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TRANSCRIPT
NO
OMe
O
O
O O
HO
t
Chase BruggemanCEM 852 Presentation
2/8/2020
(Max-Planck-Institut für Kohlenforschung)
Synthesis of Backbone 1
OH NovozymeVinyl Acetate (4 equiv.)
OH
(R)-1-octen-3-ol (34 %, > 99 % e.e.)(S) isomer forms 1-octen-3-yl acetate
OHBr
NaH (1.8 equiv.)THF,
O
93%
1.7 equiv.
0 °C rt, 1 h 0 °C rt, 16 h
Synthesis of Backbone 1
O
THF, -78 °C, 4 h93%
OHn-BuLi (1.2 equiv.) NH4Cl
H2O
OTBS
79 % over two steps
TBSCl (1.2 equiv.)imidazole (1.5 equiv.)CH2Cl2
, 0 °C rt, 4 h
Synthesis of Backbone 1
1.3 equiv.OsO4
(0.2 mol %),
acetone, CH2Cl2, rt, 6 h
OTBSOTBS
ON O
OH
OH
NaIO4 (1.5 equiv.)
pyridine (2 equiv.)1,4-dioxane/water 3/1 v/v
rt, 45 min
OTBSO
69 % over two steps
1.1 equiv.ZnCl2
(2 equiv.)
CH2Cl2, rt, 3 h
NS
TBSO
Synthesis of Backbone 1
NS
TBSOCl
O
N
SH 1 equiv.Et3N (1.5 equiv.)
THF, 30 min 91 %NS
89 %
O (Me3Si)2NLi (1.2 equiv.)TBSCl (1.2 equiv.)
DMF (3 equiv.)THF, -78 °C, 2 h
OTBSO
69 % over two steps
1.1 equiv.ZnCl2
(2 equiv.)
CH2Cl2, rt, 3 h
NS
TBSOOTBSO
O
90%, d.r = 6:1
Synthesis of Backbone 1OTBSO
O
MeNH(OMe)·HCl AlMe3 (3 equiv.)
CH2Cl2, 0 °C rt, 1 h
OTBSOH
N
O
OMe3 equiv. rt, 2h
96 %
pyridine (2 equiv.)CH2Cl2, 0 °C rt, 1 h
TMSCl (1.1 equiv.)
t-BuLi (4 equiv.)THF, -78 °C, 30 min
OTBS
I
2.5 equiv.CeCl3·2LiCl (2 equiv.)THF, -78 °C, 5 min OTBS
Li
-78 °C, 1 h
OTBSOTMSOTBSO OHO3S
cat.
CH2Cl2/MeOH0 °C, 5 min
OTBSOHOTBSO
87% over three steps
Synthesis of Backbone 1
TiClCl
5 mol %MgBr
2.5 equiv. Et2O, 0 °C, 10 min
OH
0 °C rt, 4 h
I2 (3.5 equiv.)
-78 °C 0 °C, 1 h
OH
I
45 %
TBSCl (1.1 equiv.)imidazole (2 equiv.)THF, 0 °C rt, 16 h
OTBS
I
68 %
Synthesis of Backbone 1
OTBSOHOTBSO O2N
O
H
3 equiv.SmI2
(40 mol%)
THF, -25 °C, 3h
OTBSOTBSO
O
O2N
OH
62 %Me3O·BF4
(7 equiv.),
CH2Cl2, 0 °C rt
"proton sponge" (9 equiv.)
N N
OTBSOTBSO
O
O2N
MeO
90 %
K2CO3 (1.5 equiv.)
THF/MeOH 1:10 °C
OTBSOHTBSO
MeO
63 %rt, 20 h
Synthesis of Backbone 1
OTBSOTBSO
MeO
O(EtO)2OP
CH2Cl2, 0 °C, 15 min
PO
OOHO
O
(3 equiv)
N C N
N+ HCl
-EDC
(2 equiv.) rt, 10 min
OTBSOHTBSO
MeO
72 %
NO
OMe
O
O
O O
HO
Synthesis of Backbone 2Fe(NO3)3·9H2O (0.3 mol %)
NH3, Na0 (3 equiv.), -47 °C, 1 hMeI (1.5 equiv.)Cl
Cl undecane, -47 °C rt, 1 h 51 %
In parallel:
OH OHO
19:1 E/Z
Ti(OiPr)4 (4 mol%),
O
O OO
D-(-)-Diisopropyltartrate (6 mol%)
t-BuOOH (1.5 equiv.), CH2Cl2, mol. sieve, -20 °C, 18h 78%, er 4.6:1
Synthesis of Backbone 2
OHOHn-BuLi (2 equiv.)
2.2 equivCH2Cl2, -78 °C, 0.5 h
Et2AlCl (2 equiv.)
toluene, 0 °C, 3 h
OHO
CH2Cl2, 0 °C, overnight 95%, 10:1 mixture of isomers
OPyridine (5 equiv.)TsCl (1.1 equiv.)CH2Cl2, 0 °C to rt, 6 h
OTsOH
N
NDBU, 2 equiv
CH2Cl2, 0 °C to rt, 18 h97%
83%
Synthesis of Backbone 2
OH
Ph3P (1.05 equiv.)Br2
(1.05 equiv.)
