CHEM 341: Synthesis Notes

Chapter 11: Synthesis

Why Organic Synthesis?

  • To make naturally-occurring compounds: Useful synthesis of biologically active compounds that are difficult or impossible to obtain in sufficient quantities from natural sources.
    • Example: Taxol (Anti-cancer agent)
      • Obtaining 300 mg of Taxol (one dose for a cancer patient) requires sacrificing a 100-year-old yew tree.
      • Synthetic organic chemistry provides methods to synthesize Taxol.
      • Approved by the U.S. Food & Drug Administration in 1992 for treating breast cancer, lung cancer, and melanoma.

Top 30 Small Molecule Pharmaceuticals (2018 Retail Sales)

  • Examples:
    • Eliquis (Apixaban): \$9.871 Billion (Cardiovascular Diseases)
    • Revlimid (Lenalidomide): \$9.685 Billion (Oncology)
    • Xarelto (Riveroxaban): \$6.58 Billion (Cardiovascular Diseases)
    • Imbruvica (Ibrutinib): \$6.205 Billion (Oncology)
    • Lyrica (Pregabalin): \$5.216 Billion (Neurological Disorders)
    • Genvoya: \$4.624 Billion (Infectious Diseases)
    • Tecfidera (Dimethyl Fumarate): \$4.296 Billion (Neurological Disorders)
    • Ibrance (Palbociclib): \$4.118 Billion (Oncology)
    • Januvia (Sitagliptin): \$3.686 Billion (Diabetes)
    • Xtandi (Enzalutamide): \$3.649 Billion (Oncology)
    • Triumeq (Abacavir, Dolutegravir, Lamivudine): \$3.522 Billion (Infectious Diseases)
    • Zytiga (Abiraterone Acetate): \$3.498 Billion (Oncology)
    • Mavyret (Glecaprevir, Pibrentasvir): \$3.438 Billion (Infectious Diseases)
    • Gilenya (Fingolimod): \$3.341 Billion (Neurological Disorders)
    • Advair (Salmeterol): \$3.33 Billion (Respiratory Disorders)
    • Truvada (Emtricitabine, Tenofovir Disoproxil): \$3.33 Billion (Infectious Diseases)
    • Invega Sustenna (Paliperidone Palmitate): \$2.997 Billion (Neurological Disorders)
    • Symbicort (Budesonide, Formoterol): \$2.928 Billion (Respiratory Disorders)
    • Spiriva (Tiotropium): \$2.926 Billion (Respiratory Disorders)
    • Jardiance (Empagliflozin): \$2.726 Billion (Diabetes)
    • Velcade (Bortezomib): \$2.400 Billion (Oncology)
    • Sprycel (Dasatinib): \$2.309 Billion (Oncology)
    • Janumet (Metformin, Sitagliptin): \$2.283 Billion (Diabetes)
    • Lipitor (Atorvastatin): \$2.275 Billion (Cardiovascular Diseases)
    • Tivicay (Dolutegravir): \$2.228 Billion (Infectious Diseases)
    • Jentadueto (Linagliptin): \$2.207 Billion (Diabetes)
    • Alimta (Pemetrexed): \$2.18 Billion (Oncology)
    • Pomalyst (Pomalidomide): \$2.154 Billion (Oncology)
    • Afinitor (Everolimus): \$2.133 Billion (Oncology)
    • Nexium (Esomeprazole): \$2.04 Billion (Gastrointestinal Disorders)

The Story of Quinine Synthesis

  • Quinine is a medication used to treat malaria and babesiosis.
  • Cinchona trees are the natural source of quinine.
  • The total synthesis of quinine spanned over 150 years.
  • It launched a thousand research projects.
  • It is an organic chemistry legend.

Retrosynthetic Analysis

  • Definition: Planning an organic synthesis by working backward from the target molecule to simpler starting compounds.
  • Process:
    • Target molecule (Z)
    • Immediate precursor (Y): Z can be synthesized from Y using certain reagents.
    • Earlier precursor (X): Y can be synthesized from X using certain reagents.
    • Next earlier precursor (W): X can be synthesized from W using certain reagents.
    • Starting compound (A): W can be synthesized from A using certain reagents.
  • Solve for the last step in the synthesis first.

Generating Possible Precursors

  • Generate as many possible precursors as possible to identify different synthetic routes.
  • The target molecule can have multiple 1st precursors (A, B, C), and each 1st precursor can have multiple 2nd precursors (a, b, c, d, e, f).

Retrosynthetic Analysis Questions

  • Key Questions:
    1. Is there a change in the carbon skeleton during the synthesis?
    2. Is there a change in the identity of the functional group, and/or its location?

Example Retrosynthetic Analysis

  • Goal: Convert an alcohol to an alkyne.
  • Analysis:
    1. Carbon skeleton: No change.
    2. Functional group: Alcohol converted to alkyne, position unchanged.
  • Working Backwards:
    • Focus on the last step.
    • Consider reactions that can be used to make an alkyne.
      • Elimination of vicinal dihalides.
  • Vicinal Dihalides Formation: Made by addition reaction to an alkene, identifying a reactant to produce the final product.
  • Alcohol to Alkene: Alcohol can be converted to an alkene via a dehydration (elimination) reaction.
  • Process: Convert the alcohol to a tosylate, then eliminate with a non-nucleophilic base.

Example (gem-dibromide)

  • Gem-dibromide came from addition of HBr across a C \equiv C bond

Disconnection, Synthons, and Synthetic Equivalents

  • Retrosynthetic analysis:

Ph - CH3 \implies Ph^+ + ^-CH3

H3C^- \implies H3C - I
Ph^+ \implies Ph - Na

Synthesis

  • Ph - Na + H3C - I \implies Ph - CH3
  • Reagents: NaNH2, liq. NH3, -30°C (via an SN2 reaction)
  • Ph - CH3 + HBr (excess) \implies Ph - CH3Br_2