1. SOLID PHASE CHEMISTRY

2. Contents- Introduction Solid Support Linkers, Anchors
Protecting Groups
Coupling Reagents
Deprotecting Groups
Application In peptide synthesis
Advantages
Disadvantages

3. Introduction
Solid phase synthesis was developed by B. Merrifield, It is of the particular interest in the field of Peptide synthesis.
Solid-Phase Synthesis focuses on chemical reactions of substrates attached to solid supports.
Including methods for attachment and detachment from the supports.

4. Eg. Solid phase Synthesis of a dipeptide
Z-NH-CH-COOH + Cl-CH2 R Z-NH-CH-COO-CH2 NH2-CH-COO-CH2 Z-NH-CH-COX + NH2-CH-COO-CH2 R1 R

5. CONT…….
Z-NH-CH-CO-NH-CH-COO-CH2 R1 R NH2-CH-NH-CH-COOH + R1 R solid support Z protecting group

6. Problems with Traditional Synthesis
1 chemist 1 molecule
Can only make one molecule at a time.
Each synthesis very time consuming
Multistep syntheses have loss at each step
Purification of products very time-consuming between steps.
Yields can be low and produces very few molecules at a time for testing.

7. Solid Support
Resin act as a solid support for a solid phase synthesis.
The term solid support used to denote the matrix upon which chemical reaction is performed.
It is a copolymer of styrene and divinylbenzene.

8. Types Crosslinked Polystyrene -Styrene+Divinylbenzene
-Most widely used
-Hydrophobic

9. PEG Grafted Supports
-Tentagel
- 1-2% crosslinked polystyrene
- More flexible
-Hydrophilic

10. Inorganic Supports-
-Glass beads as a inorganic supports
- High mechanical strength
-Negligible swelling

11. Properties:- Chemical stability Mechanical stability
It must swell extensively in the solvents used for the synthesis;
Peptide-resin bond should be stable during the synthesis;
Peptide-resin bond can be cleaved effectively at the end of the synthesis.

12. Linker, Anchors
The linker that is bound to the resin is called anchor.
Remains at the resin after cleavage.
Resin
Linker
Resin
Anchor

13. linker
Bifunctional spacer molecules which contain on one end a functional group for attachment to the solid support and on the other end a selectively cleavable group onto which the starting molecule is attached.

14. Anchors
Types :
1) Benzylic Halide Type Resin-
i. Merrifield resin. =

15. Anchor
ii. Trityl chloride resin.

16. Anchor
2) Benzylic alcohols Type Resin -
Wang resin

17. Anchor
3)Benzylic amines Type Resin-
Rink amide resin

18. Anchor
4) Aromatic aldehyde Type Resin-
Bal resin

19. Protecting Groups
A fragment bound to functional group that blocks the reactivity of that group.
Good protecting groups are easily attached and removed using mild reaction condition.

20. Protecting Groups
Acid Protection

21. The most common acid protecting group used is the methyl ester.
It is stable in most coupling reaction and deprotection reaction conditions.
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.
Alanine allyl ester

22. Protecting Groups
Amine Protection

23. There are two standard types of N-protecting groups used, the Boc and Fmoc group.
N-Boc cleavage
N-Fmoc cleavage

24. Protecting Groups
Protection of the R-group

25. hydroxyl groups (Ser), thiol groups (Cys), amines (Lys) and
Some of the different R-groups that must be protected before coupling are
hydroxyl groups (Ser), thiol groups (Cys), amines (Lys) and
carboxylic acids (Asp).

26. Coupling Reagents
In the coupling reactions of peptide synthesis the carboxyl group of the acylating amino acid is activated.
The care should be taken in selecting the activation method to avoid racemization.

27. Coupling Reagents HOBt- (N- Hydroxy benztriazole)
HOAt- (1- Hydroxy-7-aza- benztriazole)
HBTU- (O-benztriazole-N,N,N’,N’-tetramethyl-uronium-hexafluoro
phosphate)
HATU- 2-(1H-7-Azabenzotriazol-1-yl)--1,1,3,3-tetramethyl uronium
hexafluorophosphate 27

28. Deprotecting Groups
It is the cleavage of the side-chain protecting groups.
For protecting group such as Boc using Trifluoroacetic acid (TFA) the deprotecting groups like HF and Trifluoromethanesulfonic acid (TFMSA) have been used.

29. Deprotecting Groups Mild Acids : e.g. Trifluoroacetic acid.
Hydrochloric acid.
Methanesulfonic Acid.
Alkaline condition :
e.g. Piperidine in dimethylformamide.

30. Solid Phase Synthesis Mechanism & Application
R. Bruce Merrifield
7/15/1921–5/14/2006
Nobel prize in chemistry 1984

31. Peptide Synthesis
CH2 CH
Treating the polymeric support with chloromethyl methyl ether (ClCH2OCH3) and SnCl4 places ClCH2 side chains on some of the benzene rings.

32. Peptide Synthesis
CH2 CH
CH2Cl
The side chain chloromethyl group is a benzylic halide, reactive toward nucleophilic substitution.

33. Peptide Synthesis
CH2 CH
CH2Cl
The chloromethylated resin is treated with the Boc-protected C-terminal amino acid. Nucleophilic substitution occurs, and the Boc-protected amino acid is bound to the resin as an ester.

34. Peptide Synthesis
CH2 CH
CH2Cl R O –
BocNHCHCO

35. Peptide Synthesis Next, the Boc protecting group is removed with HCl.
CH2 CH
BocNHCHCO R O
Next, the Boc protecting group is removed with HCl.

36. Peptide Synthesis HOBt-promoted coupling adds the second amino acid
H2NCHCO R
CH2 CH O
HOBt-promoted coupling adds the second amino acid

37. Peptide Synthesis Remove the Boc protecting group. NHCHCO R O CH2 CH
BocNHCHC R'
Remove the Boc protecting group.

38. Peptide Synthesis Add the next amino acid and repeat. CH2 CH NHCHCO R
H2NCHC R'
Add the next amino acid and repeat.

39. Peptide Synthesis
CH2 CH
NHCHCO R O
NHCHC R' C +
H3N
peptide
Remove the peptide from the resin with HBr in CF3CO2H

40. Peptide Synthesis
CH2 CH
CH2Br
NHCHCO R O
NHCHC R' C +
H3N
peptide

41. Advantages of Solid Phase Synthesis
Synthetic intermediates don’t have to be isolated.
Quick process.
Reagents simply washed away each step.
Can be automated with robots!!

42. Disadvantages to Solid Phase Synthesis
All the synthesis can’t be done on solid phase.
Typically, kinetics not the same.
Unsuitable for solvent assisted chemical reaction.
High viscosity in reactant system.
Insufficient purity if reaction steps are incomplete.

43. REFERENCES www.google.co.in www.discoveryofsps.com www.wikipedia.org
Introduction to medicinal chemistry 3rd edition by Patric.

44. Thank You!