Site-specific C-functionalization of free-(NH) peptides and glycine derivatives via direct C–H bond functionalization Liang 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 and short peptides with nucleophiles is described. The present method provides 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 stereocenters in the peptides could be maintained. Because the functionalized Fig. 1. C-functionalization of N terminus of peptides. peptides could easily be deprotected and carried onto the next coupling process, our approach provides a useful tool for the peptide- based biological research. globally in the year 2000 (29). Although the Strecker synthesis (30–32), the Ugi reaction (33–36) and the Petasis reaction (37–39) amino acid ͉ C–C bond formation ͉ peptide modification are important tools to construct arylglycine derivatives; direct arylation of glycine derivatives or glycine moieties in peptides would ecent advances in proteomics demands innovative methods to be more powerful in cases where the glycine moiety is already Rrapidly generate and modify peptides and amino acids. Direct present. Herein, we wish to report the detailed study of a general and site-specific modification of amino acids and peptides takes method for site-specific C arylation, vinylation, alkynylation, and CHEMISTRY advantage of the existing structure and provides a convenient way indolylation of ␣-C–H bonds of glycines and short peptides at the to generate large arrays of diverse amino acids and peptides for N terminus (Fig. 1). biomedical applications. For amino acid C modifications, known methods include: alkylation of ␣-carbanions (preformed by depro- Results and Discussions tonation with a strong base) (1–4), via radicals [␣-bromination by Alkynylation of Glycine Derivatives. To find a general method to N-bromosuccinimide (5, 6) or UV photolysis in the presence of modify natural amino acids rapidly, we need a reaction system that di-tert-butyl peroxide (7)], the Claisen rearrangements (8, 9), and can directly activate the ␣-C–H bonds of an amino amide with high the recently reported palladium-catalyzed arylation of an amide chemo- and regioselectivity. The design of our methodology is to (10–14). In the field of peptide synthesis, stepwise mounting of catalytically generate, in situ, an electrophilic glycine inter- amino acids via solution and solid phase techniques has been mediate, which can be intercepted by a nucleophile to form a prevalent ever since they were first developed (15, 16). In another ␣-functionalized glycine derivative. scenario, direct site-specific C-functionalization of peptides pro- By using N-PMP (p-methoxyphenyl) glycine amide derivatives as vides an ideal approach that takes advantage of the preexisting the amine substrate, phenylacetylene as the nucleophile, in the peptides and provides rapid access to diverse peptide libraries for presence of CuBr as catalyst, TBHP as oxidant, the coupling biological studies. Recently, by using enolate chemistry, O’Donnell reaction proceeded very well at room temperature. The best solvent (17–19) and Maruoka (3, 4, 20–22) reported an elegant method to was found to be dichloromethane; other nonchlorinated solvents introduce alkyl groups into activated N-terminal glycine unit of a such as THF, 1,6-dioxane, and toluene afforded low yields of the short-chain peptide. However, a general method for site-specifically coupling product (Table 1). Under the optimized conditions, var- introducing various functional groups, leading to more elaborated ious glycine derivatives were coupled with aromatic alkynes (Table functionalized peptides such as aryl peptides, vinyl peptides, or 2). Secondary (Table 2, entries 1, 2, 3, and 4) and tertiary (Table 2, alkynyl peptides, still does not exist. This is largely because of the entry 5) amides all reacted well. For the aromatic alkyne counter- insurmountable difficulty in distinguishing the ␣-C–H bonds of part, 4-ethynylbiphenyl (Table 2, entry 6), 1-bromo-4-ethynylben- each amino acid unit in peptides by using existing methods. zene (Table 2, entry 7), and 4-ethynyltoluene (Table 2, entry 8) all Recently, we discovered that the ␣-C–H bond of tertiary amines or afforded the corresponding products in good yields. However, glycine derivatives can be alkylated by using a copper-catalyzed 2-methoxyphenylacetylene (Table 2, entry 9) is less reactive than cross-coupling reaction (23–25). We also made the preliminary the other substrates, indicating that the steric hindrance on the observation that glycine amides could be alkynylated in the pres- alkyne retarded its reactivity. In the meantime, R1 being a substi- ence of glycine ester to alkynylated glycine amide (23). An inter- tuted amine moiety is also very important for the success of this esting and important nonproteinogenic class of amino acids is the transformation. When R1 was switched to an OEt group (Table 2, arylglycines. It has attracted more and more attention because the entry 10), the coupling reaction did not occur at all at room frequency of isolating arylglycines has increased rapidly in the past few decades. For example, vancomycin (26–28), which was the first glycopeptide antibiotic discovered, contains a heptapeptide in Author contributions: C.-J.L. designed research; L.Z. and O.B. performed research; L.Z. and which three of the amino acid residues are arylglycines. Besides that, C.-J.L. analyzed data; and C.-J.L. wrote the paper. arylglycines are important intermediates in the commercial pro- The authors declare no conflict of interest. duction of ␤-lactam antibiotics. Phenylglycine (ampicillin, cefa- This article is a PNAS Direct Submission. chlor) and p-hydroxyphenylglycine (amoxicillin, cefadroxil) are the Freely available online through the PNAS open access option. predominant representatives in this family. According to World 1To whom correspondence should be addressed. E-mail: [email protected]. Health Organization (WHO) data, ampicillin and amoxicillin to- This article contains supporting information online at www.pnas.org/cgi/content/full/ tally accounted for almost half of the ␤-lactam antibiotics produced 0809052106/DCSupplemental.

