1. An Introduction to Medicinal Chemistry 3/e COMBINATORIAL CHEMISTRY
Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 14
COMBINATORIAL CHEMISTRY
Part 1: Sections 14.1 – 14.4

2. Contents
Part 1: Sections 14.1 – 14.4
1. Definition
2. Solid Phase Techniques
2.1. Advantages
2.2. Requirements
2.3. Examples of Solid Supports (2 slides)
2.4. Anchor or linker
Merrifield resin for peptide synthesis (chloromethyl group)
Wang resin (2 slides)
Rink resin (2 slides)
Dihydropyran resin (2 slides)
3. Parallel Synthesis
3.1. Houghton’s Tea Bag Procedure
3.2. Automated parallel synthesis (2 slides)
3.3. Automated parallel synthesis of all 27 tripeptides from 3 amino acids (2 slides)
4. Mixed Combinatorial Synthesis (21 slides)
[41 slides]

3. 1. DEFINITION
The automated synthesis of a large number of compounds in a short time period using a defined reaction route and a large variety of reactants
Normally carried out on small scale using solid phase synthesis and automated synthetic machines
Parallel synthesis
Single product formed in each reaction vessel
Useful for SAR and drug optimisation
Synthesis of mixtures
Mixtures of compounds formed in each reaction vessel
Useful for finding lead compounds

4. 2. SOLID PHASE TECHNIQUES
Reactants are bound to a polymeric surface and modified whilst still attached. Final product is released at the end of the synthesis
2.1 Advantages
Specific reactants can be bound to specific beads
Beads can be mixed and reacted in the same reaction vessel
Products formed are distinctive for each bead and physically distinct
Excess reagents can be used to drive reactions to completion
Excess reagents and by products are easily removed
Reaction intermediates are attached to bead and do not need to be isolated and purified
Individual beads can be separated to isolate individual products
Polymeric support can be regenerated and re-used after cleaving the product
Automation is possible

5. 2. SOLID PHASE TECHNIQUES
2.2 Requirements
A resin bead or a functionalised surface to act as a solid support
An anchor or linker
A bond linking the substrate to the linker. The bond must be stable to the reaction conditions used in the synthesis
A means of cleaving the product from the linker at the end
Protecting groups for functional groups not involved in the synthesis

6. 2. SOLID PHASE TECHNIQUES
2.3 Examples of Solid Supports
Partially cross-linked polystyrene beads hydrophobic in nature
causes problems in peptide synthesis due to peptide folding
Sheppard’s polyamide resin - more polar
Tentagel resin - similar environment to ether or THF
Beads, pins and functionalised glass surfaces

7. 2. SOLID PHASE TECHNIQUES 2.3
Beads must be able to swell in the solvent used, and remain
stable
Most reactions occur in the bead interior
Starting material,
reagents and solvent
Swelling
Linkers

8. 2. SOLID PHASE TECHNIQUES
2.4 Anchor or linker
A molecular moiety which is covalently attached to the solid support, and which contains a reactive functional group
Allows attachment of the first reactant
The link must be stable to the reaction conditions in the synthesis but easily cleaved to release the final compound
Different linkers are available depending on the functional group to be attached and the desired functional group on the product
Resins are named to define the linker e.g. Merrifield
Wang
Rink

9. 2.4.1 Merrifield resin for peptide synthesis (chloromethyl group)
Linker
Peptide
Release from
solid support

10. Wang resin
Linker
Linking functional group
Bead
Linker

11. 2.4.2 Wang resin piperidine deprotection Carboxylic acid Carboxylic

12. Rink resin
Linking functional group
Linker

13. Rink resin
Carboxylic
acid
Primary
amide
cleavage

14. Dihydropyran resin
Linker
Linking functional group

15. Dihydropyran resin
Alcohol
Alcohol

16. 3. Parallel Synthesis
Aims
To use a standard synthetic route to produce a range of analogues, with a different analogue in each reaction vessel, tube or well
The identity of each structure is known
Useful for producing a range of analogues for SAR or drug optimisation

