Combinatorial Chemistry and Synthesis on Solid Support
Burkhard König
University of Regensburg
Outline
I. Solid phase synthesis
1. Polymers, resins, supports2. Linkers3. Analytical techniques
Solid phase synthesis protocols and automatization
4. Peptide Synthesis
a) Protecting groups (- CO2H, -NH2, side chain=
Special topic: Photoremovable protecting groupsb) Coupling methods
5. Oligonucleotides6. Sugars7. Special topic: Immobilization of catalysts
Outline
II. Liquid phase synthesisPolyethylenglycol, Linear Polymers, Isomerization reactions, Metathesis
III. Polymer supported reagents
IV. Combinatorial Chemistry
1. Library synthesisa) in solution, parallel synthesisb) on solid supportc) split and combine, one bead one compound
2. Deconvolution and Tagging3. Dynamic combinatorial Chemistry and virtual libraries
Outline
V. Diversity oriented synthesis (DOS)
Principle and examples
Molecular complexity
VI. Complexity Generating Reactions
Tandem cycloadditions and rearrangements, radical cascade reactions, transition metal catalyzed reactions, mixed tandem reactions, mulit-component reactions
VII. Chemical Diversity
Building blocks, functional groups, stereochemistry,
molecular framework, examples of diversity from biosynthesis
An incomplete list of relevant literature reviews
Current Opinion in Chemical Biology (2000) 4, Issue 4 - available online.
Schreiber, S. L. (2000). Science 287, 1964-1968.
Szostak, J. W. (1997). Introduction: Combinatorial Chemistry. ChemicalReviews 97, 347-348.
Pirrung, M. C. (1997). Spatially Addressable Combinatorial Libraries.Chemical Reviews 97, 473-488.
Osborne, S. E., and Ellington, A. D. (1997). Nucleic Acid Selection and theChallenge of Combinatorial Chemistry. Chemical Reviews 97, 349-370.
Nefzi, A., Ostresh, J. M., and Houghten, R. A. (1997). The Current Status ofHeterocyclic Combinatorial Libraries. Chemical Reviews 97, 449-472.
Pinilla, C., Appel, J., Blondelle, S., Dooley, C., Dorner, B., Eichler, J.,Ostresh, J., and Houghten, R. A. (1995). A Review Of the Utility Of SolublePeptide Combinatorial Libraries. Biopolymers 37, 221-240.
Lam, K. S., Lebl, M., and Krchnak, V. (1997). The''One-Bead-One-Compound'' Combinatorial Library Method. ChemicalReviews 97, 411-448.
Baldwin, J. J., and Henderson, I. (1996). Recent Advances In theGeneration Of Small-Molecule Combinatorial Libraries - Encoded SplitSynthesis and Solid-Phase Synthetic Methodology. Medicinal ResearchReviews 16, 391-405.
Lowe, G. (1995). Combinatorial Chemistry. Chemical Society Reviews 24,329-340.
Terrett, N. K., Gardner, M., Gordon, D. W., Kobylecki, R. J., and Steele, J.(1995). Combinatorial Synthesis - the Design Of Compound Libraries andTheir Application to Drug Discovery. Tetrahedron 51, 8135-8173.
Gallop, M. A., Barrett, R. W., Dower, W. J., Fodor, S. P. A., and Gordon, E.M. (1994). Applications Of Combinatorial Technologies to Drug Discovery .1.Background and Peptide Combinatorial Libraries. Journal Of MedicinalChemistry 37, 1233-1251.
Gordon, E. M., Barrett, R. W., Dower, W. J., Fodor, S. P. A., and Gallop, M.A. (1994). Applications Of Combinatorial Technologies to Drug Discovery .2.Combinatorial Organic Synthesis, Library Screening Strategies, and FutureDirections. Journal Of Medicinal Chemistry 37, 1385-1401.
Current Opinion in Chemical Biology (2000) 4, Issue 4 - available online.
Schreiber, S. L. (2000). Science 287, 1964-1968.
Szostak, J. W. (1997). Introduction: Combinatorial Chemistry. ChemicalReviews
Current Opinion in Chemical Biology (2000) 4, Issue 4 - available online.
Schreiber, S. L. (2000). Science 287, 1964-1968.
Szostak, J. W. (1997). Introduction: Combinatorial Chemistry. ChemicalReviews 97, 347-348.
Pirrung, M. C. (1997). Spatially Addressable Combinatorial Libraries.Chemical Reviews 97, 473-488.
Osborne, S. E., and Ellington, A. D. (1997). Nucleic Acid Selection and theChallenge o
97, 347-348.
Pirrung, M. C. (1997). Spatially Addressable Combinatorial Libraries.Chemical Reviews 97, 473-488.
Osborne, S. E., and Ellington, A. D. (1997). Nucleic Acid Selection and theChallenge of Combinatorial Chemistry. Chemical Reviews 97, 349-370.
Nefzi, A., Ostresh, J. M., and Houghten, R. A. (1997). The Current Status ofHeterocyclic Combinatorial Libraries. Chemical Reviews 97, 449-472
f Combinatorial Chemistry. Chemical Reviews 97, 349-370.
Nefzi, A., Ostresh, J. M., and Houghten, R. A. (1997). The Current Status ofHeterocyclic Combinatorial Libraries. Chemical Reviews 97, 449-472.
Pinilla, C., Appel, J., Blondelle, S., Dooley, C., Dorner, B., Eichler, J.,Ostresh, J., and Houghten, R. A. (1995). A Review Of the Utility Of SolublePeptide Combinatorial Libraries. Biopolymers 37
.
Pinilla, C., Appel, J., Blondelle, S., Dooley, C., Dorner, B., Eichler, J.,Ostresh, J., and Houghten, R. A. (1995). A Review Of the Utility Of SolublePeptide Combinatorial Libraries. Biopolymers 37, 221-240.
Lam, K. S., Lebl, M., and Krchnak, V. (1997). The''One-Bead-One-Compound'' Combinatorial Library Method. ChemicalReviews 97, 411-448.
Baldwin, J. J., and Henderson, I. (1996). Recent Advanc
, 221-240.
Lam, K. S., Lebl, M., and Krchnak, V. (1997). The''One-Bead-One-Compound'' Combinatorial Library Method. ChemicalReviews 97, 411-448.
Baldwin, J. J., and Henderson, I. (1996). Recent Advances In theGeneration Of Small-Molecule Combinatorial Libraries - Encoded SplitSynthesis and Solid-Phase Synthetic Methodology. Medicinal ResearchReviews 16, 391-405.
Lowe, G. (1995). Combinatorial Ch
es In theGeneration Of Small-Molecule Combinatorial Libraries - Encoded SplitSynthesis and Solid-Phase Synthetic Methodology. Medicinal ResearchReviews 16, 391-405.
Lowe, G. (1995). Combinatorial Chemistry. Chemical Society Reviews 24,329-340.
Terrett, N. K., Gardner, M., Gordon, D. W., Kobylecki, R. J., and Steele, J.(1995). Combinatorial Synthesis - the Design Of Compound Libraries andTheir
emistry. Chemical Society Reviews 24,329-340.
Terrett, N. K., Gardner, M., Gordon, D. W., Kobylecki, R. J., and Steele, J.(1995). Combinatorial Synthesis - the Design Of Compound Libraries andTheir Application to Drug Discovery. Tetrahedron 51, 8135-8173.
Gallop, M. A., Barrett, R. W., Dower, W. J., Fodor, S. P. A., and Gordon, E.M. (1994). Applications Of Combinatorial Technologies to Drug Disc
Application to Drug Discovery. Tetrahedron 51, 8135-8173.
Gallop, M. A., Barrett, R. W., Dower, W. J., Fodor, S. P. A., and Gordon, E.M. (1994). Applications Of Combinatorial Technologies to Drug Discovery .1.Background and Peptide Combinatorial Libraries. Journal Of MedicinalChemistry 37, 1233-1251.
Gordon, E. M., Barrett, R. W., Dower, W. J., Fodor, S. P. A., and Gallop, M.A. (1994). Applicati
overy .1.Background and Peptide Combinatorial Libraries. Journal Of MedicinalChemistry 37, 1233-1251.
Gordon, E. M., Barrett, R. W., Dower, W. J., Fodor, S. P. A., and Gallop, M.A. (1994). Applications Of Combinatorial Technologies to Drug Discovery .2.Combinatorial Organic Synthesis, Library Screening Strategies, and FutureDirections. Journal Of Medicinal Chemistry 37, 1385-1401.
Bodanszky, M. (1993). Principles of Peptide Synthesis, 2nd Edition.Springer-Verlag: New York.
Crowley, J. I., Rapoport, H. (1976). Solid-Phase Organic Synthesis: Novelty orFundamental Concept. Accounts of Chemical Research 9, 135 - 144.
Fréchet, J. M. (1981). Synthesis and Applications of Organic Polymers AsSupports and Protecting Groups. Tetrahedron 37, 663 - 683.
Gait, M. J., Ed. (1984). Oligonucleotide Synthesis: A Practical Approach.IRL Press: Washington, D. C.
Letsinger, R. L. (1983). Chemical Synthesis of Oligonucleotides: a SimplifiedApproach. Genetic Engineering 5, 191-207.
Leznoff, C. C. (1974). The Use of Insoluble Polymer Supports in OrganicChemical Synthesis. Chemical Society Reviews 3, 65 - 85.
Leznoff, C. C. (1978). The Use of Insoluble Polymer Supports in GeneralOrganic Synthesis. Accounts of Chemical Research 11, 327 - 333.
Merrifield, B. (1986). Solid Phase Synthesis. Science 232, 341 - 347.(This is a transcript of Merrifield's Nobel Award address.)
Neckers, D. C. (1978). Solid Phase Synthesis. Chemtech, 108 - 116
Overberger, C. G., Sannes, K. N. (1974). Polymeric Reagents in OrganicSynthesis. Angewandte Chemie International Edition in English 13, 99 - 104.
Patchornik, A., Kraus, M. A. (1975). The Use of Polymeric Reagents in OrganicSythesis. Pure and Applied Chemistry 43, 503 - 526.
Bodanszky, M. (1993). Principles of Peptide Synthesis, 2nd Edition.Springer-Verlag: New York.
Crowley, J. I., Rapoport, H. (1976). Solid-Phase Organic Synthesis: Novelty orFundamental Concept
Bodanszky, M. (1993). Principles of Peptide Synthesis, 2nd Edition.Springer-Verlag: New York.
Crowley, J. I., Rapoport, H. (1976). Solid-Phase Organic Synthesis: Novelty orFundamental Concept. Accounts of Chemical Research 9, 135 - 144.
Fréchet, J. M. (1981). Synthesis and Applications of Organic Polymers AsSupports and Protecting Groups. Tetrahedron 37, 663 - 683.
Gait, M. J., Ed.
. Accounts of Chemical Research 9, 135 - 144.
Fréchet, J. M. (1981). Synthesis and Applications of Organic Polymers AsSupports and Protecting Groups. Tetrahedron 37, 663 - 683.
Gait, M. J., Ed. (1984). Oligonucleotide Synthesis: A Practical Approach.IRL Press: Washington, D. C.
Letsinger, R. L. (1983). Chemical Synthesis of Oligonucleotides: a SimplifiedApproach. Genetic Engineering 5,
(1984). Oligonucleotide Synthesis: A Practical Approach.IRL Press: Washington, D. C.
Letsinger, R. L. (1983). Chemical Synthesis of Oligonucleotides: a SimplifiedApproach. Genetic Engineering 5, 191-207.
Leznoff, C. C. (1974). The Use of Insoluble Polymer Supports in OrganicChemical Synthesis. Chemical Society Reviews 3, 65 - 85.
Leznoff, C. C. (1978). The Use of Insoluble Polymer Sup
191-207.
Leznoff, C. C. (1974). The Use of Insoluble Polymer Supports in OrganicChemical Synthesis. Chemical Society Reviews 3, 65 - 85.
Leznoff, C. C. (1978). The Use of Insoluble Polymer Supports in GeneralOrganic Synthesis. Accounts of Chemical Research 11, 327 - 333.
Merrifield, B. (1986). Solid Phase Synthesis. Science 232, 341 - 347.(This is a transcript of Merrifield's Nobe
ports in GeneralOrganic Synthesis. Accounts of Chemical Research 11, 327 - 333.
Merrifield, B. (1986). Solid Phase Synthesis. Science 232, 341 - 347.(This is a transcript of Merrifield's Nobel Award address.)
Neckers, D. C. (1978). Solid Phase Synthesis. Chemtech, 108 - 116
Overberger, C. G., Sannes, K. N. (1974). Polymeric Reagents in OrganicSynthesis. Angewandte Chemie Internation
l Award address.)
Neckers, D. C. (1978). Solid Phase Synthesis. Chemtech, 108 - 116
Overberger, C. G., Sannes, K. N. (1974). Polymeric Reagents in OrganicSynthesis. Angewandte Chemie International Edition in English 13, 99 - 104.
Patchornik, A., Kraus, M. A. (1975). The Use of Polymeric Reagents in OrganicSythesis. Pure and Applied Chemistry 43, 503 - 526.
I. Solid phase synthesisSynthesis on solid (polymer) support
Why should you care about solid-phase synthesis ?
Even if it were the case that the only successful solid-phase chemistries ever performed were the synthesis of oligopeptides and oligonucleotides, it would be difficult to overstate their importance. These advances created entire new areas of research, and have served as the underpinning for almost all modernbiochemistry and molecular biology.
Two other primary reasons for caring about solid-phase synthesis:
Its interesting!
It served as the basis for much of the early efforts in combinatorial chemistry.
A little history of solid-phase synthesis
Bruce Merrifield1984 Nobel Prize in ChemistryBorn July 21, 1921
1960's: Solid-phase peptide and oligonucleotide synthesis get started.
1970's: Continued development ofsolid-phase peptide and oligosynthesis, including the developmentof effective apparati for automatedsynthesis.
1970's: Synthetic organic chemistsbegin to explore solid-phase organicsynthesis. While interesting, nocompelling case is made for actuallybothering to do organic chemistry onsolid support, and by 1980 mostefforts have stagnated.
1980's: Peptide chemists andbiologists get interested in figuring outhow to make truly huge numbers ofpeptides (and screen them forbiological activity). This leads to thedevelopment of the first combinatoriallibraries.
1980's (late): Interest insolid-phase organic synthesis isrenewed, in both academia and thepharmaceutical industry.Adaptation of "modern" syntheticreactions to the solid-phasebegins.
1990's: Continued improvements in the rate at which potential drugcandidates can be screened (high-throughput screening) lead virtuallyevery major pharmaceutical company to delve into the combinatorialsynthesis of non-peptide, non-oligonucleotide pharmacophores.
1960's: Solid-phase peptide and oligonucleotide synthesis get started.1960's: Solid-phase peptide and oligonucleotide synthesis get started.
1970's: Continued development ofsolid-phase peptide and oligosynthesis, including the developmentof effective apparati for automatedsynthesis.
1970's: Continued development ofsolid-phase peptide and oligosynthesis, including the developmentof effective apparati for automatedsynthesis.
1970's: Synthetic organic chemistsbegin to explore solid-phase organicsynthesis. While interesting, nocompelling case is made for actuallybothering to do organic chemistry onsolid support, and by 1980 mostefforts have stagnated.
1970's: Synthetic organic chemistsbegin to explore solid-phase organicsynthesis. While interesting, nocompelling case is made for actuallybothering to do organic chemistry onsolid support, and
1970's: Synthetic organic chemistsbegin to explore solid-phase organicsynthesis. While interesting, nocompelling case is made for actuallybothering to do organic chemistry onsolid support, and by 1980 mostefforts have stagnated.
1980's: Peptide chemists andbiologists get interested in figuring outhow to make truly huge numbers ofpeptides (and screen them forbiological activity). This leads to thedevelopment of the first combinatoriallibraries.
1980's: Peptide chemists andbiologists get interested in figuring outhow to make truly huge numbers ofpeptides (and screen them forbiological activity). This leads to thedevelopment of the firs
1980's: Peptide chemists andbiologists get interested in figuring outhow to make truly huge numbers ofpeptides (and screen them forbiological activity). This leads to thedevelopment of the first combinatoriallibraries.
1980's (late): Interest insolid-phase organic synthesis isrenewed, in both academia and thepharmaceutical industry.Adaptation of "modern" syntheticreactions to the solid-phasebegins.
1980's (late): Interest insolid-phase organic synthesis isrenewed, in both academia and thepharmaceutical industry.Adaptation of "modern" syntheticreactions to the solid-phasebegins.
1990's: Continued improvements in the rate at which potential drugcandidates can be screened (high-throughput screening) lead virtuallyevery major pharmaceutical company to delve into the combinatorialsynthesis of non-peptide, non-oligonucleotide pharmacophores.
1990's: Continued improvements in the rate at which potential drugcandidates can be screened (high-throughput screening) lead virtuallyevery major pharmaceutical company to delve into the combinato
1990's: Continued improvements in the rate at which potential drugcandidates can be screened (high-throughput screening) lead virtuallyevery major pharmaceutical company to delve into the combinatorialsynthesis of non-peptide, non-oligonucleotide pharmacophores.
