Eric Beaulieu Thursday April 10 th, 2008 Asymmetric Fluorination.
58
Eric Beaulieu Thursday April 10 th , 2008 Asymmetric Fluorination
-
Upload
ezra-lyons -
Category
Documents
-
view
216 -
download
0
Transcript of Eric Beaulieu Thursday April 10 th, 2008 Asymmetric Fluorination.
Eric BeaulieuThursday April 10th, 2008
Asymmetric Fluorination
2
Outline
•Introduction: -Fluorine facts -Why incorporate fluorine in organic molecules -Examples of fluorinated molecules
•Methods of Accessing Fluorine Bearing Chiral Centers : -Enzymatic kinetic resolution -Fluorinated enolates -Nucleophilic fluorination -Electrophilic fluorination: -Substrate-controlled (chiral auxiliaries) -Agent-Controlled
•Conclusion / Acknowledgements
3
Fluorine Facts
19FAtomic Number : 9
Relative Atomic Mass: 18.998Group # 17 (halogens)
Quantum # I = ½ (like 1H), abundance ≈ 100%
Element Van der Waals radii (Å)
Electronegativity (Pauling)
F 1.47 3.98
O 1.52 3.44
N 1.55 3.04
C 1.70 2.55
H 1.20 2.2
Bond Average
Bond Strength (KJ/Mol)
Average Bond Length
(Å)
C-F 485 1.39
C-C 356 1.53
C-O 336 1.43
C-H 416 1.09
4
Why Incorporate Fluorine Into Organic Molecules ?
•Biologically active/useful compounds-electronegativity of fluorine influences the effect of neighbouring functionalities-C-F bond strength renders it resistant to metabolic processes-incorporation of fluorine usually increases lipid solubility (bioavailability ) -synthesis of isosteric analogues of drugs-useful for studying biochemical processes
Filler, R., Kobayashi, Y. in Biomedical Aspects of Fluorine Chemistry, Eds. Kodansha/Elsevier Biomedical Press, 1982
F
F
F
F
F
F n
•Organofluorine materials -fluoroplastics: ie Teflon (PTFE)
-fluoroelastomers (gaskets, hoses, wiring insulation…) -liquid crystals
•Synthetic building blocks-where fluorine serves as a leaving group-to construct complex fluorine containing molecules
5
Why Incorporate Fluorine Into Organic Molecules ?
Isostere of O vs H
Element Van der Waals radii (Å)
Electronegativity (Pauling)
F 1.47 3.98
O 1.52 3.44
N 1.55 3.04
C 1.70 2.55
H 1.20 2.2
Bond Average
Bond Strength (KJ/Mol)
Average Bond Length
(Å)
C-F 485 1.39
C-C 356 1.53
C-O 336 1.43
C-H 416 1.09
Smart, B. E. in Organofluorine Chemistry: Principles and Commercial Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum Press: New York, 1994; Chapter 3, pp 57-88.
6
Vinyl Fluorides as Peptide (Amide) Bond Isosteres
H2N
R1
O
HN
R2
O
OH H2N
R1
F R2
O
OH
dipeptide dipeptide isostere
•Non-hydrolyzable bond
•No rotational freedom
Taguchi, T. et al. J. Fluorine Chem. 2006, 127, 627.
7
Fluorinated Activity-based Fluorescent Protease Probe
Yao, S. Q. et al. Chem. Commun. 2004, 1512
HN
F
HN
O
OO
NH
O
N
NO
AA-NH
OI
NH
FNH
O
R
O
HN-AA
O B
NH
FNH
O
R
HN-AA
O B O
hydrolysis
proteasepocket
active site
Nu
Nu
AA NH
NH
O
R
B
Nu
+
F
NH2
NH
O
R
B
Nu
covalent bond between enzyme and remainin molecule
R
quinolimine methideintermediate
8
Example of a Fluorinated Drug: Advair Diskus®
Me
F
F
O
Me
HOMe
H
OH
O SF
Advair Diskus®(fluticasone propionate)
GlaxoSmithKlineAsthma Medication
9
Metabolic Oxidation Inhibition by Fluorine
OHMe
O
OH
H
O
Me
HO
H
H
cortisol
OHMe
O
OH
H
O
Me
O
H
H
OHMe
O
OH
H
O
Me
HO
F
H
9-fluorocortisol
OHMe
O
OH
H
O
Me
O
F
H
11-hydroxysteroid dehydrogenase
NADP+ NADPH
11-hydroxysteroid dehydrogenase
NADP+ NADPH
cortisone
X
metabolicoxidation
Back, D. J. et al. J. Steroid Biochem. Mol. Biol. 1993, 46, 833.
