Jeremy Sanders

1
Dynamic Combinatorial Chemistry
An introduction
Jeremy Sanders University of Cambridge
2
Brief history of dynamic combinatorial
chemistry A fashionable new name for an old idea

• Cambridge-style Dynamic Combinatorial Chemistry
  was conceived as a general idea in Dublin on
  Thursday 17th September 1992
• Independently developed as a general idea by
  Lehn
• The name first appeared in two independent
  publications by Lehn and by Sanders in November
  1997
• Many isolated experiments using the idea to
  solve specific problems in previous 30 years
• True origin in 19th and early 20th
  century? Emil Fischer Carbohydrate
  chemistry Alfred Werner Coordination chemistry

3
Brief history of dynamic combinatorial
chemistry Jean-Marie Lehn

• 1995

4
Brief history of dynamic combinatorial
chemistry Jean-Marie Lehn
A dynamic combinatorial library of carbonic
anhydrase inhibitors

• 1997 Ivan Huc, Proc. Natl.Acad.Sci. USA

5
Brief history of dynamic combinatorial
chemistry Alexey Eliseev

• 1997

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Brief history of dynamic combinatorial
chemistry D. L. Venton
A cocktail of peptidases used to generate what we
would call a dynamic library of peptides from
which recognition should give amplification

• 1996, Biopolymers

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Brief history of dynamic combinatorial
chemistry David Lynn

• 1992

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Brief history of dynamic combinatorial
chemistry Darryl Rideout

• Self-assembly of cytotoxins in vivo using
  hydrazone chemistry
• Science, 1986, 233, 561

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Brief history of dynamic combinatorial
chemistry Daryl Busch

• 1962

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Brief history of dynamic combinatorial
chemistry Cambridge

• Cambridge-style Dynamic Combinatorial Chemistry
  was conceived over lunch in Dublin on Thursday
  17th September 1992
• Our first grant proposal was submitted in
  September 1993
• Paul Brady's first experiments began in October
  1993
• The first paper was submitted to Chem Comm in
  October 1995 and published early in 1996

