HO H OH Chase Bruggeman O OH H OH - Chemistry...CEM 852 Presentation. 4/11/2020. 1 O OH HO H OH OH O...
Transcript of HO H OH Chase Bruggeman O OH H OH - Chemistry...CEM 852 Presentation. 4/11/2020. 1 O OH HO H OH OH O...
Chase BruggemanCEM 852 Presentation
4/11/2020
1
OOH
HO
HOH
OHO
H
Luo et al. JACS 2019, 141, 20048
(–)-Oridonin
• Biological activity:• Anti-inflammatory• Leukemia treatment
• Produced by Rabdosia rubescens plant• Structural features:
• Three contiguous C-6 rings• Terminal alkene on C-7 ring• Cyclic hemiacetal
2
OOH
HO
HOH
OHO
H
Luo et al. JACS 2019, 141, 20048
Nazarov interrupted by nucleophilic alkene attack on 5-membered ring
3
BnO
H
OBn
H
O
BnO
H
OBn
H
O LA-
Si
Key Intermediate
OOH
HO
HOH
OHO
H
Luo et al. JACS 2019, 141, 20048
Synthesis involves joining & building upon two 6-membered rings
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OOH
HO
HOH
OHO
H
SiO
OBnBnO
Br
OBnBnO
Si
O
+(+)-9 (+)-10
Luo et al. JACS 2019, 141, 20048
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(+)-9 Synthesis begins with dimethyl cyclohexanone
O Br
O
1660%
DMF (8 eq)CHCl3, 0 °C, 50 min
PBr3 (4 eq)
CHCl3, 0 to 70 °C, 40 h15
88 mmol
Luo et al. JACS 2019, 141, 20048
6
Aldehyde converted to ester by Pinnickoxidation, then methylation
Br
O
O
1767%
2 steps
16124 mmol
NaH2PO4 (0.25 eq)
H2O2 (1 eq)
NaClO2 (1.4 eq)
H2O, MeCN, 0 to 30 °C, 3 h
K2CO3 (1 eq)
MeI (1.1 eq)DMF, rt, overnightBr
O
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Ketone formed via chromate ester
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Br
O
O
1845%
O
1788.4 mmol
AcOH (14 eq)Ac2O (4 eq)35 °C, 1 h
CrO3 (1.7 eq)
CH2Cl2, rt, 3 h
Br
O
O
Luo et al. JACS 2019, 141, 20048
Stereochemistry introduced with chiral boron compound
8Luo et al. JACS 2019, 141, 20048
Br
OHOH
(+)-1978%
98% ee
N BO
H
BH3·SMe2 (1.6 eq)
THF, 0 °C, 1.5 h(S)-oxazaborolidine (1.2 eq)18
19.2 mmolTHF, -40 °C, overnight
Br
O
O
O
Alcohols protected as benzyl ethers
9
Br
OBnBnO
(+)-967%
(+)-1949 mmol
NaH (5 eq)THF, 0 °C, 1 h
BnBr (4.8 eq)0 to 30 °C, 40 hBr
OHOH
Luo et al. JACS 2019, 141, 20048
(+)-10 synthesis begins with methyl cyclohexenone
10
O
Si (i-Bu)2AlH (2.4 eq)THF, 0 to 55 °C, 5 h Si
Al(i-Bu)2
2 eq
CuCl2·2H2O (0.004 eq)NHC-Ag (0.004 eq)
THF, 0 °C, overnight
O
Si
(+)-2052%
86% ee
S160 mmol
N+N
SO3- Ag
NHC-Ag2
Luo et al. JACS 2019, 141, 20048
Silyl group homologated in two steps:1) Removal by ICl
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O
I
(+)-2173%
(+)-2011.9 mmol
diglyme (3 eq)ICl (2.5 eq)
hexafluoro-isopropanol40 °C, 5 minO
Si
Luo et al. JACS 2019, 141, 20048
Silyl group homologated in two steps:2) Pd-catalyzed addition
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O
Si
(+)-2276%
(+)-218.63 mmol
ZnBr2 (4.2 eq)
Et2O, rt, overnightSi MgCl Si ZnBr
Pd(MeCN)2Cl2 (0.1 eq)
DMF, 45 °C, 4 h
4 eqO
I
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Ketone converted to ester via tosyl ester:1) Tosylation
13
(+)-2216.5 mmol
NaN(SiMe3)2 (1.2 eq)
diglyme (2 eq)t-BuOMe, -78 °C, 2 h
Comins' Reagent (1.2 eq)2 h, -78 °C
NNCl
S
S
CF3
OO
OO CF3
Si
OO
Si
SCF3O
O
Luo et al. JACS 2019, 141, 20048
Ketone converted to ester via tosyl ester:2) Palladium catalyzed coupling
