controlled, radical-mediated c-h functionalization · generate more reactive radical via...
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Synthesis of 1,3-Diols via Controlled, Radical-Mediated C-H Functionalization
Chen, K.; Richter, J. M.; Baran, P. S. J. Amer. Chem. Soc. 2008, 130, 7247-7249.
Literature Group Presentation Wynter Gilson August 1, 2008
Introduction
Previous work on 1,3-diol synthesis. 1,3-diol synthesis inspired by HLF rxn. Challenges of this method. Use of this method towards synthesis of
natural compounds. Comparison of selectivity of C-H bond
activation with other methods.
Previous work on 1,3-diol synthesis
R1 R2
OH
R1 R2
OH
Direct oxidation
or
R1 H
O
Me R2
O
R1 R2
O
R1 R2
OH
Aldol (reduction)Conjugate addition (reduction)
Allylic hydration
R1 R2
OHOH
Chen, K.; Richter, J. M.; Baran, P. S. J. Amer. Chem. Soc. 2008, 130, 7247-7249.
Inspiration from the Hofmann-LÖffler-Freytag (HLF) reaction
*Reaction is 99 years old.
*Considered one of the first directed C-H activation reactions ever reported.
Kurti, L.; Czako, B., Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press: Burlington, MA, 2005; p 208.
R1 N R2
XNX
H R2
R1NR1
R2
Base R1 = alkyl, aryl, HR2 = alkyl, acyl, HX = Cl, Br, I
General HLF reaction
2) radical initiator
H
1) acid
Incorporating HLF rxn into 1,3-diol synthesis
R1
O
R2
O
NHR
R1
OH
R2
OH1. HLF Reaction
2. Hydrolysis
Modified HLF reaction
O NR
R1 R2
O
E
O O
NR
R1 R2
F
D
A
Chen, K.; Richter, J. M.; Baran, P. S. J. Amer. Chem. Soc. 2008, 130, 7247-7249.
R1
O
R2
O
NBrRHa
HbR1
O
R2Br
O
RHN
CB
Incorporating HLF rxn into 1,3-diol synthesis
R1
O
R2
O
NHR
R1
OH
R2
OH1. HLF Reaction
2. Hydrolysis
Modified HLF reaction
O NR
R1 R2
O
E
O O
NR
R1 R2
F
D
A
Chen, K.; Richter, J. M.; Baran, P. S. J. Amer. Chem. Soc. 2008, 130, 7247-7249.
R1
O
R2
O
NBrRHa
HbR1
O
R2Br
O
RHN
CB
First Challenge
* Most N-bromocarbamates gave < 30 % conversion
* Trifluoroethyl carbamate gave more reactive N-centered radical
Chen, K.; Richter, J. M.; Baran, P. S. J. Amer. Chem. Soc. 2008, 130, 7247-7249.
R1
O
R2
O
NBrRHa
HbR1
O
R2Br
O
RHN
CB
Generate more reactive radical via trifluoro-
acetylisoleucine methyl ester
CO2MeHN
H
H
F3C
O BrO
O CO2MeNHH
H
F3C
OCCl4, 23°C1h, dark
light
23°C
CO2MeHN
BrCH2
H
H
F3C
O
Br
NH2
O
OH
Branched CarbonChain
Two Sterocenters
Target Site
a) Reddy, L. R.; Reddy, B. V. S.; Corey, E. J. Org. Lett. 2006, 8, 2819-2821. b) Duhamel, L.; Ple, G.; Angibaud, P. ; Desmurs, J. R. Synth. Commun. 1993, 23, 2423-2433. c) Beebe, R.R.; Wolfe, J. W.; J. Org. Chem. , 1970, 35, 2056-2057.
Variation of trifluoro-acetyl moiety
CO2MeHN
BrCH2
H
H
F3C
Oi-Pr2NEt
THF23°C
1. THF
2. K2CO3, MeOH, 0°C
NaSCOMeO
N CO2MeH
H
OF3C
NaIMe2CO
AgNO3, 1:1 THF-H2O23°C, 91%
CO2MeHN
ICH2
H
H
F3C
O
CO2MeHN
SHCH2
H
H
F3C
O
CO2MeHN
HOCH2
H
H
F3C
O
Reddy, L. R.; Reddy, B. V. S.; Corey, E. J. Org. Lett. 2006, 8, 2819-2821.
Applying trifluoro compounds to 1,3-diol synthesis
OH OCF3CH2NCOO
NH
CF3
97 %
CH3CO2BrO
O
NBr
CF3
O
O
NH
CF3
BrPhCF3, CBr4
hv, 100 Wflood lamp
Chen, K.; Richter, J. M.; Baran, P. S. J. Amer. Chem. Soc. 2008, 130, 7247-7249.
