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Alternatives in the Design of Chemical Synthesis
A B+
cat.
AB
• Combining process and medicinal chemistryCombining process and medicinal chemistry• Designing for all desired targetsDesigning for all desired targets• Avoiding unnecessary complicationAvoiding unnecessary complication
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical Synthesis
The Target MoleculesBr
O
HNS
N
OO
1
23
4
4a
5 6 6a 78
911
1010a
10b
Euthyroideone A
N
NOH
Arnoamine A
1
2
34
4a 4b
56
7
7a
8
91010a
1111a
10b
1213
Euthyroides episcopalis Cystodytes sp.
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical Synthesis
Planning for Multiple Targets
• Natural products are interconnected by virtue of their Natural products are interconnected by virtue of their biosynthesis from ubiquitous starting materialsbiosynthesis from ubiquitous starting materials
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical Synthesis
Planning for Multiple Targets
• In the case of new natural products the In the case of new natural products the connectivity may be deduced based on our connectivity may be deduced based on our understanding of chemical reactivityunderstanding of chemical reactivity
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical Synthesis
Planning for Multiple Targets
• In the case of new natural products the In the case of new natural products the connectivity may be deduced based on our connectivity may be deduced based on our understanding of chemical reactivityunderstanding of chemical reactivity
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
The Euthyroideones
• Due to the unusual structural features of the Due to the unusual structural features of the euthyroideones they represent a trivial case of euthyroideones they represent a trivial case of mappingmapping
BrO
HNS
N
OO B
BrO
HNS
N
OO C
BrO
HNS
N
OO A
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The EuthyroideonesBr
O
HNS
N
OO A
BrO
HNS
N
OO B
BrO
HNS
N
OO C
BrO
HNS
N
OO
• Euthyroideones B and C appear to be oxidationEuthyroideones B and C appear to be oxidationproducts of euthyroideone Aproducts of euthyroideone A
• The hypothetical fully unsaturated euthyroideone The hypothetical fully unsaturated euthyroideone cannot be disregarded as a possible precursorcannot be disregarded as a possible precursor
• However, since the overall structure shows a highHowever, since the overall structure shows a highoxidation state it may be assumed that B and C ariseoxidation state it may be assumed that B and C ariseby further oxidation of Aby further oxidation of A
BrO
HNS
N
OO A
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Deconstructing the Skeleton
BrO
HNS
N
OO
HO
HNSO2
N
BrHO
HNS
N
Br
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Deconstructing the Skeleton
HO
HNS
N
HO
HNS
NH2
HO
HNS
N
Br
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Deconstructing the Skeleton
HO
HNS
NH2
H2N SH
O
NH2O
HO
HOS
NH3
H3N
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Reaction Discovery
HO
SHO
H3N
HN
CBz HO
SHO
H3N
HN
CBz
Br
It is important to remember that reagents may participate inmultiple reaction types.
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
Reaction Discovery
HO
SHO
H3N
HN
CBz
BrO
SO
H3N
HN
CBz
Br
Bromine is also an oxidant
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Reaction DiscoveryO
SO
H3N
HN
CBz
Br-H2O O
SN
HN
CBz
Br
H
Cl
HO
SHN
HN
CBz
Br
Cl
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Reaction Discovery
HO
SHN
HN
CBz
Br
Cl
HO
SH2N
NH3
Br
Cl
The point at which the CBzfalls off is unclear
This unusual transformation provides a product with manyof the features of the desired target molecule
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
Reaction Discovery
HO
SH2N
NH3
Br
Cl
This is particularly striking since it provides a means ofdifferentiating the two reactive aromatic positions
BrO
HNS
N
OO
vs.HO
SHO
H3N
HN
CBz
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
Reaction Design
HO
SH2N
NH3
Br
Cl
BrO
HNS
N
OO
???
Since the literature lacks a transformation capable of linkingthese two structures,
we must move on to other approacheswe must create one
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
Reaction DesignHO
SH2N
NH3
Br
Cl
O
SH2N
Br
NHCl
HO
SH2N
NBr
Cl
H
CH2O
The obstacle that presents itself in the elaboration of thisstructure is the reversibility of the Pictet-Spengler reaction
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
Reaction DesignHO
SHN
NBr
Cl
H
O
OO
SHN
Br
NHCl
OO
O
SHN
Br
NH
HO
SHN
Br
N
K2CO3Cl
HO
H2NS
NH3
Br
Cl
Cl OH
OOH
Replacing formaldehyde with glyoxilic acid provides a meansof making the cyclization irreversible.
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
The Euthyroideones
O
HNS
NH
Br BrO
HNS
N
OO
X
The seemingly trivial methylation/oxidation necessary tocomplete this synthesis proved unworkable, and completionof the synthesis remains an elusive goal.
