CHEM 4485: Advanced Topics in Organic Chemistry: Bioorganic Chemistry Spring 2017: MW 9:30

CHEM 4485: Advanced Topics in Organic Chemistry: Bioorganic Chemistry Spring 2017: MW 9:30 – 10:45 AM; TLC 2105

Instructor: Dr. Partha Ray (TLC 2123; phone: 678-839-6023; email: [email protected])

Course Summary: You will be introduced to the chemistry of biologically important organic compounds and we will discuss the discovery, synthesis, and mechanism of action of a variety of selected pharmaceutical/agricultural agents. You will use, and build on, the concepts and principles learned in general organic chemistry and see how they are applied to the drug discovery process.

Textbook: The textbook you should already have from taking Organic Chemistry I & II “Organic Chemistry” by John McMurry (8th or 9th edition) is recommended.

Topics:

A Brief Introduction to Asymmetric Synthesis

1. Use of Naturally occurring chiral compounds as building blocks 2. Resolution 3. Methods of asymmetric synthesis a. Substrate-controlled methods b. Auxiliary-controlled methods c. Reagent-controlled methods d. Catalyst controlled methods

Carbohydrates

1. Glycoside formation ( vs. ) 2. A General Strategy for Stereoselective Glycosylations, Geert-Jan Boons and Co. J. Am. Chem. Soc., 2005, 127, 12090-12097. 3. Polysaccaride Synthesis: Glycal Assembly Method 4. Carbohydrate Vaccines: Linear Synthesis of the Tumor-Associated Carbohydrate Antigens Globo- H, SSEA-3, and Gb3, Peter H. Seeberger and Co. J. Org. Chem., 2002, 67, 6659-6670. 5. Formal Synthesis of Anticoagulant Drug Fondaparinux Sodium, Xiang Dai et. al., J. Org. Chem., 2016, 81, 162-184.

Prostaglandins

1. Biosynthesis 2. The Asprin Story 3. General Synthesis of Prostaglandins by E. J. Corey 4. Prostaglandins derivatives as Drugs

5. Stereocontrolled Organocatalytic Synthesis of Prostaglandin PGF2 in Seven Steps, Varinder K. Aggarwal and Co. Nature, 2012, 489, 278-281.

Steroids

1. Biosynthesis 2. Biomimetic Synthesis by W. S. Johnson 3. Search for a non-toxic insecticide: Mimics of the ecdysteroid insect hormone

Amino Acids and Peptides

1. The Amidomalonate Synthesis 2. Enantioselective Synthesis of Amino Acids 3. Synthesis of L-DOPA by Knowles (Monsanto) 4. Peptide Synthesis: General Strategy 5. Automated Peptide Synthesis: The Merrifield Solid-Phase Technique 6. Glutathione and Acetaminophen Overdose

