D. PAVIA CHEMISTRY 425a/552
CHEMISTRY OF NATURAL PRODUCTS
THE 2007 COURSE WILL CONCENTRATE ON ALKALOIDS
The lectures will use alkaloids for most of the structure proof and
biosynthetic examples discussed, although the basic concepts of acetogenins,
terpenes, and steroids will also be included. The course will consist of
graded problem sets, or projects, and a term paper or posterdetailing the
isolation, structure proof, absolute stereochemistry, and biosynthesis of a
natural product. The term paper will require you to find and read original
literature references. This will include library work using Chem Abstracts,
Beilstein and SSciFinder Scholar, as well as the standard review compilations
of natural product chemistry.
TEXTS
D. L. Pavia, Lecture Notes for Natural Products Chemistry, WWU Chemistry.
Website = http://atom.chem.wwu.edu/dept/facstaff/pavia/425pavia.html
R.E.Schultes, A.Hofmann and C.Ratsch, Plants of the Gods (rev.),
Healing Arts Press (1998)
RECOMMENDED (also on reserve)
M. Hesse, Alkaloids-Nature's Curse or Blessing?, Wiley-VCH (2002).
P.M.Dewick, Medicinal Natural Products - A Biosynthetic Approach, 2nd ed.,
Wiley (2001)
We will also use books (on reserve) and journals in the Library.
LECTURE TOPICS
1. What is a "natural product"?
Primary metabolism in plants
Primary vs. secondary metabolites
2. Definition of an "alkaloid"
Classification schemes
- by plant origin, by structural feature, by biosynthetic pathway
Theories of the function of alkaloids in plants
3. Amino acid biochemistry
Coenzymes, Cofactors and Enzymes
Pyridoxyl-5'-phosphate, FAD, NAD, ATP
Oxidative deamination, decarboxylation, transamination
Reductive amination
Deaminases
4. beta-Phenylethylamines
Ephedrine, Tyramine, Hordenine, Mescaline
Plant aromatic hydroxylases
S-Adenosylmethionine as nature's methylating agent
Alkaloid methylation patterns
Formation of methylenedioxy groups
Peyote and Anhalonium alkaloids - biosynthesis
5. Origin of heterocyclic rings from specific amino acids
alpha-Amino acids
Ornithine, lysine, phenylalanine, tyrosine, tryptophan
beta-Amino acids
Nicotinic acid, anthranilic acid
Biosynthesis of benzylisoquinoline alkaloids
(+)-Demethylcoclaurine and Papaverine
6. Part One: Isolation and Structure Proof of Atropine (Classical Methods)
The work of Richard Willst„tter (1895-1903)
Short History of Atropine and Solanaceous Alkaloids - Ethnobotany
Isolation and Purification
Resolution of Atropine to give Hyoscyamine
Hydrolysis of Atropine to racemic Tropic acid and Tropine
Structure Proof and Synthesis of Tropic Acid
Structure Proof of Tropine
Standard Classical Alkaloid Methods
Elemental Analysis
Exhaustive Methylation, Hoffmann and Emde Degradations
Von Braun Degradation
Kuhn-Roth Method
7. Part Two: Atropine - The Absolute Configuration Work of Gabor Fodor (ca. 1960)
Absolute Configuration of Tropic Acid
(by relation to L-(+)-alanine)
Absolute Configuration of Tropine
(by intramolecular group relationships and infrared spectroscopy)
Verification of Structure by Synthesis and X-ray Crystallography
Other Tropane Alkaloids
Cocaine, Scopalamine
8. Glycolysis and the Citric acid cycle
Synthetic and Energetic Functions of ATP
Coenzyme A, Thiamine, Biotin, Lipoic Acid
Importance of PEP and Pyruvic acid
9. Natural Products derived from Acetyl Coenzyme A
Polyketide Chains - Acetogenins
Fungal Metabolites
Tetracyclines and Other Macrolides
10. Terpenes
Isoprene Rule
Mevalonic Acid Pathway
Biosynthesis of Terpenes
Head-to-tail: Monoterpenes, Terpenes, Sesquiterpenes and Diterpenes
Dimerization tail-to-tail: Triterpenes and Tetraterpenes
Squalene and beta-Carotene
Carbon-13 Studies with Acetic Acid show Alternate Carbon Labeling
11. Steroid Biosynthesis
Cyclization of Squalene from chair-boat-chair-boat folding
Lanosterol - mammals
Cycloartenol - plants
12. Biosynthesis of other Tri- and Tetraterpenes
Different modes of folding Squalene (chair-chair-chair-chair, etc.)