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
The Pyridoacridines
• The Arnoamines are part of a larger class ofThe Arnoamines are part of a larger class ofnatural products – the pyridoacridinesnatural products – the pyridoacridines
N
Acridine Pyridoacridine
NH
N
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
The Pyridoacridines
• The arnoamines are part of a larger class ofThe arnoamines are part of a larger class ofnatural products – the pyridoacridinesnatural products – the pyridoacridines
Dopamine-derived pyridoacridine
NH
N
NR2
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The Pyridoacridines
Dopamine-derived pyridoacridines
N
NN
SO
N
N
HN
N
S
O
OH
NH
N
NH2
N
S
N
N
HN
O
R
SMe
NH
N
NH2
HN O
SR'
NH
N
HN
OH
R
SMe
HN
O
R
N
N
N
N
N
O
HO
OH
OH
N
N
HN
O
R
N
N
HN
O
R
Oleic
NH
N
HN
OH
R
OH
N
N
NH2
O
NH
N
NH2
OH
OH
N
N
HN
O
R
OMe NH
N
H
OH
O
NH
N
MeO
OH
O
NH
N
HO
OH
O
N
NOMe
NH
OO
N
NOMe
NH
O
O
NH
N
N
OH
O
H
N
NO
N
O
NH
NOH
N
N
NO
NNH
NOH
NRN
NOH
N
O
R
NH
N
N
HN O
S
NH
N
N
HN O
S
O
N
N HN O
S
N
NH
N
HN
HN O
S
NH
N
N
N
SNH
N
N
N
S
O
N
NN
S
N
NH
N
HN
N
S
N
N
N
N
S N
NN
S
NH
N
N
OH
NH
N
N
OH
R
N
NOH
NH
N
HN
OH
NH
N
NH2
OH
N
NOMe
N
NO
N
O
N
NN
S
N
N
N
N
N
S
N
NOH
NH
N
HN
OMe
R
SMe
NH
N
HN
N
S
R
NH
N
MeO
OMe
O
N
N HN O
S
N
N
NOH
NH
O
O
N
NOH
NH
OO
NH
N
NH
HN O
SR'
R
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The Arnoamines
B
N
NOMe
• The Arnoamines are related by methylationThe Arnoamines are related by methylation
• The Arnoamines are part of a larger class ofThe Arnoamines are part of a larger class ofnatural products – the pyridoacridinesnatural products – the pyridoacridines
N
N
A
N
NOH
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
The Arnoamines
• Arnoamine A may be related to the other Arnoamine A may be related to the other pyridoacridines by side chain cyclizationpyridoacridines by side chain cyclization
A
N
NOH
B
N
NOMe
N
NOH
NH
NOH
R3N
NH
NOH
H3N
Styelsamine D
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
The Arnoamines
• Styelsamine D was designated the primary Styelsamine D was designated the primary target since it appears to be central to all target since it appears to be central to all dopamine-derived pyridoacridines dopamine-derived pyridoacridines
A
N
NOH
B
N
NOMe
N
NOH
NH
NOH
R3N
NH
NOH
H3N
Styelsamine D
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Styelsamine B
NH2
H3N
O
OHOH
N OH
2 AgI
OO
N OH
NH
H3N
O 2 AgI
ArNH2
OO
N OH
CeIII
OHOH
N OH
NH
H3N
O
2 Ag0
2 Ag0
NH
N
N
OH
OH
H
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Styelsamine B NH
NOH
H3N
OO
N OH
NH
H3N
O
OO
N OH
N
H
NH3
HO
OO
N OH
N
H3N
OH
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisMechanism for SynthesisMechanism for Synthesis
Styelsamine B NH
NOH
H3N
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Styelsamine B NH
NOH
H3N
OO
N OH
N
H
NH3
HO
H2O
NOH
N OH
NH
H
OO
N OH
N
NH3
NO
N OH
N
H
H2O
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The Pyridoacridine Family
NH
N
HN
OH
R
NH
N
NH2
OH
styelsamine DE. latericius2
N
N
HN
O
R
N
N
N
O
HO
OH
R=acetylstyelsamine BE. latericius2
R=acetylcystodytin JC. dellechiaje6
R=tigloylcystodytin BC. dellechiaje7,19 R=3,3-dimethylacryloyl
cystodytin AC. dellechiaje6,7,19
cystodytin CC. dellechiaje7
[O]H2O
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisMechanism for SynthesisMechanism for Synthesis
The Pyridoacridine Family
N
NN
SO
N
N
HN
N
S
O
OH
NH
N
NH2
N
S
N
N
HN
O
R
SMe
NH
N
NH2
HN O
SR'
NH
N
HN
OH
R
SMe
HN
O
R
N
N
N
N
N
O
HO
OH
OH
N
N
HN
O
R
N
N
HN
O
R
Oleic
NH
N
HN
OH
R
OH
N
N
NH2
O
NH
N
NH2
OH
OH
N
N
HN
O
R
OMe NH
N
H
OH
O
NH
N
MeO
OH
O
NH
N
HO
OH
O
N
NOMe
NH
OO
N
NOMe
NH
O
O
NH
N
N
OH
O
H
N
NO
N
O
NH
NOH
N
N
NO
NNH
NOH
NRN
NOH
N
O
R
NH
N
N
HN O
S
NH
N
N
HN O
S
O
N
N HN O
S
N
NH
N
HN
HN O
S
NH
N
N
N
SNH
N
N
N
S
O
N
NN
S
N
NH
N
HN
N
S
N
N
N
N
S N
NN
S
NH
N
N
OH
NH
N
N
OH
R
N
NOH
NH
N
HN
OH
NH
N
NH2
OH
N
NOMe
N
NO
N
O
N
NN
S
N
N
N
N
N
S
N
NOH
NH
N
HN
OMe
R
SMe
NH
N
HN
N
S
R
NH
N
MeO
OMe
O
N
N HN O
S
N
N
NOH
NH
O
O
N
NOH
NH
OO
NH
N
NH
HN O
SR'
R
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Mechanism for SynthesisMechanism for Synthesis
The Big Picture
• Take into account all desired target molecules as a guide Take into account all desired target molecules as a guide to synthetic designto synthetic design
• Be willing to explore new reaction chemistryBe willing to explore new reaction chemistry• One unknown step may be preferable to several known One unknown step may be preferable to several known
stepssteps