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What is the best route to new synthetic
receptors? Catalysts, sensors, absorbents
Guest
Host
12
Do we understand molecular recognition?
Host, guest and complex are solvatedSmaller
surface area of complex means less solvation
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Do we understand molecular recognition?
Host, guest and complex are solvatedSmaller
surface area of complex means less solvation ?
binding liberates an unpredictable numberof
solvent molecules
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Do we understand molecular recognition?
Host, guest and complex are solvatedSmaller
surface area of complex means less solvation ?
binding liberates an unpredictable numberof
solvent molecules Recognition is always a
delicate balance of intermolecular forces and
competing complexes
15
What is the best route to new synthetic
receptors? Two different approaches
Design Decide on targetMake itStudy it
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What is the best route to new synthetic
receptors? Two different approaches
Design Decide on targetMake itStudy it Can
readily make systematic changes
17
Porphyrins as supramolecular building blocks A
general design for potentially catalytic receptors
Metal centres provide binding and activation
sites Control size, geometry, flexibility by
systematic variation of linker
Harry Anderson, 1988
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Redirecting a DielsAlder reaction Competing
pathways controlled by hostguest chemistry
Christopher Walter, 199193
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Redirecting a DielsAlder reaction Competing
pathways controlled by hostguest chemistry
First lecture describing these results was at an
RSC meetingin Dublin, 17 September 1992 Several
years' work for one result.
Over lunch, Fraser Stoddart and Chris Hunter
pointed out that this is not a general solution
to the problem or recognition and catalysis. Need
proof reading, error checking, and selection of
the successful
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Some Selection Approaches Using biological
machinery
Catalytic antibodiesCombinatorial biosynthesis
of antibodies using immune response to a
transition state analogue template (hapten)
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Some Selection Approaches Using biological
machinery
Catalytic antibodiesCombinatorial biosynthesis
of antibodies using immune response to a
transition state analogue template (hapten)
Directed evolution of enzymes and
ribozymesCombinatorial (bio)synthesis under
selective pressure
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Conventional Combinatorial Chemistry
Each member (M1... Mn) of the library consists
of building blocks (A, B, C. ) joined by a
robust bond
M1 ABC
M2 BAC
M3 ACB
M4 CAB
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Dynamic Combinatorial Chemistry
Each member (M1... Mn) of the library consists
of building blocks (A, B, C. ) joined by dynamic
covalent or non-covalent bonds Connections
between building blocks are in flux, continuously
being made and broken
M1 ABC
M2 BAC
M3 ACB
M4 CAB
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Dynamic Combinatorial Chemistry
Each member (M1... Mn) of the library consists
of building blocks (A, B, C. ) joined by dynamic
covalent or non-covalent bonds Connections
between building blocks are in flux, continuously
being made and broken Composition is responsive
addition of a template T1 that selectively binds
one member will bias the equilibrium
M1
M2
T1
M3
M3T1
M4
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Dynamic Combinatorial Chemistry
Each member (M1... Mn) of the library consists
of building blocks (A, B, C. ) joined by dynamic
covalent or non-covalent bonds Connections
between building blocks are in flux, continuously
being made and broken Composition is responsive
addition of a template T1 that selectively binds
one member will bias the equilibrium Turn off
equilibrium to fix, isolate and identify
successful structure
M1
M2
T1
M3
M3T1
M4
We create solutions that evolve in response to
external stimuli
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Dynamic Combinatorial Chemistry Some possible
directions
Use a ligand to make an ideal receptor
Use a receptor to make an ideal ligand
Optimise a self-folding structure
Generate self-assembled aggregates
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Dynamic Combinatorial Chemistry Some possible
directions
Use a ligand to make an ideal receptor
Use a receptor to make an ideal ligand
Optimise a self-folding structure
Generate self-assembled aggregates
28
Dynamic Combinatorial Chemistry Some possible
directions
Use a ligand to make an ideal receptor
Use a receptor to make an ideal ligand
Optimise a self-folding structure
Generate self-assembled aggregates
29
Dynamic Combinatorial Chemistry Some possible
directions
Use a ligand to make an ideal receptor
Use a receptor to make an ideal ligand
Optimise a self-folding structure
Generate self-assembled aggregates
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A complex space to explore Two simultaneous
orthogonal chemistries
Templating interactions
Building block design and diversity
Exchange chemistry
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A complex space to explore Two simultaneous
orthogonal chemistries
Templating interactions
Building block design and diversity
Exchange chemistry
Not to mention solvent, temperature..
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Which interactions can we use in templating?
Hydrogen bonding Aromatic ?? interactions
Metalligand coordination Cation?
interactions Aromatic donoracceptor
interactions Hydrophobic effects
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Properties of the Ideal Reaction Isoenergetic
exchange reaction
Operates at low concentration (mM) without excess
of one component Can be turned on
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Properties of the Ideal Reaction Isoenergetic
exchange reaction
Operates at low concentration (mM) without excess
of one component Can be turned on Mild conditions
compatible with templating by non-covalent
interactions
35
Properties of the Ideal Reaction
Operates at low concentration (mM) without excess
of one component Can be turned on Mild conditions
compatible with templating by non-covalent
interactions Can be turned off for isolation of
robust products
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Reversible reactions for dynamic chemistry So
far..
Base-catalysed transesterification Pd-catalyse
d allyl transesterification Transacetalisation
Michael addition of thiols Enzyme-catalyzed
aldol condensation Nitro-aldol (Henry)
reaction Alkene metathesis Reversible
DielsAlder Thioester exchange Metalligand
coordination chemistry Hydrogen bonding CN
bond exchange (imines, oximes, hydrazones) Disu
lfide exchange
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A key exchange reaction Imine formation and
exchange
H

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A key exchange reaction Imine formation and
exchange
H

