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Vol. 8, No. 1

Chemical Ligation

Chemical Ligation by Click Chemistry Native Chemical Ligation Staudinger Ligation Diphenylphosphinemethanethiol: efficacious for traceless Organic Azides and Staudinger ligation Azide Sources Functionalized 

Introduction Vol. 8 No. 1 More and more researchers face the task of selectively combining large , attaching molecular probes, or covalently Aldrich Chemical Co., Inc. immobilizing substrates on surfaces. In particular when biopolymers Sigma-Aldrich Corporation and bioconjugates are involved there is an urgent need for mild and 6000 N. Teutonia Ave. biocompatible reaction conditions. A toolbox of several powerful Milwaukee, WI 53209, USA chemical ligation techniques already exists and is continually being expanded. In this issue of ChemFiles, we provide an overview of modern To Place Orders chemical ligation methods and introduce highly innovative and Telephone 800-325-3010 (USA) unique new tools for research at the interface between chemistry FAX 800-325-5052 (USA) and biology. The most prominent chemical ligation techniques (click chemistry, native chemical ligation, and Staudinger ligation) will be discussed. A comprehensive listing of available organic azides and functionalized alkynes rounds off this Customer & Technical Services issue of ChemFiles with valuable building blocks for click chemistry or Staudinger ligation. Customer Inquiries 800-325-3010 If you are unable to find the specific reagent you need, “Please Bother Us.” with your Technical Service 800-231-8327 suggestions at [email protected], or contact your local Sigma-Aldrich® office SAFC™ 800-244-1173 Introduction (see back cover). Custom Synthesis 800-244-1173 Flavors & Fragrances 800-227-4563 International 414-438-3850 CPR Let Discovery Put High Throughput 24-Hour Emergency 414-438-3850 Web Site sigma-aldrich.com Back in Your Operation! Email [email protected]

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ChemFiles (ISSN 1933–9658) is a publication of About Our Cover Aldrich Chemical Co., Inc. Aldrich is a member of the The cover structure depicts diphenylphosphinemethanethiol, the most efficacious Sigma-Aldrich Group. © 2008 Sigma-Aldrich Co. reagent known today to induce traceless Staudinger ligations (Raines ligation reagent). Diphenylphosphinemethanethiol can be obtained easily from the shelf-stable precursor 670359 by removing the acetyl and protective groups. 

Chemical Ligation by Click Chemistry—A “Click” Away from Discovery

The traditional process of drug discovery based on natural In an extensive study Finn and co-workers only recently showed secondary metabolites has often been slow, costly, and labor- that tris(2-benzimidazolylmethyl)amines (general structure in intensive. Even with the advent of combinatorial chemistry Figure 2) are the most promising family of accelerating ligands and high-throughput screening in the past two decades, the for the Cu catalyzed azide- cycloaddition reaction from generation of leads is dependent on the reliability of the individual among more than 100 mono-, bi-, and polydentate candidates.10 reactions to construct the new molecular framework. Under both preparative (high concentration, low catalyst loading) and dilute (lower concentration, higher catalyst Click chemistry is a newer approach to the synthesis of drug- loading) conditions, these tripodal benzimidazole derivatives give like molecules that can accelerate the drug discovery process

substantial improvements in rate and yields, with convenient Chemistry Click by Ligation Chemical by utilizing a few practical and reliable reactions. Sharpless and workup to remove residual Cu and ligand. co-workers have defined what makes a click reaction: one that is wide in scope and easy to perform, uses only readily available A new reagent developed by Carolyn R. Bertozzi and co-workers reagents, and is insensitive to oxygen and water. In fact, water is eliminates the toxicity to living cells that is usually associated with in several instances the ideal reaction , providing the best the catalyzed Huisgen 1,3-dipolar cycloaddition.11 By using yields and highest rates. Reaction work-up and purification uses a difluorinated cyclooctyne (Figure 3) instead of the usual terminal benign and avoids chromatography.1 alkyne a rapid cycloaddition reaction takes place even without a catalyst. The ring strain and the electron-withdrawing difluoro Of the reactions comprising the click universe, the “perfect” group activate the alkyne for copper-free click chemistry. This example is the Huisgen 1,3-dipolar cycloaddition of alkynes to method was used to attach fluorescent labels to cells with azide- azides to form 1,4-disubsituted-1,2,3-triazoles (Scheme 1). The containing sialic in their surface glycans. Thus, it was possible copper(I)-catalyzed reaction is mild and very efficient, requiring no to study the dynamics of glycan trafficking in living cells over the protecting groups and no purification in many cases.2 The azide course of 24 hours with no indication that the reaction or the and alkyne functional groups are largely inert towards biological labels perturb the process. This is an impressive example of how molecules and aqueous environments, which allows the use of copper-free click chemistry can be used as a biologically friendly the Huisgen 1,3-dipolar cycloaddition in target guided synthesis3 method to label and track biomolecules in living cells. and activity-based profiling,4 or the ligation of biopolymers to probes or surfaces.5 For example, Carell and co-workers Sigma-Aldrich® proudly offers a choice of catalysts and ligands demonstrated the labelling of alkyne modified DNA oligomers for the Huisgen cycloaddition reaction. Later sections in this issue with fluorescence probes by click chemistry.6 present a comprehensive overview of available organic azides, azide sources, and alkynes that may be applied in click chemistry. The triazole has similarities to the ubiquitous amide moiety found in nature. Thus triazole formation was used for the otherwise If you want to learn about hot new product additions to the difficult macrocyclization of a cyclic tetrapeptide analog to a click chemistry universe and other innovative areas of chemical potent tyrosinase inhibitor.7 synthesis as soon as they become available, please check our regularly updated product highlights at sigma-aldrich.com/ Additionally triazoles are nearly impossible to oxidize or reduce. chemicalsynthesis. This is a main reason why material science has discovered Huisgen cycloadditions as major ligation tools in diverse areas such as References: (1) For recent reviews, see: (a) Kolb, H. C.; Sharpless, K. B. Drug Discovery polymer science or nanoelectronics.8 Today 2003, 8, 1128. (b) Kolb, H. C. et al. Angew. Chem. Int. Ed. 2001, 40, 2004. (2)(a) Rostovtsev, V. V.; Green, L.G.; Fokin, V.V.; Sharpless, K.B. Angew. Chem. Int. Ed. Using Cu(II) salts with ascorbate has been the method of 2002, 41, 2596. (b) Tornøe, C. W. et al. J. Org. Chem. 2002, 67, 3057. (3)(a) Manetsch, choice for the preparative synthesis of 1,2,3-triazoles, but it is R. et al. J. Am. Chem. Soc. 2004, 126, 12809. (b) Lewis, W.G. et al. Angew. Chem. Int. Ed. 2002, 41, 1053. (4) Speers, A. E. J. Am. Chem. Soc. 2003, 125, 4686. (5) Wolfbeis, problematic in bioconjugation applications. However, O.S. Angew. Chem. Int. Ed. 2007, 46, 2980. (6) Gierlich, J.; Burley, G.A.; Gramlich, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine, TBTA (Figure 1), P.M.E.; Hammond, D.M.; Carell, T. Org. Lett. 2006, 8, 3639. (7) Bock, V.D.; Perciaccente, has been shown to effectively enhance the copper-catalyzed R.; Jansen, T.P.; Hiemstra, H.; Maarseveen, J.H. Org. Lett. 2006, 8, 919. (8) Lutz, J.-F. 9 Angew. Chem. Int. Ed. 2007, 46, 1018. (9) Chan, T.R. et al. Org. Lett 2004, 6, 2853. cycloaddition without damaging biological scaffolds. (10) Rodionov, V. O.; Presolski, S. I.; Gardinier, S.; Lim, Y.-H.; Finn, M. G. J. Am. Chem. Soc. 2007, 129, 12696. (11) Baskin, J.M.; Prescher, J.A.; Laughlin, S.T.; Agard, N.J.; Chang, P.V.; Miller, I.A.; Lo, A.; Codelli, J.A.; Bertozzi, C.R. PNAS 2007, 104, 16793.

