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Celebrating a Decade of Excellence in Microwave Peptide Synthesis

01 May 2012

For the past decade our customers have been using Biotage's microwave synthesis systems for solid phase synthesis of peptides, peptoids and peptidomimetics. In celebration of this decade of excellence, we sat down together with one of the microwave pioneers, Professor Adolf Gogoll at Uppsala University, for a chat on microwaves, peptide chemistry and exploding glass vials.

An Early Adopter

In 2002, Adolf Gogoll and Máté Erdélyi published one of the first scientific papers describing the use of precise microwave irradiation in solid phase peptide synthesis. Ten years later, their paper is still heavily cited as one of the originators of this technique.

“We knew we were early with this, but since publication we haven’t really focused on improving peptide synthesis. My interest as a scientist is not in method development. I just need methods that work” says Adolf Gogoll, Professor of Organic Chemistry at Uppsala University, Sweden.

- Why did you try microwaves for peptide synthesis?

“We thought we could really save time using microwaves, especially when creating peptides with artificial amino acids such as aniline derivatives, which are much less reactive. We first published a microwave accelerated version of the Sonogashira reaction in 2001. This reaction can take three days to complete at room temperature, but with microwaves we got it down to fifteen minutes. A recent review in Chemical Society Reviews cites us as the ones demonstrating that microwave accelerated peptide synthesis actually works.”

- Which were the greatest challenges for MW-synthesis to work?

“Microwaves had a reputation of damaging resins and creating optical isomers of the peptides. My doctoral candidate heard these rumors at several conferences, and that really challenged us to try it. Our resin turned out fine, the technique was fast and we had no problems at all with racemization. We could show clean NMR-spectra to back this up.”

- Describe peptide lab reality in the early 2000’s.

“People were experimenting with kitchen microwave ovens and making their own reaction vials. Temperature control was hopeless, and three or four times a day a vial would explode. Synthetic chemistry was highly manual – my doctoral candidate constructed his own “synthesis robot” using an electric drill which rotated the vials and stirred the reagents. After about two hours of reaction he would stop, remove the vials, filter, wash, add the next reagent and start the cycle again.”

- Which are the greatest improvements since then?

“Automation has come a long way. We can load the system and go home for the night. Generally, temperature control has improved significantly and vial explosions are much less frequent.”

- So what is on the peptide chemist’s wish-list today?

"Well, we can easily make our peptides, but the greatest problem today is purification. The biggest peptide we synthesized had 42 amino acids. It took a couple of days to synthesize but almost three months to purify! So maximum yield in each step is essential, and microwaves have been of great benefit here."

Selected User Publications

From the Personal Chemistry (now Biotage) Smith Synthesizer through to the Biotage® Initiator and now the current range of dedicated microwave peptide synthesizers such as the new Initiator+ Alstra, Biotage continues to provide tools for the global peptide community to enable the rapid synthesis of difficult and standard peptides in higher purity and yield.

Pedersen, S. L.; Tofteng, A. P.; Malik, L.; Jensen, K. J. Microwave heating in solid-phase peptide synthesis. Chem. Soc. Rev201241, 1826-1844.

Aditya, A; Kodadek, T. Incorporation of Heterocycles into the Backbone of Peptoids to Generate Diverse Peptoid-Inspired One Bead One Compound Libraries. ACS Comb. Sci. 201214,164–169.

Erdmanna, R. S.; Wennemers, H. Conformational Stability of Collagen Triple Helices Functionalized in the Yaa Position by Click Chemistry Org. Biomol. Chem.201210, 1982-1986.

Tofteng, A. P.; Malik, L.; Pedersen, S. L.; Sørensen, K. K.; Jensen, K. J. Microwave heating in solid-phase peptide synthesis: Rise of the robots. Chim. Oggi. 201129, 28-31.

Wild, D.; Frischknecht, M.; Zhang, H.; Morgenstern, A.; Bruchertseifer, F.; Boisclair, J.; Provencher-Bolliger, A.; Reubi, J. C.; Maecke, H. R. Alpha- versus Beta-Particle Radiopeptide Therapy in a Human Prostate Cancer Model (213Bi-DOTA-PESIN and 213Bi-AMBA versus 177Lu-DOTA-PESIN). Cancer Res. 2011, 71, 1009-1018.

Boja, P.; Won, S. W. ; Suh, D. H. ; Chu, J.; Park, W. K.; Lim, H. J. Synthesis and Biological Activities of (4-Arylpiperazinyl)piperidines as Nonpeptide BACE 1 Inhibitors. Bull. Korean Chem. Soc201132, 1249-1252.

