chemfiles vol. 7, no. 2 - peptide synthesis

2007VOLUME 7NUMBER 2

Peptide Synthesis

COUPLING REAGENTS

NEW UNNATURALAMINO ACIDS

NEW TOOLS FORPEPTIDE PEGYLATION

FLUOROUS PEPTIDESYNTHESIS

Key intermediate stage during the -OAt-mediatedcoupling of two D-alanines

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IntroductionPeptides 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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Vol. 7 No. 2

Aldrich Chemical Co., Inc.Sigma-Aldrich Corporation6000 N. Teutonia Ave.Milwaukee, WI 53209, USA

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ChemFiles is a publication of Aldrich Chemical Co., Inc. Aldrich is a member of the Sigma-Aldrich Group. © 2007 Sigma-Aldrich Co.

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About Our CoverThe 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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Coupling ReagentsIn 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).

H2NO

OR1

PG1HN

O

OPGO

R1ONH

PGNR2

2PG

PG1

OH

ONH

PGNR2

2PG

PGO peptide bond

Amino Acid I Amino Acid II Dipeptide

Activation Coupling

X

ONH

PGNR2

2PG

-HX

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. Tetrahedron2002, 60, 2447.

Azide FormationAzide 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]

PO

OO

N3

72935-10ML-F 10 mL72935-50ML-F 50 mL

Diphenyl phosphoryl azide, 97%DPPA(C6H5O)2P(O)N3

FW: 275.2[26386-88-9]

PO

OO

N3

178756-5G 5 g178756-25G 25 g178756-100G 100 g

Diphenyl phosphoryl azide, technical, >90%DPPA(C6H5O)2P(O)N3

FW: 275.2[26386-88-9]

PO

OO

N3

79627-10ML 10 mL79627-50ML 50 mL

Acid Halogenation ReagentsThe 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,2-trimethyl-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 (Fluoro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate) and BTFFH (Fluoro-N,N,N’,N’-bis(tetramethylene)formamidiniumhexafluorophosphate) 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%(CH3)2C=C(Cl)N(CH3)2FW: 133.62[26189-59-3] Cl

N

498270-5ML 5 mL

Chloro-N,N,N’,N’-bis(tetramethylene)formamidiniumtetrafluoroborate, purum, >97.0% (AT)C9H16BClF4N2

FW: 274.49[115007-14-2]

N N+

Cl

BF4-

23957-1G-F 1 g23957-5G-F 5 g23957-25G-F 25 g

PyClU, purum, >98.0% (CHN)C9H16N2Cl · PF6

FW: 332.65[135540-11-3]

N N+

Cl

PF6-

23955-1G-F 1 g23955-5G-F 5 g23955-25G-F 25 g

Chloro-N,N,N’,N’-tetramethylformamidiniumhexafluorophosphate, purum, >98.0% (T)C5H12ClF6N2PFW: 280.58[207915-99-9]

N N+

Cl

PF6-

09658-5G 5 g09658-25G 25 g

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

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Fluoro-N,N,N’,N’-tetramethylformamidiniumhexafluorophosphate, puriss., >99.0%TFFH[FC[=N(CH3)2]N(CH3)2]PF6

FW: 264.12[164298-23-1]

N N+

F

PF6-

47440-1G-F 1 g47440-5G-F 5 g

Fluoro-N,N,N’,N’-tetramethylformamidiniumhexafluorophosphate, 97%TFFH[FC[=N(CH3)2]N(CH3)2]PF6

FW: 264.12[164298-23-1]

N N+

F

PF6-

520330-1G 1 g520330-5G 5 g

PhosgenePhosgene 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.

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

Cartridge for Phosgene Generation, 0.02 mole 8COCl2FW: 98.92[75-44-5]

519758-1PAK 1 Pak519758-5PAK 5 Pak

Cartridge for Phosgene Generation, 0.05 mole 8COCl2FW: 98.92[75-44-5]

519766-1PAK 1 Pak519766-5PAK 5 Pak

Triphosgene, reagent grade, 98%Cl3COCOOCCl3FW: 296.75[32315-10-9] O

CO

O

Cl3C CCl3

330752-5G 5 g330752-25G 25 g330752-100G 100 g

Phosgene solution, purum, ~20% in tolueneCOCl2FW: 98.92[75-44-5] Cl

CCl

O

79380-100ML 100 mL79380-500ML 500 mL

Thiophosgene, 97%CSCl2FW: 114.98[463-71-8] Cl

CCl

S

115150-5G 5 g115150-25G 25 g115150-100G 100 g

Thiophosgene, technical, ~90%CSCl2FW: 114.98[463-71-8] Cl

CCl

S

89030-25ML 25 mL89030-100ML 100 mL

Fluoro-N,N,N’,N’-bis(tetramethylene)formamidiniumhexafluorophosphate, >99.0%BTFFHC9H16F7N2PFW: 316.2[164298-25-3]

N N+

F

PF6-

17380-5G 5 g17380-25G 25 g

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

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CarbodiimidesCarbodiimide-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-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide). Furthermore EDC or EDAC allow peptide coupling in alcohol or aqueous solutions involving proteins or peptide cyclizations.1

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

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

N,N’-Dicyclohexylcarbodiimide, puriss., >99.0%DCCC6H11N=C=NC6H11

FW: 206.33[538-75-0]

NC

N

36650-100G 100 g36650-500G 500 g36650-2.5KG 2.5 kg

N,N’-Dicyclohexylcarbodiimide, 99.0% DCCC6H11N=C=NC6H11

FW: 206.33[538-75-0]

NC

N

D80002-25G 25 gD80002-100G 100 gD80002-1KG 1 kg

N,N’-Dicyclohexylcarbodiimide solution, purum, ~1 M in methylene chlorideDCCC6H11N=C=NC6H11

FW: 206.33[538-75-0]

NC

N

36652-100ML 100 mL

N,N’-Dicyclohexylcarbodiimide solution, 1.0 M in methylene chlorideDCCC6H11N=C=NC6H11