R2 1 mol% CuSO4 N N 2 N N 5 mol% sodium ascorbate N N R

1 N N R H O/tBuOH 2:1 1 R 2 R R rt, 8 h N R = H or -(CH ) CO K Scheme 1 N 2 4 2 N N

N N N R Figure 2 N

N N N O R F N N N H F N N R = fluorescent dye or biotin Figure 3 Figure 1

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Click Catalysts and Ligands Chloro(pentamethylcyclopentadienyl)(cycloocta- 8 )ruthenium(II) Copper(II) acetate, 98% CH C18H27ClRu 3 Cupric acetate FW 379.93 H3C CH3 O CH H3C 3 C4H6CuO4 2+ H3C O Cu Cl Ru FW 181.63 2 [142‑71‑2] 667234-250MG 250 mg 326755-25G 25 g 667234-1G 1 g 326755-100G 100 g Pentamethylcyclopentadienylbis(triphenylphosphine)ruthe- Copper(I) bromide, 98% nium(II) chloride

CuBr Cuprous bromide Chloro(pentamethylcyclopentadienyl)bis(triphenylphos- CH3 BrCu ­phine)ruthenium(II) H3C CH3

FW 143.45 C46H45ClP2Ru H3C Ru CH3 [7787‑70‑4] FW 796.32 Ph3P Cl PPh3 212865-50G 50 g [92361‑49‑4] 212865-250G 250 g 673293-250MG 250 mg 212865-1KG 1 kg 673293-1G 1 g

Copper(I) iodide, 98% (+)-Sodium L-ascorbate, ≥98% Cuprous iodide CuI L(+)-Ascorbic acid sodium salt; Vitamin C sodium salt HO ONa

CuI C6H7NaO6 O O OH

Chemical Ligation FW 190.45 FW 198.11 by Click Chemistry [7681‑65‑4] [134‑03‑2] OH 205540-50G 50 g A7631-25G 25 g 205540-250G 250 g A7631-100G 100 g 205540-1KG 1 kg A7631-500G 500 g A7631-1KG 1 kg Copper(II) sulfate, ≥99% 8 Cupric sulfate CuSO4 TentaGel™ TBTA

CuO4S Tris[(1-benzyl-1H-1,2,3- NN FW 159.61 triazol-4-yl)methyl]amine, N [7758‑98‑7] polymer bound N N H C1297-100G 100 g N N N N N C1297-500G 500 g O N Copper(II) sulfate pentahydrate, ≥98.0% 696773-250MG 250 mg Cupric sulfate pentahydrate CuSO4 • 5H2O Tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine, 97% CuO4S · 5H2O FW 249.69 TBTA N N N [7758‑99‑8] C30H30N10 98.0-102.0% (ACS specification) FW 530.63 N N N N 209198-5G 5 g N 209198-100G 100 g N N 209198-250G 250 g 678937-50MG 50 mg 209198-500G 500 g 678937-500MG 500 mg 209198-2.5KG 2.5 kg

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Native Chemical Ligation Native chemical ligation usually relies on the location of suitable Xaa–Cys ligation sites, spaced at intervals no greater than about 40 residues in the target sequence. However, Introduction: Xaa–Cys sites in a protein’s polypeptide chain are often limiting: of Peptides and Cys residues are rare or even absent in many proteins, or only Despite competition by recombinant DNA techniques, the present in an unsuitable position. Yan and Dawson introduced an synthetic preparation of peptides and proteins offers approaches approach that allows Xaa–Ala ligation sites, with a Cys residue to protein engineering that are beyond the realm of biology and used in place of the native Ala residue. Subsequent desulfurization the limitations of the genetic code. Unlike nature, purely synthetic of the ligation product with freshly prepared 18 methods allow the design of peptides entirely from scratch and the produces the native target sequence. Recently, this methodology furnishing of protein analogs with virtually any unnatural residue. has been extended by Kent and co-workers to the synthesis of Cys-containing peptides by ligating fragments at Xaa–Ala Ligation Chemical Native Chemical faces certain limitations though. junctions.19 Using acetamidomethyl (Acm) side chain protecting Solution-phase synthesis methods are suitable for peptides with groups for Cys residues other than the ligation site, efficient and a chain length of up to ten amino (Figure 1). Solid-phase selective desulfurization of the ligation site is feasible. peptide synthesis (SPPS) broadens the range of accessible peptides by dramatically enhancing speed and efficiency of the synthesis. References: (12) Dawson, P.E.; Muir, T.W.; Clark-Lewis, I.; Kent, S.B.H. Science, 1994, 266, 776. (13) Wieland, T.; Bokelmann, E.; Bauer, L.; Lang, H.U.; Lau, H. Justus Liebigs Still the maximum chain length of the peptides prepared by SPPS Ann. Chem. 1953, 583, 129. (14) Torbeev, V.Y.; Kent, S.B.H. Angew Chem. Int. Ed. 2007, is limited to about 50 amino acid residues. 46, 1667. (15) Cole, P.A. J. Am. Chem. Soc. 2006, 128, 4192. (16) Watzke, A. et al. Angew. Chem. Int. Ed. 2006, 45, 1408. (17) Johnson, E.C.B.; Kent, S.B.H. J. Am. Chem. The development of chemoselective reactions to give a native Soc. 2006, 128, 6640. (18) Yan, L.Z.; Dawson, P.E. J. Am. Chem. Soc. 2001, 123, 526. at the site of ligation allows the synthesis of (19) Pentelute, B.L.; Kent, S.B.H. Org. Lett. 2007, 9, 687. proteins by joining smaller peptides synthesized previously by SPPS. The challenge of this approach is to form an amide bond chemoselectively in the presence of amino acid side chains presenting free amines (Lys) and carboxylates (Glu/Asp). Ideally, no � Solution-phase peptide synthesis protecting groups should be used and all chemical transformations Only small peptides (chain length < 10 aa) should take place under mild conditions that are compatible with � Solid-phase peptide synthesis biological environments. The most powerful technique of this kind Medium sized peptides (chain length < 50 aa) is Native Chemical Ligation (NCL) that was introduced by Kent and co-workers in 1994 (Scheme 1).12 Prior to this work, Wieland had � Native chemical ligation observed the condensation of peptide thioesters in early, pioneering Peptides and smaller proteins (chain length < 200 aa) 13 investigations. Meanwhile, Native Chemical Ligation has enabled � Expressed protein ligation the synthesis of many moderate-size proteins and glycoproteins, Chemically modifi ed proteins (chain length > 500 aa) culminating in the assembly of a 203 amino acid HIV protease covalent dimer.14 Some innovative applications and improved � Staudinger ligation procedures for NCL will be presented later in this chapter. Modifi cation, immobilization, or combination of peptides Expressed Protein Ligation (EPL) finally combines the strengths Figure 1 of molecular biology and chemical synthesis by filling the SH gap between chemistry and biology. A protein expressed by O O 2 1 + 2 1 peptide recombinant DNA techniques can be extended with synthetic peptide SR H2N peptide peptide S peptide fragments post-translationally. In recent examples, Cole NH2 and co-workers used EPL for the C-terminal attachment of a small phosphorylated synthetic peptide.15 Waldmann, Goody, and SH co-workers demonstrated the EPL synthesis of an azide-modified O N-Ras protein and its site-specific immobilization onto a phosphine- peptide1 N peptide2 H functionalized glass surface by means of the Staudinger ligation.16 Scheme 1

Native Chemical Ligation O OH ONa Native Chemical Ligation allows the combination of two S HS O unprotected peptide segments by the reaction of a α-thioester O HS MESNa MPAA with a -peptide (Scheme 1). The result of this reaction is Figure 2 a native amide bond at the ligation site, rendering this method highly attractive for the synthesis of large peptides. Usually, α-alkylthioesters are used because of their ease of preparation. Since they are rather unreactive, the ligation reaction is catalyzed by in situ transthioesterification with thiol additives. The most common thiol catalysts to date have been either a mixture of thiophenyl/benzyl mercaptan, or 2-mercaptoethanesulfonate (MESNa). In a recent study, it was shown that MESNa is a poor catalyst, requiring reaction times of typically 24–48 hours. It is outperformed by far by certain aryl thiols. Using 4-mercaptophenylacetic acid (MPAA), proteins can be synthesized much more rapidly (Figure 2). Chemical ligations are typically complete in less than an hour and with high yields.17

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4-Mercaptophenylacetic acid, 97% Fmoc-Cys(Acm)-OH, ≥95.0% (HPLC, sum of )

C8H8O2S OH Nα-Fmoc-S-acetaminomethyl-L-cysteine O O

FW 168.21 O C21H22N2O5S H3C N S OH HS H HN [39161‑84‑7] FW 414.47 Fmoc 653152-1G 1 g [86060‑81‑3] 653152-5G 5 g 47603-5G 5 g Sodium 2-mercaptoethanesulfonate, ≥98.0% (RT) Fmoc-Cys(Acm)-Wang resin O O O Coenzyme M sodium salt; HS-CoM Na; Nα-Fmoc-S-acetaminomethyl-L-cysteine HS S ONa 2-Mercaptoethanesulfonic acid sodium salt; MESNA 4-benzyloxybenzyl ester polymer-bound S N CH3 H O HN C2H5NaO3S2 Fmoc FW 164.18 [19767‑45‑4] 47613-1G-F 1 g 63705-10G 10 g H-Cys(Acm)-2-ClTrt resin 63705-50G 50 g S-Acetamidomethyl-L-cysteine 2-chlorotrityl ester polymer-bound S-Acetamidomethyl-L-cysteine hydrochloride, ≥99.0% (AT) 94399-1G-F 1 g H-Cys(Acm).HCl O O • HCl TentaGel S PHB-Cys(Acm)Fmoc C6H12N2O3S · HCl H3C N S OH H N -Fmoc-S-acetamidomethyl-L-cysteine 4-[poly(ethylenoxy)]benzyl ester FW 228.70 NH2 α [28798‑28‑9] polymer-bound 00320-1G 1 g 86383-5G 5 g Boc-Cys(Acm)-OH, ≥96.0% (T) Boc-Cys(Acm)-PAM resin L Boc-S-acetamidomethyl-L-cysteine O O Boc-S-(acetamidomethyl)- -cysteine bound to PAM resin 61254-1G-F 1 g C11H20N2O5S H3C N S OH H FW 292.35 HN Boc Native Chemical Ligation [19746‑37‑3] 15376-5G 5 g

