Synthesis and Applications of Fluorinated ⍺-Amino Acids
Overview and Recent Advances
Sébastien CardinalMacMillan Group Meeting
Princeton University11/15/2017
reference
Introduction Interest of artificial amino acids Unique properties of the C-F bond Natural fluorinated amino acid
Applications of fluorinated α-amino acids Protein engineering Medicinal chemistry 19F-NMR 18F-PET
Incorporation of fluorinated α-amino acids
Synthesis of fluorinated α-amino acids Strategy I Strategy II Strategy III Strategy IV Strategy V Strategy VI
Outlines
reference
reference
Peptides and proteins occupy innumerous biological functions Metabolic Structural
Serve as inspiration in many research fields New therapeutic agents Biomaterials
Appealing features Low toxicity Structural simplicity Low immune response
Intrinsic limitations Enzymatic degradation (protease) Thermic stability Denaturation in organic solvents
The use of non-canonical amino acids may overcome some of those limitations D-α-amino acids β-amino acids Artificial amino acids
Artificial amino acids expand the functional diversity and open the way to tailored protein design
IntroductionInterest of Artificial α-Amino Acids
reference
referenceBuer, B. C.; Marsh, E. N. G. Protein Sci. 2012, 21, 453.Cametti, M.; Crousse, B.; Metrangolo, P.; Milani, R.; Resnati, G. Chem. Soc. Rev. 2012, 41, 31.
Minor steric impact F: smallest Van der Waals radius after H and Ne
Major electronic impact F: most electronegative element Inverted polarization vs C-H
Unique features of the C-F bond Often described as the strongest organic bond (BDE up to 544 KJ/mol) Most polar covalent bond Can influence polarization on adjacent bonds Low polarizability of C-F can give rise to “Fluorous effect”
Fluorous effect Auto-segregation of fluorine-rich organic species Intermolecular: fluorous phase Intermolecular: fluorophile domain on protein
C-H → C-F Bond Substitution
reference
Can those unique features be explored in peptide/protein engineering ?
Fluorinated α-amino acids (α-AAF)
referenceOdar, C.; Winkler, M.; Wiltschi, B. Biotechnol. J. 2015, 10, 427.
4-Fluoro-L-threonine (4F-Thr): only natural α-AAF known Produced by Streptomyces cattleya (Gram-positive) Antibiotic agent Not identified in any peptide or protein so far
Biosynthesis involves incorporation of fluoride by a fluorinase enzyme
Natural Fluorinated α-Amino Acid
reference
O
HO OH
NSN
N N
NH2
NH2HO
O O
HO OH
NN
N N
NH2F
O
HO OH
FOPO3
2—
OPO32—F
OH
OH
O
H
OF
O-
O
NH3+
FOH
OH
OF
L-Thr
NAD+NADH
4FT transaldolase
Fluorinase
F-acetyldehydedehydrogenase
CH3CHO
F- L-Met PO43- adenine
Isomerase
Aldolase
FDA phosphorylase
referenceOdar, C.; Winkler, M.; Wiltschi, B. Biotechnol. J. 2015, 10, 427.
Incorporation of Inorganic Fluoride by Fluorinase Enzyme
reference
referenceMerkel, L.; Schauer, M.; Antranikian, G.; Budisa, N. ChemBioChem 2010, 11, 1505. Berger, A. A.; Völler, J.-S.; Budisa, N.; Koksch, B. Acc. Chem. Res. 2017, 50, 2093.
Many properties can be influenced by the substitution of canonical α-amino acids by fluorinated analogues Protein folding Protein-protein interactions Ribosomal translation Lipophilicity Acidity/basicity character Optimal pH Stability: temperature, protease, organic solvents
Example: lipophilicity vs.VdW volume of side chains a-AAF can fill a desired space but with a different lipophilicity from α-AA
Often claimed to generally improve stability and properties in out-of-field literature
But, not that simple !
Application of α-AAFProtein Engineering: General Considerations
reference
« Fluorine has been shown to impart often favourable but seldom predictable properties to peptides and proteins »
-Beate Koksch (2017)-
(ProProGly)10(ProHypGly)10(ProFlpGly)10
NH
CO2H
F
Flp
NH
CO2H
Hyp
NH
CO2H
Pro
HO
referenceHolmgren, S. K.; Taylor, K. M.; Bretscher, L. E.; Raines, R. T. Nature 1998, 392, 666.
