Chemfiles Vol. 8, Supplement Ii - Fluoroflash Products For Synthesis & Separation

Supplement II, 2008

FluoroFlash Products for Synthesis & Separation ®

F luoroFlash Tags for Solution Phase Synthesis FluoroFlash Scavengers and Reagents Sigma-Aldrich® and Fluorous Technologies, Inc. are partnering to bring you easier, faster, and more robust purifications.

FluoroFlash SPE Cartridges for Fluorous Separations

Simplify Purification with FluoroFlash® Products! In partnership with Fluorous Technologies, Inc., Sigma-Aldrich® is pleased to offer a wide range of fluorous products that allow for faster, more robust purifications. By combining fluorous tags with fluorous solid phase extraction (F-SPE), researchers can quickly and efficiently purify complex chemical mixtures. In this brochure you will find a representative listing of applications and FluoroFlash® products available through Sigma-Aldrich at research scale to support this important new separation technology.

Non-fluorous

General Concept: Fluorous chemistry is a novel tagging and separation technology based on the use of perfluoroalkyl (fluorous) domains. Fluorous-tagged molecules can be readily separated from non-fluorous molecules exploiting fluorophilicity.

Fluorous tagging

Fluorous separation

Fluorous

Features and Benefits of Fluorous Chemistry:

Key Applications:

• Complete solution phase chemistry – highly adaptable • Orthogonal mechanism of separation – very selective • Based on fluorinated materials – chemically inert • Applicable to numerous molecular classes – broad utility • Compatible with standard lab equipment – easily integrated

• Medicinal Chemistry • Parallel Synthesis • Combinatorial Chemistry • Catalysis • Peptide & Carbohydrate Synthesis • Microwave-assisted Organic Synthesis

Useful References: Besides the information in this brochure, you can learn much more about fluorous techniques at the Sigma-Aldrich website portal: sigma-aldrich.com/fluorous. There you will find application notes, ChemFiles, a Cheminar™ on fluorous chemistry, Aldrichimica Acta articles and many other useful references.

Technical Support: Fluorous Technologies, Inc. may be contacted by phone (412-826-3050) or email ([email protected]) to answer any questions you may have about fluorous products and applications.

sigma-aldrich.com/fluorous

Order: sigma-aldrich.com/order

Technical service: sigma-aldrich.com/techinfo

FluoroFlash® Tags for Solution Phase Synthesis FluoroFlash® tags are perfluoroalkyl modified versions of traditional protecting groups familiar to synthetic chemists. These tags have reactivity profiles very similar to the traditional protecting group, but have the added benefit of providing a phase tag for purification. FluoroFlash tags are a solution phase alternative to solid phase synthesis strategies. The fluorous-tagged materials are easily separated from non-tagged components by F-SPE.

Benefits of FluoroFlash Tags:

Fluorous BOC protection used in combinatorial synthesis

• Solution phase kinetics • Broad reaction compatibility • Reaction monitoring by TLC, GC, LC, NMR, etc. • Readily scalable

F17 Boc-ON (55118)

CO2H HN

CO2H N

THF:H2O 90%

DIPEA

HN

NHR' N F-Boc

O

R" X NHR'

2) F-SPE

EDCI, HOBt 2) F-SPE

F-Boc

O

1) TFA

O

1) H2N R'

R"

NHR' 96-member library

N

Application example of a fluorous PMB protecting group used in the multistep synthesis of natural product Radicicol A

OH O

C8F17

1) NaH, Cl3CCN

1) Grubbs II cat.

F-PMB

O

2)

F-PMB

O

O

O

1)TBAF

O O

O

F-PMB

F-SPE

O

Br

F-SPE

1) t-BuLi TBDPSO

Br2, NaOMe

O B

O B O

F17 PMB-OH (97071)

2)

F-PMB

O

OH

TBDPSO

O

7 steps

2) I2, PPh3

OEOM

I

O

F-SPE

O

F-PMB Radicicol A

OEOM O

3) EOMCl F-SPE

Dakas, P.-Y. et al, Angew. Chem. Intl. Ed. 2007, 46, 6899

Benzyl OH

Boc C8F17

O

N

Ph

Boc

OH

C8F17 C8F17

CN

O

N

Benzyl OH

Ph

OH

C8F17

Sigma-Aldrich® offers a full line of FluoroFlash tags. Representative examples are shown in the tableCNbelow. FluoroFlash tags are also available in other Benzyl OH OH perfluorocarbon chain lengths. For a Boc complete listing of Navailable products, please visit sigma-aldrich.com/fluorous. Ph C8F17

Product No.

