Development of Synthetic Approaches for the
Systematic Exploration of Chemical Space
www.asn.leeds.ac.uk
Prof. Adam Nelson
School of Chemistry, University of Leeds, UK
[email protected]
Current research themes
Chemical biology
Synthetic Chemistry
Current research themes
Chemical biology
Directed evolution of
novel enzymes for
synthetic chemistry
Synthetic Chemistry
Directed evolution of enzymes for
application in parallel synthesis
HO HO
O
HO
HO
sialic acid
aldolase
O
OH
O
AcHN
HO OH
CO2H
NHAc
OH
HO
CO2H
directed
evolution
R2
R1 OH O
N
O
X
O
R1R2N
CO2H
X
OH
O
CO2H
O OH
with Alan Berry, Gavin Williams, Tom Woodhall
Creation of complementary enzymes for
diastereoselective CC bond formation
R
R2 OH O
1N
O
mutant 1
O
CO2H
X
mutant 2
2
R2
R
OH
OH
R1 N
R1 N
OH
CO2H
O
X
CO2H
O
X
O HO
O
J. Am. Chem. Soc. 2006, 128, 16238
with Alan Berry, Gavin Williams, Tom Woodhall
Current research themes
Chemical biology
Synthetic Chemistry
Directed evolution of
novel enzymes for
synthetic chemistry
Synthetic strategies
Chemical
genetics
Synthesis of bioactive
ligands and libraries
Tools for elucidating stem
cell biology mechanisms
Role of GSK-3 in regulating murine
embryonic stem cell self-renewal
H
N
O
N
O
N
H
N
O
N
O
N
OH
Control
5 M
0.5 M
400 m scale bar
In the presence of leukaemia inhibitory factor, inhibition of GSK-3 robustly
enhances self-renewal of murine embryonic stem cells
Chem. Biol. 2009, 16, 15 (highlight: Cell Stem Cell 2009, 4, 98) with Welham
In sharp contrast, differentiation of
human ESCs is promoted!
2 M
TOPFlash luciferase
reporter assay
SOX17
DAPI
HNF4
DAPI
0
2
5 M
50 m scale bar
Chemically-directed differentiation yields definitive endoderm, which has the
capacity to generate hepatocyte-like cells
J. Cell Sci 2011, 124, 1992
with Welham
Current research themes
Chemical biology
Synthetic Chemistry
Directed evolution of
Synthetic strategies
novel enzymes for
synthetic chemistry Diverse lead-like
Natural productmolecules
Chemical
genetics
inspired libraries
Synthesis of bioactive
ligands and libraries
Tools for elucidating stem
cell biology mechanisms
The Organic Chemistry Universe is
“Top
Heavy”
25 million cyclic
100
Percentage of compounds
compounds
in CAS registry
80
HO
60
O
O
O
40
O
H
20
0
0
20
40
60
80
100
2.5 million
frameworks
Cumulative percentage of frameworks
See A. H. Lipkus et al, J. Org. Chem. 2008, 73, 4443
The Organic Chemistry Universe is
“Top
Heavy”
25 million cyclic
100
Percentage of compounds
compounds
in CAS registry
80
60
O
40
20
0
0
20
40
60
80
100
2.5 million
frameworks
Cumulative percentage of frameworks
See A. H. Lipkus et al, J. Org. Chem. 2008, 73, 4443
The Organic Chemistry Universe is
“Top
Heavy”
25 million cyclic
100
Percentage of compounds
compounds
in CAS registry
80
1.3 million frameworks seen in
just one compound!
60
Half of the compounds based on
0.25% of the frameworks
40
17% of compounds based on
just 30 frameworks!
20
0
0
20
40
60
80
100
2.5 million
frameworks
Cumulative percentage of frameworks
See A. H. Lipkus et al, J. Org. Chem. 2008, 73, 4443
Synthetic approaches to skeletallydiverse small molecules
1. Natural product-like molecules of
unprecedented scaffold diversity
H
HO
O
OH OH
2. Skeletally-diverse drug like
cores
H
N
N
H
OH
O
Designed to retain lead-like
properties after derivatisation
Natural Products: Inspiration for
libraries of useful ligands?
Natural Products: Inspiration for
libraries of useful ligands?
