fluorous chemistry in sar development
TRANSCRIPT
Introduction to Fluorous ChemistrySeparation TechniquesReaction Strategies
Transformation Based Fluorous ApplicationsAcylation reactionsScavenging reactionsMitsunobu reactionsOther reactions
Array and Library Applications
Recent AdvancementsReverse fluorous SPEHeavy fluorous liquid-liquid extraction
Conclusions
Presentation Outline
What is Fluorous Chemistry?
Fluorous phase is a third Fluorous phase is a third phase orthogonal to organic phase orthogonal to organic and aqueous phases.and aqueous phases.
Fluorous molecules can be Fluorous molecules can be separated from other separated from other molecules based on molecules based on fluorophilicity.fluorophilicity.
Molecules can be rendered Molecules can be rendered fluorous by the attachment fluorous by the attachment of fluorous domains.of fluorous domains.
organic
fluorous
organic
fluorous
aqueous
Fluorous Versions of Organic Molecules
C6F13
Ph2P
ON
PhOSi
C8F17
ON
PhOSi(CH)3
NH
Ph
CO2H
O
O NH
Ph
CO2H
O
OF17C8
(C6F13CH2CH2)3SnH
Fluorous compounds with permanent fluorinated domains:
Fluorous compounds with temporary fluorinated domains (tags):
PPh3
Bu3SnH
Fluorous domains generally have little or no effect on reactivity, but provide a handle for facile separation
Fluorous Separation Methods
organic
fluorous
aqueous
Liquid-Liquid Extraction“Heavy” fluorous technique
Generally requires large F content, ~60%
Fluorous Solid Phase Extraction (F-SPE)“Light” fluorous technique
Separates fluorous from non-fluorous
No fluorous solvents used
Fluorous Chromatography (F-HPLC)Separates fluorous from fluorous
More fluorous = Greater retention
Fluorous Solid Phase Extraction
T
fluorous silica gel
FFF
O OO
T
F FF
O
O
O
T
F
F
fluorophobic solvent
F
fluorophilic solvent
Silica
O
Si(Me)2
Rf
Organic wash Fluorous wash
Curran, D. P. Synlett. 2001, 9, 1488.
A Light Fluorous Technique
1. Load sample 2. Wash non-fluorous dye with MeOH-H2O (85:15)
3. Wash fluorous dyewith MeOH
O
O
NH
F
C7F15O
O
NH
NH
C4H9
C4H9
Fluorous Dye(orange)
Non-fluorous Dye(blue)
Fluorous SPE: Dye Demonstration
Solution Phase Fluorous Synthesis
Fluorous tagged molecules can be analyzed by TLC, IR, MS, Fluorous tagged molecules can be analyzed by TLC, IR, MS, NMR and readily separated by FNMR and readily separated by F--SPE or FSPE or F--HPLCHPLC
F Substratereagent
F Product + By-product
Curran, D. P. Angew. Chem. Int. Ed. Eng. 1998, 37, 1175.