FW: 206.33[538-75-0]

NC

N

379115-100ML 100 mL379115-800ML 800 mL

N,N’-Dicyclohexylcarbodiimide solution, purum, ~1 M in NMPDCCC6H11N=C=NC6H11

FW: 206.33[538-75-0]

NC

N

36651-100ML-F 100 mL36651-250ML-F 250 mL

WSC, N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide,purum, >97.0%EDC, WSCC8H17N3

FW: 155.24[1892-57-5]

NC

N NCH3

CH3H3C

39391-10ML 10 mL39391-50ML 50 mL

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

NC

N NCH3

CH3H3C

424331-5G 5 g

1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide EDC methiodideC2H5N=C=N(CH2)3N(CH3)3IFW: 297.18[22572-40-3]

NC

N N+H3C CH3

H3C CH3

I-

165344-1G 1 g165344-10G 10 g

N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimidehydrochloride, BioChemika, >99.0%EDC hydrochloride, EDACC8H17N3 · HClFW: 191.7[25952-53-8]

NC

N NCH3

CH3H3C

HCl

03449-1G 1 g03449-5G 5 g03449-25G 25 g

N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimidehydrochloride, SigmaUltraEDC hydrochloride, EDACC8H17N3 · HClFW: 191.7[25952-53-8]

NC

N NCH3

CH3H3C

HCl

E1769-1G 1 gE1769-5G 5 gE1769-10G 10 gE1769-25G 25 g

N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimidehydrochloride, purum, >98.0%EDC hydrochloride, EDACC8H17N3 · HClFW: 191.7[25952-53-8]

NC

N NCH3

CH3H3C

HCl

03450-1G 1 g03450-5G 5 g03450-25G 25 g

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N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimidehydrochloride, commercial grade, powderEDC hydrochloride, EDACC8H17N3 · HClFW: 191.7[25952-53-8]

NC

N NCH3

CH3H3C

HCl

E7750-5G 5 gE7750-10G 10 gE7750-25G 25 gE7750-100G 100 gE7750-1KG 1 kgE7750-5KG 5 kg

N,N’-Diisopropylcarbodiimide, purum, >98.0%DIC(CH3)2CHN=C=NCH(CH3)2

FW: 126.2[693-13-0]

NC

N

38370-25ML 25 mL38370-100ML 100 mL38370-500ML 500 mL

N,N’-Diisopropylcarbodiimide, 99%DIC(CH3)2CHN=C=NCH(CH3)2

FW: 126.2[693-13-0]

NC

N

D125407-5G 5 gD125407-25G 25 gD125407-100G 100 gD125407-1KG 1 kg

1-tert-Butyl-3-ethylcarbodiimide, 99%BEC(CH3)3CN=C=NC2H5

FW: 126.2[1433-27-8]

NC

N

426393-1G 1 g426393-5G 5 g

N-Cyclohexyl-N’-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate, puriss., >99.0% CMCC14H26N3O · C7H7O3SFW: 423.57[2491-17-0]

NC

NN+

O

CH3CH3-O3S

29469-5G 5 g29469-25G 25 g

N-Cyclohexyl-N’-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate, puriss., >97.0%CMCC14H26N3O · C7H7O3SFW: 423.57[2491-17-0]

NC

NN+

O

CH3CH3-O3S

29470-5G 5 g29470-25G 25 g

N-Cyclohexyl-N’-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate, 95%CMCC14H26N3O · C7H7O3SFW: 423.57[2491-17-0]

NC

NN+

O

CH3CH3-O3S

C106402-5G 5 gC106402-25G 25 g

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

NC

N

235563-1G 1 g235563-5G 5 g

N,N’-Di-tert-butylcarbodiimide, purum, >99.0% (GC)(CH3)3CN=C=NC(CH3)3FW: 154.25[691-24-7]

NC

N

34640-5ML 5 mL34640-25ML 25 mL

1,3-Di-p-tolylcarbodiimide, 96%CH3C6H4N=C=NC6H4CH3

FW: 222.29[726-42-1]

NC

N

H3C

CH3

D219800-1G 1 gD219800-5G 5 g

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Imidazolium Derived ReagentsN-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

Kiso developed modified imidazolium reagents like CIP (2-Chloro-1,3-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-1-yloxytris(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 gradeCDIC7H6N4OFW: 162.15[530-62-1]

O

NNN N

115533-5G 5 g115533-10G 10 g115533-25G 25 g115533-100G 100 g

1,1’-Carbonyldiimidazole, purum, >97.0%CDIC7H6N4OFW: 162.15[530-62-1]

O

NNN N

21860-5G 5 g21860-25G 25 g21860-100G 100 g

1,1’-Carbonyl-di-(1,2,4-triazole), technical, >90%CDTC5H4N6OFW: 164.12[41864-22-6]

O

NNN

N NN

21861-5G 5 g

1,1’-Carbonyl-di-(1,2,4-triazole), ~90%CDTC5H4N6OFW: 164.12[41864-22-6]

O

NNN

N NN

C2956-5G 5 g

Oxalic acid diimidazolide, technical, >90% (NT) C8H6N4O2

FW: 190.16[18637-83-7]

NN

N N

O O

75749-5G 5 g75749-25G 25 g

Oxalic acid diimidazolide, technical gradeC8H6N4O2

FW: 190.16[18637-83-7]

NN

N N

O O

366439-1G 1 g366439-5G 5 g

2-Chloro-1,3-dimethylimidazolidinium chloride, purum, >97.0%DMCC5H10Cl2N2

FW: 169.05[37091-73-9]

Cl-N N+

Cl

24374-10G-F 10 g24374-50G-F 50 g

2-Chloro-1,3-dimethylimidazolidinium chlorideDMCC5H10Cl2N2

FW: 169.05[37091-73-9]