Malik, L.; Tofteng, A. P.; Pedersen, S. L.; Jensen, K. J. Automated ‘X-Y’ robot for peptide synthesis with microwave heating: application to difficult peptide sequences and protein domains. J. Pept. Sci. 201016, 506–512.

Pedersen, S. L.; Sørensen, K. K.; Jensen, K. J. Semi-automated microwave-assisted SPPS: Optimization of protocols and synthesis of difficult sequences. Biopolymers (Pept Sci). 201094, 206-212.

Yao, N.; Fung, G.; Malekan, H.; Ye, L.; Kurth, M. J.; Lam, K. S. Facile synthesis of glycosylated Fmoc amino acid building blocks assisted by microwave irradiation. Carbohyd. Res. 2010345, 2277–2281.

Höck, S.; Martib, R.; Riedla, R.; Simeunovic, M. Thermal Cleavage of the Fmoc Protection Group. CHIMIA 201064, 200-202.

Socha, A. M.; Tan , N. Y.;. LaPlante, K. L; Sello, J. K. Diversity-oriented synthesis of cyclic acyldepsipeptides leads to the discovery of a potent antibacterial agent. Bioorg. Med. Chem. 201018, 7193–7202.

Anderson, L.; Zhou, M.; Sharma, V.; McLaughlin, J. M., Santiago, D. N.; Fronczek, F. R.; Guida, W.C.; McLaughlin, M. L. A Facile Iterative Synthesis of 2,5-Terpyrimidinylenes as Non-peptidic a-Helical Mimics. J. Org. Chem. 201075, 4288–4291.

Thygesen, M. B.; Sørensen,K. K.; Cló, E.; Jensen, K. J. Direct chemoselective synthesis of glyconanoparticles from unprotected reducing glycans and glycopeptide aldehydes. Chem. Commun. 2009, 6367-6369.

Elgersma, R. C.; van Dijk, M.; Dechesne, A. C.; van Nostrum, C. F.; Hennink, W. E.; Rijkersa, D. T. S.; Liskamp, R. M. J. Microwave-assisted click polymerization for the synthesis of Ab(16–22) cyclic oligomers and their self-assembly into polymorphous aggregates. Org. Biomol. Chem. 20097, 4517–4525.

Christ, E.; Wild, D.; Forrer, F.; Brändle, M.; Sahli, R.; Clerici, T.; Gloor, B.; Martius, F.; Maecke, H.; Reubi, J. C. Glucagon-Like Peptide-1 Receptor Imaging for Localization of Insulinomas. J. Clin. Endocrinol. Metab. 200994. 4398-4405.

Park, J. W.; Lee, K. H. Synthesis of Peptide Amides on Safety-catch Resin with Microwave Irradiation. Bull. Korean Chem. Soc. 200930, 2475-2478.

Kuil, J.; Branderhorst , H. M.; Pieters ,R. J.; de Mol N. J.; Liskamp, R. M. J. ITAM-derived phosphopeptide-containing dendrimers as multivalent ligands for Syk tandem SH2 domain. Org. Biomol. Chem.20097, 4088-4094.

Dohm, M. T.; Seurynck-Servoss, S. L.; Seo, J.; Zuckermann, R. N.; Barron, A. E. Close mimicry of lung surfactant protein B by “clicked” dimers of helical, cationic peptoids. Biopolymers (Pept Sci), 200992, 538-553.

Marinec, P. S.; Evans, C. G.; Gibbons, G. S.; Tarnowski, M. A.; Overbeek, D.L. ; Gestwicki, J. E. Synthesis of orthogonally reactive FK506 derivatives via olefin cross metathesis. Bioorg. Med. Chem. 200917, 5763–5768.

van Dijk, M.; Mustafa, K. ; Dechesne, A. C.; van Nostrum, C. F.; Hennink, W. E.; Rijkers, D. T. S.; Liskamp, R. M. J. Synthesis of Peptide-Based Polymers by Microwave-Assisted Cycloaddition Backbone Polymerization. Biomacromolecules 2008, 9, 2834–2843.

Armstrong, A. F.; Oakley, N.; Parker, S.; Causey, P. W.; Lemon, J.; Capretta, A.; Zimmerman, C.; Joyal, J.; Appoh, F.; Zubieta, J.; Babich, J. W.; Singh, G.; Valliant, J. F. A robust strategy for the preparation of libraries of metallopeptides. A new paradigm for the discovery of targeted molecular imaging and therapy agents. Chem. Commun. 2008, 5532-5534.

