total synthesis of platencin - ccc/upcmldccc.chem.pitt.edu/wipf/current literature/shuli_5.pdf ·...
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Total Synthesis of Platencin
OH
HO2C NH
OMe
H
O
OH
Platencin
K. C. Nicolaou,* G. Scott Tria, David J. EdmondsAngew. Chem. Int. Ed. 2008, 47, 1780-1783.
Shuli MaoCurrent Literature Presentation
02-16-2008
Shuli Mao @ Wipf Group 1 2/16/2008
BackgroundEmergence of bacterial resistance to all known classes of antibiotics made discovery of new antibiotics critical
New discovery should emphasize on novel mode of action
Two poor inhibitors (cerulenin and thiolactomycin) were reported toward FabF (IC50=1.5-13 µg/mL) with poor antibacterial activity(Staphylococcus aureus MIC 64 µg/mL)
Fatty acids are required for bacterial survival and their biosynthesis is catalyzed by condensing enzyme FabF
O
O O
H2NMe
Cerulenin
S
HO
O
Thiolactomycin
Shuli Mao @ Wipf Group 2 2/16/2008
Platensimycin and Platencin
Both were isolated from strains of Streptomyces platensis
Merck scientists discovered 1 inhibits FabF (IC50=0.29µM) [FabH (IC50=247µM)]while 2 inhibits both FabF (IC50=4.6µM) and FabH (IC50=9.2µM)through a target-based, whole-cell, high throughput screening assayof 250,000 compounds
Nature 2006, 441, 358-361.PNAS 2007, 104, 7612-7616.
Both has an amide linker, but 1 has a pentacyclic core with a cyclic ether ringwhile 2 has a tetracyclic core
Both exhibits broad-spectrum antibacterial activity but 2 is more potent
Shuli Mao @ Wipf Group 3 2/16/2008
in vitro Gram-positive Activity
Linezolid: synthetically derived agent in clinical use since 2000
PNAS 2007, 104, 7612-7616.
ON
O
F
NONHAc
linezolid (ZyvoxTM)
Shuli Mao @ Wipf Group 4 2/16/2008
Plausible Biogenesis from Isoprenoid PrecursorsDMAPP: dimethylallyl pyrophosphateIPPP: isopentenyl pyrophosphateGGPP: geranyl geranyl phrophosphate
Precursor feeding experiment is in progress.
Shuli Mao @ Wipf Group 5 2/16/2008
Docking Experiment
E. Coli condensing enzyme active site of FabH with docked platensimycin (green) and platencin (cyan).
ACIE 2007, 46, 4684-4688.Shuli Mao @ Wipf Group 6 2/16/2008
Docking Experiment
E. Coli condensing enzyme active site of FabF with docked platensimycin (green) and platencin (cyan).
ACIE 2007, 46, 4684-4688.Shuli Mao @ Wipf Group 7 2/16/2008
Synthesis of PlatensimycinK.C.Nicolaou: 1st racemic; 1st asymmetric; chiral pool based synthesis
ACIE 2006, 45, 7086-7090.; ACIE 2007, 46, 3942.; ACIE 2008, 47, 944-946.
Barry B. Snider: formal synthesis to core 2
OL 2007, 9, 1825-1828.
O
O
SmI2, HFIP
46%, dr=2:1
O
HO
TFA
87%
O
OMe
O
EtO
4 steps
O
TBSO
4 steps
Nicolaou intermediate
Shuli Mao @ Wipf Group 8 2/16/2008
Synthesis of PlatensimycinHisashi Yamamoto: enantioselective synthesis to core 9
JACS 2007, 129, 9534-9535.
Arun K. Ghosh: enantioselective synthesisto core 2
OL 2007, 9, 4013-4016.
Others:E.J.Corey: OL 2007, 9, 4921-4923.Johann Mulzer: ACIE 2007, 46, 8074-8075.Krishna P. kaliappan: OL 2007, 9, 2417-2419.
Shuli Mao @ Wipf Group 9 2/16/2008
Two Isosteres of Platensimycin:Synthesized by Nicolaou Group
ACIE 2007, 46, 4712-4714.; JACS 2007, 129, 14850-14851.
