Total Synthesis of BE-43472B O O O O HO Me Me H Me OH OH O OH B E-43472B
Total Synthesis of BE-43472B. PhD Work with Prof. André B. Charette.
Apr 01, 2015
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Total Synthesis of BE-43472B
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
PhD Work with Prof. André B. Charette
NH
HO
H3C OH
()-Julifloridine
N
NPh
R*
R
X
X = H, OR
N nPr
NH
CO2H
N R
NH
O
Ph
CF3
CF3
( )-L-733,061
NHPh
( )-N-Boc-coniine
L-Pipecolic acid
Boc Boc
NH
CO2H
OH
trans-Disusbtitutedtetrahydropyridines
(2S,3S)-3-Hydroxy-pipecolic acid
The Scripps Research InstituteLa Jolla, California
The Scripps Research Institute
World's largest, private non-profit biomedical research facilityFounded in 1961 by Frank Dixon, M.D.
289 Faculty members815 Postdoctoral fellows235 Graduate students
1,500 technical and administrative support personnel
The Scripps Research Institute
K. C. Nicolaou - Chairman of chemistry dept.Barry K. Sharpless - Nobel laureatePhil S. BaranDale BogerCarlos F. Barbas IIIJin-Quan YuAlbert EschenmoserKim D. JendaRichard LernerPeter SchultzJulius Rebek Jr. Director, Skaggs Institute for Chemical Biology
BE-43472B
Organism inhibited IC50, M
MRSA, ATCC 43300
Methicilin-resistant Straphylococcus aureus
0.15
VRE, ATCC 51299
Vancomycin resistant Enterococcus faecalis
2.0
HCT-116
Human cancer cells
3.3
New structural class among known antimicrobial agents
OO
O
O
HO
Me
MeH
Me
OH
OHOOH
OH O
O
OH
Me
Chrysophanol
HO
O
OHO
Me
OMe
H
H2O
1,4-addition
Friedel-CraftFr iedel-Craft
plausiblebiosynthesis
Isolated from marine streptomycete collected in Puerto Rico
Chrysophanol dimer linked in tetrahydrofuran rings with an incorporated acetaldehyde molecule
Socha, A. M.; Rowley D. C. et al. J. Nat. Prod. 2006, 69, 1070.
BE-43472B Retrosynthesis
OO
O
O
HO
Me
MeH
MeOH
OHOOH
OH
O
O
HO
Me
Me
OPg
OHOOBn
OHO
TBDPSO
OPg
OOOBn
OH
Me
Me
Me
OOMe
OMe
O
Me
PMB
ketalformation
nucleophilic chrysophanolderivative
quinone Michael acceptor
aromatizationdeprotection
1
34
4a
98
11
9a 12
10
8'
9'
10'
9'
1'
14
4'
5
Me
OH
OOH O
O
HX
Me
OMEM
TBDPSO Me
OH O
O
13
O
OMe
MeO
O
Me
Me
OPg
OHOOBn
O
PMB
O
Me
TBDPS
X
conjugateaddition
X
oxidation
+
Model Studies
OOMe
OMe
OMe
MeO
1. LHMDS, -78 °CTHF
2. OO
O
OMe
MeO
OHO
O
OMe
MeO
O
MeO
OMeMeO
OMe
H
OHO
O
OMe
MeO
O
MeO
OMeMeO
OMe
H
+
95%, 1:1 d.r .
aromatization
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Model Studies
OOMe
OMe
OMe
MeO
1. LHMDS, -78 °CTHF
2. OO
O
OMe
MeO
OHO
O
OMe
MeO
O
MeO
OMeMeO
OMe
H
OHO
O
OMe
MeO
O
MeO
OMeMeO
OMe
H
+
95%, 1:1 d.r .
