Myers’ Synthesis of Dynemicin A. Andrew G. Myers 140 publications to date (1981) B.S. at MIT –...
-
Upload
juliana-grant -
Category
Documents
-
view
224 -
download
1
Transcript of Myers’ Synthesis of Dynemicin A. Andrew G. Myers 140 publications to date (1981) B.S. at MIT –...
![Page 1: 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.](https://reader030.fdocuments.net/reader030/viewer/2022020721/56649ceb5503460f949b7566/html5/thumbnails/1.jpg)
Myers’ Synthesis of Dynemicin A
![Page 2: 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.](https://reader030.fdocuments.net/reader030/viewer/2022020721/56649ceb5503460f949b7566/html5/thumbnails/2.jpg)
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.
![Page 3: 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.](https://reader030.fdocuments.net/reader030/viewer/2022020721/56649ceb5503460f949b7566/html5/thumbnails/3.jpg)
Enediyne Antibiotics
calicheamicin
neocarzinostatin chromophore
kedarcidin chromophore
dynemicin A
esperamicin
![Page 4: 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.](https://reader030.fdocuments.net/reader030/viewer/2022020721/56649ceb5503460f949b7566/html5/thumbnails/4.jpg)
Bioactivity – Intercalation and cleavage of DNA
-Enediyne antibiotics cleave both strands of DNA!-Irreversible damage-Anti-tumor activity
![Page 5: 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.](https://reader030.fdocuments.net/reader030/viewer/2022020721/56649ceb5503460f949b7566/html5/thumbnails/5.jpg)
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
![Page 6: 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.](https://reader030.fdocuments.net/reader030/viewer/2022020721/56649ceb5503460f949b7566/html5/thumbnails/6.jpg)
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
![Page 7: 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.](https://reader030.fdocuments.net/reader030/viewer/2022020721/56649ceb5503460f949b7566/html5/thumbnails/7.jpg)
Retrosynthesis
![Page 8: 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.](https://reader030.fdocuments.net/reader030/viewer/2022020721/56649ceb5503460f949b7566/html5/thumbnails/8.jpg)
Part 1 – Construction of the A, B, C rings
22, 68 % 23, 15%
![Page 9: 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.](https://reader030.fdocuments.net/reader030/viewer/2022020721/56649ceb5503460f949b7566/html5/thumbnails/9.jpg)
Attempted construction enediyne bridge
1,4-elimination
1,2-methoxy shift
![Page 10: 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.](https://reader030.fdocuments.net/reader030/viewer/2022020721/56649ceb5503460f949b7566/html5/thumbnails/10.jpg)
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
![Page 11: 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.](https://reader030.fdocuments.net/reader030/viewer/2022020721/56649ceb5503460f949b7566/html5/thumbnails/11.jpg)
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
![Page 12: 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.](https://reader030.fdocuments.net/reader030/viewer/2022020721/56649ceb5503460f949b7566/html5/thumbnails/12.jpg)
Part 3 – Addition of the D, E rings via an intermolecular Diels-Alder reaction
Model Diels-Alder reaction.
![Page 13: 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.](https://reader030.fdocuments.net/reader030/viewer/2022020721/56649ceb5503460f949b7566/html5/thumbnails/13.jpg)
X-ray crystal structure of dynemicin analog 85
dynemicin analog 85
Analogs and 3-D structure
![Page 14: 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.](https://reader030.fdocuments.net/reader030/viewer/2022020721/56649ceb5503460f949b7566/html5/thumbnails/14.jpg)
The Myers Group