Tagged SubstratesTagged Substrates
Fluorous Reagents/ScavengersFluorous Reagents/Scavengers
Substrate ProductF Reagent
+ F By-product
Two Fundamental Approaches
Fluorous/ResinFluorous/Resin--PPhPPh33ComparisonComparison
C6F13
PPh2
H2OH2N
CO2H
60oCTHF, rt, 1 h
(93% yield, >98% purity)
FluoroFlashTM
SPE100% conversion
N3
CO2H
PPh2 H2OH2N
CO2H
THF, rt36 hours
rt-60oC
Filter/Wash
Concentrate 26-60% conversion (>86% purity)
36 hours
3 h
Craig Lindsley, Merck (Tetrahedron Lett. 2002, 43, 4467)
BocHN OH
O
N3
N3
H
H H
N
N N
NNH2
OO
O N3
O
N3
N
HNO
OOH
Me
OON3
HOOH
OH
OH
O
N3Cl
BocHN OH
O
NH2
NH2
H
H H
O
H2N
N
HNO
OOH
Me
OONH2
HOOH
OH
OH
N
N N
NNH2
OO
O NH2
O
NH2Cl
entry RN3 RNH2 yield (%) purity (%)
1
2
3
4
5
6
86
91
88
92
82
80
98/95
98/95
98/95
98/95
95/92
97/93
Common Transformations in SAR Development
Acylation of amine core21%
Acylation of acid core17%
Mitsunobu reaction12%
Nucleophilic substitution8%
Urea formation8%
Sulfonylation7%
O-alkylation3%
Suzuki coupling3%
Sonagashira2%
S-alkylation2%
Reductive amination17%
Data courtesy of Dr. Steve Djuric, Abbott Laboratories
N Cl
F19C9
N
N
N
Cl
F13C6(CH2)3O O(CH2)3C6F13
OH
SF17C8F17C8 N C N+
-
fluorous Mukaiyama's salt fluorous CDMT FluoMar fluorous DCCPF6
•Facilitate acylation reactions• Facile purification by F-SPE• Design Flexibility
• Solution Phase or Hybrid Solid/Solution Phase
Fluorous Acylation ReactionsCoupling Reagents
Acylation of amine core21%
Acylation of acid core17%
Fluorous Acylation Reactions
OH
OR
NHCbzN
N
N
Rf6(CH2)3O
O
O(CH2)3Rf6
O
R
CbzHN
NH2
R'
CO2Me
CbzHN
R
O
NH
R'
O
OMe
NMM
f-CDMT
Entry Amide/Peptide Yield(%) Lit. yield(%)1 Cbz-Ala-Ala-OMe 98 942 Cbz-Pro-Ser-OMe 96 893 Cbz-Phe-Met-OMe 91 734 Cbz-Ala-Ala-Ala-OMe 93 75
Markowicz, M.W.; Dembinski, R. Synthesis, 2004, 80.
• No racemization observed• f-CDMT suitable for use with α,α-disubstituted acids• FSPE purification possible
Fluorous Acylation Reactions
NBOC
CO2H
S Rf8
OH NBOC
O
O
S Rf8
N
O
O
S Rf8
O
R'
N
O
O
R'NHR''
DIC, DMAP
1) deprotection
2) acylation
R''NH2
71% ~75%
21-100%
50 oC, 5h, THF
Chen, C.H.T. and Zhang, W. Org. Lett. 2003, 5, 1015.
• All intermediates and final products purified by FSPE
• FluoMar used as a tag as well as an activating group
• FluoMar can be recovered and reused
Fluorous Acylation Reactions
Sn O Sn
ClRf6
Rf6Cl
Rf6
Rf6
Sn O
Rf6
Rf6
Otera Curran
2 2
Entry Ester or Acid Alcohol Product Yield(%)
1 Ph(CH2)2CO2Et PhCH=CH2OH 100
2 PhCH=CH2CO2Et PhCH=CH2OH 99
3 Ph(CH2)2CO2H BnOH Ph(CH2)2CO2Bn 99
4 Ph(CH2)2CO2H borneol 63
5 CH2=CH(CH2)8CO2H BnOH CH2=CH(CH2)8CO2Bn 93
R'COOR(H) + R''OH
tin oxide(2-10mol%)
R'COOR''+ ROHmonophasic or biphasic
OPh
O
Ph
OPh
O
Ph
OPh
O
Fluorous Scavenging
F Scavenger
F Scavenged
+ +F-SPE
Clean product(excess) (excess)
A Strategic Alternative to Resin bound Scavengers
or F-LLE
Both reaction and scavenging carried out in homogenous solution phase
Favorable solution phase kineticsComplete reaction monitoring, i.e. TLC, GC, LC, NMRAdaptable to SPE, HPLC or liquid extraction workup
Complete control of reagent stoichiometry
Electrophilic Fluorous Scavengers
Acylation of acid core17%
Reductive amination17%
Nucleophilic substitution8%
Urea formation8%
Sulfonylation7%
O-alkylation3%
Electrophilic Fluorous Scavengers
NNH
PhO
N
O O NN
O
NH
Ph
CH2Cl2+
1.5 -3.0 equiv
25 oCX X
0 20 40 60 80 100 1200
20
40
60
80
100
Y A
xis
Title
X Axis Title
F1.5eq PS1.5eq PS3.0eq Org1.5eq
• Solution phase kinetics• Less equivalents used• Decreased loss of desired product• Greater generality
Electrophilic Fluorous Scavengers
NCX NH
X
NRR'F17C8 NCOR-NH-R'
1.5 equiv.
