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Myers’ Synthesis of Dynemicin A

Myers’ Synthesis of Dynemicin A. 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

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Myers’ Synthesis of Dynemicin A

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  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: Neocarzinostatinchromophore, N1999A2, kedarcidinchromophore, dynemicin A. • Methodology development.

  3. Enediyne Antibiotics calicheamicin dynemicin A neocarzinostatinchromophore esperamicin kedarcidinchromophore

  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 dynemicinA (Z)-enediyne motif: • NicolaouShreiber Magnus Wender • First full synthesis of dynemicin A analog: • Shreiber • First full synthesis of dynemicin A: • Danishefsky

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

  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 Model studies used to explain stereospecificity • 11:1 (29:30) • Pseudoequatorial Me in 29 group leads to staggered • product (thermodynamically favorable)

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

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

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

  14. The Myers Group

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