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Lee, Yoon-Sik
Polymer-Supported Reagent & Catalyst for Organic Synthesis
School of Chemical & Biological Engineering, Seoul National University
[email protected] October 22-24, 2008
1. Solid-Phase Organic Synthesis (SPOS) 2. Supported Reagents & Catalysts
3. Polymer-Supported Reagents & Catalysts 4. Ideal Resins
Contents
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Solid-Phase Organic Synthesis (SPOS)
- Concepts of SPOS
- History of Sold-Phase Synthesis - Advantages & Disadvantages
1. Reagents bind covalently to a polymer thru a linker.
2. Reaction occurs on a polymer matrix.
3. Purification: filtering & washing 4. Separation of product & polymer
Concepts of the SPOS
Polymer Products
Linker
Solution Phase Organic Synthesis Solid Phase Organic Synthesis
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History of Solid-Phase Organic Synthesis
Bruce Merrifield (1963)
- Nobel prize 1984
“ for his development of methodology
for chemical synthesis on a solid matrix”
- Peptide Coupling
- Amino acids as Building Blocks - Repeating single steps
- Later Applied for DNA, RNA,
& Poyssacharide Synthesis
R. B. Merrifield J. Am. Chem. Soc. 1963, 85, 2149-2154
Product
[ Solid Phase Organic Synthesis ]
Advantages & Disadvantages
Why is Solid-Phase Organic Synthesis Fancy ?
( compare to “Traditional Solution-Phase Organic Synthesis” )
Minimal solubility problems.
Simplified purification. => Time saving process.
Improved reaction yields by using excess reagents.
Simplified manipulation of small quantities.
Site isolation between FG’s.
Automation is possible.
Can be applied to multi-step process.
=> Synthesis by Robot.
7 Takayuki Doi, Shinichiro Fuse, S. Miyamoto, K. Nakai, D. Sasuga, Takashi Takahashi, 7/42
Chem. Asian. J., 2006, 1(3), 370-383
1st Solid-Phase Organic Synthesizer :
Robot Chemists
<A formal total synthesis of Taxol aided by an automated synthesizer>
“We decided to make Taxol with just one student and a robot.” – explained by Takahashi. T.
- Professor. Takashi Takahashi at Tokyo Institute of Technology
Disadvantages
Excess chemicals are consumed (Reagents, Solvents)
Expensive process (Polymer resins, Solvent, ..)
Complicated reaction control
Slow reaction rates
Special substrates needed
Small volume yield
Advantages & Disadvantages
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Supported Reagents & Catalysts
- Supported Reagents in Organic Synthesis - Multiple use of Supported Reagents
- Multiple Supported Reagents System
Other Advantages
Potential for recycling, Higher stability, Reduced Toxicity,
Simple Reaction Monitoring by TLC, Automation, Simplified product isolation
Supported Reagents & Catalysts
Solid-phase Synthesis
Solution-phase Synthesis
Supported Reagents & Catalysts
Use of excess reagent √ √
Easy of work up √ √
Minimal purification √ √
Easy of reaction monitoring √ √
Simple chemistry set up √ √
Large size libraries √ √
High quantities √ √
- Supported Reagents & Catalysts can combine the benefits of solid-phase and solution-phase chemistry.
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Simple Case : no by-Products
Substrate Clean Product
Solution Phase
Reagent
Strengths
Advantages of Solution-Phase Rxn.
Convenience of Solid-Phase Rxn.
No Chromatography Needed
Supported Reagents in Organic Synthesis
Limitations
Low Loading Levels Slow Reaction Rates Large Excess Needed
Supported Reagents in Organic Synthesis
Linear Synthesis Route
Reagent
One-Pot
Reagent
Reagent
Clean Product
Reagent
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Supported Reagents in Organic Synthesis
Scavengers Methods
‘Catch-and-Release’ Methods
Substrate
Clean Product
Reagent Scavenger
Scavenged
Clean Product (Excess)
(Excess)
Capture
Remove by Filtration
Filter and Wash to Purify
Release Captured
Supported Reagents in Organic Synthesis
Convergent Synthesis Routes
Reagent
Reagent
Reagent Reagent
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Supported Reagents in Organic Synthesis
Split Synthesis Routes
Novel Building Blocks or Fragment Molecule Sets
Reagent
Reagent Reagent
Reagent
Multiple Use of Supported Reagents
Various Examples
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Multi-Supported Reagents System
Various Examples
Janda K. et al.Org. Lett., 2, 2205-2207 (2000) Parlow et al. Tetrahedron Lett., 36, 1395-1396 (1995) 1)
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