.
Angew. Chem. Int. Ed. 2004, 43, 4884.
58
Mechanistic Implications of Asymmetric
Autocatalysis with Amplification of ee

• eeprod eemax x eeaux
• Catalyst with perfect selectivity (eemax 1)
  leads to a best cast scenario of maintaining but
  not amplifying ee.
• Catalyst with slightly less than perfect
  selectivity (i.e. eemax lt 1) leads to product ee
  that is lower than catalyst ee.

For an autocatalytic reaction (with several
cycles), the product ee is better described
as eeprod eeaux x (TON 1)(eemax -
1) where TON is defined as the moles of
substrate converted per mole of catalyst
initially present.
This simple representation of asymmetric
autocatalysis does not correspond to the
observation of amplification of ee by Soai and
coworkers.
Blackmond, D.G. Adv. Synth. Catal. 2002, 344,
156. Blackmond, D.G. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5732.
59
Mechanistic Implications of Asymmetric
Autocatalysis with Amplification of ee
In order for amplification to be realized, an
autocatalyst must not only be capable of
reproducing itself, but it must also serve as an
agent to effect suppression of production of its
enantiomer.
Blackmond, D.G. Adv. Synth. Catal. 2002, 344, 156.
60
Reaction Progress Kinetic Analysis
Blackmond, D.G. McMillan, C.R. Ramdeehul, S.
Schorm, A. Brown, J.M. J.Am. Chem. Soc. 2001,
123, 10103.
61
Noyori Model for Asymmetric Alkylzinc Additions
to Aldehydes
Khetero ? 2Khomo
Khetero 2Khomo
For amplification
Experimental observations
Blackmond, D.G. McMillan, C.R. Ramdeehul, S.
Schorm, A. Brown, J.M. J.Am. Chem. Soc. 2001,
123, 10103.
62
Dimers Are the Catalysts
Active catalysts
Inactive catalyst
Kdimer 4 ( Khetero / Khomo )2 (SR)2 / (RR)
x (SS)
Blackmond, D.G. McMillan, C.R. Ramdeehul, S.
Schorm, A. Brown, J.M. J.Am. Chem. Soc. 2001,
123, 10103. Blackmond, D.G. Tetrahedron
Asymmetry 2006, 17, 584.
63
Effect of Reagent Stoichiometry on Rate Laws
rate law is only applicable to reactions
employing stoichiometric amounts of aldehyde and
(i-Pr)2Zn
Conditions aldehyde0 0.1 M, 10 mol
catalyst (0.22 ee), 1.8 equiv. (i-Pr)2Zn
Buono, F. G. Blackmond, D. G. J. Am. Chem. Soc.
2003, 125, 8978.
64
Second-Order Dependence in Aldehyde
Second-order dependence in aldehyde
rate k aldehyde2 catalyst
kinetic model
kinetic model
kinetic model
2.0 equiv. (i-Pr)2Zn
3.6 equiv. (i-Pr)2Zn
1.8 equiv. (i-Pr)2Zn
This rate law implies that two molecules of
aldehyde and one homochiral dimer catalyst are
involved in the transition state.
Buono, F. G. Blackmond, D. G. J. Am. Chem. Soc.
2003, 125, 8978.
65
Preparation of 15N-labeled Starting Materials
Gridnev, I.D. Serafimov, J.M. Brown, J.M.
Angew. Chem. Int. Ed. 2004, 43, 4884. Shibata,
T. Yonekubo, S. Soai, K. Angew. Chem. Int. Ed.
1999, 38, 659.
66
Association of (i-Pr)2Zn with the Catalyst
N-Zn association -10.2 kcal/mol
O-Zn-O association -6.5 kcal/mol
Gridnev, I.D. Serafimov, J.M. Brown, J.M.
Angew. Chem. Int. Ed. 2004, 43, 4884. Gridnev,
I.D. Brown, J.M. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5727.
67
Explaining the High Level of Chiral Induction
Schiaffino, L. Ercolani, G. Angew. Chem. Int.
Ed. 2008, 47, 6832.
68
Explaining the High Level of Chiral Induction
Schiaffino, L. Ercolani, G. Angew. Chem. Int.
Ed. 2008, 47, 6832.
69
Hydrocarbons as Chiral Initiators
7.0 mol , gt 99.5 ee
9.8 mol , 0.54 ee
93 yield, 93 ee
92 yield, 62 ee
88 yield, 56 ee
95 yield, 95 ee
6.2 mol , gt 99.5 ee
11 mol , 0.13 ee
Sato, I. Yamashima, R. Kadowaki, K. Yamamoto,
J. Shibata, T. Soai, K. Angew. Chem. Int. Ed.
2001, 40, 1096.
70
Progress Towards Absolute Asymmetric Synthesis
The initial very slight excess of the S
enantiomer (ca. 0.00005 ee) has increased 630
000 fold while the minor R enantiomer has only
increased by a factor of 950.
Sato, I. Urabe, H. Ishiguro, S. Shibata, T.
Soai, K. Angew. Chem. Int. Ed. 2003, 42, 315.
71
Absolute Asymmetric Synthesis A Thought
Experiment
Siegel, J. S. Chirality 1998, 10, 24. Soai, K.
Sato, I. Shibata, T. Komiya, S. Hayashi, M.
Matsueda, Y. Imamura, H. Hayase, T. Morioka,
H. Tabira, H. Yamamoto, J. Kowata, Y.
Tetrahedron Asymmetry 2003, 14, 185.
72
Absolute Asymmetric Synthesis

• A common misconception (re. racemic mixtures)
• Racemates are composed of identical amounts of
  both enantiomers.

Siegel, J. S. Chirality 1998, 10, 24. Soai, K.
Sato, I. Shibata, T. Komiya, S. Hayashi, M.
Matsueda, Y. Imamura, H. Hayase, T. Morioka,
H. Tabira, H. Yamamoto, J. Kowata, Y.
Tetrahedron Asymmetry 2003, 14, 185.
73
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