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Combinatorial Organic Synthesis: The Use of Fast Ρ NMR Analysis for Gel Phase Reaction Monitoring, J. Org. Chem. 1994, 59, 7588.
42. Fitch, W. L.; Detre, G.; Holmes, C. P.; Shoolery, J. N.; Keifer, P. A. High-Resolution !H NMR in Solid-Phase Organic Synthesis, J. Org. Chem. 1994,
43. Garigipati, R. S.; Adams, B.; Adams, J. L.; Sarkar, S. K. Use of Spin Ehco Magic Angle Spinning lH NMR in Reaction Monitoring in Combinatorial Organic Synthesis, J. Org. Chem. 1996, 61, 2911.
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Solid-Phase Organic Synthesis. Edited by Kevin Burgess Copyright © 2000 John Wiley & Sons, Inc. ISBNs: 0-471-31825-6 (Hardback); 0-471-22824-9 (Electronic)
POLYMER-ASSISTED SOLUTION-PHASE METHODS FOR CHEMICAL LIBRARY SYNTHESIS
+ ---------------------> +
capture group captured byproduct
DANIEL L. FLYNN Amgen
RAJESH V. DEVRAJ and JOHN J. PARLOW Searle/Monsanto Life Sciences Company
The requirement for life sciences disciplines to discover and optimize small molecules with a heightened sense of capacity and timeliness has led to an explosion in methodologies to synthesize organic compounds in greater
150 POLYMER-ASSISTED SOLUTION-PHASE METHODS
numbers and with increased efficiency. A major impetus for this requirement arose from the advent of ultra-high throughput biological screening technologies. Genomics will soon make it possible to screen compounds for activities against a myriad of potential targets of pharmaceutical and agricultural importance, thus accentuating the need for large numbers of synthetic small molecules. This triad of genomics, robust high-throughput screening, and responsive high-throughput chemical synthesis looks to become a powerful paradigm for life sciences discovery research.
During the early part of this decade, most efforts in high-throughput synthesis utilized solid phase organic synthesis (SPOS) techniques.1"3 SPOS was a natural outgrowth of earlier methods used to synthesize peptides and oligonucleotides.4 This method has several advantages over traditional solution-phase synthesis:
Excesses of solution-phase reactants and reagents can be used to drive reactions to completion; these reagents can then be washed away from polymer-bound intermediates.
The split-mix synthesis technique can allow geometric numbers of compounds to be prepared using an arithmetic number of reaction chambers.5
Chemical6-8 or radio frequency 910 tagging methods can be used for compound identification.
However, there are also some serious practical and theoretical constraints, including the following:
Tethering of library intermediates to polymer supports requires a functionality devoted to this role; hence all library members are typically endowed with the same functional group.
Attachment of library substrates to the support and final release of library products introduce two additional steps in a synthesis.
Heterogeneous reactions must conform to high specifications (conversions -98% for each step) if multiple steps are to provide reasonably pure products.
Materials released from the polymer support tend to be contaminated with truncated intermediates.
5.1. INTRODUCTION 151
Specialized analytical tools are required to monitor reactions and purities of polymer-supported intermediates.
With the exception of one-step multicomponent reactions, solid-phase organic syntheses are linear, because convergent sequences would require removal of intermediates from the polymer support.11
Many laboratories have investigated alternative solution-phase strategies for preparing combinatorial libraries to overcome these limitations of solid-phase organic synthesis.12-15 This chapter reviews advances that have been made over the last two years in polymer-assisted syntheses.16-18 This approach is in many ways complementary to solid-phase organic synthesis. In polymer-assisted solution-phase strategies, the polymer supports are used to tether reactants, reagents, or catalysts rather than to tether library members. Functionalized supports are also often used to chemoselectively sequester solution-phase reaction species (e.g., excess reactants) during purification. Additionally, soluble bifunctional (chemically tagged) reagents can be used to mediate solution-phase reactions, with the bifunctional tag serving a post-reaction trafficking role to mediate purification. In summary, polymer-assisted solution-phase methods:
do not require attachment of library members to a support;