H/Nu
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A key exchange reaction Hydrazone formation
H
Acetal Latent aldehyde
Hydrazide
Aryl hydrazone Relatively robust Peptide-like
H-bonding
Mark Simpson, Graham Cousins, Sally-Ann Poulsen,
19982000
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A key exchange reaction Hydrazone exchange
H/Nu
Mark Simpson, Graham Cousins, Sally-Ann Poulsen,
19982000
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Design of Hydrazone Building Blocks
Graham Cousins, Sally-Ann Poulsen, 1998
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Hydrazone Building Blocks Dipeptides based on
proline
pPF
Graham Cousins, Sally-Ann Poulsen, Jingyuan Liu
19982005
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Peptide-Hydrazone Libraries of Macrocycles Dipepti
des based on proline
PF2
PF3
5 mM monomer 43 equiv. TFA CHCl3/DMSO 955
PF4
pPF
PF6
PF5
Isolated species re-equilibratewith acid to
regenerate original library
Sarah Roberts, Ruby Lam, 20024
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Peptide-Hydrazone Libraries of Macrocycles Dipepti
des based on proline
PV4
2 mM monomer 100 mM TFA CHCl3/MeOH 982
PV2
PV3
Library distribution depends on subtle structural
features
Jingyuan Liu, 2005
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Peptide-Hydrazone Libraries Manipulating the
equilibrium distribution
Capture and amplification of monomeric
intermediate which is generally present at
concentration too low to detect
Ricardo Furlan, 2000
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Peptide-Hydrazone Libraries Manipulating the
equilibrium distribution
Ricardo Furlan, 2000
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Ammonium ion pair binding by cyclic peptides A
literature precedent
Strong binding of ion pairs in organic solvents
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Ammonium ion pair binding by cyclic peptides A
dynamic combinatorial approach?
Insert exchangeable CN bond
mPro
Graham Cousins, 2000
49
Dynamic library derived from mPro monomer Kinetic
distribution
mPro
CHCl3 TFA
Initial mixture of kinetic products mP2, mP3..
mPn
Time
90 mP2 at equilibrium
Graham Cousins, 2000
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Dynamic library derived from mPro
monomer Thermodynamic distribution
Proof reading and editing
mPro
CHCl3 TFA
Initial mixture of kinetic products mP2, mP3..
mPn
Time
90 mP2 at equilibrium
Graham Cousins, 2000
51
Dynamic library derived from mPro
monomer Templated amplification by acetylcholine
mPro
CHCl3 TFA
85 mP3
Initial mixture of kinetic products mP2, mP3..
mPn
Time
90 mP2 at equilibrium
Graham Cousins, 2000
52
Dynamic library derived from mPro
monomer Templated amplification by acetylcholine
CHCl3 TFA
mPro
CHCl3 TFA
85 mP3
Initial mixture of kinetic products mP2, mP3..
mPn
Time
Templating allows preparative scale isolation
of a receptor which is otherwise inaccessible
90 mP2 at equilibrium
Graham Cousins, 2000
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Dynamic library derived from mPro
monomer Templated amplification by acetylcholine
Dimer mP2
Trimer mP3
No Template
Graham Cousins, 2000
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How to isolate receptors from complex libraries?
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How to isolate receptors from complex
libraries? Immobilisation of template
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Peptide-Hydrazone Libraries Immobilisation of
template
90 mP2 at equilibrium in solution
Predominantly mP3 on bead
Sarah Roberts, 2001
57
Peptide-Hydrazone Libraries Diastereoselectivity
in amplification
LL-Dimer
pPF
Ricardo Furlan, Sarah Roberts, Jingyuan Liu, 2002
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Peptide-Hydrazone Libraries Another new
acetylcholine receptor
pPF
5 mM monomer CHCl3/DMSO 955
Initiate reaction by addition of 43 equiv. TFA
Sarah Roberts, Ruby Lam, 20024
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Peptide-Hydrazone Libraries Another new
acetylcholine receptor
Kinetic linear intermediates form initially then
disappear
New receptor
Ruby Lam, 2003
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Peptide-Hydrazone Libraries Another new
acetylcholine receptor
5 mM monomer 43 equiv. TFA CHCl3/DMSO 955
No template
Sarah Roberts, Ruby Lam, 20024
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Peptide-Hydrazone Libraries Another new
acetylcholine receptor
5 mM monomer 43 equiv. TFA CHCl3/DMSO 955
No template
New receptor, 70 yield
M 2341 "Hexamer"
Acetylcholine
Sarah Roberts, Ruby Lam, 20024
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New acetylcholine receptors What is the structure
