Catalysis of Substitution Reactions on Heterocycles Bound to a Solid Phase [email_address]
Catalysis of Substitution Reactions on Heterocycles Bound to a Solid Phase
Levoglucosan based Libraries epoxide opening epoxide opening difficult alkylation or acylation avoid glycosidic scission O...
 
 
Schematic Representation of Resins crosslink shrunken resin (poorly solvated) compound bound to the polymer Reactions can ...
 
 
 
 
 
The Synthesis of Purine Derivatives on Polymeric Supports <ul><li>Potential Targets  </li></ul><ul><li>Development of the ...
Purines may bind to Proteins in different ways They address nucleoside binding pockets
Nucleoside Cofactors Lead us to Drug Targets 1 . Many cofactors contain nucleoside motifs 2. Nucleosides or nucleoside cof...
i, ii: Attachment to the polymer iii:  6-Substitution iv:  2-Substitution v:  Bromination vi:  Stille coupling vii: Cleava...
Immobilization of 2,6-dichloropurine
C6-Substitution
C6-Substitution Reaction temperature has to be 53°C to avoid substitution on C2 for very nucleophilic amines (N-CH 2 CH 2 ...
Sustitution on C2 * rest is starting mat.
<ul><li>The mechanism for aminations and Suzuki-couplings is similar. </li></ul><ul><li>Amines and boronates couple under ...
Two Types of Bromine Complexes Were Investigated Synthesis:   Reactivity:
Modification of the Polymeric Support by the Brominating agent Bromine-complex Br-content of resin, treated with the Bromi...
5% conversion no reaction:  complete conversion: side reactions: not tolerated groups:  activated aromatics: bromination a...
The Reactivity of the Bromine Complex  in dry Benzene:  <ul><li>disproportionation is very slow </li></ul><ul><li>little e...
The  Reactivity  of the Bromine Complex  in wet Benzene:  Side chain oxidations are not mediaded by the solid phase. They ...
Proposed Mechanism for the Modification at C2   i: Br 2 -complex; ii: H 2 O
Dehalogenation during Suzuki couling conditions   ArB(OH) 2  Pd-cat Attempted Synthesis to Yield 2,6,8-Trisubstituted Puri...
Substitution on C8 dppp:
Selection of Buildingblocks: 1) Size and shape constraints:  selection of privileged structures based on modeling previous...
The Synthesis is performed on PS-Beads PS-beads 60 mg  per Kan Rf -transponders with unique  ID Read only ! Reading interv...
The Sort and Combine Strategy How to make 125 single molecules having 3 points of diversity using : <ul><li>5 Building Blo...
1st and 2nd Combinatorial Step <ul><li>125 MiniKans TM  with Rf Transponders sorted into 5 reaction flasks </li></ul>5 x  ...
<ul><li>Flasks 3rd: Redistribution into 5 Reaction   </li></ul>1 x  A E B 1 x  B E B 1 x  C E B 1 x  D E B 1 x  EE B 1 x  ...
SynthMan Plan synthesis Perform synthesis Purify & Analyze compounds Archive data & stock HPLC Weighing full Dilution Impo...
Immobilization of 2,6-Dichloropurine
Addition of Resin slurry to IRORI MiniKans
Sort & Combine transponder Sort Kans redistribute
Washing of Kans TM  in Bulk By R. Gallarini, S. Vinzenz,W. Brill
Sorting of Kans Into  Racks prior to Cleavage: Last step of Sort-and-Combine Method
TFA Transponder TFA-Cleavage
Preparative HPLC-MS Purification <ul><li>LC-MS, MicroMass “platform LC” </li></ul><ul><li>Gilson-Autosampler adapted to ho...
MicroMass LC-MS HPLC-MS correlation of fractions with expected mass fraction location LC-fractions crude reaction mixtures...
High-throughput purification   Crude sample Fraction collection by LC/MS Result of purification Confirmation of identity H...
Evaporation
Automated weighing system Throughput: 1 rack / hr
Recycling of used Kans By S. Vinzenz,W.Brill
Batch-Registration of Compounds by Synthman
Achnowledgement Modeling: E. Jacoby Synthman: R. Fäh, H.-P. Moessner Synthesis: S. Müller, J. Schaub, C. Riva-Toniolo*, D....
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Substitutions On Heterocycles