Benefits often associated with solid-phase synthesis
• Minimized Solubility Problems
• Simplified Purification
• Improved Reaction Yields
• Simplified Manipulation of Small Molar Quantities
• Site Isolation
Why Use Solid Phase Synthesis?
SS
SS
SS
SS
S S S S
Purification of compounds bound to the solid support from those in solution is accomplished by simple filtration
This allows the use of a large excess of reagents, improving the efficiency of many transformations
The solid support can be used to compartmentalize library members, permitting the use of split-pool synthesis
1. Polymers, resins, supports
Book Chapters
Barany, G., Kempe, M. (1997). The Context of Solid-Phase Synthesis.In: A Practical Guide to Combinatorial Chemistry. Czarnik, A. W., DeWitt,S. H., Eds. (ACS: Washington, D. C.) Chapter 3.
Früchtel, J. S., Jüng, G. (1996). Polymer Supported Organic Synthesis:A Review. In: Combinatorial Peptide and Non-Peptide Libraries. Jüng,G., Ed. (VCH: New York) Chapter 2.
Novabiochem (2001). The Combinatorial Chemistry Catalog.
Rapp, W. E. (1996). PEG Grafted Polystyrene Tentacle Polymers:Physico-Chemical Properties and Application to Chemical Synthesis. InCombinatorial Peptide and Non-Peptide Libraries. Jüng, G., Ed. (VCH:New York) Chapter 16.
Rapp, W. E. (1997). Macro Beads as Microreactors: New Solid-PhaseSynthesis Methodology. In Combinatorial Chemistry. Wilson, S. R.;Czarnick, A. W., Eds. (Wiley&Sons: New York) Chapter 4.
Review Articles
Vaino, A. R. and Janda, K. D. (2000). Solid-Phase Organic Synthesis: A CriticalUnderstanding of the Resin. Journal of Combinatorial Chemistry, 2, 579-596.
Guillier,F., Orain, D. and Bradley, M. (2000). Linkers and Cleavage Strategies inSolid-Phase Organic Synthesis and Combinatorial Chemistry. ChemicalReviews, 100, 2091-2157.
Book Chapters
Barany, G., Kempe, M. (1997). The Context of Solid-Phase Synthesis.In: A Practical Guide to Combinatorial Chemistry. Czarnik, A. W., DeWitt,S. H., Eds. (ACS: Washington, D
Book Chapters
Barany, G., Kempe, M. (1997). The Context of Solid-Phase Synthesis.In: A Practical Guide to Combinatorial Chemistry. Czarnik, A. W., DeWitt,S. H., Eds. (ACS: Washington, D. C.) Chapter 3.
Früchtel, J. S., Jüng, G. (1996). Polymer Supported Organic Synthesis:A Review. In: Combinatorial Peptide and Non-Peptide Libraries. Jüng,G., Ed. (VCH: New York) Ch
. C.) Chapter 3.
Früchtel, J. S., Jüng, G. (1996). Polymer Supported Organic Synthesis:A Review. In: Combinatorial Peptide and Non-Peptide Libraries. Jüng,G., Ed. (VCH: New York) Chapter 2.
Novabiochem (2001). The Combinatorial Chemistry Catalog.
Rapp, W. E. (1996). PEG Grafted Polystyrene Tentacle Polymers:Physico-Chemical Properties and Application to Chemical Synthesis
apter 2.
Novabiochem (2001). The Combinatorial Chemistry Catalog.
Rapp, W. E. (1996). PEG Grafted Polystyrene Tentacle Polymers:Physico-Chemical Properties and Application to Chemical Synthesis. InCombinatorial Peptide and Non-Peptide Libraries. Jüng, G., Ed. (VCH:New York) Chapter 16.
Rapp, W. E. (1997). Macro Beads as Microreactors: New Solid-PhaseSynthesis Methodol
. InCombinatorial Peptide and Non-Peptide Libraries. Jüng, G., Ed. (VCH:New York) Chapter 16.
Rapp, W. E. (1997). Macro Beads as Microreactors: New Solid-PhaseSynthesis Methodology. In Combinatorial Chemistry. Wilson, S. R.;Czarnick, A. W., Eds. (Wiley&Sons: New York) Chapter 4.
Review Articles
Vaino, A. R. and Janda, K. D. (2000). Solid-Phase Organic Synthesis: A Cri
ogy. In Combinatorial Chemistry. Wilson, S. R.;Czarnick, A. W., Eds. (Wiley&Sons: New York) Chapter 4.
Review Articles
Vaino, A. R. and Janda, K. D. (2000). Solid-Phase Organic Synthesis: A CriticalUnderstanding of the Resin. Journal of Combinatorial Chemistry, 2, 579-596.
Guillier,F., Orain, D. and Bradley, M. (2000). Linkers and Cleavage Strategies inSolid-Phase Organic Synthesis and Com
ticalUnderstanding of the Resin. Journal of Combinatorial Chemistry, 2, 579-596.
Guillier,F., Orain, D. and Bradley, M. (2000). Linkers and Cleavage Strategies inSolid-Phase Organic Synthesis and Combinatorial Chemistry. ChemicalReviews, 100, 2091-2157.
1. Polymers, resins, supports
X Y Z
first resin-boundintermediate, MW = 100
second resin-boundintermediate, MW = 250
final resin-boundintermediate, MW = 400
1.1 g
(9 wt % substrate)
1.25 g
(20 wt % substrate)
1.4 g
(29 wt % substrate)
X Y Z
first resin-boundintermediate, MW = 100
first resin-boundintermediate, MW = 100
second resin-boundintermediate, MW = 250
second resin-boundintermediate, MW = 250
final resin-boundintermediate, MW = 400
final resin-boundintermediate, MW = 400
1.1 g
(9 wt % substrate)
1.1 g
(9 wt % substrate)
1.25 g
(20 wt % substrate)
1.25 g
(20 wt % substrate)
1.4 g
(29 wt % substrate)
1.4 g
(29 wt % substrate)
Typical loading: 1 mmol / g of resin
or 200 pm / bead (for 100 μm aminomethylpolystyrene ~ 5 x 106 beads / g)
1. Polymers, resins, supports
Polystyrene Resins
= polystyrene/DVB copolymer(0.5 - 5% cross-linking)
= polystyrene/DVB copolymer(8 - 50% cross-linking)
= polystyrene/Kel-F
= PEPS film
Cheap; excellent chemical stability;good to ca. 110 - 130 °C at 1% DVB;slightly higher at 2% DVB.
Cheap; excellent chemical stability;remarkable thermal and mechanicalstability; very poor swellingcharacteristics → low loadings. Oftencalled "macroreticulate" resin.
Polystyrene grafted onto polyethylenefilm. Improved thermal, mechanicalstability, but lower loading.
Polystyrene ResinsPolystyrene Resins
= polystyrene/DVB copolymer(0.5 - 5% cross-linking)
= polystyrene/DVB copolymer(0.5 - 5% cross-linking)
= polystyrene/DVB copolymer(8 - 50% cross-linking)
= polystyrene/DVB copolymer(8 - 50% cross-linking)
= polystyrene/Kel-F= polystyrene/Kel-F
= PEPS film= PEPS film
Cheap; excellent chemical stability;good to ca. 110 - 130 °C at 1% DVB;slightly higher at 2% DVB.
Cheap; excellent chemical stability;good to ca. 110 - 130 °C at 1% DVB;slightly higher at 2% DVB.
Cheap; excellent chemical stability;remarkable thermal and mechanicalstability; very poor swellingcharacteristics → low loadings. Oftencalled "macroreticulate" resin.
Cheap; excellent chemical stability;remarkable thermal and mechanicalstability; very poor swellingcharacteristics → low loadings. Oftencalled "macroreticulate" resin.
Polystyrene grafted onto polyethylenefilm. Improved thermal, mechanicalstability, but lower loading.
Polystyrene grafted onto polyethylenefilm. Improved thermal, mechanicalstability, but lower loading.
1. Polymers, resins, supports
Polyamide Resins
= Pepsyn polyamide,a copolymer of:
H2C H2C
O
NH2
O
HN
NH
O
CH2
NH
HN
O
CH2
O
BocHN
= Pepsyn K Pepsin occluded in keiselguhr (silica)matrix. Excellent longevity; used incontinuous flow SPPS.
Very polar resins; excellent swelling inDMF, H2O; essentially no swelling inCH2Cl2.
Polyamide ResinsPolyamide Resins
= Pepsyn polyamide,a copolymer of:
= Pepsyn polyamide,a copolymer of:
H2CH2C H2CH2C
O
NH2NH2
O
HNHN
NHNH
O
CH2CH2
NHNH
HNHN
O
CH2CH2
O
BocHNBocHN
= Pepsyn K= Pepsyn K Pepsin occluded in keiselguhr (silica)matrix. Excellent longevity; used incontinuous flow SPPS.
Pepsin occluded in keiselguhr (silica)matrix. Excellent longevity; used incontinuous flow SPPS.
Very polar resins; excellent swelling inDMF, H2O; essentially no swelling inCH2Cl2.
Very polar resins; excellent swelling inDMF, H2O; essentially no swelling inCH2Cl2.
1. Polymers, resins, supports
Polyamide resins (continued)
= Sparrow amide resin,a copolymer of:
H2C H2C
O
N
O
HN
HN
CH3
CH3
O
CH2
H2NCH2
= Polyhipe, a copolymer of the following in amacroreticulate polystyrene/DVB matrix
H2C H2C
O
N
O
NOCH3
CH3
CH3
CH3 O
Polyamide resins (continued)Polyamide resins (continued)
= Sparrow amide resin,a copolymer of:
= Sparrow amide resin,a copolymer of:
H2CH2C H2CH2C
O
N
O
HNHN
HNHN
CH3CH3
CH3CH3
O
CH2CH2
H2NH2NCH2CH2
= Polyhipe, a copolymer of the following in amacroreticulate polystyrene/DVB matrix
= Polyhipe, a copolymer of the following in amacroreticulate polystyrene/DVB matrix
H2CH2C H2CH2C
O
N
O
NOCH3OCH3
CH3CH3
CH3CH3
CH3CH3 O
1. Polymers, resins, supports
Poly(ethylene glycol) - containing resins
= PEG-PS, PEG covalently graftedonto preformed polystyrene/
1% DVB copolymer
= POE-PS (Tentagel), PEGpolymerized onto
polystyrene/1% DVBcopolymer
Lower mechanical and thermal stabilitythan polystyrene, but much bettersolvent spectrum. (Resin swells inanything but hexanes.)
A couple other resins you might see
HOO
OH
n
= Polyethylene pins, with a grafted crown of:
O O
CH3
n
OH
Poly(ethylene glycol) - containing resinsPoly(ethylene glycol) - containing resins
= PEG-PS, PEG covalently graftedonto preformed polystyrene/
1% DVB copolymer
= PEG-PS, PEG covalently graftedonto preformed polystyrene/
1% DVB copolymer
= POE-PS (Tentagel), PEGpolymerized onto
polystyrene/1% DVBcopolymer
= POE-PS (Tentagel), PEGpolymerized onto
polystyrene/1% DVBcopolymer
Lower mechanical and thermal stabilitythan polystyrene, but much bettersolvent spectrum. (Resin swells inanything but hexanes.)
Lower mechanical and thermal stabilitythan polystyrene, but much bettersolvent spectrum. (Resin swells inanything but hexanes.)
A couple other resins you might seeA couple other resins you might see
HOHOO
OHOH
n
= Polyethylene pins, with a grafted crown of:= Polyethylene pins, with a grafted crown of:
O O
CH3CH3
n
OHOH
1. Polymers, resins, supports
Inorganic support materials
Controlled pore glass (CPG); oligonucleotide synthesis
controlled pore ceramics (CPS); high thermal stabilty
Cellulose
Spot synthesis on paper
1. Polymers, resins, supports
+
2 - 20 mol%
+
2 - 20 mol%2 - 20 mol%
Cl
Merrifield JACS 1963, 85, 2149.
CH3OCH2Cl
SnCl4
ClCl
Merrifield JACS 1963, 85, 2149.Merrifield JACS 1963, 85, 2149.
CH3OCH2ClCH3OCH2Cl
SnCl4SnCl4
• Cross-Linking imparts mechanical stability and improved diffusion and swelling properties to the resin
Effects of Crosslinking
Without cross-linking, each polymer chain can dissolve under thermodynamically favored conditions
Cross-linking can induce some sites of ‘permanent entanglement’ maintaining structural integrity
Introduction of functional groups
Br
Li
Br2, Tl(III)
n-BuLibetter p- vs o-regioselectivity
n-BuLi,TMEDA
more convenient
BrBr
LiLi
Br2, Tl(III)Br2, Tl(III)
n-BuLibetter p- vs o-regioselectivity
n-BuLibetter p- vs o-regioselectivity
n-BuLi,TMEDA
more convenient
n-BuLi,TMEDA
more convenient
Introduction of functional groups
Li
SCH3
OHPPh2
CO2H
i. O2ii. H–
i. CO2ii. H+
CH3SSCH3
ClPPh2
LiLi
SCH3SCH3
OHOHPPh2PPh2
CO2HCO2H
i. O2ii. H–i. O2ii. H–
i. CO2ii. H+i. CO2ii. H+
CH3SSCH3CH3SSCH3
ClPPh2ClPPh2
For leading references on resin preparations, see the review byFréchet: Tetrahedron 1981, 37, 663.
For leading references on resin preparations, see the review byFréchet: Tetrahedron 1981, 37, 663.
Structure of resins
OH
OH
OH
OH
HO
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2CH2Cl2
CH2Cl210 - 200 μmResin Bead
a few AngstromsBead Section
Structure of a resin bead......
OHOH
OHOH
OHOH
OHOH
HOHO
CH2Cl2CH2Cl2
CH2Cl2CH2Cl2
CH2Cl2CH2Cl2
CH2Cl2CH2Cl2
CH2Cl2CH2Cl2
CH2Cl2CH2Cl2CH2Cl2CH2Cl2
CH2Cl2CH2Cl210 - 200 μm10 - 200 μmResin BeadResin Bead
a few Angstromsa few AngstromsBead SectionBead Section
Structure of a resin bead......Structure of a resin bead......Schematic representation of a macroporous solid-phase supportSchematic representation of a macroporous solid-phase supportSchematic representation of a macroporous solid-phase support
Cl NH2 OH
Br
HOH
O O
Commercially available functional groups grafted onto PS resins
ClCl NH2NH2 OHOH
BrBr
HOHOH
O O
Commercially available functional groups grafted onto PS resinsCommercially available functional groups grafted onto PS resins
Mesh size
Tentagel
PEG-Polystyrene graft polymers
‘Swollen’ state : Permeable to solvent and reagent
‘Shrunken’ state
Swelling of Polymer by Solvent
Swelling properties
Swelling properties of resins
90 μm (TentaGel)0.75 mmol/ g350 pmol/ beadCa. 180 ng/ bead
200 μm (PS)1.05 mmol/ g4 nmol/ beadCa. 2 μg/ bead
500 μm (PS)1.05 mmol/ g60 nmol/ bead
Ca. 30 μg/ bead
Diffusion Efficiency
Practical Considerations in Choosing a Solid Support
• Mode of attachment and cleavage of materials from the resin (linker)
• Compatibility of the chemistry planned for the library synthesis
• The amount of material desired (loading level)
• Size - affects efficiency of diffusion within the polymer (reaction rates!)
• A linker covalently connects molecules to the solid support, and should provide a means for their chemical attachment and cleavage
• Stability of the linker affects the scope of the chemistry that can be employed in the library synthesis
• Many linkers are adapted from protecting group chemistry
Resin Linker
XAttachment
Resin Linker Molecule
Synthetic Steps
Resin Linker Molecule
Cleavage
Molecule
2. Linkers
General structure
Cleavage conditions
Acid-labile benzylalcohol anchors
Amide linkers
Linkers
Benzylic linkers
X= H, Wang linker:
X= OMe, Sasrin linker:
Sieber linker:
Acid Labile Linkers
• Many historically important resins (Merrifield, Wang, Sasrin, Sieber, Rink resins) have linkers that are cleaved under acidic conditions
• Acidic conditions were intended to prevent racemization of amino acids during solid phase peptide synthesis
O
O R
OX
O
NH
R
OO
O
HO R
H2N R
O1-3% TFA
CH2Cl2
CH2Cl2
50% TFA
Linkers
Cleavage by nucleophiles
Catch and release
Nucleophile Labile Linkers
Kaiser Oxime linker
• Advantage: Introduction of diversity in cleavage step
• Difficulty: Often too reactive for common nucleophilic reaction conditions
NO
NO2
R
O
R1 NH2
R1
HN R
O
Linkers
Internal nucleophilic cleavage
Linkers
„Traceless“ linkers
• This type of linker creates a C-C or a C-H bond at the site of cleavage– C-H bond generation : Si-Ge linker (protonolysis or radical reduction)
– C-C bond generation
Ellman J. et al. JOC, 1995, 60, 6006.