HO
H
OH
O
HO
O
O
O
O
O
O
OH
OH
NH2
O
HO
H
H
HO
O
(+)-Brefeldin A
inhibits Arf1p and, hence,
protein trafficking
from ER to Golgi
Lovastatin inhibits
HMG-CoA reductase
(anticholesterol agent)
OH
HO
C10H21
Discodermolide
inhibits microtubule
polymerisation
O
O
OH
10-Hydroxyasimicin
binds to mitochondrial complex I
(fungicide and anti-tumour agent)
OH
O
O
O
Natural Products: Inspiration for
libraries of useful ligands?
HO
H
OH
O
HO
O
O
O
O
O
O
OH
OH
NH2
O
HO
H
H
HO
O
(+)-Brefeldin A
inhibits Arf1p and, hence,
protein trafficking
from ER to Golgi
Lovastatin inhibits
HMG-CoA reductase
(anticholesterol agent)
OH
HO
C10H21
Discodermolide
inhibits microtubule
polymerisation
O
OH
O
O
OH
10-Hydroxyasimicin
binds to mitochondrial complex I
(fungicide and anti-tumour agent)
O
O
Natural Products: Inspiration for
libraries of useful ligands?
HO
H
OH
O
HO
O
O
O
O
O
O
OH
OH
NH2
O
HO
H
H
HO
O
(+)-Brefeldin A
inhibits Arf1p and, hence,
protein trafficking
from ER to Golgi
Lovastatin inhibits
HMG-CoA reductase
(anticholesterol agent)
OH
HO
C10H21
Discodermolide
inhibits microtubule
polymerisation
O
OH
O
O
OH
10-Hydroxyasimicin
binds to mitochondrial complex I
(fungicide and anti-tumour agent)
O
O
Natural Products: Inspiration for
libraries of useful ligands?
HO
H
OH
O
HO
O
O
O
O
O
O
OH
OH
NH2
O
HO
H
H
HO
O
(+)-Brefeldin A
inhibits Arf1p and, hence,
protein trafficking
from ER to Golgi
Lovastatin inhibits
HMG-CoA reductase
(anticholesterol agent)
OH
HO
C10H21
Discodermolide
inhibits microtubule
polymerisation
O
OH
O
O
OH
10-Hydroxyasimicin
binds to mitochondrial complex I
(fungicide and anti-tumour agent)
O
O
Inspiration from Alkaloid Natural
Products
HO
H
H
N
O
HO
Morphine
N
H
Me
N
H
H
HO
Strychnine
with Sarah Murrison, Christian Einzinger, Steve Bartlett and Dan Tetlow
Inspiration from Alkaloid Natural
Products
R
1
N
N
N
H
N
R2
N
R1N R2
O
80-90%
For similar cascades, see: S. A. Raw and R. J. K. Taylor,
J. Am. Chem. Soc. 2004, 126, 12260.
with Sarah Murrison, Christian Einzinger, Steve Bartlett and Dan Tetlow
Inspiration from Alkaloid Natural
Products
R
1
N
N
N
H
N
N
R2
R1N R2
O
N
N
R1N R2
R2
N 1
2
N RN R
N
with Sarah Murrison, Christian Einzinger, Steve Bartlett and Dan Tetlow
Inspiration from Alkaloid Natural
Products
R1
N
N
N
H
N
O
N
R2
R1N R2
R4
O
R3
R4
O
R3
O
N
R4
O
R1N R2
N
H
ca. 10 analogues
R3
OH
N
C
O
N
4
R
O
R3
O
N
R1N R2
N
H
R1N R2
N
H
ca. 10 analogues
Yields from imine typically 65-95%
with Sarah Murrison, Christian Einzinger, Steve Bartlett and Dan Tetlow
Substituents can control the scaffold
R1
R1 N
HN
N
N
R1
R1 N
N
N
O
R4
R5
4
R
O
N
N
R2
R3
H
N
R1
Bu
N
H
R4
R3
O
R3
O
R2 Bu
O
3
R
N
N
H
R3
N
HN
O
O R1
R2 N
O
N
O
N
R1N R2
R1N R2
N
H
R1
N
N
N
with Sarah Murrison
Aim
To develop reliable methodology for the diversityoriented synthesis of ‘natural product-like’ molecules
Important guiding features:
• broadly similar structural features to natural
products but targeting different regions of
biologically-relevant chemical space
• high skeletal, stereochemical and substitutional
diversity
• amenable to parallel synthesis
Aim
Simple
building blocks
ca. 5 reaction
types
Skeletally diverse
products
Angew. Chem. Int. Ed. 2009, 48, 104 (VIP article)
See also following News and Views articles in Nature (Schreiber), Nature
Chem. Biol. (Waldmann); Highlights in Angew. Chem. (Spring) and Nature
Chem; follow-up articles in C&E News and Science (editors’ choice); and
selection by Biology Faculty of 1000.