of the new hexamer?
Formed rapidly with other simple macrocycles
PF6
M 2341
New receptor
Evolves very slowly over days
M 2341
Ruby Lam, Ana Belenguer, 2003
63
New acetylcholine receptors What is the structure
of the new hexamer?
Mass spec mass spec Fragmentation by collision
pPF2
pPF3
New receptor
pPF1
M 2341
PF6
pPF1
pPF2
pPF3
pPF4
pPF5
Ruby Lam, Ana Belenguer, 2003
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New acetylcholine receptors What is the structure
of the new hexamer?
A Catenane Two macrocyclic trimers,interlocked
but not covalently linked
M 2341
Ruby Lam, Ana Belenguer, 2003
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New acetylcholine receptors What is the structure
of the new hexamer?
pPF2
pPF3
pPF1
pPF1
pPF2
pPF3
pPF4
pPF5
Ruby Lam, Ana Belenguer, 2003
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New acetylcholine receptors Why is the catenane
amplified?
Amplifying a hexamer from a library of small
oligomers is expensive in DS Requires the
template to have high binding affinity and
selectivity
Ruby Lam, 2004
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New acetylcholine receptors Why is the catenane
amplified?
Ruby Lam, 2004
68
New acetylcholine receptors Template binds
selectively to a single conformer
No template
1 Eq Acetylcholine
Ruby Lam, Christoph Naumann, 2004
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New acetylcholine receptors Template binds
selectively to a single conformer
700 MHz NMR analysis TOCSY, NOESY, HMQC
Bound template prevents rotation of rings
Spectrum too simple Symmetry does not allow
full3D structure determination
Ruby Lam, Christoph Naumann, 2004
70
New acetylcholine receptors More diverse
libraries and mixed catenanes
LL-pPF LL-pPV 11 mixed library in CHCl3DMSO
955
Ruby Lam, Jingyuan Liu, 2005
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Disulfide formation and exchange Dynamic
combinatorial chemistry in water
pH gt 7
Control over exchange No exchange when thiol is
protonated No exchange when all thiol is oxidised
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Disulfide formation and exchange Dynamic
combinatorial chemistry in water
Sijbren Otto, 1999
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Disulfide chemistry in organic solvents Synthesis
and templating of oligoporphyrins
A monomer for disulfide exchange chemistry
Amy Kieran, 2002
74
Metalloporphyrin Coordination Selectivity
depends on central metal ion
One axial ligand N-selective Fast exchange (ms)
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Disulfide chemistry in organic solvents Synthesis
and templating of oligoporphyrins
Amy Kieran, 2002
76
Disulfide chemistry in organic solvents Synthesis
and templating of oligoporphyrins
Major product
Minor product
Amy Kieran, 2002
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Disulfide chemistry in organic solvents Synthesis
and templating of oligoporphyrins
Dominant product Host can adjust to optimum
geometry
Amy Kieran, 2002 Structure solution by Andrew
Bond, 2002
78
Disulfide chemistry in organic solvents Synthesis
and templating of oligoporphyrins
Dominant product Host can adjust to optimum
geometry
Amy Kieran, 2003
79
Disulfide chemistry in organic solvents Synthesis
and templating of oligoporphyrins
Dominant product Host can adjust to optimum
geometry
Amy Kieran, 2003
80
Disulfide chemistry in organic solvents Synthesis
and templating of oligoporphyrins
Amy Kieran, 2003
81
Dynamic combinatorial chemistry Some
fundamental questions
Are all amplified molecules good receptors?Are
all good receptors amplified?
Peter Corbett, 2003
82
Some thought experiments A single building block
Smaller oligomers are generally favoured on
entropic grounds
83
Some thought experiments A single building block
At low template concentrations template most
binding energy is released by amplifying the best
receptor
Kay Severin (Lausanne) Peter Corbett, Sijbren
Otto 2003
84
Equilibria lead to population distributions
85
Equilibria lead to population distributions Can
we derive equilibrium constants from populations?
No need to isolate individual speciesNo need to
measure individual binding constants
86
Selection approach to catalysis
87
Selection approach to catalysis
88
Selection approach to catalysis
Catalysts recognise the transition state better
than starting material or product
89
Dynamic combinatorial chemistry Summary
Dynamic equilibria in solution are responsive
to external stimuli
90
Dynamic combinatorial chemistry Summary
Dynamic equilibria in solution are responsive
to external stimuli Templates amplify
complementary receptors with unpredicted
structures