Classic example: stabilization of the folded triple helix structure of collagen at high temperature
Applications of α-AAFProtein Engineering
reference
referenceBerger, A. A.; Völler, J.-S.; Budisa, N.; Koksch, B. Acc. Chem. Res. 2017, 50, 2093.
Interest for peptides in medicinal chemistry Low toxicity Simple structure / synthesis Low immune response
Drawbacks of peptides in medicinal chemistry Biodisponibility Low membrane permeability Enzymatic cleavage
Impact of fluorine in medicinal chemistry 150 fluorinated small molecules reaching the market since 1950 In 2010, 20% of all administered drugs 30% by 2017
Applications of α-AAFMedicinal Chemistry of Peptides
reference
Can α-AAF help to overpass those limitations ?
Can this impact be translated to peptides ?
referenceKollonitsch, J.; et al. Nature 1978, 274, 906.Seki, M.; Suzuki, M.; Matsumoto, K. Biosci. Biotechnol. Biochem. 1993, 57, 1024.
Because of their resemblance with canonical a-amino acids, some α-AAF can act as inhibitors Known action on amino acid decarboxylase enzymes Inhibition of the production of biologically relevant amines, including:
α-(difluoromethyl)ornithine (DMDO) Commercial name: Eflornithine Treatment of hirsutism and African trypanosomiasis (sleeping sickness) Inhibitor or ornithine decarboxylase Acts on putrescine biosynthesis
Applications of α-AAFInhibitors
reference
DMDO
H2NO
OH
H2N CHF2
NH2HO
HODopamine
HNN
NH2 H2NNH2
Histamine Putrescine
19F-NMR spectra of a peptide bearing a Tyr(C4H9) at 500nM
referenceSalwiczek, M.; Mikhailiuk, P. K.; Afonin, S.; Komarov, I. V.; Ulrich, A. S.; Koksch, B. Amino Acids 2010, 39, 1589.Tressler, C. M.; Zondlo, N. J. Org. Lett. 2016, 18, 6240.
Widely used non-native NMR-active nucleus for interpretation of biological structure and functions
Many advantages No marking necessary No background in biological systems Sensible Can be used at biorelevant concentrations
Some α-AAF specifically designed as NMR probes
Applications of α-AAF19F-NMR Spectroscopy
NH2
CO2H
H
F3C
CF3-BpgUlrich
Tyr(C4H9)Zondlo
NH2
CO2H
H
O
F3C
F3CF3C
referenceKotzerke, J.; et al. Eur. J. Nucl. Med. Mol. Imag. 2003, 30, 1004.Nodwell, M. B.; Britton, R.; et al. J. Am. Chem. Soc. 2017, 139, 3595.
18F : t1/2 = 109.77 min
18F-PET mainly used in oncology
Main marker used: 18F-FDG (18F)-fluorodeoxyglucose Discrimination of cancer cells due to their higher metabolism
Consumption of α-amino acids also higher in cancer cells α-AAF explored as new markers Better resolution in some cases
α-AAF could also be used for more refine analysis Marking based on active transport events Transport protein LAT1 upregulated in cancer cells
Applications of α-AAF18F-Positron Emission Tomography (18F-PET)
reference
O
OH
O
NH218F
[18F]-F-TYR
referenceCarpentier, C.; Godbout, R.; Otis, F.; Voyer, N. Tetrahedron Lett. 2015, 56, 1244.Devillers, E.; Pytkowicz, J.; Chelain, E.; Brigaud, T. Amino Acids 2016, 48, 1457.
� A lot of α-AAF can be used in the context of SPSS
��Coupling in solution can overpass compatibility issues with problematic α-AAF
Incorporation of Fluorinated α-Amino Acids in Peptides and ProteinsSynthetic Incorporation with Solid-Phase Peptide Synthesis (SPSS)
reference
O
OFmocHN
Me
Me
O
ONH
Me
MeOHN
FO
FmocHN
Me
1) Piperidine/DMF 2) HATU, NMM, Fmoc-F-Ala-OH
3) Piperidine/DMF 4) HATU, NMM, Fmoc-F-Ala-OH
24% yield
O
O
Cl
Me
Me
NMM (2.2 equiv)(1.1 equiv)
H2NO
OHMeF3C
Poorly Nu- amineNot suitable for standard SPPS
+H3NO
Ot-BuMeF3C
Cl
1)
2)
(0.9 equiv)
NH
O
Ot-BuMeF3CO
FmocHNOH
OFmocHN
Me
Me
81% yield
Protected dipeptideSuitable for SPPS
(R)-α-Tfm-Ala-OH
Me
Me
referenceHackenberger, C. P. R.; Schwarzer, D. Angew. Chem., Int. Ed. 2008, 47, 10030.