Name

55118

F17 Boc-ON

04537

14944

F17 Silane

O

O O

O

iPr SiH iPr SH

O

O

C6F13

N

C8F17 Trityl F17 C8OH

O

O SH O O F26

O O Fmoc-Cl O

O O

O

OH

C6F13 PMB-OH

O

C8F17 O F177,060,850. O C8and FluoroFlash reagents and sorbents are products of Fluorous Technologies, Inc. Use of these products may be protected by U.S. Patents 6,156,896; 5,859,247; 5,777,121 O PMB-OH FluoroFlash is a registered trademark of Fluorous Technologies, Inc. FluoMar is a trademark of Fluorous Technologies, Inc. C8F17

C6F13

Cl

OH

O

C8F17

FluoMarC8F17 C6F13 C8F17 Fmoc-Cl

C6F13 O

O

Ph OH

S

SH

N

O OHO Cl

Ph

O

C8F17

FluoMar Fmoc-Cl

O C6F13 O N

C8F17

Ph SH OH

OH

FluoMar

F17 FluoMar™

Cbz-OSu C F 672262 8 17

Ph

Trityl OH FluoMar

O O OH

O

C8FC17 8F17 Fmoc-Cl C6F13

OH

Ph CN

N

Fmoc-Cl PMB-OH Cbz-OSu

O

PMB-OH C8F17 PMB-OH

O

OH

C8F17

N Ph

iPr SiH iPr

C8F17 C8F17

Fmoc-Cl F17 C8FluoMar

O

C8F17

PMB-OH

40829

O

Benzyl OH OH Ph Ph Structure Trityl OH C8F17 OH Benzyl OH OH C8F17 C8F17

Ph F17 Ph Trityl-OH SH

Silane C F17 O Cbz-OSuC8F17 C88F17

N

O

Ph O

C8F17

OH

Ph

OH

Silane FluoMar OO

Ph

NOH Ph iPrName O SiH CN iPr Benzyl-OH F17

672475 CTrityl FluoMar 8F17 OH

O

C8F17 Cbz-OSu

F17 PMB-OH

Trityl OH

O

C8F17

F17 Cbz-OSu Cbz-OSu

97071

C8F17 Benzyl OH Trityl OH Boc Product No.C F C8F817 17 Silane 19563 C8CF817F17 Boc

CN iPr N Ph Structure Silane C8F17 SiH O C8F17 iPr CN O N Ph C8F17 O O iPr CN Silane SiH C8F17 iPr O iPr O Silane SiH N Cbz-OSu C8F17 iPrO O Boc

O

SH

C6F13

O O O

Cl

Fmoc-Cl C6F13

C6F13 O

Cl

OH

C6F13

O

Cl

O

O O

Cl

C6F13

FluoroFlash® Scavengers and Reagents FluoroFlash® scavengers and reagents are analogous to solid phase supported scavengers and reagents that are commonly used in solution phase synthesis strategies. FluoroFlash scavengers, reagents, and their byproducts can be readily removed by F-SPE.