Traceless Linkers
Si
NHBn NHBn
H
r.t.
TFA
O
HO
O OR O
N
S Ru
PCy3
PhPCy3Cl
Cl
HO
O OR O
N
S
cat.
Olefin metathesis
Nicolaou KC et al. ACIEE, 1997, 36, 2097.
Ellman J. et al. JACS, 1996, 118, 3055.
Safety-catch linker
Kenner’s sulfonamide linker
• A “safety-catch” linker can solve the reactivity problem with a two step cleavage
• 1) An activation step that is orthogonal to common functional groups
• 2) Cleavage of the activated linker under mild conditions
SNH
R'
O O OS
N R'
O O O
R' NH
O
activation cleavageVery stable
NBr
iPr2NEt, DMSO CN
dilute BnNH2
Bn
Alkylsilyl Linker - Fluoride Labile
Ellman J. et al. JOC, 1997, 62, 6102. Foley MA et al. J. Comb. Chem. 2001, 3, 312.
**
Si
MeMeMe
Me
OMe *
Si
MeMeMe
Me
OMe
Si
MeMeMe
Me
O NHFmoc
*
HO NHFmoc
Br
HO NHFmoc
Tl(OAc)3
Br2/ CH2Cl2
1 % DVB-CL-PS500- 560 um
96 %
127 nmol/ bead
cat. Pd(PPh3)4
NaOH, THF, 40 h
98 %124 nmol/ bead
6.0 eq. TfOH2.0 eq. 2,6-lutidine
1.5 eq.
114 nmol/ bead90 %
1. HF-pyr. THF
2. TMSOMe
B
• Mild cleavage conditions compatible with various functional groups• Designed for attachment through an alcohol
• Compatibile with strong anionic, cationic, oxidative, and reductive conditions
Krafft GA et al. JACS, 1988, 110, 301.
Photo-labile linker
• Photolytic conditions can be very mild and selective
• Dimerization of the support-bound nitroso by-product sometimes hampers further cleavage
• Aryl nitro group is incompatible with some organometallic chemistry
O
MeO
NO2
Me
O
O
R
HO R
O
O
MeO
N
Me
O
O
hν, 350 nm+
2. Linkers - overview
Linkers Cleaved by Strong Acid
HO R
O
Merrifield Resin
Carbamate resin
HO R
O
PAM resin
H2N R
O
BHA resin
Thioester resin
strong acid
HS R
O
O R
O
O NH
O
R
NH
O O
O
R
NH
R
O
NH
O S
O
R
HF, CF3SO3H
HF
RNH2
CF3SO3H
HF
Linkers Cleaved by Strong AcidLinkers Cleaved by Strong Acid
HOHO R
O
Merrifield ResinMerrifield Resin
Carbamate resinCarbamate resin
HOHO R
O
PAM resinPAM resin
H2NH2N R
O
BHA resinBHA resin
Thioester resinThioester resin
strong acidstrong acid
HSHS R
O
O R
O
O NHNH
O
R
NHNH
O O
O
R
NHNH
R
O
NHNH
O S
O
R
HF, CF3SO3HHF, CF3SO3H
HFHF
RNH2RNH2
CF3SO3HCF3SO3H
HFHF
Linkers Cleaved by Moderate Acid
Rink Amide resin (X = NH)Rink Acid resin (X = O)
TFA/CH2Cl2HX R
O
X R
O
OCH3
H3CO
NH
O
O OCH3
OCH3
HN
O
R
PAL resin
moderate
H2N R
O
acid
O
O R
OWang resin
95% TFA
HO R
O
DHPP resin
O
O
O
H3C CH3
O R
O
moderate
HO R
O
acid
Linkers Cleaved by Moderate AcidLinkers Cleaved by Moderate Acid
Rink Amide resin (X = NH)Rink Acid resin (X = O)Rink Amide resin (X = NH)Rink Acid resin (X = O)
TFA/CH2Cl2TFA/CH2Cl2HXHX R
O
X R
O
OCH3OCH3
H3COH3CO
NHNH
O
O OCH3OCH3
OCH3OCH3
HNHN
O
R
PAL resinPAL resin
moderatemoderate
H2NH2N R
O
acidacid
O
O R
OWang resinWang resin
95% TFA95% TFA
HOHO R
O
DHPP resinDHPP resin
O
O
O
H3CH3C CH3CH3
O R
O
moderatemoderate
HOHO R
O
acidacid
2. Linkers - overview
Linkers Cleaved by Moderate Acid
PAB resin
NH
O
O
Acid-labile carbamate resin
O
Dihydropyran resin
CHA resin
O
O
NH
O
O
O
O
R
moderate acid
HO R
O
O NH
O
R
moderate
acid
O OR
O
NH R
O
moderate
ac id
H2N R
O
CH3OH, Δ
RNH2
ArSO3HROH
Linkers Cleaved by Moderate AcidLinkers Cleaved by Moderate Acid
PAB resinPAB resin
NHNH
O
O
Acid-labile carbamate resinAcid-labile carbamate resin
O
Dihydropyran resinDihydropyran resin
CHA resinCHA resin
O
O
NHNH
O
O
O
O
R
moderate acidmoderate acid
HOHO R
O
O NHNH
O
R
moderatemoderate
acidacid
O OR
O
NHNH R
O
moderate
ac id
H2NH2N R
O
CH3OH, ΔCH3OH, Δ
RNH2RNH2
ArSO3HArSO3HROHROH
NH
O
O
X
(H3C)3Si
SAL resin (X = NH)SAC resin (X = O)
O
RHX R
Omoderate
acidor F–
Silicon-based Resins
SiO
R RR'
Silyl ether resin
moderate acid
or F–R'OH (R, R = Ph, iPr)
Pbs resin
NH
O
O
HN
Si
O
tBuO
R
O
HO R
O
Ramage resin
NH
O
O
O
RHO R
O
Si(CH3)3
F–
F–
NHNH
O
O
X
(H3C)3Si(H3C)3Si
SAL resin (X = NH)SAC resin (X = O)SAL resin (X = NH)SAC resin (X = O)
O
RHXHX R
Omoderatemoderate
acidor F–acidor F–
Silicon-based ResinsSilicon-based Resins
SiSiO
R RR'R'
Silyl ether resinSilyl ether resin
moderate acidmoderate acid
or F–or F–R'OHR'OH (R, R = Ph, iPr)(R, R = Ph, iPr)
Pbs resinPbs resin
NHNH
O
O
HNHN
SiSi
O
tButBuO
R
O
HOHO R
O
Ramage resinRamage resin
NHNH
O
O
O
RHOHO R
O
Si(CH3)3Si(CH3)3
F–
F–F–
2. Linkers - overview
Linkers Cleaved by Weak Acid
XAL resin (Sieber amide resin)
SASRIN resin
O
O
O
O
NH
O
R
H2N R
O
O
O R
O
OCH3 HO R
O
O
O R
Trityl resin (X = H)2-Chlorotrityl resin (X = Cl)
X HO R
O
1% TFA
1% TFA
AcOH
CH2Cl2
CH2Cl2
CH2Cl2
Linkers Cleaved by Weak AcidLinkers Cleaved by Weak Acid
XAL resin (Sieber amide resin)XAL resin (Sieber amide resin)
SASRIN resinSASRIN resin
O
O
O
O
NHNH
O
R
H2NH2N R
O
O
O R
O
OCH3OCH3 HOHO R
O
O
O R
Trityl resin (X = H)2-Chlorotrityl resin (X = Cl)Trityl resin (X = H)2-Chlorotrityl resin (X = Cl)
X HOHO R
O
1% TFA1% TFA
1% TFA1% TFA
AcOHAcOH
CH2Cl2CH2Cl2
CH2Cl2CH2Cl2
CH2Cl2CH2Cl2
Linkers Cleaved by Base or Nucleophiles
NH
O
N
OCH3
O
R R'MgCl
R' R
O
Weinreb amide resin
LAH
H R
O
NH
O
NO2
O
O
Rpiperidine
HO R
O
NPE resin
NH
Fm resin
Opiperidine
HO R
O
NH
HMFA resin
O
OR
O
O
O
Rpiperidine
HO R
O
Linkers Cleaved by Base or NucleophilesLinkers Cleaved by Base or Nucleophiles
NHNH
O
N
OCH3OCH3
O
R R'MgClR'MgCl
R'R' R
O
Weinreb amide resinWeinreb amide resin
LAHLAH
H R
O
NHNH
O
NO2NO2
O
O
Rpiperidinepiperidine
HOHO R
O
NPE resinNPE resin
NHNH
Fm resinFm resin
Opiperidinepiperidine
HOHO R
O
NHNH
HMFA resinHMFA resin
O
OR
O
O
O
Rpiperidinepiperidine
HOHO R
O
2. Linkers - overview
Linkers Cleaved by Base or Nucleophiles
X
O
R
Let's not forget Merrifield resin...
R'OH, base
R'O R
O
LAH
HO R'
X = O, S
Linkers Cleaved by Base or NucleophilesLinkers Cleaved by Base or Nucleophiles
X
O
R
Let's not forget Merrifield resin...Let's not forget Merrifield resin...
R'OH, baseR'OH, base
R'OR'O R
O
LAHLAH
HOHO R'R'
X = O, SX = O, S
NH
NH
S
O
O
O
OR
O O
OR
Finally, a couple derived from early oligo work
NH4OHROH
NH4OHROH
NHNH
NHNH
S
O
O
O
OROR
O O
OROR
Finally, a couple derived from early oligo workFinally, a couple derived from early oligo work
NH4OHNH4OHROHROH
NH4OHNH4OHROHROH
Photocleavable Linkers
NH
O
ONb resin (X = O)Nonb resin (X = NH)
X
NO2
R
O
hν
wet CH3CNHX R
O
NH
Holmes resin (X = O, NH)
O
O
NO2
OCH3
CH3
X R
O
hνHX R
O
O
CH3
O R
O
hνHO R
O
α-Methylphenacyl ester resin
NH
NH
O
Geysen resin
hν
wet CH3CNH2N R
O
Brown, B. B., Wagner, D. S., and Geysen, H. M. (1995). Molecular Diversity 1, 4-12.
RO
NO2
Photocleavable LinkersPhotocleavable Linkers
NHNH
O
ONb resin (X = O)Nonb resin (X = NH)ONb resin (X = O)Nonb resin (X = NH)
X
NO2NO2
R
O
hνhν
wet CH3CNwet CH3CNHXHX R
O
NHNH
Holmes resin (X = O, NH)Holmes resin (X = O, NH)
O
O
NO2NO2
OCH3OCH3
CH3CH3
X R
O
hνhνHXHX R
O
O
CH3CH3
O R
O
hνhνHOHO R
O
α-Methylphenacyl ester resinα-Methylphenacyl ester resin
NHNH
NHNH
O
Geysen resinGeysen resin
hνhν
wet CH3CNwet CH3CNH2NH2N R
O
Brown, B. B., Wagner, D. S., and Geysen, H. M. (1995). Molecular Diversity 1, 4-12.Brown, B. B., Wagner, D. S., and Geysen, H. M. (1995). Molecular Diversity 1, 4-12.
RO
NO2NO2
2. Linkers - overview
"Traceless" Linkers
O
Veber's resin
O Si
O
Showalter's resin
NH
O
Ellman's resin
Janda's resin
O
OSi
RCH3
H3C
R
strong acid
H3C CH3
R
R
strong acid
or F–
Si
iPr iPr
R Rstrong acid
or F–
O
O
NH
CF3
SR
Bu3SnH, AIBN, Δ
or Raney Ni, H2
H R
Janda, et al. (1996). Tetrahedron Letters 37, 6491-6494.
"Traceless" Linkers"Traceless" Linkers
O
Veber's resinVeber's resin
O SiSi
O
Showalter's resinShowalter's resin
NHNH
O
Ellman's resinEllman's resin
Janda's resinJanda's resin
O
OSiSi
RCH3CH3
H3CH3C
R
strong acid
H3CH3C CH3CH3
R
R
strong acidstrong acid
or F–or F–
SiSi
iPriPr iPriPr
R Rstrong acidstrong acid
or F–or F–
O
O
NHNH
CF3CF3
SR
Bu3SnH, AIBN, ΔBu3SnH, AIBN, Δ
or Raney Ni, H2or Raney Ni, H2
H R
Janda, et al. (1996). Tetrahedron Letters 37, 6491-6494.Janda, et al. (1996). Tetrahedron Letters 37, 6491-6494.
Kenner's "safety catch" resin
SNH
O O O
Ri CH2N2
ii HO–HO R
O
SCAL resin
NH
O
O HN
S S
O
H3C
O
CH3
O
R
(CH3)3SiCl, PPh3or
(EtO)2P(S)SHH2N R
OTFA
DSB resin
NH
O
O
S
H3C
CH3
R
O
H3C O
HO R
O
ii TFA
i (CH3)3SiCl, PPh3
Kenner's "safety catch" resinKenner's "safety catch" resin
SNHNH
O O O
Ri CH2N2i CH2N2
ii HO–ii HO–HOHO R
O
SCAL resinSCAL resin
NHNH
O
O HNHN
S S
O
H3CH3C
O
CH3CH3
O
R
(CH3)3SiCl, PPh3or
(EtO)2P(S)SH
(CH3)3SiCl, PPh3or
(EtO)2P(S)SHH2NH2N R
OTFATFA
DSB resinDSB resin
NHNH
O
O
S
H3CH3C
CH3CH3
R
O
H3CH3C O
HOHO R
O
ii TFAii TFA
i (CH3)3SiCl, PPh3i (CH3)3SiCl, PPh3
3. Analytical techniques
Off bead analysis
• Cleavage, then use of conventional analytical techniques (e.g. LC, MS, NMR)• Requires high sensitivity and high throughput format
Example: LC-UV/ MSS
OH OH
N
O
HOPh
Ph
Kaiser test
On bead analysis
1) Colorimetric methods, Kaiser test
Kaiser test
On bead analysis
1) Colorimetric methods, Kaiser test
NMR
On bead analysis
2) MAS-NMR ( Magic angle spinning NMR )
Magic angle rotor (left), rotor spinning at the magic angle (right)
OO
Si
O
O
OMe
O
OOO
MAS- NMR spectrum (600 MHz)
Single bead IR
On bead analysis
3) Single-bead FT-IR microspectrometry
O
O
DIC, DMAP, DMFO
O
O OH
HO
O O
Beads in IR cell
Wavelength(cm-1)
4. Peptide Synthesis
Insulin
Protecting groups for -NH2
Benzoyloxycarbonyl groupCarbobenzoxy (Cbo) or Z (Zervas) group
Introduction
Protecting groups for -NH2
Benzoyloxycarbonyl groupCarbobenzoxy (Cbo) or Z (Zervas) group
Cleavage
Protecting groups for -NH2
Tert-Butoxycarbonyl group (Boc)
Introduction
Di-tert-butyl-biscarbonatePyrocarbonate
Protecting groups for -NH2
Cleavage
tert-Butoxycarbonyl group (Boc)
TFA
Protecting groups for -NH2
Introduction: Fmoc-Cl, Fmoc-Suc
Fluorenyl-9-methoxycarbonyl group (Fmoc)
Cleavage
Protecting groups for -COOH
All kinds of esterscleavage
Protecting groups for -COOH
Carboxyl protecting groups which can be activated for coupling
hydrazide carbamate
transform into azide
Protecting groups for side chain functional groups
Guanodinium group
Di-acylation or nitration;No perfect protecting group available
Protecting groups for side chain functional groups
Imidazole
Amino protecting groupsProtection often necessary to increasesolubility.
H
cleavage
Protecting groups for side chain functional groups
Thiole
Strong nucleophile, easily oxidized – must be protected in peptide synthesis.
cleavage
Protecting groups for side chain functional groups
Hydroxy groups
Protection usually not necessary in peptide synthesis. Exceptions: Large excess of amino acid used; solubility reasons
cleavage
Protecting groups for side chain functional groups
Indole, thioether
Protection usually not necessary in peptide synthesis. Caution: Alkylation of thioether by carbenium ion possible
Protecting groups for side chain functional groups
Amides
Protection usually not necessary in peptide synthesis. Exception: Amides with solubility problems; cyclization as side reaction
Protecting groups for side chain functional groups
ϖ-Amino- and carboxy groups
Differentiation between α- and ϖ-functional groups necessary
Protecting groups for side chain functional groups
ϖ-Amino- and carboxy groups
Special topic: Photocleavable protecting groups and linkers
Norrish-type II: ortho-nitrobenzyl alcohols
C. G. Bochet, J. Chem. Soc., Perkin Trans. 1 2002, 125 - 142.
Photocleavable protecting groups
Norrish-type II: ortho-nitrobenzyl alcohols
C. G. Bochet, J. Chem. Soc., Perkin Trans. 1 2002, 125 - 142.
Photocleavable protecting groups
Norrish-type II: ortho-nitrobenzyl alcohols
Different reaction pathway iffunctional group to be protected islinked in β-position
C. G. Bochet, J. Chem. Soc., Perkin Trans. 1 2002, 125 - 142.
Photocleavable protecting groups
Norrish-type II: ortho-nitrobenzyl alcohols
Protecting group for ketones:
Photocleavable protecting groups
Norrish-type II: ortho-nitrobenzyl alcohols
Array synthesis:
Photocleavable protecting groups
Norrish-type II: Phenacyl esters
Protection of acids.Fast release trigger forbiological stimulants.