aromatization
OOMe
OMe
OMe
MeO
1. LHMDS, -78 °CTHF
2. OO
O
OMe
MeO
OHO
O
OMe
MeO
O
MeO
OMeMeO
OMe
Br
OHO
O
OMe
MeO
HO
O
OMeO
OMe
63%
BrCAN
93%
MeCN, H2O
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Chrysophanol Derivative Synthesis
OOMe
OMe
O
Me
PMB
Br 1. LHMDS
2. NBS
51%
1. t-BuLi, TMEDA
2. DMFMe
NEt2
OOPMB
OMe
OH
OOH1. (COCl)2; Et2NH
2. PMB-Cl, K2CO3
Me
NEt2
OOPMB
67%
1. TMSCN, KCN, 18-C-62. AcOH
Me
OOPMB
O
CN
1. LHMDS,
2. Me2SO4, Cs2CO3
OOMe
OMe
O
Me
PMB
70%, 2 steps
80%40%, 2 steps
O
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Chrysophanol Derivative Synthesis
Me
OOPMB
O
LiNC
O OO
CN
O
Me
PMB Li
O
OO
O
O
Me
PMB
OOH
OH
O
Me
PMB
H
H
OOMe
OMe
O
Me
PMB
- LiCN
Me2SO4
Cs2CO3
Hauser annulation
OOMe
OMe
O
Me
PMB
Br 1. LHMDS
2. NBS
51%
1. t-BuLi,TMEDA
2. DMFMe
NEt2
OOPMB
OMe
OH
OOH1. (COCl)2; Me2NH2Cl
2. PMB-Cl, K2CO3
Me
NEt2
OOPMB
67%
1. TMSCN, KCN,18-C-6
2. AcOH
Me
OOPMB
O
CN
1. LHMDS2. 2-cyclohexen-1-one
3. Me2SO4, Cs2CO3
OOMe
OMe
O
Me
PMB
70%, 2 steps
80%40%, 2 steps
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Chiral Diene Synthesis and Diels-Alder Reaction
Me I
OMEM
Me CHO
OTBDPS
1. CrCl2, NiCl2
2. MOM-Cl EtNi-Pr2
Me
OMEM
TBDPSO
OMOM
Me
4:1 d.r.Me
OH1. Red-Al; I2
2. MEM-Cl EtNi-Pr2
85%(2 steps)
89-92%, 2 steps
Me
OMEM
TBDPSO
OMOM
Me
+
s-BuLi-78 °C
Me
OMEM
TBDPSO Me
69-76%
OH O
O
MeTBDPSO
Me
OMEMOOH
OH
H
H
H
5:1 r.r.81% combined yield
Me
OMEM
OTBDPS
Me
O O
O
H
H
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
E-Reduction of Propargylic Alcohol
1st report by Corey in 1967 (LiAlH4 + 2 MeOH)Red-Al introduced 15 years later by Denmark
MeI
MEMO
Me
OH1. Red-Al; I2
2. MEM-Cl EtNi-Pr2
85%(2 steps)
Me
OAl
O
HO
H
Na
HAl
O
OO
OH
Na
H
MeNa
OAl
RO
H
1. I22. MEM-Cl
H
MeAlO
HOR
excess(1.5 equiv)
Na
Chiral Diene Synthesis and Diels-Alder Reaction
Me I
OMEM
Me CHO
OTBDPS
1. CrCl2, NiCl2
2. MOM-Cl EtNi-Pr2
Me
OMEM
TBDPSO
OMOM
Me
4:1 d.r.Me
OH1. Red-Al; I2
2. MEM-Cl EtNi-Pr2
85%(2 steps)
89-92%, 2 steps
Me
OMEM
TBDPSO
OMOM
Me
+
s-BuLi-78 °C
Me
OMEM
TBDPSO Me
69-76%
OH O
O
MeTBDPSO
Me
OMEMOOH
OH
H
H
H
5:1 r.r.81% combined yield
Me
OMEM
OTBDPS
Me
O O
O
H
H
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Ether 1,4-Elimination
Me
OMEM
TBDPSO
OMOM
Me
Me
Me
OMEM
OH
H
HH
O
MOM
TBDPS
LiMe
OMEM
TBDPSO Me
s-BuLi
Me
OMEM
TBDPSO
OMOM
Me
Me
Me
O MEM
O H
HH
H
O
MOM
TBDPS
Li
Me
OMEM
TBDPSO Me
s-BuLi
Me
O
TBDPSO Me
Me
O
TBDPSO Me
OO
O
Me
H Li
Chiral Diene Synthesis and Diels-Alder Reaction
Me I
OMEM
Me CHO
OTBDPS
1. CrCl2, NiCl2
2. MOM-Cl EtNi-Pr2
Me
OMEM
TBDPSO
OMOM
Me
4:1 d.r.Me
OH1. Red-Al; I2
2. MEM-Cl EtNi-Pr2
85%(2 steps)
89-92%, 2 steps
Me
OMEM
TBDPSO
OMOM
Me
+
s-BuLi-78 °C
Me
OMEM
TBDPSO Me
69-76%
OH O
O
MeTBDPSO
Me
OMEMOOH
OH
H
H
H
5:1 r.r.81% combined yield
Me
OMEM
OTBDPS
Me
O O
O
H
H
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Quinone Acceptor Synthesis – Initial Hopes
MeTBDPSO
Me
OMEMOOH
OH
H
H
MeTBDPSO
Me
OHOOH
OH
H
H
MEMdeprotection
oxidation,epoxidation
MeTBDPSO
Me
HOOOH
OH
Obase
H
MeTBDPSO
Me
OOOH
OH
OH
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Quinone Acceptor Synthesis – Initial Hopes
MeTBDPSO
Me
OMEMOOH
OH
H
H
MeTBDPSO
Me
OHOOH
OH
H
H
MEMdeprotection
oxidation,epoxidation
MeTBDPSO
Me
HOOOH
OH
Obase
H
MeTBDPSO
Me
OOOH
OH
OH
MeTBDPSO
Me
OOH
OHH
MeTBDPSO
Me
OMEMOOH
OH
H
H Me
OOH
O
ZnBr2, HCl, etc.
