Site-specific C-functionalization of free-(NH) peptidesand glycine derivatives via direct C–Hbond functionalizationLiang Zhao, Oliver Basle, and Chao-Jun Li1

Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 2K6, Canada.

Edited by Jack Halpern, University of Chicago, Chicago, IL, and approved January 14, 2009 (received for review September 11, 2008)

A copper-catalyzed �-functionalization of glycine derivatives andshort peptides with nucleophiles is described. The present methodprovides ways to introduce functionalities such as aryl, vinyl, alkynyl,or indolyl specifically to the terminal glycine moieties of small pep-tides, which are normally difficult in peptide modifications. Further-more, on functionalization, the configurations of other stereocentersin the peptides could be maintained. Because the functionalizedpeptides could easily be deprotected and carried onto the nextcoupling process, our approach provides a useful tool for the peptide-based biological research.

amino acid � C–C bond formation � peptide modification

Recent advances in proteomics demands innovative methods torapidly generate and modify peptides and amino acids. Direct

and site-specific modification of amino acids and peptides takesadvantage of the existing structure and provides a convenient wayto generate large arrays of diverse amino acids and peptides forbiomedical applications. For amino acid C modifications, knownmethods include: alkylation of �-carbanions (preformed by depro-tonation with a strong base) (1–4), via radicals [�-bromination byN-bromosuccinimide (5, 6) or UV photolysis in the presence ofdi-tert-butyl peroxide (7)], the Claisen rearrangements (8, 9), andthe recently reported palladium-catalyzed arylation of an amide(10–14). In the field of peptide synthesis, stepwise mounting ofamino acids via solution and solid phase techniques has beenprevalent ever since they were first developed (15, 16). In anotherscenario, direct site-specific C-functionalization of peptides pro-vides an ideal approach that takes advantage of the preexistingpeptides and provides rapid access to diverse peptide libraries forbiological studies. Recently, by using enolate chemistry, O’Donnell(17–19) and Maruoka (3, 4, 20–22) reported an elegant method tointroduce alkyl groups into activated N-terminal glycine unit of ashort-chain peptide. However, a general method for site-specificallyintroducing various functional groups, leading to more elaboratedfunctionalized peptides such as aryl peptides, vinyl peptides, oralkynyl peptides, still does not exist. This is largely because of theinsurmountable difficulty in distinguishing the �-C–H bonds ofeach amino acid unit in peptides by using existing methods.Recently, we discovered that the �-C–H bond of tertiary amines orglycine derivatives can be alkylated by using a copper-catalyzedcross-coupling reaction (23–25). We also made the preliminaryobservation that glycine amides could be alkynylated in the pres-ence of glycine ester to alkynylated glycine amide (23). An inter-esting and important nonproteinogenic class of amino acids is thearylglycines. It has attracted more and more attention because thefrequency of isolating arylglycines has increased rapidly in the pastfew decades. For example, vancomycin (26–28), which was the firstglycopeptide antibiotic discovered, contains a heptapeptide inwhich three of the amino acid residues are arylglycines. Besides that,arylglycines are important intermediates in the commercial pro-duction of �-lactam antibiotics. Phenylglycine (ampicillin, cefa-chlor) and p-hydroxyphenylglycine (amoxicillin, cefadroxil) are thepredominant representatives in this family. According to WorldHealth Organization (WHO) data, ampicillin and amoxicillin to-tally accounted for almost half of the �-lactam antibiotics produced

globally in the year 2000 (29). Although the Strecker synthesis(30–32), the Ugi reaction (33–36) and the Petasis reaction (37–39)are important tools to construct arylglycine derivatives; directarylation of glycine derivatives or glycine moieties in peptides wouldbe more powerful in cases where the glycine moiety is alreadypresent. Herein, we wish to report the detailed study of a generalmethod for site-specific C arylation, vinylation, alkynylation, andindolylation of �-C–H bonds of glycines and short peptides at theN terminus (Fig. 1).

Results and DiscussionsAlkynylation of Glycine Derivatives. To find a general method tomodify natural amino acids rapidly, we need a reaction system thatcan directly activate the �-C–H bonds of an amino amide with highchemo- and regioselectivity. The design of our methodology is tocatalytically generate, in situ, an electrophilic glycine inter-mediate, which can be intercepted by a nucleophile to form a�-functionalized glycine derivative.

