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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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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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• 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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• 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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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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Deconstructing the Skeleton

Br

O

HN

S

N

OO

HO

HN

SO2

N

Br

HO

HN

S

N

Br

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HO

HN

S

N

HO

HN

S

NH2

HO

HN

S

N

Br

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HO

HN

S

NH2

H2N SH

O

NH2O

HO

HO

S

NH3

H3N

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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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Reaction Discovery

HO

S

HO

H3N

HN

CBz

BrO

S

O

H3N

HN

CBz

Br

Bromine is also an oxidant

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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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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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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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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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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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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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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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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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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

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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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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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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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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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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Styelsamine B NH

N

OH

H3N

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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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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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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

HomeAlternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical Synthesis

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

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Home Alternatives in the Design of Chemical Synthesis Combining process and medicinal chemistryCombining process and medicinal chemistry Designing for