Cl-N N+

Cl

529249-25G 25 g

2-Chloro-1,3-dimethylimidazolidinium tetrafluoroborate, purum, >96.0%CIBC5H10BClF4N2

FW: 220.40[153433-26-2]

BF4-N N+

Cl

24377-1G-F 1 g24377-5G-F 5 g

2-Chloro-1,3-dimethylimidazolidinium hexafluorophosphate, purum, >98.0%CIPC5H10ClF6N2PFW: 278.56[101385-69-7]

PF6-N N+

Cl

24375-1G-F 1 g24375-5G-F 5 g24375-25G-F 25 g

2-Chloro-1,3-dimethylimidazolidinium hexafluorophosphate, 98%CIPC5H10ClF6N2PFW: 278.56[101385-69-7]

PF6-N N+

Cl

420336-1G 1 g420336-5G 5 g

2-Fluoro-1,3-dimethylimidazolidinium hexafluorophosphate, puriss., >98.5%DFIHC5H10F7N2PFW: 262.11[164298-27-5]

PF6-N N+

F

17381-5G 5 g17381-25G 25 g

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Phosphonium SaltsPhosphonium 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-disubstitutedamino 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

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.; Alberi-cio, 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.

(Benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate, purum, >98.0%BOP, Castro’s reagentC12H22F6N6OP2

FW: 442.28[56602-33-6]

NN

N

OP+

N

N

H3C CH3

CH3

CH3NCH3H3C

PF6-

12802-5G-F 5 g12802-25G-F 25 g12802-100G-F 100 g

(Benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate, 97%BOP, Castro’s reagentC12H22F6N6OP2

FW: 442.28[56602-33-6]

NN

N

OP+

N

N

H3C CH3

CH3

CH3NCH3H3C

PF6-

226084-1G 1 g226084-5G 5 g

(Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, 98%PyBOP®

C18H28N6OP · PF6

FW: 520.39[128625-52-5]

NN

N

O P+

NN

NPF6

-

377848-1G 1 g377848-5G 5 g

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

C18H28N6OP · PF6

FW: 520.39[128625-52-5]

NN

N

O P+

NN

NPF6

-

12805-1G-F 1 g12805-5G-F 5 g12805-25G-F 25 g

(7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, 96%PyAOPC17H27F6N7OP2

FW: 521.38[156311-83-0]

N NN

N

O P+

NN

NPF6

-

535303-1G 1 g535303-5G 5 g

Bromotris(dimethylamino)phosphonium hexafluorophosphate, purum, >98.0%BroPBrP[N(CH3)2]3PF6

FW: 388.07[50296-37-2]

BrP+N

N

CH3H3C

H3CH3C

NH3C CH3

PF6-

18570-1G 1 g18570-5G 5 g18570-25G 25 g

Bromotris(dimethylamino)phosphonium hexafluorophosphate, 98%BroPBrP[N(CH3)2]3PF6

FW: 388.07[50296-37-2]

BrP+N

N

CH3H3C

H3CH3C

NH3C CH3

PF6-

420107-250MG 250 mg

Chlorotripyrrolidinophosphonium hexafluorophosphate, >98.0%PyCloPC12H24ClN3P · PF6

FW: 421.73[133894-48-1]

ClP+N

NN

PF6-

26564-1G-F 1 g26564-5G-F 5 g26564-25G-F 25 g

Bromotripyrrolidinophosphonium hexafluorophosphate, >95.0%PyBroP®

C12H24BrF6N3P2

FW: 466.18[132705-51-2]

BrP+N

NN

PF6-

18565-1G 1 g18565-5G 5 g18565-25G 25 g

3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one, 98%DEPBTC11H14N3O5PFW: 299.22[165534-43-0]

NNN

OO

PO

OO

CH3

CH3

495964-5G 5 g

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Uronium and Guanidinium SaltsThe 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.

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[4,5-b]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-substitutedamino 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

HN

N

NH

NOTES

H

H

TESO CO2HO

HN

OTBS

O

HN

ONH

N

TBSO

OO

NHTroc

O

NHTBSO

O

NH

O

HNN

OTBS

OO

TrocHN

HO2C

1. Pb/Cd, THF, aq NH4OAc, 1.5 h2. HATU, HOAt, DIEA, DMF, rt, 28 h3. TBAF, AcOH, THF, rt, 55 h

34 % for 3 steps

HN

N

NH

NOTES

H

H

TESOO

HN

OTBS

O

HN

O

NH

N

TBSO

OO

NH

O

NHTBSO

O

NH

HN

N

OTBS

OO

HN

O

O

O

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

O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, purum, >98.0%HBTUC11H16F6N5OPFW: 379.24[94790-37-1]

NN

N+

PF6-N

N+

O-

12804-1G-F 1 g12804-5G-F 5 g12804-25G-F 25 g

O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate, 97%TBTUC11H16N5O · BF4

FW: 321.08[125700-67-6]

NN

N+

BF4-N

N+

O-

12806-5G-F 5 g12806-25G-F 25 g12806-100G-F 100 g12806-250G-F 250 g

O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, purum, >98.0%HATUC10H15F6N6OPFW: 380.23[148893-10-1]

N

NN

N+

PF6-N

N+

O-

11373-1G 1 g11373-5G 5 g11373-25G 25 g

O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, 97%HATUC10H15F6N6OPFW: 380.23[148893-10-1] N

NN

N+

PF6-N

N+

O-

445460-1G 1 g 445460-5G 5 g445460-25G 25 g

O-(Benzotriazol-1-yl)-N,N,N’,N’-bis(tetramethylene)uronium hexafluorophosphate, purum, >98.0%HBPyUC15H20F6N5OPFW: 431.32[105379-24-6]

NN

NPF6

-

O

N

N+

12809-1G-F 1 g12809-5G-F 5 g12809-25G-F 25 g

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

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

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. Tetrahe-dron 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.