By using N-PMP (p-methoxyphenyl) glycine amide derivatives asthe amine substrate, phenylacetylene as the nucleophile, in thepresence of CuBr as catalyst, TBHP as oxidant, the couplingreaction proceeded very well at room temperature. The best solventwas found to be dichloromethane; other nonchlorinated solventssuch as THF, 1,6-dioxane, and toluene afforded low yields of thecoupling product (Table 1). Under the optimized conditions, var-ious glycine derivatives were coupled with aromatic alkynes (Table2). Secondary (Table 2, entries 1, 2, 3, and 4) and tertiary (Table 2,entry 5) amides all reacted well. For the aromatic alkyne counter-part, 4-ethynylbiphenyl (Table 2, entry 6), 1-bromo-4-ethynylben-zene (Table 2, entry 7), and 4-ethynyltoluene (Table 2, entry 8) allafforded the corresponding products in good yields. However,2-methoxyphenylacetylene (Table 2, entry 9) is less reactive thanthe other substrates, indicating that the steric hindrance on thealkyne retarded its reactivity. In the meantime, R1 being a substi-tuted amine moiety is also very important for the success of thistransformation. When R1 was switched to an OEt group (Table 2,entry 10), the coupling reaction did not occur at all at room

Author contributions: C.-J.L. designed research; L.Z. and O.B. performed research; L.Z. andC.-J.L. analyzed data; and C.-J.L. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

Freely available online through the PNAS open access option.

1To whom correspondence should be addressed. E-mail: cj.li@mcgill.ca.

This article contains supporting information online at www.pnas.org/cgi/content/full/0809052106/DCSupplemental.

Fig. 1. C-functionalization of N terminus of peptides.

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temperature; whereas switching R1 to a phenyl group (Table 2,entry 11) afforded a mixture of unidentified compounds. Thisindicates that R1 being a substituted amine moiety could probablyreduce the oxidation potential of the substrate and stabilize theimine intermediate being generated.

Arylation of Glycine Derivatives. With the success of alkynylation, wethen examined the C-functionalization with other nucleophiles.Among all of the examined nucleophiles, such as tributylphenyltin,trimethylphenylsilane, and phenylboronic acid, only phenylboronicacid afforded the desired arylation product. With 10 mol% CuBrand 1.0 equiv TBHP in 1,2-dichloroethane (DCE), the arylationreaction proceeded efficiently at 100 °C, affording the couplingproduct in 75% isolated yield, using a slight excess of N-PMP glycineamide (1.5 equiv, Table 3, entry 3). Other nonchlorinated solvents,such as THF, 1,6-dioxane, or toluene, afforded low yields of thecoupling product (Table 3, entries 4–8). With this result in hand, wethen briefly investigated the scope of this arylation reaction (Table4). Aryl boronic acids bearing electron-donating groups (Table 4,entries 2 and 5), a weak electron-withdrawing group (Table 4, entry4), or a steric hindered functional group (Table 4, entry 3) allafforded the corresponding coupling products in good yields.Heterocyclic boronic acids (Table 4, entries 7 and 9) and vinylbo-ronic acid (Table 4, entry 8) underwent the coupling reactionsmoothly as well. However, arylboronic acids bearing strong elec-tron-withdrawing groups (Table 4, entries 10 and 11) were nonre-active under the optimized conditions. Other N-PMP glycine amidederivatives reacted equally well with arylboronic acids (Table 4,entries 12 and 13). However, the coupling reaction did not proceedat all when N-PMP glycine amides without hydrogen on the amidenitrogen (Table 4, entries 15 and 16) or an N-PMP glycine ester(Table 4, entry 14) was used. These results suggested a potentialapproach for site-specific functionalization of peptides via thecurrent methods.

�-Functionalization of Peptides. Having succeeded in the function-alization of glycine derivatives, we decided to tackle the morechallenging task of functionalizing peptides. Considering that �-aryl

peptides are more prevalent in nature and more important synthonsin organic syntheses, we decided to focus on the arylation ofpeptides. Simple dipeptides (Table 5, entries 1–8) and tripeptides(Table 5, entries 12–19) all reacted with arylboronic acids, affordingthe coupling products in good yields in most cases. The scope ofarylboronic acids is very similar to the one examined for N-PMPglycine amide. A dipeptide (Table 5, entry 2) and tripeptides (Table5, entry 18 and 19) with an amino acid moiety other than glycinealso afforded the cross-coupling products. Interestingly, similardiastereoselectivities were observed when the preexisting chiralcenter is either one (Table 5, entry 2) or two (Table 5, entry18 and19) amino acid units away from the N-terminal glycine moiety.

