Chemfiles Vol. 7, No. 2 - Peptide Synthesis

2007 VOLUME 7 NUMBER 2

Peptide Synthesis COUPLING REAGENTS NEW UNNATURAL AMINO ACIDS NEW TOOLS FOR PEPTIDE PEGYLATION FLUOROUS PEPTIDE SYNTHESIS

Key intermediate stage during the -OAt-mediated coupling of two D-alanines

sigma-aldrich.com

2

Introduction

Vol. 7 No. 2

Introduction

Peptides play a crucial role in fundamental physiological and biochemical functions of life. For decades now, peptide research is a continuously growing field of science. Sigma-Aldrich is proud of being able to meet all your needs in chemical peptide synthesis offering more than 2,600 products related to this field. You can obtain all the necessary tools for solution- and solid-phase peptide synthesis conveniently from a single source. You can choose between 2,100 natural and unnatural amino acid building blocks to design your peptide, and select the coupling method for the most efficient synthesis. Finally, you will find all required reagents for functionalization, manipulation and analysis of your products. This ChemFiles highlights a comprehensive listing of coupling reagents available through Sigma-Aldrich and introduces new, unnatural amino acid building blocks, tools for PEGylation, and products for fluorous-phase peptide synthesis and separation. For more information, and access to our complete range of chemistry products, visit our Web site at sigma-aldrich.com/gochem. If you are unable to find a building block, reagent or any other product for your peptide synthesis projects, we welcome your request and will use it to broaden our product range even further. “Please Bother Us” with your suggestions at [email protected], or contact your local Sigma-Aldrich office (see back cover).

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s i g m a - a l d r i c h . c o m

About Our Cover The cover graphic shows the key intermediate stage during the -OAt-mediated coupling of two D-alanines (for improved clarity Hydrogen atoms have been omitted and both amino acids are represented as their unprotected derivatives). The generated D-Ala-D-Ala dipeptide is the main recognition sequence for the powerful antibiotic vancomycin. During the coupling reaction the nucleophilic amino group of one D-alanine attacks the -OAt-activated carbonyl group of another D-alanine. In the process, the pyridine nitrogen of the -OAt-moiety accelerates the aminolysis of the active ester through intramolecular base catalysis. This neighbouring group effect explains the high efficiency of HOAt derived peptide coupling reagents like HATU.

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3

Coupling Reagents

Diphenyl phosphoryl azide, technical, >90%

Amino Acid I

2

PG

PGN

N H

R

2

2

OH

PG

PGN

O Activation

N H

Amino Acid II O H2 N PGO O R1 1 PG

R2

X -HX O

Dipeptide peptide bond 2

PG

PGN

N H

R2

O

H N O

O R1

Coupling

PGO

PG1

Scheme: Simplified general mechanism of peptide bond formation.

All coupling methods have the same reaction principle in common: after activation of the carboxy group of the first amino acid, the second amino acid can form the peptide bond by a nucleophilic attack of its amino group. In order to prevent uncontrolled peptide bond formation the amino group of the first amino acid and all functional side chain groups need to be reversibly blocked. Repeated de-blocking, activation, and coupling build the peptide to its desired final sequence. A broad variety of coupling reagents available through Sigma-Aldrich will be presented and discussed. For further reading, detailed reviews are available.1,2 References: (1) Goodman, M. Methods of Org. Chem. (Houben-Weyl) add. and suppl. vol. to the 4th ed., Vol. E 22 a, 2002, pp. 425–888. (2) Han, S.-Y.; Kim, Y.-A. Tetrahedron 2002, 60, 2447.

O

O P N3 O

10 mL 50 mL

Acid Halogenation Reagents The generation of an acid chloride is an obvious way to activate the carboxy group for amide bond formation. However, practical application of acid chlorides in peptide synthesis is restricted, because they are prone to side reactions and racemization. In spite of this disadvantage, acid chlorides are frequently recommended to link extremely hindered or achiral amino acids. 1-Chloro-N,N,2trimethyl-1-propenylamine, developed by Ghosez, enables the conversion of carboxylic acids into the corresponding chlorides under strictly neutral conditions.1 This method was successfully applied by Fürstner in the total synthesis of Caloporoside and Roseophilin.2 The most notable advance in acid halogenation has been the introduction of fluoroamidinium salts by Carpino.3 Compared to the chlorides, the acid fluorides show greater stability towards water and a relative lack of conversion to the corresponding oxazolones upon treatment with organic bases. TFFH (FluoroN,N,N’,N’-tetramethylformamidinium hexafluorophosphate) and BTFFH (Fluoro-N,N,N’,N’-bis(tetramethylene)formamidinium hexafluorophosphate) are stable, non-hygroscopic salts. They act in situ as fluorinating reagents and are suitable both for solution syntheses and for SPPS (Solid-Phase Peptide Synthesis). References: (1) Haveaux, B.; Dekoker, A.; Rens, M.; Sidani, A. R.; Toye, J.; Ghosez, K. Org. Synth. 1980, 59, 26. (2) Fürstner, A.; Konetzki, I. J. Org. Chem. 1998, 63, 3072. (3) Carpino, L. A.; El-Faham, A. J. J. Am. Chem. Soc. 1995, 117, 5401.

1-Chloro-N,N,2-trimethyl-1-propenylamine, 96%

Azide Formation Azide coupling procedures were introduced by Curtius as one of the first successful strategies for the synthesis of peptides. For a long time they were thought to be the only racemisation free method. A very convenient way to form N-acylamino acid azides is to apply DPPA (diphenyl phosphoryl azide). This method is particularly useful in cyclization reactions of peptides.1,2 DPPA can also be used in the preparation of urethanes by reaction with alcohols. References: (1) Hoffmann, E.; Beck-Sickinger, A. G.; Jung, G. Liebigs Ann. Chem 1991, 585. (2) Yamada, T.; Omote, Y.; Nakamura, Y.; Miyazawa, T.; Kuwata, S. Chem. Lett. 1993, 1583.

Diphenyl phosphoryl azide, purum, >98.0% DPPA (C6H5O)2P(O)N3 FW: 275.2 [26386-88-9] 72935-10ML-F 72935-50ML-F

O

O P N3 O

N Cl

498270-5ML

5 mL

Chloro-N,N,N’,N’-bis(tetramethylene)formamidinium tetrafluoroborate, purum, >97.0% (AT) C9H16BClF4N2 FW: 274.49 [115007-14-2]

Cl N+

N

BF4-

23957-1G-F 23957-5G-F 23957-25G-F

C9H16N2Cl · PF6 FW: 332.65 [135540-11-3] 10 mL 50 mL

O

(CH3)2C=C(Cl)N(CH3)2 FW: 133.62 [26189-59-3]

1g 5g 25 g

PyClU, purum, >98.0% (CHN)

Diphenyl phosphoryl azide, 97% DPPA (C6H5O)2P(O)N3 FW: 275.2 [26386-88-9] 178756-5G 178756-25G 178756-100G

DPPA (C6H5O)2P(O)N3 FW: 275.2 [26386-88-9] 79627-10ML 79627-50ML

O P N3 O

Cl N+

N

PF6-

23955-1G-F 23955-5G-F 23955-25G-F

1g 5g 25 g

Chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate, purum, >98.0% (T) 5g 25 g 100 g

C5H12ClF6N2P FW: 280.58 [207915-99-9] 09658-5G 09658-25G

To discuss how our expertise can benefit your next scale-up project or to obtain a quote, contact your local Sigma-Aldrich office or visit www.safcglobal.com

Cl N

N+

PF6-

5g 25 g

Coupling Reagents

In principle, the seemingly simple formation of a peptide bond can be accomplished using all the procedures available in organic chemistry for the synthesis of carboxylic acid amides. However, due to the presence of various functional groups in natural and unnatural amino acids and particularly the requirement for full retention of chiral integrity, the coupling of amino acids and peptides under mild conditions can be challenging. A plethora of coupling reagents has been developed superseding each other in efficiency and suitability for specific applications (e.g., solid-phase peptide synthesis or fragment condensation).

4

Fluoro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate, puriss., >99.0% TFFH [FC[=N(CH3)2]N(CH3)2]PF6 FW: 264.12 [164298-23-1] 47440-1G-F 47440-5G-F

Fluoro-N,N,N’,N’-bis(tetramethylene)formamidinium hexafluorophosphate, >99.0% F +

N

N

PF6-

1g 5g

BTFFH C9H16F7N2P FW: 316.2 [164298-25-3] 17380-5G 17380-25G

F PF6-

N+

N

5g 25 g

Coupling Reagents

Fluoro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate, 97% TFFH [FC[=N(CH3)2]N(CH3)2]PF6 FW: 264.12 [164298-23-1] 520330-1G 520330-5G

F N

N+

PF6-

1g 5g

Phosgene

Cartridge for Phosgene Generation, 0.02 mole

Phosgene is an extremely versatile reagent allowing easy access to isocyanates, ureas, carbamates, carbonates, acyl and alkyl chlorides.1 Many of these can be used as reactive intermediates in peptide coupling reactions. As a dehydrating agent, phosgene can also lead to isocyanides, cyanides, and carbodiimides. Though highly toxic itself byproducts resulting from reactions with phosgene are harmless. When treated with alkaline solution, only biocompatible salts are formed like sodium chloride or carbonate.