Me
OHOH
O HH
- HO-MEM
- TBDPS-X
- acetaldehyde
- H2
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Quinone Acceptor Synthesis – Initial Hopes
MeTBDPSO
Me
OMEMOOH
OH
H
H
MeTBDPSO
Me
OHOOH
OH
H
H
MEMdeprotection
oxidation,epoxidation
MeTBDPSO
Me
HOOOH
OH
Obase
H
MeTBDPSO
Me
OOOH
OH
OH
MeTBDPSO
Me
OOH
OHH
MeTBDPSO
Me
OMEMOOH
OH
H
H Me
OOH
O
ZnBr2, HCl, etc.
Me
OHOH
O HH
- HO-MEM
- TBDPS-X
- acetaldehyde
- H2
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Quinone Michael Acceptor Synthesis
MeTBDPSO
Me
OMEMOOH
OH
H
H
m-CPBA
MeTBDPSO
Me
OMEMOOH
OH
H
H
O
93%9:1 d.r.
CH2Cl2
TBDPSO
O
OMEMOOH
OH
H
H
OH
Me O
Me Cl
+
2%
OH
HOH
CH3
OMEMH
H3CO
H
TBDPS
Conformation confirmedwith NOE and J
NOE
MeTBDPSO
Me
OMEMOOH
OH
OH
OH
H
20%
CDCl3
OO
OHO O
O CH3
HHH
H3CH3C
OR3Si
HO
conformationaccording to J
5:1 d.r .
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Quinone Michael Acceptor Synthesis
MeTBDPSO
Me
OMEMOOH
OH
OMnO2
88%
very stable
MeTBDPSO
Me
OMEMOOH
OH
H
H
O
MEMdeprotection
MeTBDPSO
Me
OHOOH
OH
O
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Quinone Michael Acceptor Synthesis
MeTBDPSO
Me
OMEMOOH
OH
O
MeTBDPSO
Me
OMEMOOBn
OH
O
35%
BnBr
Ag2O
TBDPSO
OH
OMEMOOBn
OH
OH
Me
Me
+
TBDPSO
Me
OMEMOOBn
OH
OH
OH
Me
+
30% 5%
hydrolysis happened in purification
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Quinone Michael Acceptor Synthesis
MeTBDPSO
Me
OMEMOOH
OH
O
MeTBDPSO
Me
OMEMOOBn
OH
O
35%
BnBr
Ag2O
TBDPSO
OH
OMEMOOBn
OH
OH
Me
Me
+
TBDPSO
Me
OMEMOOBn
OH
OH
OH
Me
+
30% 5%
hydrolysis happened in purification
MeTBDPSO
Me
OMEMOOH
OH
O
MeTBDPSO
Me
OMEMOOBn
OH
O
90% crude yield
BnBr
Ag2O
4-MeC6H4CO2H
CH2Cl2
TBDPSO
OH
OOOBn
OH
OH
Me
Me
20-40%, 2 steps
1. Ac2O2. SmI2
TBDPSO
OH
OOOBn
OH
Me
Me
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Quinone Michael Acceptor Synthesis
MeTBDPSO
Me
OMEMOOH
OH
O
MeTBDPSO
Me
OMEMOOBn
OH
O
35%
BnBr
Ag2O
TBDPSO
OH
OMEMOOBn
OH
OH
Me
Me
+
TBDPSO
Me
OMEMOOBn
OH
OH
OH
Me
+
30% 5%
hydrolysis happened in purification
MeTBDPSO
Me
OMEMOOH
OH
O
MeTBDPSO
Me
OMEMOOBn
OH
O
90% crude yield
BnBr
Ag2O
4-MeC6H4CO2H
CH2Cl2
TBDPSO
OH
OOOBn
OH
OH
Me
Me
20-40%, 2 steps
MeTBDPSO
OMEMOOBn
OH
Me
'wet', air
OH
OH
MeTBDPSO
OHOOBn
OH
MeOH
OH
epoxidehydrolysis
MEM ether
hydrolysis
air oxidation
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Quinone Michael Acceptor Synthesis
MeTBDPSO
Me
OMEMOOH
OH
H
H
HH2, Pd/C
MeTBDPSO
Me
OMEMOOH
OH
H
H
60%, 1 isomer
MeTBDPSO
Me
OMEMOOBn
OH
MeTBDPSO
Me
OMEMOOH
OH
Ag2O
MnO2 BnBr
70%, 2 steps
HCl, MeOH
MeTBDPSO
Me
OHOOBn
OH
IBX
MeTBDPSO
Me
OOOBn
OH
91%, 2 steps
MeOH
MeCN50 °C
CH2Cl2
5:1 r.r.