Second Challenge
R1
O
R2Br
O
RHN
O O
NR
R1 R2
DC
Chen, K.; Richter, J. M.; Baran, P. S. J. Amer. Chem. Soc. 2008, 130, 7247-7249.
R1
O
R2
O
NHR
R1
OH
R2
OH1. HLF Reaction
2. Hydrolysis
Modified HLF reaction
R1
O
R2
O
NBrRHa
Hb
O NR
R1 R2
O
E
F
B
A
Second Challenge
R1
O
R2Br
O
RHN
O O
NR
R1 R2
DC
Chen, K.; Richter, J. M.; Baran, P. S. J. Amer. Chem. Soc. 2008, 130, 7247-7249.
R1
O
R2
O
NHR
R1
OH
R2
OH1. HLF Reaction
2. Hydrolysis
Modified HLF reaction
R1
O
R2
O
NBrRHa
Hb
O NR
R1 R2
O
E
F
B
A
Second Challenge
O
O
O
OHOHK2CO3
(69 % isolated overall)
O
O
NH
CF3
BrAg2CO3
O
N
O
CF3
AcOH
Aliphatic Cases:
Ph
O
Ph
O
ONaOMe
Ph
OH
Ph
OH
(91 % isolated, dr 1:1)
Benzylic Cases:
Chen, K.; Richter, J. M.; Baran, P. S. J. Amer. Chem. Soc. 2008, 130, 7247-7249.
Synthesis of 1,3-diol
OH OCF3CH2NCOO
NH
CF3
97 %
CH3CO2BrO
O
NBr
CF3
O
O
NH
CF3
BrO
O
OOHOH
PhCF3, CBr4hv, 100 Wflood lamp
Ag2CO3
then AcOH
K2CO3
(69 % isolated overall)
Chen, K.; Richter, J. M.; Baran, P. S. J. Amer. Chem. Soc. 2008, 130, 7247-7249.
Scope of 1,3-diol synthesis
Chen, K.; Richter, J. M.; Baran, P. S. J. Amer. Chem. Soc. 2008, 130, 7247-7249.
Synthesis of natural products OH OH
70 %, dr 8:1
Previous synthesis: 4 steps, 12%
OHOH
42 %
9 Previous synthesis
Chen, K.; Richter, J. M.; Baran, P. S. J. Amer. Chem. Soc. 2008, 130, 7247-7249.
OH
OH
HO
36 % dr 3:2
α = isorengyolβ = rengyol
Previous synthesis: 13 steps, 29 %
8 steps, 3.2%, dr 3:1
Comparison of selectivity of tertiary C-H bond activation
White Fe-based catalyst
Fe
N
NNCCH3N
NCCH#N
(SbF6)2Targets remote tertiary position
XH H
XHO H
O O
Curci [O] (dioxirane)
Gives both alchohol and ketone products.
OOHH
__________________________________________________
a) Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R. J. Amer. Chem. 1989, 111, 6749-6757. b) Chen. M. S.; White, M. C. Science 2007, 318, 783-787.
Curci method’s proposed mechanism
H
OO
OOHOHO OHO
OHO O OH
I
II III
Curci method
90 min90 % yield
OO
F3C
(77) (7) (16)
OO
F3C
OH O2 min97 % yield
(58) (42)
OOHOH
OO
F3C
OO
F3C
OH
O96 % yield10 % conversion
95 % yield14 % conversion10 min
80 min
White’s method
MeO
O
H
MeO
O
HO
O
H
H H
White's catalyst (5 mol %)AcOH (50 mol %)
H2O2 (1.2 eq)
CH3CN, rt,30 min
White's catalyst (5 mol %)AcOH (50 mol %)
H2O2 (1.2 eq)
CH3CN, rt,30 min
White's catalyst (5 mol %)H2O2 (1.2 eq)
CH3CN, rt,30 min
OO
OO
OOMeO
O
MeO
O
O
O
HO
O O
48 %
27 %
70%
17 %
41 %
not observed
Electronic:
Steric:
Directed:
Chen. M. S.; White, M. C. Science 2007, 318, 783-787.
Comparison of selectivity of tertiary C-H bond activation
O HcHbHa
Hd
O
NH
CF3
Hd O
Ha
Hb
Hc
NH
O
F3C
•White catalyst selective for Ha.
•Curci non-selective
•This work selective for Hc.
Chen, K.; Richter, J. M.; Baran, P. S. J. Amer. Chem. Soc. 2008, 130, 7247-7249.
Conclusion
Only method for conversion of alcohols to 1,3-diols.
Practical method using simple reagents. Capable of installing hydroxy functionality in a
late stage thereby reducing unproductive chemical manipulations.