John J. Parlow

Solution-phase chemical library synthesis using polymerassisted purification techniques

During the past few years, polymer-assisted solution-phase synthesis has become a prevalent method for the parallel synthesis of chemical libraries. This methodology allows for intermediate and final product purification by various resin-based sequestration techniques, which allow for the removal of excess reactants, by-products or side products from solution-phase reactions. The methodology has continued to expand, providing the practitioner with a broad range of ingenious purification methods, allowing single-step transformations as well as multistep syntheses to be performed in solution. The polymer-assisted solution-phase technology is currently being utilized for both the synthesis of lead generation and lead optimization libraries in the pharmaceutical arena and has also expanded into other disciplines.

Simultaneous multistep synthesis using polymeric reagents

Abstract A synthesis was accomplished involving three transformations using three different polymeric reagents simultaneously in one reaction vessel to afford 2-[[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]oxy]-1-phenylethanone ( 4 ).

In Situ Chemical Tagging: Tetrafluorophthalic Anhydride as a “Sequestration Enabling Reagent” (SER) in the Purification of Solution-Phase Combinatorial Libraries

Abstract A specific example of a Sequestration Enabling Reagent (SER), tetrafluorophthalic anhydride, is used in the purification of solution-phase reactions involving amines with electrophiles. The SER is added to an incomplete reaction mixture containing product, amine, and electrophile. The SER covalently reacts with remaining amine, affording a derivatized amine with an artificially-imparted acid tag. This “tagged” amine is now sequesterable by the same CMR/R polyamine resin used to sequester the electrophile and both are easily removed from the reaction mixture affording pure product.

The use of anion exchange resins for the synthesis of combinatorial libraries containing aryl and heteroaryl ethers

Abstract Quaternary ammonium exchange resins (Amberlite® IRA-900) were prepared that contained each a mixture of ten aryloxides and heteroaryloxides. The feasibility of generating combinatorial libraries containing aryl and heteroaryl ethers was demonstrated by reacting the resins with a single electrophile (n-butyl bromide) to afford mixtures of ether products. The advantages of using quaternary ammonium exchange resins over solution phase chemistry to prepare this library are discussed.

Solution-phase parallel synthesis of a benzoxazinone library using complementary molecular reactivity and molecular recognition (CMR/R) purification technology

Abstract A solution-phase synthesis of a benzoxazinone library is described. The five-step synthesis is accomplished using combinations of complementary molecular reactivity and molecular recognition (CMR/R) purification concepts, including reactant-sequestering resins, reagent-sequestering resins, sequestration-enabling-reagents, reaction-quenching resins, as well as the judicious use of polymeric reagents. The multi-step synthesis affords the desired benzoxazinone products in excellent purities and yields. This study demonstrates that multi-step library syntheses can be performed in solution-phase, and that utilization of CMR/R purification strategies as the sole method of purification can lead to products of high purity.

Chemically-tagged Mitsunobu reagents for use in solution-phase chemical library synthesis.

A general method for high-throughput product purification of Mitsunobu reactions is described. Tagged phosphine and azodicarboxylate reagents are used to synthesize individual library members in solution-phase. Workup and purification are easily accomplished by post-reaction sequestration of the tagged reagents and reagent byproducts by a complementary functionalized ion exchange resin. The reagents are utilized in a 3 step library synthesis.

Polymer-assisted solution phase synthesis: a general method for sequestration of byproducts formed from activated acyl-transfer reactants

Abstract Typical amide bond-forming reactions involving amines with activated esters are purified by the use of complementary molecular reactivity/molecular recognition (CMR/R) resins, which sequester both the excess activated ester and the byproducts (leaving group) generated. It is also shown by HPLC analysis that this strategy effectively removes many of the common byproducts generated from reactions involving activated esters, carbonates, and carbamates.

High-throughput purification of solution-phase periodinane mediated oxidation reactions utilizing a novel thiosulfate resin

Abstract A simple and efficient methodology for sequestering byproducts and excess starting reagent from the solution-phase Dess-Martin and Grieco-Dess-Martin periodinane mediated oxidation of primary or secondary alcohols to aldehydes or ketones is described. The periodinane oxidations are carried out under mild conditions followed by treatment with a novel thiosulfate resin which reduces any remaining I(V) and I(III) periodinane species to an I(I) species. Quantitative removal of the I(I) species from the solution is achieved by using a base functionalized resin followed by filtration and evaporation to afford highly pure aldehyde or ketone products. Utilization of this sequestration methodology for periodinane mediated oxidations allows for the high-throughput purification and work-up of parallel reaction chambers and is highly amenable to automation procedures.

Discovery of a herbicidal lead using polymer-bound activated esters in generating a combinatorial library of amides and esters.

SummaryA combinatorial library containing mixtures of amides and esters was prepared through solid-phase chemistry. The advantages of using solid-phase chemistry over solution-phase chemistry to prepare this library are discussed. The library was screened through a high-throughput whole organism herbicidal assay upon which a mixture containing amides was found to have herbicidal activity. Deconvolution of the mixture providedN-(3-benzoylphenyl)-3-(1,1-dimethylethyl)-1-methyl)-1H-pyrazole-5-carboxamide as a herbicidal lead with broadleaf and narrowleaf pre-emergence herbicidal activity as low as 100 g/ha on some weed species. This study represents the first report of an agrochemical discovered using a combinatorial approach.

A mixed resin bed for the quenching and purification of tetrabutylammonium fluoride mediated desilylating reactions.

A polymer-bound calcium sulfonate resin is prepared and used to sequester tetrabutylammonium fluoride. The simultaneous use of the calcium sulfonate resin with a sulfonic acid resin is used for the quenching and purification of desilylating reactions involving tetrabutylammonium fluoride as the reagent. Employment of this resin workup technique eliminates the need for a liquid-phase extractive protocol allowing the procedure to be easily automated.