DMF
MeTBDPSO
Me
OOO
OH
NO2
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Fragments Coupling and Aromatization
OOMe
OMe
O
Me
PMB
OO
OMe
MeO
O
Me
Me
Me
OHOOBn
O
TBDPS
PMB
1. LHMDS, THF
31%, 1:1 crude d.r.(epimerizes to 1:19 d.r. over silica gel)
MeTBDPSO
Me
OOOBn
OH
oxidation
no reaction
Bn, PMB deprotection
retro-Michael
decomposition
Me
OHO
O
OBn
Me
OHO
O
OH
Side products other than retro-Michael
2. conditions
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Fragments Coupling Attempts
OOMe
OMe
O
Me
PMB
1. LHMDS, THF no fragment coupling product
MeTBDPSO
Me
OOOBn
OH
Br
2.
OOMe
OMe
O
Me
PMB
1. LHMDS
2. NCS
OOMe
OMe
O
Me
PMB
Cl
64%
1. LHMDS, THFno reaction
MeTBDPSO
Me
OOOBn
OH
2.
OOMe
OMe
OMe
MeO
1. LHMDS, THFno f ragment coupling product
MeTBDPSO
Me
OOOBn
OH
Br
2.From model studies
Real system
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Fragments Coupling and Aromatization
OOMe
OMe
O
Me
PMBOOMe
OMe
O
Me
PMB
F
98%
1. LHMDS, THF, -78 °C
2. (PhSO2)2NF
1. LHMDS, THF
MeTBDPSO
Me
OOOBn
OH
2.
OO
OMe
MeO
O
Me
Me
Me
OHOOBn
O
TBDPS
PMB
oxidation/aromatization
retro-Michael
decomposition
9-11%1:1 d.r.
F
CANBF3•OEt2imidazole
AcONa
Bu2BOTf (1.0 equiv)
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Fragments Coupling and Aromatization
OTBDPSMe
Me
OOOBn
OH
O
Me
OMe
OMe
OMOM
1. LHMDS, THF, -78 °C
OOMe
OMe
O
Me
MOM
NBS, AIBN
benzene
52%Br
2. OO
OMe
MeO
O
Me
Me
Me
OHOOBn
O
TBDPS
MOM
49%, 1:1 crude d.r.(Br and quinone equatorial)
no reaction
retro-Michael
decomposition
MOM-deprotection
Br
aromatizationconditions
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
1,4-Addition Attempts
OOMe
OMe
O
Me
PMB
Br1. LHMDS
2. NBS
OMOMOMe
OMe
O
Me
PMB
Br1. DBU
2. MOMCl
60% (2 steps)
OOMe
OMe
O
Me
PMB
Br
69%
Mg, CuI, THF
MeTBDPSO
Me
OOOBn
OH
MeTBDPSO
Me
OHOOBn
OHH
20%+ dehalogenated aromatic
caused by in situ reducing metal?
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
1,4-Addition Attempts
PhMgBrCuI, Me2S
MeTBDPSO
Me
OOOBn
OH
MeTBDPSO
Me
OHOOBn
OHH
15%
PhB(OH)2[Rh(C2H4)2Cl]2
MeTBDPSO
Me
OOOBn
OH
MeTBDPSO
Me
OHOOBn
OHH
8%
KOH 1Mdioxane
H
OHOOBn
Me
OH
TBDPSO MeH
OOOBn
Me
OH
TBDPSO Me
H
H
OOHOBn
Me
OHTBDPSO Me
Reduction product Diels-Alder kindof hydroquinone isomer
hydroquinone
Reduction product might come f rom radical transfer from a too highly nucleophilic species,i.e. high reduction potential of nucleophile with high oxidation potential of electrophile.