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Catalysis of substitution reactions on heterocycles bound to a solid phase
Seminar in honor of Prof. Marv Caruthers, Boulder, CO, USA, 2001

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Substitutions On Heterocycles

  1. 1. Catalysis of Substitution Reactions on Heterocycles Bound to a Solid Phase [email_address]
  2. 2. Catalysis of Substitution Reactions on Heterocycles Bound to a Solid Phase
  3. 3. Levoglucosan based Libraries epoxide opening epoxide opening difficult alkylation or acylation avoid glycosidic scission O O X O O O N H 2 R 1 R 2 R 3 Pd mediated coupling Pd mediated coupling
  4. 6. Schematic Representation of Resins crosslink shrunken resin (poorly solvated) compound bound to the polymer Reactions can only be performed, if reagents can diffuse through the gelphase of the beads. The polymer has to be solvated with the appropriate solvent to form such a phase. swollen resin (solvated)
  5. 12. The Synthesis of Purine Derivatives on Polymeric Supports <ul><li>Potential Targets </li></ul><ul><li>Development of the Chemistry </li></ul><ul><li>Designing the Synthesis </li></ul><ul><li>Selection of Building Blocks </li></ul><ul><li>The Sort & Combine Method </li></ul><ul><li>Performing the Synthesis with IRORI-MiniKans TM </li></ul><ul><li>Workup, Purification and Archiving </li></ul>
  6. 13. Purines may bind to Proteins in different ways They address nucleoside binding pockets
  7. 14. Nucleoside Cofactors Lead us to Drug Targets 1 . Many cofactors contain nucleoside motifs 2. Nucleosides or nucleoside cofactors are involved in all important cellular processes. DNA synthesis RNA synthesis protein synthesis carbohydrate synthesis and oligomerization lipid synthesis and processing synthesis of homo and heterocyclic aromatics signaling via phosphoylation and sulfatation signaling as second messenger or hormone alkylation and dealkylation of DNA and other substrates. 3. Nucleoside binding sites are not optimized toward very tight binding!
  8. 15. i, ii: Attachment to the polymer iii: 6-Substitution iv: 2-Substitution v: Bromination vi: Stille coupling vii: Cleavage Reaction Scheme
  9. 16. Immobilization of 2,6-dichloropurine
  10. 17. C6-Substitution
  11. 18. C6-Substitution Reaction temperature has to be 53°C to avoid substitution on C2 for very nucleophilic amines (N-CH 2 CH 2 NH 2 , C-CH 2 CH 2 NH 2 piperazines, piperidines). No C2-substitution even at 70°C: anilines, benzylamines, morpholin, primary amines with higher order of substitution on their Ca
  12. 19. Sustitution on C2 * rest is starting mat.
  13. 20. <ul><li>The mechanism for aminations and Suzuki-couplings is similar. </li></ul><ul><li>Amines and boronates couple under the same conditions </li></ul><ul><li>A wide selection of building blocks possible </li></ul><ul><li>Reaction temperatures compatible with Kans. </li></ul>Sustitution on C2
  14. 21. Two Types of Bromine Complexes Were Investigated Synthesis: Reactivity:
  15. 22. Modification of the Polymeric Support by the Brominating agent Bromine-complex Br-content of resin, treated with the Bromine Complex (EA)