10
Accessing Fluorine Bearing Chiral Centers
R R'
R''FR
F
OEt
O
Enzymatic kinetic resolution
RF
OTMS
R'
+ R'' + Cat*
FluorinatedEnolates
NucleophilicFluorination
R R'
LGR''+ " F "
ElectrophilicFluorination
RR''
OM
R'
+ " F "
11
Enzymatic Kinetic Resolution
EtO2C CO2Et
Me FTriacylglycerol Lipase(Candida cylindracea)
pH 7.3 Buffer solution HO2C CO2Et
Me F
EtO2C CO2Et
Me FCelulase
(Trichoderma viride)
pH 7.3 Buffer solution HO2C CO2Et
Me F
87% yield91% ee
70% yield56% ee
F
CO2EtLipase
(Pseudomonas)
pH 7.0 Buffer solution60 % conversion
F
CO2Et
F
CO2H+
> 99% ee > 69% ee
F
CO2EtLipase
(Pseudomonas)
pH 7.0 Buffer solution40 % conversion
F
CO2Et
F
CO2H+
90% ee
Kitazume, T. et al. J. Org. Chem. 1986, 51, 1003.
Kalaritis, P. et al. J. Org. Chem. 1990, 55, 812.Kalaritis, P., Regenye, R. W. Org. Synth. 1990, 69, 10.
12
Enzymatic Kinetic Resolution
EtO2C CO2Et
Me FTriacylglycerol Lipase(Candida cylindracea)
pH 7.3 Buffer solution HO2C CO2Et
Me F
EtO2C CO2Et
Me FCelulase
(Trichoderma viride)
pH 7.3 Buffer solution HO2C CO2Et
Me F
87% yield91% ee
70% yield56% ee
Kitazume, T. et al. J. Org. Chem. 1986, 51, 1003.
Kalaritis, P. et al. J. Org. Chem. 1990, 55, 812.Kalaritis, P., Regenye, R. W. Org. Synth. 1990, 69, 10.
F
CO2EtLipase
(Pseudomonas)
pH 7.0 Buffer solution60 % conversion
F
CO2Et
F
CO2H+
> 99% ee > 69% ee
F
CO2EtLipase
(Pseudomonas)
pH 7.0 Buffer solution40 % conversion
F
CO2Et
F
CO2H+
90% ee
13
Allylation of Fluorinated Silyl Enol Ethers
Paquin, J-F. et al. J. Am. Chem. Soc. 2007, 129, 1034.
OTMS
F
+ OCO2Et
[Pd(C3H5)Cl]2 (1.25 mol%)1 (3.1 mol%)
TBAT (35 mol%)toluene, 40oC
OF
85% yield92% ee
PPh2
O
N
1
TBAT = Ph3SiF2.NBu4
14
Nucleophilic Fluorination
Hara, S. et al. Tetrahedron 1999, 55, 4947.
Hex OHO
(i-PrO)2TiF2, Et4NF-4HF
95 % ee
Hex OH 73% yield95% ee
OH
F
Wakselman, C. et al. J. Org. Chem. 1979, 44, 3406.
n-C6H13
OH
n-C6H13
FDAST 48% yield
98% ee
NSF
F
FDAST
15
Attempt at Kinetic Resolution in Nucleophilic Fluorination
OTMS
O
EtO
N
OMe
SF30.5 equiv. OTMS
O
EtO
F
O
EtO+
50 % ee 16 % ee
R
OR
R'NSF
F
F
R
OR
R'
SF
FN
F
+R
F
R'
Sampson, P., Hann, G. L. J. Chem. Soc. Chem. Commun. 1989, 1650.
Yields and stereochemistry of products not reported!