C. G. Bochet, J. Chem. Soc., Perkin Trans. 1 2002, 125 - 142.
RO
OH
Photocleavable protecting groups
Norrish-type II: Phenacyl esters
Photolabile linkers and resins
F. Guiller, D. Orain, M. Bradley, Chem. Rev. 2000, 100, 2091 - 2157.
Photocleavable linkers
F. Guiller, D. Orain, M. Bradley, Chem. Rev. 2000, 100, 2091 - 2157.
C. G. Bochet, J. Chem. Soc., Perkin Trans. 1 2002, 125 - 142.
Current developments
Selective deprotectionby light of differentwavelength
M. Kessler, R. Glatthar, B. Giese, C.G. Bochet, Org. Lett. 2003, 5, 1179 - 1181.
Current developments
M. Kessler, R. Glatthar, B. Giese, C.G. Bochet, Org. Lett. 2003, 5, 1179 - 1181.
Current developments
Selective deprotectionby light of differentwavelength
M. Kessler, R. Glatthar, B. Giese, C.G. Bochet, Org. Lett. 2003, 5, 1179 - 1181.
Current developments
Coupling methods
Azide coupling: No racemization, but very slow
Coupling methods
Anhydride and mixed anhydride method
Wrong way !
Coupling methods
sym anhydride method
Maximum yield: 50 % !
Coupling methods
N-Carboxylic acid anhydride method
1,3-Oxazolidin-2,5-dione
Peptide synthesis in aqueoussolution
Repeat steps
Coupling methods
Carbodiimide method (DCC, EDC)
DCC in situ activeEster formation withadditives
Coupling methods
Active esters
Synthesis of cyclic peptides
PFP esterring closure
Coupling methods
Active ester: 8-Chinolyl ester as internal base
Coupling methods
In situ formation of active esters
Expensive reagents !
Coupling methods
Segment coupling – native chemical ligation
Coupling methods
Segment coupling – native chemical ligation
Synthesis of interleukin 8(IL-8)
Solution synthesis of large peptides
Sakakibara strategy: Pac = Phenylacyl ester; WSCI = water soluble carbodiimide
Solution synthesis of large peptides
Sakakibara strategy: How far can we go?
Purification and characterisation of peptides
Typical analytical methods
Solid phase synthesis protocols
Merrifield synthesis
PAM anchor group
PAM anchor
Automated peptide synthesis
Protecting group tactics
Boc/Bzl
MBHA = p-methyl benzhydrylamide anchor
Protecting group tactics
Fmoc/tBu
Anchor groups in solid phase peptide synthesis
cleavage
Racemization during peptide synthesis
Enol formation
Racemization during peptide synthesis
Oxazolonmechanism
Racemization during peptide synthesis
Coupling reagents
Biochemical peptide synthesis
Transformation ofmRNA into DNA
Biochemical peptide synthesis
Schematic procedurefor preparationof recombinant proteins
Biochemical peptide synthesis
Recombinant proteinsIn medicinal chemistry
5. Oligonucleotides
Nucleotides
Nucleosides
Phosphorylated Nucleosides
Oligonucleotide
DNA double strand – B DNA
DNA double strand – A DNA
Physical parameters of nucleobases
Tautomeres ?
Watson – Crick Basenpairing
C - G T - A
Reversed Watson – Crick Basepairing
Wooble Basenpairing
T - A
U - G
Shifted by oneposition
Hoogsteen Basenpairing
A - T A - T
Watson-Crickhydrogen bondacceptor site
Oligonucleotide Synthesis
Synthesis of nucleosides
Route A
Route A – Hilbert Johnson reaction
Route A – Hilbert Johnson reaction
Route A – Silyl Hilbert Johnson reaction
Route A – Silyl Hilbert Johnson reaction
reactions at differentpositions possible
Route A – Silyl Hilbert Johnson reaction (2nd example)
Route B
Route C – assembly of the nuclobase
Route to a non-naturalFlavin nucleobase
Route C
Pseudo-Uridine
Wyosine
Stereoselective synthesis of α- and β-nucleosides
Selective β-nucleoside synthesis
Stereoselective synthesis of α- and β-nucleosides
β-nucleoside
Stereoselective synthesis of α- and β-nucleosides
Selective α-nucleoside synthesis
Synthesis of nucleotides and oligonucleotides
Chemistry of phosphoric and phosphinic acid esters
Hydrolysis of phosphoric acid triesters
Hydolysis of phosphoric acid triesters
Synthesis of phosphoric acid esters
Phosphoramidite route
H-Phosphonate route
Automated DNA synthesis
First nucleotide in DNA synthesis
Automated DNA synthesis
Each nucleotide addition requires four steps1. Detritylation2. Activation and Coupling3. Capping4. Oxidation
Repeat steps for next nucleotide
Phosphoramidite
Detritylation
The dimethoxy-trityl protecting group of the 5´-OH group needs to be removed, so that the next base can be added. Trichloroacetic acid (TCA) is used as reagentfor cleavage.
Activation and coupling
Protonation activates the leaving group
Activation and coupling
Capping
To prevent uncoupled nucleotides from reacting in the next step, which leadsto wrong sequence
Oxidation
How far can we go ?
DNA synthesis: 100 nanomole scale*
Nominal charge, couldbe as low as US $ 3.00 (see "S&H")
US $ 0.29 per base, no setup fee
All other countries
From CAN $ 1.00 to CAN $ 18 (see "S&H")
CAN $ 0.39 per base, no setup fee
Canada
From US $ 1.00 to US $ 18.00 (see "S&H")
US $ 0.29 per base, no setup fee
USA
Shipping and handlingPrice per base**(no setup fee!)
Customer'scountry
*Only customers with accounts in good standing are eligible for this scale. All orders at the 100 nmole scale must be placedusing our special order form in Microsoft Excel format, please e-mail us your request. 100 nmole (0.1 micromole) synthesisscale will yield typically 0.040-0.150 micromole (40-150 nmole) final product for a regular size, standard purity oligo.Guaranteed minimum 40 nmole for regular size (up to 25-mer) oligos, standard purity (desalted). For longer oligos, 9 OD260 guaranteed minimum (standard purity). Standard purity includes free desalting. All oligos are quantified and three different units of measure are provided to the customer. The relation between these three units is calculated by a computer, but as an approximation for a 20 base long oligo, 50 nmole equals approx. 10 OD260 units or 300 microgram.
**Oligos longer than 35 bases, which are ordered without additional purification, will be supplied with no replacementwarranty.
Commercial suppliers
Synthesis of a synthetic gene
Synthesis of a synthetic gene
Synthesis of a synthetic gene
Washington Post, July 17, 2002
Synthesis of phosphate monoesters
Pyrophosphates of biological relevance
Synthesis of pyrophosphates
Biochemical methods - The principle of PCR
Denaturation at 94°C
Annealing at 54°C
The three major steps:
Extension at 72°C
Biochemical methods - The principle of PCR
Biochemical methods - The principle of PCR
Use of PCR in in vitro random selection
DNA strand
known sequencerandom sequence
SELEX = systematic evolution of ligands by experimental enrichtment
Use of PCR in in vitro random selection
Aptamere
Intramere
Ribozyme
Aptamere
Didesoxy DNA sequencing
DNA strand to be sequenced
template strand, labeled with 32P
reaction vessel withdidesoxythymidine-5´-triphosphate
reaction vessel withdidesoxycytidine-5´-triphosphate
Didesoxy DNA sequencing
Long oligo´s5´
Short oligo´s3´
Yellow = CGreen = GRed = TBlue = A
Didesoxy DNA sequencing
DNA chips
in complexmixture
6. Sugars
Protecting groups in carbohydrate synthesis
Protecting groups in carbohydrate synthesis
Transglycosylation
Transglycosylation
OR
OR
Trichloroacetamidate activation
Thermodynamic controlled reaction:α-anomere; anomeric effect
Kinetically controlled reaction:β-anomere
R.R. Schmidt, W. Kinzy, Adv, Carbohydr. Chem. Biochem. 1994, 50, 21.
Thioglycosides
Activation of a protected glycoside
Oligosaccharide synthesis
Segement synthesis and coupling
Oligosaccharide synthesis
Examples of Solid phase oligosaccharide synthesis
Danishefsky's Strategies for SPS of Oligosaccharides - Cartoon Form
Danishefsky, et al. (1995). A Strategy for a Convergent Synthesis of N-LinkedGlycopeptides on a Solid Support. Science 169, 202 - 204.
Danishefsky, et al. (1995). Major Simplifications in Oligosaccharide SynthesesArising from a Solid-Phase Based Method: An Application to the Synthesis ofthe Lewis b Antigen. Journal of the American Chemical Society 117, 5712 -5719.
Danishefsky's Strategies for SPS of Oligosaccharides - Cartoon FormDanishefsky's Strategies for SPS of Oligosaccharides - Cartoon Form
Danishefsky, et al. (1995). A Strategy for a Convergent Synthesis of N-LinkedGlycopeptides on a Solid Support. Science 169, 202 - 204.
Danishefsky, et al. (1995). Major Simplifications in Oligosaccharide SynthesesArising from a Solid-Phase Based Method: An Application to the Synthesis ofthe Lewis b Antigen. Journal of the American Chemical Society 117, 5712 -5719.
Danishefsky, et al. (1995). A Strategy for a Convergent Synthesis of N-LinkedGlycopeptides on a Solid Support. Science 169, 202 - 204.
Danishefsky, et al. (1995). Major Simplifications in Olig
Danishefsky, et al. (1995). A Strategy for a Convergent Synthesis of N-LinkedGlycopeptides on a Solid Support. Science 169, 202 - 204.
Danishefsky, et al. (1995). Major Simplifications in Oligosaccharide SynthesesArising from a Solid-Phase Based Method: An Application to the Synthesis ofthe Lewis b Antigen. Journal of the American Chemical Society 117, 5712 -5719.
O
O
PO
PO
O
O
PO
PO
O
OHO
PO
PO
O
O
PO
PO HO
O
O
PO
PO
O
O
PO
PO HO
O
O
PO
PO
O
O
O
PO
PO HO
O
O
PO
PO OH
O
O
OP
PO
OPO
PO
HOEtc.
O
O
POPO
POPO
O
O
POPO
POPO
O
OHOHO
POPO
POPO
O
O
POPO
POPO HOHO
O
O
POPO
POPO
O
O
POPO
POPO HOHO
O
O
POPO
POPO
O
O
O
POPO
POPO HOHO
O
O
POPO
POPO OHOH
O
O
OPOP
POPO
OPOPO
POPO
HOHOEtc.Etc.
Si(iPr)2Cl
Home-madepolystyrenederivative
OO
O
O
OO
O
O
OH
Si
OO
O
O
O
iPriPr
CH2Cl2, iPr2NEtDMAP
OO
H3C
CH3
Si
OO
O
O
O
iPriPr
O
H
H
OO
O
O
OH
ZnCl2, THF
Si
O
iPriPr
O
O
O
O
HO OO
O
O
Si
O
iPriPr
O
O
O
O
HO
OO
H3C
CH3
O
H
H
OO
O
O
OH
ZnCl2, THF
OO
H3C
CH3
OO
Si(iPr)2ClSi(iPr)2Cl
Home-madepolystyrenederivative
Home-madepolystyrenederivative
OO
O
O
OO
O
O
OHOH
SiSi
OO
O
O
O
iPriPriPriPr
CH2Cl2, iPr2NEtDMAP
CH2Cl2, iPr2NEtDMAP
OO
H3CH3C
CH3CH3
SiSi
OO
O
O
O
iPriPriPriPr
O
H
H
OO
O
O
OHOH
ZnCl2, THFZnCl2, THF
SiSi
O
iPriPriPriPr
O
O
O
O
HOHO OO
O
O
SiSi
O
iPriPriPriPr
O
O
O
O
HOHO
OO
H3CH3C
CH3CH3
O
H
H
OO
O
O
OHOH
ZnCl2, THFZnCl2, THF
OO
H3CH3C
CH3CH3
OO
Si
O
iPriPr
O
O
O
O
HOO
O
O
O
O
HOO
O
O
O
O
1) DMDO, DCM
2) ZnCl2, THF
OO
OPh
HO
Si
O
iPriPr
O
O
O
O
HOO
O
O
O
O
HOO
O
O
O
O
OH
OO
OPh
O
1) DMDO, DCM
2) ZnCl2, THF
OO O
OHBnO
BnO
OBn BnO
OBn
Si
O
iPriPr
O
O
O
O
HOO
O
O
O
O
HOO
O
O
O
O
OH
OO
OPh
O
OO O
OBnO
BnO
OBn BnO
OBnHO
Cleaved from resin by treatmentwith TBAF/AcOH in MeOH
SiSi
O
iPriPriPriPr
O
O
O
O
HOHOO
O
O
O
O
HOHOO
O
O
O
O
1) DMDO, DCM1) DMDO, DCM
2) ZnCl2, THF2) ZnCl2, THF
OO
OPhPh
HOHO
SiSi
O
iPriPriPriPr
O
O
O
O
HOHOO
O
O
O
O
HOHOO
O
O
O
O
OHOH
OO
OPhPh
O
1) DMDO, DCM1) DMDO, DCM
2) ZnCl2, THF2) ZnCl2, THF
OO O
OHOHBnOBnO
BnOBnO
OBnOBn BnOBnO
OBnOBn
SiSi
O
iPriPriPriPr
O
O
O
O
HOHOO
O
O
O
O
HOHOO
O
O
O
O
OHOH
OO
OPhPh
O
OO O
OBnOBnO
BnOBnO
OBnOBn BnOBnO
OBnOBnHOHO
Cleaved from resin by treatmentwith TBAF/AcOH in MeOHCleaved from resin by treatmentwith TBAF/AcOH in MeOH
OH
Solid-Phase Synthesis of a Heptasaccharide Phytoalexin Elicitor
OO
NO2
OO
Nicolaou, et al. (1997). A General and Highly Efficient Solid Phase Synthesis ofOligosaccharides. Total Synthesis of a Heptasaccharide Phytoalexin Elicitor.Journal of the American Chemical Society 119, 449 - 450.
OBzBzO
BzO
OTDS
Home-made polystyrenederivative
OO
OBzBzO
BzO
OTDS
OHO
OBzBzO
BzO
OTDS
hν, THF
95%
CsCO3, DMF
> 90% by mass gain
O
OH
HOHO
HO
OHO
OH
HOHO
O O
OHHO
OO
OH
HOHOHO
O O
OH
HOHO
O O
OHHO
O
OO
OH
HOHOHO
I
O
O2N
An example utilizing thioglycoside donors.........
OHOH
Solid-Phase Synthesis of a Heptasaccharide Phytoalexin ElicitorSolid-Phase Synthesis of a Heptasaccharide Phytoalexin Elicitor
OO
NO2NO2
OO
Nicolaou, et al. (1997). A General and Highly Efficient Solid Phase Synthesis ofOligosaccharides. Total Synthesis of a Heptasaccharide Phytoalexin Elicitor.Journal of the American Chemical Society 119, 449 - 450.
Nicolaou, et al. (1997). A General and Highly Efficient Solid Phase Synthesis ofOligosaccharides. Total Synthesis of a Heptasaccharide Phytoalexin Elicitor.Journal of the American Chemi
Nicolaou, et al. (1997). A General and Highly Efficient Solid Phase Synthesis ofOligosaccharides. Total Synthesis of a Heptasaccharide Phytoalexin Elicitor.Journal of the American Chemical Society 119, 449 - 450.
OBzOBzBzOBzO
BzOBzO
OTDSOTDS
Home-made polystyrenederivative
Home-made polystyrenederivative
OO
OBzOBzBzOBzO
BzOBzO
OTDSOTDS
OHOHO
OBzOBzBzOBzO
BzOBzO
OTDSOTDS
hν, THFhν, THF
95%95%
CsCO3, DMFCsCO3, DMF
> 90% by mass gain> 90% by mass gain
O
OHOH
HOHOHOHO
HOHO
OHOHO
OHOH
HOHOHOHO
O O
OHOHHOHO
OO
OHOH
HOHOHOHOHOHO
O O
OHOH
HOHOHOHO
O O
OHOHHOHO
O
OO
OHOH
HOHOHOHOHOHO
I
O
O2NO2N
An example utilizing thioglycoside donors.........An example utilizing thioglycoside donors.........
