alternatives in the design of chemical synthesis

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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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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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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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HO

HNS

N

HO

HNS

NH2

HO

HNS

N

Br

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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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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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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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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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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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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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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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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

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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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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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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Alternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisMechanism for SynthesisMechanism for Synthesis

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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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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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

HomeAlternatives in the Design of Chemical SynthesisAlternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsPlanning for Multiple Targets

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

alternatives in the design of chemical synthesis

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