Limitations of SPSS
Coupling of fragments in solution may be used for longer sequences
Incorporation of Fluorinated α-Amino Acids in Peptides and ProteinsSynthetic Incorporation Into Larger Peptide/Proteins
reference
Compatibility issues with some α-AAF
Specific protecting groups requiredNot suitable for more than 50-100 α-AA
Relies on native translational machinery of the cellIncorporates the modified α-AA at every position occupied by the parental α-AA
Needs strains of bacteria that are auxotrophic for the parental α-AAα-AAF has to be sufficiently similar to its natural analog
Particularly suitable for monoofluorated α-AAF
referenceOdar, C.; Winkler, M.; Wiltschi, B. Biotechnol. J. 2015, 10, 427.
Residue specific
Incorporation of Fluorinated α-Amino Acids Into Peptides and ProteinsIn Vivo Ribosomal Translation of Non-Canonical α-Amino Acids
reference
Suppressor tRNARecognizes stop codon (via anti-codon)
Incorporates artificial α-AA in the protein
Mutant aaRSBrings together artificial α-AA and suppressor tRNA
Nonsense suppression: associate one of the three stop codons with an artificial α-AADesign of an appropriately engineered pair: aminoacyl tRNA synthetase (aaRS) / Suppressor tRNA
Corresponding sequence needs to be implemented in the genetic code in order to express the desired protein
referenceOdar, C.; Winkler, M.; Wiltschi, B. Biotechnol. J. 2015, 10, 427.Biava, H.; Budisa, N. Engineering in Life Sciences 2014, 14, 340.
Site specific
Incorporation of Fluorinated α-Amino Acids Into Peptides and ProteinsIn Vivo Ribosomal Translation of Non-Canonical α-Amino Acids
reference
Rely on the same translational machineryNeed prior extraction and partial purification of cellular material
More tunable systems
referenceEaston, C. J.; et al. Chem.–Eur. J. 2013, 19, 6824.
Recently developed as in vitro alternatives to the in vivo approaches
Other enzymes can be added to promote other transformations
Incorporation of Fluorinated α-Amino Acids Into Peptides and ProteinsCell-Free Ribosomal Translation of Non-Canonical α-Amino Acids
reference
PhtHNO
OMeMe
MeF
H2NO
OHMe
MeF
O
H2NO
Me Me
Problematic isolation
H2NO
NHNH2
Me
MeF
Deprot.
S30 extractin vitro
H2NO
OHMe
MeF S30 extract
in vitro
Undesired lactone
Protein containg(S)-4-fluoroleucine
NH2NH2
RF
CO2H NH2
N*
CO* R
RF *FAmine or nitrogen function
Carbox. acid or oxygenated function
Fluorinated side chain
Non fluorinated side chain
Fluorinating agent
Amino acid Cα
R
CO* N*
CO*
N*
RF *F
Synthesis of α-AAF: Proposed Classification
Approach AInstallation of functionalities
(Strategies 1-5)
Approach BFluorination of side chain
(Strategy 6)
RF
CO2H NH2
N*
CO* R
RF *FAmine or nitrogen function
Carbox. acid or oxygenated function
Fluorinated side chain
Non fluorinated side chain
Fluorinating agent
Amino acid Cα
CO*
N*
RF
Synthesis of α-AAF: Proposed Classification
Approach AInstallation of functionalities
(Strategies 1-5)
RF
CO2H NH2
N*
CO* R
RF *FAmine or nitrogen function
Carbox. acid or oxygenated function
Fluorinated side chain
Non fluorinated side chain
Fluorinating agent
Amino acid Cα
RF
CO* N*
Strategy I
N* CO*
RF
N*
RFCO*
Strategy III
RF
CO*
N*
Strategy II
Strategy IV
Synthesis of α-AAF: Proposed Classification [Approach A]
CO2H NH2
RF
Strategy V
H
O
Me
F3C
1) KCN, NH4ClNH4OH
2) HCl (aq)NH2
Me
F3C
COOH
Me
O 1) NaCN NH4Cl
2) HClNH2
COOH
FMe
F
R1 R2
O
R1 R2
CNHO
R1 R2
CNH2NCN-
(NH4)2CO3CN-
HNNH
O
O
R1
R2 H3O+ or OH-
NH3 or NH4Cl
R1 R2
OHH2N
Strecker reaction
Bucherer-Bergs reaction
H3O+
referenceBergmann, E. D.; Shani, A. J. Chem. Soc. 1963, 3462.Muller, N. J. Fluorine Chem. 1987, 36, 163.