Aim
H
OH
N
Ns
OH
OH
NsN
O
O
ca. 5 reaction
types
Skeletally diverse
Simple building
products
blocks
HO
H
HO
O
OH OH
HO
Ph
H
OH
OH OH
Angew. Chem. Int. Ed. 2009, 48, 104 (VIP article)
See also following News and Views articles in Nature (Schreiber), Nature
Chem. Biol. (Waldmann); Highlights in Angew. Chem. (Spring) and Nature
Chem; follow-up articles in C&E News and Science (editors’ choice); and
selection by Biology Faculty of 1000.
Fluorous-tagged synthesis
A fluorous tag can be used as an alternative to solid support
The approach combines the benefits of solution phase and solid phase chemistry
FluorousSolid Phase Extraction (FSPE) allows rapid purification
O
HN
C4H9
O
HN
O
HN
C4H9
O
F
non-fluorinated
eluted with 8:2 MeOHH2O
(fluorophobic wash)
C7F16
fluorinated
eluted with MeOH
(fluorophilic wash)
Science, 1997, 275, 823; Synlett, 2001,1488
An iterative DOS approach
HO
OAc
HO
O
HO
OAc
HO
O
O
OAc
OAc
HO
HO
OAc
O
OTBS
HO
OAc
OAc
C8F17
Ts
N
O
NHNs
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
OH
Ph
An iterative DOS approach
HO
OAc
HO
O
HO
OAc
HO
O
O
OAc
OAc
HO
HO
OAc
O
OTBS
HO
OAc
OAc
C8F17
Ts
N
O
NHNs
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
OH
Ph
An iterative DOS approach
HO
OAc
HO
O
HO
O
O
OAc
OAc
HO
HO
OAc
O
OTBS
HO
OAc
OAc
C8F17
Ts
N
O
Ns
N
OAc
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
OH
Ph
An iterative DOS approach
HO
OAc
HO
O
HO
O
O
OAc
OAc
HO
HO
OAc
O
OTBS
HO
OAc
OAc
C8F17
Ts
N
O
Ns
N
OH
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
OH
Ph
An iterative DOS approach
HO
OAc
HO
O
HO
O
OAc
O
OAc
OAc
OH
HO
HO
Ph
OAc
O
OTBS
O
HO
HO
OAc
C8F17
Ts
N
O
Ns
N
OH
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
An iterative DOS approach
HO
OAc
HO
O
HO
O
OAc
O
OAc
OAc
OH
HO
HO
Ph
OAc
O
OTBS
O
HO
BriPr2Si
OAc
C8F17
Ts
N
O
Ns
N
O
OH
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
An iterative DOS approach
HO
OAc
HO
O
HO
O
O
OAc
OAc
HO
HO
OAc
C8F17
Ts
N
O
Ns
N
O
O
OH
Ph
OAc
O
OTBS
HO
OAc
O
Si
i
Pr2
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
An iterative DOS approach
HO
OAc
HO
O
HO
O
O
OAc
OAc
HO
HO
OAc
C8F17
Ts
N
O
Ns
N
O
O
OH
Ph
OAc
O
OTBS
HO
OAc
[Ru]
O
Si
i
Pr2
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
An iterative DOS approach
HO
OAc
HO
O
HO
O
O
OAc
OAc
HO
HO
OAc
C8F17
Ts
N
O
Ns
N
[Ru]
O
O
Si
i
Pr2
OH
Ph
OAc
O
OTBS
HO
OAc
O
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
An iterative DOS approach
HO
OAc
HO
O
HO
O
O
OAc
HO
OAc
HO
OAc
O
OTBS
HO
OAc
OAc
C8F17
Ts
N
O
Ns
N
H
H
[Ru]
O
SiiPr2