COCl2 FW: 98.92 [75-44-5]

In cooperation with Buss ChemTech, Sigma-Aldrich offers a safe and reliable phosgene generation kit giving simple access to small quantities of high purity, gaseous phosgene exactly when needed, while no transport and storage of liquid phosgene is necessary. The generator converts safe triphosgene into phosgene on demand using a patented catalyst (licensed from “BUSS ChemTech AG” U.S. Patent 6,399,822 B1 and foreign equivalents apply).2 Phosgene generation can be stopped at any time. A total containment approach eliminates the risk that phosgene can reach the environment. References: (1) Babad, H.; Zeiler, A. G. Chem. Rev. 1973, 73, 75. (2) Eckert, H.; Forster, B. Angew. Chem. Int. Ed. 1987, 26, 894.

Cartridge for Phosgene Generation, Starter Kit

8

Contains one 0.02 mole cartridge (519758), hose connector with sealing lips, Viton tubing, dosimeter badge, and instructions for use. 519782-1KT

1 Kit

8

519758-1PAK 519758-5PAK

1 Pak 5 Pak 8

Cartridge for Phosgene Generation, 0.05 mole COCl2 FW: 98.92 [75-44-5] 519766-1PAK 519766-5PAK

1 Pak 5 Pak

Triphosgene, reagent grade, 98% Cl3COCOOCCl3 FW: 296.75 [32315-10-9]

Cl3C

O

O C

O

330752-5G 330752-25G 330752-100G

CCl3

5g 25 g 100 g

Phosgene solution, purum, ~20% in toluene COCl2 FW: 98.92 [75-44-5]

Cl

O C

Cl

79380-100ML 79380-500ML

100 mL 500 mL

Thiophosgene, 97% CSCl2 FW: 114.98 [463-71-8]

Cl

S C

Cl

115150-5G 115150-25G 115150-100G

5g 25 g 100 g

Thiophosgene, technical, ~90% s i g m a - a l d r i c h . c o m

Application example for the Phosgene Generation Starter Kit 519782-1KT.

CSCl2 FW: 114.98 [463-71-8] 89030-25ML 89030-100ML

To order: Contact your local Sigma-Aldrich office (see back cover), or visit www.sigma-aldrich.com/order.

Cl

S C

Cl

25 mL 100 mL

5

Carbodiimides

In solid-phase peptide synthesis, diisopropylcarbodiimide (DIC) is especially helpful due to the enhanced solubility of its urea derivatives.

N

C

N

100 g 500 g 2.5 kg

N,N’-Dicyclohexylcarbodiimide, 99.0%

N

C

N

25 g 100 g 1 kg

N,N’-Dicyclohexylcarbodiimide solution, purum, ~1 M in methylene chloride DCC C6H11N=C=NC6H11 FW: 206.33 [538-75-0] 36652-100ML

N

C

N

100 mL

N,N’-Dicyclohexylcarbodiimide solution, 1.0 M in methylene chloride DCC C6H11N=C=NC6H11 FW: 206.33 [538-75-0] 379115-100ML 379115-800ML

N

C

N

100 mL 800 mL

N,N’-Dicyclohexylcarbodiimide solution, purum, ~1 M in NMP DCC C6H11N=C=NC6H11 FW: 206.33 [538-75-0] 36651-100ML-F 36651-250ML-F

H3C

N

C

CH3 N CH3

N

10 mL 50 mL

N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide, polymerbound, 200–400 mesh, extent of labeling: 0.5–1.5 mmol/g loading, 2% cross-linked with divinylbenzene EDC, WSC H3C

N

C

CH3 N CH3

N

424331-5G

5g

EDC methiodide C2H5N=C=N(CH2)3N(CH3)3I FW: 297.18 [22572-40-3] 165344-1G 165344-10G

N,N’-Dicyclohexylcarbodiimide, puriss., >99.0%

DCC C6H11N=C=NC6H11 FW: 206.33 [538-75-0] D80002-25G D80002-100G D80002-1KG

EDC, WSC C8H17N3 FW: 155.24 [1892-57-5] 39391-10ML 39391-50ML

1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide

Reference: (1) Nozaki, S. J. Peptide Res. 1999, 54, 162.

DCC C6H11N=C=NC6H11 FW: 206.33 [538-75-0] 36650-100G 36650-500G 36650-2.5KG

WSC, N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide, purum, >97.0%

N

C

H3C H3C

N

C

N

CH3 N+ CH3

I-

1g 10 g

N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride, BioChemika, >99.0% EDC hydrochloride, EDAC C8H17N3 · HCl FW: 191.7 [25952-53-8] 03449-1G 03449-5G 03449-25G

H3C

N

C

N

CH3 N CH3

HCl

1g 5g 25 g

N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride, SigmaUltra EDC hydrochloride, EDAC C8H17N3 · HCl FW: 191.7 [25952-53-8] E1769-1G E1769-5G E1769-10G E1769-25G

H 3C

N

C

N

CH3 N CH3

HCl

1g 5g 10 g 25 g

N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride, purum, >98.0% EDC hydrochloride, EDAC C8H17N3 · HCl FW: 191.7 [25952-53-8] 03450-1G 03450-5G 03450-25G

H3C

N

100 mL 250 mL

To discuss how our expertise can benefit your next scale-up project or to obtain a quote, contact your local Sigma-Aldrich office or visit www.safcglobal.com

N

C

N

CH3 N CH3

HCl

1g 5g 25 g

Coupling Reagents

Carbodiimide-mediated peptide coupling remains to the most frequently used technique. As a major advantage, carbodiimides do not require prior activation of the carboxylic acid. Dicyclohexylcarbodiimide (DCC) has been predominantly used and is now well established. Since the generated urea derivatives as byproducts often have similar solubilities as the desired peptides, water-soluble carbodiimides have been developed whose corresponding ureas are readily separated by extraction with water. The most popular carbodiimide of this kind is EDC (N-(3Dimethylaminopropyl)-N’-ethylcarbodiimide). Furthermore EDC or EDAC allow peptide coupling in alcohol or aqueous solutions involving proteins or peptide cyclizations.1

6

N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride, commercial grade, powder

Coupling Reagents

EDC hydrochloride, EDAC C8H17N3 · HCl FW: 191.7 [25952-53-8] E7750-5G E7750-10G E7750-25G E7750-100G E7750-1KG E7750-5KG

H3C

N

C

N-Cyclohexyl-N’-(2-morpholinoethyl)carbodiimide metho-ptoluenesulfonate, puriss., >97.0% CH3 N CH3

N

HCl

5g 10 g 25 g 100 g 1 kg 5 kg

N,N’-Diisopropylcarbodiimide, purum, >98.0% DIC (CH3)2CHN=C=NCH(CH3)2 FW: 126.2 [693-13-0] 38370-25ML 38370-100ML 38370-500ML

N

C

N

25 mL 100 mL 500 mL

CMC C14H26N3O · C7H7O3S FW: 423.57 [2491-17-0] 29470-5G 29470-25G

N

C

N

CH3 N+

-O3S

CH3

O

5g 25 g

N-Cyclohexyl-N’-(2-morpholinoethyl)carbodiimide metho-ptoluenesulfonate, 95% CMC C14H26N3O · C7H7O3S FW: 423.57 [2491-17-0] C106402-5G C106402-25G

N

C

N

CH3 N+

-O3S

CH3

O

5g 25 g

N,N’-Di-tert-butylcarbodiimide, 99% (CH3)3CN=C=NC(CH3)3 FW: 154.25 [691-24-7]

N

C

N

235563-1G 235563-5G

N,N’-Diisopropylcarbodiimide, 99% DIC (CH3)2CHN=C=NCH(CH3)2 FW: 126.2 [693-13-0] D125407-5G D125407-25G D125407-100G D125407-1KG

N

C

1g 5g

N

N,N’-Di-tert-butylcarbodiimide, purum, >99.0% (GC) 5g 25 g 100 g 1 kg

1-tert-Butyl-3-ethylcarbodiimide, 99%

(CH3)3CN=C=NC(CH3)3 FW: 154.25 [691-24-7]

N

C

N

34640-5ML 34640-25ML

5 mL 25 mL

1,3-Di-p-tolylcarbodiimide, 96%

BEC (CH3)3CN=C=NC2H5 FW: 126.2 [1433-27-8] 426393-1G 426393-5G

N

C

CH3C6H4N=C=NC6H4CH3 FW: 222.29 [726-42-1]

N

1g 5g

H3C N

C

N

D219800-1G D219800-5G

N-Cyclohexyl-N’-(2-morpholinoethyl)carbodiimide metho-ptoluenesulfonate, puriss., >99.0% CMC C14H26N3O · C7H7O3S FW: 423.57 [2491-17-0] 29469-5G 29469-25G

N

C

N

CH3 N+

-O3S

CH3

O

5g 25 g

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To order: Contact your local Sigma-Aldrich office (see back cover), or visit www.sigma-aldrich.com/order.