Zhang, S.; Arvidsson, P. I. Facile Synthesis of N -protected Amino Acid Esters Assisted by Microwave Irradiation. Int. J. Pept. Res. Ther. 200814, 219-222.

Joshi, B. P.; Park, J. W.; Kim, J. M.; Lohani, C. R.; Cho, H.; Lee, K. H. Application of microwave method to the solid phase synthesis of pseudopeptides containing ester bond. Tetrahedron Lett. 200849, 98-01.

Crestey, F.; Witt, M.; Frydenvang, K.; Stærk, D.; Jaroszewski, J. W.; Franzyk, H. Microwave-Assisted Ring-Opening of Activated Aziridines with Resin-Bound Amines. J. Org. Chem. 200873, 3566-3569.

Lietard, J.; Meyer, A.; Vasseur, J. J.; Morvan, F. New Strategies for Cyclization and Bicyclization of Oligonucleotides by Click Chemistry Assisted by Microwaves. J. Org. Chem. 200873, 191-200.

Díaz-Mochón, J.J.; Fara, M.A.; Sanchez-Martin, R.M.; Bradley, M. Peptoid dendrimersmicrowave-assisted solid-phase synthesis and transfection agent evaluation. Tetrahedron Lett. 200849, 923-926.

Mero, A.; Pasut, G.; Via, L. D.; Fijten, M. W. M.; Schubert, U. S.; Hoogenboom, R. Veronese, F. M. Synthesis and characterization of poly(2-ethyl 2-oxazoline)-conjugates with proteins and drugs: Suitable alternatives to PEG-conjugates? J. Con. Rel. 2008125, 87–95.

Dondoni, A.; Massi, A.; M. Aldhoun. Hantzsch-Type Three-Component Approach to a New Family of Carbon-Linked Glycosyl Amino Acids. Synthesis of C-Glycosylmethyl Pyridylalanines. J. Org. Chem. 200772, 7677-7687.

Dijkgraaf, I.; Rijnders, A. Y.; Soede, A.; Dechesne, A. C.; van Esse, G. W.; Brouwer, A. J.; Corstens, F. H. M.; Boerman, O. C.; Rijkers, D. T. S.; Liskamp, R. M. J. Synthesis of DOTA-conjugated multivalent cyclic-RGD peptide dendrimers via 1,3-dipolar cycloaddition and their biological evaluation: implications for tumor targeting and tumor imaging purposes. Org. Biomol. Chem. 20075, 935–944.

Park, M. S.; Oh, H. S.; Cho, H.; Lee, K. H. Microwave-assisted solid-phase synthesis of pseudopeptides containing reduced amide bond. Tetrahedron Lett. 200748, 1053-1056.

Brandt, M.; Gammeltoft, S.; Jensen, K. J. Microwave Heating for Solid-Phase Peptide Synthesis: General Evaluation and Application to 15-mer Phosphopeptides. Int. J. Pept. Res. Ther200612, 349–357.

Evans, C. G.; Wisén, S.; Gestwicki, J. E. Heat Shock Proteins 70 and 90 Inhibit Early Stages of Amyloid β-(1-42) Aggregation in VitroJ. Biol. Chem. 2006281, 33182–33191.

Fara, M. A.; Díaz-Mochón, J. J.; Bradley, M. Microwave-assisted coupling with DIC/HOBt for the synthesis of difficult peptoids and fluorescently labelled peptides - a gentle heat goes a long way. Tetrahedron Lett. 200647, 1011-1014.

Wipf, P.; Werner, S.; Woo, G. H. C.; Stephenson, C. R. J.; Walczak, M. A. A.; Coleman, C. M.; Twining, L. A. Application of divergent multi-component reactions in the synthesis of a library of peptidomimetics based on γ-amino-α,β-cyclopropyl acids. Tetrahedron200561, 11488-11500.

Wipf, P.; Xiao, J.; Geib, S. J. Imine Additions of Internal Alkynes for the Synthesis of Trisubstituted (E)-Alkene and Cyclopropane Peptide Isosteres. Adv. Synth. Catal. 2005347, 1605-1613.

Mukade, T.; Dragoli, D. R.; Ellman, J. A. Parallel Solution-Phase Asymmetric Synthesis of α-Branched Amines. J. Comb. Chem. 20035, 590–596.

Sauer, D. R.; Kalvin, D.; Phelan, K. M. Microwave-Assisted Synthesis Utilizing Supported Reagents: A Rapid and Efficient Acylation Procedure. Org. Lett. 20035, 4721-4724.

Erdélyi, M.; Gogoll, A. Rapid Microwave-Assisted Solid Phase Peptide Synthesis. Synthesis, 200211, 1592–1596.

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