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Friedel-Crafts Fragments Coupling Attempts
OTBDPSMe
Me
OOOBn
OH
H
OHOOBn
Me
OH
Me OTBDPS
O
Me
OMe
OMe
OHPMB
CH2Cl2
OOMe
OMe
O
Me
PMB
Br DBU
DMF
74% 19%
OTBDPSMe
Me
OOOBn
OH
OH
Me
O
O
OH
Lewis or protic acid
H
OHOOBn
Me
OH
Me OTBDPS
OTBDPSMe
Me
OOOH
OH
or
or no reaction
or decomposition
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
New Strategy
OH O
O
OMe O
O
Me
OMOM
OH
O
O
Br
Pd(PPh3)4CuI, 65%
Me
OMEM
HO Me
OMEMMeO
O
O
MOMO
Me
OOH
O
HMe
Me OHH
benzenereflux77%
OMe O
O
OMOM
Me
Me3Sn
OMe OMe
OMe
OMOM
Me
Br 1. CAN, 77%
2. (Me3Sn)2 Pd(PPh3)4 94%
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Reversal of the Diene Electronics
OH O
O
OMe O
O
Me
OMOM
Me
OMEM
HO Me
OMEMMeO
O
O
MOMO
Me
OOH
O
HMe
Me OHH
benzenereflux77%
OH O
O
OMe O
O
Me
OMOM
Me
HO Me
MeO
O
O
MOMO
Me
OOH
O
HOTBS
TBSO
MeHOH
Me
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Diene Synthesis
TBSO
Me
Me OH
1. TBAF; 93%MeO
Me
Me OTBS
33% (47% RSM)
OEtO
Me
Me OTBSMe OTBS
OH
Me PPh3
OEtO
+CH2Cl2
rt
92%
1. H2NOMe•HClMe2AlCl
2. MeLi, Et2O
77%
2. LDA; TBSOTf
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Diels-Alder with New Diene
TBSO
Me
Me OH
1. TBAF; 93%MeO
Me
Me OH
33% (47% RSM)
OEtO
Me
Me OTBSMe OTBS
OH
Me PPh3
OEtO
+CH2Cl2
rt
92%
1. H2NOMe•HClMe2AlCl
2. MeLi, Et2O
77%
2. LDA; TBSOTf
OH O
O
OMe O
O
Me
OH
OO
O
O
HO
Me
MeH
OOHH
OTBS
Me
CH2Cl2, sealed tube85 °C, 48 h;
toluene, Dean-Stark135 °C, 24 h
98%, 2:1 dr
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Diels-Alder with New Diene
TBSO
Me
Me OH
OH O
O
OMe O
O
Me
OHMeO
O
O
HO
Me
OOH
O
HOTBS
MeHOH
Me
OO
O
O
HO
Me
MeH
OOHH
OTBS
Me
CH2Cl2,
MeO
O
O
O
Me
OOHH
OTBS
HMe
OHOMe
H
MeOH
OO
O
O
HO
Me
MeH
OOHH
OTBS
Me
toluene,
- MeOH
98%, 2:1 dr
OO
O
O
HO
Me
MeH
MeOH
OHOOH
BE-43472B
Completion of the Synthesis
OO
O
O
HO
Me
MeH
OOHH
OTBS
Me
OO
O
O
HO
Me
MeH
OOH
O
Me
OH
OO
O
O
HO
Me
MeH
OH
MeOH
O
S
S
OO
O
O
HO
Me
MeH
OH
MeOH
O
1. m-CPBA2. HFpyridine
3. SeO2, AcOH
88%
1. HSCH2CH2SH, BF3OEt2;
2. 0.1 M HCl / H2O
Raney-Ni
MeOH
63%
45% (19% RSM)
t-BuOOH
DBU
OO
O
O
HO
Me
MeH
OH
MeOH
O
84% (+ 7% epimer)
O
h (Hg lamp)
benzene
OO
O
O
HO
Me
MeH
OH
MeOH
O
77%
OH
Photochemical Epoxide Rearrangement
OO
O
O
HO
Me
MeH
OH
MeOH
OO
h (Hg lamp)
benzene
OO
O
O
HO
Me
MeH
OH
MeOH
O OH
OO
O
O
HO
Me
MeH
OH
MeOH
OO
OO
O
O
HO
Me
MeH
OH
MeOH
O O
H
OO
O
O
HO
Me
MeH
OH
MeOH
OH O
1,4-H shift
n *
Nicolaou, K. C.; Lim, Y.-H.; Becker, J.; Lemire, A.; Neubauer, T.; Montero, A. J. Am. Chem. Soc. 2009, 131, 14812.
Acknowledgments
Prof. K. C. Nicolaou
Research group members
Yee-Hwee Lim
Jochen Becker
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