CH3

1g 5g

7

Oxalic acid diimidazolide, technical grade

N-Acylimidazoles were recognized in the early 1950s as reactive intermediates suitable for the acylation of amino compounds. The search for better coupling reagents than DCC led to the development of CDI (1,1’-carbonyldiimidazole) and related carbonylimidazoles.1 For practical considerations it should be noted that moisture must be carefully excluded during work with CDI. Also, CDI excess should be avoided. Apart from peptide synthesis, carbonyldiimazoles find use as an efficient replacement for highly toxic phosgene in the preparation of carbamates and ureas from alcohols and amines.2,3

C8H6N4O2 FW: 190.16 [18637-83-7]

Kiso developed modified imidazolium reagents like CIP (2-Chloro1,3-dimethylimidazolidinium hexafluorophosphate) as new peptide coupling reagents and later as new esterification reagents to avoid the toxic HMPA by-product of the BOP reagent (benzotriazol-1yloxytris(dimethylamino)phosphonium hexafluorophosphate).4 CIP was successfully applied to the coupling of a,a-dialkylated amino acids and proved to be especially efficient in combination with HOAt (1-hydroxy-7-azabenzotriazole).5 References: (1) Staab, H. A. Angew. Chem. Int. Ed. Engl. 1962, 1, 351. (2) Staab, H. A. Justus Liebigs Ann. Chem. 1957, 609, 83. (3) Staab, H. A. Justus Liebigs Ann. Chem. 1957, 609, 75. (4) Akaji, K.; Kuriyama, N.; Kimura, T.; Fujiwara, Y.; Kiso, Y. Tetrahedron Lett. 1992, 33, 3177. (5) Albericio, A.; Bailén, F. M.; Chinchilla, R.; Dodsworth, D. J.; Nájera, C. Tetrahedron 2001, 57, 9607.

1,1’-Carbonyldiimidazole, reagent grade CDI C7H6N4O FW: 162.15 [530-62-1] 115533-5G 115533-10G 115533-25G 115533-100G

N

N

N

N

O

5g 10 g 25 g 100 g

1,1’-Carbonyldiimidazole, purum, >97.0% CDI C7H6N4O FW: 162.15 [530-62-1] 21860-5G 21860-25G 21860-100G

N

N

N

N

O

5g 25 g 100 g

1,1’-Carbonyl-di-(1,2,4-triazole), technical, >90% CDT C5H4N6O FW: 164.12 [41864-22-6] 21861-5G

N N

N

N N

N

O

5g

N N

N

N N

N

O

5g

Oxalic acid diimidazolide, technical, >90% (NT) C8H6N4O2 FW: 190.16 [18637-83-7]

O

O

N

N

N

75749-5G 75749-25G

O

N

N

N

N

366439-1G 366439-5G

1g 5g

2-Chloro-1,3-dimethylimidazolidinium chloride, purum, >97.0% DMC C5H10Cl2N2 FW: 169.05 [37091-73-9] 24374-10G-F 24374-50G-F

Cl N+

N

Cl-

10 g 50 g

2-Chloro-1,3-dimethylimidazolidinium chloride DMC C5H10Cl2N2 FW: 169.05 [37091-73-9] 529249-25G

Cl N+

N

Cl-

25 g

2-Chloro-1,3-dimethylimidazolidinium tetrafluoroborate, purum, >96.0% CIB C5H10BClF4N2 FW: 220.40 [153433-26-2] 24377-1G-F 24377-5G-F

Cl N+

N

BF4-

1g 5g

2-Chloro-1,3-dimethylimidazolidinium hexafluorophosphate, purum, >98.0% CIP C5H10ClF6N2P FW: 278.56 [101385-69-7] 24375-1G-F 24375-5G-F 24375-25G-F

Cl N+

N

PF6-

1g 5g 25 g

2-Chloro-1,3-dimethylimidazolidinium hexafluorophosphate, 98% CIP C5H10ClF6N2P FW: 278.56 [101385-69-7] 420336-1G 420336-5G

Cl N+

N

PF6-

1g 5g

2-Fluoro-1,3-dimethylimidazolidinium hexafluorophosphate, puriss., >98.5%

1,1’-Carbonyl-di-(1,2,4-triazole), ~90% CDT C5H4N6O FW: 164.12 [41864-22-6] C2956-5G

O

DFIH C5H10F7N2P FW: 262.11 [164298-27-5] 17381-5G 17381-25G

N

5g 25 g

To discuss how our expertise can benefit your next scale-up project or to obtain a quote, contact your local Sigma-Aldrich office or visit www.safcglobal.com

F N

N+

PF6-

5g 25 g

Coupling Reagents

Imidazolium Derived Reagents

8

Phosphonium Salts

Coupling Reagents

Phosphonium salts are powerful and easy-to-use peptide coupling reagents that allow in situ generation of active esters. After the recognition of chlorotris(dimethylamino)phosphonium as the activating species in the tris(dimethylamino)phosphine/CCl4 system and the importance of HOBt as an additive in peptide coupling, Castro proposed BOP (benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate) as a suitable coupling reagent. Thereafter, various groups proved the efficiency of BOP and it has become widely used.1,2 Since the utilization of BOP involves the handling of the toxic and carcinogenic HMPA, the viable alternative PyBOP has been developed where the dimethylamino groups are replaced by pyrrolidine substituents. PyBOP shows comparable performance to BOP, in some cases even better.3 Numerous other variations of BOP have been reported among which the HOAt analogue to PyBOP, PyAOP, excels especially in the coupling of sterically hindered amino acids.4 The halophosphonium compounds BroP or PyCloP are efficient reagents when coupling N-methylamino acids or a,a-disubstituted amino acids.5 Recently, Goodman reported the new DEPBT (3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) with superior performance as coupling reagent. It proved to be especially suitable for PNA synthesis, where it yielded significantly better results than even HATU.6,7

PyBOP® C18H28N6OP · PF6 FW: 520.39 [128625-52-5]

PyAOP C17H27F6N7OP2 FW: 521.38 [156311-83-0]

3

12802-5G-F 12802-25G-F 12802-100G-F

5g 25 g 100 g

(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, 97% BOP, Castro’s reagent C12H22F6N6OP2 FW: 442.28 [56602-33-6]

N

H3C CH3 N CH3 N N P+ N CH3 O N H3C CH3

PF6-

226084-1G 226084-5G

1g 5g

377848-1G 377848-5G

N O

N P+ N N

BroP BrP[N(CH3)2]3PF6 FW: 388.07 [50296-37-2]

N N N

N O

PF6-

N P+ N N

1g 5g

H3C CH3 N H3C N P+ Br PF6H3C N H3C CH3

1g 5g 25 g

H3C CH3 N H3C N P+ Br PF6H3C N H3C CH3

420107-250MG

250 mg

Chlorotripyrrolidinophosphonium hexafluorophosphate, >98.0% PyCloP C12H24ClN3P · PF6 FW: 421.73 [133894-48-1]

N N P+ Cl N

PF6-

26564-1G-F 26564-5G-F 26564-25G-F

PyBroP® C12H24BrF6N3P2 FW: 466.18 [132705-51-2]

N N

1g 5g 25 g

1g 5g 25 g

Bromotripyrrolidinophosphonium hexafluorophosphate, >95.0%

(Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, 98% PyBOP® C18H28N6OP · PF6 FW: 520.39 [128625-52-5]

PF6-

N P+ N N

Bromotris(dimethylamino)phosphonium hexafluorophosphate, purum, >98.0%

Bromotris(dimethylamino)phosphonium hexafluorophosphate, 98% PF6-

O

535303-1G 535303-5G

(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, purum, >98.0% H3C CH3 N CH3 N N P+ N CH3 O N H C CH3

N N

(7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, 96%

References: (1) Hudson, D. J. Org. Chem. 1988, 53, 617. (2) Rivaille, P.; Gautron, J. P.; Castro, B.; Milhaud, G. Tetrahedron 1980, 36, 3413. (3) Coste, J.; Le Nguyen, D.; Castro, B. Tetrahedron Lett. 1990, 31, 205. (4) Carpino, L. A.; El-Faham, A.; Minor, C. A.; Albericio, F. J. Chem. Soc., Chem. Commun. 1988, 201. (5) Coste, J.; Frérot, E.; Jouin, P. J. Org. Chem. 1994, 59, 2437. (6) Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Goodman, M. Organic Lett. 1999, 1, 91. (7) Tedeschi, T.; Corradini, R.; Marchelli, R.; Pushl, A.; Nielsen, P. E. Tetrahedron: Asymm. 2002, 13, 1629.

