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Microreactors for peptide synthesis: looking through the eyes of twenty first century !!!

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Abstract

The twenty first century has witnessed several advances in synthetic chemistry, among them microreactors. It is expected that these devices will have a considerable impact on synthetic organic chemistry since they offer a wide range of applications in various fields. Perhaps the synthesis of peptides deserves mention in this regard as these molecules are emerging as therapeutics and offer several advantages over the so-called small molecules. This minireview does not aim to address microreactors in detail, but explains various peptide synthesis methods that involve microfluidic techniques, highlighting the need for further improvement and expansion of microdevices/microreactors.

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References

  • AlTpTe C, Vulpescu L, Cousseau P, Renaud P, Maurer R, Renken A (2000) IMRET 4: 4th International Conference on Microreaction Technology (Atlanta, USA), American Institute of Chemical Engineers Topical Conference Proceedings, p 71

  • Anzenbacher P, Palacios MA (2009) Polymer nanofibre junctions of attolitre volume serve as zeptomole-scale chemical reactors. Nat Chem 1:80–86

    CAS  PubMed  Google Scholar 

  • Baxendale IR, Ley SV, Smith CD, Tranmer GK (2006) A flow reactor process for the synthesis of peptides utilizing immobilized reagents, scavengers and catch and release protocols. Chem Commun 14:4835–4837

    Article  Google Scholar 

  • Becker H, Gartner C (2000) Polymer microfabrication methods for microfluidic analytical applications. Electrophoresis 21:12–26

    Article  CAS  PubMed  Google Scholar 

  • Chan WC, Bycroft BW, Evans DJ, White PD (1995) A novel 4-aminobenzyl ester-based carboxy-protecting group for synthesis of atypical peptides by Fmoc-But solid-phase chemistry. J Chem Soc Chem Commun 2209–2210

  • Cheng RP, Gellman SH, DeGrado WF (2001) β-Peptides: from structure to function. Chem Rev 101:3219–3232

    Article  CAS  PubMed  Google Scholar 

  • Chow AW (2002) Lab-on-a-chip: opportunities for chemical engineering. AIChE J 48:1590–1595

    Article  CAS  Google Scholar 

  • Christensen PD, Johnson SWP, McCreedy T, Skeleton V, Wilson NG (1998) The fabrication of micro-porous silica structures for microreactor technology. Anal Commun 35:341–343

    CAS  Google Scholar 

  • Coste J, Frérot E, Jouin P (1991) Oxybenzotriazole free peptide coupling reagents for N-methylated amino acids. Tetrahedron Lett 32:1967–1970

    CAS  Google Scholar 

  • de Mello A, Wootton R (2002) But what is it good for? Applications of microreactor technology for the fine chemical industry. Lab Chip 2:7N–13N

    PubMed  Google Scholar 

  • Ehrfeld (1995) DECHEMA-monographs, DECHEMA, Frankfurt, p 132

  • Ehrfeld W, Lehr H (1995) Deep X-ray lithography for the production of three-dimensional microstructures from metals, polymers and ceramics. Radiat Phys Chem 45:349–365

    CAS  Google Scholar 

  • Ehrfeld W, Hessel V, Haverkamp V (1999) Ullmann’s encyclopedia of industrial chemistry, 6th edn. Wiley, Weinheim

    Google Scholar 

  • Ehrfeld W, Hessel V, LDwe H (2000a) Microreactors. Wiley, Weinheim

    Google Scholar 

  • Ehrfeld W, Hessel V, Kiesewalter S, LDwe H, Richter T, Schiewe J (2000) Microreaction Technology—IMRET 3, In: Ehrfeld W (ed) Proceedings of the 3rd International Conference on Microreaction Technology, Springer, Berlin, p 14

  • Ehrfeld W, Hessel V, Lowe H (2000c) Microreactors: new technology for modern chemistry. Wiley, Weinheim

    Google Scholar 

  • Fletcher PDI, Haswell SJ, Paunov VN (1999) Theoretical considerations of chemical reactions in microreactors operating under electroosmotic and electrophoretic control. Analyst 124:1273–1282

    CAS  Google Scholar 

  • Fletcher PDI, Haswell SJ, Pombo-Villar E, Warrington BH, Watts P, Wong SYF, Zhang X (2002) Microreactors: principles and applications in organic synthesis. Tetrahedron 58:4735–4757

    CAS  Google Scholar 

  • Flogel O, Codee JDC, Seebach D, Seeberger PH (2006) Microreactor synthesis of β-peptides. Angew Chem Int Ed 45:7000–7003

