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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
HN
S
N
O
O
1
2
3
4
4a
5 66a
7
8
911
1010a
10b
Euthyroideone A
N
N
OH
Arnoamine A
1
2
3
44a 4b
5
6
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
Br
O
HN
S
N
O
OB
Br
O
HN
S
N
O
OC
Br
O
HN
S
N
O
OA
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
The EuthyroideonesBr
O
HN
S
N
O
OA
Br
O
HN
S
N
O
OB
Br
O
HN
S
N
O
OC
Br
O
HN
S
N
O
O
• 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
Br
O
HN
S
N
O
OA
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
Deconstructing the Skeleton
Br
O
HN
S
N
OO
HO
HN
SO2
N
Br
HO
HN
S
N
Br
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
Deconstructing the Skeleton
HO
HN
S
N
HO
HN
S
NH2
HO
HN
S
N
Br
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
Deconstructing the Skeleton
HO
HN
S
NH2
H2N SH
O
NH2O
HO
HO
S
NH3
H3N
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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
S
HO
H3N
HN
CBzHO
S
HO
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
S
HO
H3N
HN
CBz
BrO
S
O
H3N
HN
CBz
Br
Bromine is also an oxidant
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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
O
S
O
H3N
HN
CBz
Br
-H2O O
S
N
HN
CBz
Br
H
Cl
HO
S
HN
HN
CBz
Br
Cl
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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
S
HN
HN
CBz
Br
Cl
HO
S
H2N
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
S
H2N
NH3
Br
Cl
This is particularly striking since it provides a means ofdifferentiating the two reactive aromatic positions
Br
O
HN
S
N
OO
vs.HO
S
HO
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
S
H2N
NH3
Br
Cl
Br
O
HN
S
N
OO
???
Since the literature lacks a transformation capable of linkingthese two structures,
we must move on to other approaches
we 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
S
H2N
NH3
Br
Cl
O
S
H2N
Br
NH
Cl
HO
S
H2N
N
Br
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 Design
HO
S
HN
N
Br
Cl
H
O
O
O
S
HN
Br
NH
Cl
OO
O
S
HN
Br
NH
HO
S
HN
Br
N
K2CO3Cl
HO
H2N
S
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
HN
S
NH
Br Br
O
HN
S
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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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets
The Pyridoacridines
Dopamine-derived pyridoacridines
N
N
N
S
O
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
O
H
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
N
OMe
NH
OO
N
N
OMe
NH
O
O
NH
N
N
OH
O
H
N
N
O
N
O
NH
N
OH
N
N
N
O
NNH
N
OH
N
RN
N
OH
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
N
N
S
N
NH
N
HN
N
S
N
N
N
N
S N
N
N
S
NH
N
N
OH
NH
N
N
OH
R
N
N
OH
NH
N
HN
OH
NH
N
NH2
OH
N
N
OMe
N
N
O
N
O
N
N
N
S
N
N
N
N
N
S
N
N
OH
NH
N
HN
OMe
R
SMe
NH
N
HN
N
S
R
NH
N
MeO
OMe
O
N
N HN O
S
N
N
N
OH
NH
O
O
N
N
OH
NH
OO
NH
N
NH
HN O
SR'
R
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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
B
N
N
OMe
• 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
N
OH
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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
N
OH
B
N
N
OMe
N
N
OH
NH
N
OH
R3N
NH
N
OH
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
N
OH
B
N
N
OMe
N
N
OH
NH
N
OH
R3N
NH
N
OH
H3N
Styelsamine D
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisMechanism for SynthesisMechanism for Synthesis
Styelsamine B
NH2
H3N
O
OH
OH
N OH
2 AgI
O
O
N OH
NH
H3N
O2 AgI
ArNH2
O
O
N OH
CeIII
OH
OH
N OH
NH
H3N
O
2 Ag0
2 Ag0
NH
N
N
OH
O
H
H
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisMechanism for SynthesisMechanism for Synthesis
Styelsamine B NH
N
OH
H3N
O
O
N OH
NH
H3N
O
O
O
N OH
N
H
NH3
HO
O
O
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
N
OH
H3N
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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisMechanism for SynthesisMechanism for Synthesis
Styelsamine B NH
N
OH
H3N
O
O
N OH
N
H
NH3
HO
H2O
N
OH
N OH
NH
H
O
O
N OH
N
NH3
N
O
N OH
N
H
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
NH
N
HN
OH
R
NH
N
NH2
OH
styelsamine D
E. latericius2
N
N
HN
O
R
N
N
N
O
HO
O
H
R=acetyl
styelsamine B
E. latericius2
R=acetyl
cystodytin J
C. dellechiaje6
R=tigloyl
cystodytin B
C. dellechiaje7,19R=3,3-dimethylacryloyl
cystodytin A
C. dellechiaje6,7,19
cystodytin C
C. 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
N
N
S
O
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
O
H
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
N
OMe
NH
OO
N
N
OMe
NH
O
O
NH
N
N
OH
O
H
N
N
O
N
O
NH
N
OH
N
N
N
O
NNH
N
OH
N
RN
N
OH
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
N
N
S
N
NH
N
HN
N
S
N
N
N
N
S N
N
N
S
NH
N
N
OH
NH
N
N
OH
R
N
N
OH
NH
N
HN
OH
NH
N
NH2
OH
N
N
OMe
N
N
O
N
O
N
N
N
S
N
N
N
N
N
S
N
N
OH
NH
N
HN
OMe
R
SMe
NH
N
HN
N
S
R
NH
N
MeO
OMe
O
N
N HN O
S
N
N
N
OH
NH
O
O
N
N
OH
NH
OO
NH
N
NH
HN O
SR'
R
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Planning for Multiple TargetsPlanning for Multiple TargetsMechanism for SynthesisMechanism for Synthesis
The Big Picture
• Take into account all desired target molecules as a Take into account all desired target molecules as a guide to synthetic designguide to 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