first total synthesis of (-) - lomaiviticin aglycon · sharpless asymmetric dihydroxylation et...
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First Total Synthesis of (-) - Lomaiviticin Aglycon
Herzon, JACS 2011 ASAP
Amber Gietter May 16, 2011
Seth Herzon • Born in Philly in 1979 • 1997 graduated from Valley Forge Military Academy • 2002 graduated from Temple
– Researched under Professor Grant R. Krow • 2006 graduated with PhD from Harvard
– Worked under Dr. Andrew G. Myers – Developed enantioselective syntheses of the complex
antiproliferative alkaloids avrainvillamide and stephacidin B. • 2006 postdoced at University of Illinois, Urbana-Champaign
– Professor John F. Hartwig • 2008 he joined the Yale Chemistry Department as an Assistant
Professor of Chemistry.
http://www.chem.yale.edu/faculty/herzon.html
The Lomaiviticin Family Symmetry, Diazos and Oxygens
All composed of monomeric unit called
diazofluorene!N2
Lomaiviticin Aglycon • Isolated from the fermentation broth of Micromonospora
lomaivitiensis in 2001 – Marine invertebrate
• Shown to be active as an antitumor antibiotic • Some strains are potent DNA damaging agents • Lomaiviticin Aglycon was synthesized because Lomaiviticin A and B
have not yet succesfully be synthesized. – Hope to have the same anticancer activity and be able to test on
large scale – Hope to used in stem cell research
http://www.chem.yale.edu/faculty/herzon.html http://pubs.acs.org/cen/news/89/i06/8906news5.html
Is That A Clam?!
The Thought Process Use the symmetry in the molecule (aka copy nature)
- This allows for a simpler synthesis and allows coupling at the very end
But it’s not that easy: “A lot of blood, sweat and tears went into
creating that bond,” Herzon said. “After that, the rest of the
process was relatively easy.”
http://stemcells.sujanani.com/news/?p=23002463
The Issues But there are some issues: - Use of strong acids or bases can lead to tautomerization
The rate of the dimerization may be too slow to produce acceptable yields
Oxidative couplings of diazofluorenes (such as above) had never been used in synthesis
Retrosynthetic Analysis
Me
OH1
Et
O
OO
MesTMS
6
O
O
Br
Br
MOMO
MOMO7
O
OBr
MOMO
MOMO
OO
O
Mes
Et
8
O
O
MOMO
MOMO
OO
O
Mes
Et
N2
O
O
MOMO
OMOM
OO
O
Mes
EtN2O
O
OMOM
MOMO
O O
O
Mes
EtN2R R'
+
Lomaiviticin Aglycon
The Approach Me
OH
TIPSClMe
OTIPS
1) Li, NH3Birch Reduction
2) (DHQD)2PHAL K2OsO4, K3Fe(CN)6
Sharpless AsymmetricDihydroxylation
Et
OTIPS
OHOH
Pd(OAc)2, O2,DMSO
SaegusaOxidation
Et
O
OHOH
MesCH(OCH3)2PPTS
Et
O
OO
Mes
TMSCH2MgCl, CuITMSCl, Et3N, HMPA
then Pd(OAc)2Cuperate then
Saegusa Oxidation
Et
O
OO
MesTMS
O
O
Br
Br
MOMO
MOMO
TASF(Et)O
OBr
MOMO
MOMO
OO
O
Mes
Et
TASF(Et) S+NEt2Et2N
NEt2Si- MeMe
F
F
Me
O
O
Br
Br
HO
HO
MOMCl, i-Pr2NEtDCM
O
O
Br
Br
MOMO
MOMO
OMe
OMe
O
O
O
Br
Br
AlCl3, NaClheat
1 23
4
567
8
9
10 11 7
Some Mechanisms
Et
OTIPS
OHOH
PdOAc
AcOEt
OTIPS+
OHOH
PdOAc
-OAcEt
O
OHOH
PdOAc
B-H elim-(HPdOAc) Et
O
OHOH
Saegusa Oxidation
O
TMSCH2CuMgClO CuMgCl
TMS
TMSClO TMS
TMS
-(CuCl2, Mg)RepeatSaegusaMechanism Et
O
OO
MesTMS
6
Cuperate than Saegusa Oxidation
The Set Up
O
OBr
MOMO
MOMO
OO
O
Mes
Et
8
Pd(OAc)2Polymersupported PPh3
Ag2CO3
O
OH
MOMO
MOMO
OO
O
Mes
Et
12
TfN3, DMAP
O
O
MOMO
MOMO
OO
O
Mes
Et
13a
O
O
MOMO
MOMO
OO
O
Mes
Et
13b
N2 N2
+
diastereomers that can be seperated by column
TMSOTf, Et3N
O
O
MOMO
MOMO
OO
OTMS
Mes
Et
N2
The End O
O
MOMO
MOMO
OO
OTMS
Mes
Et
N2
O
O
MOMO
OMOM
OO
O
Mes
EtN2O
O
OMOM
MOMO
O O
O
Mes
EtN2 O
O
MOMO
OMOM
OO
O
Mes
EtN2O
O
OMOM
MOMO
O O
O
Mes
EtN2
+ S S'R R'
TFA, TBHP TFA, MeOHO OH
Mn(C5H2F6O2)3PhH
(this is allthat worked)
Coupling Mechanism
OO
O
Mes
Et
OO
O
Mes
Et
OO
O
Mes
Et
TMS
Mn(III)
OO
O
Mes
EtMn(II)
OO
O
Mes
Et.
OO
O
Mes
Et.
The Author’s Rationales Stereochemical Reasoning for 22
-Top face more accessible
Intermediate between 22 and 3
Summary • 11 step total synthesis from commerical SM • Over comes difficulty of coupling diazofluorene
monomers to form lomaiviticins • Most steps can effectively be done on gram
scale • Able to avoid aromatizing the diazoflurene
backbone by using the soluable, fully saturated manganese (hexafluoroacetylacetonate)
THANK YOU!!!!