f-isatoic anhydride or
1.0 equiv.
X = O or S X = O or S
Entry X Amine Scavenger Product Yield (purity)
1 O f-IA 100% (>95%)
2 O f-isocyanate 100% (95%)
3 S f-IA 100% (95%)
4 S f-isocyanate 34% (95%)
NH NH
N
OPh
NH
NH2
NH
NH
O
NH
Ph
NH
NH2
NH
NH
S
NH
Ph
NN NH
NN N
S
NH
Ph
Zhang, W. et al, Tetrahedron Lett. 2003, 44, 2065.
Electrophilic Fluorous Scavengers
ONMe2
OPh ClNMe2+
1) THF
2) Rf8CH2CH2SO2Cl (1.0 equiv)
3) FSPE88%, >98% purity1.3 equiv. 1.0 equiv
_Na
O
F
OHSPh
FSHPh+
1) PS-DIEA (1.5 equiv)
2) fluorous epoxide (1.0 equiv)
3) FSPE90%, >96% purity
1.0 equiv 1.3 equiv
NH2
ClSO2ClPh
NH
SO2
Ph+
1) PS-DIEA (1.5 equiv)
2) Rf8CH2CH2SOCl2 (1.0 equiv)
3) FSPE80%, >95% purity1.3 equiv. 1.0 equiv.
Lindsley, C.W. et al, Tetrahedron Lett. 2002, 43, 4225
Nucleophilic Fluorous Scavengers
Reductive amination17%
Urea formation8%
Acylation of amine core21%
Sulfonylation7% O-alkylation
3%
S-alkylation2%
Nucleophilic Fluorous Scavengers
NH2NH
Ph
3) FSPE 84%, >98% purity1.0 equiv.
1) PhCHO (1.5 equiv) PS-CNBH3
2) Rf8CH2CH2NH2 (1.0 equiv)
PhNH2
tBuO
OBr tBuO
ONH
Ph+
1) PS-DIEA (1.5 equiv)
2) Rf8CH2CH2SH (1.0 equiv)
3) FSPE94%, >98% purity1.0 equiv.1.3 equiv.
NH2PhNCO NH
NHBn
O
1) (1.0 equiv)
2) Rf8CH2CH2NH2 (1.0 equiv)
3) FSPE93%, >98% purity1.3 equiv.
Lindsley, C.W. et al, Tetrahedron Lett. 2002, 43, 4225
Fluorous Mitsunobu Reactions
RCO2H
CH2CH2C8F17Ph2P
O NN O
O
OC6F13
C6F13
RCO2R'+ R'OH
16 examples in high yield, high purity
F-SPE easily removes fluorinated byproductsHydrazide + Phosphine Oxide in a single purification
Liquid-liquid extraction possible
Fluorous Phosphines & f-DEAD Reagent
Dandapani, S.; Curran, D. P. Tetrahedron, 2002, 58, 3855.
Mitsunobu reaction12%
Fluorous Mitsunobu Reactions
Entry Reactants Conditions% Yield
(% purity)
TPP, DIAD 951
ff--TPP, fTPP, f--DIADDIAD 92(99)
TPP, DIAD 942
ff--TPP, fTPP, f--DIADDIAD 94(96)
TPP, DIAD 753
ff--TPP, fTPP, f--DIADDIAD 60(97)
TPP, DIAD 744
ff--TPP, fTPP, f--DIADDIAD 55(97)OHMeO
n-H13C6 OH+
SO2NHtBOCMe n-H13C6 OH+
(CH2)3CO2HO2N OHtBu+
OH FOH
+
O N N OO
OF13C6
C6F13
f-DIAD
Dandapani, S.; Curran, D. P. Org. Lett, 2004, submitted.