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Staudinger Ligation The phosphine reagent can be synthesized from aminoterephthalic acid methyl ester by diazotization, followed by iodination and Introduction subsequent Pd-catalyzed phosphinylation (Scheme 4). The reaction between an azide and a phosphine forming The free acid moiety allows the easy attachment of a wide an aza-ylide was discovered almost a century ago by Nobel choice of molecular probes to the phosphine reagent by standard Prize laureate Herrmann Staudinger. It has found widespread esterification or amidation procedures. Thus, a fluorescence label application in chemical synthesis, but only recently its value as or different detection probe can be linked to any biomolecule a highly chemoselective ligation method for the preparation of that has been equipped with an azide function by the Staudinger bioconjugates has been recognized.20 Both reactive functionalities ligation even in living cells (Scheme 5). involved in this reaction are bioorthogonal to virtually all naturally The following paragraph shows how GlycoProfile™ azido sugars existing functionalities in biological systems and readily combine at can be incorporated into glycan structures in vivo, and be used to Ligation Staudinger room temperature tolerating an aqueous environment. These ideal attach a FLAG® phosphine probe chemically. conditions make it possible to exploit the Staudinger ligation even in the complex environment of living cells. Staudinger and Meyer first reported in 1919 that azides react H3CO O H3CO O H3CO O smoothly with triaryl phosphines to form iminophosphoranes 1) NaNO2 Pd(OAc)2 (1%) NH HCl/H2O I Ph2PH 21 2 PPh2 after elimination of nitrogen (Scheme 1). This imination reaction 2) KI, H2O Et3N, MeOH proceeds under mild conditions, almost quantitatively, and without 57 % 69 % noticeable formation of any side products. O OH O OH O OH 393673 650064 The resulting iminophosphorane with its highly nucleophilic Scheme 4 nitrogen atom can also be regarded as an aza-ylide (Scheme 2). It may be intercepted with almost any kind of electrophilic target HN H CO O O reagent. Common pathways include aqueous hydrolysis forming 3 target O a primary amine and a phosphine(V) oxide in the so-called PPh2 NN N PPh2 Staudinger reduction. Quenching with or yields imines, which is known as the aza-. Even carbonyl electrophiles with low reactivity, like amides or esters, react with O O O O iminophosphoranes, especially if the reaction can take place probe probe Scheme 5 intramolecularly (Scheme 3). References: (20) Köhn, M.; Breinbauer, R. Angew. Chem. Int. Ed. 2004, 43, 3106. (21) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635. (22) Saxon, E.; Bertozzi, C.R. Science 2000, 287, 2007.

1-Methyl 2-iodoterephthalate, 90% P + NN N P N + N2 O C9H7IO4

FW 306.05 OCH3 HO Scheme 1 I O 650064-1G 1 g R3P N R3P N R' R' 650064-10G 10 g Scheme 2 1-Methyl-2-aminoterephthalate, 98% H N R1 1 O N R R2 C9H9NO4 O H R3 FW 195.17 OCH H O 3 2 R2 R3 [60728‑41‑8] HO NH2 O R R P N 393673-5G 5 g 1 R R O 393673-25G 25 g R3 R2 NC O R2 N H - R3PO 2-(Diphenylphosphino)terephthalic acid, 1-methyl 4-penta- fluorophenyldiester, 97% N R1 2 1 2 R NC N R R 1-Methyl-4-(pentafluorophenyl)-2-(diphenyl- O HN R3 Scheme 3 phosphino)-1,4-benzenedicarboxylate F OCH3 C H F O P F O 27 16 5 4 P FW 530.38 O F F Nontraceless Staudinger Ligation F Bertozzi et al. pioneered the application of the Staudinger reaction as a ligation method for bioconjugates. In the course of 679011-25MG 25 mg their studies on the metabolic engineering of cell surfaces they 679011-100MG 100 mg designed a phosphine with an ester moiety as an intramolecular 2-(Diphenylphosphino)benzoic acid, 97% electrophilic trap. After formation of the iminophosphorane from C H O P O the newly designed phosphine reagent and an azide, the ester 19 15 2 FW 306.30 moiety captures the aza-ylide in a fast intramolecular cyclization OH [17261‑28‑8] reaction before hydrolysis with water can occur. This process P ultimately produces a stable amide bond.22

454885-1G 1 g 454885-5G 5 g

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GlycoProfile™ Azido Sugars N-Azidoacetylmanno­amine, Acetylated 8 The GlycoProfile™ Azido Sugar portfolio consists of three ManNaz O RO N3 peracetylated azido sugars that may be incorporated into glycan C16H22N4O10 HN O structures chemically or by using existing biosynthetic pathways FW 430.37 OR OR O of mammalian cells.23 Orthogonally to chemical and biological RO R = * CH3 carbohydrate or peptide synthesis, the azide moiety offers an ideal anchor to attach the modified glycan to surfaces, labels, peptides, A7605-1MG 1 mg or proteins. Labelling even works in vivo by using an alternative A7605-5MG 5 mg metabolic-system approach. The acetyl groups increase cell N-Azidoacetylgalacto­amine, Acetylated 8 permeability and allow the unnatural sugars to easily pass through O GalNaz OR the cell membrane. Carboxyesterases remove the acetyl groups once RO C H N O R = * CH the monosaccharide is in the cell. Cells metabolize the azido sugars 16 22 4 10 O 3 FW 430.37 OR OR using glycosyltransferases and express the sugars on the terminus HN of a glycan chain both intracelullarly and on the cell surface, leaving N3 the azido group unreacted. N-Azidoacetylmannosamine may also O be introduced into the sialic acid pathway. A phosphine A7480-1MG 1 mg ® probe containing a detection epitope such as the FLAG peptide A7480-5MG 5 mg can be selectively bound to the glycan by Staudinger Ligation, resulting in a post-translationally modified glycoprotein that is N-Azidoacetylgluco­amine, Acetylated 8 detected in vivo by using a FLAG®-specific antibody. This approach GlcNaz RO

permits the analysis of pathways that are regulated by particular C16H22N4O10 O O glycan post-translational modifications as well as the monitoring of FW 430.37 OR OR RO R = * CH3 the intracellular glycosylation process itself. HN Staudinger Ligation N3 O

OAc A7355-1MG 1 mg AcO O OAc A7355-5MG 5 mg AcO GalNAz NH N3 O Metabolic cell labeling

OAc AcO O AcO O NH

N3 O

O

CH3 O Staudinger R .. FLAG P ligation

FLAG-PhosphineR

OAc AcO Puzzled by Glycobiology? O AcO O NH O NH O The Glycobiology Analysis Manual is a must-have

R O FLAG P Labeled reference guide for the fields of glycoproteomics and glycoprotein glycomics. The Manual features: Profiling O-type glycoproteins by metabolic labeling with an • Innovative products and kits Glycobiology azido GalNAc analog (GalNAz) followed by Staudinger ligation Analysis Manual with a phosphine probe (FLAG-phosphine). • Updated and expanded 2nd edition technical content Reference: (23)(a) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007. (b) Saxon, E.; Bertozzi, C. R. Annu. Rev. Cell. Dev. Biol. 2001, 17, 1. (c) Bertozzi, C. R.; Kiessling, L. L. • Structural and functional Science 2001, 291, 2357. (d) Dube, D. H.; Prescher, J. A.; Quang, C. N.; Bertozzi, C. R. reviews Proc. Natl. Acad. Sci 2006, 103, 4819. Whether you are an expert Q Glycan Labeling and Analysis GlycoProfile FLAG–Phosphine conjugate 8 Q Glycoprotein Purification and Detection Tools for Glycoproteomics and G Q Chemical and Enzymatic in carbohydrate biology and Deglycosylation lycomics Q Enzymatic Synthesis and N-[4-Carbomethoxy-3-(diphenylphosphino) O Degradation OCH chemistry or just getting benzoyl]-Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys 3 C H N O P started in glycomics, the 62 75 10 23 P FW 1359.29 DYKDDDK Glycobiology Analysis Manual provides the products and methods you need to solve your glycomics puzzle! GPHOS1-1MG 1 mg GPHOS1-5X1MG 5 × 1 mg Visit sigma.com/glycomanual and request your copy.

