Organic Chemistry HPO Lecture 1 Notes

Lecture 1: The Trouble With Synthesis

Professor Laura Malins (organic chemistry academic researcher).
Group focuses on the chemistry and synthesis of biologically relevant molecules.
Developing new ways of constructing molecules (methodology development).

Lecture 1: Why we synthesize molecules and what types of molecules we might like to target as organic chemists.
Lecture 2: Applying that synthesis specifically in the context of making drugs (med chem and the development of therapeutic strategies to target diseases).
Lecture 3: Peptide and protein-based drugs and total synthesis of a protein or enzyme.

The field is completely open; if you can imagine a molecule that obeys the laws of chemistry, you can tackle its synthesis.
Inspiration often comes from nature (natural products) or from designed molecules.
Examples:
- Tetrodotoxin (TTX): A neurotoxin from puffer fish.
- Anti-HIV drug: Note the variety of functional groups and stereochemistry.
- Dodecahedron: A molecule of theoretical interest.
- Designed molecule: Buckminsterfullerene and porphyrin used for photovoltaics.
Humans can make these molecules using various bond-forming strategies.

Natural compounds: Inspired by nature, often sources for therapeutics.
Unnatural/designed compounds: Combining aspects of nature in new ways.
Total synthesis allows assembling molecules in any way, as long as fundamental rules of chemistry are followed.

Nature can photosynthesize sugars from CO2, water, and sunlight.
These sugars can be converted into different classes of natural products.
From common precursors (carbon in CO2), a lot of structural diversity can be obtained.
Sugar can be converted into: saccharides, polysaccharides, nucleic acids (DNA, RNA), oligonucleotides.
Glycolysis can break down sugar into carbon and oxygen-containing components.
Highlighted classes: peptides, proteins, alkaloids, isoprenoids, polyketides, and fatty acids.

Have a long carbon chain and polar head groups like an acid (e.g., palmitic acid).
Found in animal fats and vegetable oils.
Spermaceti: Produced by the sperm whale and used in ointments and candle wax.
Arachidonic acid: Undergoes cyclization to form prostaglandin (a hormone).
Can be converted into sex pheromones.

Characterized by many oxygens and unsaturation (aromatic rings and double bonds).
Comprised of repeating units of carbonyls (C=O) and methylene groups (CH2).
Derived from precursors with alternating carbonyl and CH2 groups.
Biologically active (e.g., griseofulvin, lovastatin).
Aflatoxin is very toxic.
Serve specific roles within biological systems.
Polyketides are a huge rich source of therapeutic compounds.

Composed of amino acids.
Assembled by the ribosome (using DNA as a template) or via non-ribosomal pathways (enzymatic).
Non-ribosomal pathways lead to structural variety (cross-links, macrocycles, carbohydrate units).
Example: Vancomycin
- Has an amide backbone but is made non-ribosomally.
- Glycopeptide antibiotic isolated from soil bacteria.
- Used to treat life-threatening infections.
- Disrupts cell wall biosynthesis via hydrogen bonding to D-ala-D-ala.
- Bacteria develop resistance by changing to D-ala-D-lac.
- Chemists synthesize vancomycin analogs to overcome resistance.
Peptide hormones (e.g., oxytocin).
- Known as the love hormone.
Human insulin: Important therapeutic for diabetes.
Erythropoietin: Therapy to improve red blood cell count.

Natural Product: A subgroup of carbon-based compounds made inside a living thing (but can be synthesized by people).
Chemical Synthesis: Construction of compounds over discrete steps involving chemical reactions by synthetic or non-biological means.
Organic Synthesis: Doesn't distinguish between biological and chemical methods.
Biosynthesis: Nature constructs compounds via biological means.
Total Synthesis: Making a target structure (usually a natural product) from much simpler starting materials.
Semi-Synthesis: Target structure prepared from a similar starting material, with nature doing the majority of the work.
Formal Synthesis: Preparing a compound that has previously been converted into the target.

No one way to do it; target structures are too diverse.
Not always fantastic at predicting the outcomes of reactions.
Computer-based approaches are improving but are still inferior to human understanding.

One step with 100% yield (doesn't happen).
Reality: Stepwise, building parts of the molecule. As the reactions continue yields go down.

If the average yield per step is 90% (good), doing that 20 times makes the overall yield go down drastically.
Overall\ Yield = (Average\ Yield)^{Number\ of\ Steps}
0.9^{20} = 0.12
If the average yield is 80%, the 20-step yield is only 1.1%.
0.8^{20} = 0.011
To improve synthesis, design new reactions or better targets.

Draw and view the target in as many ways as possible.
Flip it, rotate it, and look at it from different faces.
Use model kits or computer models to visualize three-dimensionality.
Focus on the carbon skeleton.
Consider functional groups as decoration, strip down the extra bits to identify the core.
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