16
Enantioselective Electrophilic Fluorination: Two Strategies
Substrate-Controlled Agent-Controlled
RR''
OM
*
R'
"F "+ RR''
O
*R' F
RR''
OM*
R'
"F "+ RR''
O
R' F
Enantioselectivity induced by the stereochemistry of the substrate
Enantioselectivity induced by the stereochemistry of the fluorinating agent
17
Substrate-Controlled Stereoselective Electrophilic Fluorination
NO
R1 R2
O O
R3 NO
R1 R2
OLi
O
R3Cl+
Stereoselectivity induced by the Evans oxazolidinone
RR''
OM
*
R'
"F "+ RR''
O
*R' F
NO
R1 R2
O
R''
OM
R'
"F "+ R''
O
R' FNO
R1 R2
O
18
Substrate-Controlled Stereoselective Electrophilic Fluorination
Entry R1 R2
1 Absolute stereochemistry not determined
R3 Yield (%)
1
2
3
4
Ph Me 97 88
H
Ph
H
i-Pr
Me
i-Pr
n-C4H9
n-C4H9
t-Bu
t-Bu
de (%)
96 85
96 86
97 80
6 Ph Me Ph 86 86
5 Ph Me Bn 89 84
Davis, F. A., Han, W. Tetrahedron Lett. 1992, 33, 1153.
NO
R1 R2
O O
R3
NO
R1 R2
O O
R3
F
SO2
N
O2S
F
1)LDA, THF
2)
19
NO
Ph Me
O O
F
NO
Ph Me
O O
Ph
F
97 % de
94 % de
hydrolysis
hydrolysis
O
F
HO
O
Ph
F
HO
LiOH LiOOH
87 % ee89 % Yield
90 % ee86 % Yield
69 % ee82 % Yield
78 % ee80 % Yield
NO
Ph Me
O O
R3
F
HOPh
F
No RacemizationLiBH4
Substrate-Controlled Stereoselective Electrophilic Fluorination: Removal of the Chiral
Auxiliary
Davis, F. A., Han, W. Tetrahedron Lett. 1992, 33, 1153.
20
Derivatization to Chiral -Fluoro Carbonyl Compounds
NO
Ph Me
O O
R
F
R'
O
R
FMeN
O
R
F
MeONHMe.HClAlMe3
MeOR'MgBr
1 32
Entry R Yield (%) ee (%)
1
2
3
4
Ph 77 77 >97
Me
CH2=CH-
80
95
>97
>97
>97
Yield (%)
85 96
76 >97
80 >97
5 Complexe mixture
1 2 3
de (%)
>97
>97
>97
ee (%)
Me
R`
Ph
CH2=CH-
Ph
Ph
Davis, F. A., Kasu, P. V. N. Tetrahedron Lett. 1998, 39, 6135.
Ph 77 >97>97
Ph 77 >97>97
21
Application of the Substrate-Controlled Asymmetric Fluorination for the Synthesis of a Fluoro-sugar
Davis, F. A. et al. J. Org. Chem. 1997, 62, 7546.
BnO OH BnO Cl
O1. Jones [O] 92%
2. SOCl21 2
HN O
Me Ph
O
BnO N
O
O
Me Ph
O
3
1. NaHMDS2. NFSI (inverse addition)
PhO2SN
PhO2SF = NFSI
BnO N
O
O
Me Ph
O
4 (97:3 dr)
F
LiBH4BnO OH
5 (>97% ee)
F
n-BuLi
74%
78% 93%
22
Application of the Substrate-Controlled Asymmetric Fluorination for the Synthesis of a Fluoro-sugar
Davis, F. A. et al. J. Org. Chem. 1997, 62, 7546.
BnO O
6
F
Dess-Martin 95%
H
(EtO)2P CH2CO2Et
O
71%
BnO
F
CO2EtBnO OH
5 (>97% ee)
F
7
BnO
F
CO2Et
8
AD-mix-
85%
DMP, cat. PTSA
OH
OH
BnO
F
9
CO2Et
OO
HO
F
10
CO2Et
OO
H2/Pd/C
97%
1. DIBAL-H2. H3O+
3. Ac2O, Py 79% 3 steps
O OAc
OAc
OAc
F
11(1:1 mixture of anomers)
NaH
87%
23
Substrate-Controlled Asymmetric Fluorination
•Reliable method with de’s up to 97%
•Two extra steps are necessary (installation and removal of the auxiliary)
•Ideally, the chiral carbon-fluorine bond would be formed enantioselectively in one step
24
Agent-Controlled Enantioselective Electrophilic Fluorination
SO O
N FRR''
OM
R'
+ RR''
O
R' FR
R''
OM
*
R'
"F "+ RR''
O
R' F
Lang, R. W., Differding, E. Tetrahedron Lett. 1988, 29, 6087.