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Traceless Staudinger Ligation Although the previously described methods for Staudinger ligations work well even in biological environments, a modification HS P forming a native amide bond without leaving the unnatural phosphine oxide moiety in the product would be more attractive yet. In 2000, the groups of Bertozzi and Raines simultaneously Figure 1 introduced alternative ligation strategies.24 Based on the same O O working principle as the nontraceless Staudinger Ligation the 1 + 1 auxiliary phosphine reagent can be cleaved from the product after R SR' HS PPh2 R S PPh2 the ligation is completed leaving a native amide bond. Thus, the 2 N3 R total chemical synthesis of proteins and glycopeptides is enabled overcoming the limitations of native chemical ligation (NCL) of a O O Ligation Staudinger 2 H2O 1 R 1 + R N R S P Ph2 Cys residue at the ligation juncture. H - HSCH POPh 2 2 -N R2 Among the suitable phosphine reagents for traceless Staudinger Scheme 6 ligations, diphenylphosphinemethanethiol (Figure 1), developed by Raines and co-workers, exhibits the best reactivity profile and has 670359 O BH3 BH already found widespread application. This Raines ligation reagent NaOMe, MeOH 3

S PPh2 HS PPh is first acylated. Treatment with an azide leads to the formation of rt, 95% 2 an aza-ylide. The nucleophilic nitrogen atom of the aza-ylide then DABCO® 1) 95% TFA, 1 h 2) DIPEA, rt attacks the , cleaving the thioester. Hydrolysis of the , 40 °C 95% rearranged product finally produces a native amide and liberates the 95% 25 auxiliary as its phosphine(V) oxide (Scheme 6). O NaOH, MeOH

S PPh2 HS PPh2 It’s recommended to use a freshly prepared Raines ligation reagent 94% Scheme 7 because it has only a limited stability. In this issue of ChemFiles, ® Sigma-Aldrich proudly introduces new product 670359 as a HS shelf-stable, convenient source for this highly useful reagent PH+ (sold under license for research and development purposes H+ H+ N N only. U.S. Patent 6,974,884 and related patents apply). In the x 3 Cl- acetylthiomethyldiphenylphosphine borane complex 670359, Figure 2 the thiol and phosphine moiety are protected as acetyl ester and borane adduct, respectively. The active Raines ligation reagent can Acetylthiomethyl-diphenylphosphine 8 be liberated easily by treatment with DABCO® at 40 °C followed borane complex, ≥98.0% by basic ester cleavage (Scheme 7). Hackenberger and co-workers C15H18BOPS showed that acidic deprotection of the phosphine-borane was FW 288.15 O advantageous in glycopeptide and cyclopeptide preparations.26 [446822‑71‑5] H3B P S CH3 In the latter case, a linear peptide with terminal azide and phosphine-borane groups was synthesized by SPPS. 95% TFA was used to deprotect the phosphine and the amino acid side chains 670359-250MG 250 mg simultaneously in a single step. Diisopropylethylamine (DIPEA) was 670359-1G 1 g then added to trigger the peptide macrocyclization by traceless 1,4-Diazabicyclo[2.2.2]octane, 98% Staudinger ligation, yielding cyclic Microcin J25 with 21 amino acids. DABCO; TED; Triethylenediamine Other Staudinger ligation induced macrocyclizations have been N C6H12N2 N published previously by Maarseveen and co-workers, who FW 112.17 successfully used the Raines ligation reagent for the synthesis [280‑57‑9] 27 of a series of medium-sized lactams. Wong and co-workers D27802-25G 25 g reported the synthesis of 14 different glycopeptides through the D27802-100G 100 g traceless Staudinger Ligation.28 For this work, they also developed D27802-500G 500 g a protease-catalyzed method to selectively introduce an N-terminal D27802-2KG 2 kg azido group into an unprotected polypeptide, as it was needed for 1,4-Diazabicyclo[2.2.2]octane hydrochloride, polymer-bound the subsequent ligation reaction. Dabco chloride resin; TED-Cl resin Most recently, Raines and co-workers introduced a water-soluble N Cl N variant of their reagent carrying dimethylamino groups (Figure 2). This substrate mediates the rapid ligation of equimolar substrates 578282-5G 5 g in water. In a pilot experiment, traceless Staudinger ligation was 578282-25G 25 g integrated with expressed protein ligation (EPL), revealing future Dabco 33-LV 29 opportunities in modern protein chemistry. 1,4-Diazabicyclo[2.2.2]octane solution N References: (24)(a) Saxon, E.; Armstrong, C.R.; Bertozzi, C.R. Org. Lett. 2000, 2, 2141. C6H12N2 N (b) Nilsson, B.L.; Kiessling, L.L.; Raines, R.T. Org. Lett. 2000, 2, 1939. (25) Soellner, M.B.; FW 112.17 Nilsson, B.L.; Raines, R.T. J. Am. Chem. Soc. 2006, 128, 8820. (26) Kleineweischede, [280‑57‑9] R.; Jaradat, D.; Hackenberger, P.R. Contributions at the 8th German Peptide Symposium 2007, Heidelberg, Germany. (27) David, O.; Meester, W.J.N.; Bieräugel, H.; Schoemaker, 290734-100ML 100 mL H.E.; Hiemstra, H.; van Maarseveen, J.H. Angew. Chem. Int. Ed. 2003, 42, 4373. (28) Liu, 290734-500ML 500 mL L.; Hong, Y.-Y., Wong, C.-H. ChemBioChem 2006, 7, 429. (29) Tam, A.; Soellner, M.B.; Raines, R.T. J. Am. Chem. Soc. 2007, 129, 11421.

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Organic Azides and Azide Sources Azidotris(diethylamino)phosphonium bromide C H BrN P CH3 CH3 12 30 6 Br Since the preparation of the first organic azide, phenyl azide, FW 369.28 H3C N CH3 by Peter Griess in 1864 this energy-rich and versatile class of [130888‑29‑8] N P N H C CH compounds has enjoyed considerable interest. In more recent 3 N3 3  ≥97.0% (AT) years, completely new perspectives have emerged, notably the use of organic azides for peptide synthesis, combinatorial 11556-1G 1 g synthesis, heterocycle synthesis, and the ligation or modification of 11556-5G 5 g biopolymers.30 The most prominent fields of application today are  98% Huisgen 1,3-dipolar cycloadditions, and different variants of the 380822-1G 1 g Staudinger ligation.

Benzenesulfonyl azide, functionalized silica gel The azido group can also be regarded as a protecting group for O

coordinating primary amines, especially in sensitive substrates Si S N3 like complex carbohydrates or peptidonucleic acids (PNA).31 O 32 For example, it is stable to metathesis conditions. 590274-5G 5 g ® Sigma-Aldrich is offering a broad range of organic azides for your Benzenesulfonyl azide, polymer-bound research. Additionally a wide choice of azide sources facilitates the preparation of tailor-made organic azides. O SN3 An elegant way to produce organic azides from unactivated O Organic Azides olefins was recently reported by Carreira and co-workers. A 572977-5G 5 g

catalyst, that is easily prepared from Co(BF4)2 · 6H2O and a Schiff and Azide Sources 4-Carboxybenzenesulfonazide, 97% , allows hydroazidation with p-toluenesulfonyl azide (TsN3) to yield alkyl azides. Mono-, di-, and trisubstituted olefins are 4-(Azidosulfonyl)benzoic acid O S N3 C7H5N3O4S tolerated in this reaction, and complete Markovnikov selectivity is O FW 227.20 HO observed (Scheme 1).33 [17202‑49‑2] O References: (30) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem. Int. Ed. 340138-2.5G 2.5 g 2005, 44, 5188. (31) Debaene, F.; Winssinger, N. Org. Lett. 2003, 5, 4445. (32) Kane- mitsu, T.; Seeberger, P.H. Org. Lett. 2003, 5, 4541. (33) Waser, J.; Nambu, H.; Carreira, Cesium azide, 99.99% E.M. J. Am. Chem. Soc. 2005, 127, 8294. CsN CsN3 3 FW 174.93

Ph Ph [22750‑57‑8] t-Bu 510181-5G 5 g NCO2K 510181-25G 25 g OH R'' R'' t-Bu 6 mol% R Cobalt(II) tetrafluoroborate hexahydrate, 99% R + TsN3 R' 6 mol% Co(BF4)2 · 6 H2O N R' 3 B2CoF8 · 6H2O Co(BF4)2 • 6H2O 30 mol% t-BuOOH, silane EtOH, 23 °C, 2-24 h FW 340.63 Scheme 1 [15684‑35‑2] 399957-25G 25 g 399957-100G 100 g Azide Sources Diphenyl phosphoryl azide 4-Acetamidobenzenesulfonyl azide, 97% DPPA; Phosphoric acid diphenyl ester azide O O O P O p-ABSA C12H10N3O3P N S N3 3 C8H8N4O3S O FW 275.20 O FW 240.24 [26386‑88‑9] H3C N [2158‑14‑7] H  97% 404764-5G 5 g 178756-5G 5 g 404764-25G 25 g 178756-25G 25 g Azide exchange resin,azide on Amberlite IRA-400 178756-100G 100 g  ≥90% (HPLC) 368342-10G 10 g 368342-50G 50 g 79627-50ML 50 mL Azidotrimethylsilane, 95% Diphenylphosphoryl azide, polymer-bound