N

N

12805-1G-F 12805-5G-F 12805-25G-F

BroP BrP[N(CH3)2]3PF6 FW: 388.07 [50296-37-2] 18570-1G 18570-5G 18570-25G

BOP, Castro’s reagent C12H22F6N6OP2 FW: 442.28 [56602-33-6]

s i g m a - a l d r i c h . c o m

(Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, purum, >97.0%

PF6-

1g 5g

N N P+ Br PF6N

18565-1G 18565-5G 18565-25G

1g 5g 25 g

3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one, 98% DEPBT C11H14N3O5P FW: 299.22 [165534-43-0] 495964-5G

To order: Contact your local Sigma-Aldrich office (see back cover), or visit www.sigma-aldrich.com/order.

O

N

N N

O

O P O O

CH3

CH3

5g

9

Uronium and Guanidinium Salts

For a long time, the active HBTU and its family were believed to possess an uronium structure, but intensive studies provided evidence for the formulation of guanidinium N-oxides.1 Nevertheless, by custom, they are still called uronium type reagents. Unlike carbodiimides or phosphonium reagents, uronium salts could form tetramethylguanidinium derivatives with free amines. To circumvent this side reaction, excess reagent should be avoided and pre-activation of the carboxylic acid component is recommended. Besides HBTU and TBTU, several other members of the uronium family are worthy of attention. The 7-aza-analogue of HBTU called HATU (1-[Bis-(dimethylamino)methyliumyl]-1H-1,2,3-triazolo[4,5b]pyridine-3-oxide hexafluorophosphate) can be considered today’s gold standard of peptide coupling reagents. It has been used for difficult amide bond formation in solution and solid-phase (e.g., PNAs) synthesis.2 It is especially superior for macrocyclization, fragment condensation, and the coupling of N-substituted amino acids. Danishefsky reported an impressive example for the application of HATU in a late step of the total synthesis of Hemastatin with HATU simultaneously connecting two peptide macrocycles.3

TBSO

OTBS

H N

HN N N H

CO2H O

TESO

O O N O O HO2C

N

OTES

N H H

NHTroc

H N

HN

TBSO

O N N H

O

O O

O O NH

O

O

O O

O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, purum, >98.0% HBTU C11H16F6N5OP FW: 379.24 [94790-37-1]

N

N+

PF6-

N N N+ O-

12804-1G-F 12804-5G-F 12804-25G-F

1g 5g 25 g

O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate, 97% TBTU C11H16N5O · BF4 FW: 321.08 [125700-67-6]

N

N+

BF4-

N N N+ O-

12806-5G-F 12806-25G-F 12806-100G-F 12806-250G-F

5g 25 g 100 g 250 g

O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, purum, >98.0%

H N N

NH

N H

TBSO

34 % for 3 steps

References: (1) Carpino, L. A. et al. Angew. Chem. Int. Ed. 2002, 41, 441. (2) Uhlmann, E.; Peymann, A.; Breipohl, G.; Will, D. W. Angew. Chem. Int. Ed. 1998, 37, 2796. (3) Kamencka, T. M.; Danishefsky, S. J. Chem. Eur. J. 2001, 7, 41. (4) Chen, S.; Xu, J. Tetrahedron Lett. 1992, 33, 647. (5) Sabatino, G.; Mulinacci, B.; Alcaro, M.C.; Chelli, M.; Rovero, P.; Papini, A.M. Lett. Pept. Sci. 2002, 9, 119. (6) Pon, R. T.; Yu, S.; Sanghvi, Y. S. J. Org. Chem. 2002, 67, 856. (7) Knorr, R. et al. Tetrahedron Lett. 1989, 30, 1927. (8) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Peptides 1990, 62. (9) Bailin, M. A. et al. J.Org. Chem. 1999, 64, 8936.

TrocHN

H H N

O

The new thiouronium reagent TOTT (S-(1-Oxido-2-pyridyl)N,N,N’,N’-tetramethylthiuronium tetrafluoroborate) is ideally suited for the rapid and high-yielding preparation of primary amides when reacted with carboxylic acids and ammonium chloride.9

OTBS

1. Pb/Cd, THF, aq NH4OAc, 1.5 h 2. HATU, HOAt, DIEA, DMF, rt, 28 h 3. TBAF, AcOH, THF, rt, 55 h

HATU C10H15F6N6OP FW: 380.23 [148893-10-1]

N

N+

PF6-

N N N+ O-

N

11373-1G 11373-5G 11373-25G

1g 5g 25 g

OTBS

O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, 97%

HN

H H N TESO

N

O N

OTES

N H H TBSO

O N H

O

O

N

H N

O

OTBS

O NH

Scheme: Application of HATU in the simultaneous cyclization of two linked peptide strands for the synthesis of Hemastatin.

Substitution of HBTU’s dimethylamino groups by pyrrolidine residues as in HBPyU leads to less racemization during peptide coupling.4 Introducing an electron-withdrawing group into the benzotriazole moiety enhances the reactivity. Accordingly HCTU and TCTU show improved performance in difficult or hindered couplings and cyclizations when compared to HBTU.5 HCTU has also proven suitability for tandem oligonucleotide coupling on solid phase supports in a competitive study.6 TDBTU, TPTU, HOTU and TOTU are recommended for fragment condensation and other critical cases leading to minimal racemization.7 TSTU and HSTU are less efficient than their HOBt and HOAt derived analogues. They compensate for the disadvantage

HATU C10H15F6N6OP FW: 380.23 [148893-10-1]

N

N+

PF6-

N N N+ O-

N

445460-1G 445460-5G 445460-25G

1g 5g 25 g

O-(Benzotriazol-1-yl)-N,N,N’,N’-bis(tetramethylene)uronium hexafluorophosphate, purum, >98.0% HBPyU C15H20F6N5OP FW: 431.32 [105379-24-6] 12809-1G-F 12809-5G-F 12809-25G-F

To discuss how our expertise can benefit your next scale-up project or to obtain a quote, contact your local Sigma-Aldrich office or visit www.safcglobal.com

N N N O

N+

PF6-

N

1g 5g 25 g

Coupling Reagents

The special need of SPPS for rapid and highly efficient coupling reagents led to the development of several new reagents starting from BOP (Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate). The HOBt (N-Hydroxybenzotriazole) derived components HBTU and TBTU today belong to the most widely used reagents for peptide coupling and feature a broad application spectrum. HBTU and TBTU differ only by their counterions hexafluorophosphate or tetrafluoroborate, respectively. A comparison study showed that these anions have no significant influence on the coupling rate or racemization.

with greater stability in aqueous solvent mixtures allowing the modification of proteins.8

10

O-Benzotriazol-1-yl-N,N,N’,N’-bis(pentamethylene)uronium hexafluorophosphate, 98%

O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N’,N’tetramethyluronium tetrafluoroborate, purum, >98.0%

HBPipU C17H24F6N5OP FW: 459.37 [190849-64-0]

TOTU C2H5O2CC(CN)=NOC[N(CH3)2]=N(CH3)2BF4 FW: 328.07 [136849-72-4] 02580-1G 02580-5G 02580-25G

N N N O

N+

PF6-

N

420271-1G

1g

Coupling Reagents

O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’8 tetramethyluronium hexafluorophosphate, purum, >98.0% HCTU C11H15ClF6N5OP FW: 413.69 [330645-87-9]

N N N O

Cl

N+

PF6-

N

04936-5G-F 04936-25G-F 04936-100G-F

5g 25 g 100 g 8

O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’tetramethyluronium, purum, >98.0% TCTU C11H15BClF4N5O FW: 355.53 [330641-16-2]

N N N O

Cl

N+

BF4-

N

78133-5G-F 78133-25G-F 78133-100G-F

5g 25 g 100 g

O

N

N N

N+

O

BF4-

N

1g 5g 25 g

s i g m a - a l d r i c h . c o m

02576-1G 02576-5G 02576-25G

BF4-

N

1g 5g 25 g

TOTU C2H5O2CC(CN)=NOC[N(CH3)2]=N(CH3)2BF4 FW: 328.07 [136849-72-4] 382469-1G 382469-5G

CN O

N

N+

O

O

BF4-

N

1g 5g

N,N,N’,N’-Tetramethyl-O-(N-succinimidyl)uronium hexafluorophosphate, purum, >99.0% HSTU C9H16F6N3O3P FW: 359.21 [265651-18-1] 09668-1G 09668-5G 09668-25G

O N+

N O

PF6-

N

O

1g 5g 25 g

TSTU C9H16BF4N3O3 FW: 301.05 [105832-38-0] 385530-1G 385530-5G

O N+

N O

BF4-

N

O

1g 5g

Dipyrrolidino(N-succinimidyloxy)carbenium , purum, >98.0% O N+

N O

PF6-

N

O

O N

N+

O

BF4-

N

1g 5g 25 g

O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N’,N’tetramethyluronium hexafluorophosphate, purum, >97.0% HOTU C10H17F6N4O3P FW: 386.23

N+

O

O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N’,N’tetramethyluronium tetrafluoroborate, 98%

HSPyU C13H20F6N3O3P FW: 411.28 [207683-26-9]

O-(2-Oxo-1(2H)pyridyl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate, purum, ≥ 99.0% TPTU C10H16BF4N3O2 FW: 297.06 [125700-71-2] 37347-1G 37347-5G 37347-25G

N O

N,N,N’,N’-Tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate, 97%

O-(3,4-Dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N’,N’tetramethyluronium tetrafluoroborate, purum, >99.0% TDBTU C12H16BF4N5O2 FW: 349.09 [125700-69-8] 37345-1G-F 37345-5G-F 37345-25G-F

CN O

CN O

N O

N+

O

PF6-

N

85971-1G 85971-5G 85971-25G

1g 5g 25 g

S-(1-Oxido-2-pyridyl)-N,N,N’,N’8 tetramethylthiuronium tetrafluoroborate, purum, >95.0% TOTT C10H16BF4N3OS FW: 313.12 [255825-38-8] 94623-5G-F 94623-25G-F

1g 5g 25 g

To order: Contact your local Sigma-Aldrich office (see back cover), or visit www.sigma-aldrich.com/order.

