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Solid-Phase Synthesis of Pyrrole Derivatives through a Multicomponent Reaction Involving Lys Containing Peptides Yahya E Jad, Santosh Kumar Gudimella, Thavendran Govender, Beatriz G. de la Torre, and Fernando Albericio ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.8b00006 • Publication Date (Web): 14 Feb 2018 Downloaded from http://pubs.acs.org on February 15, 2018

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ACS Combinatorial Science

Solid-Phase Synthesis of Pyrrole Derivatives through a Multicomponent Reaction Involving Lys Containing Peptides Yahya E. Jad,1‡ Santosh K. Gudimella,1,2‡ Thavendran Govender,1 Beatriz G. de la Torre,*1,3 Fernando Albericio*1,2,4,5 1

Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, University Road, Westville, Durban 4001, South Africa 2

School of Chemistry and Physics, University of KwaZulu-Natal, University Road, Westville, Durban 4001, South Africa

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KRISP, College of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa 4

5

Department of Organic Chemistry, University of Barcelona, 08028-Barcelona, Spain

CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Barcelona 08028, Spain

KEYWORDS Multicomponent reaction, solid-phase peptide synthesis, combinatorial libraries, pyrrole.

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ABSTRACT

The synthesis of pyrroles has received considerable attention because of their biological and pharmaceutical activities.

Herein we describe a solid-phase multicomponent reaction that

utilizes Lys as a N donor, β-nitrostyrenes, 1,3-dicarbonyl compounds, and FeCl3 as an easily accessible catalyst under microwave irradiation affords the subsequent pyrrole derivatives in high conversions. The strategy combines three of the most powerful tools in modern synthetic chemistry: the solid-phase mode, the microwave activation and a multicomponent reaction. The excellent results in terms of rapidity, versality, and purity obtained herein support once again that this combined strategy is efficient for gaining chemical diversity.

Introduction Pyrrole derivatives are important N-containing heterocyclic compounds because of its diverse pharmaceutical activity, presence in natural products,1 and use as electrical conducting materials.2 Moreover, they exhibit various biological activities such as antibacterial, anticancer, anti-HIV, anti-inflammatory, antitumor, antioxidant, and antifungal.3 As a result, the development of various methods for preparing pyrroles has long been a topic in synthetic chemistry. The most convenient methods to prepare pyrrole scaffolds are Hantzsch4 and Paal– Knorr5 reactions. Solid-phase organic synthesis (SPOS) is receiving much attention due to its wide range of applications in the construction of heterocyclic compounds6 and other small molecules.7 SPOS is derived from the solid-phase peptide synthesis strategy,8 shows many advantages for the preparation of compounds that require rather fewer steps. There is an absence of tedious workups while providing the possibility of using large excesses of reagents to drive the reactions to completion. In addition, all reactions and transformations are carried out in the


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same reactor with no significant mechanical losses even at the µmol scale, which very often is enough for a first screening of the potential applications. This approach facilitates higher overall chemical yields in shorter reaction periods with considerably reduction of chemical waste when compared with traditional chemistry carried out in solution. SPOS is also attractive since it permits the use of metals that can be almost completely removed from the reaction medium through extended washings and filtrations. In this regard, Lewis acid-catalyzed solid phase synthesis of heterocyclic structures has always been a fascinating topic.9 The recent years have been witness to an increasing interest in the preparation of peptideheterocyclic chimeras in medicinal chemistry programs.10 The preparation of pyrroles by a multicomponent reaction (MCR) involving amines, β-nitrostyrene, and 1,3-dicarbonyl compounds in the presence of Lewis acid catalysts have been used very often in solution.11 Herein, we report an efficient method based in that MCR for the solid-phase synthesis of peptide-pyrrole chimeras building up the pyrrole on the ε-amino function of a lysine (Lys) residue (Scheme 1).12 MCRs are ideal for diversity-oriented synthesis, easy to be implemented, and can be considered under the umbrella of the green chemistry because they show a high atom efficiency.13