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0809052106 PNAS Early Edition ͉ 1of6 Downloaded by guest on October 2, 2021 *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.

temperature; whereas switching R1 to a phenyl group (Table 2, peptides are more prevalent in nature and more important synthons entry 11) afforded a mixture of unidentified compounds. This in organic syntheses, we decided to focus on the arylation of indicates that R1 being a substituted amine moiety could probably peptides. Simple dipeptides (Table 5, entries 1–8) and tripeptides reduce the oxidation potential of the substrate and stabilize the (Table 5, entries 12–19) all reacted with arylboronic acids, affording imine intermediate being generated. the coupling products in good yields in most cases. The scope of arylboronic acids is very similar to the one examined for N-PMP Arylation of Glycine Derivatives. With the success of alkynylation, we glycine amide. A dipeptide (Table 5, entry 2) and tripeptides (Table then examined the C-functionalization with other nucleophiles. 5, entry 18 and 19) with an amino acid moiety other than glycine Among all of the examined nucleophiles, such as tributylphenyltin, also afforded the cross-coupling products. Interestingly, similar trimethylphenylsilane, and phenylboronic acid, only phenylboronic diastereoselectivities were observed when the preexisting chiral acid afforded the desired arylation product. With 10 mol% CuBr center is either one (Table 5, entry 2) or two (Table 5, entry18 and and 1.0 equiv TBHP in 1,2-dichloroethane (DCE), the arylation 19) amino acid units away from the N-terminal glycine moiety. reaction proceeded efficiently at 100 °C, affording the coupling To examine the scope of this method for peptide modifications, product in 75% isolated yield, using a slight excess of N-PMP glycine other nucleophiles such as phenylacetylene (Table 5, entry 9 and 20) amide (1.5 equiv, Table 3, entry 3). Other nonchlorinated solvents, and indole (Table 5, entry 10 and 21) were also tested. The coupling such as THF, 1,6-dioxane, or toluene, afforded low yields of the reactions went very well at conditions even milder than with coupling product (Table 3, entries 4–8). With this result in hand, we arylboronic acids. It should also be noted that all of the function- then briefly investigated the scope of this arylation reaction (Table alizations occurred exclusively at the N terminus of the peptides 4). Aryl boronic acids bearing electron-donating groups (Table 4, without any scrambling on other amino acid moieties. entries 2 and 5), a weak electron-withdrawing group (Table 4, entry 4), or a steric hindered functional group (Table 4, entry 3) all Importance of N-PMP Protecting Group. As it is well known, there are afforded the corresponding coupling products in good yields. other useful protecting groups for nitrogen compounds, such as Heterocyclic boronic acids (Table 4, entries 7 and 9) and vinylbo- benzyl, Boc (butoxycarbonyl), and Ts (p-toluene sulfonamide). ronic acid (Table 4, entry 8) underwent the coupling reaction Accordingly, the protected dipeptides with those protecting groups smoothly as well. However, arylboronic acids bearing strong elec- were synthesized and tested for the oxidative coupling reactions tron-withdrawing groups (Table 4, entries 10 and 11) were nonre- with phenyl boronic acid (Table 6). However, no desired coupling active under the optimized conditions. Other N-PMP glycine amide product was obtained by using those protecting groups, which derivatives reacted equally well with arylboronic acids (Table 4, illustrates the importance of the N-PMP group in the oxidative entries 12 and 13). However, the coupling reaction did not proceed coupling process. at all when N-PMP glycine amides without hydrogen on the amide nitrogen (Table 4, entries 15 and 16) or an N-PMP glycine ester Racemization Test. Traditional methods to functionalize amino acid (Table 4, entry 14) was used. These results suggested a potential derivatives are not applicable to peptide modifications due to not approach for site-specific functionalization of peptides via the only the site-specificity issue, but also the fact that the most popular current methods. method to functionalize amino acid derivatives is via the enolate chemistry, which usually requires the use of an excess amount of ␣-Functionalization of Peptides. Having succeeded in the function- strong bases such as potassium tert-butoxide or lithium diisopropyl alization of glycine derivatives, we decided to tackle the more amide (LDA). Therefore, the ␣-protons adjacent to the amides in challenging task of functionalizing peptides. Considering that ␣-aryl most cases cannot tolerate such strong basic conditions and would

2of6 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0809052106 Zhao et al. Downloaded by guest on October 2, 2021 *NMR yields using an internal standard. DCE, dichloroethane; DME, dime- thoxyethane; THF, tetrahydrofuran; NP, no product.