To examine the scope of this method for peptide modifications,other nucleophiles such as phenylacetylene (Table 5, entry 9 and 20)and indole (Table 5, entry 10 and 21) were also tested. The couplingreactions went very well at conditions even milder than witharylboronic acids. It should also be noted that all of the function-alizations occurred exclusively at the N terminus of the peptideswithout any scrambling on other amino acid moieties.

Importance of N-PMP Protecting Group. As it is well known, there areother useful protecting groups for nitrogen compounds, such asbenzyl, Boc (butoxycarbonyl), and Ts (p-toluene sulfonamide).Accordingly, the protected dipeptides with those protecting groupswere synthesized and tested for the oxidative coupling reactionswith phenyl boronic acid (Table 6). However, no desired couplingproduct was obtained by using those protecting groups, whichillustrates the importance of the N-PMP group in the oxidativecoupling process.

Racemization Test. Traditional methods to functionalize amino acidderivatives are not applicable to peptide modifications due to notonly the site-specificity issue, but also the fact that the most popularmethod to functionalize amino acid derivatives is via the enolatechemistry, which usually requires the use of an excess amount ofstrong bases such as potassium tert-butoxide or lithium diisopropylamide (LDA). Therefore, the �-protons adjacent to the amides inmost cases cannot tolerate such strong basic conditions and would

*Reaction conditions: glycine derivative (0.10 mmol), alkyne (0.30 mmol), TBHP (18 �L, 5–6 M in decane), CuBr (0.01 mmol), CH2Cl2 (0.2 mL).†NMR yields using an internal standard. DCE, dichloroethane; DME, dimethoxyethane; THF, tetrahydrofuran; NP, no product.

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racemize quickly. To test whether our present method can stillmaintain the preexisting chiral center on the peptide, we used theoptically pure compound 6a. Under the standard reaction condi-

tions, the coupling product 8a was generated without any race-mization of the adjacent stereocenter (Scheme 1).*

Deprotection of PMP Group and Further Functionalization. To test thecompatibility of this functionalization method with state-of-the-artpeptide syntheses, the functionalized glycine derivative 9 was depro-tectedreadilybyTCCAtoafford theaminesalt10.Compound10couldthen be coupled with Fmoc-Gly efficiently by using HBTU/HOBt ascoupling reagents to afford the desired peptide 11 (Scheme 2).

Mechanism of CDC Reactions. For the arylation reaction, a tentativemechanism involving an iminol intermediate is proposed (Scheme3). First, CuBr/TBHP initiated a dehydrogenative oxidation of 12to give the imino amide intermediate 13, which will tautomerize tothe iminol form 14. Then, the newly formed hydroxyl group from14 coordinates with phenylboronic acid to give intermediate 15.After that, the phenyl group will be delivered to the imine bond.Final hydrolysis affords the �-aryl glycine derivative 16. Because ofthe presence of the PMP group, only the CH2 adjacent to the Nterminus can be functionalized. This mechanism is consistent withthe results that tertiary amides (Table 4, entries 15 and 16) did notreact at all because of the lack of a hydrogen on the amides totautomerize to the iminol form. It is also consistent with the absenceof reactivity with N-PMP glycine ethyl ester (Table 4, entry 14). Tosupport our proposed mechanism, the imino amide intermediate 17was synthesized by oxidation of N-PMP dipeptide. Compound 17was then heated with phenylboronic acid in DCE at 100 °C. Evenin the absence of CuBr, the reaction still proceeded well, affordingthe final coupling product with good yields (Scheme 4).

ConclusionAn efficient way to functionalize glycine derivatives and shortpeptides with various nucleophiles is described. Alkynyl, aryl, vinyl,and indolyl can all be introduced to the �-position of the terminalglycine moieties. In the meantime, the configurations of otherstereocenters in the peptide are maintained. The current methodcould also be easily integrated into subsequent peptide syntheses.With the advantages of site specificity, mild conditions, compati-bility with different nucleophiles and simple experimental proce-dure, this peptide modification method is expected to provide

*The retention times of the two newly formed diastereomers were compared with theracemic compound by using HPLC analysis. No observation of the peak at 15.6 minindicates that the stereo center on the alanine moiety was not destroyed. Details of theexperiment and explanations can be found in SI Appendix.

*Reaction conditions: glycine derivative (0.30 mmol), alkyne (0.90 mmol), TBHP(54 �L, 5–6 M in decane), CuBr (0.03 mmol), CH2Cl2 (0.5 mL).