O
O
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
OH
Ph
An iterative DOS approach
HO
OAc
HO
O
HO
O
O
OAc
OAc
HO
HO
OAc
O
OTBS
HO
OAc
OAc
C8F17
Ts
N
[Ru]
O
Ns
N
H
H
O
SiiPr2
O
O
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
OH
Ph
An iterative DOS approach
HO
OAc
HO
O
HO
O
O
OAc
OAc
HO
HO
OAc
O
OTBS
HO
OAc
OAc
[Ru]
C8F17
Ts
N
O
Ns
N
H
H
O
SiiPr2
O
O
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
OH
Ph
An iterative DOS approach
HO
OAc
HO
OAc
O
HO
O
O
OAc
HO
HO
OAc
O
OTBS
HO
OAc
OAc
Ns
N
H
H
OH
OH
O
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
OH
Ph
An iterative DOS approach
HO
OAc
HO
OAc
O
HO
OAc
HO
O
O
OAc
HO
HO
OAc
OH
Ph
OAc
O
OTBS
HO
OAc
'spiro'
'fused'
'diene'
'terminating'
'open chain'
Ns
N
H
H
OH
OH
O
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
Skeletally diverse natural productlike compounds: Iteration 1
OH
OH
OH
OH
OH
NHNs
NHNs
NHNs
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
Skeletally diverse natural productlike compounds: Iteration 1
OH
O
HiPr2Si
OAc
OH O
H Pr2Si
OAc
i
O
O
OH O
H Pr2Si
i
OH O
i
H Pr2Si
H
NNs
HO
OAc
OAc
OAc
OH
O
HiPr2Si
H
NNs
HO
H
NNs
HO
O
OAc
OAc
OAc
1. Mitsunobu or silyl ether formation; 2. FSPE
with Chris Cordier, Stuart Leach and Daniel Morton
Skeletally diverse natural productlike compounds: Iteration 1
O
OAc
O
Si
i
Pr2
>98% (98%)
O
O
Si
i
Pr2
O
Si
i
Pr2
Ns
N
OAc
OAc
O
O
Si
Pr2
O
O
O
OAc
i
61% (>95%)
OAc
Ns
N
OAc
86%
OAc
90%
Si
i
Pr2
O
58% (>95%)
85% (>95%)
O
O
Ns
N
OAc
92%
1. Mitsunobu or silyl ether formation; 2. FSPE
with Chris Cordier, Stuart Leach and Daniel Morton
Skeletally diverse natural productlike compounds: Iteration 1
O
OH
O
Si
i
Pr2
>98% (>95%) [4 h]
O
O
OH
>98% [52 h]
O
Si
i
Pr2
Si
i
Pr2
O
OH
O
O
Si
Pr2
O
O
OH
i
>98% [10 h]
OAc
Ns
N
[no reaction after 100 h]
Ns
N
O
>98% [48 h]
Si
i
Pr2
O
O
OH
96%
OH
>95%
Ns
N
OH
98%
1. NH3, MeOH; 2. FSPE
with Chris Cordier, Stuart Leach and Daniel Morton
Skeletally diverse natural productlike compounds: Iteration 2
Ns
N
OH
Ns
N
OH
Ns
N
OH
Ns
N
OH
Ns
N
OH
Ns
N
OH
O
Si
O
iPr
2
OH
O
Si
iPr
O
OH
2
Linker and Mitsunobu reactions: J. Org. Chem 2008, 73, 2752
Silaketal formation: Org. Biomol. Chem. 2008, 6, 1734
Skeletally diverse natural productlike compounds: Iteration 2
Ns
N
Ns
N
OH
i
H Pr2Si
O
OH
2Si
HiPr
O
Ph
Ns
N
OH O
i
H Pr2Si
Ns
N
OH
NNsH
O
Ns
N
O
Ns
N
OH
HiPr 2Si
O
Si
iPr
2
O
OH
HO
O
Ph
O
O
OH
H
NsN
O
O
Si
iPr
2
HiPr2Si
O
OH
Ph
1. Mitsunobu or silyl ether formation; 2. FSPE
with Chris Cordier, Stuart Leach and Daniel Morton
