Using New Tagging Strategies for Solution Phase Parallel Synthesis

ACS 224th Fall National Meeting Aug. 20, 02, Boston, MA

Fluorous Synthesis: Using New Tagging Strategies for Solution Phase Parallel Synthesis Wei Zhang, Christine H.-T. Chen, Dennis P. Curran Fluorous Technologies, Inc. www.fluorous.com

Combinatorial Chemistry for Drug Discovery High Throughput Screening

Identification of Biological Target

Genomics

Lead Discovery

Lead Optimization

Combinatorial Chemistry

Drug Candidate

Solid-Phase Organic Synthesis (SPOS) in Combinatorial Chemistry P + Substrate attachment

P

Substrate

reagents solid phase conditions

P

Product + excess reagents

filtration

P

Product

detachment P + Product removal of polymer by filtration

Solid Phase Vs Solution Phase Synthesis

.. .. .. .. .

Solid Phase

.. .. .. ..

Solution Phase

Advantages:

rapid purification by filtration split-pool mixture synthesis excess reagent can be used automation possible

literature reactions can be used intermediate analysis possible favorable reaction kinetics large scale possible

Disadvantages:

unfavorable reaction kinetics link/cleavage steps required re-inventing organic chemistry difficult to purify intermediates limitation on scale

mixture synthesis is difficult automation is more difficult repeated purification needed reaction completion is difficult

Fluorous Synthesis and Separation Fluorous synthesis uses tag-based separation strategy; a solution-phase alternative of solidphase synthesis that combines the advantages of solid- and solution-phase syntheses: Easy product separation „ Favorable reaction kinetics „ Less amount of reagents „ Intermediate analysis and purification „ Mixture synthesis possible „

C&EN Chemistry Highlights 2001

What are Fluorous Molecules? Fluorous molecules consist of an organic domain and a highly fluorinated domain. The organic domain controls reactivity and the fluorinated domain controls separation

Organic Fluorous

O F17C8

CN

N

O N Ph

F-Protecting Group (F-Boc-ON)

O

O

C8F17 O

F-Scavenger (F-Isatoic Anhydride)

Fluorous Separations LLE

SPE

HPLC

No fluorous solvent is needed!

organic aqueous fluorous

Separation of F-Molecules by FluoFlashTM Silica Gel A modified sorbent with a highly fluorinated domain F Si

F F

F F

F F F

O Si

F F

F F

F F

F F

F

Selective retention of fluorous molecules from nonfluorous molecules (F-SPE) „ Separation of a fluorous mixture based on fluorine content (F-HPLC) „

FluoroFlashTM Solid Phase Extraction (SPE) Separate Fluorous Compounds from Organics fluorophilic solvent

fluorophobic solvent O

F

O

F

O

F F

Silica

fluorous silica gel

O

F

F F

O

Si(Me) 2

O

Rf

F

O

T

T

T organic fraction

fluorous fraction

Curran, D. P. Synlett 2001, 1488

F

Fluorous Parallel Synthesis „

Use Fluorous Reagents/Scavengers F

Reagent

Substrate „

Product

Use Tagged Substrates F

Substrate

reaction

F

Product

Fluorous tagged molecules, can be analyzed by TLC, IR, MS, NMR and separated by F-SPE or HPLC Curran, D. P. Angew. Chem. Int. Ed. Eng. 1998, 37, 1175

Fluorous Mitsunobu Reactions Fluorous Phosphines & DEAD Reagents

P

RCO2H

+

CH2CH2C6F13

R'OH C6F13

RCO2R'

O O

3

N

O

N

C6F13

O

F-SPE easily removes fluorous by-products: hydrazine and phosphine oxide Dandapani, S.; Curran, D. P. Tetrahedron, 2002, 58, 3855 Dobbs, A. P.; McGregor-Johnson, C. Tetrahedron Lett. 2002, 43, 2807

Fluorous Scavengers Alternative to Solid-Phase Scavengers F Scavenger

+

F-SPE

+

(excess)

(excess) F

„ „

clean product

Scavenged

Fast scavenging in a homogeneous system Scavenged compounds removed by F-SPE

Electrophilic Scavenger Scavenging amines with isatoic anhydride

O

O

+ R1R2NH

MeO

H N

HO

O

MeO

42%

67%

OH NR1R2

O

O MeO

purity > 90%

N

H N

HO

O

MeO

O

F-SPE

(1.5 eq)

HO

C8F17

N

O

N N

N

O

MeO

62%

O

MeO

58%

Electrophilic Scavenger Scavenging amines with F-isocyanate NCX +

NCO

C8F17 R1R2NH

NR1R2 X

F-SPE

(1.5 eq)