ON+

N+

S

BF4-

N

5g 25 g

11

Miscellaneous Coupling Reagents Propylphosphonic anhydride (T3P®)1 is a very efficient, nontoxic coupling reagent especially suited for connecting sterically hindered amino acids. A further advantage is the easy removal of byproducts by extraction of the crude product with water.2 Mukaiyama introduced pyridinium reagents like 2-chloromethylpyridinium iodide to peptide chemistry, which found application in the synthesis of a b-lactam carbacepham skeleton.3

References: (1) T3P is a registered trademark of Clariant. (2) Klose, J. et al. Chem. Commun. 1999, 1847. (3) Berrien, J.-F.; Billon, M.-A.; Husson, H.-P. J. Org. Chem. 1995, 60, 2922. (4) Kaminski, Z. J. Synthesis 1987, 917. (5) Kaminski, Z. J.; Paneth, P.; Rudzinski, J. J. Org. Chem. 1998, 63, 4248. (6) Falchi, A.; Giacomelli, G.; Porcheddu, A.; Taddei, M. Synlett 2000, 275. CDMT

NMM

Cl N MeO

N N

O

THF, rt, 30 min

N

100 %

+ OMe

ClN+ N

MeO

N OMe

N

Scheme: Reaction of CDMT with NMM to the powerful acylating agent DMTMM.

Propylphosphonic anhydride solution, 50 wt. % in ethyl acetate C9H21O6P3 FW: 318.18 [68957-94-8]

O O O P

O P O O

Propylphosphonic anhydride solution, technical, ~50% in ethyl acetate

81799-10ML 81799-50ML 81799-250ML

O P O

25 mL 100 mL

2-Chloro-1-methylpyridinium iodide, purum, >97.0% (AT) C6H7ClIN FW: 255.48 [14338-32-0]

IN+ Cl CH3

25270-25G 25270-100G

25 g 100 g

2-Chloro-1-methylpyridinium iodide, 97% C6H7ClIN FW: 255.48 [14338-32-0]

IN+ Cl CH3

198005-10G 198005-25G 198005-100G

10 g 25 g 100 g

2-Chloro-4,6-dimethoxy-1,3,5-triazine, purum, >98.0% Cl N H3C

O

N O

N

CH3

5g 25 g

2-Chloro-4,6-dimethoxy-1,3,5-triazine, 97% CDMT C5H6ClN3O2 FW: 175.57 [3140-73-6] 375217-5G

Cl N H3C

O

N O

N

CH3

5g

4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, purum, >98.0% 10 mL 50 mL

DMTMM C10H17ClN4O3 FW: 276.72 [3945-69-5] 74104-1G-F 74104-5G-F

O O O P

O

P

431303-10ML 431303-50ML

C9H21O6P3 FW: 318.18 [68957-94-8]

O P

O O P

81801-25ML 81801-100ML

CDMT C5H6ClN3O2 FW: 175.57 [3140-73-6] 24320-5G-F 24320-25G-F

DMTMM O

C9H21O6P3 FW: 318.18 [68957-94-8]

P O

O P O

10 mL 50 mL 250 mL

To discuss how our expertise can benefit your next scale-up project or to obtain a quote, contact your local Sigma-Aldrich office or visit www.safcglobal.com

O N+ CH3 N H3C

O

Cl-

N N

O

CH3

1g 5g

Coupling Reagents

Cyanuric chloride has been used for the preparation of acyl chlorides, amides and peptides. The cyanuric chloride derivative CDMT (2-chloro-4,6-dimethoxy-1,3,5-triazine) yields highly reactive esters with carboxylic acids that can then be used as powerful acylating agents for amines and the less nucleophilic, alcohols.4 The activation is performed in presence of a base, preferentially NMM (N-methylmorpholine). In situ NMM and CDMT form the intermediate DMTMM. DMTMM can be isolated and used as coupling reagent independently.5 In contrast to CDMT, DMTMM does not require pre-activation of the carboxylic acid. The coupling efficiency of DMTMM in SPPS was found to be comparable to PyBOP while racemization could be kept below the detection limit.6

Propylphosphonic anhydride solution, technical, ~50% in DMF

12

New Unnatural Amino Acids Unnatural amino acids are utilized as chiral building blocks, conformational constraints, molecular scaffolds, or pharmacologically active compounds. They represent a nearly infinite array of diverse structural elements for the development of new therapeutic drugs. Small-molecule combinatorial libraries containing unnatural amino acid residues already show remarkable impact on drug discovery processes. Novel short-chain peptide ligand mimetics with both enhanced biological activity and improved proteolytic resistance are drug candidates in today’s R&D pipelines of pharmaceutical companies. Sigma-Aldrich is pleased to introduce 40 new additions to its unique and broad portfolio of more than 700 unnatural amino acids.

New Unnatural Amino Acids

8

Fmoc-D-b-Homophe-OH, purum, >97.0% (HPLC) C25H23NO4 FW: 401.45 [209252-16-4]

Fmoc NH

O OH

18074-500MG-F

500 mg 8

Trans-2-(Boc-amino)-cyclohexanecarboxylic acid, purum, >98.0% (TLC) C12H21NO4 FW: 243.3 [209128-50-7]

O

OH H N

BOC

29293-1G-F

1g 8

trans-2-(Fmoc-amino)-cyclohexanecarboxylic acid, purum, >98.0% (HPLC)

b-amino Acids 8

(cis)-3-Aminobicyclo[2.2.1]heptane-2-carboxylic acid hydrochloride, purum, >98.0% (TLC) C8H13NO2 · HCl FW: 191.66

NH2

HCl

C22H23NO4 FW: 365.42 [381241-08-3]

O

OH H N

Fmoc

28319-1G-F

1g

OH O

1g

N OH

5g

C12H21NO4 FW: 243.3 [63216-49-9]

8

O

OH H N

NH

O OH

1g 5g

8

cis-2-(Fmoc-amino)-cyclohexanecarboxylic acid, purum, >98.0% (HPLC) O

OH H N

OH NH2

30254-500MG-F

OH

500 mg

8

2-(4-Boc-piperazino)-2-[2-(trifluoromethyl)phenyl] acetic acid, purum, >95.0% (HPLC) F3C

OH

BOC

O

N

38903-500MG-F

500 mg 8

2-(4-Boc-piperazino)-2-phenylacetic acid, purum, >97.0% (HPLC) C17H24N2O4 FW: 320.38

HCl

8

cis-2-Amino-2-methylcyclopentanecarboxylic acid hydrochloride, purum, >98.0% (CHN)

OH

N BOC

O

N

16298-500MG-F

500 mg 8

3-(Trifluoromethyl)-DL-phenylglycine, purum, >98.0% (HPLC)

O NH2

39927-500MG-F

HCl

500 mg 8

cis-2-Aminocycloheptanecarboxylic acid hydrochloride, purum, >98.0% (TLC) HO

O

Phenylglycine Derivatives

500 mg

HO

NH

N

8

cis-2-Amino-2-methylcyclohexanecarboxylic acid hydrochloride, purum, >98.0% (CHN)

C7H13NO2 · HCl FW: 179.64 [156292-34-1]

O

Fmoc

1g

O

O

C18H23F3N2O4 FW: 388.38

29294-1G-F

C8H15NO2 · HCl FW: 193.67 [202921-88-8]

C12H15NO4 FW: 237.25 [83509-88-0]

BOC

1g

C22H23NO4 FW: 365.42 [194471-85-7]

8

Z-b-Homoala-OH, purum, >98.0%

61669-500MG-F

36314-1G-F

s i g m a - a l d r i c h . c o m

O

NH2 O

cis-2-(Boc-amino)-cyclohexanecarboxylic acid, purum, >98.0% (TLC)

11252-500MG-F

O

39599-1G 39599-5G

11585-5G-F

C8H15NO2 · HCl FW: 193.67

C12H15NO4 FW: 237.25

8

4-Amino-nicotinic acid, purum, >97.0% (HPLC) C6H6N2O2 FW: 138.12 [7418-65-7]

8

Z-DL-b-Homoalanine, purum, >98.0% (HPLC)

08356-1G-F

C9H8F3NO2 FW: 219.16 [242475-26-9]

O F3C

OH NH2

53636-500MG-F

500 mg 8

Methyl 2-(4-Boc-piperazino)-2-(2-pyridyl)acetate, purum, >95.0% (HPLC)

O NH2

HCl

C17H25N3O4 FW: 335.4

N

500 mg

O

19578-500MG-F To order: Contact your local Sigma-Aldrich office (see back cover), or visit www.sigma-aldrich.com/order.