alpha-Onocerin, beta-Amyrin, Dammarenediols, Malbaricol
13.Shikimic Acid Pathway
Phenylalanine and Tyrosine Biosynthesis
Phenylpropane and Phenylmethane Natural Products
14. Isolation and Structure Proof of Morphine, Codeine and Thebaine (Opium Alkaloids)
Short History of Morphine, Codeine and Heroin - Ethnobotany
150 Years of Chemistry
Classical Structure Work
The Anomalous Hoffmann Degradations
The work on Methylmorphenol (a Phenanthrene)
Locating the Oxygen Functions on the Skeleton
KOH Fusions and Acetolysis
The Pschorr Phenanthrene Synthesis
Phenanthraquinones
Hydroxycodeine - a Bit of Serendipity
The Importance of UV Spectroscopy
alpha- and beta- Codeimethine Revisited (Hoffman products)
Locating the Nitrogen Bridge and the Double Bond
Contributions of Sir Robert Robinson
15. Biosynthesis of Morphine-Codeine-Thebaine
Time-delayed Radioactive Labelling Studies - Growth in a 14C-CO2 atmosphere
Appearance of Labels with Time to Determine the Biosynthetic Sequence
16. Radioactive Incorporation Studies
Feeding Methods and Problems
False Incorporation or Lack of Incorporation
Inverse Isotopic Dilution Methods
Percentage Incorporation
17. Quinine - A Case Study of Radioactive Methods used by Edward Leete
Short History of Quinine - Ethnobotany
Synthesis of Labeled Tryptophan from 15N-NH3 and 14C-HCOOH
Synthesis of 14C-Labeled Geraniol
Wick Feeding of Cinchona succuriba seedlings
Degradation Chemistry of Quinine - How do You Find the Positions of the Labels?
Determining the Positions of the Radioactive Labels
Proposed Biosynthetic Route for Quinine - Some Surprises
18. A Brief Introduction to Medicinal Chemistry
Pharmacology of Morphine and Heroin
Endorphins
Agonists and Antagonists
The Search for a Non-Addicting Synthetic Analgesic
Demerol, Methadone, Vycodan, Naloxone and Others
19. Some Modern Methods
Aspidospermine (NMR and IR)
Spegazzidinine (Mass Spectrometry)
Using Known Fragmentation Patterns
20. Using NMR to Perform Non-Radioactive Labeling of Biosynthetic Intermediates.
15N and 13C - Enhanced Peak Intensities
21. Whatever special topics that time permits will finish the course.
______
There is no single text that is adequate for this class.
We will rely on lecture presentations, notes, and optional readings in Hesse
(Alkaloids)and DeWick (Medicinal Natural Products - A Biosynthetic Approach).
There will also be optional readings in Schultes (Plants of the Gods).
Most of my notes are available online as PowerPoint presentations.
Copies are also available in the bookstore if you wish to purchase a complete set.
A number of important texts are placed on reserve in the library.
Required problem sets are given out at regular intervals, and they will have
specific due-dates. Expect periodic quizzes and there will be two mid-term exams.
Some library work will be required, as will the use of SciFinder Scholar for online
literature searching.
In lieu of a final, expect to either write a paper, or prepare and present a
arge-format PowerPoint poster, that will require use of the original literature.
Posters will typically be a group (2 students) project, except for graduate students
who will work independently. Students will be required to use ChemDraw for drawing
chemical structures.
You should work on problem sets independently - not as a group
(except when specified otherwise). Keep in mind University policies
on academic honesty.