Installation of carboxylic acid and amine functionalities on a carbonyl precursor
Examples in the synthesis of α-AAF: Strecker reaction
Strategy IMethodologies from Classic α-Amino Acid Chemistry
reference
R1 R2
O
R1 R2
CNHO
R1 R2
CNH2NCN-
(NH4)2CO3CN-
HNNH
O
O
R1
R2 H3O+ or OH-
NH3 or NH4Cl
R1 R2
OHH2N
Strecker reaction
Bucherer-Bergs reaction
H3O+
referenceTolman, V. Amino Acids 1996, 11, 15.
Installation of carboxylic acid and amine functionalities on a carbonyl precursor
Examples in the synthesis of α-AAF: Bucherer-Bergs reaction
Strategy IMethodologies from Classic α-Amino Acid Chemistry
reference
F3CCHO
(NH4)2CO3NaCN
HNNH
O
O
F3C Ba(OH)2 COOH
NH2
F3C
F3CS
CHO
1) (NH4)2CO3, NaCN2) NaOH
3) HClF3C
S COOH
NH2
referenceTolman, V. Amino Acids 1996, 11, 15.Walborsky, H. M.; Baum, M. E. J. Org. Chem. 1956, 21, 538.
Direct amination with ammonia
Azide as nucleophilic aminating agent
Strategy IIClassic Amination Reactions
reference
Br2
O
CO2EtF3C 1) NH3
2) H3O+F3C
COOH
NH2
OH
FO
CO2Li NH3 (aq)
NaBD4
FCO2H
H2N D
F3CCOOEt
Br
NaN3 F3CCOOEt
N3
1) H2 / Pd
2) H3O+F3C
COOH
NH2
F3CCOOH
F3CCOOH
Br
NH3 (l)F3C
COOH
NH2
referenceUneyama, K.; Katagiri, T.; Amii, H. J. Synth. Org. Chem. Jpn 2002, 60, 1069.Abid, M.; Teixeira, L.; Torok, B. Org. Lett. 2008, 10, 933.
Imines can be reduced by organomettallic reagents
Chiral imines can influence stereoselectivity on following reaction at Cα
Strategy IIVia the Formation of an Imine
reference
F3C CO2t-Bu
NPMP MgCl
F3CCO2t-BuHN
PMP
1) CAN
2) HCl (aq)
98%(from α-ketoester) 95%
F3CCO2HH2N
F3C CO2Et
N
Me
Ph
NH N
H
1) TfOH, CH2Cl2
2) Pd(OH)2/C, H2F3C CO2Et
OPh Me
NH2
92%
CO2EtNH2
F3C
82%90% ee
referenceLarsson, U.; Carlson, R.; Leroy, J. Acta Chem. Scand. 1993, 47, 380.
Amination directed by Evans auxilairy
Strategy IIStereoselective Amination
reference
LiN O
O
Bn
Et3NPivCl
F3CF2CF2C
O
N O
O
Bn
Bu2BOTf,(iPr)2NEt
then NBSF3CF2CF2C
O
N O
O
Bn
TMGA
Br
F3CF2CF2C
O
N O
O
BnN3
F3CF2CF2C
O
OHNH2
1) LiOOH
2) H2, Pd/C
87 %
36%, 2 steps75%, 2 steps
92:8 dr
CF2CF2CF3
O
HO
3 other α-AAFprepared
77-97% yield> 98:2 dr
referenceChiu, H. P.; Cheng, R. P. Org. Lett. 2007, 9, 5517.Biava, H.; Budisa, N. J. Fluorine Chem. 2013, 156, 372.
Ezymatic transamination
Kinetic resolution
Strategy IIObtention of Single Stereoisomer with Biocatalysts
reference
R
RO
OEtO
O
OH
R
R
H2N
1) Na2CO3 (aq)
2) phenylalanine dehydrogenase, formate dehydrogenase
NADH, HCOONH4 (aq), pH 8.5
F3CMe O
OHHN
O
F3CMe
Br
COOH
1) NH3 (aq)
2) Ac2O, NaOH
48%, 2 steps
F3CO
OHNH2
Me
29%
Aspergilus mellus acylase I
pH 7.5
39%, 99% ee (R = CF3)46%, 98% ee (R = CF2H)
referenceBiava, H.; Budisa, N. Watanabe, H.; Hashizume, Y.; Uneyama, K. Tetrahedron Lett. 1992, 33, 4333. Amii, H.; Kishikawa, Y.; Kageyama, K.; Uneyama, K. J. Org. Chem. 2000, 65, 3404.