Scheme 1. Synthesis of peptide-pyrrole chimeras

Results and discussion


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The tripeptide (1) with an unprotected side-chain of the Lys was chosen as a model peptide. It was prepared on a Rink-amide polystyrene resin, which allows for the release of the product by a simple treatment with trifluoroacetic acid (TFA). Elongation of the peptide chain was accomplished by using fluorenylmethyloxycarbonyl (Fmoc) as a temporal protecting group of the α-amino function of the amino acids and the 4-methoxytrityl (Mtt) for the side-chain of the Lys, which was removed by TFA-DCM (2:98). β-Nitrostyrene (2) and ethyl acetoacetate (3) were also initially selected as model reactants to determine the optimum Lewis acid catalyst and the reaction time under microwave assisted irradiation (100 °C) 11d in DMF (Table 1). We have focused on inexpensive, available and easily accessible catalysts.14 DMF was used as a solvent because it is the mostly used solvent for peptide synthesis and it is compatible with all commercially available resins.15 The reaction was carried in the presence of 0.5 equiv of AlCl3 in DMF at 100 °C under microwave irradiation for 10 and 30 min but none of the desired product was observed after cleavage with TFA even upon increasing the amount of AlCl3 to 1 equiv (Table 1, # entries 1-3). With the use of ZnCl2 as catalyst, we were pleased to observe the formation of the pyrrole 4 (14.5% conversion) with 0.5 equiv of this Lewis acid after 30 min (Table 1, # entry 5). A gradual increase in the conversion (45.4%) was observed when 1 equiv. of ZnCl2 was used in just 10 min (Table 1, # entry 6). Finally, FeCl3 rendered the best results with shorter reaction times (10 min) and 0.5 equiv. (Table 1, # entries 7-12). Throughout this preliminary study, it was noticed that there was a tendency of the Fmoc group to be prematurely removed. It was only stable in the presence of 0.5 equiv of AlCl3 (Table 1, # entries 1 and 2), and with shortest times (10 min) of FeCl3 (Table 1, # entries 7 and 10). The instability of the Fmoc group in front of Lewis catalysts was already reported in the literature.16


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Table 1. Optimization of the reaction condition. a

Catalyst

Equiv

Time (min)

% Conversion

Fmoc removal

AlCl3

0.5

10

NA

No

30

NA

No

1

10

NA

Yes

0.5

10

NA

Yes

30

14.5

Yes

1

10

45.4

Yes

0.5

10

62

No

8

20

11.3

Yes

9

30

15.2

Yes

10

41.4

No

11

20

23

Yes

12

30

15

Yes

1 2 3 4

ZnCl2

5 6 7

10

FeCl3

1

a

Reaction conditions: Peptide (1), 4-methylnitrostyrene (2a, 6 equiv.), ethyl acetoacetate (3b, 6 equiv) and catalyst in DMF (0.5 mL) at 100 °C under microwave irradiation. Thus, it can be concluded that the best conditions are FeCl3 (0.5 equiv.) as catalyst at shorter times (10 min). On the other hand, although the Fmoc group was stable in these conditions, the next series of reactions were carried out with the N-acetyl form of the peptide in order to avoid any risk of Fmoc removal.


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Fmoc-SPPS FmocNH

H-Phe-Lys-Ala-NH Mtt

Ac2O (3 equiv) DIEA (3 equiv) DMF 30 min NO2

Ac-Phe-Lys-Ala-NH N

X R O

X

2 (a-o) 6 equiv

O

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Ac-Phe-Lys-Ala-NH Mtt

i) 2% TFA in DCM (5 30 s) ii) 5% DIEA in DCM (5 30 s)

O R

3 (a or b) 6 equiv

FeCl3 (0.5 equiv), DMF, MW, 100 C, 10 min

Ac-Phe-Lys-Ala-NH NH2 6

7 (a-o)

TFA/H2O/TIS (95:2.5:2.5) Ac-Phe-Lys-Ala-NH2 N R X

O 8 (a-o)

Scheme 2. Synthesis of peptide-pyrrole derivatives To study the scope and the limitations of this synthetic strategy, a small library of pyrroles was prepared using two 1,3-dicarbonyl compounds and eight β-nitrostyrene (Scheme 2). The overall results summarized in Figure 1 could be classified as excellent. Acetylacetone (8a-i) performed slightly better than ethyl acetoacetate (8j-o). Analysing the nitrostyrene component, those bearing electron-donating (Me, OMe and OBn), or electron-withdrawing (Br and Cl) groups reacted smoothly under the optimized conditions and gave the desired products in good to high conversions (8a-g, 8i–n). However, nitrostyrenes bearing an –OH group gave comparatively less conversion to the products (8h and 8o) which can be explained by the absence of the protecting group on the phenolic OH. This is well exemplified in the ethyl acetate derivative (8o) with a conversion of just 40%, but that it could be considered acceptable.


