Lecture 1 - Why Synthesize Molecules?

Why Synthesize Molecules?

Introduction

  • Professor Laura Malins introduces the three-part organic chemistry HPO lecture series.
  • Her research group focuses on the chemistry and synthesis of biologically relevant molecules, including peptides, proteins, and small molecule active therapeutics.
  • The group develops new ways of constructing molecules, akin to finding new ways to piece together Lego bricks to build complex structures.

Overview of the Lecture Series

  • Lecture 1: Focuses on why we synthesize molecules and the types of molecules targeted by organic chemists.
  • Lecture 2: Discusses the application of synthesis in making drugs, focusing on medicinal chemistry and the development of therapeutic strategies to target diseases.
  • Lecture 3: Covers peptide and protein-based drugs and the total synthesis of a protein or enzyme, a challenge that began a century ago with Emile Fisher's Nobel Prize in 1902.

Types of Molecules Synthesized

  • The field of organic chemistry is open, allowing chemists to synthesize virtually any molecule that obeys chemical laws.
  • Many synthesized molecules are inspired by nature (natural products), while others are entirely designed.
  • Examples include:
    • Tetrodotoxin (TTX): A neurotoxin from puffer fish.
    • Anti-HIV drug: Illustrates the complexity in terms of stereochemistry and diverse functionalities.
    • Dodecahedron: A molecule of theoretical interest due to its geometric shape.
    • Designed molecule: A Buckminsterfullerene-porphyrin construct used for photovoltaics, enabling electron transfer.

Natural vs. Unnatural Compounds

  • Organic chemists synthesize both natural compounds (inspired by nature) and unnatural or designed compounds.
  • Total synthesis allows for combining elements in novel ways, provided fundamental chemical rules are followed and molecules are stable.

Natural Products

  • Natural products encompass various classes, with the synthesis resembling organic chemical reactions of life.
  • Plants use CO_2, water, and sunlight to photosynthesize sugars, which are then converted into different classes of natural products.
  • Sugars can be converted into saccharides and polysaccharides, and with the addition of amino acids, they can form nucleic acids (DNA, RNA, oligonucleotides).
  • Glycolysis can break down sugars into other carbon and oxygen-containing components, serving as precursors to different natural products.
  • Classes of natural products include peptides, proteins, alkaloids, isoprenoids, polyketides, and fatty acids.

Fatty Acids

  • Fatty acids typically have a long carbon chain and a polar head group (e.g., palmitic acid).
  • Animal fats and vegetable oils feature fatty acids.
  • Examples:
    • Spermaceti: Produced by sperm whales and used in ointments and candle wax.
    • Arachidonic acid: Can undergo cyclization to form prostaglandin.
    • Gypsy moth sex pheromone: Illustrates how common structural elements can lead to diverse functions.

Polyketides

  • Polyketides are characterized by numerous oxygen atoms and unsaturation (aromatic rings and double bonds).
  • They consist of repeating units of carbonyl (C=O) and methylene (CH_2) groups.
  • Many polyketides are biologically active.
  • Examples:
    • Griseofulvin and Lovastatin: Therapeutic molecules.
    • Aflatoxin: Very toxic.
    • Serve as a rich source of therapeutic compounds like antibiotics and anticancer drugs.

Isoprenoids

  • Isoprenoids are made from repeating units of isoprene (5-carbon unit).
  • Isoprene units assemble in various ways to form longer carbon chains.
  • The term "isoprenoids" implies oxygenation.
  • Examples:
    • Menthol, Cholesterol, Taxol.
    • Lycopene: The pigment in tomatoes.
  • Isoprene linking units are crucial in generating many pigments observed in nature.

Peptides and Proteins

  • Peptides and proteins are composed of amino acids, assembled by the ribosome (using DNA as a template).
  • Peptides can also be composed via non-ribosomal pathways, leading to structural variety.
  • Examples:
    • Vancomycin: A glycopeptide antibiotic isolated from soil bacteria, containing an amide backbone, cross-links, macrocycles, and carbohydrate units.
    • Glycopeptide antibiotic used to treat life threatening infections.