Installation of an ester on an imidoyl halide
Strategy IIIPalladium-Catalyzed Alkoxycarbonylation
reference
Pd2(dba)3 (20 mol%)CO (1 atm), ROH
K2CO3Toluene
Rf I
NPMP
Rf CO2R
NPMP
F3C CO2Bn
NPMP
F3C CO2Et
NPMP
C7F15 CO2Et
NPMP
95% 98% 43% 79%
CO2Et
NPMP
FF
F
F FF3C CO2iPr
NPMP
49%
referenceVukelić, S.; Ushakov, D. B.; Gilmore, K.; Koksch, B.; Seeberger, P. H. Eur. J. Org. Chem. 2015, 2015, 3036.
Formation and hydrolysis of an α-aminonitrile in a semi-continuous process
Strategy IIIPhotooxidative Cyanation
reference
RF NH2
TPP, O2TMSCN, TBAF
420 nm, MeTHF-50 oC
Flow (τres = 4 min)
RF NH2
HCl (30% aq)AcOH
110 oCFlow (τres = 37 min)
CN
NH3
RF
O
OH
Cl
NH3
O
OH
ClNH3
O
OH
Cl
F
NH3
O
OH
ClF
NH3
O
OH
F3C
50%, 2 steps67%, 2 steps64%, 2 steps CF3
CF3
NH2
O
OHF3C
60%, 2 steps 63%, 2 steps
Cl Cl
referenceLi, G. Y.; van der Donk, W. A. Org. Lett. 2007, 9, 41.
� Preparation of protected γ-difluorothreonine from ascorbic acid
Strategy IVDeoxofluoration Followed by Amination
reference
OO
OHHO
OHOH
HO
OCO2Me
OBn
69%
1) DIBAL
2) DAST CH2Cl2
OO
CHF2
OBn
1) H3O+
2) TBSCl3) Tf2O, py4) NaN3, DMF
TBSO CHF2
OBn
N3
1) H2, Pd(OH)22) FmocCl, NaHCO3
3) t-BuBr, Ag2O
4) HF, py5) Jones [O]
HO CHF2
OtBu
NHFmoc
O
ascorbic acid
3 steps47%
67%
68%46%
referenceRaasch, M. S. J. Org. Chem. 1958, 23, 1567.Tolman, V. Amino Acids 1996, 11, 15.
Erlenmeyer synthesis (azlactone) - First α-AAF synthesis (1932)
SN2 reaction with an alkyl halide
Strategy VExploiting Basicity of Cα on the Glycine Moiety
reference
CH3COCH3H2O
NH
O
CF3
HOH2N
O
CF3
OH
CF3
O
H NHCOCH3
COOH AC2O NaOAc
NO
H3C
O
CF3
84%
1) H2, Pd/C2) HCl
40%, 2 steps
Ac
81%
EtONaEtOH HF, H2O
H2N COOH
CO2Et
CO2Et
H
AcHN
AcHN CO2EtEtO2C
F Br
F F
63% 27%
referenceTeegardin, K. A.; Weaver, J. D. Chem. Commun. 2017, 53, 4771.
