1. Is a Solid Support only a Protective Group?

2. R C X H Drugs are polyfunctional molecules
to provide the highest density of chemical functionalities
with well-defined orientation in space per surface. X R
Various functional groups H
Hydrophobic residues C
- electron clouds
Polar residues

3. How to deal with polyfunctional compounds?
deprotection
protection
work up
purification

4. Advantage of polymeric support
immobilization
cleavage
wash
wash
wash
evaporation
(purification)
Rapid procedure
The physical properties of the polymer differ from those of small molecules facilitating isolation

5. Schematic representation of resins
swollen resin
(solvated)
shrunken resin
(poorly solvated)
cross link
compound bound
to the polymer
Reactions can only be performed, if reagents can diffuse through the gel phase of the beads. The polymer has to be solvated with the appropriate solvent to form such a phase.

6. Resin: Amorphous polymer
Polymeric support: Chemically inert carrier of
linker, spacer and scaffold.
Spacer: provides distance between support and linker rotational and vibrational freedom of scaffold provides higher (solution-like) reactivity of scaffold
Linker: allows selective cleavage of scaffold from polymeric support

7. Fixing nucleophiles on “Rink resin”
Isolated yields of recovered TFA-salts after cleavage with 20% TFA in DCM.

8. Fixing piperazin on “Rink resin”
Brill, W. K.-D.; Schmidt, E.; Tommasi, R. A. Synlett (1998), (8),

9. The principle of “infinite dilution”
The regidity of the resin prevents double attack

10. Immobilization of purines

11. C6-Substitution A B C

12. Reactions of linker under too acidic conditions
Basic

13. C6-Substitution
53°C to avoid substitution on C2 for very nucleophilic amines
(N-CH2CH2NH2, C-CH2CH2NH2 piperazines, piperidines).
No C2-substitution even at 70°C:
anilines, benzylamines, morpholin, primary amines with higher order of substitution on their Ca

14. Reaction of two neighboring molecules

15. Interactions of purines with each other on a solid support
Brill :
Interactions of purines with each other
on a solid support
Batch 1 is hydrolysable, batch 2 is not.
Batch 1:
Batch 2:

16. Heat-shock disrupts rigid resin structure and allows further reaction
Brill :
Heat-shock disrupts rigid resin structure and allows further reaction
Batch 2:

17. Schematic representation of resins
swollen resin
(partially loaded)
Non-covalent crosslinks
Non-covalent crosslinks prevent further loading of resin
More rapidly diffusing reagents might cause side reactions usually not observed in solution phase

18. Reaction Scheme

19. Reaction Scheme

20. Two types of bromine complexes were investigated
Synthesis:
Reactivity:

21. Where is the resin being modified?
Can the bromine be eliminated?

22. Modification of the polymeric support by the brominating agent
Bromine-complex
Br-content of resin, treated with the Bromine Complex (EA)

23. The resin was modified on the side chains
The bromine can be eliminated.
NMP prevents modification of the resin
The linker may be modified, but the modification is tolerable –
linker properties are not changed a lot.

24. Reactivity of the bromine complex with purines:
Solvent: NMP
no reaction:
5% conversion
complete
conversion:
R1: H, alkyl, R1’: alkyl
R2: H, alkyl, R2’: H, alkyl
tolerated groups: CONR2, CONRH CONH2,
ether functions, aromatics more
deactivated than Bn
side reactions:
not tolerated groups:
activated aromatics: bromination
amines: many oxidation products

25. The reactivity of the bromine complex in dry benzene:
disproportionation is very slow
little electrophilic substitution
oxidizing power is enhanced relative to reactions in NMP
Selective side reactions:

26. The reactivity of the bromine complex in wet benzene:
Side chain oxidations are not mediated by the solid phase.
They work are observed also in solution phase.

27. Proposed mechanism for the modification at C2
i: Br2-complex; ii: H2O
Riva-Toniolo, C.; Mueller, S.; Schaub, J.; Brill, W. K.-D. Molecular Diversity (2003), 6(1), 43-53

28. Diversification of cinnolines on solid phase

29. Diversification of cinnolines on solid phase

30. Acylation of SP by cinnolines
4-chlorobenzylamine
aromat. C-H
out of plane
strech NH
4-chlorobenzylamide
NO-
strech
aromat. C-H
out of plane
incomplete
complete

31. Analysis of resins by MAS-1H-NMR
High Resolution MAS- 1H-NMR
Analysis of resins by MAS-1H-NMR
Homonuclear Dipolar Couplings & Magnetic Susceptibility-induced Linebroadenings removed by 1-3 kHz MAS*
and Magnetic Susceptibility Matching
Probe Technology (Nano Probe)
* MAS = 54°44’ (3cos2 -1 = 0)
Gradients & Inverse Detection Capability
NanoProbe 40l Cell

32. 1H-MAS-NMR analysis of acylation of SP by cinnolines

33. Cinnolines become trapped in resin before reacting

34. Alkylation
Sereni, L.; Tato, M.; Sola, F.; Brill, W, K.-D. Tetrahedron (2004), 60(38),

35. Synthesis of oxadiazoles on solid phase

36. The LP-TFAA mediated cyclization gives three productsB C
The SP-TFAA mediated cyclization gives two products, but never B
Only R1 is released as acid, never R2