Mechanism of Action – Vancomycin

  • Vancomycin disrupts the biosynthesis of the peptidoglycan wall in bacteria by forming a hydrogen bond with the D-ala D-ala dipeptide unit.O on the carbonyl can form a hydrogen bond to H.
  • Hydrogen bonds are key interactions.
  • Bacteria develop resistance by changing the peptidoglycan wall component to D-ala D-lac.
  • The bacteria overcomes resistance via repulsion, as now there are two oxygen atoms so no hydrogen bond can form.
  • Synthetic chemists have created analogs of vancomycin to overcome this resistance pathway, such as swapping out the carbonyl oxygen for an NH group.

Peptide Hormones

  • Oxytocin: Known as the love hormone, released during childbirth and by pets.
  • Human Insulin: An important therapeutic for managing blood glucose levels in diabetes.
  • Erythropoietin: Used to improve red blood cell count but controversially used by athletes to enhance performance.

Alkaloids

  • Alkaloids are often isolated from plants and are characterized by the abundance of nitrogen atoms, often in heterocycles.
  • Examples include morphine, lysergic acid, cocaine, nicotine, quinine (antimalarial), and penicillin.
  • Penicillin's synthesis was a significant focus during World War II for treating wounded soldiers.

Terminology in Synthesis

  • Natural Product: A carbon-based compound made inside a living organism that can also be synthesized by chemists.
  • Chemical Synthesis: The construction of compounds over a number of discrete steps via chemical reactions by synthetic or non-biological means.
  • Organic Synthesis: A broader term that can include both biological and chemical methods.
  • Biosynthesis: The way nature constructs compounds, usually over a number of distinct steps, each involving a chemical reaction by biological means.
  • Total Synthesis: The process of making a target structure, usually a natural product, from much simpler starting materials.
  • Semi-Synthesis: A process in which a target structure is prepared from a similar starting material.
  • Partial Synthesis: A synthesis that begins with a very similar starting material to the target molecule.
  • Formal Synthesis: When a compound is prepared that has previously been converted into a target.

Motivations for Chemical Synthesis

  • To make sufficient quantities of a material.
  • To study useful (e.g., biological) properties of a target molecule.
  • To demonstrate the utility of a synthetic method.
  • To demonstrate a synthetic strategy or concept.
  • To demonstrate progress in synthetic power and efficiency.
  • To validate a hypothetical biosynthetic pathway (biomimetic synthesis).
  • To train synthetic chemists.
  • Personal accomplishment.
  • Historically, to provide definitive proof in verifying a proposed structure, although modern tools have largely replaced this.

Challenges and Strategies in Synthesis

  • No single strategy fits all synthesis due to the diversity of target structures.
  • Current methods lack the ability to accurately predict outcomes.
  • AI and machine learning are revolutionizing the field, but human intellect is still essential.
  • Developing new synthetic strategies, particularly for new bonds and reactions, remains a challenge.
  • There are no perfect chemical syntheses; ideal synthesis is a one-step process with 100% yield from simple, inexpensive materials.
  • Synthesis is typically stepwise, wherein the yield decreases dramatically. If average yield per step is 90%, the overall yield becomes very low.
Yield = (Yield per step)^{number of steps}
  • This is called the arithmetic (geometric) demon. Long synthesis have a huge consequence.
  • Options for the better synthesis are to think about designing either new reaction or designing better targets (simplify).
final yield = (0.9)^{20} =0.12 or 12%
final yield = (0.8)^{20} =0.011 or 1.1%

Examples of Simplifying Synthesis

  • Halichondrin B (32 stereocenters): Produced by a marine sponge; a really great anti-cancer molecule. But its difficult to extract synthetically.
  • Developed a synthetic version which is Eribulin A pharmaceutical company, was to make a fully synthetic version is arribulin and it turns out that all of this stuff here is not really important actually to the biological activity, right? So you can chop all that off and you can end up with a much simpler drug.

Multi-Step Chemical Synthesis

  • Involves starting with a commercially available material and undergoing various transformations to build complexity.
  • Steps may include installing oxygens, oxidation reactions, removing methyl groups, cyclization, and deprotection.
  • Protecting groups mask functional groups to prevent them from reacting, allowing for on-demand liberation for further transformations.

General Guide for Synthesis

  • Draw and view the target in as many ways as possible.
  • Focus on the carbon skeleton and consider functional groups as decoration.
  • Think about and talk about the structure, its functional groups, and their reactivity.
  • Simplify the problem to make it more manageable.
  • Everything should be made as simple as possible, but not simpler (Albert Einstein).