†Isolated yields are based on amine, and NMR yields using an internal standardaregiveninparentheses.NA,notavailable;NR,noreaction;ND,notdetermined.

*NMR yields using an internal standard. DCE, dichloroethane; DME, dime-thoxyethane; THF, tetrahydrofuran; NP, no product.

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synthetic pathways for the increasingly important proteomics andpeptide-based pharmaceutical research.

Materials and MethodsGeneral Information. 1H NMR spectra were recorded on Varian 300-, 400-, and500-MHz spectrometers and the chemical shifts (�) were reported in parts permillion (ppm). The peak patterns are indicated as follows: s, singlet; d, doublet; t,triplet; dd, doublet of doublet; m, multiplet; q, quartet. The coupling constants,J, are reported in hertz (Hz). 13C NMR spectra were obtained at 75, 100, and 125MHz and referenced to the internal solvent signals (central peak is 77.0 ppm inCDCl3 or 40.4 ppm in DMSO-d6). CDCl3 was used to get NMR spectra unlessotherwise mentioned. HRMS were made by McGill University. Thin-layer chro-matography was performed by using Sorbent Silica Gel 60 F254 TLC plates andvisualized with UV light. Flash column chromatography was performed overSORBENT silica gel 30–60 �m. All reagents were weighed and handled in air atroom temperature. All reagents were purchased from Aldrich, Strem, and Acrosand used without further purification.

General Procedure for Preparation of PMP-Protected Glycine Derivatives; 2-(4-Methoxyphenylamino)-N-methylacetamide. 2-Bromoacetyl bromide (2.4 g, 1.2mmol) in CH2Cl2 (10 mL) was added dropwise to a mixture of MeNH2 (1.0 g, 30wt% in H2O, 1.0 mmol) and K2CO3 (1.66 g, 1.2 mmol) in CH2Cl2/H2O (30 mL/10 mL)at 0 °C. The mixture was then allowed to warm up to room temperature andstirred for 6 h. Then, the organic layer was separated and the aqueous layer was

extracted with CH2Cl2 (3 � 5 mL). The organic layers were combined and driedover Na2SO4, and CH2Cl2 was removed in vacuo. Subsequently, EtOH (5 mL),p-anisidine (1.23 g, 1 mmol), and NaOAc (0.84 g, 1 mmol) were added to theresidue. The resulting mixture was refluxed for 6 h and was filtered. The solventof the filtrate was removed in vacuo. Recrystallization (CH2Cl2/hexanes) gave thepure product 2-(4-methoxyphenylamino)-N-methylacetamide (1.5 g, 80% yield).

General Procedure for the Preparation of PMP-Protected Peptide Derivatives;N-(N-p-Methoxyphenylglycyl)-Glycine Ethyl Ester. SOCl2 (3.6 g, 30 mmol) wasaddedslowly toEtOH(30mL)at0 °C.After stirringat this temperature for10min,glycine(0.75g,10mmol)wasaddedtothesolution.Then, thereactionwasstirredat 70 °C for 3 h. EtOH was removed in vacuo. The resulting solid was then mixedwith CH2Cl2 (30 mL) and NEt3 (2.2 g, 22 mmol). The reaction mixture was cooledto �78 °C, and BrCH2COBr (2.0 g, 10 mmol) was added dropwise to the solutionat this temperature. The solution was allowed to warm up to room temperatureand the stirring was continued for 6 h. After that, the solution was washed withH2O (10 mL). The organic layer was dried over Na2SO4, and CH2Cl2 was removedin vacuo to afford BrCH2CONHCH2CO2Et (1.8 g, 81%). NaOAc (0.50 g, 6 mmol),p-anisole (0.74 g, 6 mmol), and BrCH2CONHCH2CO2Et (1.1 g, 5 mmol) weresuccessively added to EtOH (4 mL). The reaction tube was heated at 80 °C for 6 h.EtOH was removed in vacuo and the residue was dissolved in CH2Cl2 (20 mL) andwashedwithH2O(5mL).Theorganic layerwasdriedoverNa2SO4,andCH2Cl2 wasremoved in vacuo. Flash column chromatography on silica gel by using ethylacetate/hexanes (1:1) furnished the final product N-(N-p-methoxyphenylglycyl)-glycine ethyl ester (0.95 g, 72% yield).