25
Synthesis of the First Enantioselective Electrophilic Fluorination Reagent
Oppolzer, W. et al. Tetrahedron 1986, 42, 4035.Lang, R. W., Differding, E. Tetrahedron Lett. 1988, 29, 6087.
SOO
O OHS
OOO Cl
PCl5
SOO
O NH2
NH3
S NOO
NaOMe(cat.)
SO O
LiAlH4NH
10 % F2 in N2 NaF
SO O
NF76 % 75 %
94 % 74 % 99 %
26
The First Enantioselective Electrophilic Fluorination
Lang, R. W., Differding, E. Tetrahedron Lett. 1988, 29, 6087.
Entry Substrate Product1
1 Absolute stereochemistry not determined
OFCO2Et
O
CO2Et
O
CO2Et
O
CO2EtF
FCO2Et
CO2Et
O O
F
Base Solvent Temp. (oC) Yield (%)
1
2
3
4
NaH Et2O 0 – r.t. 70 63
LiH
LDA
LDA
Et2O
THF
THF
0 – r.t.
r.t.
-78 – r.t.
-78 – r.t.
ee (%)
<10 31
35 27
35 <5
RR''
O
R'
+ R
O
SOO
N
1.0 equiv. 1.2 to 1.5 equiv.
Base, Solvent , Temp.
R'R''F
F
27
Problematic Secondary Reaction
RR''
O
R'
+ R
O
S OO
NR'
F
H
M
R''+
SO O
N
+ MF
S OO
N
F
Me
Low yields (< 34 %)Low ee (< 10 %)
Lang, R. W., Differding, E. Tetrahedron Lett. 1988, 29, 6087.
28
N-Fluoro-Camphorsultams
O
Me
O
MeF
S OO
NF
Cl
Cl
1. NaHMDS, -78oC, THF
2.
76% ee, 53% yield
•Further investigations by Davis and co-workers did not lead to significant advances with these sultams.
•Best Result:
•Poor yields and poor to mediocre selectivity
•Derivatization of the fluorinating reagent to increase selectivity is limited
•Synthesis of the fluorinating reagent is not practical and potentially dangerous (F2 gas)
Davis, F. A. et al. J. Org. Chem. 1998, 63, 2273
29
Towards the Discovery of New Enantioselective Electrophilic Fluorination Reagents
Requirements:
•Abundant source of chirality
•Possess a site where an electrophilic fluorine can be appended such as nitrogen…
Amino Acid derivatives
30
Amino Acid Inspired Electrophilic Fluorination Agents
Me
Ph
NHR
4 R = Ts5 R = Ms
NaH, FClO3Me
Ph
NR
6 R = Ts (52%)7 R = Ms (13%)
F
Takeuchi, Y. et al. Chem. Pharm Bull. 1997, 45, 1085.
CO2Et
Ph
NHNaH, FClO3 or F2/H2, KF
XCO2Et
Ph
NF
TsTs
1
1) LiAlH42)Ac2O, Py
Ph
NHOAc NaH, FClO3
Ts
Ph
NOAc
Ts
F
27%
2 3
31
Amino Acid Inspired Electrophilic Fluorination Agents
Takeuchi, Y. et al. Chem. Pharm Bull. 1997, 45, 1085.
Entry Substrate Fluorinating agent Product1 Yield (%)
2
5
7
10
ee (%)
1
3
4
6
9
8
R1
O
R3
R2
H
1. Base, THF, -40 to 0oC, 30 min.
2. Fluorinating agent, -40 to 0oC, 3hR1
O
R3
R2
F*
O
Bn
O
CO2Et
Ph
O
Me
CO2Et
O
BnF
O
CO2EtF
Ph
O
Me
CO2EtF
Base
6
3
7
7
3
6
7
6
6
3
LDA
NaH
NaH
NaH
LDA
KHMDS
LDA
NaH
NaH
NaH
54
6
30
9
48
6
14
18
8
26
23
6
6
53
8
20
21
4
6 21
1 Absolute stereochemistry not determined
32
Amino Acid Inspired Electrophilic Fluorination Agents
Me
Ph
NTs
F
O
Bn
O
BnFBase
54% ee, 26% yield (LDA)48% ee, 53% yield (KHMDS)
Takeuchi, Y. et al. Chem. Pharm Bull. 1997, 45, 1085.