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Si
OO
(+)-2363%
2 steps
Si
O
Pd(OAc)2 (0.12 eq)
PPh3 (0.24 eq)
COEt3N (1.63 eq)
MeOH, DMF, 45 °C, 2 hSCF3O
O
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Ester converted to aldehyde via Weinrebamide
15
(+)-238.48 mmol
n-BuLi (7.8 eq)
THF, -78 °C to rt, 10 minrt, 1.5 h
CH3NHOCH3·HCl (4 eq)
THF, -78 °C, 1 h
Si
ONO
Si
OO
Si(+)-1070%
2 stepsO
(i-Bu)2AlH (2.25 eq)1.5 h, -78 °C
Luo et al. JACS 2019, 141, 20048
Blocks 9 and 10 connected via vinyl lithium
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Br
OBnBnO
(+)-91.1 eq
t-BuLi (2.2 eq)Et2O, -78 °C, 30 min
Si(+)-10
5.85 mmol1 eq
O
Et2O, -78 °C, 110 minSi
OH
OBnBnO
Luo et al. JACS 2019, 141, 20048
Secondary alcohol oxidized by dichromate
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SiOH
OBnBnO
Cornforth reagent (1.1 eq)DMF, 0 °C, 3 h
NH+Cr
O-O
O
OCr
O-
O
O
2
SiO
OBnBnO
(+)-8b61%
2 steps
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Interrupted Nazarov commences with Lewis acid
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SiO
OBnBnO
(+)-8b1.75 mmol
EtAlCl2 (1.5 eq)
CH2Cl2/THF 20:1 v/v40 °C, 22 h
BnO
H
OBn
H
O
Luo et al. JACS 2019, 141, 20048
Alkene converted to conjugated carbonyl with singlet oxygen
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BnO
H
OBn
H
O
HN
N
NH
N
TPP (0.56 mol%)hv, O2
(1 atm)
CDCl3, rt, 36 h
DMAP (0.024 eq)
pyridine (0.3 eq)Ac2O (0.9 eq)
rt, 5 h
N
N
BnO
H
OBn
H
O
O
(-)-2543%
2 steps
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Aldehyde cleaved with Wilkinson’s catalyst
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BnO
H
OBn
H
O
O
(-)-253.38 mmol
RhCl(PPh3)3 (1 eq)
toluene, reflux, 4 h
BnO
H
OBn
H
O
(-)-2667%
Luo et al. JACS 2019, 141, 20048
Vinyl lithium adds to ketone
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BnO
H
OBn
H
O
(-)-262.47 mmol
Br4 eq
t-BuLi (7.5 eq)Et2O, -78 °C, 30 min
Li
Et2O, -78 °C to 0 °C, 80 min
BnO
H
OBn
H
HO
Luo et al. JACS 2019, 141, 20048
mCPBA selectively oxidizes bisubstitutedalkene
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BnO
H
OBn
H
HO
mCPBA (2 eq)NaHCO3
(10 eq)
CH2Cl2
Cl
O
OOH
BnO
H
OBn
H
O
H
HHO
(-)-2770%
2 steps
Luo et al. JACS 2019, 141, 20048
Ring expanded by radical bromine addition
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BnO
H
OBn
H
O
H
HHO
(-)-272.08 mmol
NO
O BrNBS (1.2 eq)
silica gelCH2Cl2, rt, 30 min
BnO
HO
HOBn
O
H
H
Br
(-)-2889%
Luo et al. JACS 2019, 141, 20048
Primary halide converted to vicinal diol by RuO4, then OsO4
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BzO
HO
OH
HOBz
OH
O
H
H
(-)-3070%
2 steps
BzO
HO
HOBz
O
H
H
BnO
HO
HOBn
O
H
H
Br(-)-28
1.86 mmol
NaIO4 (8 eq)
RuCl3·3H2O (2 eq)MeCN/CCl4
1:1 v/v
pH 7 bufferrt, 2.5 h
NMO (5 eq)OsO4
(0.05 eq)
acetone/H2O 8:1 v/v40 °C, 30 min
O
N+O
Luo et al. JACS 2019, 141, 20048
Lewis acid opens epoxide & rearranges rings
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OHBzO
HO
OH
HOBz
OH
(-)-3157%
BzO
HO
OH
HOBz
OH
O
H
H
(-)-300.88 mmol
EtAlCl2 (3 eq)
toluene, 0 °C to rt, 2 h
Luo et al. JACS 2019, 141, 20048
Ether groups deprotected to form hemiacetal