Oxazolone enolates can be used to perform nucleophilic aromatic substitution
Fully substituted α-amino esters also accessible
Strategy VUse of Oxazolone as α-Amino Acid Template
reference
ArF-F
α-AAF (%)
ON
O
Ph
HN
O
OHO
Ph
ArF
1) ArF-F (1 equiv)TMG (2 equiv)ACN, -20 oC
2) HCl (aq)
COCH3F
F
F
FF
N F
F
F
FF
CF3F
F
F
FF
CNF
F
F
FF
87 86 82 78
ON
O
Ph
1) DIEA (10 equiv)ACN
2) TFA, MeOHBzHN
RCO2Me
NF
F
F
F
N F
F
F
FF
(1 equiv)
80% (R = Me)74% (R = i-Bu)79% ( R = CH2CH2SMe)71% (R = Bn)
R
RF
CO2H NH2
N*
CO* R
RF *FAmine or nitrogen function
Carbox. acid or oxygenated function
Fluorinated side chain
Non fluorinated side chain
Fluorinating agent
Amino acid Cα
R
CO* N*
CO*
N*
RF *F
Synthesis of α-AAF: Proposed Classification
Approach AInstallation of functionalities
(Strategies 1-5)
Approach BFluorination of side chain
(Strategy 6)
RF
CO2H NH2
N*
CO* R
RF *FAmine or nitrogen function
Carbox. acid or oxygenated function
Fluorinated side chain
Non fluorinated side chain
Fluorinating agent
Amino acid Cα
R
CO* N*
*F
Synthesis of α-AAF: Proposed Classification
Approach BFluorination of side chain
(Strategy 6)
reference
Smith, R. W.; et al J. Fluorine Chem. 1987, 37, 267. Kollonitsch, J.; Marburg, S.; Perkins, L. M. J. Org. Chem. 1976, 41, 3107.
Kollonitsch, J.; Barash, L. J. Am. Chem. Soc. 1976, 98, 5591.Janzen, A. F.; Wang, P. M. C.; Lemire, A. E. J. Fluorine Chem. 1983, 22, 557.
Fluorination of canonical α-AA with F2
XeF2 and CF3OF also explored
Strategy VIPioneering Works
reference
COOH
HONH2
F2/N2COOH
HONH2
F
H2N COOH
SH
H2N COOH
F
H2N COOH
FF
80%NH2
CO2Me
SMe
NH2
CO2Me
SFH2C
CF3OF, hvH2N COOH H2N COOH
F
F2/N2
XeF2
referenceZhang, X. G.; Ni, W. J.; van der Donk, W. A. J. Org. Chem. 2005, 70, 6685.
Preparation of α-AAF from Garner’s aldehyde
Strategy VIDeoxofluorination on Side Chain
reference
ONBoc
H
O
ONBoc
O
H DIBAL
THFO
NBocOH
HONHFmoc
FCrO3/H2SO4
HONHFmoc
F
O
86% 69%
56%
DAST
1) HCl (4N)
2) FmocCl NaHCO3
Ph2P=CHCHO
Toluene
NSF3
MeMe
ONBoc
F
80%32%
referenceKieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem., Int. Ed. 2007, 46, 754. Gadais, C.; Saraiva-Rosa, N.; Chelain, E.; Pytkowicz, J.; Brigaud, T. Eur. J. Org. Chem. 2017, 2017, 246.
Trifluoromethylation of L-cysteine
Togni’s reagent has shown potential for late-stage functionnalisation on tripeptides
Strategy VIAddition of Trifluoromethyl Radical
reference
BocHN
Me
O
NH
O
S
HN CO2tBu
Me
Me
2
CF3SO2NatBuOOH (80%)
MeCN/MeOH
R1 O
ONH
SH
IO
Me Me
CF3
CH2Cl2, -78 oC
R2
82% (R1 = Me, R2 = Boc)99% (R1 = Et, R2 = H)84% (R1 = Me, R2 = Ac)42% (R1 = Bn, R2 = Boc)
R1 O
ONH
SCF3
R2
BocHN
Me
O
NH
O
S
HN CO2tBu
Me
Me
1) TCEPMeOH/H2O
2) Togni’s reagentCH2Cl2, -78 oC
21%
CF3
R1 O
ONH
S
R2
2
referenceLi, S.-G.; Portela-Cubillo, F.; Zard, S. Z. Org. Lett. 2016, 18, 1888.
Trifluoromethylation of protected vinyl glycine by a CF3 radical generated from a xanthate
Other type of fluorinated side chains accessed from different olefins
Strategy VIVia the Addition of a Xanthate
reference
NO
O
Cl3C
F3C
52%, 2 steps
N CO2Me
Boc
CO2Me
NHCbz
F3C
O
60%, 2 steps 53%, 2 steps
CO2Me CO2MeLauroyl peroxide
AcOEt, refluxNHCbz NHCbz
F3C
SCSOEt H3PO2, TEAAIBN
Dioxane, reflux
CO2Me
NHCbz
F3C
72% 76%
CF3
SF3C
S
OEt
referenceLi, S.-G.; Portela-Cubillo, F.; Zard, S. Z. Org. Lett. 2016, 18, 1888.