si

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O-Benzotriazol-1-yl-N,N,N’,N’-bis(pentamethylene)uronium hexafluorophosphate, 98%HBPipUC17H24F6N5OPFW: 459.37[190849-64-0]

NN

NPF6

-

O

N

N+

420271-1G 1 g

O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’- 8tetramethyluronium hexafluorophosphate, purum, >98.0%HCTUC11H15ClF6N5OPFW: 413.69[330645-87-9]

NN

NPF6

-

O

N

N+Cl

04936-5G-F 5 g04936-25G-F 25 g04936-100G-F 100 g

O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’- 8tetramethyluronium, purum, >98.0%TCTUC11H15BClF4N5OFW: 355.53[330641-16-2]

NN

NBF4

-

O

N

N+Cl

78133-5G-F 5 g78133-25G-F 25 g78133-100G-F 100 g

O-(3,4-Dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate, purum, >99.0%TDBTUC12H16BF4N5O2

FW: 349.09[125700-69-8]

BF4-

NNN

OO N+

N

37345-1G-F 1 g37345-5G-F 5 g37345-25G-F 25 g

O-(2-Oxo-1(2H)pyridyl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate, purum, ≥ 99.0%TPTUC10H16BF4N3O2

FW: 297.06[125700-71-2]

BF4-

N

OO N+

N

37347-1G 1 g37347-5G 5 g37347-25G 25 g

O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N’,N’-tetramethyluronium hexafluorophosphate, purum, >97.0%HOTUC10H17F6N4O3PFW: 386.23

PF6-

N

CNO

N

N+

O

O

02576-1G 1 g02576-5G 5 g02576-25G 25 g

O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N’,N’-tetramethyluronium tetrafluoroborate, purum, >98.0%TOTUC2H5O2CC(CN)=NOC[N(CH3)2]=N(CH3)2BF4

FW: 328.07[136849-72-4]

BF4-

N

CNO

N

N+

O

O

02580-1G 1 g02580-5G 5 g02580-25G 25 g

O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N’,N’-tetramethyluronium tetrafluoroborate, 98%TOTUC2H5O2CC(CN)=NOC[N(CH3)2]=N(CH3)2BF4

FW: 328.07[136849-72-4]

BF4-

N

CNO

N

N+

O

O

382469-1G 1 g382469-5G 5 g

N,N,N’,N’-Tetramethyl-O-(N-succinimidyl)uronium hexafluorophosphate, purum, >99.0%HSTUC9H16F6N3O3PFW: 359.21[265651-18-1]

PF6-N O

N

N+

O

O

09668-1G 1 g09668-5G 5 g09668-25G 25 g

N,N,N’,N’-Tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate, 97%TSTUC9H16BF4N3O3

FW: 301.05[105832-38-0]

BF4-N O

N

N+

O

O

385530-1G 1 g385530-5G 5 g

Dipyrrolidino(N-succinimidyloxy)carbenium , purum, >98.0%HSPyUC13H20F6N3O3PFW: 411.28[207683-26-9]

PF6-N O

N

N+

O

O

85971-1G 1 g85971-5G 5 g85971-25G 25 g

S-(1-Oxido-2-pyridyl)-N,N,N’,N’- 8tetramethylthiuronium tetrafluoroborate, purum, >95.0%TOTTC10H16BF4N3OSFW: 313.12[255825-38-8]

BF4-S

N

N+N+O-

94623-5G-F 5 g94623-25G-F 25 g

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Miscellaneous Coupling ReagentsPropylphosphonic anhydride (T3P®)1 is a very efficient, non-toxic 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-chloromethyl-pyridinium iodide to peptide chemistry, which found application in the synthesis of a b-lactam carbacepham skeleton.3

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

References: (1) T3P is a registered trademark of Clariant. (2) Klose, J. et al. Chem. Com-mun. 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.

N

N

N

MeO OMe

Cl

+

N

O THF,rt, 30 min

100 %N

N

N

MeO OMe

N+

O Cl-

CDMT NMM DMTMM

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

Propylphosphonic anhydride solution, 50 wt. % in ethyl acetateC9H21O6P3

FW: 318.18[68957-94-8]

PO

PO

PO

O

O

O

431303-10ML 10 mL431303-50ML 50 mL

Propylphosphonic anhydride solution, technical, ~50% in ethyl acetateC9H21O6P3

FW: 318.18[68957-94-8]

PO

PO

PO

O

O

O

81799-10ML 10 mL81799-50ML 50 mL81799-250ML 250 mL

Propylphosphonic anhydride solution, technical, ~50% in DMFC9H21O6P3

FW: 318.18[68957-94-8]

PO

PO

PO

O

O

O

81801-25ML 25 mL81801-100ML 100 mL

2-Chloro-1-methylpyridinium iodide, purum, >97.0% (AT)C6H7ClINFW: 255.48[14338-32-0]

N+

CH3

Cl

I-

25270-25G 25 g25270-100G 100 g

2-Chloro-1-methylpyridinium iodide, 97%C6H7ClINFW: 255.48[14338-32-0]

N+

CH3

Cl

I-

198005-10G 10 g198005-25G 25 g198005-100G 100 g

2-Chloro-4,6-dimethoxy-1,3,5-triazine, purum, >98.0%CDMTC5H6ClN3O2

FW: 175.57[3140-73-6]

N

N

N

O OH3C CH3

Cl

24320-5G-F 5 g24320-25G-F 25 g

2-Chloro-4,6-dimethoxy-1,3,5-triazine, 97%CDMTC5H6ClN3O2

FW: 175.57[3140-73-6]

N

N

N

O OH3C CH3

Cl

375217-5G 5 g

4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride, purum, >98.0%DMTMMC10H17ClN4O3

FW: 276.72[3945-69-5]

N

N

N

O OH3C CH3

N+

O

CH3 Cl-

74104-1G-F 1 g74104-5G-F 5 g

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Am

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Aci

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New Unnatural Amino AcidsUnnatural 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.