    Google Scholar 

  • Fredrickson CK, Fan ZH (2004) Macro-to-micro interfaces for microfluidic devices. Lab Chip 4:526–533

    CAS  PubMed  Google Scholar 

  • Fuse S, Mifune Y, Takahashi T (2014) Efficient amide bond formation through a rapid and strong activation of carboxylic acids in a microflow reactor. Angew Chem Int Ed 53:851–855

    CAS  Google Scholar 

  • Gavriilidis A, Angeli P, Cao E, Yeong KK, Wan YSS (2002) Technology and applications of microengineered reactors. Trans Inst Chem Eng Part A 80:3–30

    CAS  Google Scholar 

  • Geyer K, Codee JDC, Seeberger PH (2006) Microreactors as tools for synthetic chemists-the chemists’ round bottomed flask of the 21st century? Chem Eur J 12:8434–8442

    CAS  PubMed  Google Scholar 

  • Grover WH, von Muhlen MG, Manalis SR (2008) Teflon films for chemically-inert microfluidic valves and pumps. Lab Chip 8:913–918

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hessel V, Lowe H (2002) Mikroverfahrenstechnik: komponenten—Anlagenkonzeption—Anwenderakzeptanz—Teil 2. Chem Ing Tech 74:185–207

    CAS  Google Scholar 

  • Hessel V, Hardt S, Lowe H (2004) Chemical micro process engineering: Fundamentals, modelling and reactions. Wiley, Weinheim

    Google Scholar 

  • Hessel V, Lçwe H, Schçnfeld (2005a) Micromixers—a review on passive and active mixing principles. Chem Eng Sci 60:2479–2501

    CAS  Google Scholar 

  • Hessel V, Lob P, Lowe H (2005b) Development of microstructured reactors to enable organic synthesis rather than subduing chemistry. Curr Org Chem 9:765–787

    CAS  Google Scholar 

  • Hessel V, Kolb G, de Bellefon C (2005c) Preface Catal Today 110:1

  • Jahnisch K, Hessel V, Lowe H, Baerns M (2004) Chemistry in microstructured reactors. Angew Chem Int Ed 43:406–446

    Google Scholar 

  • Jebrail MJ, Nr AHC, Rai V, Hili R, Yudin AK, Wheeler AR (2010) Synchronized synthesis of peptide-based macrocycles by digital microfluidics. Angew Chem Int Ed 49:8625–8629

    CAS  Google Scholar 

  • Jensen KF (2001) Microreaction engineering—is small better? Chem Eng Sci 56:293–303

    CAS  Google Scholar 

  • Jensen KF (2006) Silicon-based microchemical systems: characteristics and applications. MRS Bull 31:101–107

    CAS  Google Scholar 

  • Jäckel K-P (1996) Microtechnology: application opportunities in the chemical industry. In: Ehrfeld W (ed) Microsystem technology for chemical and biological microreactors. DECHEMA Monographs, vol 132, VCH, Weinheim, p 29

  • Kates SA, Nuria A, Sole M, Beyermann M, Barany G, Albericio F (1996) Optimized preparation of deca(l-alanyl)-l-valinamide by 9-fluorenylmethyloxycarbonyl (Fmoc) solid-phase synthesis on polyethylene glycol-polystyrene (PEG-PS) graft supports with 1,8-diazobicyclo [5.4.0]-undec-7-ene (DBU) deprotection. Pept Res 9:106–113

    CAS  PubMed  Google Scholar 

  • Kikutani Y, Horiuchi T, Uchiyama K, Hisamoto H, Tokeshi M, Kitamori T (2002) Glass microchip with three-dimensional microchannel network for 2 × 2 parallel synthesis. Lab Chip 2:188–192

    CAS  PubMed  Google Scholar 

  • Kiwi-Minsker L, Renken A (2005) Microstructured reactors for catalytic reactions. Catal Today 110:2–14

    CAS  Google Scholar 

  • Knitter R, Gohring D, Risthaus P, Hausselt J (2001) Microfabrication of ceramic microreactors. Microsyst Technol 7:85–90

    Google Scholar 

  • Kockmann N, Brand O, Fedder GK (2006) Micro process engineering. Wiley, Weinheim

    Google Scholar 

  • Kolb G, Hessel V (2004) Microstructured reactors for gas phase reactions. Chem Eng J 98:1–38