91
Dynamic combinatorial chemistry Summary
Dynamic equilibria in solution are responsive
to external stimuli Templates amplify
complementary receptors with unpredicted
structures Different templates amplify
different receptors from the same library
92
Dynamic combinatorial chemistry Summary
Dynamic equilibria in solution are responsive
to external stimuli Templates amplify
complementary receptors with unpredicted
structures Different templates amplify
different receptors from the same
library Immobilised templates can
simultaneously amplify, isolate and purify
receptors
93
Dynamic combinatorial chemistry Summary
Dynamic equilibria in solution are responsive
to external stimuli Templates amplify
complementary receptors with unpredicted
structures Different templates amplify
different receptors from the same
library Immobilised templates can
simultaneously amplify, isolate and purify
receptors Transition state analogues can
amplify catalysts with unpredicted structures
94
Dynamic combinatorial chemistry Summary
Dynamic equilibria in solution are responsive
to external stimuli Templates amplify
complementary receptors with unpredicted
structures Different templates amplify
different receptors from the same
library Immobilised templates can
simultaneously amplify, isolate and purify
receptors Transition state analogues can
amplify catalysts with unpredicted
structures Synthesis under thermodynamic
control can be very efficient
95
Dynamic combinatorial chemistry Summary
Dynamic equilibria in solution are responsive
to external stimuli Templates amplify
complementary receptors with unpredicted
structures Different templates amplify
different receptors from the same
library Immobilised templates can
simultaneously amplify, isolate and purify
receptors Transition state analogues can
amplify catalysts with unpredicted
structures Synthesis under thermodynamic
control can be very efficient Simulations can
guide experimental design
96
Different approaches to synthesis Summary
Covalent synthesis Covalent bonds Robust,
Dominated by DH
Supramolecular synthesis Non-covalent
bonds Fragile, solvent dependent Delicate
balance between DH and DS
97
Different approaches to synthesis Summary
Covalent synthesis Covalent bonds Robust,
Dominated by DH Kinetic control of bond
formation No proof reading
Supramolecular synthesis Non-covalent
bonds Fragile, solvent dependent Delicate
balance between DH and DS Thermodynamic control
of bond formation Proof reading of "incorrect"
structures
98
Different approaches to synthesis Summary
Covalent synthesis Covalent bonds Robust,
Dominated by DH Kinetic control of bond
formation No proof reading Difficult access to
very large structures
Supramolecular synthesis Non-covalent
bonds Fragile, solvent dependent Delicate
balance between DH and DS Thermodynamic control
of bond formation Proof reading of "incorrect"
structures Good access to very large structures
99
Different approaches to synthesis Summary
Covalent synthesis Covalent bonds Robust,
Dominated by DH Kinetic control of bond
formation No proof reading Difficult access to
very large structures Good access to disfavoured
structures
Supramolecular synthesis Non-covalent
bonds Fragile, solvent dependent Delicate
balance between DH and DS Thermodynamic control
of bond formation Proof reading of "incorrect"
structures Good access to very large
structures Limited access to disfavoured
structures
100
Different approaches to synthesis Summary
Covalent synthesis under thermodynamic
control Covalent bonds Robust, Dominated by
DH Thermodynamic control of bond formation Proof
reading of "incorrect" structures Good access to
very large structures Limited access to
disfavoured structures
101
Different approaches to synthesis Summary
Covalent synthesis under thermodynamic
control Covalent bonds Robust, Dominated by
DH Thermodynamic control of bond formation Proof
reading of "incorrect" structures Good access to
very large structures Templating gives access
to otherwise disfavoured structures
102
Different approaches to synthesis Summary
Covalent synthesis under thermodynamic
control Covalent bonds Robust, Dominated by
DH Thermodynamic control of bond formation Proof
reading of "incorrect" structures Good access to
very large structures Templating gives access
to otherwise disfavoured structures
We have created solutions that evolve in response
to external stimuli
103
Dynamic combinatorial chemistry Looking ahead
Answering 21st century questions, often with
19th century chemistry Requires 21st century
analytical techniques HPLC, MSn, computational
and statistical analysis New analytical
techniques may be the rate-determining step