b-amino Acids

(cis)-3-Aminobicyclo[2.2.1]heptane-2-carboxylic acid 8hydrochloride, purum, >98.0% (TLC)C8H13NO2 · HClFW: 191.66

NH2

OOH

HCl

08356-1G-F 1 g

4-Amino-nicotinic acid, purum, >97.0% (HPLC) 8C6H6N2O2

FW: 138.12[7418-65-7]

O

OH

N

NH2

11585-5G-F 5 g

cis-2-(Boc-amino)-cyclohexanecarboxylic acid, 8purum, >98.0% (TLC)C12H21NO4

FW: 243.3[63216-49-9]

HN

BOC

OHO

36314-1G-F 1 g

cis-2-(Fmoc-amino)-cyclohexanecarboxylic acid, 8purum, >98.0% (HPLC)C22H23NO4

FW: 365.42[194471-85-7]

HN

Fmoc

OHO

29294-1G-F 1 g

cis-2-Amino-2-methylcyclohexanecarboxylic acid 8hydrochloride, purum, >98.0% (CHN)C8H15NO2 · HClFW: 193.67[202921-88-8]

NH2

OHO

HCl

30254-500MG-F 500 mg

cis-2-Amino-2-methylcyclopentanecarboxylic acid 8hydrochloride, purum, >98.0% (CHN)C7H13NO2 · HClFW: 179.64[156292-34-1] HCl

OHO

NH2

39927-500MG-F 500 mg

cis-2-Aminocycloheptanecarboxylic acid 8hydrochloride, purum, >98.0% (TLC)C8H15NO2 · HClFW: 193.67

HCl

OHO

NH2

11252-500MG-F 500 mg

Fmoc-D-b-Homophe-OH, purum, >97.0% (HPLC) 8C25H23NO4

FW: 401.45[209252-16-4] OH

ONHFmoc

18074-500MG-F 500 mg

Trans-2-(Boc-amino)-cyclohexanecarboxylic acid, 8purum, >98.0% (TLC)C12H21NO4

FW: 243.3[209128-50-7]

HN

O OH

BOC

29293-1G-F 1 g

trans-2-(Fmoc-amino)-cyclohexanecarboxylic acid, 8purum, >98.0% (HPLC)C22H23NO4

FW: 365.42[381241-08-3]

HN

O OH

Fmoc

28319-1G-F 1 g

Z-DL-b-Homoalanine, purum, >98.0% (HPLC) 8C12H15NO4

FW: 237.25

OH

ONHO

O

39599-1G 1 g39599-5G 5 g

Z-b-Homoala-OH, purum, >98.0% 8C12H15NO4

FW: 237.25[83509-88-0]

OH

ONHO

O

61669-500MG-F 500 mg

Phenylglycine Derivatives

2-(4-Boc-piperazino)-2-[2-(trifluoromethyl)phenyl] 8acetic acid, purum, >95.0% (HPLC)C18H23F3N2O4

FW: 388.38

O

OHN

N

F3C

BOC

38903-500MG-F 500 mg

2-(4-Boc-piperazino)-2-phenylacetic acid, purum, 8>97.0% (HPLC)C17H24N2O4

FW: 320.38

O

OHN

NBOC

16298-500MG-F 500 mg

3-(Trifluoromethyl)-DL-phenylglycine, purum, 8>98.0% (HPLC)C9H8F3NO2

FW: 219.16[242475-26-9]

O

OHNH2

F3C

53636-500MG-F 500 mg

Methyl 2-(4-Boc-piperazino)-2-(2-pyridyl)acetate, 8purum, >95.0% (HPLC)C17H25N3O4

FW: 335.4N

N

OCH3O

NBOC

19578-500MG-F 500 mg

13


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ral

Am

ino

Acid

s

Alanine Derivatives

4-(Hydroxymethyl)-D-phenylalanine, purum, 8>97.0% (HPLC)C10H13NO3

FW: 195.22

O

OHNH2HO

43667-500MG 500 mg

Boc-3-(1,2,4-triazol-1-yl)-Ala-OH, purum 8C10H16N4O4

FW: 256.26 N

O

OHHN

BOC

N

N

50996-500MG-F 500 mg

Boc-3-(1-pyrazolyl)-Ala-OH, purum, >97.0% (HPLC) 8C11H17N3O4

FW: 255.27[21012-18-0]

N

O

OHHN

BOC

N

67387-500MG-F 500 mg

Boc-4,5-dehydro-Leu-OH dicyclohexylamine salt, 8purum, >96.0% (HPLC)C11H19NO4 · C12H23NFW: 410.59[87720-54-5]

O

OH

HN

HNBOC

11578-50MG 50 mg

Fmoc-3-(1,2,4-triazol-1-yl)-Ala-OH, purum, 8>97.0% (HPLC)C20H18N4O4

FW: 378.38 N

O

OHHN

Fmoc

N

N

53229-500MG-F 500 mg

Fmoc-3-(1-pyrazolyl)-Ala-OH, purum, >97.0% (HPLC) 8C21H19N3O4

FW: 377.39 N

O

OHHN

Fmoc

N

51916-500MG-F 500 mg

L-a-Neopentylglycine, purum, >98.0% (TLC) 8C7H15NO2

FW: 145.2[57224-50-7]

OH

O

NH2

73489-1G-F 1 g73489-5G-F 5 g

Proline Derivatives

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

HClNH O

OH

06541-500MG-F 500 mg

(S)-a-Allyl-proline hydrochloride, purum, >98.0% (TLC) 8C8H13NO2

FW: 155.19[129704-91-2] N

HO

OH

06594-500MG-F 500 mg

Boc-(R)-4-(3,4-difluorobenzyl)-L-proline, purum, 8>97.0% (HPLC)C17H21F2NO4

FW: 341.35N O

OH

BOCF

F

40372-500MG-F 500 mg

Boc-(R)-4-[2-(trifluoromethyl)benzyl]-L-proline, 8purum, >98.0% (HPLC)C18H22F3NO4