  16. 23. 5% conversion no reaction: complete conversion: side reactions: not tolerated groups: activated aromatics: bromination amines: many oxidation products Reactivity of the Bromine Complex with Purines: Solvent: NMP R 1 : H, alkyl, R 1 ’: alkyl R 2 : H, alkyl, R 2 ’: H, alkyl tolerated groups: CONR 2 , CONRH CONH 2 , ether functions, aromatics more deactivated than Bn
  17. 24. The Reactivity of the Bromine Complex in dry Benzene: <ul><li>disproportionation is very slow </li></ul><ul><li>little electrophilic substitution </li></ul><ul><li>oxidizing power is enhanced relative to reactions in NMP </li></ul>Selective side reactions:
  18. 25. The Reactivity of the Bromine Complex in wet Benzene: Side chain oxidations are not mediaded by the solid phase. They work are observed also in solution phase .
  19. 26. Proposed Mechanism for the Modification at C2 i: Br 2 -complex; ii: H 2 O
  20. 27. Dehalogenation during Suzuki couling conditions ArB(OH) 2 Pd-cat Attempted Synthesis to Yield 2,6,8-Trisubstituted Purines
  21. 28. Substitution on C8 dppp:
  22. 29. Selection of Buildingblocks: 1) Size and shape constraints: selection of privileged structures based on modeling previous screening results, docking excercises 2) Availability of building blocks: emphasis on proprietary building blocks, commercial building blocks 3) Chemtox considerations: exclusion of: -NO 2 ,-NO,-N 2 + , I, -I=O, -N 3 , heavy metals, alkylating agents, acylating agents, hydrazines, SH, aniline-functions in product 4) Tests of building blocks (several hundred reactions) 5) Generation of a virtual library with the building blocks which work: Agreement to rule of 5 checked, exclusion of dramatic outliers 6) Final selection for Synthesis
  23. 30. The Synthesis is performed on PS-Beads PS-beads 60 mg per Kan Rf -transponders with unique ID Read only ! Reading interval: 0.1s RF-frequency: 125 KHz Reading distance : 1 cm reusable many times ! 1 per Kan Now all Kans can be distinguished 1 cm
  24. 31. The Sort and Combine Strategy How to make 125 single molecules having 3 points of diversity using : <ul><li>5 Building Blocks : A , B , C , D, E </li></ul><ul><li>5 Vessels: </li></ul>1 2 3 4 5
  25. 32. 1st and 2nd Combinatorial Step <ul><li>125 MiniKans TM with Rf Transponders sorted into 5 reaction flasks </li></ul>5 x A -- 5 x A -- 5 x A -- 5 x A -- 5 x A -- 5 x B -- 5 x B -- 5 x B -- 5 x B -- 5 x B -- 5 x C -- 5 x C -- 5 x C -- 5 x C -- 5 x C -- 5 x D -- 5 x D -- 5 x D -- 5 x D -- 5 x D -- 5 x E -- 5 x E -- 5 x E -- 5 x E -- 5 x E -- Washing 125 Kans TM in bulk 2nd Redistribution into 5 reaction flasks 5 x AA - 5 x B A - 5 x C A - 5 x D A - 5 x E A - 5 x A B - 5 x BB - 5 x C B - 5 x D B - 5 x E B - 5 x A C - 5 x B C - 5 x CC - 5 x D C - 5 x E C - 5 x A D - 5 x B D - 5 x C D - 5 x DD - 5 x E D - 5 x A E - 5 x B E - 5 x C E - 5 x D E - 5 x EE - Washing 125 Kans TM in bulk
