Myers Synthesis of Dynemicin A Andrew G Myers

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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

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, N 1999 A 2, kedarcidin chromophore, dynemicin A. – Methodology development.

calicheamicin dynemicin A Enediyne Antibiotics neocarzinostatin chromophore esperamicin kedarcidin chromophore

calicheamicin dynemicin A Enediyne Antibiotics neocarzinostatin chromophore esperamicin kedarcidin chromophore

Bioactivity – Intercalation and cleavage of DNA -Enediyne antibiotics cleave both strands of DNA!

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

Previous work • Partial construction of dynemicin A (Z)-enediyne motif: – Nicolaou • Shreiber First full synthesis of dynemicin A analog: – Shreiber • First full synthesis of dynemicin A: – Danishefsky Magnus Wender

Initial strategies Strategy 1 Issue: Cyclization to form B ring was unsuccessful Strategy 2

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

Retrosynthesis

Retrosynthesis

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

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

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

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

Part 2 – Construction enediyne bridge Model studies used to explain stereospecificity 11: 1

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)

Attempted addition of the D, E rings via an intermolecular Diels-Alder reaction – model

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

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

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

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

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

The Myers Group

The Myers Group

Total Syntheses of Di and TriOmethyl Dynemicin ATotal Syntheses of Di and TriOmethyl Dynemicin A
HMMBased Speech Synthesis Concatenative Synthesis HMM Synthesis AHMMBased Speech Synthesis Concatenative Synthesis HMM Synthesis A
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Logical Systems Synthesis Logical Synthesis Basic Gate SynthesisLogical Systems Synthesis Logical Synthesis Basic Gate Synthesis
Genome Synthesis Synthetic Cells DNA Synthesis Genome SynthesisGenome Synthesis Synthetic Cells DNA Synthesis Genome Synthesis
Texture Synthesis Su chunmiao Texture Synthesis Texture synthesisTexture Synthesis Su chunmiao Texture Synthesis Texture synthesis
Protein Synthesis PROTEIN SYNTHESIS n Protein synthesis involvesProtein Synthesis PROTEIN SYNTHESIS n Protein synthesis involves
Transcription Translation Protein Synthesis Protein Synthesis Protein synthesisTranscription Translation Protein Synthesis Protein Synthesis Protein synthesis
PROTEIN SYNTHESIS Jessica Hawley PROTEIN SYNTHESIS Protein SynthesisPROTEIN SYNTHESIS Jessica Hawley PROTEIN SYNTHESIS Protein Synthesis
THE SYNTHESIS ESSAY What is synthesis Definition SynthesisTHE SYNTHESIS ESSAY What is synthesis Definition Synthesis