O
O
OBzBzO
BzO
OTBDPS
OOAc
OAcAcO
AcO
OAc
OSPh
OAcAcO
AcO
OAcO
SPhOBz
BzOBzO
OTBDPS
OSPh
OBzFmocOBnO
OTBDPSThe Monomers
i. HF•Py, THF
ii. DMTST, 4AMS, Aiii. NEt3, CH2Cl2
O
O
OBzBzO
BzO
O
OOBz
HOBnO
OTBDPS
i. DMTST, 4AMS, B
ii. HF•Py, THF
O
OBzBzO
BzO
O
O
OBz
BnOO
O
OAcAcO
AcOAcO
i. DMTST, 4AMS, C
ii. HF•Py, THF
OH
The Iterative HPE Synthesis
O
NO2
O
O
NO2
O
O
NO2
O
A
B
C
O
O
OBzOBzBzOBzO
BzOBzO
OTBDPSOTBDPS
OOAcOAc
OAcOAcAcOAcO
AcOAcO
OAcOAc
OSPhSPh
OAcOAcAcOAcO
AcOAcO
OAcOAcO
SPhSPhOBzOBz
BzOBzOBzOBzO
OTBDPSOTBDPS
OSPhSPh
OBzOBzFmocOFmocOBnOBnO
OTBDPSOTBDPSThe MonomersThe Monomers
i. HF•Py, THFi. HF•Py, THF
ii. DMTST, 4AMS, Aiii. NEt3, CH2Cl2
ii. DMTST, 4AMS, Aiii. NEt3, CH2Cl2
O
O
OBzOBzBzOBzO
BzOBzO
O
OOBzOBz
HOHOBnOBnO
OTBDPSOTBDPS
i. DMTST, 4AMS, Bi. DMTST, 4AMS, B
ii. HF•Py, THFii. HF•Py, THF
O
OBzOBzBzOBzO
BzOBzO
O
O
OBzOBz
BnOBnOO
O
OAcOAcAcOAcO
AcOAcOAcOAcO
i. DMTST, 4AMS, Ci. DMTST, 4AMS, C
ii. HF•Py, THFii. HF•Py, THF
OHOH
The Iterative HPE SynthesisThe Iterative HPE Synthesis
O
NO2NO2
O
O
NO2NO2
O
O
NO2NO2
O
A
B
C
O
OBzBzO
BzO
O
O
OBz
BnOO
O
OAcAcO
AcOAcO
O
OOBz
BzOBzO
OH
i. DMTST, 4AMS, A
ii. NEt3, CH2Cl2
O
OBzBzO
BzO
O
O
OBz
BnOO
O
OAcAcO
AcOAcO
O
OOBz
BzOBzO
O
OOBz
HOBnO
OTBDPS
i. DMTST, 4AMS, B
ii. HF•Py, THF
O
OBzBzO
BzO
O
O
OBz
BnOO
O
OAcAcO
AcOAcO
O
OOBz
BzOBzO
O
OOBz
BnO
OH
OO
OAcAcO
AcO
OAc
DMTST, 4AMS, B
O
NO2
O
O
NO2
O
O
NO2
OO
OBzOBzBzOBzO
BzOBzO
O
O
OBzOBz
BnOBnOO
O
OAcOAcAcOAcO
AcOAcOAcOAcO
O
OOBzOBz
BzOBzOBzOBzO
OHOH
i. DMTST, 4AMS, Ai. DMTST, 4AMS, A
ii. NEt3, CH2Cl2ii. NEt3, CH2Cl2
O
OBzOBzBzOBzO
BzOBzO
O
O
OBzOBz
BnOBnOO
O
OAcOAcAcOAcO
AcOAcOAcOAcO
O
OOBzOBz
BzOBzOBzOBzO
O
OOBzOBz
HOHOBnOBnO
OTBDPSOTBDPS
i. DMTST, 4AMS, Bi. DMTST, 4AMS, B
ii. HF•Py, THFii. HF•Py, THF
O
OBzOBzBzOBzO
BzOBzO
O
O
OBzOBz
BnOBnOO
O
OAcOAcAcOAcO
AcOAcOAcOAcO
O
OOBzOBz
BzOBzOBzOBzO
O
OOBzOBz
BnOBnO
OHOH
OO
OAcOAcAcOAcO
AcOAcO
OAcOAc
DMTST, 4AMS, BDMTST, 4AMS, B
O
NO2NO2
O
O
NO2NO2
O
O
NO2NO2
O
O
OAcAcO
AcO
OAc
O
OBzBzO
BzO
O
OOBz
BnOO O
OAcAcO
AcOAcO
O
OOBz
BzOBzO
O
OOBz
BnO
O
OO
OAcAcO
AcOAcO
i. hν, THF
ii. Ac2O, NEt3
O
OAcAcO
AcO
OAc
OAcO
OBzBzO
BzO
O
OOBz
BnOO O
OAcAcO
AcOAcO
O
OOBz
BzOBzO
O
OOBz
BnO
O
OO
OAcAcO
AcOAcO
ca. 20% overall fromfirst resin-bound sugar!
protected solid-phaseoligosaccharide
i. hν, THF
ii. NaOCH3, CH3OHiii. H2, Pd, CH3OH
95% for two steps
O
NO2
O
O
OAcOAcAcOAcO
AcOAcO
OAcOAc
O
OBzOBzBzOBzO
BzOBzO
O
OOBzOBz
BnOBnOO O
OAcOAcAcOAcO
AcOAcOAcOAcO
O
OOBzOBz
BzOBzOBzOBzO
O
OOBzOBz
BnOBnO
O
OO
OAcOAcAcOAcO
AcOAcOAcOAcO
i. hν, THFi. hν, THF
ii. Ac2O, NEt3ii. Ac2O, NEt3
O
OAcOAcAcOAcO
AcOAcO
OAcOAc
OAcOAcO
OBzOBzBzOBzO
BzOBzO
O
OOBzOBz
BnOBnOO O
OAcOAcAcOAcO
AcOAcOAcOAcO
O
OOBzOBz
BzOBzOBzOBzO
O
OOBzOBz
BnOBnO
O
OO
OAcOAcAcOAcO
AcOAcOAcOAcO
ca. 20% overall fromfirst resin-bound sugar!ca. 20% overall fromfirst resin-bound sugar!
protected solid-phaseoligosaccharide
protected solid-phaseoligosaccharide
i. hν, THFi. hν, THF
ii. NaOCH3, CH3OHiii. H2, Pd, CH3OHii. NaOCH3, CH3OHiii. H2, Pd, CH3OH
95% for two steps95% for two steps
O
NO2NO2
O
2) Strategies Utilizing Support-Bound Acceptors
O
Glycosyl sulfoxides
S
PivO
PivO
PivO
OH
O
O
PivO
PivO
PivO
OTr
SPh
O
Tf2O, DTBMP-78 to -60 oC
OS
PivO
PivO
PivO O
O
PivO
PivO
PivO
OTr
O
1. TFA
2.
O
PivO
PivO
PivO
OTr
SPh
O
Tf2O, DTBMP-78 to -60 oC
OS
PivO
PivO
PivO O
O
PivO
PivO
PivO
O
O
PivO
PivO
PivO
OTr
O
Cleavage from resinachieved with:
Hg(OCOCF3)2, water,RT, 5 h> 50 % overall yield
> Coupling efficiency believedto exceed 90%; resin cleavage ~70-75%
Yan, L.; Taylor, C. M.; Goodnow, R.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 6953.
2) Strategies Utilizing Support-Bound Acceptors2) Strategies Utilizing Support-Bound Acceptors
O
Glycosyl sulfoxidesGlycosyl sulfoxides
S
PivOPivO
PivOPivO
PivOPivO
OHOH
O
O
PivOPivO
PivOPivO
PivOPivO
OTrOTr
SPhPh
O
Tf2O, DTBMP-78 to -60 oCTf2O, DTBMP-78 to -60 oC
OS
PivOPivO
PivOPivO
PivOPivO O
O
PivOPivO
PivOPivO
PivOPivO
OTrOTr
O
1. TFA1. TFA
2.2.
O
PivOPivO
PivOPivO
PivOPivO
OTrOTr
SPhPh
O
Tf2O, DTBMP-78 to -60 oCTf2O, DTBMP-78 to -60 oC
OS
PivOPivO
PivOPivO
PivOPivO O
O
PivOPivO
PivOPivO
PivOPivO
O
O
PivOPivO
PivOPivO
PivOPivO
OTrOTr
O
Cleavage from resinachieved with:
Hg(OCOCF3)2, water,RT, 5 h
Cleavage from resinachieved with:
Hg(OCOCF3)2, water,RT, 5 h> 50 % overall yield
> Coupling efficiency believedto exceed 90%; resin cleavage ~70-75%
> 50 % overall yield> Coupling efficiency believed
to exceed 90%; resin cleavage ~70-75%
Yan, L.; Taylor, C. M.; Goodnow, R.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 6953.Yan, L.; Taylor, C. M.; Goodnow, R.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 6953.
Kahne, D., et al. (1996). Parallel Synthesis and Screening of a Solid PhaseCarbohydrate Library. Science 274, 1520 - 1522.
OO
O
OH
HO
OH OHOH
OH NHAc
OHThe known antigen for Bauhinia purpurea lectin:
NH2 PEG-PS(Tentagel) HOBt, HBTU, NMP
S O
O
HN
AcO OO
O
N3
S O CO2H
Ph
HOO
OO
N3
Ph
O
PivO
PivO
OPiv
PivO
OS
PivO
PivO
OPiv
PivOPh
O
TfOH, THF, –65 °C
S O
O
HN
OO
OO
N3
Ph
i. P(CH3)3, THFii. AcCl, NEt3,
CH2Cl2
iii. 20% TFA/CH2Cl2iv. LiOH, THF,
CH3OH
OO
O
OH
HO
OH OHOH
OH NHAc
S O
O
HN
Combinatorial Synthesis of a Disaccharide Library
H2NNH2
DMF
Kahne, D., et al. (1996). Parallel Synthesis and Screening of a Solid PhaseCarbohydrate Library. Science 274, 1520 - 1522.
Kahne, D., et al. (1996). Parallel Synthesis and Screening of a Solid PhaseCarbohydrate Library. Science 274, 1520 - 1522.
OO
O
OHOH
HOHO
OHOH OHOHOHOH
OHOH NHAcNHAc
OHOHThe known antigen for Bauhinia purpurea lectin:The known antigen for Bauhinia purpurea lectin:
NH2NH2 PEG-PS(Tentagel)PEG-PS
(Tentagel) HOBt, HBTU, NMPHOBt, HBTU, NMP
S O
O
HNHN
AcOAcO OO
O
N3N3
S O CO2HCO2H
PhPh
HOHOO
OO
N3N3
PhPh
O
PivOPivO
PivOPivO
OPivOPiv
PivOPivO
OS
PivOPivO
PivOPivO
OPivOPiv
PivOPivOPhPh
O
TfOH, THF, –65 °CTfOH, THF, –65 °C
S O
O
HNHN
OO
OO
N3N3
PhPh
i. P(CH3)3, THFii. AcCl, NEt3,
CH2Cl2
i. P(CH3)3, THFii. AcCl, NEt3,
CH2Cl2
iii. 20% TFA/CH2Cl2iv. LiOH, THF,
CH3OH
iii. 20% TFA/CH2Cl2iv. LiOH, THF,
CH3OH
OO
O
OHOH
HOHO
OHOH OHOHOHOH
OHOH NHAcNHAc
S O
O
HNHN
Combinatorial Synthesis of a Disaccharide LibraryCombinatorial Synthesis of a Disaccharide Library
H2NNH2H2NNH2
DMFDMF
AcO OO
O
N3
SAr
Ph
AcO OO
O
N3SAr
Ph
AcOO
N3SAr
OOPh
AcOO
N3
SArOOPh AcO
ON3
OPMB
OPMB
SAr
AcO OO
O
OPMB
SAr
Ph
OSOPh
PivO
PivO
OPiv
PivO
O
SOPh
PivOPivO
OPiv
OPiv
OSOPh
O
O
OPiv
OPMB
OSOPh
PivOPivO
OPiv
PivO
OO
SOPh
O
O
CH3
N3
O
O SOPhOPiv
PivO
PivOPivO
O SOPhOPiv
H3C
PivON3
O SOPhOPiv
H3C
PivOOPiv
O
SOPh
N3
H3C
OO
O
O
SOPh
OPMBH3C
OO
O
O
PivO
PivO
OPiv
PivO
OSOPhO
PivO
OPiv
PivO
OSOPhPivO
OPiv
PivO
O
O
PivOPivO
OPiv
PivO
Glycosyl donors:
Acylation agents:
Ac2O, iBuCOCl, BuCOCl, PhCOCl, D-Ac-Ala-OH, L-Ac-Ala-OH, MeOCO2Cl
COClCOCl
COCl
O2N
NO2
FI
N CO2HN+ CO2H
O–
S COCl
O OO C NCH3 H3C S Cl
O
O
S C NCH3
OOO
H2C
AcOAcO OO
O
N3N3
SArSAr
PhPh
AcOAcO OO
O
N3N3SArSAr
PhPh
AcOAcOO
N3N3SArSAr
OOPhPh
AcOAcOO
N3N3
SArSArOOPhPh AcOAcO
ON3N3
OPMBOPMB
OPMBOPMB
SArSAr
AcOAcO OO
O
OPMBOPMB
SArSAr
PhPh
OSOPhSOPh
PivOPivO
PivOPivO
OPivOPiv
PivOPivO
O
SOPhSOPh
PivOPivOPivOPivO
OPivOPiv
OPivOPiv
OSOPhSOPh
O
O
OPivOPiv
OPMBOPMB
OSOPhSOPh
PivOPivOPivOPivO
OPivOPiv
PivOPivO
OO
SOPhSOPh
O
O
CH3CH3
N3N3
O
O SOPhSOPhOPivOPiv
PivOPivO
PivOPivOPivOPivO
O SOPhSOPhOPivOPiv
H3CH3C
PivOPivON3N3
O SOPhSOPhOPivOPiv
H3CH3C
PivOPivOOPivOPiv
O
SOPhSOPh
N3N3
H3CH3C
OO
O
O
SOPhSOPh
OPMBOPMBH3CH3C
OO
O
O
PivOPivO
PivOPivO
OPivOPiv
PivOPivO
OSOPhSOPhO
PivOPivO
OPivOPiv
PivOPivO
OSOPhSOPhPivOPivO
OPivOPiv
PivOPivO
O
O
PivOPivOPivOPivO
OPivOPiv
PivOPivO
Glycosyl donors:Glycosyl donors:
Acylation agents:Acylation agents:
Ac2O, iBuCOCl, BuCOCl, PhCOCl, D-Ac-Ala-OH, L-Ac-Ala-OH, MeOCO2ClAc2O, iBuCOCl, BuCOCl, PhCOCl, D-Ac-Ala-OH, L-Ac-Ala-OH, MeOCO2Cl
COClCOClCOClCOCl
COClCOCl
O2NO2N
NO2NO2
FI
N CO2HCO2HN+N+ CO2HCO2H
O–O–
S COClCOCl
O OO C NCH3NCH3 H3CH3C S ClCl
O
O
S C NCH3NCH3
OOO
H2CH2C
3) Bidirectional Glycosylation Strategy
OHOBnO
BnO
SEt
O
HN
O
O
O
O
acceptor bound
OBnOBnO
BnOO CCl3
NH
BnO
TMSOTf
O
BnOBnO
SEt
O
NHO
O
O
O
OBnOBnO
BnO
BnO
O
O
O
O
OH
O
O
NIS/TMSOTfdonor bound
O
BnOBnO
O
NHO
O
O
O
OBnOBnO
BnO
BnO
O
O
O
O
O
O
O
NaOMe, MeOH
O
BnOBnO
OBnOBnO
BnO
BnO
O
O
O
O
O
O
O
HO
3) Bidirectional Glycosylation Strategy3) Bidirectional Glycosylation Strategy
OHOHOBnOBnO
BnOBnO
SEtSEt
O
HNHN
O
O
O
O
acceptor boundacceptor bound
OBnOBnOBnOBnO
BnOBnOO CCl3CCl3
NHNH
BnOBnO
TMSOTfTMSOTf
O
BnOBnOBnOBnO
SEtSEt
O
NHNHO
O
O
O
OBnOBnOBnOBnO
BnOBnO
BnOBnO
O
O
O
O
OHOH
O
O
NIS/TMSOTfNIS/TMSOTfdonor bounddonor bound
O
BnOBnOBnOBnO
O
NHNHO
O
O
O
OBnOBnOBnOBnO
BnOBnO
BnOBnO
O
O
O
O
O
O
O
NaOMe, MeOHNaOMe, MeOH
O
BnOBnOBnOBnO
OBnOBnOBnOBnO
BnOBnO
BnOBnO
O
O
O
O
O
O
O
HOHO
O
OHOBnO
BnO
SEt
O
HN
O
O
O
O
Generation of a small carbohydrate library........Monomers
OHOBnO
BnO
BnOOMe
O
BnOBnO
OHBnO
OMe
O
BnOBnO
HO OBn
OBn
Couple witheach monomer
OTHPOBnO
BnO
O
O
HN
O
O
O
O
OMe
products obtained asmixture of anomers
1. AcOH/H2O
6 compounds total OSEt
BnO OBn
BnO
OBn
NIS/TMSOTf
OOOBnO
BnO
O
O
OMe
O
BnO OBn
BnO
OBn
1. NaOMe
2. H2/Pd
OOOHO
HO
O
OH
OMe
O
HO OBn
HO
OH
OBn
OBn
OH
Boons and Zhu in "Solid Support Oligosaccharide Synthesis andCombinatorial Carbohydrate Libraries," P. Seeburger, ed.; WileyInterscience, New York, pp. 201-211.