Anti-folates as Anti-cancer Drugs

1. Biosynthesis of Tetrahydrofolate (THF) 2. Conversion of THF to 5,10-Methylene THF 3. Conversion of Uridine monophosphate to Thymidine monophosphate 4. Mechanism of Action (MOA) of 5-Flurouracil 5. Brief History of Anti-folates as Anti-cancer Drugs 6. Discovery of 5,10-Dideazatetrahydrofolic acid (DDATHF) Taylor, E. C.; Harrington, P. J.; Fletcher, S. R.; Beardsley, G. P.; Moran, R. G. J. Med. Chem. 1985, 28, 914-921. Synthesis of the Antileukemic Agents 5,10-Dideazaaminopterin and 5,10-Dideaza- 5,6,7,8-tetrahydroaminopterin. 7. De novo Purine Biosynthesis Pathway 8. Structural Features of 5,10-Dideaza-5,6,7,8-tetrahydrofolate That Determine Inhibition of Mammalian Glycinamide Ribonucleotide Formyltransferase, Baldwin et. al.; Biochemistry, 1991, 30, 1997-2006. 9. Asymmetric Synthesis of Lometrexol ((6R)-5,10-Dideaza-5,6,7,8-tetrahydrofolic Acid); Barnett et. al. J.; Org. Chem. 1994, 59, 7038-7045. 10. Asymmetric Synthesis of Dideazafolate Antitumor Agents via Amidomethylation of Nonracemic Oxazolidinone Imidates. Synthesis of LY 309887, a Cytotoxic Dideazafolate Analog Related to Lometrexol, Barnett et. al., Tetrahedron Letters, 1997, 38, 735-738. 11. Synthesis of a Pyrimido[4,5-b]azepine Analog of 5,10-Dideaza-5,6,7,8-tetrahydrofolic Acid (DDATHF), Taylor and Dowling, Bioorganic & Medicinal Chemistry Letters, 1997, 7, 453-456. 12. Synthesis of N-{[4-(2-Amino-4(3H)-oxo-5,6,7,8tetrahydro-(9H)-pyrimodo[4,5-b]azepin-6- yl)methyl]benzoyl}-L-glutamic Acid and Two of its Conformationally-Restricted Analogs, Read, Miller, and Ray, Tetrahedron, 1999, 55, 373-392. 13. Studies Towards the Synthesis of pyrimido[4,5-e][1,4]diazepine-based folates as Potential Anti- tumor Drugs: Work at UWG by the Ray Group: (a) Parker, Hughes, Parker, and Ray, Heterocyclic Communications, 2002, 8, 419-422; (b) Huddleston, Harris, Nguyen, and Ray, Heterocyclic Communications, 2004, 10, 405-406; (c) Frick, McAtee, McAtee, and Ray, Heterocyclic Communications, 2011, 17, 17-19; (d) Gann and Ray, Heterocyclic Communications, 2015, 21, 349-353. 14. Discovery of Anti-cancer Drug Pemetrexed: Taylor et. al. J. Med Chem. 1992, 35, 4450-4454 and J. Org Chem. 2001, 66, 3726-3738. 15. Rational Design, Synthesis, Evaluation, and Crystal Structure of a Potent Inhibitor of Human GAR Tfase: 10-(Trifluoroacetyl)-5,10-dideazaacylic-5,6,7,8-tetrahydrofolic Acid; Dale Boger and co. Biochemistry, 2003, 42, 6043-6056. 16. Structural and Enzymatic Analysis of Tumor-Targeted Antifolates That Inhibit GARFT; Aleem Gangjee and co. Biochemistry, 2016, 55, 4574-4582. 17. Tumor Targeting with Novel Pyridyl 6-Substituted Pyrrolo[2,3-d]pyrimidine Antifolates via Cellular Uptake by Folate Receptor  and the Proton-Coupled Folate Transporter and Inhibition of De Novo Purine Biosynthesis, Gangjee and co. J. Med. Chem. 2018, 61, 2027-2040.

Grade: Your grade will be based on the average of 4 tests (25% each)

A: 85-100; B: 75-84; C: 60-74; D: 50-59; F: 0-49

Test Dates:

First Test: January 30

Second Test: February 25

Third Test: March 27

Fourth Test: April 29

Office hours: MW: 12 PM – 2 PM

TR: 2 PM – 5 PM

Note: Extra credit is not allowed for this class, and work competed for another class will not be accepted in this class. All communications outside of class should be via campus mail (myUWG), and you are expected to check your mail regularly.

Learning Outcomes

1. Reason and think analytically in solving problems and making decisions in matters involving bioorganic chemistry. Attainment of this learning outcome will be reflected by the students ability to understand the reactions and synthesis of natural products as well as the mechanism of action and synthesis of selected medicinal agents.

2. Apply a basic understanding of the systematic methods of scientific inquiry, principles and procedures to investigate problems. Attainment of this learning outcome will be reflected by the students ability to use chemical logic to describe the mechanisms of new organic reactions not covered in general organic chemistry.

3. To communicate matters of organic synthesis with clarity. Attainment of this learning outcome will be reflected by the students ability to successfully complete written and oral assignments, and examinations.

All Students Please Note!

For important policy information, i.e., the UWG Honor Code, Email, and Credit Hour policies, as well as information on Academic Support and Online Courses, please review the information found in the Common Language for Course Syllabi documentation at http://www.westga.edu/assetsDept/vpaa/Common_Language_for_Course_Syllabi.pdf. Additions and updates are made as institution, state, and federal standards change, so please review it each semester.