Trimethylsilyl azide CH3 DPPA polymer-bound; PS-DPPA O H C Si N C3H9N3Si 3 3 O P O CH3 FW 115.21 N3 [4648‑54‑8] 668168-1G 1 g 155071-10G 10 g 668168-5G 5 g 155071-50G 50 g 668168-25G 25 g Azidotrimethyltin(IV), 97% Lithium azide solution LiN C3H11N3Sn LiN3 3 FW 207.85 FW 48.96 [1118‑03‑2] [19597‑69‑4] 349488-1G 1 g  20 wt. % in H2O 349488-5G 5 g 480525-25G 25 g 480525-100G 100 g

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Potassium 2-(3,5-di-tert-butyl-2-hydroxybenzylideneamino)- α-Azidoisobutyric acid solution 2,2-diphenylacetate, 95% 2-Azido-2-methylpropionic acid O H C C H N O 3 OH N-(3,5-di-tert-butylsalicylidene)-2- 4 7 3 2 H C 3 N amino-2,2-diphenylacetate CH3 FW 129.12 3 H3C OK C H KNO N [2654‑97‑9] 29 32 3 H3C FW 481.67 O OH  ~15% in heptane (T) CH H3C 3 52916-10ML-F 10 mL CH3 52916-50ML-F 50 mL 676551-250MG 250 mg 676551-1G 1 g  ~15% in heptane (T) 59955-10ML-F 10 mL

Sodium azide Sources Azide and Azides Organic Azidomethyl phenyl sulfide, 95% N3Na NaN3 FW 65.01 Phenylthiomethyl azide S N3

[26628‑22‑8] C7H7N3S  99.99+% (metals basis) FW 165.22 [77422‑70‑9] 438456-5G 5 g 244546-1G 1 g 438456-25G 25 g  ≥99.0% (T) 6-(4-Azido-2-nitrophenylamino)hexanoic acid N-hydroxy- 71290-10G 10 g succinimide ester, ≥90%

71290-100G 100 g N-Succinimidyl 6-(4-azido- O O O2N N3 71290-500G 500 g 2-nitroanilino)hexanoate N O C16H18N6O6 N  ≥99% H FW 390.35 O 13412-100G-R 100 g [64309‑05‑3] 13412-6X100G-R 6 × 100 g A3407-50MG 50 mg 13412-250G-R 250 g 13412-1KG-R 1 kg (2S,3R,4E)-2-Azido-4-octadecene-1,3-diol 13412-6X1KG-R 6 × 1 kg D-Sphingosine azide OH 13412-20KG-R 20 kg CH(CH2)12CH3 C18H35N3O2 HO N Tetrabutylammonium azide FW 325.49 3 [103348‑49‑8] C16H36N4 H3C CH3 N - A0456-1MG 1 mg FW 284.48 N3 H C CH3 [993‑22‑6] 3 A0456-5MG 5 mg 651664-5G 5 g 4-Azidophenacyl bromide 651664-25G 25 g 4’-Azido-2-bromoacetophenone; 4-Azido- O α-bromoacetophenone Br C H BrN O Organic Azides 8 6 3 N3 FW 240.06 1-Azidoadamantane, 97% [57018‑46‑9]

N3 A6057-500MG 500 mg C10H15N3 FW 177.25  ≥98.0% (HPLC) [24886‑73‑5] 11550-250MG-F 250 mg 276219-1G 1 g 11550-1G-F 1 g 276219-5G 5 g 4-Azidophenyl isothiocyanate, 97% 4-Azidoaniline hydrochloride, 97% NCS C7H4N4S 4-Aminophenyl azide hydrochloride NH2 • HCl FW 176.20 C H N · HCl N3 6 6 4 N [74261‑65‑7] FW 170.60 3 359564-500MG 500 mg [91159‑79‑4] 359556-250MG 250 mg 2,6-Bis(4-azidobenzylidene)-4-methylcyclohexanone 359556-1G 1 g C21H18N6O O (4S)-4-[(1R)-2-Azido-1-(benzyloxy)ethyl]-2,2-dimethyl-1,3- FW 370.41 [5284‑79‑7] dioxolane N3 N3  97% CH3 C14H19N3O3 N3 FW 277.32 283029-5G 5 g O OO  ≥90% (HPLC, calc. based on dry substance)

H3C CH3 14528-10G 10 g 573213-1G 1 g 4,4’-Diazido-2,2’-stilbenedisulfonic acid disodium [3aS-(3aα,4α,5β,7aα)]-5-Azido-7-bromo-3a,4,5,7a-tetra- salt hydrate, 97% hydro-2,2-dimethyl-1,3-benzodioxol-4-ol, 99% N C14H8N6Na2O6S2 · xH2O – + 3 SO3 Na FW 466.36 (Anh) • xH2O C9H12BrN3O3 Br

O – + FW 290.11 CH3 SO3 Na N3 [171916‑75‑9] O CH3 N3 OH 363227-10G 10 g

493406-500MG 500 mg

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7-(Diethylamino)coumarin-3-carbonyl azide, ≥95% (HPLC) O-(2-Aminoethyl)-O′-(2-azidoethyl)nonaethylene glycol, O ≥90% (oligomer purity) C14H14N4O3

FW 286.29 N3 Azido-PEG-amine (n=10) O H2N N3 [157673‑16‑0] 10 H3C N O O C22H46N4O10 FW 526.62 CH 3 [912849‑73‑1] 31755-25MG 25 mg 77787-500MG-F 500 mg Ethidium bromide monoazide, ≥95% (HPLC) O-(2-Aminoethyl)-O′-(2-azidoethyl)pentaethylene glycol, 3-Amino-8-azido-5-ethyl-6-phenylphenanthridinium bromide; Ethidium ≥90% (oligomer purity) monoazide bromide Azido-PEG-amine (n=6) O C H BrN H N N

21 18 5 2 C H N O 6 3 FW 420.31 14 30 4 6 FW 350.41 [58880‑05‑0] 76172-500MG-F 500 mg E2028-5MG 5 mg O-(2-Azidoethyl)-O-[2-(diglycolyl-amino)ethyl]heptaethylene Ethyl azidoacetate solution glycol, ≥90% (oligomer purity) C4H7N3O2 O Azido-PEG-acid (n=8) O N3 FW 129.12 O CH3 HO O C22H42N4O12 N [637‑81‑0] 8 N3 HO FW 554.59 O

Organic Azides  ~30% in methylene chloride (NMR) [846549‑37‑9] 88539-50ML-F 50 mL 71613-500MG-F 500 mg and Azide Sources  ~25% in toluene (NMR) 11-Azido-3,6,9-trioxaundecan-1-amine, ≥90% (GC) 77213-25ML-F 25 mL 1-Amino-11-azido-3,6,9-trioxaundecane; O-(2-Aminoethyl)-O’-(2-  ~25% in (NMR) azidoethyl)diethylene glycol; 2-{2-[2-(2- O O H N O N 93528-25ML-F 25 mL Azidoethoxy)ethoxy]ethoxy}ethylamine 2 3 C8H18N4O3 4-Methoxybenzyloxycarbonyl azide, 95% FW 218.25 4-Methoxybenzyl azidoformate O [134179‑38‑7]

C9H9N3O3 O N3 17758-1ML 1 mL FW 207.19 17758-5ML 5 mL H3CO [25474‑85‑5] 152854-5G 5 g Azido Carbohydrates 152854-25G 25 g 2-Acetamido-2-deoxy-β-D-glucopyranosyl azide 3,4,6- 8 Photobiotin acetate triacetate, ≥98.0% (HPLC) Biotin {3-[3-(4-azido-2-nitroanilino)-N-methylpropylamino]propyl­ 2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D- RO N3 amide} acetate; N-(4-Azido-2-nitrophenyl)-N’-(3-biotinylaminopropyl)- O O glucopyranosyl azide OR N’-methyl-1,3-propanediamine acetate R = * [6205‑69‑2] CH3 C23H35N9O4S · C2H4O2 O RO FW 593.70 O HN CH3 HO CH3 [96087‑38‑6] HN NH O O N CH 2 H 3 H H H N N N 671118-250MG 250 mg S O 671118-1G 1 g  ≥95% (HPLC) N3 2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-D- 8 79728-1MG 1 mg glucopyranosyl azide, ≥98.0% (HPLC)  ≥98.0% (TLC) C29H32N4O5 RO N3 56385-1MG-F 1 mg FW 516.59 O OR R = * [214467‑60‑4] Ro 15-4513 RO HN CH3 Ethyl 8-azido-6-dihydro-5-methyl-6-oxo- O 4H-imidazo[1,5-a][1,4]benzodiazepine- N O O CH3 3-carboxylate N 671215-100MG 100 mg