CH2Cl2, -30 °C, 1 h pyridine (1 equiv.), -30 °C rt, 9 h
Br
93%
Mg (2.5 equiv.)Et2O, reflux to rt, 2h
CuI (0.5 equiv.)Et2O, -40 °C, 30 min
O
Et2O, -40 °C, 4 h
0.6 equiv. OH
78 % (based on epoxide)
Synthesis of Backbone 2
OH 1.5 equiv.OsO4
(4 mol %),
acetone, water, 6 h
ON O
OHOH
OH68 %
SO3-+HN
cat.
acetone, 5 h
OHO
O
83 %
Na+O O
OOAl
-H
HRed-Al® (2 equiv.)
THF, rt, 4 h
SO3H
15 mol %wet MeOH, 40 °C, 4 d
OHOH
OH
93 %
Synthesis of Backbone 2
OHOH
OH NaIO4 (3 equiv.)
CH2Cl2, rt, 20 min
N OIO
O
O
O
PIDA (2 equiv.), TEMPO (14 mol %)
Yb(OTf)3 (7 mol %), 0 °C to rt, 1h
O
O
OH
57 %
NO
OMe
O
O
O O
HO
Joining 1 and 2
N
NOTBSO
TBSOMeO
O(EtO)2OP
DBU (1.1 equiv.)LiCl (2.5 equiv.)MeCN, 30 min.
O
O
OH
2 equiv.0 °C , 30 min
OO
O
O
MeOTBSO
TBSO
86 %
Closing the Ring
NMo
N
NOO
O
O
MeOTBSO
TBSO
8 mol %CHCl2
(5 equiv.)
toluene, 5 min
toluene, 80 °C, 3 h
+N
MoN
N
Cl
OO
O
O
MeOTBSO
TBSO
67%
Molybdenum Catalyst
Br+
NH2
P
NH 1 mol %
t-BuONa (2.7 equiv.), Pd2(dba)3 (0.5 mol %)
toluene, 80 °C, 8 h1.2 equiv.
O
Pd
Pd
3
86%
n-BuLi (1.2 equiv.)
hexane, -35 °C to rt, 12 h
67%
NLi
NMo
N
NMoCl3(THF)3
(0.5 equiv.)
Et2O, -100 °C to rt, 2.5 h
70%
Preparing for Backbone 3 Addition
OO
O
O
MeOTBSO
TBSO
67%
OO
O
O
MeOHO
HO(n-Bu)4NF (2.8 equiv.)
THF, -50 °C to -10 °C, 3 h
90%
Preparing for Backbone 3 AdditionOO
O
O
MeOHO
HOSnBu3
OO
O
O
MeOHO
HO [Cp*RuCl]4 (8 mol %)
(CH2Cl)2, 5 min, rtBu3SnH (1.1 equiv)20 min
(cod)Pd(Me)(Cl) (3 equiv.)THF, rt, 2h
PdMe
Cl
56% over two steps
OO
O
O
MeOHO
HO
Preparing for Backbone 3 Addition
OO
O
O
MeOHO
HOTBDPSCl (3 equiv.)imidazole (5 equiv.)CH2Cl2, -60 °C, 5 h
DMAPTBSCl (5 equiv.)
imidazole (10 equiv.)CH2Cl2, -60 °C, 5 h
N
N
OO
O
O
MeOTBDPSO
TBSO
71% over two steps
Preparing for Backbone 3 Addition
OO
O
O
MeOTBDPSO
TBSO n-Bu4NF/AcOH 1:1 (1.5 equiv.)THF, rt, 12 h
OO
O
O
MeOHO
TBSO
74%
MnO2 (50 equiv.)
CH2Cl2, rt, 2 h
OO
O
O
MeOO
TBSO
100%
NO
OMe
O
O
O O
HO
Backbone 3
NO O
O
LiAlH4
Et2O, -78 °C, 20 minN
O OH
94%
(COCl)2, Et3NMe2SO, CH2Cl2
NO O
91%
P O
O
O
O
O
KOt-Bu, THF-78 °C to 0 °C, 20 min
O
O
NO
86%
(i-Bu)2AlHCH2Cl2, -78 °C, 15 min
OHN
O
100%
Backbone 3NO
O
Br
PPh3
CH2Cl2, -78 °C to 0 °C, 20 minOH
NO
ON
BrProposed
NO
OMe
O
O
O O
HO
NaIO4
1,3-dioxane, H2O, 0 °C
LiPPh2
THF, 0 °C, 20 min ON
PPh2Proposed
ON
POPh2
79% over two steps
Putting it All Together
ON
POPh2
OO
O
O
MeOO
TBSO (Me3Si)2NK (2 equiv.),THF, -78 °C to 0 °C, 35 min
2 equiv.
2 equiv.Et3N (4 equiv.)
THF
Cl
Cl Cl
Cl
O
N
N
OO
O
O
MeO
TBSO
ON
30%
Rhizoxin D!
OO
O
O
MeO
TBSO
ON
pyridine, HF/pyridineTHF, rt, 48 h N
O
OMe
O
O
O O
HO
74%
NO
OMe
O
O
O O
HO
t
Thank you!
(Max-Planck-Institut für Kohlenforschung)