Xanthate acts as a CF3 ‘’resevoir’’
Strategy VIVia the Addition of a Xanthate
reference
SF3C
S
OEt
CF3S
F3CS
OEt
F3C
SF3C
S
OEt
CO2Me
CO2MeF3C SF3C
S
OEt
CO2MeF3CSCF3
+
S
EtO
F3C
CO2MeF3CSCSOEt
NHCbz
NHCbz
NHCbzNHCbz
+
referenceBey, P.; Vevert, J. P.; Van Dorsselaer, V.; Kolb, M. J. Org. Chem. 1979, 44, 2732.Seki, M.; Suzuki, M.; Matsumoto, K. Biosci. Biotechnol. Biochem. 1993, 57, 1024.
Trapping of a difluorocarbene by a carbanion generated at Cα
Strategy employed in the synthesis of eflornithine
Strategy VIDifluoromethylation with Difluorocarbene Source
reference
MeO2C N
CH3
Ph
1) LDA2) ClCHF2
3) H3O+MeO2C N
CH3
PhF2HC Deprotection
HO2C NH2
CH3F2HC
83% 91%, 2 steps
CN
CO2MeNC
CN
CO2MeNC
F2HC1) NaH, DMF
2) ClCHF2 NH2
CO2MeH2N
F2HCHCl (2N)
MeOH
HCl (6N)Propylene oxyde
NH2
CO2HH2NF2HC
Eflornithine
referenceKockinger, M.; Ciaglia, T.; Bersier, M.; Hanselmann, P.; Gutmann, B.; Kappe, C. O. Green Chem. 2017, accepted.
Use of fluoroform as a CHF2 source
Strategy VIDifluoromethylation with Difluorocarbene Source
reference
MeO2C N
R
Ph MeO2C N
R
PhF2HC
HO2C NH2
RF2HC
1) LiHMDS (2 equiv)THF
2) CHF3 (3 equiv)Flow
6N HCl
150 oC, mw
86%, 2 steps (R = Me)76%, 2 steps (R = iPr)87%, 2 steps (R = iBu)86%, 2 steps (R = CH2Ph)
NH2
CO2HH2N
F2HC
Eflornithine
76%, 2 steps
referenceBume, D. D.; Pitts, C. R.; Jokhai, R. T.; Lectka, T. Tetrahedron 2016, 72, 6031.Bloom, S.; McCann, M.; Lectka, T. Org. Lett. 2014, 16, 6338.
Visible-light sensitized benzlic C-H fluorinated with Selectfluor
Selective late-stage fluorination of benzylic position in peptides
Strategy VIBenzylic C-H Fluorination
reference
PhthNO
OH
O
5 mol%
Selectfluor (2 equiv)MeCN, Visible light
PhthNO
OH
F
80%
NPhth
MeO
NH
HN
PhF
O
O
OEt
Me
Me NPhth
O
NH
HN
O
O
OEt
Me
Me
MeMeF
NH
O
OMe
FO
NHTFAHOOC
78%1.8:1 dr
63%1.3:1 dr
34%1.8:1 dr
referenceZhang, Q.; Yin, X.-S.; Chen, K.; Zhang, S.-Q.; Shi, B.-F. J. Am. Chem. Soc. 2015, 137, 8219. Miao, J.; Yang, K.; Kurek, M.; Ge, H. Org. Lett. 2015, 17, 3738.
Pd-catalyzed fluorination using 2-(pyridin-2-yl)isopropyl (PIP) as protecting and directing group
Shi (JACS, 2015)
Ge (Org Lett, 2015)
Strategy VIBenzylic C-H Fluorination
reference
NH
O Me MeH
BrNPhth
Pd(OAc)2 (6 mol%)Selectfluor (1.05 equiv)
DCM/iPrCN, 80 oC
NH
O Me MeF
BrNPhth
73%
NH
O Me MeH
BrNPhth
Pd(OAc)2 (10 mol%)Selectfluor (2.5 equiv)
Fe(OAc)2 (0.3 equiv) Ag2CO3 (2 equiv)
DCE/iPrCN, 150 oC
NH
O Me MeF
BrNPhth
73%19:1 dr
referenceZhang, Q.; Yin, X.-S.; Chen, K.; Zhang, S.-Q.; Shi, B.-F. J. Am. Chem. Soc. 2015, 137, 8219. Miao, J.; Yang, K.; Kurek, M.; Ge, H. Org. Lett. 2015, 17, 3738.