FW: 373.37

N O

OH

BOC

CF3

38455-500MG-F 500 mg

Boc-(R)-4-[4-(trifluoromethyl)benzyl]-L-proline, 8purum, >98.0% (HPLC)C18H22F3NO4

FW: 373.37N O

OH

BOC

F3C

01336-500MG-F 500 mg

Boc-(R)-a-(4-fluorobenzyl)-Pro-OH, purum, 8>98.0% (HPLC)C17H22FNO4

FW: 323.36[706806-64-6]

NO

OH

BOC

F

67420-500MG-F 500 mg

Boc-(R)-a-(4-tert-butylbenzyl)-Pro-OH, purum, 8>97.0% (HPLC)C21H31NO4

FW: 361.48

NO

OH

BOC

39793-500MG-F 500 mg

Boc-(R)-a-(4-trifluoromethylbenzyl)-Pro-OH, 8purum, >98.0% (HPLC)C18H22F3NO4

FW: 373.37

NO

OH

BOC

CF3

42004-500MG-F 500 mg

Boc-(R)-a-allyl-Pro-OH, purum, >98.0% (HPLC) 8C13H21NO4

FW: 255.31[144085-23-4] N

O

OH

BOC

06538-500MG-F 500 mg

Boc-(R)-a-benzyl-Pro-OH, purum, >99.0% (HPLC) 8C17H23NO4

FW: 305.37[706806-60-2]

NO

OH

BOC

47079-500MG-F 500 mg

si

gm

a-

al

dr

ic

h.

co

m

14


14N

ew

Un

natu

ral

Am

ino

Aci

ds

Boc-(S)-a-(4-fluorobenzyl)-Pro-OH, purum, 8>98.0% (HPLC)C17H22FNO4

FW: 323.36[706806-65-7]

NO

OH

BOC

F

14931-500MG-F 500 mg

Boc-(S)-a-(4-tert-butylbenzyl)-Pro-OH, purum, 8>98.0% (HPLC)C21H31NO4

FW: 361.48

NO

OH

BOC

39166-500MG-F 500 mg

Boc-(S)-a-(4-trifluoromethylbenzyl)-Pro-OH, purum, 8>98.0% (HPLC)C18H22F3NO4

FW: 373.37

NO

OH

BOC

CF3

05199-500MG-F 500 mg

Boc-(S)-a-allyl-Pro-OH, purum, >98.0% (HPLC) 8C13H21NO4

FW: 255.31[706806-59-9] N

O

OH

BOC

06486-500MG-F 500 mg

Boc-(S)-a-benzyl-Pro-OH, purum, >97.0% (HPLC) 8C17H23NO4

FW: 305.37[706806-61-3]

NO

OH

BOC

76896-500MG-F 500 mg

Miscellaneous

(S)-6-Oxo-2-piperidinecarboxylic acid, purum, 8>97.0% (HPLC)C6H9NO3

FW: 143.14[34622-39-4]

NH

O

OHO

36323-1G-F 1 g36323-5G-F 5 g

2-[2-(Boc-amino)ethoxy]ethoxyacetic acid 8dicyclohexylamine salt, purum, >98.0% (TLC)C11H21NO6 · C12H23NFW: 444.61

O

OHO

ONH

BOCHN

14766-500MG-F 500 mg

8 Safe and Simple Application of Phosgene in Your Lab!Phosgene Generation KitPhosgene 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

Name Mol. Formula MW or FW CAS No. Cat. No.Cartridge for Phosgene Generation, Starter Kit

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

519782-1KT

Cartridge for Phosgene Generation, 0.02 mole COCl2 98.92 75-44-5 519758-1PAK

519758-5PAK

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

519766-5PAK

Visit sigma-aldrich.com for full details.

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

15


New

Too

ls for

Pep

tide P

EG

yla

tion

New Tools for Peptide PEGylationCirculatory 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.

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.

tert-Butyl 12-amino-4,7,10-trioxadodecanoate 8C13H27NO5

FW: 277.36[252881-74-6] O

OO

O

OH2N

83060-1G-F 1 g83060-5G-F 5 g

O,O’-Oxydiethylene-diglycolic acid 8C8H14O7

[13887-98-4]HO

OO

OOH

OO

92893-50ML 50 mL92893-250ML 250 mL

{2-[2-(Fmoc-amino)ethoxy]ethoxy}acetic acid, 8purum, >95.0%C21H23NO6

FW: 385.41[166108-71-0]

HN

OO

OH

O

Fmoc

95003-500MG-F 500 mg

2-[2-(2-Methoxyethoxy)ethoxy]acetic acid, 8technical, >90%CH3(OCH2CH2)2OCH2CO2HFW: 178.18[16024-58-1] H3C

OO

OOH

O

64732-250ML 250 mL64732-1L 1 L

Methoxypolyethylene glycol 5,000 maleimide, 8BioChemika, >90%[99126-64-4]

OO

ON

O

On

63187-1G 1 g63187-5G 5 g

O,O’-Bis[2-(succinylamino)ethyl]polyethylene glycol 8HOOCCH2CH2CONH(CH2

CH2O)nCH2CH2NHCOCH2

CH2COOHMr 10000

OO

NH

HN

n

O

O

OH

O

O

HO

14571-250MG 250 mg14571-1G 1 g


CH2O)nCH2CH2NHCOCH2

CH2COOHMr 6000

OO

NH

HN

n

O

O

OH

O

O

HO

14569-250MG 250 mg14569-1G 1 g


CH2O)nCH2CH2NHCOCH2

CH2COOHMr 20000

OO

NH

HN

n

O

O

OH

O

O

HO

14573-250MG 250 mg14573-1G 1 g


CH2O)nCH2CH2NHCOCH2

CH2COOHMr 3000

OO

NH

HN

n

O

O

OH

O

O

HO

14567-250MG 250 mg

Hycron linker 8C17H31BrO6

FW: 411.33[166668-33-3]