BOC

N

N

OCH3

500 mg

13

Alanine Derivatives 8

4-(Hydroxymethyl)-D-phenylalanine, purum, >97.0% (HPLC) C10H13NO3 FW: 195.22

C17H21F2NO4 FW: 341.35

OH F

NH2

HO

8

Boc-(R)-4-(3,4-difluorobenzyl)-L-proline, purum, >97.0% (HPLC)

N O BOC

F OH

40372-500MG-F

O

43667-500MG

500 mg 8

Boc-3-(1,2,4-triazol-1-yl)-Ala-OH, purum C10H16N4O4 FW: 256.26

O N

HN

CF3 OH

8

Boc-3-(1-pyrazolyl)-Ala-OH, purum, >97.0% (HPLC) O

HN

BOC

67387-500MG-F

500 mg 8

Boc-(R)-4-[4-(trifluoromethyl)benzyl]-L-proline, purum, >98.0% (HPLC) C18H22F3NO4 FW: 373.37

OH

N

38455-500MG-F

OH F3C

N O BOC

500 mg 01336-500MG-F

C11H19NO4 · C12H23N FW: 410.59 [87720-54-5]

OH BOC

11578-50MG

50 mg

Fmoc-3-(1,2,4-triazol-1-yl)-Ala-OH, purum, >97.0% (HPLC)

8

C20H18N4O4 FW: 378.38

OH

N HN

N

500 mg

OH N O BOC

500 mg 8

C21H31NO4 FW: 361.48

8

Fmoc-3-(1-pyrazolyl)-Ala-OH, purum, >97.0% (HPLC) O N

OH N BOC O

OH

N HN

Fmoc

51916-500MG-F

500 mg 8

L-a-Neopentylglycine, purum, >98.0% (TLC) C7H15NO2 FW: 145.2 [57224-50-7]

O

39793-500MG-F

500 mg 8

Boc-(R)-a-(4-trifluoromethylbenzyl)-Pro-OH, purum, >98.0% (HPLC) C18H22F3NO4 FW: 373.37

OH NH2

73489-1G-F 73489-5G-F

1g 5g

CF3

OH N O BOC

42004-500MG-F

Proline Derivatives 8

N(R)-a-Allyl-proline hydrochloride, purum, >98.0% (TLC) C8H13NO2·HCl FW: 191.66 [177206-69-8]

F

Boc-(R)-a-(4-tert-butylbenzyl)-Pro-OH, purum, >97.0% (HPLC)

Fmoc

53229-500MG-F

C21H19N3O4 FW: 377.39

C17H22FNO4 FW: 323.36 [706806-64-6]

67420-500MG-F

O N

8

Boc-(R)-a-(4-fluorobenzyl)-Pro-OH, purum, >98.0% (HPLC)

H N

O

HN

500 mg

8

Boc-4,5-dehydro-Leu-OH dicyclohexylamine salt, purum, >96.0% (HPLC)

OH N H

500 mg 8

Boc-(R)-a-allyl-Pro-OH, purum, >98.0% (HPLC) C13H21NO4 FW: 255.31 [144085-23-4]

HCl

OH N BOC O

06538-500MG-F

O

06541-500MG-F

500 mg

500 mg

Boc-(R)-a-benzyl-Pro-OH, purum, >99.0% (HPLC) (S)-a-Allyl-proline hydrochloride, purum, >98.0% (TLC) 8 C8H13NO2 FW: 155.19 [129704-91-2] 06594-500MG-F

N H

C17H23NO4 FW: 305.37 [706806-60-2]

OH O

500 mg

47079-500MG-F

To discuss how our expertise can benefit your next scale-up project or to obtain a quote, contact your local Sigma-Aldrich office or visit www.safcglobal.com

8

OH N BOC O

500 mg

New Unnatural Amino Acids

N O BOC

500 mg

N

C18H22F3NO4 FW: 373.37

BOC

50996-500MG-F

C11H17N3O4 FW: 255.27 [21012-18-0]

8

Boc-(R)-4-[2-(trifluoromethyl)benzyl]-L-proline, purum, >98.0% (HPLC)

OH

N

N

500 mg

14

8

Boc-(S)-a-(4-fluorobenzyl)-Pro-OH, purum, >98.0% (HPLC) C17H22FNO4 FW: 323.36 [706806-65-7]

C13H21NO4 FW: 255.31 [706806-59-9]

F

8

C21H31NO4 FW: 361.48

New Unnatural Amino Acids

500 mg 8

Boc-(S)-a-benzyl-Pro-OH, purum, >97.0% (HPLC) 500 mg

Boc-(S)-a-(4-tert-butylbenzyl)-Pro-OH, purum, >98.0% (HPLC)

OH N O BOC

06486-500MG-F

OH N O BOC

14931-500MG-F

8

Boc-(S)-a-allyl-Pro-OH, purum, >98.0% (HPLC)

C17H23NO4 FW: 305.37 [706806-61-3]

OH N BOC O

76896-500MG-F

Miscellaneous

OH N O BOC

39166-500MG-F

500 mg

Boc-(S)-a-(4-trifluoromethylbenzyl)-Pro-OH, purum, >98.0% (HPLC) C18H22F3NO4 FW: 373.37

8

8

(S)-6-Oxo-2-piperidinecarboxylic acid, purum, >97.0% (HPLC) C6H9NO3 FW: 143.14 [34622-39-4]

O

N H

OH O

36323-1G-F 36323-5G-F

CF3

1g 5g 8

2-[2-(Boc-amino)ethoxy]ethoxyacetic acid dicyclohexylamine salt, purum, >98.0% (TLC)

OH N O BOC

05199-500MG-F

500 mg

500 mg

C11H21NO6 · C12H23N FW: 444.61

BOC

N H

O

OH

O

H N

O

14766-500MG-F

500 mg

8 Safe and Simple Application of Phosgene in Your Lab! Phosgene Generation Kit Phosgene is an extremely versatile reagent allowing easy access to isocyanates, ureas, carbamates, carbonates, acyl and alkyl chlorides. As a dehydrating agent phosgene can also lead to isocyanides, cyanides and carbodiimides. In cooperation with BUSS ChemTech, Sigma-Aldrich now offers a safe and reliable phosgene generation kit giving simple access to small quantities of high-purity, gaseous phosgene exactly when needed, while no transport and storage of liquid phosgene is necessary. The generator converts safe triphosgene into phosgene on demand using a patented catalyst (U.S. patent 6,399,822 B1). Test the suitability of the generators in your own laboratory today with a starter kit and cartridges from Sigma-Aldrich.

Advantages • Easy access to small quantities of phosgene • Versatile chemistry where other reagents offer poor results • No transport or storage of liquid phosgene • Production on demand of high purity gaseous phosgene • Safe and reliable handling • Simple workup of reactions to obtain pure products • Operation scale from mmol to industrial levels

s i g m a - a l d r i c h . c o m

Name Cartridge for Phosgene Generation, Starter Kit

Solutions for the upscale to industrial production levels are available at BUSS ChemTech.

Mol. Formula

MW or FW

CAS No.

Cat. No. 519782-1KT

Contains one 0.02 mole cartridge (#519758), hose connector with sealing lips, Viton tubing, dosimeter badge, and instructions for use. Cartridge for Phosgene Generation, 0.02 mole

COCl2

98.92

75-44-5

Cartridge for Phosgene Generation, 0.05 mole

COCl2

98.92

75-44-5

519758-1PAK 519758-5PAK 519766-1PAK 519766-5PAK

Visit sigma-aldrich.com for full details.

To order: Contact your local Sigma-Aldrich office (see back cover), or visit www.sigma-aldrich.com/order.

15

New Tools for Peptide PEGylation Circulatory half-life is a key success factor of new drugs. In this respect, modification of potential candidates ranging from non-peptidic molecules to peptides and proteins with polyethyleneglycol chains (PEGs) offers numerous advantages. PEGs are non-toxic, non-immunogenic, non-antigenic, highly soluble in water and FDA approved.1 The PEGylated conjugates show a decreased degradation by metabolic enzymes and a reduction or elimination of protein immunogenicity. Thus Pettit et al. found a 50-fold enhancement of residence in the organism of PEGylated IL-15 (Interleukin).2 Sigma-Aldrich is pleased to provide you with a continuously growing and diverse portfolio of PEGs: 27 new products that will help you improve the success of your drug discovery research.