    CAS  Google Scholar 

  • Lee JN, Park C, Whitesides GM (2003) Solvent compatibility of poly(dimethylsiloxane)-based microfluidic devices. Anal Chem 75:6544–6554

    CAS  PubMed  Google Scholar 

  • Lerou JJ, Harold MP, Ryley J, Ashmead J, O’Brien TC, Johnson M, Perrotto J, Blaisdell CT, Rensi TA, Nyquist J (1996) Microsystem technology for chemical and biological microreactors, DECHEMA Monographs, In: Ehrfeld W (ed) vol. 132, VCH, Weinheim, p 51

  • Li D (2004) Electrokinetics in microfluidics, vol 2. Elsevier, Amsterdam

    Google Scholar 

  • Lohder W, Bergann L (1986) Akademie der Wissenschaften der DDR, DD 246257

  • Lowe H, Ehrfeld W, Hessel V, Richter T, Schiewe J (2000) IMRET 4: 4th International Conference on Microreaction Technology (Atlanta, USA), American Institute of Chemical Engineers Topical Conference Proceedings, p 31

  • Martynova L, Locascio LE, Gaitan M, Kramer GW, Christensen RG, MacCrehan WA (1997) Fabrication of plastic microfluid channels by imprinting methods. Anal Chem 69:4783–4789

    CAS  PubMed  Google Scholar 

  • McCormick RM, Nelson RJ, Alonso-Amigo MG, Benvegnu J, Hooper HH (1997) Microchannel electrophoretic separations of DNA in injection-molded plastic substrates. Anal Chem 69:2626–2630

    CAS  PubMed  Google Scholar 

  • McCreedy T (2000) Fabrication techniques and materials commonly used for the production of microreactors and micro total analytical systems. Trac Trends Anal Chem 19:396–401

    CAS  Google Scholar 

  • McCreedy T (2001) Rapid prototyping of glass and PDMS microstructures for micro total analytical systems and micro chemical reactors by microfabrication in the general laboratory. Anal Chim Acta 427:39–43

    CAS  Google Scholar 

  • McDonald JC, Duffy DC, Anderson JR, Chiu DT, Wu HK, Schueller OJA, Whitesides GM (2000) Fabrication of microfluidic systems in poly(dimethylsiloxane). Electrophoresis 21:27–40

    CAS  PubMed  Google Scholar 

  • Merrifield RB (1963) Solid phase peptide synthesis. 1. The synthesis of a tetrapeptide. J Am Chem Soc 85:2149–2154

    CAS  Google Scholar 

  • Pennemann H, Watts P, Haswell SJ, Hessel V, Lçwe H (2004) Benchmarking of microreactor applications. Org Process Res Dev 8:422–439

    CAS  Google Scholar 

  • Ratner DM, Murphy ER, Jhunjhunwala M, Snyder DA, Jensen KF, Seeberger PH (2005) Microreactor-based reaction optimization in organic chemistry—glycosylation as a challenge. Chem Commun 5:578–580

    Google Scholar 

  • Rolland JP, Van Dam RM, Schorzman DA, Quake SR, DeSimone JM (2004) Solvent-resistant photocurable “Liquid Teflon” for microfluidic device fabrication. J Am Chem Soc 126:2322–2323

    CAS  PubMed  Google Scholar 

  • Schubert K, Bier W, Linder G, Seidel D (1989) Herstellung und test von kompakten mikrowarmeubertragern. Chem Ing Tech 61:172–173

    CAS  Google Scholar 

  • Schubert K, Bier W, Brandner J, Fichtner M, Franz C, Linder G (1998) Process Miniaturization—IMRET 2: 2nd International Conference on Microreaction Technology (New Orleans, USA), Topical Conference Preprints In: Ehrfeld W, Rinard IH, Wegeng RS (eds.), American Institute of Chemical Engineers, p 88

  • Schubert K, Brandner J, Fichtner M, Linder G, Schygulla U, Wenka A (2001) Microstructure devices for applications in thermal and chemical process engineering. Microscale Thermophys Eng 5:17–39

    CAS  Google Scholar 

  • Schwalbe T, Autze V, Wille G (2002) Chemical synthesis in microreactors. Chimia 56:636–646

    CAS  Google Scholar 

  • Schwalbe T, Autze V, Hohmann M, Stirner W (2004) Novel innovation systems for a cellular approach to continuous process chemistry from discovery to market. Org Process Res Dev 8:440–454