  26. 33. <ul><li>Flasks 3rd: Redistribution into 5 Reaction </li></ul>1 x A E B 1 x B E B 1 x C E B 1 x D E B 1 x EE B 1 x A E C 1 x B E C 1 x C E C 1 x D E C 1 x EE C 1 x A E D 1 x B E D 1 x C E D 1 x D E D 1 x EE D 1 x A EE 1 x B EE 1 x C EE 1 x D EE 1 x EEE Washing 125 Kans TM in bulk then order into Racks : one Kan in one tube 1 x A E A 1 x B E A 1 x C E A 1 x D E A 1 x EE A 1 x A D A 1 x B D A 1 x C D A 1 x DD A 1 x E D A 1 x A C A 1 x B C A 1 x CC A 1 x D C A 1 x E C A 1 x ABA 1 x BB A 1 x C B A 1 x D B A 1 x E B A 1 x AAA 1 x B AA 1 x C AA 1 x D AA 1 x E AA 1 x A D B 1 x B D B 1 x C D B 1 x DD B 1 x E D B 1 x A C B 1 x B C B 1 x CC B 1 x D C B 1 x E C B 1 x A BB 1 x BBB 1 x C BB 1 x D BB 1 x E BB 1 x AA B 1 x B A B 1 x C A B 1 x D A B 1 x E A B 1 x A D C 1 x B D C 1 x C D C 1 x DD C 1 x E D C 1 x A CC 1 x B CC 1 x CCC 1 x D CC 1 x E CC 1 x A B C 1 x BB C 1 x C B C 1 x D B C 1 x E B C 1 x AA C 1 x B A C 1 x C A C 1 x D A C 1 x E A C 1 x A DD 1 x B DD 1 x C DD 1 x DDD 1 x E DD 1 x A C D 1 x B C D 1 x CC D 1 x D C D 1 x E C D 1 x A B D 1 x BB D 1 x C B D 1 x D B D 1 x E B D 1 x AA D 1 x B A D 1 x C A D 1 x D A D 1 x E A D 1 x A D E 1 x B D E 1 x C D E 1 x DD E 1 x E D E 1 x A C E 1 x B C E 1 x CC E 1 x D C E 1 x E C E 1 x A B E 1 x BB E 1 x C B E 1 x D B E 1 x E B E 1 x AA E 1 x B A E 1 x C A E 1 x D A E 1 x E A E
  27. 34. SynthMan Plan synthesis Perform synthesis Purify & Analyze compounds Archive data & stock HPLC Weighing full Dilution Import BB MS Import Compounds Family data Reagent data Method data Salt data Barcodes Working Sheet Preparereagents Component Database Family Database HPLC (Millennium) Structural Analysis Software for Controlling of the Production, Purification and Analyzing Process Weighing empty LC-MS (MicroMass) prep. LC Automatic Sampler (Hamilton) 2. 1. 9 16. 8. 7. 15. 6. 5. 3. 4. 14. 13. 12. 10. Archive Databases Archive Databases Automatic weighing (MicroWeight) Automated Sorting (Kan Sort) Sort to flasks and racks 11.
  28. 35. Immobilization of 2,6-Dichloropurine
  29. 36. Addition of Resin slurry to IRORI MiniKans
  30. 37. Sort & Combine transponder Sort Kans redistribute
  31. 38. Washing of Kans TM in Bulk By R. Gallarini, S. Vinzenz,W. Brill
  32. 39. Sorting of Kans Into Racks prior to Cleavage: Last step of Sort-and-Combine Method
  33. 40. TFA Transponder TFA-Cleavage
  34. 41. Preparative HPLC-MS Purification <ul><li>LC-MS, MicroMass “platform LC” </li></ul><ul><li>Gilson-Autosampler adapted to hold 2 Novartis Mega Racks = 192 samples </li></ul><ul><li>Capacity: 2 units with up to 384 samples </li></ul><ul><li>HPLC columns: 5 cm length, 2 cm diameter, 5 µm C18 </li></ul><ul><li>Gradient: optimized for each library </li></ul><ul><li>Expected MS-Peak is delivered into 10 mL glass tube </li></ul><ul><li>Micromass, UK http://www.micromass.co.uk </li></ul>
  35. 42. MicroMass LC-MS HPLC-MS correlation of fractions with expected mass fraction location LC-fractions crude reaction mixtures location of crude reaction mixtures, expected mass
  36. 43. High-throughput purification Crude sample Fraction collection by LC/MS Result of purification Confirmation of identity HPLC/UV purity : 20% HPLC/UV purity : >95%
  37. 44. Evaporation
  38. 45. Automated weighing system Throughput: 1 rack / hr
  39. 46. Recycling of used Kans By S. Vinzenz,W.Brill
  40. 47. Batch-Registration of Compounds by Synthman
  41. 48. Achnowledgement Modeling: E. Jacoby Synthman: R. Fäh, H.-P. Moessner Synthesis: S. Müller, J. Schaub, C. Riva-Toniolo*, D. Tirefort ** Purification & Registration: F. Gombert, G. Lerch, H. Wettstein Hardware: S. Vinzenz, R. Gallarini General: A. DeMesmaeker, J. Zimmermann, S. Wendeborn
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