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OHBzO
HO
OH
HOBz
OH
(-)-310.47 mmol
LiAlH4 (5 eq)
Et2O, 0 °C to rt, 4.5 hOH
HO
HOH
OH
HOH
OH
OHHO
HOH
OHO
HNaIO4
(1.38 eq)
pH 7 bufferTHF, 10 °C to rt, 3.5 h
(-)-3369%
2 steps
Luo et al. JACS 2019, 141, 20048
Inverting alcohol stereochemistry:1) Acetal protection allows selective oxidation
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OO
HO
OO
HOH
HO
HOH
OHO
H
(-)-330.214 mmol
2,2-dimethoxy propane (20 eq)p-TsOH (0.1 eq)
acetone, rt, 10 min
OI
O
OOO
O O
O
DMP (3.5 eq)DCM, 0 °C, 4 h
DMP (2 eq)DCM, rt, overnight
(-)-3466%
Luo et al. JACS 2019, 141, 20048
Inverting alcohol stereochemistry:2) Ketones reduced to new alcohols
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OHHO
HOH
OHO
H
(-)-356%
OHHO
HOH
OHO
H
(-)-3521%
Recycled to (-)-34 byprevious reaction
OO
HO
OO
H
(-)-340.0414 mmol
(i-Bu)2AlH (2 eq)CH2Cl2/Et2O 1:3 v/v
-100 °C, 5 min, then rt
ONa+O
O OAl
-H
H
Red-Al ® (3 eq)THF, rt, 1 h
+HCl (5% aq,
2 mL)
Luo et al. JACS 2019, 141, 20048
Alkene converted to conjugated carbonyl with singlet oxygen (again)
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OOH
HO
HOH
OHO
HOH
HO
HOH
OHO
H
(-)-315.6 μmol
HN
N
NH
N
TPP (3 mol%)hv, O2
CDCl3, rt, 15 h
DMAP (2 eq)
pyridine (1 eq)Boc2O (3 eq)
CH2Cl2, 0 °C, 20 min
N
N
HCl (6M, 3.8 eq)
2
(-)-Oridonin47%
Luo et al. JACS 2019, 141, 20048
Thank you!
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OOH
HO
HOH
OHO
H
NHC-Ag synthesis begins with chiral glycinol
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NH OHO
O
imidazole (3.9 eq)Et3N (2.7 eq)
SOCl2 (1.3 eq)
CH2Cl2, -50 °C to 4 °C, 13.5 hN OO
OSO
B78.4%
A16.8 mmol
May et al. Angew. Chem. Int. Ed. 2008, 47, 7358
Sulfur oxidized to leaving group by RuO4
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N OO
OSO
B13.1 mmol
RuCl3•2H2O (7 mol%)NaIO4
(1.6 eq)
pH 7 bufferCH2Cl2/MeCN 1:1 v/v
0 to 22 °C, 25 min
N OO
OS
OC
74.2%
O
May et al. Angew. Chem. Int. Ed. 2008, 47, 7358
Diethyl aniline protected with Boc group
33
NH2
61 mmol
(Boc)2O (1.1 eq)H2O, 48 h
NH
OO
D89.9%
May et al. Angew. Chem. Int. Ed. 2008, 47, 7358
Fragments joined, then protecting groups removed
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N OO
OS
OC
3.17 mmol
O
NH
OOD
1.5 eqNaH (1.7 eq)
DMF, 22 °C, 15 min
DMF, 22 °C, 12 h
H2SO4 (18 M, 13.5 eq)
dioxane, 22 °C, 48.5 hH2N HN
E77.3%
May et al. Angew. Chem. Int. Ed. 2008, 47, 7358
Aryl group added with palladium catalyst
35
H2N HN
E3.75 mmol
Br
SO
OO
(1 eq)Pd2(dba)3
(5.8 mol%)
NaOt-Bu (1.75 eq)rac-BINAP (0.175 eq)
THF, 66 °C, 15 h
NH HN
F~80%
SO
O O
O
Pd
Pd
3
Pd2(dba)3
PP
PhPh
PhPh
rac-BINAP
May et al. Angew. Chem. Int. Ed. 2008, 47, 7358
Methylene group bridges nitrogen atoms
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NH HN
SO
O O
F9.71 mmol
N+ I-
(5 eq)AcOH (15 eq)
110 °C, 1h
N N
SO
O O-
G50%
May et al. Angew. Chem. Int. Ed. 2008, 47, 7358
Catalyst dimer formed with silver oxide
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AgNO3
(10 mmol)
NaOH (40 mmol)H2O, immediate
Ag2O
(2 eq used below)N N
SO
O O-
G0.201 mmol
4Å MSTHF/benzene 1:1 v/v
80 °C, 2 h
N+N
SO3- Ag
NHC-Ag98%
2
May et al. Angew. Chem. Int. Ed. 2008, 47, 7358