OO

OO O

O

Br

96823-1G-F 1 g96823-5G-F 5 g

O,O’-Bis(2-aminoethyl)octadecaethylene glycol, 8>95% (oligomer purity)C40H84N2O19

FW: 897.1 OO

NH2H2N

18

06703-1G-F 1 g

O,O’-Bis(2-carboxyethyl)dodecaethylene glycol, 8>95% (oligomer purity)C30H58O17

FW: 690.77O

O12

O

HOO

OH

94704-1G-F 1 g

O-Methyl-undecaethylene glycol, >95% 8(oligomer purity)HO(CH2CH2O)11CH3

FW: 516.62[114740-40-8]

H3CO

O11

H

16603-500MG-F 500 mg

O-Methyl-heptaethylene glycol, >95% 8(oligomer purity)HO(CH2CH2O)7CH3

FW: 340.41[4437-01-8]

H3CO

O7

H

41749-1G-F 1 g

Octaethylene glycol, >95% (oligomer purity) 8HO(CH2CH2O)8HFW: 370.44[5117-19-1]

HOO

8

H

15879-1G-F 1 g15879-5G-F 5 g

si

gm

a-

al

dr

ic

h.

co

m

16


New

To

ols

fo

r Pep

tid

e P

EG

yla

tio

n

O-(2-tert-Butyloxycarbonylethyl)dodecaethylene 8glycol, >95% (oligomer purity)C31H62O15

FW: 674.81 HOO

12O

O

08453-500MG-F 500 mg

Methoxypolyethylene glycol 5,000 acetic acid, 8BioChemika, >80%

OO

OHn

H3CO

70718-1G-F 1 g70718-5G-F 5 g70718-25G-F 25 g

Methoxypolyethylene glycol 5,000 propionic acid, 8BioChemika, >80%

OO

nO

OHH3C

88908-1G-F 1 g88908-5G-F 5 g88908-25G-F 25 g

N-Boc-2,2’-(ethylenedioxy)diethylamine, purum, 8>95.0%C11H24N2O4

FW: 248.32[153086-78-3]

H2NO

ONH

BOC

89761-1G-F 1 g89761-5G-F 5 g

N-Boc-4,7,10-trioxa-1,13-tridecanediamine, purum, 8>97.0%C15H32N2O5

FW: 320.42 OO

O NH

H2NBOC

93113-1G-F 1 g

O-(2-Aminoethyl)-O’-[2-(Boc-amino)ethyl] 8polyethylene glycol 5000

OO

NHn

BOCH2N

671266-100MG 100 mg671266-500MG 500 mg

O-[2-(Fmoc-amino)-ethyl]-O’-(2-carboxyethyl) 8polyethylene glycol 3000

OO

n

OHHN

FmocO

669717-100MG 100 mg669717-500MG 500 mg

Octacosaethylene glycol 8HO(CH2CH2O)28HFW: 1251.49 HO

O28

H

672351-500MG 500 mg

O-(2-Mercaptoethyl)-O’-methyl-hexa(ethylene glycol) 8C15H32O7SFW: 356.48 O

OSH

6

H3C

672572-250MG 250 mg

O-(2-Carboxyethyl)-O’-(2-mercaptoethyl) 8heptaethylene glycolC19H38O10SFW: 458.56

OO

SH7

HO

O

672688-250MG 250 mg


OO

NHn

H2N BOC

671150-500MG 500 mg


OO

NHn

H2N BOC

671363-100MG 100 mg671363-500MG 500 mg

Monthly Chemistry E-Newsletter

Got ChemNews?sigma-aldrich.com/chemnews

17


Fluo

rou

s Pep

tide

Syn

thesis

Fluorous Peptide SynthesisFluorous-phase chemistry offers new synthesis and separation strategies for the synthesis of peptides in solution or in SPPS. Orthogonal to other purification procedures, Fluorous Solid-Phase 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).

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.

2-Chloro-4,6-bis[3-(perfluorohexyl)propyloxy]- 81,3,5-triazineC21H12ClF26N3O2

FW: 867.75 N

N

N

Cl

O O (CF2)5CF3F3C(F2C)5

672378-1G 1 g

4-(3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctylthio) 8phenol, >97% C14H9F13OSFW: 472.26

OH

S

(CF2)5CF3

43893-1G-F 1 g43893-5G-F 5 g

4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10- 8Heptadecafluorodecylthio)phenol, >97% C16H9F17OSFW: 572.28

OH

S

(CF2)7CF3

40829-1G-F 1 g40829-5G-F 5 g

PG

HN

O

OR1

HN

O

OR1O

NH

PGR2PG

PGPG

OH

ONH

PGR2PG

Activation

Deprotection

Capping

Cleavage

FINISHED PEPTIDE Fluorouscap-tags

Fluorouscouplingreagents

Fluorous side-chainprotecting group

Fluorousacid- or base-labileN-protecting group

Fluorouspurification tags

Fluorous Peptide Coupling Tools

2,7-Bis(1H,1H,2H,2H-perfluorooctyl)-9- 8fluorenylmethoxycarbonyl-chloridC31H17ClF26O2

FW: 950.88 (CF2)5CF3F3C(F2C)5

O

Cl O

672262-1G 1 g

2-[(4,4,5,5,6,6,7,7,7-Nonafluoro-1,1-dimethylheptyloxy)-carbonyloxyimino]-2-phenylacetonitrileC18H15F9N2O3

FW: 478.31 NC NO O

O

(CF2)3CF3

01382-1G-F 1 g

2-[(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluoro-1,1-dimethylnonyloxy) carbonyloxyimino]-2-phenylacetonitrileC20H15F13N2O3

FW: 578.32 NC NO O

O

(CF2)5CF3

11807-1G-F 1 g11807-5G-F 5 g

2-[(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Heptadecafluoro-1,1-dimethylundecyloxy)carbonyloxyimino]-2-phenylacetonitrileC22H15F17N2O3