37. SP and LP cyclization give different products
and display different solvent dependence B C A
B : C
Elemental analysis of resin after cyclization:
In a SP cyclization with 50% yield, 50% of the initial N remains on the resin
R1CO2H (A) is not released in SOCl2-mediated cyclizations

38. Not observed in THF The LP-TFAA mediated cyclization-mechanism in THF
Rate limiting
Not observed in THF

39. How deep can one view into the resin? MAS-1H-NMR
Reagents in solution
Normal 1H-NMR

40. The SP- TFAA mediated cyclization gives two products

41. The SP-TFAA mediated cyclizations proceed via different intermediates

42. The SP- TFAA mediated cyclization gives two products
Irreversible
sequestration H+ A C

43. recovery of all products
Isolated
(LP-model)
Sequestration:
recovery of all products
Detected from
LP-model A
isolated
Calc.: C30H26N2O5 + H+
Found: C
isolated

44. Attack of TFAA on SP-bound hydrazide-conformers

45. The reaction path is determined by which carbonyl was initially attacked

46. Effect of SP Crude product from solid phase Product from solid phase
after treatment
with basic cation exchanger
Crude product from liquid phase

47. Conclusion Conclusion Conclusion Conclusion Conclusion Conclusion
Resins can work as protective groups. (immobilization of amines)
Resins may sometimes provide the effect of infinite dilution (monoacylation of piperazine)
Resin attachments may migrate. (purines)
Resin-bound substrates may interact to give covalent crosslinks violating the effect of infinite dilution. (purines)
Resin-bound substrates may interact to give non-covalent crosslinks leading to rigid structures and preventing desired reactions.
(purines, cinnolines)
Resins enable reactions not observed in solution phase. (oxadiazoles)
Resins may be modified during reactions, but not all modifications cause problems. (bromination)
Conclusion
Resins can work as protective groups. (immobilization of amines)
Resins may sometimes provide the effect of infinite dilution (monoacylation of piperazine)
Resin attachments may migrate. (purines)
Resin-bound substrates may interact to give covalent crosslinks violating the effect of infinite dilution. (purines)
Resin-bound substrates may interact to give non-covalent crosslinks leading to rigid structures and preventing desired reactions.
(purines, cinnolines)
Resins enable reactions not observed in solution phase. (oxadiazoles)
Resins may be modified during reactions, but not all modifications cause problems. (bromination)
Analysis is difficult, but only needed in case of problems.
Conclusion
Conclusion
Resins can work as protective groups. (immobilization of amines)
Resins may sometimes provide the effect of infinite dilution (monoacylation of piperazine)
Resin attachments may migrate. (purines)
Resin-bound substrates may interact to give covalent crosslinks violating the effect of infinite dilution. (purines)
Resin-bound substrates may interact to give non-covalent crosslinks leading to rigid structures and preventing desired reactions.
(purines, cinnolines)
Resins enable reactions not observed in solution phase. (oxadiazoles)
Conclusion
Resins can work as protective groups. (immobilization of amines)
Resins may sometimes provide the effect of infinite dilution (monoacylation of piperazine)
Resin attachments may migrate. (purines)
Resin-bound substrates may interact to give covalent crosslinks violating the effect of infinite dilution. (purines)
Resin-bound substrates may interact to give non-covalent crosslinks leading to rigid structures and preventing desired reactions.
(purines, cinnolines)
Conclusion
Resins can work as protective groups. (immobilization of amines)
Resins may sometimes provide the effect of infinite dilution (monoacylation of piperazine)
Conclusion
Resins can work as protective groups. (immobilization of amines)
Resins may sometimes provide the effect of infinite dilution (monoacylation of piperazine)
Resin attachments may migrate. (purines)
Conclusion
Resins can work as protective groups. (immobilization of amines)
Resins may sometimes provide the effect of infinite dilution (monoacylation of piperazine)
Resin attachments may migrate. (purines)
Resin-bound substrates may interact to give covalent crosslinks violating the effect of infinite dilution. (purines)
Conclusion
Resins can work as protective groups. (immobilization of amines)

48. Conclusion
Resins can work as protective groups. (immobilization of amines)
Resins may sometimes provide the effect of infinite dilution (monoacylation of piperazine)
Resin attachments may migrate. (purines)
Resin-bound substrates may interact to give covalent crosslinks violating the effect of infinite dilution. (purines)
Resin-bound substrates may interact to give non-covalent crosslinks leading to rigid structures and preventing desired reactions.
(purines, cinnolines)
Resins enable reactions not observed in solution phase. (oxadiazoles)
Resins may be modified during reactions, but not all modifications cause problems. (bromination)
Analysis is difficult, but only needed in case of problems.

49. Eduard Felder
Ruben Tommasi
Erika Schmidt
Claudia Riva
Josette Schaub
Sascha Mueller
Sara Cesarini
Maurizio Pulici
Laura Sereni
Francesco Sola
Massimo Bartolacci
Antonio Traversone
Marco Tatò