Skeletally diverse natural productlike compounds: Iteration 2
Ns
N
O
iPr Si
2
Ns
N
O
iPr Si
2
O
O
Ph
Ns
N
Ns
N
O
O
iPr Si
2
NNsH
O
Ns
N
O
O
iPr Si
2
Ns
N
O
O
O
Ph
iPr Si
2
O
O
Si
iPr
2
NsN
O
O
O
Si
iPr
2
O
O
Ph
1. Mitsunobu or silyl ether formation; 2. FSPE
with Chris Cordier, Stuart Leach and Daniel Morton
Skeletally diverse natural productlike compounds: Iteration 2
Ns
N
O
iPr Si
2
Ns
N
O
Pr2Si
i
O
[Ru]
Ph
O
[Ru]
[Ru]
Ns
N
O
O
iPr Si
2
Ns
N
O
O
iPr Si
2
O
Ns
N
NNsH
[Ru]
Ns
N
O
O
[Ru]
O
Ph
iPr
O
Si
O
NsN
O
[Ru]
[Ru]
O
Si
O
2Si
O
[Ru]
O
Ph
1. Metathesis
with Chris Cordier, Stuart Leach and Daniel Morton
Skeletally diverse natural productlike compounds: Iteration 2
Ns
N
O
iPr Si
2
Ns
N
O
[Ru]
Ph
O
iPr Si
2
O
[Ru]
[Ru]
Ns
N
O
O
iPr Si
2
Ns
N
O
O
Ns
N
NNsH
[Ru]
Ns
N
O
iPr Si
2
O
O
[Ru]
O
Ph
iPr Si
2
O
Si
O
iPr
2
NsN
O
[Ru]
[Ru]
O
O
Si
iPr
2
O
[Ru]
O
Ph
1. Metathesis
with Chris Cordier, Stuart Leach and Daniel Morton
Skeletally diverse natural productlike compounds: Iteration 2
Ns
N
O
iPr Si
2
Ns
N
O
[Ru]
Ph
O
iPr Si
2
O
[Ru]
[Ru]
Ns
N
O
O
iPr Si
2
Ns
N
O
O
Ns
N
NNsH
[Ru]
Ns
N
O
iPr Si
2
O
O
[Ru]
O
Ph
iPr Si
2
O
Si
O
iPr
2
NsN
O
[Ru]
[Ru]
O
O
Si
iPr
2
O
[Ru]
O
Ph
1. Metathesis
with Chris Cordier, Stuart Leach and Daniel Morton
Skeletally diverse natural productlike compounds: Iteration 2
Ns
N
i
Ns
N
O
Pr2Si
O
[Ru]
Ns
N
Ph
O
O
i
Pr2Si
[Ru]
Ns
N
O
[Ru]
HH
O
Ns
N
O
i
Pr2Si O
[Ru]
O H
H
Ns
N
NNsH
[Ru]
O
Pr2Si
i
H
O
H
O
[Ru]
O
Ph
i
O
O
Si
Pr2
i
NsN
[Ru]
O
O
Si
i
Pr2
Pr2Si
O
O
[Ru]
Ph
1. Metathesis
with Chris Cordier, Stuart Leach and Daniel Morton
Skeletally diverse natural productlike compounds: Iteration 2
i
i
Pr2
Si
O O
Pr2Si O
O
Ns
N
Ph
Ns
N
[Ru]
i
Pr2 Si O
O
Ns
N
HH
H
[Ru]
i
Pr2
Si
O O
O
Ns
N
O H
O
Si
i
Pr2
H
O
NNs
Ph
[Ru]
O
[Ru]
[Ru]
Ns
N
H
Ns
N
O
[Ru]
Ns
N
O
O
[Ru]
Si
i
Pr2
i
Pr
O Si 2
O
O
Ph
[Ru]
1. Metathesis
with Chris Cordier, Stuart Leach and Daniel Morton
Skeletally diverse natural productlike compounds: Iteration 2
iPr
2Si
iPr
2
O
Si
O
O
O
Ph
iPr
NsN
iPr
2
Si O
HH
O
O
O
NsN
2
Si O
H
H
H
O H
NsN
NsN
O
NsN
O
NsN
NNs
iPr
Ns Ph
N
O
iPr Si
2
O
Ph
1. Metathesis
O
2
O Si O
iPr
2
O
Si
O
with Chris Cordier, Stuart Leach and Daniel Morton
Skeletally diverse natural productlike compounds: Iteration 2
HO
HO
OH
HO
Ph
NsN
NsN
HO
OH
HO
HO HO
HH
O
H
H
O H
NsN
NsN
NsN
NsN
O
O
NNs
Ns Ph
N
HO
HO
HO HO
Ph
HO
HO
1. HF, pyridine; 2. FSPE; 3. purify
with Chris Cordier, Stuart Leach and Daniel Morton
What can go ‘wrong’?
Competitive cyclisations
O
O
i
Si
Pr2
Ns
N
What can go ‘wrong’?