    CAS  Google Scholar 

  • Seebach D, Overhand M, Kuhnle FNM, Martinoni B, Oberer L, Hommel U, Widmer H (1996) β-Peptides: synthesis by Arndt-Eistert homologation with concomitant peptide coupling. Structure determination by NMR and CD spectroscopy and by X-ray crystallography. Helical secondary structure of a β-hexapeptide in solution and its stability towards pepsin. Helv Chim Acta 79:913–941

    CAS  Google Scholar 

  • Thayer AM (2005) Harnessing microreactions. Chem Eng News 83:43–52

    Google Scholar 

  • Valeur E, Bradley M (2005) PS-IIDQ: an efficient polymer-supported amide coupling reagent. Chem Commun 7:1164–1166

    Google Scholar 

  • Veser G (2001) Experimental and theoretical investigation of H2O oxidation in a high-temperature catalytic microreactor. Chem Eng Sci 56:1265–1273

    CAS  Google Scholar 

  • Veser G, Friedrich G, Freygang M, Zengerle R (2000) Microreaction Technology—IMRET 3: Proceedings of the 3rd International Conference on Microreaction Technology In: Ehrfeld W (ed.), Springer, Berlin, p 674

  • Wade JD, Bedford J, Sheppard C, Tregear GW (1991) DBU as an N alpha-deprotecting reagent for the fluorenylmethoxycarbonyl group in continuous flow solid-phase peptide synthesis. Pept Res 4:194–199

    CAS  PubMed  Google Scholar 

  • Watts P, Haswell SJ (2005) The application of micro reactors for organic synthesis. Chem Soc Rev 34:235–246

    CAS  PubMed  Google Scholar 

  • Watts P, Wiles C (2007) Recent advances in synthetic micro reaction technology. Chem Commun 2007:443–467

    Google Scholar 

  • Watts P, Wiles C, Haswell SJ, Pombo-Villar E, Styring P (2001) The synthesis of peptides using micro reactors. Chem Commun 11:990–991

    Google Scholar 

  • Watts P, Wiles C, Haswell SJ, Pombo-Villar E (2002a) Solution phase synthesis of β-peptides using micro reactors. Tetrahedron 58:5427–5439

    CAS  Google Scholar 

  • Watts P, Charlotte SJ, Haswell E, Pombo-Villar E (2002b) Investigation of racemisation in peptide synthesis within a micro reactor. Lab Chip 2:141–144

    CAS  PubMed  Google Scholar 

  • Wegeng RW, Call CJ, Drost MK (1996) American Institute of Chemical Engineers, Spring National Meeting, New Orleans, USA, p 1

  • Willis PA, Hunt BD, White VE, Lee MC, Ikeda M, Bae S, Pelletier MJ, Grunthaner FJ (2007) Monolithic Teflon® membrane valves and pumps for harsh chemical and low-temperature use. Lab Chip 7:1469–1474

    CAS  PubMed  Google Scholar 

  • Xia YN, Whitesides GM (1998) Soft lithography. Annu Rev Mater Sci 28:153–184

    CAS  Google Scholar 

  • Yoon TH, Park SH, Min KI, Zhang XL, Haswell SJ, Kim DP (2008) Novel inorganic polymer derived microreactors for organic microchemistry applications. Lab Chip 8:1454–1459

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Catalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban, 4001, South Africa

    Suhas Ramesh, Prabhakar Cherkupally, Beatriz G. de la Torre, Thavendran Govender, Hendrik G. Kruger & Fernando Albericio

  2. School of Chemistry, Yachay Tech, Yachay City of Knowledge, Urcuqui, Ecuador

    Beatriz G. de la Torre & Fernando Albericio

  3. School of Chemistry and Physics, University of KwaZulu-Natal, Durban, 4001, South Africa

    Fernando Albericio

  4. Institute for Research in Biomedicine (IRB), 08028, Barcelona, Spain

    Fernando Albericio

  5. CIBER-BBN, 08028, Barcelona, Spain

    Fernando Albericio

  6. Department of Organic Chemistry, University of Barcelona, 08028, Barcelona, Spain

    Fernando Albericio

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  1. Suhas Ramesh
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  2. Prabhakar Cherkupally
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  3. Beatriz G. de la Torre
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  5. Hendrik G. Kruger
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  6. Fernando Albericio
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Correspondence to Fernando Albericio.

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Ramesh, S., Cherkupally, P., de la Torre, B.G. et al. Microreactors for peptide synthesis: looking through the eyes of twenty first century !!!. Amino Acids 46, 2091–2104 (2014). https://doi.org/10.1007/s00726-014-1776-1

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