•Low yields are probably due to the low reactivity of the fluorinating reagent or its instability to the reaction conditions.
•Low ee values indicate the asymmetric environment surrounding the fluorine atom is inadequate, cyclic N-fluoro-sulfonamides (sultams) would be more rigid and possibly better at inducing enantioselectivity.
•Best results:
SN
Me
OO
F
(R)-4
33
Synthesis of a Chiral N-Fluoro-Sultam Fluorinating Reagent
SNH
O
OO
Saccharine
MeLiS
N
Me
OO MgBrS
NH
Me
OO
OCl
OS
N
Me
OOO O
Resolution (73% combined)
+
73% 70%
SN
Me
OOO O
SN
Me
OO
FS
N
Me
OO
F
1. LiOH/H2O2. 15% F2/He, KF
1. LiOH/H2O2. 15% F2/He, KF
(R)-4
1 2
(3R)-3 (3S)-3
(S)-4
47% 2 steps 62% 2 steps
Takeuchi, Y. et al. J. Org. Chem. 1999, 64, 5708.
34
Cyclic N-Fluoro-Sulfonamide Fluorinating Reagent: Results
Entry Substrate Fluorinating agent
Product IsolatedYield (%)
21
5
7
10
ee (%)
1
3
4
6
9
8
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
(S)-4
(R)-4
(R)-4
14
54
20
74
72
88
48
43
54
65
54
73
67
70
79
62
48
63
18 39
Takeuchi, Y. et al. J. Org. Chem. 1999, 64, 5708.
O
R
R
O
OR
O
R
R
O
OR
F
F
F
R
Me
Me
Et
Bn
Me
Et
Bn
Me
Et
Bn
Configuration
S
S
S
ND
S
S
S
R
ND
S
1 Reaction carried out in presence of HMPA
O
R
( )n
1. LDA, THF, -78 to 0oC, 1h
2. (R or S)-4, -40oC overnight
O
R
( )n
F
35
Proposed Transition State
NS
F
O
MeMe
O
O
Li
O
Me 1. LDA
2. (R)-4
OMe
F
Takeuchi, Y. et al. J. Org. Chem. 1999, 64, 5708.
36
Chiral N-Fluoro-Sultam Fluorinating Reagents
O
Bn
O
Bn
F
SN
Me
OO
F
(R)-4
2.
1. LDA, THF, -78oC then -40oC
88% ee, 79% yield
•Best result:
•Yields and selectivity are better but there is still room for improvement.
•Possibility of generating both enantiomers of the N-Fluoro-Sultam which lead to different enantiomers of the product.
•N-Fluoro-Sultam is not commercially available and must be prepared using F2 gas which is not ideal.
Takeuchi, Y. et al. J. Org. Chem. 1999, 64, 5708.
37
Using Transfer Fluorination to Obtain Asymmetric Electrophilic Fluorine Sources
NN
F
Cl
2BF4N + N
N Cl
BF4N +
quinuclidine SelectfluorTM
MeCN, r.t., 10 min, quant.
FBF4
Transfer Fluorination:
1. Banks, R. E. et al. J. Fluorine chem. 1995, 73, 255.2. a) Shibata, N. et al. J. Am. Chem. Soc. 2000, 122, 10728, b) Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.
N
N
OMe
OHH
NN
F
Cl
2BF4
SelectfluorTM
+ NN Cl
BF4+
N
N
OMe
OHH
F
BF4
quinine (Q) NF-Q.BF4
38
19F NMR of Transfer Fluorination
Selectfluor
Selectfluor/DHQB (1:0.5)
Selectfluor/DHQB (1:1)
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.
39
X-Ray Crystallographic Structure of NF-Q.BF4
N
H
H
HOH
N
MeO
F
BF4
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.
40
First Hit Using Transfer Fluorination to Fluorinate a Cyclic Silyl Enol Ether
QuinineSelectfluor
MeCN, 3Å M.S. r.t. 1h
Quinine /SelectfluorCombination
OSiMe3
Bn
MeCN, r.t. 2h
O
Bn
F
(R)-40% ee, 80% yield
Entry Solvent Yield (%)
1
2
4
6
MeCN 40 80
MeCN/THF (1:1)
MeCN/H2O (4:1)
DMF/THF (1:1)
ee (%)
35 76
29 49
32 61
5 DMF 30 53
3 MeCN/toluene (1:1) 37 65
Solvent scan:
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.