Competitive cyclisations
O
O
Si
iPr
2
Ns
N
i
iPr
2 Si
O
NNs
O
HO
Pr2
Si O
O
Ns
N
HO
OH
HO
Macrocycle-tethered cross-metathesis
i.e. first building block sometimes skipped
H Ns
N
H Ns
N
Skeletally diverse natural productlike compounds: Iteration 2
OH
Ns
N
Ns
N
OTBS
OTBS
Ns
N
Ns
N
OH
N
Ns
OH
OTBS
OTBS
Ns
N
OH
Ns
N
OH
N
Ns
OH
OH
OH
1. Metathesis
with Stuart Leach, Chris Cordier and Daniel Morton
Skeletally diverse natural productlike compounds: Iteration 2
i
N
Ns
Ns
N
Ns
N
Pr2
Si
O
O
Ns
N
OTBS
OTBS
O
Ns
N
O
O
O
i
i
N
Ns
Pr2 Ph
Si
O
O
i
i
Ns
N
O
OTBS
OTBS
Ns
N
Pr2
Si
O O
Pr2
Si
O
O
N
Ns
Pr2
Si
O
O
O
1. Metathesis
with Stuart Leach, Chris Cordier and Daniel Morton
Skeletally diverse natural productlike compounds: Iteration 2
N
Ns
Ns
N
i
Ns
N
Pr2
Si
O
O
Ns
N
OTBS
OTBS
O
Ns
N
O
O
O
i
i
N
Ns
Pr2 Ph
Si
O
O
i
i
Ns
N
O
OTBS
OTBS
Ns
N
Pr2
Si
O O
Pr2
Si
O
O
N
Ns
Pr2
Si
O
O
O
1. Metathesis
with Stuart Leach, Chris Cordier and Daniel Morton
Skeletally diverse natural productlike compounds: Iteration 2
NNs
Ns
N
OH
NsN
OH
Ns
N
Ns
N
OH
OH
OH
NsN
Ph
OH OH
OH OH
O
OH
NsN
O
O
O
O
O
OH
NsN
NsN
OH OH
OH
1. Metathesis
with Stuart Leach, Chris Cordier and Daniel Morton
Classification of product scaffolds
OH
H
O
OH OH
N
Ns
NH
Ns
Ns
N
Ns
N
O
HO
HO
OH OH
HO HO
OH
OH OH
HO
Ph
O
O
H H
OH
H
H
HO
OH
NsN
NNs
H
OH
O
HO
H Ns
N
NsN
HO
O
O
For an hierarchical scaffold classification, see: Waldmann et al,
J. Chem. Inf. Model., 2007, 47, 47
For the natural product scaffold ‘tree’: Proc. Natl. Acad. Sci. 2006, 103, 10606
Classification of product scaffolds
OH
H
O
OH OH
N
Ns
NH
Ns
Ns
N
Ns
N
O
HO
HO
OH OH
HO HO
OH
OH OH
HO
Ph
O
O
H H
OH
H
H
HO
OH
NsN
NNs
H
OH
HO
O
H Ns
N
NsN
HO
O
O
For an hierarchical scaffold classification, see: Waldmann et al,
J. Chem. Inf. Model., 2007, 47, 47
For the natural product scaffold ‘tree’: Proc. Natl. Acad. Sci. 2006, 103, 10606
Classification of product scaffolds
OH
H
O
OH OH
N
Ns
NH
Ns
Ns
N
Ns
N
O
HO
HO
OH OH
HO HO
OH
OH OH
HO
Ph
O
O
H H
OH
H
H
HO
OH
NsN
NNs
H
OH
HO
O
H Ns
N
NsN
HO
O
O
For an hierarchical scaffold classification, see: Waldmann et al,
J. Chem. Inf. Model., 2007, 47, 47
For the natural product scaffold ‘tree’: Proc. Natl. Acad. Sci. 2006, 103, 10606
Classification of product scaffolds
OH
H
O
OH OH
N
Ns
NH
Ns
Ns
N
Ns
N
O
HO
HO
OH OH
HO HO
OH
OH OH
HO
Ph
O
O
H H
OH
H
H
HO
OH
NsN
NNs
H
OH
HO
O
H Ns
N
NsN
HO
O
O
For an hierarchical scaffold classification, see: Waldmann et al,
J. Chem. Inf. Model., 2007, 47, 47
For the natural product scaffold ‘tree’: Proc. Natl. Acad. Sci. 2006, 103, 10606