17. Each tea bag contains beads and is labelled
3. Parallel Synthesis
3.1 Houghton’s Tea Bag Procedure 22
Each tea bag contains beads and is labelled
Separate reactions are carried out on each tea bag
Combine tea bags for common reactions or work up procedures
A single product is synthesised within each teabag
Different products are formed in different teabags
Economy of effort - e.g. combining tea bags for workups
Cheap and possible for any lab
Manual procedure and is not suitable for producing large quantities of different products

18. AUTOMATED SYNTHETIC MACHINES
3. Parallel Synthesis
3.2 Automated parallel synthesis
AUTOMATED SYNTHETIC MACHINES

19. Use beads or pins for solid phase support
3. Parallel Synthesis
3.2 Automated parallel synthesis
Wells
Automated synthesisers are available with 42, 96 or 144 reaction vessels or wells
Use beads or pins for solid phase support
Reactions and work ups are carried out automatically
Same synthetic route used for each vessel, but different reagents
Different product obtained per vessel

20. 3. Parallel Synthesis ETC
3.3 Automated parallel synthesis of all 27 tripeptides from 3 amino acids
ETC

21. 3. Parallel Synthesis 27 TRIPEPTIDES 27 VIALS
3.3 Automated parallel synthesis of all 27 tripeptides from 3 amino acids
27 TRIPEPTIDES
27 VIALS

22. 4. Mixed Combinatorial Synthesis
Aims
To use a standard synthetic route to produce a large variety of different analogues where each reaction vessel or tube contains a mixture of products
The identities of the structures in each vessel are not known with certainty
Useful for finding a lead compound
Capable of synthesising large numbers of compounds quickly
Each mixture is tested for activity as the mixture
Inactive mixtures are stored in combinatorial libraries
Active mixtures are studied further to identify active component

23. 4. Mixed Combinatorial Synthesis
The Mix and Split Method
Example
- Synthesis of all possible dipeptides using 5 amino acids
Standard methods would involve 25 separate syntheses
Combinatorial procedure involves five separate syntheses using a mix and split strategy

24. Split
Gly
Ala
Phe
Val
Ser

25. 4. Mixed Combinatorial Synthesis
The Mix and Split Method
Synthesis of all possible tripeptides using 3 amino acids

26. 4. Mixed Combinatorial Synthesis
The Mix and Split Method

27. 4. Mixed Combinatorial Synthesis
The Mix and Split Method

28. 4. Mixed Combinatorial Synthesis
The Mix and Split Method
MIX

29. 4. Mixed Combinatorial Synthesis
The Mix and Split Method
SPLIT

30. 4. Mixed Combinatorial Synthesis
The Mix and Split Method

31. 4. Mixed Combinatorial Synthesis
The Mix and Split Method

32. 4. Mixed Combinatorial Synthesis
The Mix and Split Method

33. 4. Mixed Combinatorial Synthesis
The Mix and Split Method
MIX

34. 4. Mixed Combinatorial Synthesis
The Mix and Split Method
SPLIT

35. 4. Mixed Combinatorial Synthesis
The Mix and Split Method

36. 4. Mixed Combinatorial Synthesis
The Mix and Split Method

37. 4. Mixed Combinatorial Synthesis
The Mix and Split Method

38. 4. Mixed Combinatorial Synthesis
The Mix and Split Method
No. of
Tripeptides 9 9 9

39. 4. Mixed Combinatorial Synthesis
The Mix and Split Method
No. of
Tripeptides 9 9 9
27 Tripeptides
3 Vials

40. 4. Mixed Combinatorial Synthesis
The Mix and Split Method
TEST MIXTURES FOR ACTIVITY

41. 4. Mixed Combinatorial Synthesis
The Mix and Split Method
Synthesise each tripeptide and test

42. 4. Mixed Combinatorial Synthesis
The Mix and Split Method
20 AMINO ACIDS
HEXAPEPTIDES
etc.
34 MILLION PRODUCTS
(1,889,568 hexapeptides / vial)