fluorous chemistry in sar development

Fluorous Chemistry in SAR Development

Marvin S. YuDirector

Fluorous Technologies, Inc.

October 2004

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



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


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


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



Nucleophilic substitution8%

Urea formation8%

Sulfonylation7%

O-alkylation3%


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


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.


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+


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


Urea formation8%


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+


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


TPP, DIAD 753


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

Reverse Fluorous Solid Phase Extraction

Matsugi, M. and Curran, D. P. Org Lett. 2004, 6, 2717.

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

[email protected] [email protected]

http://www.fluorous.com/

fluorous chemistry in sar development

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