Classification of product scaffolds
HN
NH
HN
N
H
N
H
NH HN
H
N
HN
O
HN
O
O
O
HN
O
O
HN
N
H
O
N
H
O
O
O
O
N
H
O
O
O
O
O
O
H
N
O
N
H
O
O
O
O
O
O
O
O
For an hierarchical scaffold classification, see: Waldmann et al,
J. Chem. Inf. Model., 2007, 47, 47
For the natural product scaffold ‘tree’: Proc. Natl. Acad. Sci. 2006, 103, 10606
Classification of product scaffolds
NsN
HN
HN
NH
N
H
N
H
HN
O
O
HN
H
N
H
N
O
O
NH
HN
O
O
N
Ns
HN
O
N
Ns
O
O
H
N
O
O
N
Ns
HN
O
O
Ph
O
O
O
O
O
O
O
O
O
Ph
O
HO
NNsH
O
O
O
O
Angew. Chem. Int. Ed. 2009, 48, 104
H
N
O
N
H
Classification of product scaffolds
NsN
NNs
NsN
NsN
Ns
N
Ns
N
N
Ns
N
Ns
NsN
OH
OH
O
O
OH
NsN
O
O
NNs
NsN
O
OH H
N
NsH
H
O
OH
NsN
O
H
O
N
Ns
O
OH OH
HO
OH
HO
HO O
Ns H
N
OH
NH
Ns
NsN
OH
O
O
OH
OH
HO
HO
Ph
H
O
O
O
H
O
O
Ns
N
O
N
Ns
OH
HO
HO HO
HO
O
H
OH
H
O
HO
O
OH
HO NsN
HO
O
OH
O
HO
O
HO
Ph
HO
H
HO
O
OH
O
O
HO
OH
HO
N
Ns
OH
HO
O
Angew. Chem. Int. Ed. 2009, 48, 104
HTS collections often focus on a
narrow range of cores
Commerical HTS
collection
(106 compounds)
N
NH
random selection
N
N
104 compounds
core analysis
N
Cl
O
N
O
Distribution of ring
systems
With Stuart Warriner
Most common saturated ring systems
in a commercial HTS library
O
N
N
826
N
844
N
384
O
102
N
129
N
N
N
N
434
N
4
4
19
none
N
N
S
3
18
N
N
N
N
N
N
N
2
5
N
N
8
N
N
N
7
N
10 others
3 others
none
4
3
1
<5
With Stuart Warriner
The Linchpin Strategy
inert
B
B
A
C
A
A
STEP 3
Nucleophilic
addition
B
A
R1
FG1
R3B(OR)2
R2
C
STEP 1
activated
O
A
C
"Linchpin"
reagent
FG1
B
STEP 2
R3
R1
B
A
C
Nu
O
R2
(Rh) JACS 1998, 120, 5579 (Miyaura)
R1
LG
R1
RMgBr (Cu) JOC 2007, 72, 2558 (Feringa)
RNH2 (Ir) ACIE 2004, 43, 4797 (Hartwig);
ACIE 2008, 47, 7652 (Helmchen)
with Steve Marsden (Leeds), David House, Gordon Weingarten and
Amanda Campbell (GSK)
Application of the Linchpin Strategy
in the Synthesis of Heterocycles
Oxidation
R1
R2
NH2
N
B(OR)2 [Rh(cod)Cl]2
KOH
R1
O
R1
R3
R2
H2N
Reduction
O
R1
R3
R2
N
H
R2
R3
R3
R1
R2
in situ
cyclisation
N
H
O
Tetrahydroquinolines with up to >99% ee accessible with
2-NHBoc boronic esters (cat. DuanPhos)
Jo Horn, John Li and Rachael Shearer
The Ir-catalysed substitution may be
extended to polar amines
2 mol% [Ir(dbcot)Cl]2
4 mol% ligand
R2NH2
OCO2Me +
R1
HN
R2
R1
4 mol% nBuNH2 ,
DMSO, 55 °C
DMSO
OH
Ph
NH
OH
N
H
Ph
85%, 93% ee
N
H
NH2
Ph
O
83%, 69% ee
N
N
H
66%, 97% ee
OH
MOMO
N
H
MOMO
COOMe
74%, d.r. 92.8
Matched
N
H
COOMe
74%, d.r. 90:10
Mismatched
S
N
H
COOMe
84%, d.r. 88:12
Matched
OH
S
N
H
COOMe
74%, d.r. 69:31
Mismatched
High levels of catalyst control are observed