Pd-catalyzed fluorination using 2-(pyridin-2-yl)isopropyl (PIP) as protecting and directing group
Shi (JACS, 2015)
Ge (Org Lett, 2015)
Strategy VIFluorination of Unactivated C-H Bonds
reference
NH
O Me MeH
NPhth
Pd(OAc)2 (10 mol%)Selectfluor (1.2 equiv)
2-Me-BAH (0.2 equiv)DCM/iPrCN, 80 oC
NH
O Me MeF
NPhth
46%99% ee
NH
O Me MeH
NPhth
Pd(OAc)2 (10 mol%)Selectfluor (2.5 equiv)
Fe(OAc)2 (0.3 equiv) Ag2CO3 (2 equiv)
DCE/iPrCN, 150 oC
NH
O Me MeF
NPhth
73%8:1 dr
Me Me
Me Me
referenceMiao, J.; Yang, K.; Kurek, M.; Ge, H. Org. Lett. 2015, 17, 3738.
Ge’s proposed mechanism invokes fluorination of a Pd(II) palladacyclic center
Strategy VIFluorination of Unactivated C-H bonds
reference
referenceZhu, R.-Y.; Tanaka, K.; Li, G.-C.; He, J.; Fu, H.-Y.; Li, S.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 7067.
Similar system driven by a Quinoline-based ligand
Strategy VIFluorination of Unactivated C-H Bonds
reference
NHAr
OH
NPhth
Pd(TFA)2 (10 mol%)Selectfluor (1.5 equiv)
L (10 mol%)
Ag2CO3 (2 equiv)Dioxane, air, 115 oC
Me NHAr
OF
NPhth
53% (Ar = (4-CF3)C6F4)> 20:1 dr
Me
N O Me
Me Me
Me
L
referenceXia, J.-B.; Zhu, C.; Chen, C. Chem. Commun. 2014, 50, 11701.Halperin, S. D.; Fan, H.; Chang, S.; Martin, R. E.; Britton, R. Angew. Chem., Int. Ed. 2014, 53, 4690.
Visible-light promoted fluorination with benzophenone
Decatungstate-catalyzed C-H fluorination of branched aliphatic with NFSI
Strategy VIFluorination of Unactivated C(sp3)-H Bonds
reference
OMe
O
NPhthMe
MeSelectfluor (1.5 equiv)
Acetophenone (20 mol%)
MeCN, 48 hOMe
O
NPhthMe
Me
85%1 example of α-AA
F
OMe
O
NH3ClMe
Me
OMe
O
NH3ClMe
Me(PHSO2)2NF (1.5 equiv)
TBADT (0.02 equiv)365 nm
MeCN/H2O 56%
F
referenceNodwell, M. B.; Britton, R.; et al. J. Am. Chem. Soc. 2017, 139, 3595.
Decatungstate-catalyzed C-H fluorination: suitable system for preparation of 18F-labeled α-AAF
Strategy VIFluorination of Unactivated C(sp3)-H Bonds
reference
Preparation/purification of marked NFSI: 10 min Reaction time: 40 min Purification time: 10 min Total process from 18F generation: 60 min Product isolated directly as formulation for IV injection
referenceNodwell, M. B.; Britton, R.; et al. J. Am. Chem. Soc. 2017, 139, 3595.
5-[18F]FHL showed a normal distribution profile in healthy mice after 60 minutes
In Vivo Biological Investigation 18F Marked α-AAF Prepared by Fluorination of Unactivated C-H Bonds
reference
referenceNodwell, M. B.; Britton, R.; et al. J. Am. Chem. Soc. 2017, 139, 3595.
5-[18F]FHL showed a normal distribution profile in healthy mice after 60 minutes
4-[18F]FL accumulation in bones reveals in vivo production of fluoride by lactonisation
In Vivo Biological Investigation 18F Marked α-AAF Prepared by Fluorination of Unactivated C-H Bonds
reference
O
O
NH3
O
O
NH3
18F
Me MeO
H3NO
Me Me
18F
Ca10(PO4)6(OH)18F
Ca10(PO4)6(OH)2
18F
MeMe
LAT1α-AA transport protein
Surexpressed in many cancer cell lines
60 min
referenceNodwell, M. B.; Britton, R.; et al. J. Am. Chem. Soc. 2017, 139, 3595.
LAT1 surexpression in tumor can be revealed by 5-[18F]FHL in PET imaging
In Vivo Biological Investigation 18F Marked α-AAF Prepared by Fluorination of Unactivated C-H Bonds
reference
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