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
– 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.
Enediyne Antibiotics
calicheamicin
neocarzinostatin chromophore
kedarcidin chromophore
dynemicin A
esperamicin
Bioactivity – Intercalation and cleavage of DNA
-Enediyne antibiotics cleave both strands of DNA!-Irreversible damage-Anti-tumor activity
Previous work• Partial construction of dynemicin A (Z)-enediyne motif:
– Nicolaou Shreiber MagnusWender
• First full synthesis of dynemicin A analog:
– Shreiber
• First full synthesis of dynemicin A:
– Danishefsky
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
Retrosynthesis
Part 1 – Construction of the A, B, C rings
22, 68 % 23, 15%
Attempted construction enediyne bridge
1,4-elimination
1,2-methoxy shift
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
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
Part 3 – Addition of the D, E rings via an intermolecular Diels-Alder reaction
Model Diels-Alder reaction.
X-ray crystal structure of dynemicin analog 85
dynemicin analog 85
Analogs and 3-D structure
The Myers Group