Paolo Tosatti
Ir-enabled synthesis of lead-like cores
P
N
R'
Paolo Tosatti
Ir-enabled synthesis of lead-like cores
BocHN
BocHN
MOMO
OCO2Me
OCO2Me
OCO2Me
Paolo Tosatti
Ir-enabled synthesis of lead-like cores
NR1R2
BocHN
NR1R2
BocHN
NR1R2
MOMO
Paolo Tosatti
Ir-enabled synthesis of lead-like cores
NR1R2
BocHN
NR1R2
BocHN
NR1R2
MOMO
Paolo Tosatti
Ir-enabled synthesis of lead-like cores
NR1R2
BocHN
NR1R2
BocHN
NR1R2
MOMO
Paolo Tosatti
Ir-enabled synthesis of lead-like cores
O
Boc N
NBn
NR1R2
BocHN
NR1R2
BocHN
NR1R2
MOMO
Paolo Tosatti
Ir-enabled synthesis of lead-like cores
O
Boc N
2
NBn
2
NR1R2
BocHN
NR1R2
2
BocHN
NR1R2
MOMO
2
Paolo Tosatti
Ir-enabled synthesis of lead-like cores
O
Boc N
O
NBn
N
H
O
OH
NR1R2
H
N
O
N
H
OH
BocHN
H
O
NR1R2
H
NH
NH
N
BocHN
O
N
NR1R2
MOMO
H
O
N
NH
H
O
NH
N
Paolo Tosatti
Ir-enabled synthesis of lead-like cores
O
Boc N
O
NBn
N
H
O
OH
NR1R2
H
N
O
N
H
OH
BocHN
H
O
NR1R2
H
NH
NH
N
BocHN
O
N
NR1R2
MOMO
H
O
N
NH
H
O
NH
N
Paolo Tosatti
Ir-enabled synthesis of lead-like cores
O
Boc N
O
NBn
N
H
O
OH
NR1R2
H
N
O
N
H
OH
BocHN
Ms
Bn
N
Ph
N Boc
H
O
NR1R2
H
NH
NH
N
BocHN
O
N
NR1R2
MOMO
P
N
H
R'
N
O
NH
H
O
NH
N
Paolo Tosatti
Ir-enabled synthesis of lead-like cores
O
Boc N
O
NBn
N
H
O
OH
NR1R2
H
N
O
N
H
OH
BocHN
Ms
Ph
Bn
N
H
O
NR1R2
NH
O
NH
N
BocHN
N Boc
H
N
NR1R2
O
HN
N
N
PMP
MOMO
P
N
H
R'
N
O
NH
H
O
NH
N
Ph
Paolo Tosatti
Robert Hodgson
Joanne Holland
Chrissie Carter
Stephen Bartlett
Neetu Kaushal
Claire Crawford
Matthew Edmundson
Chris Cordier
Mandy Bolt
Catherine Joce
Adrian Fowkes
Sarah Murrison
Martin Fisher
Nicole Timms
John Li
Adam Daniels
Tom James
Charles Lardeau
Giorgia Magnatti
Acknowledgments
PhD students
Alexis Perry
Tom Woodhall
Ben Whittaker
Alan Ironmonger
Mark Anstiss
Karen Dodd
Lorna Farnsworth
Stuart Leach
Catherine O’Leary-Steele
Rebecca White
Angela Kinnell
Tom Harman
Paolo Tosatti
Ivan Campeotto
Rachael Shearer
Mark Dow
Christian Einzinger
Jenny Stockwell
Alun Myden
Academic collaborators
Steve Marsden
Stuart Warriner
Paul Ko Ferrigno
Melanie Welham (Bath)
Postdocs
Blandine Clique
Mike Harding
Silvie Domann
Gavin Williams
Tamara Belyaeva
Stephen Worden
Teresa Damiano
Heather Bone
Gordon McKiernan
Dan Morton
Jon Shepherd
Louise Horsfall
Ieuan Davies
Jackie Ouzman
Joachim Horn
Francesco Marchetti
Sushil Maurya
Sophie Gore
Paul Maclellan
Industrial Collaborators
Ben McKeever-Abbas (AZ)
David House (GSK)
Gordon Weingarten (GSK)
Amanda Campbell (GSK)
Acknowledgments
EPSRC (Advanced Research Fellowship 2004-9)
BBSRC
Wellcome Trust
GSK
AstraZeneca