O
OHOHOBnOBnO
BnOBnO
SEtSEt
O
HNHN
O
O
O
O
Generation of a small carbohydrate library........Generation of a small carbohydrate library........MonomersMonomers
OHOHOBnOBnO
BnOBnO
BnOBnOOMeOMe
O
BnOBnOBnOBnO
OHOHBnOBnO
OMeOMe
O
BnOBnOBnOBnO
HOHO OBnOBn
OBnOBn
Couple witheach monomer
Couple witheach monomer
OTHPOTHPOBnOBnO
BnOBnO
O
O
HNHN
O
O
O
O
OMeOMe
products obtained asmixture of anomersproducts obtained asmixture of anomers
1. AcOH/H2O1. AcOH/H2O
6 compounds total6 compounds total OSEtSEt
BnOBnO OBnOBn
BnOBnO
OBnOBn
NIS/TMSOTfNIS/TMSOTf
OOOBnOBnO
BnOBnO
O
O
OMeOMe
O
BnOBnO OBnOBn
BnOBnO
OBnOBn
1. NaOMe1. NaOMe
2. H2/Pd2. H2/Pd
OOOHOHO
HOHO
O
OHOH
OMeOMe
O
HOHO OBnOBn
HOHO
OHOH
OBnOBn
OBnOBn
OHOH
Boons and Zhu in "Solid Support Oligosaccharide Synthesis andCombinatorial Carbohydrate Libraries," P. Seeburger, ed.; WileyInterscience, New York, pp. 201-211.
Boons and Zhu in "Solid Support Oligosaccharide Synthesis andCombinatorial Carbohydrate Libraries," P. Seeburger, ed.; WileyInterscience, New York, pp. 201-211.
NH2
Solid-Phase Chemical/Enzymatic Oligosaccharide Synthesis
OO
OSi
NH2
controlled-pore glass
(Gly)6NHBocOO
OSi
HN
HN
O
O
OHN
O
NH
O
NHBoc
O
NHO
OH
NHAcHOHO
HN
O
O
OHN
O
NH
O
NHBoc
Bn O
NHO
NHAcHOOO
OHHO
OH OHOH
β-1,4-galactosyltransferase
PO
P
O–O
O–O
ON
OHHO
NH
O
OOOO
OHHO
OH OH
UDP-Gal
Wong, C.-H., et al. (1994). Solid-Phase Chemical Enzymatic Synthesis ofGlycopeptides and Oligosaccharides. Journal of the American ChemicalSociety 116, 1135 - 1136.
α-2,3-sialyltransferase
PO
O–O
ON
OHHO
N
NH2
OO
HO2C
AcHNHO
HHO
OHHO
CMP-NeuAc
55%
NH2NH2
Solid-Phase Chemical/Enzymatic Oligosaccharide SynthesisSolid-Phase Chemical/Enzymatic Oligosaccharide Synthesis
OO
OSiSi
NH2NH2
controlled-pore glasscontrolled-pore glass
(Gly)6NHBoc(Gly)6NHBocOO
OSiSi
HNHN
HNHN
O
O
OHNHN
O
NHNH
O
NHBocNHBoc
O
NHNHO
OHOH
NHAcNHAcHOHOHOHO
HNHN
O
O
OHNHN
O
NHNH
O
NHBocNHBoc
BnBn O
NHNHO
NHAcNHAcHOHOOO
OHOHHOHO
OHOH OHOHOHOH
β-1,4-galactosyltransferaseβ-1,4-galactosyltransferase
PO
P
O–O–O
O–O–O
ON
OHOHHOHO
NHNH
O
OOOO
OHOHHOHO
OHOH OHOH
UDP-GalUDP-Gal
Wong, C.-H., et al. (1994). Solid-Phase Chemical Enzymatic Synthesis ofGlycopeptides and Oligosaccharides. Journal of the American ChemicalSociety 116, 1135 - 1136.
Wong, C.-H., et al. (1994). Solid-Phase Chemical Enzymatic Synthesis ofGlycopeptides and Oligosaccharides. Journal of the American ChemicalSociety 116, 1135 - 1136.
α-2,3-sialyltransferaseα-2,3-sialyltransferase
PO
O–O–O
ON
OHOHHOHO
N
NH2NH2
OO
HO2CHO2C
AcHNAcHNHOHO
HHOHO
OHOHHOHO
CMP-NeuAcCMP-NeuAc
55%55%
HN
O
O
HN
O
NH
NHBoc
Bn O
NHO
NHAcHOOO
OHO
OH OHOH
HO2C
AcHNHO
HHO
OHHO
α-chymotrypsin
HO
OHN
O
NH
O
NHBoc
Bn O
NHO
NHAcHOOO
OHO
OH OHOH
HO2C
AcHNHO
HHO
OHHO
OH3C
HO OHOH
α-1,3-fucosyltransferase
GDP-Fucose
HO
OHN
O
NH
O
NHBoc
Bn O
NHO
NHAcOOO
OHO
OH OHOH
HO2C
AcHNHO
HHO
OHHO
65%
>95%
35%+ 20% des-NeuAc
+45% starting material
HNHN
O
O
HNHN
O
NHNH
NHBocNHBoc
BnBn O
NHNHO
NHAcNHAcHOHOOO
OHOHO
OHOH OHOHOHOH
HO2CHO2C
AcHNAcHNHOHO
HHOHO
OHOHHOHO
α-chymotrypsinα-chymotrypsin
HOHO
OHNHN
O
NHNH
O
NHBocNHBoc
BnBn O
NHNHO
NHAcNHAcHOHOOO
OHOHO
OHOH OHOHOHOH
HO2CHO2C
AcHNAcHNHOHO
HHOHO
OHOHHOHO
OH3CH3C
HOHO OHOHOHOH
α-1,3-fucosyltransferaseα-1,3-fucosyltransferase
GDP-FucoseGDP-Fucose
HOHO
OHNHN
O
NHNH
O
NHBocNHBoc
BnBn O
NHNHO
NHAcNHAcOOO
OHOHO
OHOH OHOHOHOH
HO2CHO2C
AcHNAcHNHOHO
HHOHO
OHOHHOHO
65%65%
>95%>95%
35%+ 20% des-NeuAc
+45% starting material
35%+ 20% des-NeuAc
+45% starting material
7. Special topic: Immobilization of catalysts
RR
R
P P
PP
P
P
CC
NON-MISCIBLELIQUID PHASES
BIPHASIC SYSTEMS EASIER RECYCLING
CC
R
R
R
RP
P
P
P
P
PP
SEPARATION OF CATALYST?
PURITY OF PRODUCTS
HOMOGENEOUSCATALYST
• Hydrophylic
• Hydrophobic
• Fluorinated
• Ionic liquids
• Supercritical fluids
R
R
R
RP
P
P
P
P
P
PC
C
SOLIDCATALYST
RR
R
P P
PP
P
P
CC
NON-MISCIBLELIQUID PHASES
BIPHASIC SYSTEMS EASIER RECYCLING
CC
R
R
R
RP
P
P
P
P
PP
SEPARATION OF CATALYST?
PURITY OF PRODUCTS
HOMOGENEOUSCATALYST
IMMOBILIZATION METHODS
STRONG INTERACTION WEAK INTERACTION
ML*
ML*
*LM
SUPPORTCOVALENTBOND
ELECTROSTATICINTERACTION SUPPORT
[ML*]+
[ML*]+
[ML*]+
ADSORPTION SUPPORT
[ML*]
[ML*]
[ML*]
[ML*]ENTRAPMENT
TYPES OF SUPPORTS
example
solubilitysolvent
mass transportproblems
separation
number ofanchoring points
linearpolymer
polystyrene (PS)
solubledependent
no
difficult
high
cross-linkedpolymer
PS-DVB (0.5-3%)
swellabledependent
little
filtration
high
highly cross-linkedpolymer
PS-DVB (>5%)
insolubleindependent?
potential
filtration
high
inorganic
silica
insolubleindependent
potential
filtration
high
P X Y C*+ P Z C*
P X Y L*+ P Z L*
M
P X P Precursor
Grafting
Ligand synthesis in solid phase
Polymerisation
R L*(C*)R
IMMOBILISATION BY COVALENT BOND FORMATION(I) ORGANIC POLYMERS
SOLUBLE POLYMER SUPPORTS
HOMOGENEOUSREACTION
Price of membranes
INSOLUBILIZATION OFTHE SUPPORTED CATALYST
ULTRAFILTRATIONSOLUBILIZATION IN
A NON-MISCIBLE PHASE
H2C CH21. Anionic polymerisation
2. CO2
3. Me2SBH3
H(CH2CH2)nCH2OH
NH
COOHO
NH
COOPEO
OCOCHN2
polymeric ligand(PL)
(PL)4Rh2
toluene reflux O
O
Run %yield %ee
1 58 98
3 58 83
7 58 61
RECOVERING BY CENTRIFUGATIONAT ROOM TEMPERATURE
CHANGE OF SOLVENTCHANGE OFTEMPERATURE
IMMOBILISATION OF HYDROGENATION CATALYSTS: POLYMERISATION
CH2CH CH2C
CH3
O0,05 0,85
CH2C
CH3
O
O
O0,10
O
ON
Ph2P
Ph2P
90% e.e.
O
OH
CH2CH
O O
CH2OTsTsOCH2
CH2C
CH3
O
OH
O0,08 0,92
COOH
NHCOMePh
COOH
NHCOMePhMeOH
RH2
TEST REACTION
ACA
CH2CH
O O
CH2PPh2Ph2PCH2
CH2C
CH3
O
OH
O0,08 0,92NaPPh2 CATALYST
[Rh(C2H4)Cl]2
86% e.e.
(homog. 81% e.e.)
reusable in the absence of air
IMMOBILISATION OF HYDROGENATION CATALYSTS: GRAFTING
OO
HN N
O OPS
n
Tentagel (n= 60)Ph2P
PPh2
Rh+(cod)BF4-spacer
PPh2
PPh2
Ru+(cod)
O
HNPS
TEST REACTION
COOMe
O
COOMe
OH
THF/MeOH
R
H2
97% ee(rec. 90% ee)
MeOH: no reaction
EtOH: 90% ee, no reusable
Benzene/MeOH: 97% ee,
reusable once
ACA HYDROGENATION
EXAMPLES OF GRAFTING ONTO POLYMERS: AMINOALCOHOLS
N
OHMe
PS
N
Me
OH
Me Ph
PS
PS N
HO PhPh
N
Ph O
Me Me
OH
R1
R2
P
Merrifield (R1=R2=H): Synthesis in solid phase
up to 69% ee
Barlos (R1=Ph, R2=o-Cl-Ph): Grafting
94% ee
CHOOH
ZnEt2 S
5-10% cat.
TEST REACTION
92% e.e. (S)
80-89% e.e. (R)
96% e.e.
EXAMPLES OF GRAFTING ONTO POLYMERS: Mn(salen)
O
N N
O
Mn
ClOO
OO
P
TEST REACTIONS
M-CPBA, NMO
O
4% catal.-78ºC-rt
P styrene dhnapht
yield %ee yield %ee
MeOPEG 62 57 70 76
NCPS 76 51 69 73
JandaJel 81 51 71 79
Merrifield 61 35 69 78
Me 82 52 75 84
MeOO
OHn
MeO-PEG Ph
OH
n m
NCPS(non-cross-linked PS)
O O
cross-linkerin JandaJel
SYNTHESIS OF THE LIGAND IN SOLID PHASE
OPOH
CHO
tBu
TEST REACTION
M-CPBA, NMO
Ph PhO
Porous PS 61% ee
Gel-type PS 66% ee
Porous polymethacrylate 91% ee
tBu
But
HO
OPOH
tBu
N N
OPOH
tBu
N NH2
tBu
But
O
OPO
tBu
N N
Mn
OAc
POLYMERISATION OF TADDOLS
Catalyst in themain chain
Catalyst in thecross-linking points
TEST REACTION
COR
N O
O O
conv. endo/exo %ee
Ar=Ph 63 87/13 30
Ar=2-napht 92 87/13 56
30 81/19 6
OH
OH
Ar Ar
Ar Ar
O
O
H
2) Ti(OiPr)2Cl2
OH
OH
Ph Ph
O
O
1) styrene/DVBCATALYSTS
[Ru(p-cymene)Cl2]2
[Ir(cod)Cl]2
Support method conv. %ee
TEST REACTION
OTHER CATALYSTS FOR HYDROGEN TRANSFER
Ph
O
Ph
OHiPrOH
KOH
SO2
HN
NH2
Ph
Ph
+Polymerisation
O
NH
P
SO2
HN
NH2
Ph
PhGrafting
PS grafting 88 91
tentagel grafting 9 55
PS polym. 23 84
PS polym. 73 91
OH
OH
O
OM L*
O
OL-M-L*
O
OL*-M-L
IMMOBILISATION BY COVALENT BOND FORMATION (II) INORGANIC SOLIDS
Grafting (ligand or catalyst)
Ligand synthesis in solid phase
“Polymerisation” (sol-gel synthesis)
O
OSi L*-M-L
O
O
OSi L*
O
(RO)3Si L*-M-L
(RO)3Si L*Si(OR)4
Si(OR)4
INORGANIC SUPPORTS FOR COVALENT IMMOBILIZATION
SiOSiO22 quartz
silicaS
• Precipitation (hydrolysis)
• Pyrolysis SiCl4 (vapour)
• Surface area
• Porosity
(size and distribution)
• Silanol density
MESOPOROUS CRYSTALLINE SILICAS
Surfactant(template)
Control of pore size(25-100 Å, narrow distribution)
SiO
O
O
OH SiO
OOH
OHSi
O
O
O
OH
SiO
O
OHisolated geminal
vicinalSi
O
O
O
OSiMe3
"end-capped"
SILANOLGROUPS
GRAFTING THROUGH THE METAL CENTRE
OAl
Et
Cl
Et2AlCl+
(-)-menthol
-50OC
< 15% cat.
CHOCHO
TEST REACTION
+
Enantioselectivity similar to that
obtained with the analogous in
homogeneous phase.
(2 equivalents of menthol are
needed for better selectivities)31% ee
OAl
O
Cl
SILICA
POSSIBILITIES FOR SILICA FUNCTIONALIZATION
OH
OH+ (RO)3Si-R'
O
OSi
OR
R' functionalizedgroup
-(CH2)3-NHR
-(CH2)3-SH-(CH2)3-X (Cl, Br, I)
-(CH2)11-Br
-(CH2)3-NCO
-(CH2)n-CH=CH2 (0 ≤ n ≤ 6)-(CH2)2-Ph
NH2
CH2Cl
SO2Cl
O O
AlkylationImine or amide formation
Reaction with amines or alcohols(formation of secondary amines, ethers, ureas, carbamates, sulfonamides)
AlkylationRadical addition
Radical addition
Aromatic electrophilic substitution
HYDROGENATION CATALYSTS ON SILICA
COOMe
NHCOCH3Ph
COOMe
NHCOCH3Ph
SH2
TEST REACTION S D loading conv (min) % e.e.(m2/g) (nm) (μmol/m2)
310 14 0.18-0.63 100 (20-30) 91.7-93.5
100 (14-23) 92.1-94.5
370 10 0.22 99 (26) 92.5
No interactions between cationic species
(EtO)3SiHN N
O
PPh2
PPh2
a) silica/toluene
b) [Rh(cod)2]BF4
Deactivation with small pores (pore blocking?)
590 4.4 0.31 99 (90) 89.3
33 (114) 86.8
OSi
HN N
O
Ph2P
PPh2
Rh+(cod)BF4-O OEt
DIHYDROXYLATION CATALYSTS ON SILICA
PhPh
PhPh
OH
OH
TEST REACTION
K3[Fe(CN)6]/K2CO3
tBuOH/water
+ OsO4 Loss of Os
Problem of toxicity
77-88% yield99% e.e.
OSi S
O OMe N
N
MeO
OSiS
OMeON
N
OMe
O ONN
OSi
O OMe
O
N
N
NN
OSi
O OMe
O
NN
MeO
O
NN
MeO
O
EPOXIDATION CATALYSTS ON SILICA
Synthesis of the ligandin solid phase
Ph
MCPBA
NMO Ph
O
TEST REACTION
R R
(-78ºC)
R cat. time conv (%) % e.e.