8

tert-Butyl 12-amino-4,7,10-trioxadodecanoate O H2N

O

O

O

O

83060-1G-F 83060-5G-F

1g 5g 8

O,O’-Oxydiethylene-diglycolic acid C8H14O7 [13887-98-4]

O

O O

HO

O

O

OH

92893-50ML 92893-250ML

50 mL 250 mL 8

{2-[2-(Fmoc-amino)ethoxy]ethoxy}acetic acid, purum, >95.0% C21H23NO6 FW: 385.41 [166108-71-0]

Fmoc

O

H N

O

O

95003-500MG-F

O O

O

O

8

N

O

O

n

O

O

63187-1G 63187-5G

1g 5g

O,O’-Bis[2-(succinylamino)ethyl]polyethylene glycol

14571-250MG 14571-1G

H N

HO O

O

OH

N H

O

14569-250MG 14569-1G

250 mg 1g 8

O,O’-Bis[2-(succinylamino)ethyl]polyethylene glycol HOOCCH2CH2CONH(CH2 CH2O)nCH2CH2NHCOCH2 CH2COOH Mr 20000

O

H N

HO

O O

O

O

OH

N H

n

O

14573-250MG 14573-1G

250 mg 1g 8

O,O’-Bis[2-(succinylamino)ethyl]polyethylene glycol HOOCCH2CH2CONH(CH2 CH2O)nCH2CH2NHCOCH2 CH2COOH Mr 3000

O

O

H N

HO

O

O

n

O

OH

N H

O

14567-250MG

250 mg

Hycron linker

8

C17H31BrO6 FW: 411.33 [166668-33-3]

O Br

O

O

O

O

O

96823-1G-F 96823-5G-F

1g 5g 8

O,O’-Bis(2-aminoethyl)octadecaethylene glycol, >95% (oligomer purity) C40H84N2O19 FW: 897.1

H2N

O

O

NH2

18

1g 8

O,O’-Bis(2-carboxyethyl)dodecaethylene glycol, >95% (oligomer purity) C30H58O17 FW: 690.77

O HO

O

O

OH 12

O

1g 8

O-Methyl-undecaethylene glycol, >95% (oligomer purity) HO(CH2CH2O)11CH3 FW: 516.62 [114740-40-8]

H3C

O

H

O

11

16603-500MG-F

O

O

n

94704-1G-F

250 mL 1L

Methoxypolyethylene glycol 5,000 maleimide, BioChemika, >90%

HOOCCH2CH2CONH(CH2 CH2O)nCH2CH2NHCOCH2 CH2COOH Mr 10000

O O

O

OH

64732-250ML 64732-1L

[99126-64-4]

H N

06703-1G-F

8

2-[2-(2-Methoxyethoxy)ethoxy]acetic acid, technical, >90% H3C

O HO

OH

500 mg

CH3(OCH2CH2)2OCH2CO2H FW: 178.18 [16024-58-1]

HOOCCH2CH2CONH(CH2 CH2O)nCH2CH2NHCOCH2 CH2COOH Mr 6000

8

500 mg 8

O-Methyl-heptaethylene glycol, >95% (oligomer purity) HO(CH2CH2O)7CH3 FW: 340.41 [4437-01-8]

H3C

O

H

O

7

41749-1G-F

1g

O O

O n

N H

OH O

250 mg 1g

8

Octaethylene glycol, >95% (oligomer purity) HO(CH2CH2O)8H FW: 370.44 [5117-19-1] 15879-1G-F 15879-5G-F

To discuss how our expertise can benefit your next scale-up project or to obtain a quote, contact your local Sigma-Aldrich office or visit www.safcglobal.com

HO

O

H 8

1g 5g

New Tools for Peptide PEGylation

References: (1) Veronese, F. M.; Pasut, G. Drug Disc. Tod. 2005, 21, 1451. (2) Pettit, D. K. et al. J. of Biol. Chem. 1997, 272, 2312.

C13H27NO5 FW: 277.36 [252881-74-6]

8

O,O’-Bis[2-(succinylamino)ethyl]polyethylene glycol

16

8

O-(2-tert-Butyloxycarbonylethyl)dodecaethylene glycol, >95% (oligomer purity) C31H62O15 FW: 674.81

O

HO

O Fmoc

12

500 mg 8

Methoxypolyethylene glycol 5,000 acetic acid, BioChemika, >80% O

O

n

1g 5g 25 g 8

New Tools for Peptide PEGylation

Methoxypolyethylene glycol 5,000 propionic acid, BioChemika, >80% O O

1g 5g 25 g 8

N-Boc-2,2’-(ethylenedioxy)diethylamine, purum, >95.0% H2N

O

O

N H

89761-1G-F 89761-5G-F

H 2N

O

O

8

N H

O

93113-1G-F

671266-100MG 671266-500MG

O

O n

N H

28

500 mg

O-(2-Mercaptoethyl)-O’-methyl-hexa(ethylene glycol)

8

C15H32O7S FW: 356.48

SH

H3C

O

O

6

250 mg 8

O-(2-Carboxyethyl)-O’-(2-mercaptoethyl) heptaethylene glycol C19H38O10S FW: 458.56

O HO

O

O

SH

7

672688-250MG

250 mg 8

H2N

O

O n

671150-500MG

N H

BOC

500 mg 8

O-(2-Aminoethyl)-O’-[2-(Boc-amino)ethyl] polyethylene glycol 10000 O

O

671363-100MG 671363-500MG

BOC

100 mg 500 mg

Monthly Chemistry E-Newsletter

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H

O

672351-500MG

H2N

8

O-(2-Aminoethyl)-O’-[2-(Boc-amino)ethyl] polyethylene glycol 5000

HO

BOC

1g

H2N

8

O-(2-Aminoethyl)-O’-[2-(Boc-amino)ethyl] polyethylene glycol 3000

BOC

1g 5g

N-Boc-4,7,10-trioxa-1,13-tridecanediamine, purum, >97.0% C15H32N2O5 FW: 320.42

O

100 mg 500 mg

672572-250MG

OH n

88908-1G-F 88908-5G-F 88908-25G-F

C11H24N2O4 FW: 248.32 [153086-78-3]

OH n

669717-100MG 669717-500MG

HO(CH2CH2O)28H FW: 1251.49

OH

70718-1G-F 70718-5G-F 70718-25G-F

O

O

O

Octacosaethylene glycol O

H3C

H N

O

08453-500MG-F

H3C

8

O-[2-(Fmoc-amino)-ethyl]-O’-(2-carboxyethyl) polyethylene glycol 3000

sigma-aldrich.com/chemnews

To order: Contact your local Sigma-Aldrich office (see back cover), or visit www.sigma-aldrich.com/order.

n

N H

BOC

100 mg 500 mg

17

Fluorous Peptide Synthesis

Fluorous side-chain protecting group

Fluorous-phase chemistry offers new synthesis and separation strategies for the synthesis of peptides in solution or in SPPS. Orthogonal to other purification procedures, Fluorous SolidPhase Extraction (F-SPE), fluorous HPLC or fluorous liquid-liquid extraction require an additional but greatly simplifying workup of the final products. The necessary fluorous tags can be introduced by using pre-tagged reagents or through the use of tagging compounds at various stages of peptide synthesis (see scheme).

PG

N H

R2 OH

Deprotection

PG

PG

O

H N

PG

O R1

R2

N H

Capping Fluorous purification tags

Cleavage Fluorous cap-tags

C31H17ClF26O2 FW: 950.88

N

O

O

N

8

2,7-Bis(1H,1H,2H,2H-perfluorooctyl)-9fluorenylmethoxycarbonyl-chlorid

(CF2)5CF3

F3C(F2C)5

(CF2)5CF3

672378-1G

O

1g 8

4-(3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctylthio) phenol, >97% C14H9F13OS FW: 472.26

Cl

O

672262-1G

1g

2-[(4,4,5,5,6,6,7,7,7-Nonafluoro-1,1-dimethylheptyloxy)carbonyloxyimino]-2-phenylacetonitrile

OH

C18H15F9N2O3 FW: 478.31

O NC

N

O

O

S

(CF2)3CF3

(CF2)5CF3

43893-1G-F 43893-5G-F

1g 5g 8

4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10Heptadecafluorodecylthio)phenol, >97% C16H9F17OS FW: 572.28

OH

1g

01382-1G-F

2-[(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluoro-1,1dimethylnonyloxy) carbonyloxyimino]-2-phenylacetonitrile C20H15F13N2O3 FW: 578.32

O NC

N

O

O

11807-1G-F 11807-5G-F

S

(CF2)5CF3

1g 5g

(CF2)7CF3

40829-1G-F 40829-5G-F

1g 5g

2-[(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Heptadecafluoro-1,1dimethylundecyloxy)carbonyloxyimino]-2-phenylacetonitrile C22H15F17N2O3 FW: 678.34 [350716-42-6]

55118-1G-F 55118-5G-F

To discuss how our expertise can benefit your next scale-up project or to obtain a quote, contact your local Sigma-Aldrich office or visit www.safcglobal.com

O NC

N

O

O

(CF2)7CF3

1g 5g

Fluorous Peptide Synthesis

8

Cl N F3C(F2C)5

PG

Fluorous Protecting Groups

2-Chloro-4,6-bis[3-(perfluorohexyl)propyloxy]1,3,5-triazine C21H12ClF26N3O2 FW: 867.75

O R1

O

PG

O

H N

FINISHED PEPTIDE

Fluorous Peptide Coupling Tools

Fluorous coupling reagents

O

Activation

Some recent examples of fluorous peptides synthesis include the peptide synthesis on fluorous supports by Mizuno et al.,1 the solid-phase peptide synthesis with fluorous capping by Kumar and Montanari2, or the application of fluorous N-protecting groups in peptide synthesis by Overkleeft et al.3 References: (1) Mizuno, M. et al. Tetrahedron Lett. 2004, 45, 3425. (2) Kumar, K.; Montanari, V. J. Am. Chem. Soc. 2004, 126, 9528. (3) Overkleeft, H. S. et al. Tetrahedron Lett. 2003, 44, 9013.

