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Alternatives in the Design of Chemical Synthesis

Alternatives in the Design of Chemical Synthesis. Combining process and medicinal chemistry Designing for all desired targets Avoiding unnecessary complication. Alternatives in the Design of Chemical Synthesis The Target Molecules. Euthyroides episcopalis. Cystodytes sp.

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Alternatives in the Design of Chemical Synthesis

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  1. Alternatives in the Design of Chemical Synthesis • Combining process and medicinal chemistry • Designing for all desired targets • Avoiding unnecessary complication

  2. Alternatives in the Design of Chemical SynthesisThe Target Molecules Euthyroides episcopalis Cystodytes sp.

  3. Alternatives in the Design of Chemical SynthesisPlanning for Multiple Targets • Natural products are interconnected by virtue of their biosynthesis from ubiquitous starting materials

  4. Alternatives in the Design of Chemical SynthesisPlanning for Multiple Targets • In the case of new natural products the connectivity may be deduced based on our understanding of chemical reactivity

  5. Alternatives in the Design of Chemical SynthesisPlanning for Multiple Targets • In the case of new natural products the connectivity may be deduced based on our understanding of chemical reactivity

  6. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsThe Euthyroideones • Due to the unusual structural features of the euthyroideones they represent a trivial case of mapping

  7. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsThe Euthyroideones • Euthyroideones B and C appear to be oxidation • products of euthyroideone A • However, since the overall structure shows a high • oxidation state it may be assumed that B and C arise • by further oxidation of A • The hypothetical fully unsaturated euthyroideone • cannot be disregarded as a possible precursor

  8. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsDeconstructing the Skeleton

  9. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsDeconstructing the Skeleton

  10. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsDeconstructing the Skeleton

  11. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsReaction Discovery It is important to remember that reagents may participate in multiple reaction types.

  12. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsReaction Discovery Bromine is also an oxidant

  13. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsReaction Discovery -H2O

  14. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsReaction Discovery The point at which the CBz falls off is unclear This unusual transformation provides a product with many of the features of the desired target molecule

  15. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsReaction Discovery vs. This is particularly striking since it provides a means of differentiating the two reactive aromatic positions

  16. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsReaction Design ??? Since the literature lacks a transformation capable of linking these two structures, we must move on to other approaches we must create one

  17. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsReaction Design The obstacle that presents itself in the elaboration of this structure is the reversibility of the Pictet-Spengler reaction

  18. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsReaction Design Replacing formaldehyde with glyoxilic acid provides a means of making the cyclization irreversible.

  19. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsThe Euthyroideones X The seemingly trivial methylation/oxidation necessary to complete this synthesis proved unworkable, and completion of the synthesis remains an elusive goal.

  20. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsThe Pyridoacridines Pyridoacridine Acridine • The Arnoamines are part of a larger class of • natural products – the pyridoacridines

  21. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsThe Pyridoacridines Dopamine-derived pyridoacridine • The arnoamines are part of a larger class of • natural products – the pyridoacridines

  22. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsThe Pyridoacridines Dopamine-derived pyridoacridines

  23. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsThe Arnoamines • The Arnoamines are related by methylation • The Arnoamines are part of a larger class of • natural products – the pyridoacridines

  24. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsThe Arnoamines • Arnoamine A may be related to the other pyridoacridines by side chain cyclization Styelsamine D

  25. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsThe Arnoamines • Styelsamine D was designated the primary target since it appears to be central to all dopamine-derived pyridoacridines Styelsamine D

  26. Alternatives in the Design of Chemical SynthesisMechanism for SynthesisStyelsamine B

  27. Alternatives in the Design of Chemical SynthesisMechanism for SynthesisStyelsamine B

  28. Alternatives in the Design of Chemical SynthesisMechanism for SynthesisStyelsamine B

  29. Alternatives in the Design of Chemical SynthesisMechanism for SynthesisStyelsamine B

  30. Alternatives in the Design of Chemical SynthesisMechanism for SynthesisThe Pyridoacridine Family

  31. Alternatives in the Design of Chemical SynthesisMechanism for SynthesisThe Pyridoacridine Family

  32. Alternatives in the Design of Chemical SynthesisPlanning for Multiple TargetsMechanism for SynthesisThe Big Picture • Take into account all desired target molecules as a guide to synthetic design • Be willing to explore new reaction chemistry • One unknown step may be preferable to several known steps

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