H homog. 45 min 97 84
heterog. 4 h 92 89
Me homog. 45 min 81 43
heterog. 4 h 74 56
O
N N
Mn
O tBu
PhPh
N
Si OMe
O O
Cl
MCM-41
IMMOBILIZATION WITH FORMATION OF THE SUPPORT
O OH
iPrOH
KOHS
TEST REACTION
Low surface area(3-11 m2g-1)
x = 0-3
x time (d) conv (%) % e.e.
homog. 5 95 26
0 5 75 58
1 7 60 10
3 8 20 15
NH
NH
Si(OEt)3
Rh(cod)Cl
Si(OEt)3
NH
NH
Si
Rh(cod)Cl
Si
OO
O
O
OO SILICA
SILICA
x Si(OEt)4
H2O
Npht-COCH33 7 30 98
IMMOBILIZATION BY ELECTROSTATIC INTERACTION
M++
SOLID SOLUTION
+
CATIONIC
EXCHANGE
X-
X-L*L*
L
L
M+ L*L*
L
L
SOLID SOLUTION
M+M
CHARGE SITUATION
G+
metal ligand
H2
M L*L*
L
L
+
neutral
H+
TYPES OF INORGANIC SUPPORTS
CLAYS
SiO4
tetrahedra
AlO6
octahedra
~ 10 Å
+ + +
- -
-
TOT
exchangeablecations
HYDROTALCITES
[Mg0.75Al0.25(OH)2](CO3)0.125
Interlamellar space
Isomorphous substitutions: Al
exchangeableanions - -
octahedrallayer
+
+
MESOPOROUSCRYSTALLINE
SILICAS
MICROPOROUSZEOLITES
Pores: 25-100 Å
Pores: 4-10 Å
Supermicropores bypartial destruction
of the structure
HYBRID MATERIALS
TYPES OF ORGANIC SUPPORTS
POLYMERS
n m
SO3Na
p
O O O
Si
SILICA
SO3Na
(RO)3Si X
+
Silica
1) Grafting
2) Transformation(X SO3Na)
Grafted organic groups
+
Silica
synthesis
CF2CF2
CF2
SO3H CF2CF2
CF2SO3H
CF2CF2
CF2SO3H
CF2CF2
CF2SO3H
nafion-silicananocomposite
Si(OR)4
Composites
Variations:
• Main chain: -(CF2)n-
• Cross-linking: nature and degree
• Charged group: -COONa, -NR3
+
[L*-M]+X- + support [L*-M]+ + Na+X-supportNa+
L* + M+X- + support supportL* + + Na+X-Na+ M+
THE EXCHANGE PROCESS
IMPORTANCEOF SOLVENT
• Complex and leaving salt in solution
• Possible coordination to M: deplacement of chiral ligand
• Compatible with support: swelling
HYDROGENATION WITH CLAY-IMMOBILIZED CATALYSTS
COOH
NHCOCH3
COOH
NHCOCH3
H2
EtOHR
R
N
N
PPh2
Ph
PPh2
Ph
Rh(cod)
+
HECTORITE R = H70% e.e.
100% conv (1-6 h)5 cycles
PPh2
PPh2
NH2
H Me
Fe Rh(cod)
HECTORITE
+
27.
2 A
COOBu
COOBu
COOBu
COOBu
H2
R = Phhectorite 49% e.e.nontronite 0% e.e.
EFFECT OFSUPPORT
EFFECT OFSOLVENT ANDIMMOBILIZATION
% e.e. MeOH EtOH iPrOHHomog.: 15 32 56Heterog.: 64 88 84
IMMOBILIZATION ON CATIONIC SUPPORTS
HYDROTALCITE AS SUPPORT
P
Ru
PCl+
SO3-
Cl-
SO3-
SO3-
SO3-
Big size of the complex
Exchange on the externalsurface of the hydrotalcite
COOMe
COOMe
COOMe
COOMe
48% e.e.
OH OH
100% e.e.
H2
H2
Unclear points:• Need for a MgAl hydrotalcite
• Possibility of reuse
IMMOBILISATION WITHOUT LIGAND-SUPPORT BOND
• Adsorption on the surface
Hydrophylic or hydrophobic interactions
Supported liquid phase
• Entrapment into the pore system
“Ship-in-a-bottle” method
Entrapment between polymer chains
IMMOBILIZATION BY ADSORPTION
O O O
H HH
O O OS
CF3
SILICA
P
P
Rh(cod) COOCH3
NHCOCH3
COOCH3
NHCOCH3
99% e.e.
H2
hexane
HYDROGENBOND
HYDROPHOBICINTERACTION
O
SIL
ICA
O 12
O O12
NPPh2
PPh2
Rh(COD)BF4
tBuCOCOOCH3
NHCOCH3
COOCH3
NHCOCH3
93% e.e.
H2
waterPh
Ph
Glass
Organic
P
PRu
SO3Na
SO3Na
SO3Na
SO3Na
2Cl
H2O
H2O
Glass
OrganicPhase
Porouscatalystparticle
SUPPORTED LIQUID PHASE
MeO
COOH
MeO
COOHH2
(S)-naproxen
Hydrophilic phase: ethyleneglycol
Hydrophobic phase: CHCl3/cyclohexane (1:1)
Results: tof 24 h-1, 88% e.e. (r.t.)
96% e.e. (3ºC)
ENTRAPMENT INTO ZEOLITES “ship-in-a-bottle” synthesis
O
N NMn
OR2
R1 R1
R2
HH
+ Complex is toolarge to leaveAnd to be accommodated?
Mn2+
(zeolite supercage)
channel
Ligand componentsare small enough toenter the zeolitechannels
OH
CHO
R2
R1H2N NH2
HH
ENTRAPMENT INTO MEMBRANES
SiMe
Me
O SiMe
Men "curing"
+
Si
OSiMe2H
HMe2SiO OSiMe2H
OSiMe2H
P
P
Rh(cod)
OTf
P
P
Rh(cod)
OTf
COOCH3
OCOOMe
OH
90-93% e.e.
H2
solvent swelling solubility leachingPhCl 173 21 100Et2O 240 7 90acetone 15 90 62MeOH 2 162 54heptane 235 0.3 12
Entrapment of Mn(salen)
cross-linkedpolysiloxane(membraneform)
"SWELLING"
SOLVENTEFFECT
CONCLUSIONS
COVALENT BOND
ELECTROSTATIC
ADSORPTION
ENTRAPMENT
Ligand retention
Versatility
Simplicity
Without ligandmodification
Ligand modification(effect on e.e.)
Metal leaching(possible )
Ionic character
Ligand leaching(possible )
Leaching andsolubility
Complex size
Swelling and leaching
pro contra
References
• Chiral Catalyst Immobilization and Recycling; D. E. De Vos, I. F. J. Vankelecom, P. A. Jacobs, Eds.; Wiley-
VCH: Weinheim, 2000.
• Comprehensive Asymmetric Catalysis; E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Eds.; Springer-Verlag:
Berlin-Heidelberg, 1999; chapters 37 and 38.
• D. C. Sherrington, P. Hodge. Synthesis and Separations using Functional Polymers; Wiley: New York, 1988.
• W. T. Ford. Polymeric Reagents and Catalysts; ACS Symposium Series 308, American Chemical Society:
Washington, 1986.
• H.-U. Blaser, Tetrahedron: Asymmetry 1991, 3, 843.
• S. J. Shuttleworth, S. M. Allin, P. K. Sharma, Synthesis 1997, 1217.
• L. Pu, Tetrahedron: Asymmetry 1998, 9, 1457.
• L. Canali, D. C. Sherrington, Chem. Soc. Rev. 1999, 28, 85.
• Y. R. de Miguel, J. Chem. Soc. Perkin Trans. 1 2000, 4213.
• S. J. Shuttleworth, S. M. Allin, R. D. Wilson, Synthesis 2000, 1035.
• Y. R. de Miguel, E. Brulé, R. G. Margue, J. Chem. Soc. Perkin Trans. 1 2001, 3085.
• B. Clapham, T. S. Reger, K. D. Janda, Tetrahedron 2001, 57, 4637.
REVIEWS
BOOKS
II. Liquid phase synthesis
Dickerson, Tobin J.; Reed, Neal N.; Janda, Kim D. Chem. Rev. 2002, 102, 3325.
Polyglycerol
Haag, R. et. al. J. Comb. Chem., 2002, 4, 112; Haag, R. Chem. Eur. J., 2001, 7, 327
Soluble Polymers
Janda, K. D. Chem. Rev., 1997, 97, 489-509.Janda, K. D. Chem. Rev., 2002, ASAP.
LPS supported synthesis of Prostaglandins
Janda, K. D. JACS., 1997, 119, 8724-8725.
PEG-Supported Sulfoxide for Swern Oxidations
Harris, J. M, etc. J. Org. Chem., 1998, 63, 2407.
Chemical Tagging
Fluorous Method: A solution phase method
Luo, Z.; Zhang, Q.; Oderaotoshi, Y.; Curran, D. P. Science 2001, 291, 1766-1769.
Starter Library of Mappicine Analogs
Luo, Z.; Zhang, Q.; Oderaotoshi, Y.; Curran, D. P. Science 2001, 291, 1766-1769.
Automated High Throughput Purification
www.biotage.com
Wilcox’s Precipitons
Bosanac, T.; Yang, J.; Wilcox, C. S. Angew. Chem. Int. Ed. 2001, 40, 1875-1879.Bosanac, T.; Wilcox, C. S. J. Am. Chem. Soc. 2002, 124, 4194-4195.
ROM Polymerization
1st-G: Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110.2nd-G Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956.
Features of Phase Trafficking via ROMP
Impurity Trapping: Chromatography Free Mitsunobu Reaction
Barrett, A. G. M., et. al. Org. Lett. 2000, 2, 2999.Barrett, A. G. M. Chem. Bev. 2002, ASAP.
Synthesis of ROMPgel Activated Esters
Barrett, A. G. M., et. al. Org. Lett. 2000, 2, 261-264.
Acylation of Amines Using ROMPgel Supp. Esters
Barrett, A. G. M., et. al. Org. Lett. 2000, 2, 261-264.
Polymer supported Tosmic Reagent
Barrett, A. G. M., et. al. Org. Lett. 2001, 3, 271-273.
NC
Polymer supported Tosmic Reagent
Barrett, A. G. M., et. al. Org. Lett. 2001, 3, 271-273.
Sequestration of Excess Amine
Barrett, A. G. M., et. al. Org. Lett. 2000, 2, 2663-2666.
Bolm ROM-Polymer Catalyst
Bolm, C.; Dinter, C. L.; Seger, A.; Hocker, H.; Brozio, J. J. Org. Chem. 1999, 64, 5730-5731.
Radical Reactions on Soluble ROMP Supports
OO
OO Br
Ph
Br
Ph
Bu3Sn
OO
OO
PhPh
n
AIBN, PhH
80oC
n
Precipitate from tin saltswith cold MeOH
Br
OR
O
Bu3SnHZnCl2, Et3B, O2
N
O
O
H
H
O
O
OH
H
OR
O
n
CH2Cl2, -78oC
R =
Precipitate from tin saltswith cold MeOH
>90:1 de
Enholm, E. J.; Gallagher, M. E. Org. Lett. 2001, 3, 3397-3399.
Enholm, E. J.; Cottone, J. S. Org. Lett. 2001, 3, 3959-3962.
Capture-ROMP-Release: Synthesis of Amino Acids
Mukherjee, S.; Poon, K. W. C.; Flynn, D. L; Hanson, P. R., Tetrahedron Lett. 2003, 44, 7187-7190.
Reviews on polymer-bound reagents
Polymer-supported organic catalystsBenaglia, M.; Puglisi, A.; Cozzi, F. Chem. Rev. 2003, 103, 3401
Recent advances in asymmetric C-C- and C-heteroatom bond forming reactions using polymer-bound catalystsBräse, S.; Lauterwasser, F.; Ziegert, R. E. Adv. Synth. Catal. 2003, 345, 869
Whole issue dedicated to polymer-bound reagentsChem. Rev. 2002, 102, No. 10
*New tools and concepts for modern organic synthesisLey, S. V.; Baxendale, I. R. Nature Reviews: Drug Discovery 2002, 1, 573
Functionalized polymers – emerging versatile tools for solution-phase chemistry and automated parallel synthesisKirschning, A.; Monenschein, H.; Wittenberg, R. Angew. Chem. Int. Ed. Engl. 2001, 40, 650
Multi-step organic synthesis using solid-supported reagents and scavengers: a new paradigm in chemical library generationLey, S.V. et al. J. Chem. Soc., Perkin Trans. 1 2000, 3815
Solid-supported reagents in organic synthesisDrewry, D. H.; Coe, D. M.; Poon, S. Med. Res. Rev. 1999, 19, 97
Solution-phase chemical library synthesis using polymer-assisted purification techniquesParlow, J. J.; Devraj, R. V.; South, M. S. Curr. Opin. in Chem. Biol. 1999, 3, 320
Functionalized polymers: Recent developments and new applications in synthetic organic chemistryShuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis 1997, 1219.
III. Polymer supported reagents
Conventional synthesis
Solid phase synthesis
Synthesis using a solid-supported reagent
A + BRe agent
A B
A + B A BRe agent
+ BReagent
A A B
III. Polymer supported reagents
Different types of polymer-bound reagents
Reagents
Scavengers
Quenching reagents
Capture-and-release reagents
Reage nt
productsubstra te
+
productsubstrates
+Scav eng er
product
Scav eng er+
Capturing rea gen t
Capturing rea gen tRelease
product
Attaching reagents to the solid phase instead of substrates provides similar advantages:
- Ease of purification allows the use of excess reagents
Excess reagents can be removed by use of a solid phase-bound “scavenger” that reacts with or binds the excess reagent
Solid Phase Reagent and Scavenger Resins
Starting Material
Reagent
Product
Reagent+
Clean Product
Filter
Starting Material
Excess Reagent
Product
Reagent+
Clean Product
Scavenger1)
2) Filter
+
Scavenger
Reagent
Advantages
Easy workup / can be automated
Toxic or volatile reagents can be immobilized
Two incompatible reagents can be used at the same time (’wolf and lamb’)
Excess reagent can be used
Compared to solution phase chemistry
Advantages
Compared to solid phase chemistry
Easier to develop chemistry
Easier to analyze intermediates (solution)
Convergent synthesis possible
A B
C D
E
Disadvantages
Slower reaction in some cases
Leaching of metal
More expensive
Solid supports
Polystyrene
Other organic polymers (polyamides etc.)
Soluble polymeric supports (PEG, dendrimers)
Silica
Zeolites
Glass
Graphite
Cellulose
Polystyrene
Microporous polystyrene (1-4% cross-linked)
Macroporous polystyrene (30-50% cross-linked)
Hybrids (PS/PEG)
Soluble polystyrene
Plugs of microporous polystyrene
OO
OHn
How are the reagents/scavengers attached to the resin?
Covalent binding by:
- reaction with a derivatized resin
- co-polymerization of the reagent with styrene and divinylbenzene
Forming an ion-pair
Entrapment, reagent enclosed in a polystyrene network
NM e3
Cl
NaCNNM e3
CN
PPh2
+ +Functionalizedpolymer
ClLiPP h2
PPh2
Polymer-Bound Reagents
Reagent
productsubstrate
Some examples:
Oxidation
Reduction
Nucleophilic reactions
Carbon-carbon bond formation
Amide bond formation
Resin-Supported Reagents
Review: Ley, S. V. et al. J. Chem. Soc., Perkin Trans. 1 2000, 3815-4195.