Benefits of FluoroFlash Scavengers and Reagents:

Fluorous Mitsunobu reaction 1) F26 DIAD (68333)

• Solution phase kinetics • Precise stoichiometric control • Less molar equivalents required per reaction

OH Propylamine DAIB

Propylamine C8F17

NH2

F OH NH2 I(OAc) 2

Propylamine C8F17 Propylamine

DAIB

+ C8F17

C8F17

O

DAIB

2) F-SPE DAIB

NH2

C F Benzylamine 8 17I(OAc)2

F

F17 TPP (07026)

DAIB

NH2

Sigma-Aldrich offers a full line of Propylamine FluoroFlash scavengers and reagents. Representative examples are shown in the table below. I(OAc)2 DAIB C8F17 NH2 NH2 Propylamine Tin Hydride C8F17 Benzylamine Benzylamine For a complete listing of available products, pleaseCvisit sigma-aldrich.com/fluorous. F NH 8 17 2

C8F17

60% yield,

I(OAc)2

I(OAc) 2 97% purity I(OAc)2

C8F17 C8F17

SnH3 C4F9 3 C8F17 C8F17 Tin HydrideBenzylamine SnH I(OAc) 3 2 NH2 DAIB Tin Hydride SnH3 Propylamine C4F9 C4F9 C8F17 3 C8F17 C8F17 Name StructureNH2 ProductC No. Name Structure 3SnH3 NH2 Benzylamine Tin Hydride 8F17 C4F9 I(OAc)2 Tin Hydride DAIB Propylamine C8F17 3 Benzylamine NH2 06694 F17 Propylamine Tin Hydride SnH3 F27 Tin Hydride Triphenyl SnH PPh2 C8F17 NH2 C4F 9F C4F9 C SH Thiol 8 17 NH Phosphine 2 C8F17 3 C F SnH3 Tin Hydride 3 8 17 PPh2 C4F9 C8F17 Triphenyl PPh2 Benzylamine C F Triphenyl 3 8 17 SH Thiol Phosphine Thiol SH F17 Benzylamine Phosphine C8F17 07026 C8F17 Triphenylphosphine NH2 C8F17F17 PPh Tin Hydride 2 SnH Triphenyl 3 C8F17 C F Benzylamine SH ThiolIsatoic 4 9 Phosphine C8F17 3 CPPh 8F172 C8F17 Anhydride NH2 Triphenyl Tin Hydride DIAD C6F13 C6F13 SnH3 SH Thiol Phosphine PPh2 C4F9 Isatoic C8F17 Triphenyl N C8F17 C8F17 Isatoic 3 AnhydrideC8F17 F17 Thiol SH Thiol Phosphine O O DIAD C6FAnhydride CDIAD C8F17 13 6F13 68333 F26 DIAD C C F F 6 13 6 13 O O O C8F17 Isatoic O O N C8F17 PPh N2 C8F17 Triphenyl Anhydride O O DIAD C6F13 C6F13 O N O N SH Thiol Phosphine O Isatoic O O O O O ON O C8F17 F17 Isatoic Anhydride C8F17 O O C8F17 Anhydride N NC6F13 PPh2 DIAD C6F13 O Isatoic N O N Triphenyl O O O Anhydride N CSH O O Thiol 8F17 Phosphine DIAD C6F13 C6F13 C8F17 OC8O N N Ethyl F17 672378 F26 CDMT N C8F17 O O Isatoic O O Isocyanate O CDMT C6F13 O O O NCO Anhydride N N O C8FO O O Ethyl 17 C6F13 DIAD C6FEthyl O 13 N N CDMT Isocyanate C6F13 N N O F17 Ethyl Isocyanate N NCO C8F17 CDMT Isocyanate C6F13 O Isatoic NCO C8F17 O C O8F17 Ethyl Anhydride C6F13 O N Cl O N N O O DIAD CIsocyanate C F F CDMT 6 13 O 6 13 NO N O C6F13 NCO N C8F17 N C N8F17 Ethyl C6F13 O N Cl F C O I(OAc) N Cl 6 13 2CDMT F17 DAIB DAIB N N Isocyanate C6F13 OO O O NCO O O Ethyl O O C8F17 CDMT NH2 Isocyanate C6FN C6F13 O N Cl 13 N N N O NCO C8F17 C8F17 N N Ethyl C6F13 O N Cl CDMT Isocyanate C F O NCO C6F13 6 13 O N Cl C8F17 N N Ethyl CDMT Isocyanate C F O 6 13 NCO NH2 C6F13 O N Cl Tin Hydride SnH3 C8F17 C4F9 N N 3 Fluorous propylamine used as a scavenger C6F13 O N Cl NH2