Fluorous Catalysts and Scavengers
N
N
N
S
SH SH
C8F17
F17C8 NH
NHMe
S
F17C8 NN
N
CO2H
CO2H
CO2H
CO2H
Rf8
PPh2
f-TMTf-thiourea f-TAA
2
PdCl2
• Bis(f-TPP)PdCl2 suitable for various Pd catalyzed reactions• Other fluorous phosphines and ligands available• Full evaluation of scavengers underway for removal of residual Pd• Initial result with thiol resulted in 85% reduction of residual Pd
Suzuki Coupling3%
Sonagashira Coupling2%
Other Fluorous Reagents
Rf8
I(OAc)2
Rf8
NH
Ph
hypervalent iodine oxidations
Co(f-salen)
(Rf6CH2CH2)3SnH
epoxidations
Radical mediated reductions and cyclizations
Buchwald-type aminations
Rf8
OiPr
Olefin metathesis ligand
CO2H
NH2
CO2H
NH
F-BOCR1 R1
Fluorous Parallel Synthesis
CO2H
NH2
CO2H
NHBOC
BOCR1 R1
CO2H
NH2
CO2H
NHBOC
BOCR2 R2
CO2H
NH2
CO2H
NHBOC
BOCR3 R3
Non-fluorous
CO2H
NH2
CO2H
NH
R2 R2
CO2H
NH2
CO2H
NH
R3 R3
Fluorous
F-BOC
F-BOC
F-BOC
F-BOC
F-BOC
Non-fluorous: multiple chromatographic species, since separation controlled by variable domain.
Fluorous: single chromatographic species using single method on fluorous sorbent, since separation controlled by non-variable fluorous domain
Greater Productivity by Minimizing Method Development Time
Fluorous Tags
ORf8 O
ON
CN
Ph
Rf8Si
H
Rf8
O OSu
O
O
OH
Rf8
O
Rf6
Rf6 OSu
O
f-BOC-ON
f-silane
f-Cbz-OSu
f-PMB
f-Fmoc
Fluorous tags behave similar to traditional protecting groups, but provide a handle for facile purification.
Fluorous Tagged Approach
OOH
O
N
OH
NC
N
N ONH
f-BOCHNO
PhOC
NH2NH
f-BOC
N ONH
N
O N
85% 90%+
+
+
1.5 eq
1.1 eq
1.1 eq
1.0 eq
1) MW100oC, 10 min
2) F-SPE
1) TFA-THFMW,100oC,10min
2) F-SPE
•• Reaction times only 10 min for each stepReaction times only 10 min for each step•• FF--SPE replaces double scavengingSPE replaces double scavenging
Zhang, W.; Tempest, P. Tetrahedron Lett. 45 (2004) 6757–6760.
Fluorous Parallel SynthesisFluorous Parallel SynthesisLadlow, M., Warrington, B. H., Villard, A.-L. J. Comb. Chem. 2004, 6(4), 611-622.
27-memberSulfonamide Array
18-memberCarboxamide Array
Fluorous DMB
All analogs >95% purity with no HPLC
Fluorous Parallel Synthesis
R1 CO2
NH2
C8F17
R1
CO2 N
XNH
R3
R2
CHO
R1
CO2 NH
N
N X
R1
R3
O
R2
R2
R2
NaBH(OAc)3
F
R3NCXEt3N
F
95%
CH2Cl2
F-SPEX = O, S
F-SPE
Zhang, W.; Lu, Y. Org. Lett. 2003, 5, 2555
Synthesis of Hydantoin Library
• 120 compound library produced. No HPLC purification• Avg. yield = 30 mg (90% of compounds in >50% overall yield)• 88% of compounds had >90% LC purity (MS detection)
FSPE Practical Considerations• Rf8 derivatives are recommended for parallel synthesis.