Scavenger Resins
Reagents for Oxidation
O
NO
X
Ph 2P Co PP h3
Cl
ClCrO 3SiO2
KMnO4SiO2
2
Cr2O72-
NMe3
NMe3 IO4
N OsO4
NMe3 RuO 4
Reagents for Oxidation
PSP = polymer supported perruthenate
NMe3 RuO4NMe3 ClKRuO 4
ultrasound PSP
OH
PSP, O2
75 - 85 oC
O
H
> 99%
H15C7 OHH15C7 O
H83 %
toluene
as above
Hinzen, B., Lenz, R., Ley, S. V. Synthesis, 1998, 977
C OH C O
Polymer-bound sulfoxide for Swern oxidation
OH
O
SDMAP, DIC O
O
SHO t-BuOOHO
SO
O
H+
OHOPh
OH
sulfoxide
(COCl)2, Et3N
OOPh
O
as above
H
71 %
82 %
Cole, Stock, Kappel Bioorg. Med. Chem. Lett. 2002, 12, 1791
Liu, Y.; Vederas, J. C. J. Org. Chem. 1996, 61, 7856
Reagents for Oxidation C OH C O
Poly(vinylpyridinium dichromate)
NN N N
CrO3
N
+
cross-linkingagent
n
Cr2O72-
n
Fréchet, J. M. J.; Darling, P.; Farrall, M. J. J. Org. Chem. 1981, 46, 1728
OH PDC O
H
OH PDC O
98%
93%
Reagents for Oxidation C OH C O
Reagents for Oxidation
Dihydroxylation & oxidative cleavage of alkenes
L [OsO 4]
C8H17
N OsO4
Me3NO C8H17
OH
HO
90%
N N
Cl
OsO4
H
O
O
H
65%NaIO4
Nagayama, S.; Endo, M.; Kobayashi, S. J. Org. Chem. 1998, 63, 6094
Cainelli, G.; Contento, M.; Manescalchi, F.; Plessi, L. Synthesis 1989, 45
C CC C
HO OH
C O O C+
Reagents for OxidationC C
O
O
CF3
OO
PS or Tentagel
Epoxidation
COOH
O
SOOH
O
O
N N
N N
O Ru
CO
Reagents for OxidationC C
O
SO4H
O
80%
Epoxidation
SO4HO
80%
Pande, C. S.; Jain, N. Synth. Commun. 1989, 19, 1271
Oxon
Reagents for Oxidation
Epoxidation & oxidation of amines
oxirane
O
82%
OO
n
NH2oxirane
NO2
83%
N
ON
oxirane
83%
Shiney, A.; Rajan, P. K. ; Sreekumar, K. Polymer International 1996, 41, 377
Reagents for Oxidation
Asymmetric epoxidation
NMn
N
O OCl
PhPh O
O
Smith, K.; Liu, H.-C. Chem. Commun. 2002, 886
Mn-salen
O
NaOCl, 4-PPNO
37% (94% ee)
4-PPNO = 4-phenylpyridine-N-oxide
Reagents for Reduction
NMe3 BH4 NMe3 (CN)BH3
NH2
NH3
BH4BH4
C O C OH
Pd
N
HDMF
PPh3 BH4
N Zn(BH4)2
Reagents for Reduction
H
O
MeOH
OH
100%
NH2
NH3
BH4BH4
C O C OH
Rajasree, K.; Devaky, K. S. J. Appl. Polym. Sci. 2001, 82, 693; Ley, S. V. Schucht, O.; Thomas, A. W.; Murray, P. J. J. Chem. Soc., Perkin Trans 1 1999, 1251
N
O
MeO
MeO
H
BH4NMe3
NiCl2, MeOHN
MeO
MeO
H
OH
88%
Epimaritidine
Reagents for ReductionC O C NH2
NH2
Reductive amination
Scavengers can be used to remove excess aldehyde or excess amine:
N C O
NMe3H
O
H2NH
N HN+
BH4
94%
Yoon, N. M.; Kim, E. G.; Son, H. S., Choi, J. Synth. Commun. 1993, 23, 1595
Reagents for Reduction
Dehalogenation
C Br C H
HO
N
NN
N
NH2
O
OHOH
HH
HH
Br
HO
N
NN
N
NH2
O
OHOH
HH
HH
87%
SnH
SnH
Bu Bu
Gerlach, M.; Jordens, F.; Kuhn, H.; Neumann, W. P. Peterseim, M J. Org. Chem. 1991, 56, 5971
Applications
Reagents for oxidation and reduction
NCl
Cl
O
NMe3 BH4
NCl
OH
NCl
ONMe3 RuO4
H
NMe3 OH
CH3NO2 NCl
NO2
OH
NCl
NO2NMe2
CH3SO2Cl
NCl
TBDMSO
TFA
1)
2)
O
NO2NCl
OMs
NO2
NMe3 BH4
NCl
OH
NO2
N
N
CH3SO2Cl
NCl
OMs
NH2
NMe3 BH4
Several steps andpolymer-bound reagents. H
NN Cl
Epibatidine,purity > 90%
Habermann, J.; Ley, S. V.; Scott, J. S. J. Chem. Soc. Perkin Trans. 1 1999, 1253
Amide Formation
RC
OH
O
+H2N
R'
RC
NH
O
R'
NH
S
O O
NN
N
OHHO R1
O
NH
S
O O
NN
N
O R1
O
N R1
O
R2
R3
PyBrOP
R2R3NH
Pop, I. E.; Deprez, B. P.; Tartar, A. L. J. Org. Chem. 1997, 62, 2594
P
NBr
N
NPF6PyBrOP =
’Wolf and Lamb’
Ph Me
O Ph
Ph
O
NO2
PhO
Li
SO3 NH3NH2
1)
2)THF
N
HN
Ph
Ph
Reagents that are incompatible in solution can be used together when bound to a solid phase.
Cohen, B. J.; Kraus, M. A.; Patchornik, A. J. Am. Chem. Soc. 1977, 99, 4165; J. Am. Chem. Soc. 1981, 103, 7620
Polymer-bound Nucleophiles
C X C Nu
NMe3 Nu
Nu = OAr, CN, SAr, N3, NaCO3, NCO, SePh, NO2, NCS
Nucleophilic substitution
Br NMe3 CN CN
72%
Gordon, M.; DePamphilis, M. L.; Griffin, C. E. J. Org. Chem. 1963, 28, 698
Carbon-Carbon Bond Formation
Horner-Wadsworth-EmmonsC O C C
EtOP
O
CN
EtO Cl
H
O
NMe3 OH
Cl
CN
99%
+
O
PEtO
EtO
O
OEt+
H
O NMe3 OH
OEt
O
93%
Soledenko, W.; Kunz, U.; Jas, G.; Kirschning, A. Bioorg. Med. Chem. Lett. 2002, 12, 1833.
PASSflow reactor used:
Metathesis
Cross Metathesis
Ring Closing Metathesis
Ring Opening Metathesis Polymerization
R1 R2
+
catalyst R1
R2
+CM
RCM+
ROMP
[M]
R
R
[M]
R
R
n
Metathesis Catalysts
Schrock type Grubbs type
L
Ru
L
RCl
Cl
L = phosphine or carbene
N
Mo
ORRO Ph
Metathesis reactions are often difficult to purify as the catalyst
(typical 10 – 20 mol%) contaminates the product.
R1 R2
+
R1
R2
+
Metathesis
Mechanism
[M] CH2
[M]
R1
[M]
R1
[M]
R1 R2
R1
R2
R2
R1
Polymer-Bound Metathesis Catalysts
Barrett’s ”boomerang” catalysts
P
PCy3
PC y3
Ru Cl
ClL
PC y3
Ru Cl
ClLPh
+
L1 = PCy3L2 = IMes
CH 2Cl2
reflux+
Ph
NN
IMes
Ahmed, M.; Arnauld, T.; Barrett, A. G. M.; Braddock, D. C.; Procopiou, P. A. Synlett 2000, 1007
Polymer-Bound Metathesis Catalysts
Barrett’s ”boomerang” catalysts
PC y3
Ru Cl
ClL
+RuCl
ClL
PC y3
PC y3
Ru Cl
ClL
+
RR
R
unstable
PhPC y3
Ru Cl
ClLPh
Polymer-Bound Metathesis Catalysts
Recycling of Barrett’s catalyst
Cycle 1 2 3 4 5 6
% Conversion 100 100 100 88 43 7
CO 2Et
CO 2Et
PC y3
Ru ClCl
IMes CO 2Et
CO 2Et1-octene, PPh3
More Metathesis Catalysts
N N
O
MesMes
Ru
PCy3
Cl
Cl
Ph
Blechert
RuCl
Cl
PCy3
OPEG
Lamaty
PCy2
PCy2
RuClCl
Ph
Ph
Grubbs
Enantioselective Olefin Metathesis
tBu
O
O
tBu
Mo
N
iPr
iPr
Hoveyda / Schrock
O5 mol% catalyst
benzene, RT, 24 h
OH
90% conversion, 95% eemeso compound
Suzuki Reaction
Palladium-catalyzed coupling of an aryl/alkenyl halide with a boronic acid/ester.
X
A
+
AX
or
(RO)2B
B
(RO)2BB
+
or
A
B
or
A
B
or
AB
Pd-cat.
Suzuki Reaction
L2PdR1 X
L2PdR1 OR'
B(OR")2
R2
R'O B(OR")2
R1 X
NaX
R'ONa
R1
L2PdR1 R2
R2
Pd(0)L2
Mechanism
Carbon-Carbon Bond Formation
Suzuki couplingC X C(HO)2B+
Pd cat.
sp2 sp2
C C
Cl
LiPPh2
PPh2
PdLn
Ph2P [Pd]
Pd source: Pd(PPh3)4 PdCl2 Pd(CH3CN)2Cl2 Pd(dba)2 Na2PdCl4
Jang, S. Tetrahedron Lett. 1997, 38, 1793;Fenger, I.; Le Drian, C. Tetrahedron Lett. 1998, 39, 4287
Suzuki Coupling
Bu
OB
O
+Br Hex
{Pd}
NaOEt
benzene80 oC
Bu
Hex
84 %
B(OH)2 NBr
{Pd}
Na2CO3
toluene/water reflux
N+
90 - 95 %
C X C(HO)2B+Pd cat.
sp2 sp2
C C
Suzuki Coupling: Other Catalysts
C X C(HO)2B+Pd cat.
sp2 sp2
C C
Si Si
HN NH
O
OO
S [Pd]
PEG NH
O
PPh2
PdCl
OCy2P [Pd]
Pd(OAc)2 or Pd2(dba)2
UozumiHayashi
Buchwald
Zhang
Stille Coupling
O
O
SnBu 3
Br
R
1) cat. L iCl, NMP
2) NaOMe
MeO
O
R
+Pd cat.
PAr 2
Pd
Ar 2P
PdO
O
O
OPd cat. =
Advantages: Tin reagents are toxic – easier to handle if bound to a solid support.Tin byproducts often contaminate product in solution reactions.
The Pauson-Khand Reaction
+Co 2(CO )8
OR1
R2
R1
R2
The Pauson-Khand Reaction
On solid phase
O
O
Co 2(CO) 8
HO
benzene80 oC , 6 h
Oesterhydrolysis
Schore, N. E.; Najdi, S. D. J. Am. Chem. Soc. 1990, 112, 441
The Pauson-Khand Reaction
Mechanism
RS RL
Co2(CO)8
- 2 CO Co(CO)3Co(CO)3
RS
RL- CO
Co(CO)3Co(CO)2
RS
RL
R
Co(CO)3Co(CO)2
RS
RL
R
CO
alkeneinsertion Co(CO)3RS
RL
Co(CO)3
R
CO
CO insertion
Co(CO)3RS
RL
Co(CO)3
O
reductiveelimination
O
R
(CO)3Co(CO)3Co
RLRS -Co2(CO)6
O
R
RLRS
The Pauson-Khand Reaction
Using polymer-bound cobalt carbonyl
Ph2P
PPh2
Co (CO )3 Co (CO )4
Ph2P Co (CO )3
Co (CO )4
1 2
Ph2P
PPh2
Co (CO )3
Co (CO )3
3
PPh2 + Co 2(CO )8
+
THF, RT
1,4-dioxane
75 oC
Comely, A.C.; Gibson, S. E.; Hales, N. J. Chem. Commun. 2000, 305
The Pauson-Khand Reaction
Using polymer-bound cobalt carbonyl
TsN TsN O
Et O2C
Et O2C
OEt O2C
Et O 2C
70 oC, THF, 24 h
CO 50 m bar, 3
as above
61%
49%
Ph2P
PPh2
Co(CO)3
Co(CO)3
3
The Pauson-Khand Reaction
Using polymer-bound promotors
O SM eN
O
O
+
R
Co2(CO)6
+
1 2
1, THF, RT
or 2, DCE, Δ
O
R
H
H
74 - 99% yield
R = Ph, tBu, Me2(OH)C
Kerr, W. J. et al, Chem. Comm. 2000, 1467; 1999, 2551.
References
Reviews on polymer-bound organometallic reagents:
Recent advances in asymmetric C-C and C-heteroatom bond forming reactions using polymer-bound catalysts
Bräse, Lauterwasser, Ziegert Adv. Synth. Catal. 2003, 345, 869-929
Preparation of polymer-supported ligands and metal complexes for use in catalysisLeadbeater, Marco Chem. Rev. 2002, 102, 3217-3273
Recoverable catalysts and reagents using recyclable polystyrene-based supportsMcNamara, Dixon, Bradley Chem. Rev. 2002, 102, 3275-3300
Soluble polymers as scaffolds for recoverable catalysts and reagentsDickerson, Reed, Janda Chem. Rev. 2002, 102, 3325-3344
Functionalized polymers – Emerging versatile tools for solution-phase chemistry and automated parallel synthesis
Kirschning, Monenschein, Wittenberg Angew. Chem. Int. Ed. Engl. 2001, 40, 650-579
Multi-step organic synthesis using solid-supported reagents and scavengers: a new paradigm in chemical library synthesis
Ley et al. J. Chem. Soc., Perkin Trans 1 2000, 3815-4195
Scavengers
+
productsubstrates
+
Scav eng er
product
Scav eng er+
Scavengers
acidic
basic
nucleophilic
electrophilicH
O
N C O
N
CH3
CH3
N
OH
O
S
OH
O
NH2 N
NH2
NH2
Scavengers
Application
NHN
NHCl
NHN
NCl R1
NN
NCl R1
R2
NH2
NMe2
1) R1X
2)
1) R2X
BEMP
2) NH2
N NP
NN
BEM P =
Xu, W.; Mohan, R.; Morrissey, M. M. Bioorg. Med. Chem. Lett. 1998, 8, 1089
Capture and Release
+
productsubstrates
Capturing reagentCapturing reagent
Release
product
+contaminants
Capture and Release
Tamoxifen library
R2R1O
BO
BO
O
B
R2
BO
OOO
R1
XR3
Pd(dppf)Cl2, base
B
R2
OO
R2
R1
R3
R1
R3 R3
regioisomer
R2
R1
R3+
+NH
O
Si
I1)
2) 30% TFA in CH2Cl2
regioisomer+
5 x 5 library
Pt(PPh3)4
Brown, S. D.; Armstrong, R. W. J. Org. Chem. 1997, 62, 7076
Capture and Release
Synthesis of β-amino alcohols
OH O
Cl
NaH
O
O NH2
O
OH
NH
Impurities
OH O
OH
O
NH2
Capture and Release
Synthesis of β-amino alcohols using polymer-bound borane
Hori, M.; Janda, K. D. J. Org. Chem. 1998, 63, 889
OH O
Cl
NaH
O
O NH2
O
O
N
BY2
HCl
O
OH
NH
2) HBY2
1)
OPEG
BH
2
HBY2 =
Capture-Release Alkylation Utilizing Resin-Bound Sulfonyl Chloride
Rueter, J. K.; Nortey, S. O.; Baxter, E. W.; Leo, G. C.; Reitz, A. B. Tetrahedron Lett. 1998, 39, 975-978.
Capture Activation-Release:Solid-Supported DCT for Amide Synthesis
Masala, S.; Taddei, M. Org. Lett. 1999, 1, 1355-1357.
An Example of Solid Phase Reagents and Scavengers
Ley SV et al. J. Chem. Soc. Perkins. Trans. I 1999, 63, 6625.
OH
MeO
MeO
HONMe3
RuO4
NMe3
BH4
Tf2O,
N NMeO
MeO
NTf
HO
98 % 3 steps
O
MeO
MeO
H NH2
MeO
MeO
NH
HO
An extremely efficient three step reductive amination and triflation is accomplished by the use of solid phase reagents and scavengers
Application: Sildenafil (Viagra™)
HN
N
NN
O
S
OE t
NO
O
N
Sildenafil (ViagraTM)
OH
ON
N
O
S
OE t
NO
O
N
H2N
H2N
Pr
Pr
Pr =
+
1 2
Baxendale, I. R.; Ley, S. V. Bioorg. Med Chem. Lett. 2000, 10, 1983
Sildenafil, building block 1
OH
OS
OEt
NO
O
N
NHN
EtN(i- Pr)2
1)
2) Et2SO4OH
OS
OH
ClO
O
crude 1
Sildenafil, building block 2
Pr NNH
Pr O
H
NH 2NH Me EtOBr
O
N NPNN
NH 2
NM e3 CN+
cat. H+
Pr NN
O
OEt
PrHN
N
O
OEt
CNNC O
MnO2Pr NN
O
OEt
CN
BEMP
BEMP =
BEMP1)
2) NH3/MeOH
N N
NH 2
Pr NH 2
O
2
Sildenafil (Viagra™)
NN
N
HO
HOBt =PyBrOPN
PN N
BrPF6
=
OH
OS
OEt
N O
O
Ncrude 1
HOBt
PyBrOP NN
N
O
OS
OEt
N O
O
N
2
NCO
OS
OEt
N O
O
N NN
O
HN
PrNH2
HN
N
NN
O
S
OEt
N O
O
N
PrEtOH/NaOEt
MW 10 min/120 oC
Sildenafil
Natural Products via Supported Reagents
Baxendale, I. R.; Ley, S. V.; Piutti, C. Angew. Chem., Int. Ed. 2002, 41, 2194-2197Baxendale, I. R.; Brusotti, G.; Matsuoka, M.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 2002, 143-154Baxendale, I. R.; Lee, A.-L.; Ley, S. V. Synlett 2001, 1482-1484Habermann, J.; Ley, S. V.; Scott, J. S. J. Chem. Soc., Perkin Trans. 1 1999, 1253-1255Ley, S. V.; Schucht, O.; Thomas, A. W.; Murray, P. J. J. Chem. Soc., Perkin Trans. 1 1999, 1251-1252.
Epothilone
O
S
N
O
OH
O
O
H
OH
For a total synthesis of epothilone using polymer-bound reagents, see:
Storer, R. I.; Takemoto, T.; Jackson, P. S.; Ley, S. V. Angew. Chem. Int. Ed.2003, 42, 2521