Dynemicin A Andrew G Myers 140 publications to date 1981 BS at MIT undergraduate research with W R Roush 198186 Graduate studies and brief postdoctoral work under EJ Corey 1986 Began independent career California Institute of Technology ID: 462527
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Myers’ Synthesis of Dynemicin ASlide2
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 Harvard2007-2010, 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.Slide3
Enediyne Antibiotics
c
alicheamicin
n
eocarzinostatin chromophore
kedarcidin
chromophore
d
ynemicin
A
esperamicinSlide4
Bioactivity – Intercalation and cleavage of DNA
-
Enediyne
antibiotics cleave both strands of DNA!
-Irreversible damage
-Anti-tumor activitySlide5
Previous work
Partial construction of dynemicin
A (Z)-
enediyne motif:Nicolaou Shreiber Magnus WenderFirst full synthesis of dynemicin A analog:ShreiberFirst full synthesis of dynemicin A:
DanishefskySlide6
Initial strategies
Strategy 1
Strategy 2
Dynemicin
AIssue: Low yields likely because of highly reactive anthraquinone
Issue: Cyclization to form B ring was unsuccessfulSlide7
RetrosynthesisSlide8
Part 1 – Construction of the A, B, C rings
22
, 68 %
23
, 15%Slide9
Attempted construction
enediyne
bridge
1,4-elimination
1,2-methoxy shiftSlide10
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
stereospecificitySlide11
Attempted
a
ddition
of the D, E rings via an intermolecular Diels-Alder
reaction – model studies
Diels-Alder approach
Conjugate addition-
enolate
trapping
Unable to
cyclize
to
anthraquinone
Low YieldsSlide12
Part 3 – Addition of the D, E rings via an intermolecular Diels-Alder reaction
Model
Diels-Alder reaction
.Slide13
X-ray crystal structure of
dynemicin
analog
85
dynemicin analog 85Analogs and 3-D structureSlide14
The Myers Group