41
Cinchona Alkaloid Optimization
Alkaloid/Selectfluor Combination
MeCN, 0oC, 3Å M.S., 3 - 6h
OSiMe3
Bn
O
Bn
F*
Entry Alkaloid Yield (%)
2
4
6
9
35 84
ee (%)
81 83
70 100
82 100
S
Configuration
R
R
R
1 44 63R
3 54 67R
5 72 61R
7 23 94S
8 42 88R
10 70 100R
11 70 98R
quinidine
DHQB
DHQ-4-methyl-2-quinolyl ether
(DHQ)2PHAL
quinine
DHQ
DHQ-9-phenantryl ether
cinchonine
cinchonidine
(DHQ)2PYR
(DHQ)2AQN
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.
94.22 $ / mmol (Aldrich)
32.70 $ / mmol (Aldrich)
42
Modification of the Cinchona Alkaloid Hydroxyl Substituent
Entry Alkaloid -R Yield (%)
2
4
6
91 61
ee (%)
86 67
86 100
1 90 82
3 87 80
5 87 61
DHQ-4-nitrobenzoate
DHQ-acetate
DHQ-anthraquinone-2-carboxylate
DHQ-benzoate
DHQ-4-methoxybenzoate
DHQ-1-naphthalenecarboxylate
7 31 43DHQ-trifluoroacetate
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.
N
NEt
OMe
ORH
OSiMe3
Bn
O
Bn
FAlkaloid/Selectfluor Combination
MeCN, -20oC, 3Å M.S., 18h
DHQ-R
1a (R)-2a
43
Substrates : Indanones and Tetralones
DHQB/Selectfluor Combination
MeCN, -20oC, 3Å M.S., 18h
OSiMe3
R
O
R
F
( )n
N
NEt
OMe
OH
DHQB
O
Cl
( )n
1 2
Entry 1 Yield (%)
2
41
6
53 93
ee (%)
91 86
67 71
R
Configuration
R
R
1 89 99R
3 73 100R
5 40 94R
1b
1a
1e
1a
1c
1d
7 71 95S1f
n
1
1
2
1
1
2
2
R
Me
Bn
Et
Bn
Et
Me
Bn
2
2b
2a
2e
2a
2c
2d
2f
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.
1 Reaction was carried out at -40oC for 2 days
44
Application of Transfer Fluorination to the Fluorination of Esters and -Keto Esters
O
O
CO2Et *
DHQDA/Selectfluor Combination (2.0 :1.5)
MeCN/CH2Cl2 (3:4) -80oC, 3Å M.S., 6h
80% ee, 92% yield
O
O
CO2EtF
TolCO2Et
CNPh
CO2Et
CNF
87% ee, 80% yield
DHQDA/Selectfluor Combination (2.0 :1.5)
MeCN/CH2Cl2 (3:4) -80oC, 3Å M.S., 6h
N
MeO
N
HHAcO
Et
DHQDA
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.
45
NH
O
(DHQ)2PYR/Selectfluor Combination (1.5 : 1.5)
MeCN, 0oC, 3Å M.S. 2 days
82% ee, 79% yield
MeO
NH
O
MeO
F*
N N
Ph
Ph
OO
NN
MeO OMe
N
H
N
H
Et Et
HH
(DHQ)2PYR
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.
Application of Transfer Fluorination to the Fluorination of Oxindoles
46
Application of Cinchona Alkaloid N-Fluoroammonium Salts Towards the Synthesis
of MaxiPost
OO
OO
N N
MeO OMe
N
H
N
H
Et
NHF3C
O
Cl
MeO
NHF3C
O
Cl
MeO
(DHQ)2AQN/Selectfluor (1.2 : 1)MeCN/CH2Cl2 (3:4), -80oC, 18h
NN
F
Cl
2BF4
(DHQ)2AQN
SelectfluorTM
F
BMS-204352(MaxiPost)
94% yield, 84% ee
Et
MaxiPost is a maxi-K channel opener in phase III clinical trials for the treatment of acute ischemic stroke
Hewawasam, P. et al. Bioorg. Med. Chem. Lett. 2002, 12, 1023.Shibata, N. et al. J. Org. Chem. 2003, 68, 2494.