PG

Fluorous acid- or base-labile N-protecting group

18

N-[4-(3,3,4,4,5,5,6,6,6-Nonafluorohexyl) benzyloxycarbonyloxy]succinimide

4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl)benzyl alcohol, >98.0%

C18H14F9NO5 FW: 495.29

O O O

O

N O

F3C(F2C)3

00246-1G-F

1g

N-[4-(3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctyl) benzyloxycarbonyloxy] succinimide

C17H11F17O FW: 554.24 [356055-77-1]

OH F3C(F2C)7

19563-1G-F 19563-5G-F

1g 5g

1-(4-Methoxyphenyl)-1-[4-(1H,1H,2H,2Hperfluorodecyl)phenyl]-1-phenylmethyl chloride

C20H14F13NO5 FW: 595.31 [556050-48-7]

O O O

O

N O

F3C(F2C)5

8

C30H20ClF17O FW: 754.91 [865758-37-8]

Cl F3C(F2C)7

05656-1G-F 05656-5G-F

1g 5g

OCH3

672149-1G

N-[4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl) benzyloxycarbonyloxy]succinimide

Fluorous Peptide Synthesis

C22H14F17NO5 FW: 695.32 [556050-49-8]

O O O

O

N O

F3C(F2C)7

14944-1G-F 14944-5G-F

1g

1,1-Di-(4-methoxyphenyl)-1-[4-(1H,1H,2H,2Hperfluorodecyl)phenyl]methanol, 97%

8

C31H23F17O3 FW: 766.49 [865758-47-0]

OCH3

1g 5g

OH F3C(F2C)7

4-(4,4,5,5,6,6,7,7,7-Nonafluoroheptyloxy)benzyl alcohol

OCH3

C14H13F9O2 FW: 384.24

OH F3C(F2C)3

O

1g

4’-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyloxy)benzyl alcohol OH O

67772-1G-F 67772-5G-F

1g 5g

4-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11Heptadecafluoroundecyloxy)benzyl alcohol OH O

97071-1G-F 97071-5G-F

1g 5g

4-(3,3,4,4,5,5,6,6,6-Nonafluorohexyl)benzyl alcohol, >95%

C14H19F13Si FW: 462.37 [356056-14-9]

s i g m a - a l d r i c h . c o m

16638-1G-F 16638-5G-F

Si H F3C(F2C)5

OH

1g 5g

Diisopropyl(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl)silane, >95% C16H19F17Si FW: 562.38 [356056-15-0] 04537-1G-F 04537-5G-F

1g

4-(3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctyl)benzyl alcohol, >97.0% C15H11F13O FW: 454.23 [356055-76-0]

1g

Diisopropyl(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)silane, >95%

F3C(F2C)3

08431-1G-F

Si H F3C(F2C)3

00454-1G-F 00454-5G-F

C18H13F17O2 FW: 584.27

C13H11F9O FW: 354.21

C12H19F9Si FW: 362.35 [356056-13-8] 18976-1G-F

C16H13F13O2 FW: 484.25

F3C(F2C)7

1g

Diisopropyl(3,3,4,4,5,5,6,6,6-nonafluorohexyl)silane, >95%

01452-1G-F

F3C(F2C)5

672696-1G

OH F3C(F2C)5

1g 5g

To order: Contact your local Sigma-Aldrich office (see back cover), or visit www.sigma-aldrich.com/order.

Si H F3C(F2C)7

1g 5g

19

Fluorous Proteomics Reagents

Fluorous Separation Media 8

N-Succinimidyl 4,4,5,5,6,6,7,7,8,8,9,9,9tridecafluorononanoate, purum, >97.0% C13H8F13NO4 FW: 489.19

O O F3C(F2C)5

14196-1EA-F

N

O

O

41687-5MG 41687-25MG

5 mg 25 mg

N-Succinimidyl 4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11heptadecafluoroundecanoate, purum, >98.0%

8

C15H8F17NO4 FW: 589.2 [852527-45-8]

O F3C(F2C)7

F3C(F2C)3

5 pieces

FluoroFlash® SPE Cartridges, 20 grams, 60 cc tube, 40 μm particle size 08966-1EA-F

2 pieces

FluoroFlash® SPE Cartridges, 20 grams, 60 cc tube, 40 μm particle size

N3

77983-5MG 77983-25MG

5 mg 25 mg

4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11Heptadecafluoroundecyl azide, purum, >97.0%

8

06961-1EA-F

5 pieces

FluoroFlash® TLC Plates with F254 indicator, dimension 5 cm x 10 cm 16888-1EA-F

F3C(F2C)5

N3

5 mg 25 mg

N-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11Heptadecafluoroundecyl)maleimide, purum, >97.0%

8

O F3C(F2C)5

N O

40889-5MG 40889-25MG

5 mg 25 mg

N-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyl) iodoacetamide, purum, >98.0%

8 H N

10 pieces

FluoroFlash® Silica Gel, ~40 μm particle size

97087-5MG 97087-25MG

F3C(F2C)5

10 pieces

08965-1EA-F

100 g Fluorous separation using solidphase extraction: a mixture of a nonfluorous dye (blue) and a fluorous dye (orange) are loaded on a fluorous sorbent (see left-hand test tube). The nonfluorous dye can be washed with aequeous methanol (middle test tube). The fluorous dye remains on the sorbent until the elution with a fluorophilic wash (e.g. with pure methanol, right hand test tube).

I O

51526-5MG 51526-25MG

5 mg 25 mg

N-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,118 Heptadecafluoroundecyl)iodoacetamide, purum, >98.0% C13H9F17INO FW: 645.09 [852527-48-1] 55266-5MG 55266-25MG

F3C(F2C)6

H N

I O

5 mg 25 mg

The fluorous products are manufactured by Fluorous Technologies, Inc.. U.S. patents 6,156,896; 5,859,247; 5,777,121 and 6,673,539 may protect use of these compounds. FluoroFlash® is a registered trademark of Fluorous Technologies, Inc.

To discuss how our expertise can benefit your next scale-up project or to obtain a quote, contact your local Sigma-Aldrich office or visit www.safcglobal.com

Fluorous Peptide Synthesis

8

C11H9F13INO FW: 545.08 [852527-50-5]

00866-1EA-F

08967-1EA-F

O

4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyl azide, purum, >97.0%

C15H8F17NO2 FW: 557.2 [852527-40-3]

FluoroFlash® SPE Cartridges, 5 grams, 10 cc tube, 40 μm particle size

N

O

5 mg 25 mg

C11H6F17N3 FW: 503.16 [852527-61-8]

20 pieces

FluoroFlash® SPE Cartridges, 10 grams, 60 cc tube, 40 μm particle size

O

73028-5MG 73028-25MG

C9H6F13N3 FW: 403.14 [852527-60-7]

FluoroFlash® SPE Cartridges, 2 grams, 8 cc tube, 40 μm particle size

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The SIGMA-ALDRICH Group Accelerating Customers’ Success through Leadership in Life Science, ©2007 Sigma-Aldrich Co. All rights reserved. SIGMA, -, SAFC, , SIGMA-ALDRICH, ), ISOTEC, ALDRICH, ^, FLUKA, T, and SUPELCO are trademarks belonging to Sigma-Aldrich Co. and its affiliate Sigma-Aldrich Biotechnology, L.P. Riedel-de Haën® trademark under license from Riedel-de Haën GmbH. Sigma brand products are sold through Sigma-Aldrich, Inc. Sigma-Aldrich, Inc. warrants that its products conform to the information contained in this and other Sigma-Aldrich publications. Purchaser must determine the suitability of the product(s) for their particular use. Additional terms and conditions may apply. Please see reverse side of the invoice or packing slip.

High Technology and Service JJH 03/2007