Product No. 04636 07856

08686 07172

18486 16429 Propylamine C8F17

Benzylamine

Other Fluorous Technologies Products available through Sigma-Aldrich® C8F17

Thiol

SH

F • Fluorous Creagents for Proteomics and Metabolomics C F Applications Isatoic • Additional FluoroFlash tags for Protecting Group chemistry Anhydride DIAD C F C F • FluoroFlash products N Cfor F Fluorous Peptide & O O O O Synthesis O Carbohydrate O O N N • Expanded FluoroFlash Tin, Phosphine, Catalyst, and Ligand offerings Ethyl CDMT Mixture C • Fluoro Synthesis IsocyanateFlash Tags for Fluorous F O NCO C F N N • FluoroFlash Building Blocks to Design Your Custom C F O N Cl Fluorous Tags 8 17

NCO

1) benzylamine (1.0 equiv)

PPh2

Triphenyl Phosphine

2) F17 propylamine (1.0 equiv)

8 17

6 13

6 13

8 17

6 13

8 17

6 13

For more details, please visit sigma-aldrich.com/fluorous

1.3 equiv.

H N

NHBn O

(04636) 3) F-SPE

93% yield, >98% purity Lindsley, C.W. et al, Tetrahedron Lett. 2002, 43, 4225

FluoroFlash® SPE Cartridges for Fluorous Separations The separation of fluorous compounds from non-fluorous compounds using FluoroFlash® silica gel is the central theme of fluorous techniques. Fluorous solid phase extraction (F-SPE) is used for quick separations of reaction mixtures involving FluoroFlash tags, scavengers, and reagents. The separation of fluorous compounds by F-SPE is a reliable and generic procedure that resembles filtration more than chromatography. The facile separation depends primarily on the presence or absence of a light fluorous tag, not polarity or other molecular features that control traditional chromatography. A simple two-step separation involves the loading of a reaction mixture containing the fluorous-tagged molecule onto an F-SPE cartridge, washing the non-fluorous compounds away using a fluorophobic wash (typically 80:20 MeOH:water), then washing off the fluorous compounds with a fluorophilic wash, such as MeOH or THF. No fluorous solvents are necessary. The cartridge can be regenerated by washing with acetone or THF. Loading capacity for F-SPE cartridges is between 5-15% by weight of fluorous silica gel.

Fluorous Solid Phase Extraction Dye Demonstration A visual representation of the FluoroFlash solid phase extraction technique illustrates the easy separation of a fluorous-tagged product from the non-fluorous compounds through the use of colored dyes. • A mixture of a non-fluorous dye and a fluorous dye is loaded onto the F-SPE cartridge • Non-fluorous dye is washed off with a fluorophobic solvent wash, 80:20 MeOH:water. (middle test tube) • Fluorous dye is washed off with a fluorophilic solvent wash, MeOH. (right test tube) A detailed F-SPE Application Note can be found at the Sigma-Aldrich® website portal: sigma-aldrich.com/fluorous.

Benefits of FluoroFlash SPE separations: • High selectivity • Simple binary separation • Large loading capacity • No fluorous solvents needed • Cartridges recyclable up to 10 times • Automation compatible

Sigma-Aldrich offers FluoroFlash silica gel in pre-packed cartridges, in bulk, or as TLC plates. Product No.

Product

14196

FluoroFlash SPE cartridges, 2 g, 8 cc tube

Pack of 20

00866

FluoroFlash SPE cartridges, 5 g, 10 cc tube

Pack of 10

08967

FluoroFlash SPE cartridges, 10 g, 60 cc tube

Pack of 5

08966

FluoroFlash SPE cartridges, 20 g, 60 cc tube

Pack of 2

06961

FluoroFlash SPE cartridges, 20 g, 60 cc tube

Pack of 5

08965

FluoroFlash Silica Gel, 40 micron particle size

100 g

FluoroFlash TLC Plates with F254 indicator

Pack of 10

16888

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