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 the compatibility of this functionalization method with state-of-the-art CHEMISTRY peptide syntheses, the functionalized glycine derivative 9 was depro- tected readily by TCCA to afford the amine salt 10. Compound 10 could then be coupled with Fmoc-Gly efficiently by using HBTU/HOBt as coupling reagents to afford the desired peptide 11 (Scheme 2).

Mechanism of CDC Reactions. For the arylation reaction, a tentative mechanism involving an iminol intermediate is proposed (Scheme 3). First, CuBr/TBHP initiated a dehydrogenative oxidation of 12 to give the imino amide intermediate 13, which will tautomerize to the iminol form 14. Then, the newly formed hydroxyl group from 14 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 of the presence of the PMP group, only the CH2 adjacent to the N terminus can be functionalized. This mechanism is consistent with the results that tertiary amides (Table 4, entries 15 and 16) did not react at all because of the lack of a hydrogen on the amides to tautomerize to the iminol form. It is also consistent with the absence of reactivity with N-PMP glycine ethyl ester (Table 4, entry 14). To support our proposed mechanism, the imino amide intermediate 17 was synthesized by oxidation of N-PMP dipeptide. Compound 17 was then heated with phenylboronic acid in DCE at 100 °C. Even in the absence of CuBr, the reaction still proceeded well, affording the final coupling product with good yields (Scheme 4).

Conclusion An efficient way to functionalize glycine derivatives and short peptides with various nucleophiles is described. Alkynyl, aryl, vinyl, and indolyl can all be introduced to the ␣-position of the terminal glycine moieties. In the meantime, the configurations of other stereocenters in the peptide are maintained. The current method could also be easily integrated into subsequent peptide syntheses. *Reaction conditions: glycine derivative (0.30 mmol), alkyne (0.90 mmol), TBHP With the advantages of site specificity, mild conditions, compati- ␮ (54 L, 5–6 M in decane), CuBr (0.03 mmol), CH2Cl2 (0.5 mL). bility with different nucleophiles and simple experimental proce- †Isolated yields are based on amine, and NMR yields using an internal standard dure, this peptide modification method is expected to provide are given in parentheses. NA, not available; NR, no reaction; ND, not determined.

*The retention times of the two newly formed diastereomers were compared with the racemize quickly. To test whether our present method can still racemic compound by using HPLC analysis. No observation of the peak at 15.6 min maintain the preexisting chiral center on the peptide, we used the indicates that the stereo center on the alanine moiety was not destroyed. Details of the optically pure compound 6a. Under the standard reaction condi- experiment and explanations can be found in SI Appendix.

Zhao et al. PNAS Early Edition ͉ 3of6 Downloaded by guest on October 2, 2021 *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.