FW: 678.34[350716-42-6] NC N

O O

O

(CF2)7CF3

55118-1G-F 1 g55118-5G-F 5 g

Fluorous Protecting Groups

si

gm

a-

al

dr

ic

h.

co

m

18


Flu

oro

us

Pep

tid

e

Syn

thesi

s

N-[4-(3,3,4,4,5,5,6,6,6-Nonafluorohexyl)benzyloxycarbonyloxy]succinimideC18H14F9NO5

FW: 495.29O O

ON

F3C(F2C)3

O

O

00246-1G-F 1 g

N-[4-(3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctyl)benzyloxycarbonyloxy] succinimide C20H14F13NO5

FW: 595.31[556050-48-7] O O

ON

F3C(F2C)5

O

O

05656-1G-F 1 g05656-5G-F 5 g

N-[4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl) benzyloxycarbonyloxy]succinimideC22H14F17NO5

FW: 695.32[556050-49-8] O O

ON

F3C(F2C)7

O

O

14944-1G-F 1 g14944-5G-F 5 g

4-(4,4,5,5,6,6,7,7,7-Nonafluoroheptyloxy)benzyl alcohol C14H13F9O2

FW: 384.24O

OH

F3C(F2C)3

01452-1G-F 1 g

4’-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyloxy)benzyl alcoholC16H13F13O2

FW: 484.25O

OH

F3C(F2C)5

67772-1G-F 1 g67772-5G-F 5 g

4-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Heptadecafluoroundecyloxy)benzyl alcoholC18H13F17O2

FW: 584.27O

OH

F3C(F2C)7

97071-1G-F 1 g97071-5G-F 5 g

4-(3,3,4,4,5,5,6,6,6-Nonafluorohexyl)benzyl alcohol, >95%C13H11F9OFW: 354.21 OH

F3C(F2C)3

08431-1G-F 1 g

4-(3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctyl)benzyl alcohol, >97.0%C15H11F13OFW: 454.23[356055-76-0]

OH

F3C(F2C)5

16638-1G-F 1 g16638-5G-F 5 g

4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl)-benzyl alcohol, >98.0%C17H11F17OFW: 554.24[356055-77-1]

OH

F3C(F2C)7

19563-1G-F 1 g19563-5G-F 5 g

1-(4-Methoxyphenyl)-1-[4-(1H,1H,2H,2H- 8 perfluorodecyl)phenyl]-1-phenylmethyl chlorideC30H20ClF17OFW: 754.91[865758-37-8]

F3C(F2C)7

Cl

OCH3

672149-1G 1 g

1,1-Di-(4-methoxyphenyl)-1-[4-(1H,1H,2H,2H- 8perfluorodecyl)phenyl]methanol, 97%C31H23F17O3

FW: 766.49[865758-47-0]

F3C(F2C)7

OH

OCH3

OCH3

672696-1G 1 g

Diisopropyl(3,3,4,4,5,5,6,6,6-nonafluorohexyl)silane, >95%C12H19F9SiFW: 362.35[356056-13-8]

SiF3C(F2C)3

H

18976-1G-F 1 g

Diisopropyl(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)silane, >95%C14H19F13SiFW: 462.37[356056-14-9]

SiF3C(F2C)5

H

00454-1G-F 1 g00454-5G-F 5 g

Diisopropyl(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadeca-fluorodecyl)silane, >95%C16H19F17SiFW: 562.38[356056-15-0]

SiF3C(F2C)7

H

04537-1G-F 1 g04537-5G-F 5 g

19


Fluo

rou

s Pep

tide

Syn

thesis

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

FW: 489.19F3C(F2C)5 O

ON

O

O

41687-5MG 5 mg41687-25MG 25 mg

N-Succinimidyl 4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11- 8heptadecafluoroundecanoate, purum, >98.0%C15H8F17NO4

FW: 589.2[852527-45-8] F3C(F2C)7 O

ON

O

O

73028-5MG 5 mg73028-25MG 25 mg

4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyl azide, 8purum, >97.0%C9H6F13N3

FW: 403.14[852527-60-7]

F3C(F2C)3 N3

77983-5MG 5 mg77983-25MG 25 mg

4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11- 8Heptadecafluoroundecyl azide, purum, >97.0%C11H6F17N3

FW: 503.16[852527-61-8]

F3C(F2C)5 N3

97087-5MG 5 mg97087-25MG 25 mg

N-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11- 8Heptadecafluoroundecyl)maleimide, purum, >97.0%C15H8F17NO2

FW: 557.2[852527-40-3]

F3C(F2C)5 N

O

O

40889-5MG 5 mg40889-25MG 25 mg

N-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyl) 8iodoacetamide, purum, >98.0%C11H9F13INOFW: 545.08[852527-50-5]

F3C(F2C)5HN

OI

51526-5MG 5 mg51526-25MG 25 mg

N-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11- 8Heptadecafluoroundecyl)iodoacetamide, purum, >98.0%C13H9F17INOFW: 645.09[852527-48-1]

F3C(F2C)6HN

OI

55266-5MG 5 mg55266-25MG 25 mg

Fluorous Proteomics Reagents

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

14196-1EA-F 20 pieces









FluoroFlash® TLC Plates with F254 indicator, dimension 5 cm x 10 cm


FluoroFlash® Silica Gel, ~40 μm particle size

08965-1EA-F 100 g

Fluorous Separation Media

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.

Fluorous separation using solid-phase extraction: a mixture of a nonfl uorous dye (blue) and a fl uorous dye (orange) are loaded on a fl uorous sorbent (see left-hand test tube). The nonfl uorous dye can be washed with aequeous methanol (middle test tube). The fl uorous dye remains on the sorbent until the elution with a fl uorophilic wash (e.g. with pure methanol, right hand test tube).

JJH03/2007

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chemfiles vol. 7, no. 2 - peptide synthesis

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