C15H14N6O3 N3 N 8-Azidoadenosine 3′:5′-cyclic monophosphate, ~95% FW 326.31 CH3 O NH [91917‑65‑6] C10H11N8O6P 2 FW 370.22 N N R109-25MG 25 mg N3 [31966‑52‑6] N R109-100MG 100 mg O N O O P PEG Azides OH O OH A1262-5MG 5 mg O-(2-Aminoethyl)-O′-(2-azidoethyl)heptaethylene glycol, 8-Azido-cyclic adenosine diphosphate-ribose, ≥95% (HPLC) ≥90% (oligomer purity) OH OH Cyclic adenosine diphosphate-ribose 8-azide NH Azido-PEG-amine (n=8) O H2N N C H N O P 8 3 15 20 8 13 2 N C18H38N4O8 O N FW 582.31 N3 FW 438.52 O O N [150424‑94‑5] N [857891‑82‑8] HO P O P O OH O O 76318-500MG-F 500 mg OH OH A6830-.1MG 0.1 mg

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1-Azido-1-deoxy-β-D-galactopyranoside, 97% 3′-Azido-2′,3′-dideoxyuridine, ≥98% (TLC) O C6H11N3O5 HO C9H11N5O4 N FW 205.17 HO O 3 FW 253.21 HN OH [35899‑89‑9] [84472‑85‑5] HO O N OH O N3 513989-500MG 500 mg A4810-10MG 10 mg 1-Azido-1-deoxy-β-D-galactopyranoside tetraacetate, 97% RO N-Azidoacetylgalacto­amine, Acetylated 8 C14H19N3O9 RO N3 O O FW 373.32 O GalNaz OR OR RO [13992‑26‑2] R= * CH3 C16H22N4O10 R = * CH3

O Sources Azide and Azides Organic OR FW 430.37 OR OR 513970-1G 1 g HN N3 1-Azido-1-deoxy-β-D-glucopyranoside O HO A7480-1MG 1 mg C6H11N3O5 N FW 205.17 O 3 A7480-5MG 5 mg [20379‑59‑3] OH HO N-Azidoacetylgluco­amine, Acetylated 8 OH GlcNaz RO 514004-500MG 500 mg C16H22N4O10 O O

OR OR 1-Azido-1-deoxy-β-D-glucopyranoside tetraacetate FW 430.37 RO R = * CH3 RO HN C14H19N3O9 N3 N FW 373.32 RO O 3 O O OR [13992‑25‑1] R= * CH3 A7355-1MG 1 mg OR A7355-5MG 5 mg 513997-1G 1 g N-Azidoacetylmanno­amine, Acetylated 8 1-Azido-1-deoxy-β-D-lactopyranoside, 97% ManNaz O RO N HO 3 C12H21N3O10 C16H22N4O10 HN N3 O FW 367.31 O FW 430.37 OR OR O HO OH [69266‑16‑6] RO O R = * CH3 HO O OH OH A7605-1MG 1 mg

OH A7605-5MG 5 mg

514012-500MG 500 mg 1-O-tert-Butyldimethylsilyl 2-azido-2-deoxy-β-D- 3′-Azido-3′-deoxythymidine glucopyranoside 3,4,6-triacetate, 97% H C O C18H31N3O8Si 3 AZT; Azidothymidine O CH FW 445.54 O CH3 CH C10H13N5O4 HN 3 O 3 O Si CH [99049‑65‑7] O 3 FW 267.24 CH HO O N H3C O CH3 3 [30516‑87‑1] O H3C O N3 N O  ≥98% (HPLC) 3 510947-1G 1 g A2169-25MG 25 mg A2169-100MG 100 mg α-D-Mannopyranosyl azide, ≥90% (TLC) HO A2169-250MG 250 mg C6H11N3O5 A2169-1G 1 g FW 205.17 O  ≥99.0% (HPLC) OH HO HO N3 11546-100MG 100 mg 11546-500MG 500 mg M6691-100MG 100 mg 2′-Azido-2′-deoxyuridine, ≥98.0% (N) α-D-Mannopyranosyl azide tetraacetate, ≥90% (TLC) RO O 2,3,4,6-Tetra-O-acetyl-α-D-mannopyranosyl azide C9H11N5O5 C H N O O O FW 269.21 HN 14 19 3 9 OR RO FW 373.32 R= * CH [26929‑65‑7] O N 3 HO RO N O 3 G4168-100MG 100 mg OH N3 8 11544-5MG 5 mg 2,3,4-Tri-O-acetyl-β-D-xylopyranosyl azide, ≥98.0% (HPLC) 3-Azido-2,3-dideoxy-1-O-(tert-butyldimethylsilyl)- C H N O O 11 15 3 7 N β-D-arabino-hexopyranose, 98% O 3 FW 301.25 H3C O C H N O Si CH3 [53784‑33‑1] H C O 12 25 3 4 HO CH 3 3 O CH FW 303.43 O Si CH 3 O 3 O N CH3 O [189454‑43‑1] 3 CH3 OH 670790-1G 1 g 497029-250MG 250 mg 670790-5G 5 g

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Functionalized Alkynes [(1,1-Dimethyl-2-propynyl)oxy]trimethylsilane, 98% CH3 C8H16OSi H C 3 O Si CH Alkynes contain a highly versatile that FW 156.30 HC 3 CH3 may be utilized for numerous reactions such as electrophilic [17869‑77‑1] CH3 additions of hydrogen, halogens, hydrogen halides, or water; 495239-5ML 5 mL metathesis; ; oxidative cleavage; C–C coupling; and 495239-25ML 25 mL cycloadditions. Terminal alkynes may be transformed into metal and can then be submitted to nucleophilic substitution 1,1-Diphenyl-2-propyn-1-ol, 99%

with alkyl halides, forming new C–C bonds, or nucleophilic C15H12O CH addition, e.g., the . FW 208.26 HO C [3923‑52‑2] Sigma-Aldrich® furnishes a broad portfolio of alkynes consisting of more than 250 products. To see the full listing, please visit 477443-5G 5 g the organic building blocks section on Chem Product Central at: 477443-25G 25 g sigma-aldrich.com/chemprod. 2-Ethynylbenzyl , 97% From the class of cycloaddition reactions that can be performed OH with alkynes, the Huisgen 1,3-dipolar cycloaddition stands out C9H8O FW 132.16 and has found tremendous interest in recent years as the best CH representative of a “click” reaction. Alkyne building blocks with a [10602‑08‑1] second functionality are particularly useful in click chemistry. The 520039-5G 5 g second functional group allows the attachment of a of 4-Ethynylbenzyl alcohol, 97% interest that subsequently can be “clicked” conveniently to the C H O target azide. The following product list contains alkynes with a free 9 8 CH FW 132.16 HO or protected hydroxyl functional group, halogen-bearing alkynes, [10602‑04‑7] and miscellaneous other alkynes with an additional functional group.

Functionalized Alkynes 519235-5G 5 g 1-Ethynyl-1-cyclohexanol, ≥99% Hydroxylated Alkynes OH C8H12O CH tert-Butyldimethyl(2-propynyloxy)silane, 97% FW 124.18 [78‑27‑3] CH C9H18OSi 3 CH3 E51406-5ML 5 mL O Si CH3 FW 170.32 HC CH3 E51406-100ML 100 mL [76782‑82‑6] CH3 E51406-5L 5 L 495492-5ML 5 mL E51406-20L 20 L 495492-25ML 25 mL 1-Ethynylcyclopentanol, 98% 2-tert-Butyldimethylsiloxybut-3-yne, 97% C7H10O OH tert-Butyl-dimethyl-(methyl-prop-2-ynloxy)silane CH3 CH3 FW 110.15 CH O Si CH3 HC CH [17356‑19‑3] CH 3 CH3 3 130869-5G 5 g 667579-1G 1 g 667579-10G 10 g 2-(3-Fluorophenyl)-3-butyn-2-ol, 90% CH 4-(tert-Butyldimethylsilyloxy)-1-, 97% C10H9FO 3 FW 164.18 CH CH OH C10H20OSi 3 CH3 FW 184.35 HC O Si CH3 CH CH3 F [78592‑82‑2] 3 648930-1G 1 g 541672-5ML 5 mL 541672-25ML 25 mL 1-Heptyn-3-ol, 97%

C H O HC CH 3-Butyn-1-ol, 97% 7 12 3 FW 112.17 OH C4H6O HC OH [7383‑19‑9] FW 70.09 666963-1G 1 g [927‑74‑2] 666963-10G 10 g 130850-5G 5 g 130850-25G 25 g 1-Hexyn-3-ol, 90% 130850-100G 100 g CH C6H10O HC 3 3-Butyn-2-ol, 97% FW 98.14 OH [105‑31‑7] C H O OH 4 6 HC 537764-5G 5 g FW 70.09 CH3 537764-25G 25 g [2028‑63‑9] 447986-25ML 25 mL 5-Hexyn-1-ol, 96% 447986-100ML 100 mL C6H10O HC OH 3,5-Dimethyl-1-hexyn-3-ol, 99% FW 98.14 [928‑90‑5] C H O OH 8 14 CH3 302015-1G 1 g FW 126.20 HC CH3 CH3 302015-5G 5 g [107‑54‑0] 302015-25G 25 g 278394-100ML 100 mL 278394-500ML 500 mL