*Reaction conditions; aryl boronic acid (0.20 mmol), glycine derivative (0.30 mmol), TBHP (36 �L, 5–6 M in decane), CuBr (0.02 mmol), DCE (0.5 mL).†Isolated yields are based on aryl boronic acid, and NMR yields using an internal standard are given in parentheses. ND, not determined; NA, not available; NR,no reaction.

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General Procedure for the Alkynylation of Glycine and Peptide Derivatives.2-(4-Methoxyphenylamino)-N-methyl acetamide (59 mg, 0.30 mmol), CuBr (4.2mg, 0.03 mmol), phenylacetylene (90 mg, 0.90 mmol), TBHP (54 �L, 5–6 M in

decane) were successively added into a test tube with CH2Cl2 (0.5 mL). The testtube was purged with argon. Then, the mixture was stirred for 15 h at roomtemperature,filteredthroughasmallpadofsilicagel,andconcentrated invacuo.Flash chromatography by using ethyl acetate/hexanes gradient eluent (1/4 to 1/2)furnished the final product (60 mg, 68% in yield).

General Procedure for the Arylation of Glycine and Peptide Derivatives. N-PMP-Gly-Gly-OEt (80 mg, 0.30 mmol) and CuBr (2.8 mg, 0.02 mmol) were dissolved in

Scheme 1.

*Reaction conditions: aryl boronic acid (0.20 mmol), peptide (0.30 mmol), TBHP (36 �L, 5–6 M in decane), CuBr (0.02 mmol), DCE (0.5 mL).†Isolated yields are based on aryl boronic acid, and NMR yields using an internal standard are given in parentheses.‡d.r. (diastereomer ratio) was determined by HPLC analysis. d.r. of the product is 4:5.§Reaction was performed using peptide as the limiting reagent at 70 °C, phenylacetylene was used at 3.0 equiv.¶Reactions were performed using peptide as the limiting reagent at room temperature, indole was used at 1.5 equiv.�Reaction was performed using dipeptide as the limiting reagent at room temperature in DCM, diethyl zinc was used at 2 equiv.**d.r. (diastereomer ratio) was determined by HPLC analysis. d.r. of the product is 3:5.

*NMR yields using an internal standard. NP, no product.

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DCE (0.5 mL), TBHP (36 �L, 5–6 M in decane) was then added. The solution wasstirred at room temperature for 10 min, followed by the addition of PhB(OH)2 (25mg, 0.2 mmol). The test tube was capped and stirred at 100 °C for 6 h. Then, thereaction mixture was filtered through a small pad of silica gel and concentratedin vacuo. Flash column chromatography on silica gel by using ethyl acetate/hexanes (1/5 to 1/3) furnished the final coupling product (52 mg, 77% yield).

General Procedure for the Deprotection of PMP-Gly(Ph)-OEt and SubsequentCoupling Reaction with Fmoc-Gly. To a stirred solution of compound N-PMP-Gly(Ph)-OEt (27 mg, 0.1 mmol) in CH3CN/H2O (1 mL/1 mL), HCl (100 �L, 2M), andtrichloroisocyanuric acid (TCCA) (12 mg, 0.1 mmol) were successively added. Thereaction mixture was stirred at room temperature for 4 h, and CH3CN was laterremoved in vacuo. The aqueous solution was extracted with CH2Cl2 (2 � 1 mL),and water in the aqueous solution was then removed in vacuo at 40 °C. Theresulting residue was used for the next step without further purification. Theresidue was dissolved in DMF (0.5 mL). Then HBTU (38 mg, 0.1 mmol), HOBt (14mg, 0.1 mmol), N,N-diisopropyl ethyl amine(DIPEA) (25 �L, 0.25 mmol), andFmoc-Gly (30 mg, 0.1 mmol) were successively added. The reaction mixture wasstirred at room temperature for 10 h. H2O (5 mL) was added to quench thereaction. The product was extracted with EtOAc (3 � 2 mL). The EtOAc layer wasdried over Na2SO4. After evaporation of the EtOAc in vacuo, the product wasisolated by using flash column chromatography on silica gel eluting with ethylacetate/NEt3 (100/3) (25 mg, 57% yield).

Supporting Information. For general reaction procedures, diffraction details,and characterization of products, see supporting information (SI) Appendix.

ACKNOWLEDGMENTS. This work was supported by the Canada Research Chair(Tier I) Foundation (C.-J.L.), the Canada Foundation for Innovation, NaturalSciences and Engineering Research Council (Canada), and McGill University.

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Scheme 2.

Scheme 4.

Scheme 3. Proposed mechanism for the arylation reaction.

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