Shuli Mao @ Wipf Group 10 2/16/2008
Retrosynthetic Analysis of PlatencinOH
HO2C NH
OMe
H
O
OH
OHNH2
O
H
O
TMSEO
+
OH
amidation
alkylation to constructquaternary center
aldol condensation
OH
OHNO2
O
OMe
HOSEM
homoallyl radicalrearrangement
HOSEM
O
SMeS
HOSEM
O
Michael addition
Au-catalyzedcyclization
OSEM
TIPSO
OH
O
Shuli Mao @ Wipf Group 11 2/16/2008
Synthesis of Aniline Derivative
OH
OHNO2
O
OMe
Known
a) nBu2SnOOH
TMS
b) H2, 10% Pd/C, 100%
OH
OHNH2
O
TMSEO
61%
P. Heretsch, A. Giannis Synthesis 2007, 17, 2614-2616.
Previous synthesis: 5 steps, 36% from commercially available compound
ACIE 2006, 45, 7086-7090.
OH
OHNO2
a) NaH, MOMCl, 82%
b) H2, Pd/C, 99%
OMOM
OMOMNH2
c) Boc2O, 99%
d) nBuLi, MeOC(O)CN, 54%e) 205oC, MW, 83%
OMOM
OMOMNH2MeO2C
$
Present synthesis: 2 steps, 61% from known compound
Shuli Mao @ Wipf Group 12 2/16/2008
Synthesis of Tetracyclic Core
OMe
OMe
MeO
a) BnNHCO2Me, 89%
b) TBSOTf, 87%
N
TBSO
Bn CO2Me
Known
OHc) SO3
.Py, DMSO
N Cl 53%
O
NCO2MeBn
CHO
TBSO
d) 5mol% CrIII-salen catalyst
92%
e) LAH, then aq HCl, 63%, 93%eef) SEMCl, 94%
O
OSEMg) TIPSOTf, 97%
TIPSO
OSEM
K. C. Nicolaou, G. Scott Tria, David J. Edmonds Angew. Chem. Int. Ed. 2008, 47, 1780-1783.
Shuli Mao @ Wipf Group 13 2/16/2008
Synthesis of Tetracyclic Core (Cont’d)
TIPSO
OSEM h) 2mol% [AuCl(PPh3)]2mol% AgBF4, 94%
OSEM
O
OSEM
O
i) allylMgCl,CuBr.Me2S
74%
OSEM
O
SMeS
j) NaBH4, 97%k) KHMDS, CS2, MeI, 100%
l) nBu3SnH,cat AIBNOSEM
HOSEM
CH2
HOSEM
m) cat PdCl2,CuCl, O250% (2 steps)
MeH
OSEM
On) TASF80% (BRSM) H
O
Me OHo) TPAP, NMO54% Me
HO
O
p) NaOH, 99%
O
H
Shuli Mao @ Wipf Group 14 2/16/2008
X-ray of Hemiacetal Intermediate
H
OMe
OH
Shuli Mao @ Wipf Group 15 2/16/2008
Completion of the Synthesis
O
Hq) KHMDS, MeI, 68%
r) KHMDS, allyl iodide, 86%
OMe
H s) Hoveyda-Grubbs II cat.
BO
O
MeMe
MeMe
OMe
HBO
O
MeMe
MeMe
t) Me3NO
OMe
HOHC
u) NaClO2
39% (3 steps)
OMe
HHOOC
OH
OHNH2
O
TMSEO
v) HATU, 61%
OH
NH
OMe
H
O
OH
O
TMSEOw) TASF, 93%
OH
NH
OMe
H
O
OH
O
OH
Platencin
Shuli Mao @ Wipf Group 16 2/16/2008
Summary
• First enantioselective synthesis of platencin was achievedin 22 steps (longest linear sequence) with a yield of 0.76%
• Key transformations are: homoallyl radical rearrangement and Au-catalyzed cyclization
• Future work will involve the synthesis of platencin analogs and the exploration of other synthetic routes toward platencin
• Platencin is a potent and dual inhibitor of FabH and FabF; it exhibitsbroad-spectrum antibacterial activity against many Gram-positive pathogens that show resistance to current antibiotics
Shuli Mao @ Wipf Group 17 2/16/2008