47
Cinchona Alkaloid Directed Electrophilic Fluorination
•Best Result:
DHQB/Selectfluor Combination
MeCN, -20oC, 3Å MS, 18h
OSiMe3
Bn
O
R
F
N
NEt
OMe
OH
DHQB
O
Cl
1a 2a
91% ee, 86% yield
•Good yields and enantioselectivities with a broader substrate scope.
•Chiral fluorinating reagent easily prepared in situ.
•Different substrate types require different alkaloids
•Stoichiometric amount of chiral fluorinating reagent necessary. A catalytic amount would be ideal…
48
The First Catalytic Enantioselective Electrophilic Fluorination
NN
F
Cl
2BF4+
SelectfluorTM
TiCl4 (5 mol %) MeCN, r.t., 1h, quant.
Ph O
O O
Et
Me
Ph O
O O
Et
Me F
NN
F
Cl
2BF4+
SelectfluorTM
(1.2 equiv.)
cat. (5 mol %) MeCN, r.t., 15 min.
Ph O
O O
Me
Cl
Ti
ClMeCN NCMe
O O
OO
R
R
R
R
R = 1-Naphthyl
cat =
Ph O
O O
Me F*
90% ee, 80%-95% yield
Togni, A., Hintermann, L. Angew. Chem. Int. Ed. 2000, 39, 4359.
49
Lewis Acid Catalyzed Enantioselective Electrophilic Fluorination of -Keto Esters
Entry Substrate n Product Yield (%)
2
5
ee (%)
1
3
4
6
7
1
1
1
1
2
2
99
93
99
99
95
99
83
71
84
76
66
88
86
75
R
Ad
t-Bu
t-Bu
L-Men
Ad
t-Bu
t (h)
2
2
3
2
3
2
18
Shibata, N., Toru, T. et al. Angew. Chem. Int. Ed. 2005, 44, 4204.
O
CO2R( )n
O
( )n
CO2R
Et
O
Me
CO2CHPh2
O
OR
O
OO
N NO
PhPh
dbfox-Ph
PhO2SN
F
SO2Ph
NFSI
NFSI (1.2 equiv.), dbfox-Ph (0.11 equiv.)Ni(ClO4)2.6H2O (0.1 equiv.), 4 Å M.S, CH2Cl2, R.T.
O
OR
O
F*
O
CO2R( )n
F
O
( )n
CO2RF
Et
O
Me
CO2CHPh2
F
50
Lewis Acid Catalyzed Enantioselective Electrophilic Fluorination of Oxindoles
Entry Substrate Product Yield (%)
2
ee (%)
1
3
96
93
83
72
73
75
R
Ph
Me
t (h)
5
35
18
Shibata, N., Toru, T. et al. Angew. Chem. Int. Ed. 2005, 44, 4204.
NO
Boc
R
NO
Boc
RF
F3C NO
Cl
MeO
BocF3C N
O
Cl
MeO
F
Boc
OO
N NO
PhPh
dbfox-Ph
PhO2SN
F
SO2Ph
NFSI
NFSI (1.2 equiv.), dbfox-Ph (0.11 equiv.)Ni(ClO4)2.6H2O (0.1 equiv.), 4 Å M.S, CH2Cl2, R.T.
NO
R'
R
NO
R'
R
Boc Boc
F*
51
Optimized Subtrate-Catalyst Complex
O
O
N
N
O
Ni
O
O
O
HO H
Shibata, N., Toru, T. et al. Angew. Chem. Int. Ed. 2005, 44, 4204.
52
Positive Nonlinear Effect
OO
Ot-Bu
OO
Ot-Bu
XNFSI (1.2 equiv.) or CF3SO2Cl (1.2 equiv.)
dbfox-Ph (0.11 equiv.) Ni(ClO4)2.6H2O
4Å M.S., CH2Cl2
X = F or Cl
Shibata, N., Toru, T. et al. Angew. Chem. Int. Ed. 2005, 44, 4204.
Product ee %
53
Enantioselective Fluorination of Malonates
Entry Lewis acid Yield (%)ee (%)t (h)
1 89 9748
2 7 6248
Ni(ClO4)2.6H2O
Mg(ClO)2
3 98 9015Zn(OAc)2
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
4 96 7124Zn(OAc)2 toluene
5 68 5262Zn(OAc)2 Et2O
6 86 4962Zn(OAc)2 EtOH
Shibata, N., Toru, T. Angew. Chem. Int. Ed. 2008, 47, 164.