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3-Hydroxyphenylacetylene 2-Phenyl-3-butyn-2-ol, ≥98%

3-Ethynylphenol C H O CH3 CH 10 10 CH C8H6O FW 146.19 OH FW 118.13 HO [127‑66‑2] [10401‑11‑3] 212997-5G 5 g 632023-1G 1 g 212997-25G 25 g 632023-5G 5 g 212997-100G 100 g 2-Methyl-3-butyn-2-ol, 98% 1-Phenyl-2-propyn-1-ol, 98%

Dimethyl ethynyl carbinol CH3 (±)-α-Ethynylbenzyl alcohol; (±)-3-Hydroxy-3-phenyl-1- HO C H O HC OH ; 1-Phenylpropargyl alcohol; (±)-1-Phenyl-2- CH 5 8 CH3

FW 84.12 propyn-1-ol Alkynes Functionalized

[115‑19‑5] C9H8O 129763-5ML 5 mL FW 132.16 129763-100ML 100 mL [4187‑87‑5] 129763-1L 1 L 226610-1G 1 g 226610-10G 10 g 5-Methyl-1-hexyn-3-ol, 97% CH , 99% C7H12O HC 3

FW 112.17 OH CH3 2-Propyn-1-ol HC OH [61996‑79‑0] C3H4O 666971-1G 1 g FW 56.06 666971-5G 5 g [107‑19‑7] P50803-5ML 5 mL 3-Methyl-1-penten-4-yn-3-ol, 98% P50803-100ML 100 mL Ethynyl methyl vinyl carbinol HO P50803-500ML 500 mL HC CH C6H8O 2 P50803-1L 1 L FW 96.13 CH3 [3230‑69‑1] 1,1,1-Trifluoro-2-phenyl-3-butyn-2-ol, 96% CF 493023-5G 5 g C10H7F3O 3 FW 200.16 CH OH 3-Methyl-1-pentyn-3-ol, 98% [99727‑20‑5] Ethyl ethynyl methyl carbinol; Meparfynol HO 553298-500MG 500 mg C H O HC CH3 6 10 CH3 553298-1G 1 g FW 98.14 [77‑75‑8] 3-Trimethylsiloxy-1-propyne, 98%

137561-100ML 100 mL (Propargyloxy)trimethylsilane; Trimethyl(propargyloxy) CH3 O Si CH 137561-500ML 500 mL silane; Trimethyl(2-propynyloxy)silane; HC 3 O-(Trimethylsilyl)propargyl alcohol CH3

1-Octyn-3-ol, 96% C6H12OSi

C8H14O OH FW 128.24 HC FW 126.20 CH3 [5582‑62‑7] [818‑72‑4] 374423-1G 1 g 127280-10G 10 g 374423-10G 10 g 127280-50G 50 g 3-(Trimethylsilyloxy)-1-butyne, 97% 127280-250G 250 g 2-(Trimethylsilyloxy)-3-butyne CH3 O Si CH3 1-Pentyn-3-ol, 98% C7H14OSi HC CH3 FW 142.27 CH C5H8O HC CH3 3 FW 84.12 OH [17869‑76‑0] [4187‑86‑4] 632031-5G 5 g E28404-1G 1 g 632031-25G 25 g E28404-10G 10 g 10-Undecyn-1-ol, ≥95.0% (GC) 4-Pentyn-1-ol, 97% C H O HC 11 20 OH C H O OH FW 168.28 5 8 HC FW 84.12 [2774‑84‑7] [5390‑04‑5] 94195-1ML 1 mL 302481-5G 5 g 302481-25G 25 g 4-Pentyn-2-ol, ≥98% (±)-4-Pentyn-2-ol OH

C5H8O HC CH3 FW 84.12 [2117‑11‑5] 268992-1G 1 g 268992-5G 5 g 268992-25G 25 g

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Halogenated Alkynes 3-Chloro-1-ethynylbenzene, 97% C H Cl 8 5 CH (3,5-Bis(trifluoromethyl)phenylethynyl)trimethylsilane, 97% FW 136.58 C H F Si F3C [766‑83‑6] Cl 13 12 6 CH FW 310.31 3 Si CH3 630268-1G 1 g [618092‑28‑7] CH3 630268-5G 5 g F3C 597805-5G 5 g 6-Chloro-1-, 98%

1-Bromo-2-butyne, 99% C6H9Cl HC Cl FW 116.59 C4H5Br H3C [10297‑06‑0] FW 132.99 Br [3355‑28‑0] 469777-5ML 5 mL 469777-25ML 25 mL 427292-1G 1 g 427292-5G 5 g 3-Chloro-3-methyl-1-butyne, 97% CH 1-Bromo-2-ethynylbenzene, 95% C5H7Cl 3 FW 102.56 HC Cl C H Br CH3 8 5 CH [1111‑97‑3] FW 181.03 [766‑46‑1] Br 301345-1G 1 g 301345-5G 5 g 494178-1G 1 g 301345-25G 25 g 1-Bromo-4-ethynylbenzene, 97% 1-Chloro-2-, 98% C8H5Br Br CH C8H13Cl Cl CH (CH ) CH FW 181.03 FW 144.64 3 2 3 2 [766‑96‑1] [51575‑83‑8] Functionalized Alkynes 206512-1G 1 g 442860-1G 1 g 1-Bromo-2-, 97% 442860-10G 10 g Br C5H7Br 5-Chloro-1-pentyne, 98% FW 147.01 H3C Cl C5H7Cl HC [16400‑32‑1] FW 102.56 429538-1G 1 g [14267‑92‑6] 429538-10G 10 g 244376-5G 5 g (2-Bromophenylethynyl)trimethylsilane, 98% 244376-25G 25 g CH C11H13BrSi 3 (5-Chloro-1-pentynyl)trimethylsilylsilane, 97% Si CH3 FW 253.21 CH CH3 1-Chloro-5-trimethylsilyl-4-pentyne Cl 3 [38274‑16‑7] Br Si CH3 C8H15ClSi 484695-5G 5 g FW 174.74 CH3 [77113‑48‑5] (3-Bromophenylethynyl)trimethylsilane, 97% 595918-5G 5 g CH C11H13BrSi 3 FW 253.21 Si CH3 1-Chloro-4-(phenylethynyl), 98% CH3 [3989‑13‑7] Br C H Cl 14 9 Cl 510971-5G 5 g FW 212.67 [5172‑02‑1] (4-Bromophenylethynyl)trimethylsilane, 98% 510750-1G 1 g C H BrSi CH3 11 13 510750-5G 5 g FW 253.21 Br Si CH3 CH [16116‑78‑2] 3 (3-Chlorophenylethynyl)trimethylsilane, 98% 494011-5G 5 g CH C11H13ClSi 3 494011-25G 25 g FW 208.76 Si CH3 CH3 [227936‑62‑1] Cl 1-Chloro-2-ethynylbenzene, 98% 597708-1G 1 g (2-Chlorophenyl) CH 597708-5G 5 g C8H5Cl FW 136.58 Cl (4-Chlorophenylethynyl)trimethylsilane, 97% [873‑31‑4] CH C11H13ClSi 3 465305-1G 1 g FW 208.76 Cl Si CH3 465305-5G 5 g [78704‑49‑1] CH3 1-Chloro-4-ethynylbenzene, 98% 563447-5G 5 g 563447-25G 25 g (4-Chlorophenyl)acetylene Cl CH C8H5Cl 1,4-Dichloro-2-butyne, 99% FW 136.58 C4H4Cl2 Cl [873‑73‑4] FW 122.98 Cl 206474-1G 1 g [821‑10‑3] D59607-5G 5 g D59607-25G 25 g D59607-100G 100 g

