1. Myers’ Synthesis of Dynemicin A

2. Andrew G. Myers 140 publications to date (1981) B.S. at MIT – undergraduate research with W. R. Roush. (1981-86) Graduate studies and brief post-doctoral work under E.J. Corey. (1986) Began independent career – California Institute of Technology – By 1994, became full professor. (1998) Moved to Harvard – 2007-2010, Served as chair of the chemistry department. Dr. Meyer’s research focuses on the synthesis of medically/biologically active compounds for human medicine development. – Convergent, practical, and scalable syntheses. – Enediyne antibiotics synthesized: Neocarzinostatin chromophore, N1999A2, kedarcidin chromophore, dynemicin A. – Methodology development.

3. Enediyne Antibiotics calicheamicin neocarzinostatin chromophore kedarcidin chromophore dynemicin A esperamicin

4. Bioactivity – Intercalation and cleavage of DNA -Enediyne antibiotics cleave both strands of DNA! -Irreversible damage -Anti-tumor activity

5. Previous work Partial construction of dynemicin A (Z)-enediyne motif: – NicolaouShreiberMagnusWender First full synthesis of dynemicin A analog: – Shreiber First full synthesis of dynemicin A: – Danishefsky

6. Initial strategies Strategy 1 Strategy 2 Dynemicin A Issue: Low yields likely because of highly reactive anthraquinone Issue: Cyclization to form B ring was unsuccessful

7. Retrosynthesis

8. Part 1 – Construction of the A, B, C rings 22, 68 % 23, 15%

9. Attempted construction enediyne bridge 1,4-elimination 1,2-methoxy shift

10. Part 2 – Construction enediyne bridge 11:1 (29:30) -Pseudoequatorial Me in 29 group leads to staggered product (thermodynamically favorable) Model studies used to explain stereospecificity

11. Attempted addition of the D, E rings via an intermolecular Diels-Alder reaction – model studies Diels-Alder approach Conjugate addition-enolate trapping Unable to cyclize to anthraquinoneLow Yields

12. Part 3 – Addition of the D, E rings via an intermolecular Diels-Alder reaction Model Diels-Alder reaction.

13. X-ray crystal structure of dynemicin analog 85 dynemicin analog 85 Analogs and 3-D structure

14. The Myers Group