X = O, S

H N

purity > 90% N

H N

H N X

X = O, 52% X = S, 98%

H N

H N X

X = O, 100% X = S, 80%

N

NH H N

N X

X = O, 100% X = S, 68%

H N

N O

X = O, 100% X = S, 96%

Nucleophilic Scavenger Scavenging halides with F-thiol R1 N H +

1) base

3

F-SPE

R

Br excess

R2

R1 N 2 R

2) C6F13CH2CH2SH

R3

purity > 85% F

O N

O OMe

N

N

95%

N

N

95%

N

90%

N

93%

F

O

O

N

F

N

OMe

N N

87%

N

F

N N

N

92%

Zhang, W.; Curran, D. P.; Chen, C. H-T. Tetrahedron, 2002, 58, 3871

Fluorous Thiol Tag H N

C8F17 Cl

Cl

flash column

Cl

S

CF3

N

N

N

S

C8F17CH2CH2SH

N

C8F17

SPE

N

major

CF3

[o]

N

N N

N N

N

N

N

CF3

91%

N

N N

CF3

79%

N

SPE

N

N

N N

CF3

purity > 90%

O N

R1XH

N

O N

R1X

N N

N S

N N

N N

CF3

82%

N

N N CF3

76%

N

F-SPE of Intermediate and Product interm ediate

after SPE

C 8 F 17

C DC l3

S N N

crude

N

N CF 3

product

CD C l3

after SPE

Ph

N N N

N N

crude

N CF 3

FluoMarTM Alternative of Marshall Resin O

O

Boc N

O

O

deprot.

OH S

+ C8F17

F

F-SPE

Boc

OH FluoMarTM

H N

O

N

H N

R1

H N

O

O Cl

Cl

100%

F-SPE

R2

N

O

O

100%

O

N

O

O

H N

O

N

O

90%

H N

O

N

O

N

amidation

H N

O

S

N-acylation

N

S

O

37%

R1

F

Fluorous Protecting Group: Boc-ON

O O

C8F17

F-Boc-ON

CN O N Ph

Amine R1R2NH EDCI, HOBt

F-SPE

+

CO2H HN

NaOH

FBoc N

CO2H

THF/H2O

F-SPE

O

1. TFA 3

O

R N

FBoc N NR1R2

2.

R3 X

NR1R2

FBoc-protected and deprotected amides purified by F-SPE Luo, Z.; Read, R. W.; Williams, J. W.; Curran, D. P. J. Org. Chem. 2001, 4261.

Products for Fluorous Synthesis FluoroFlash Reagent DEAD, phosphines, and scavengers

FluoroFlash Protecting Groups/Tags Boc, silanes, t-butyl, Cbz, PMB, thiols, and FluoMar

FluoroFlash Purification Tools fluorous silica gel, SPE cartridges; HPLC columns

For ordering information: www.fluorous.com

Acknowledgements Q

Q

University of Pittsburgh Q Prof. Dennis Curran and coworkers

Q

Prof. Peter Wipf Q Dr. Fu-Mei Lin Q

FTI Q Dr.

Phil Yeske, COO Q Dr. Robert Luo Q Dr. Tad Nagashima Q Mr. Kyle Derstine Q Ms. Christine Chen Q Mr. Jeff Irwin

University of Pittsburgh Center for Combinatorial Chemistry

Q

$$$ Support NIH SBIR Grants Q Innovation Works Q Albany Molecular Research, Inc. Q

Selected References General Reviews Gladysz, J. A.; Curran, D.P. Tetrahedron 2002, 58, 3823. Curran, D.P. In Stimulating Concepts in Chemistry; Wiley-VCH, 2000; p25. Curran, D.P. Angew. Chem. Int., Ed. Engl. 1998, 37, 1175. Fluorous Separations Curran, D.P. Synlett 2001, 1488. Fluorous Mixture Syntheses Zhang, W.; Luo, Z.; Chen, C.; Curran, D.P. J. Am. Chem. Soc. 2002, in press. Luo, Z. Y.; Zhang, Q. S.; Curran, D.P. et al Science 2001, 291, 1766. Curran, D.P.; Furukawa, T. Org. Lett., 2002, 4; 2233. Fluorous Scavengers Zhang, W.; Curran, D.P.; Chen, C. H.-T. Tetrahedron 2002, 58, 3871. Lindsley, C. W.; Zhao, Z.; Leister, W. Tetrahedron Lett. 2002, 43, 4225. Fluorous Reagents Dandapani, S.; Curran, D.P Tetrahedron 2002, 58, 3855. Crich, D.; Neelamkavil, S. Tetrahedron 2002, 58, 3865. Fluorous Protecting Groups Luo, Z.Y.; Williams, J.; Read, R.W.; Curran, D.P. J. Org. Chem. 2001, 4261.