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3,4-Dichlorophenylacetylene, 97% 1-Ethynyl-2-fluorobenzene, 97% 1,2-Dichloro-4-ethynylbenzene; 3,4-Dichloro- C H F Cl CH 8 5 CH 1-ethynylbenzene FW 120.12 Cl F C8H4Cl2 [766‑49‑4] FW 171.02 467006-250MG 250 mg [556112‑20‑0] 467006-1G 1 g 672890-1G 1 g 1-Ethynyl-3-fluorobenzene, 98% (2,4-Difluorophenylethynyl)trimethylsilane, 96% C H F 8 5 CH CH C11H12F2Si 3 FW 120.12 FW 210.30 F Si CH3 [2561‑17‑3] F CH3 [480438‑92‑4] F 519405-5G 5 g Alkynes Functionalized 563471-1ML 1 mL 563471-5ML 5 mL 1-Ethynyl-4-fluorobenzene, 99% C H F 8 5 F CH (3,5-Difluorophenylethynyl)trimethylsilane, 98% FW 120.12 F C11H12F2Si [766‑98‑3] CH3 FW 210.30 Si CH3 404330-1G 1 g [445491‑09‑8] CH3 404330-5G 5 g F 589330-5G 5 g 4-Ethynyl-1-fluoro-2-methylbenzene, 97% H C 1-Ethynyl-3,5-bis(trifluoromethyl)benzene, 97% C9H7F 3 FW 134.15 F CH F C C10H4F6 3 [351002‑93‑2] FW 238.13 CH [88444‑81‑9] 521205-1G 1 g F3C 521205-5G 5 g 630241-1G 1 g 2-Ethynyl-α,α,α-trifluorotoluene, 97% 1-Ethynyl-2-trifluoromethylbenzene 1-Ethynyl-2,4-difluorobenzene, 97% CH C9H5F3 C8H4F2 F CH FW 170.13 CF3 FW 138.11 [704‑41‑6] [302912‑34‑1] F 521183-1G 1 g 556440-5G 5 g 3-Ethynyl-α,α,α-trifluorotoluene, 97% 1-Ethynyl-3,5-difluorobenzene, 97% C H F C H F F 9 5 3 CH 8 4 2 FW 170.13 FW 138.11 CH [705‑28‑2] F3C [151361‑87‑4] F 557331-5G 5 g 590177-1G 1 g

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4-Ethynyl-α,α,α-trifluorotoluene, 97% 1-[(Trimethylsilyl)ethynyl]-4-(trifluoromethyl)benzene, 97%

C9H5F3 [4-(Trifluoromethyl)phenyl](trimethylsilyl)acetylene CH3 F3C CH F C Si CH FW 170.13 C12H13F3Si 3 3 [705‑31‑7] FW 242.31 CH3 556432-5G 5 g [40230‑95‑3] 563439-5ML 5 mL (2-Fluorophenylethynyl)trimethylsilane, 96% 563439-25ML 25 mL CH3 C11H13FSi FW 192.30 Si CH3 CH3 [480439‑33‑6] F Miscellaneous Alkynes 571407-5G 5 g N-tert-Amyl-1,1-dimethylpropargylamine, 98% 571407-25G 25 g H CH3 C10H19N N FW 153.26 HC CH3 (4-Fluorophenylethynyl)trimethylsilane, 97% CH H3C CH3 3 CH [2978‑40‑7] C11H13FSi 3 FW 192.30 F Si CH3 514934-5G 5 g CH3 [130995‑12‑9] N-tert-Butyl-1,1-dimethylpropargylamine, 97% 563463-5ML 5 mL C H N H 9 17 N CH3 563463-25ML 25 mL HC FW 139.24 CH3 H C CH (4-Iodophenylethynyl)trimethylsilane, 97% [1118‑17‑8] 3 CH3 3 CH 513695-5G 5 g C11H13ISi 3 FW 300.21 I Si CH3 CH Cyclopropylacetylene, 97% [134856‑58‑9] 3 Ethynylcyclopropane HC 640751-1G 1 g C5H6

Functionalized Alkynes 640751-5G 5 g FW 66.10 Propargyl bromide solution [6746‑94‑7] 3-Bromo-1-propyne HC 663018-5G 5 g Br 663018-25G 25 g C3H3Br FW 118.96 1,3-Diethynylbenzene, 97% [106‑96‑7] C H 10 6 CH  80 wt. % in xylene FW 126.15 530409-50G 50 g [1785‑61‑1] HC 530409-125G 125 g 632104-1G 1 g Propargyl chloride, 98% 632104-5G 5 g 3-Chloro-1-propyne HC 1,4-Diethynylbenzene, 96% C H Cl Cl 3 3 C H FW 74.51 10 6 HC CH [624‑65‑7] FW 126.15 [935‑14‑8] 143995-5G 5 g 632090-5G 5 g 143995-25G 25 g Propargyl chloride solution 3-Dimethylamino-1-propyne, 97% N,N-Dimethylpropargylamine; CH3 3-Chloro-1-propyne HC N,N-Dimethyl-2-propynylamine N C H Cl Cl HC CH3 3 3 C H N FW 74.51 5 9 FW 83.13 [624‑65‑7] [7223‑38‑3]  70 wt. % in toluene 143065-5G 5 g 384321-100ML 100 mL 143065-25G 25 g 4-(Trifluoromethoxy) phenylacetylene, 97% 1,1-Dimethyl-N-tert-octylpropargylamine, 96%

4-Ethynyl-1-(trifluoromethoxy) benzene H CH3 F3CO CH C13H25N N CH3 HC C9H5F3O FW 195.34 CH3 H C CH3 CH FW 186.13 [263254‑99‑5] 3 CH3 3 [160542‑02‑9] 513709-1G 1 g 672858-1G 1 g 2-Ethynylaniline, 98% 1-[(Trimethylsilyl)ethynyl]-3-fluorobenzene, 97% C8H7N CH CH C11H13FSi 3 FW 117.15 Si CH FW 192.30 3 [52670‑38‑9] NH2 CH3 [40230‑96‑4] F 597651-1G 1 g 563269-5G 5 g 597651-5G 5 g 1-[(Trimethylsilyl)ethynyl]-3-(trifluoromethyl)benzene, 98% 3-Ethynylaniline, ≥98% 1-(3’-Trifluoromethylphenyl)-2-(trimethylsilyl)acetylene C H N 8 7 CH CH3 C12H13F3Si FW 117.15 Si CH3 FW 242.31 [54060‑30‑9] H2N CH3 [40230‑93‑1] F C 3 498289-5G 5 g 562661-5ML 5 mL 562661-25ML 25 mL

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4-Ethynylaniline, 97% 2-Methyl-3-butyn-2-amine, 95% 8

1-Amino-4-ethynylbenzene 3-Amino-3-methyl-1-butyne; NH2 H2N CH HC CH3 C8H7N 1,1-Dimethylpropargylamine CH3 FW 117.15 C5H9N [14235‑81‑5] FW 83.13 481122-5G 5 g [2978‑58‑7] 687189-5G 5 g 4-Ethynylbiphenyl, 97% C H N-Methylpropargylamine, 95% 14 10 CH FW 178.23 3-Methylamino-1-propyne H N HC CH [29079‑00‑3] C4H7N 3

521175-5G 5 g FW 69.11 Alkynes Functionalized [35161‑71‑8] 1-Ethynylcyclohexene, 99% 150223-1G 1 g C H 8 10 CH 150223-5G 5 g FW 106.17 [931‑49‑7] N-Methyl-N-propargylbenzylamine, 97% CH 316571-5G 5 g Pargyline N 316571-25G 25 g C11H13N CH3 FW 159.23 1-Ethynylcyclohexylamine, 98% [555‑57‑7]

C8H13N NH2 M74253-5G 5 g CH FW 123.20 M74253-25G 25 g [30389‑18‑5] 1,8-Nonadiyne, 98% 177024-1G 1 g 177024-5G 5 g C9H12 HC CH FW 120.19 1-Ethynyl-3,5-dimethoxybenzene [2396‑65‑8] H CO C10H10O2 3 161306-10G 10 g FW 162.19 CH [171290‑52‑1] 1,7-Octadiyne, 98% H3CO CH 98% (CP) C8H10 HC FW 106.17 588520-1G 1 g [871‑84‑1] 588520-5G 5 g 161292-1G 1 g 4-Ethynyl-N,N-dimethylaniline, 97% 161292-10G 10 g 4-Dimethylaminophenylacetylene; H3C N CH Propargylamine, 98% 1-Ethynyl-4-dimethylaniline H3C 3-Amino-1-propyne; 2-Propynylamine HC C10H11N NH2 FW 145.20 C3H5N [17573‑94‑3] FW 55.08 [2450‑71‑7] 592609-1G 1 g 592609-5G 5 g P50900-1G 1 g P50900-5G 5 g 1-Ethynyl-2-nitrobenzene, 98% P50900-25G 25 g CH C8H5NO2 Propargylamine hydrochloride, 95% FW 147.13 3-Amino-1-propyne hydrochloride; HC • HCl [16433‑96‑8] NO2 2-Propynylamine hydrochloride NH2 519456-5G 5 g C3H5N · HCl 1-Ethynyl-4-nitrobenzene, 97% FW 91.54 [15430‑52‑1] C8H5NO2 O2N CH FW 147.13 P50919-1G 1 g [937‑31‑5] P50919-10G 10 g 519294-1G 1 g Tripropargylamine, 98% 519294-5G 5 g CH C9H9N N 1-Ethynyl-4-phenoxybenzene, 97% FW 131.17 HC CH [6921‑29‑5] C H O 14 10 HC O FW 194.23 T84964-5G 5 g [4200‑06‑0] 521213-1G 1 g 521213-5G 5 g 1,6-Heptadiyne, 97%

C7H8 HC CH FW 92.14 [2396‑63‑6] 407437-1G 1 g

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