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All compounds are characterized by HPLC and HRMS. Furthermore, four derivatives 8f, 8g, 8i and 8k were also characterized by NMR in order to confirm the proposed structure.

Figure 1. Pyrroles synthesized from different nitrostyrenes and 1,3-dicarbonyl compounds (HPLC purity of the crude products after cleavage is indicated within the brackets).


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Conclusion In summary, we have established a solid-phase synthesis of peptide-pyrrole chimeras through a multicomponent reaction. Employing this methodology, various pyrrole derivatives, built on Lys-peptide, were efficiently synthesized using β-nitrostyrene, and 1,3-dicarbonyl compounds under microwave conditions employing FeCl3 as an easily accessible catalyst. Our strategy combines three of the most powerful tools in modern synthetic chemistry: the solid-phase mode, the microwave activation and a MCR. The excellent results in terms of rapidity, versality, and purity support once again that this combined strategy is really efficient for gaining chemical diversity. The use of the methodology outlined herein is currently carried in our laboratory for the preparation of more complex peptide chimeras.

ASSOCIATED CONTENT Supporting Information includes all experimental details, HPLC chromatograms, HRMS and NMR spectra. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. *E-mail: [email protected] or [email protected]. Author Contributions


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Experimental part was carried out by the first two authors. The manuscript was written through contributions of all authors.

All authors have given approval to the final version of the

manuscript. ‡These authors contributed equally. ACKNOWLEDGMENT The work was funded in part by the following: National Research Foundation (NRF) and the University of KwaZulu-Natal (South Africa); and the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) (CTQ2015-67870-P) and the Generalitat de Catalunya (2017 SGR 1439) (Spain). REFERENCES 1. Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Lamellarins and Related Pyrrole-Derived Alkaloids from Marine Organisms. Chem. Rev. 2008, 108, 264. 2. (a) Groenendaal, L.; Meijer, E. W.; Vekemans, J. A. J. M. “Electronic Materials: The Oligomer Approach,” K. M. Allen and G. Wegner, Eds., Wiley-VCH, Weinheim, 1997. (b) Ramanavicius, A.; Ramanaviciene, A.; Malinauskas, A. Electrochemical sensors based on conducting polymer-polypyrrole. Electrochem. Acta 2006, 51, 6025. 3. Huffman, J. W.; Padgett, L. W. Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes. Curr. Med. Chem., 2005, 12, 1395. 4. Hantzsch, A. Neue Bildungsweise von Pyrrolderivaten. Ber. Dtsch. Chem. Ges. 1890, 23, 1474. 5. Knorr, L. Synthese von Pyrrolderivaten. Ber. Dtsch. Chem. Ges. 1884, 17, 1635. 6. (a) Nicolaou, K. C.; Montagnon, T.; Ulven, T.; Baran, P. S.; Zhong, Y.-L.; Sarabia, F. Novel chemistry of α-tosyloxy ketones: Applications to the solution- and solid-phase synthesis

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Julia, I. G.; Ghotas, E.; Robert, A. B. Peptide−Heterocycle Hybrid Molecules: SolidPhase Synthesis of a 400-Member Library of N-Terminal 2-Iminohydantoin Peptides. J. Comb. Chem., 2006, 8, 237. (d) Seth Horne, C. W.; David, S.; Reza Ghadiri, M. A Heterocyclic Peptide Nanotube. J. Am. Chem. Soc., 2003, 125, 9372. (e) Freidinger, R. M. Design and Synthesis of Novel Bioactive Peptides and Peptidomimetics. J. Med. Chem., 2003, 46, 5553. (f) Baird, E. E.; Dervan, P. B. Solid phase synthesis of polyamides containing imidazole and pyrrole amino acids. J. Am. Chem. Soc. 1996, 118, 6141. 11. (a) Estévez, V.; Villacampa, M.; Menéndez, J. C. Multicomponent reactions for the synthesis of pyrroles. Chem. Soc. Rev., 2010, 39, 4402 (b) Sharma, A.; Piplani, P. Microwave-activated Synthesis of Pyrroles: A Short Review. J. Heterocyclic Chem., 2017, 54, 27. (c) Maiti, S.; Biswas, S.; Jana, U. Iron(III)-Catalyzed Four-Component Coupling

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Solid-Phase Synthesis of Pyrrole Derivatives ... - ACS Publications

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