NFSI (1.2 equiv.), dbfox-Ph (0.11 equiv.)Lewis acid (0.1 equiv.), 4 Å M.S, solvent, reflux
MeO2C CO2t-Bu
H CH2Ph
MeO2C CO2t-Bu
F CH2Ph
racemic
OO
N NO
PhPh
dbfox-Ph
PhO2SN
F
SO2Ph
NFSI
54
Substrate Scope and Functional Group Compatibility
Entry 1 Yield (%)
2
4
6
96 94
ee (%)
99 93
98 85
24
t (h)
36
15
1 98 9015
3 99 9024
5 99 9524
1b
1d
1f
1a
1c
1e
7 90 81241g
R
Et
Bu
OPh
CH2Ph
Me
Ph
SPh
8 93 91181h NPht
9 97 93241i NPht(4-Br)
Shibata, N., Toru, T. Angew. Chem. Int. Ed. 2008, 47, 164.
NFSI (1.2 equiv.), dbfox-Ph (0.11 equiv.)Zn(OAc)2 (0.1 equiv.), 4 Å M.S, CH2Cl2, reflux
MeO2C CO2t-Bu
H R
MeO2C CO2t-Bu
F R
1a-iracemic
2a-i
55
Synthesis of Fluoro-Alacepril
Shibata, N., Toru, T. Angew. Chem. Int. Ed. 2008, 47, 164.
MeO2C CO2t-Bu
MeFLiAl(Ot-Bu)3H (5.0 equiv.)
THF, -78oC to R.T.
85%CO2t-Bu
MeFHO
1. TsCl (1.2 equiv.), pyridine CHCl3, 0oC to R.T.2. TFA(5.0 equiv.), CH2Cl2 0oC to R.T.
73% (2 steps)
CO2H
MeFTsO
EDCl (1.2 equiv.), HOBt (1.2 equiv.)DIPEA (2.0 equiv.), CH2Cl2, 0oC to R.T.
67%
HN
t-BuO2C
(1.05 equiv.)
MeFTsO
O
N
t-BuO2C
2c 3
4 5
MeFAcS
O
N
O NH
HO2C
Me
AcS
O
N
O NH
HO2C
Alacepril Fluoro-Alacepril
Angiotensin-converting enzyme (ACE) inhibitor
used as an antihypertensivedrug
56
Synthesis of Fluoro-Alacepril
MeFTsO
O
N
t-BuO2C
1. NaH (3.0 equiv.) CH3COSH (3.0 equiv.) DMF, 0oC to 80oC2. TFA (5.0 equiv.), CH2Cl2 0oC to R.T.
73% (2 steps)
MeFAcS
O
N
CO2H
EDCl (1.3 equiv.), HOBt (1.3 equiv.) Et3N (2.5 equiv.), CH2Cl2, 0oC to R.T.2. TFA (5.0 equiv.), CH2Cl2, R.T.
60% (2 steps)
(1.0 equiv.)t-BuO2C
NH2
1.
MeFAcS
O
N
O NH
HO2C
5 6
Fluoro-Alacepril
Shibata, N., Toru, T. Angew. Chem. Int. Ed. 2008, 47, 164.
57
Conclusion
•Organofluorine compounds are important for a variety of reasons
•Fluorine bearing chiral centers are accessible using four different methods
•The substrate-controlled electrophilic fluorination method is reliable however it requires additional steps
•The agent-controlled electrophilic fluorination method allows us to install the fluorine atom and the chirality in one step
•Excellent enantiomeric excesses and high yields can be obtained with -keto esters and malonates using a catalytic amount of an asymmetric catalyst
58
Acknowledgements
• Professor Louis Barriault• Current Research Group:
• Patrick Ang• Steve Arns• Francis Barabé• Geneviève Bétournay• Marie-Christine Brochu• Anik Chartrand• Anna Chkrebtii• Christiane Grisé• Patrick Lévesque• Daniel Newbury• Jason Poulin• Maxime Riou• Catherine Séguin
• Past Group Members
ONTARIO GRADUATE SCHOLARSHIP PROGRAM (OGS)
