Short Peptide Synthesis

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1 Short Peptide Synthesis Keith ó Proinsias 8 th February 2010

2 Introduction Amide bond and basic amide synthesis Solution phase peptide synthesis Protecting groups required for peptide synthesis Coupling reagents used in peptide synthesis Solid phase peptide synthesis

3 The Amide Bond Some of the main properties of the amide bond is it s low basicity, which is useful in purification, and it s stability, due to resonance. H H Basic amide synthesis is the reaction of a carboxylic acid and an amine with the loss of water. -H CH H 2 ' H

4 Basic Synthesis At the beginning acid chlorides where used. H S 2 Cl Cl + H 2 ' base H ' + HCl ot good for peptide synthesis mainly due to racemisation occurring. Advanced rganic Chemistry- eaction Mechanisms by Brukner,., 2002, 216

5 Solution Phase Peptide Synthesis H 2 CH Acid Protection H 2 CPG ' PGH CH Coupling PGH ' H CPG H 2 ' H CH Dimer Deprotection H 2 ' H CPG ' PGH CH Coupling PGH H ' H CPG H 2 H ' H CH Triemer

6 Planning For Solution Phase Peptide Synthesis Before starting. Choose the C-terminal protecting group Choose the -terminal protecting group Choose protecting groups for any other -group on the amino acids Choose the coupling reagent

7 Protecting Groups Acid Protection H 2 H

8 Protecting Groups The most common acid protecting group used is the methyl ester. It is stable in most coupling reaction and deprotection reaction conditions. Difficult to selectively remove. H 2 Alanine methyl ester Depending on what type of coupling reaction and with what amino acids will be used other acid protecting groups can be used, such as the allyl ester. H 2 Alanine allyl ester

9 Protecting Groups Amine Protection H 2 H

10 Protecting Groups There are two standard types of -protecting groups used, the Boc and Fmoc group. H 3 C CH 3 CH 3 -Boc cleavage BocH CH 50% TFA in DCM H 2 CH Glycine -Fmoc cleavage FmocH CH 20% Piperidine in DMF H 2 CH Glycine

11 Protecting Groups ther protecting groups that can be used are Cbz and more recently the osyl group. CBZ Leggio, A.; Gioia, M.L.D.; Perri, F.; Liguori, A. Tetrahedron, 2007, 63,

12 Protecting Groups Protection of the -group H 2 H

13 Protecting Groups Some of the different -groups that must be protected before coupling are hydroxyl groups (Ser), thiol groups (Cys), amines (Lys) and carboxylic acids (Asp). H CH HS CH H 2 Serine (Ser) H 2 Cysteine (Cys) H 2 CH HC CH H 2 Lysine (Lys) H 2 Aspartic Acid (Asp)

14 Protecting Groups Base Sensitive Protecting Groups Used in -Boc protected peptide synthesis. Ph Si Ph TBDPS H 2 CH S H 2 CH Cleavage : 2M ah (aq) EtH (1:1) Fm Cleavage : 20% Piperidine in DMF H CH CH H 2 H 2 Fmoc Cleavage : 20% Piperidine in DMF Fm Cleavage : 20% Piperidine in DMF Greene, T.W.; Wuts, P.G.M. Protecting groups in organic synthesis, Fourth edition, Wiley-interscience, ew York, 2006.

15 Protecting Groups Acid Sensitive Protecting Groups Used in -Fmoc protected peptide synthesis. ormally the t-butyl, Boc or Trityl group is used. Cleaved using 5-50% TFA in DCM. Ph Ph CH S CH Ph Trityl H 2 t-butyl H 2 CH H CH H 2 H 2 t-butyl Boc Greene, T.W.; Wuts, P.G.M. Protecting groups in organic synthesis, Fourth edition, Wiley-interscience, ew York, 2006.

16 Protecting Groups ther Protecting Groups Allyl Alloc Cleavage: Pd(PPh 3 ) 4 S 2 osyl Cleavage: Thiophenol PMB Cleavage: Ceric Ammonium itrate (CA) Greene, T.W.; Wuts, P.G.M. Protecting groups in organic synthesis, Fourth edition, Wiley-interscience, ew York, 2006.

17 Protecting Groups There are some exception were an unprotected amino acid, such as serine, can be used without being protected. othman, D.M.; Vazquez, M.E.; Vogel, E.M.; Imperiali, B., rg. Lett., 2002, 4,

18 Coupling eagents C, -Dicyclohexylcarbodimide (DCC) C DMAP -(3-Dimethylaminopropyl)- -ethylcarbonate (EDC)

19 rganic Chemistry by Bruce, Coupling eagents

20 Coupling eagents acemisation of an activated amino acid PG H PG PG X X= Activator base PG PG PG Formation of oxazolone intermediates

21 Coupling eagents HBt H HAt H PF 6 (BF 4 ) PF 6 Me 2 Me 2 Me 2 Me 2 HBTU (TBTU) HATU P PF 6 P PF 6 Br P PF 6 PyBrP BP PyBP

22 Coupling eagents Mechanism of HBTU Coupling + Me 2 Me 2 Me 2 Me 2 H ' + H '-H + Me 2 Me 2

23 Coupling reagents BP coupling reagent Brink, H.T.; ijkers, D.T.S.; J. rg. Chem., 2006, 71, 1824

24 Coupling reagents PyBrP coupling reagent Anderson,.J.; Coleman, J.E.; Tetrahedron Lett., 1997, 38,

25 Coupling reagents Synthesis of new coupling reagents. Wischnat, Tetrahedron Lett., 2003, 44,

26 Coupling reagents Synthesis of new coupling reagents El-Faham, A.; Albericio, F., rg. Lett., 2007, 9,

27 Solid Phase Peptide Synthesis Solid Phase Vs Solution Phase Fast production of long peptides by increasing the amount of reactant. Quick purification by filtration. Automated or manual option. Advantages Disadvantages Easily scaled up from mg to kg. o need for excess reactants or expensive machinery. Expensive resin and can require specialised equipment. Limited scale-up. More difficult to purify. Longer reaction time

28 Solid Phase Peptide Synthesis The first step is to deprotect the amino group to produce a free amine. It can then be coupled to another - protected amino acid. By deprotecting the final -amino group and cleaving the peptide from the resin after peptide chain elongation, using the appropriate cleavage conditions, the peptide is isolated. Chan, W.; White, P. Fmoc Solid Phase Peptide Synthesis, xford, ew York, 2000.

29 Solid Phase Peptide Synthesis The resin is not completely spherical, with the reaction only occur on the surface of the resin. There are cavities were the coupling takes place and is the reason why swelling is very important before coupling can occur. Types of esin. You buy commercially available pre-loaded resins. Different resins can be cleaved under basic (-Boc) or acidic (-Fmoc) conditions. Depending on the resin the final peptide can have an amide or acid C-terminal.

30 Solid Phase Peptide Synthesis Merrifield Bubbler esin - Amino acids - Coupling reagents - Base - Solevnt Sinter itrogen Vacuum 1. Add resin to column. 2. Swell resin using DMF and bubbling with emove solvent using vacuum. 4. To cleave the first -protecting group the appropriate deprotecting reagent is added. 5. Bubble 2 and then remove solvent under vacuum and wash with DCM. 6. Add DMF plus coupling reagent, base and -protected amino acid. 7. Bubble 2 until reaction is complete. 8. emove solvent and wash with DCM. Chan, W.; White, P. Fmoc Solid Phase Peptide Synthesis, xford, ew York, 2000.

31 Thank You For Your Attention Any Questions?

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