• Most organic solvents can be used without issue. If solvationis a problem, the addition of BTF can help.
• Always try and design reactions to contain either one organic or one fluorous species.
•Generally run using a SPE vacuum manifold available from numerous vendors
• Fluorous TLC and HPLC can be valuable analytical tools for SPE evaluation.
FSPE Practical Considerations
• Maximum loading capacity of 20%, although 10-15% is recommended.
• Cartridge should be pre-treated with 80:20 MeOH:H2O and sample loaded using a minimum of solvent.
• First wash 80:20 MeOH:H2O and second wash 100% MeOH.
• Cartridge can be reused multiple times after washing with THF.
Reverse Fluorous Solid Phase ExtractionA Light Fluorous Technique
Matsugi, M. and Curran, D. P. Org Lett. 2004, 6, 2717.
Standard FSPEfluorous stationary phasefluorophobic mobile phase
non-fluorous compounds washed
Reverse FSPEstandard stationary phase
fluorous mobile phasefluorous compounds washed
Fluorous L-L Extraction
ON
O
O
F17C8
ON
O
O
(F13C6CH2CH2)3Si
ON
O
O
(H17C8)3Si
light fluorous IA heavy fluorous IA alkyl IA
• Curran reported in 1999 that tris-silane based scavengers did not have sufficiently high partition coefficients to be useful.
• Numerous liquid-liquid supports and catalysts reported using 6 or more fluorous chains.
• Very little reported in solvent tuning as a method to influencepartition coefficients.
Heavy Fluorous Scavenging
NNH Ph
ON
O
O
R NRR'NH
O
R+ HNRR'
1) DMF, Δ
2) 5% H2O
3) extraction solvent4) separate and analyze
NNHO
O
Entry Amine Scavenger % in extraction solvent
% in 5% H2O in DMF
1 light ND >99.7
2 heavy 99 1
3 alkyl 88 12
4 heavy 98 2
5 alkyl 84 16
6 heavy 98 2
7 alkyl 38 62NH
NH2
CO2H
L-L Extraction of Organic Controls
S
N
NH
SO O
NH2
S
N
NH
SO O
NH
BrO
F
NH
NH
O
OMe
N
O
NPhMeO
O
MeO
OPh
Cl
SO2NHC8H17
NO2
1.36 1.71
2.61 5.15 3.72
3.13
• 10 organic controls partitioned between 1:1 FC-72:HFE-7100 / 5% H2O in DMF.
• cLog P ranging from 1.36 – 5.65. All partitioned >99% in organic solvent
• No solubility problems at 50 mg in 1 mL.
Other Emerging Fluorous Applications
Fluorous Biphasic CatalysisFluorous Biphasic Catalysis
Fluorous Triphasic SeparationsFluorous Triphasic Separations
Isotope Labeled SynthesesIsotope Labeled Syntheses
Oligomer SynthesisOligomer SynthesisOligosaccharidesOligosaccharidesOligonucleotidesOligonucleotidesPeptidesPeptides
Proteomics ApplicationsProteomics Applications
Chemical Reaction Compatibility
• IonicEnolate, Grignard, lithiate, cationic
• Free RadicalCyclization, dehalogenation, deoxygenation
• Lewis AcidicFriedel-Crafts acylation, BBr3
• Transition metal catalyzedSuzuki, Heck, Buchwald, Stille, Co, Rh
• Reduction/oxidationLAH, hydrogenation, H2O2, Swern
Technology Synergies
• Fluorous Supplements Existing Technologies- Automated chromatography- Resin supported chemistry- Multi-component reaction platforms
• Compatible with Emerging Technologies- Microwave Assisted Synthesis- scCO2 chromatography
• No Additional Capital Equipment Necessary
“Chemistry Solution to Chemistry Problems”
How to Contact FTI
www.fluorous.comPhone: 412-826-3050
Fax: 412-826-3053