ϫ synthetic pathways for the increasingly important proteomics and extracted with CH2Cl2 (3 5 mL). The organic layers were combined and dried peptide-based pharmaceutical research. over 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 the Materials and Methods residue. The resulting mixture was refluxed for 6 h and was filtered. The solvent of the filtrate was removed in vacuo. Recrystallization (CH Cl /hexanes) gave the General Information. 1H NMR spectra were recorded on Varian 300-, 400-, and 2 2 pure product 2-(4-methoxyphenylamino)-N-methylacetamide (1.5 g, 80% yield). 500-MHz spectrometers and the chemical shifts (␦) were reported in parts per million (ppm). The peak patterns are indicated as follows: s, singlet; d, doublet; t, General Procedure for the Preparation of PMP-Protected Peptide Derivatives; triplet; dd, doublet of doublet; m, multiplet; q, quartet. The coupling constants, N-(N-p-Methoxyphenylglycyl)-Glycine Ethyl Ester. SOCl (3.6 g, 30 mmol) was J, are reported in hertz (Hz). 13C NMR spectra were obtained at 75, 100, and 125 2 added slowly to EtOH (30 mL) at 0 °C. After stirring at this temperature for 10 min, MHz and referenced to the internal solvent signals (central peak is 77.0 ppm in glycine (0.75 g, 10 mmol) was added to the solution. Then, the reaction was stirred CDCl or 40.4 ppm in DMSO-d ). CDCl was used to get NMR spectra unless 3 6 3 at 70 °C for 3 h. EtOH was removed in vacuo. The resulting solid was then mixed otherwise mentioned. HRMS were made by McGill University. Thin-layer chro- with CH2Cl2 (30 mL) and NEt3 (2.2 g, 22 mmol). The reaction mixture was cooled matography was performed by using Sorbent Silica Gel 60 F254 TLC plates and to Ϫ78 °C, and BrCH2COBr (2.0 g, 10 mmol) was added dropwise to the solution visualized with UV light. Flash column chromatography was performed over at this temperature. The solution was allowed to warm up to room temperature ␮ SORBENT silica gel 30–60 m. All reagents were weighed and handled in air at and the stirring was continued for 6 h. After that, the solution was washed with room temperature. All reagents were purchased from Aldrich, Strem, and Acros H2O (10 mL). The organic layer was dried over Na2SO4, and CH2Cl2 was removed and used without further purification. in 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) were General Procedure for Preparation of PMP-Protected Glycine Derivatives; 2-(4- successively added to EtOH (4 mL). The reaction tube was heated at 80 °C for 6 h. Methoxyphenylamino)-N-methylacetamide. 2-Bromoacetyl bromide (2.4 g, 1.2 EtOH was removed in vacuo and the residue was dissolved in CH2Cl2 (20 mL) and mmol) in CH2Cl2 (10 mL) was added dropwise to a mixture of MeNH2 (1.0 g, 30 washed with H2O (5 mL). The organic layer was dried over Na2SO4, and CH2Cl2 was wt% in H2O, 1.0 mmol) and K2CO3 (1.66 g, 1.2 mmol) in CH2Cl2/H2O (30 mL/10 mL) removed in vacuo. Flash column chromatography on silica gel by using ethyl at 0 °C. The mixture was then allowed to warm up to room temperature and acetate/hexanes (1:1) furnished the final product N-(N-p-methoxyphenylglycyl)- stirred for 6 h. Then, the organic layer was separated and the aqueous layer was glycine ethyl ester (0.95 g, 72% yield).

4of6 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0809052106 Zhao et al. Downloaded by guest on October 2, 2021 CHEMISTRY

*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. ʈReaction 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.

General Procedure for the Alkynylation of Glycine and Peptide Derivatives. decane) were successively added into a test tube with CH2Cl2 (0.5 mL). The test 2-(4-Methoxyphenylamino)-N-methyl acetamide (59 mg, 0.30 mmol), CuBr (4.2 tube was purged with argon. Then, the mixture was stirred for 15 h at room mg, 0.03 mmol), phenylacetylene (90 mg, 0.90 mmol), TBHP (54 ␮L, 5–6 M in temperature, filtered through a small pad of silica gel, and concentrated in vacuo. 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

*NMR yields using an internal standard. NP, no product. Scheme 1.

Zhao et al. PNAS Early Edition ͉ 5of6 Downloaded by guest on October 2, 2021 Scheme 2.

␮ DCE (0.5 mL), TBHP (36 L, 5–6 M in decane) was then added. The solution was Scheme 4. stirred at room temperature for 10 min, followed by the addition of PhB(OH)2 (25 mg, 0.2 mmol). The test tube was capped and stirred at 100 °C for 6 h. Then, the reaction mixture was filtered through a small pad of silica gel and concentrated General Procedure for the Deprotection of PMP-Gly(Ph)-OEt and Subsequent in vacuo. Flash column chromatography on silica gel by using ethyl acetate/ Coupling Reaction with Fmoc-Gly. To a stirred solution of compound N-PMP- hexanes (1/5 to 1/3) furnished the final coupling product (52 mg, 77% yield). Gly(Ph)-OEt (27 mg, 0.1 mmol) in CH3CN/H2O (1 mL/1 mL), HCl (100 ␮L, 2M), and trichloroisocyanuric acid (TCCA) (12 mg, 0.1 mmol) were successively added. The reaction mixture was stirred at room temperature for 4 h, and CH3CN was later removed in vacuo. The aqueous solution was extracted with CH2Cl2 (2 ϫ 1 mL), and water in the aqueous solution was then removed in vacuo at 40 °C. The resulting residue was used for the next step without further purification. The residue was dissolved in DMF (0.5 mL). Then HBTU (38 mg, 0.1 mmol), HOBt (14 mg, 0.1 mmol), N,N-diisopropyl ethyl amine(DIPEA) (25 ␮L, 0.25 mmol), and Fmoc-Gly (30 mg, 0.1 mmol) were successively added. The reaction mixture was stirred at room temperature for 10 h. H2O (5 mL) was added to quench the reaction. The product was extracted with EtOAc (3 ϫ 2 mL). The EtOAc layer was dried over Na2SO4. After evaporation of the EtOAc in vacuo, the product was isolated by using flash column chromatography on silica gel eluting with ethyl acetate/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, Natural Scheme 3. Proposed mechanism for the arylation reaction. Sciences and Engineering Research Council (Canada), and McGill University.

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