Recent advances in polymer-assisted solution-phase chemical library synthesis and purification

Current Opinion in Drug Discovery and Development

Volumn 1, Issue 1, 1998, Pages 41-50

  Flynn, Daniel L ^a   Devraj, Rajesh V ^a   Parlow, John J ^a  

^a MONSANTO COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0002369226     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (36)

1. Gordon EM, Gallop MA, Patel, DV: Strategy and tactics in combinatorial organic synthesis. Applications to drug discovery. Ace Chem Res (1996) 29:144-154. This review provides an excellent account on advances made (through 1996) in the application of solid phase organic synthesis for small molecule chemical library construction.
2. Thompson LA, Ellman JA: Synthesis and applications of small molecule libraries. Chem Rev(1996) 96:555-600. This review provides an excellent account on advances made (through 1996) in the application of solid phase organic synthesis for small molecule chemical library construction. See reference [1].
3. Hermkins PHH, Ottenheigm HCJ, Rees D: I: Solid-phase organic reactions. Il: A review of the literature Nov 95-Nov 96. Tetrahedron (1996) 53:5643-5678. This review provides a bibliographic summary of the types of reactions developed for solid phase synthesis, through 1996.
4. Cheng S, Comer DD, Williams JP, Myers PL, Boger DU Novel solution-phase strategy for the synthesis of chemical libraries containing small organic molecules. J Am Chem See (1996) 118:2567-2573. This is a seminal paper describing the use of liquid phase extraction as a purification technology for the construction of chemical libraries in solution-phase.
5. Cheng S, Tarby CM, Comer DD, Williams JP, Caporale LH, Myers PL, Boger DL: A solution-phase strategy for the synthesis of chemical libraries containing small organic molecules: a universal and dipeptide mimetic template. Bioorg Med Chem (1996) 4:727-737.
6. Curran DP, Hadida S: Tris(2-{perfluorohexyl)ethyl)tin hydride: A new fluorous reagent for use in traditional organic synthesis and liquid phase combinatorial synthesis. JAm Chem Soc{1996) 118:2531-2532. This seminal paper discloses the use of fluorous-tagged reagents and fluorous phase extraction of non-tagged product species away from organic products. This synthesis/purification technology provides a quite useful and general methodology for solution-phase chemical library preparation.
7. Studer A, Hadida S, Ferritto R, Kirn S-Y, Jeger P, Wipf P, Curran DP: Fluorous synthesis: a fluorous-phase strategy for improving separation efficiency in organic synthesis. Science (1997) 275:823-826.
8. Kaldor SW, Siegel MG, Fritz JE, Dressman BA, Hahn PJ: Use of solid supported nucleophiles and electrophiles for the purification of non-peptide small molecule libraries. Tetrahedron Lett (1996) 37:7193-7196. This is the first report of the use of polymer-supported chemical functional groups to remove complementary reactants from solutionphase as a means of purifying solution-phase chemical library reactions.
9. Flynn DL, Crich JZ, Devraj RV, Hockerman SL, Parlow JJ, South MS, Woodard S: Chemical library purification strategies based on principles of complementary molecular reactivity and molecular recognition. JAm Chem 5oc(1997) 119:4874-4881. This paper describes a broad-based technology for purifying solution-phase chemical library reactions which includes reactantsequestering resins, by-product-sequestering resins, resins which sequester chemically-tagged bifunctional reagents from solutionphase, and resins which perform reaction quenching.
10. Booth RJ, Hodges JC: Polymer-supported quenching reagents for parallel purification. J Am Chem Soc (1997) 119:4882-4886. This paper discloses the use of functionalized resins to remove excesses of solution-phase reactants from chemical library reactions, and also highlights the use of the method for the controlled synthesis of solution-phase mixtures.
11. Keating TA, Armstrong RW: Postcondensation modifications of Ugi four-component condensation products: 1Isocyanocyclohexene as a convertible isocyanide. Mechanism of conversion, synthesis of diverse structures, and demonstration of resin capture. J Am Chem See (1996) 118:2574-2583. This is the first report on the concept of transient resin capture (covalent bond mediated capture) of solution-phase products as a means of purifying chemical library intermediates. Subsequent release of the captured product affords purified compounds for biological screening.
12. Brown SD, Armstrong RW: Synthesis of tetrasubstituted ethylenes on solid support via resin capture. J Am Chem Soc(1996) 118:6331-6332. This paper describes the covalent capture of vinyl boronlc ester intermediates by covalent bond formation to a polymer-tethered aryl iodide. Release of the tethered, purified products from the resin support is accomplished by TFA-mediated release from a silyltraceless linker.
13. Kaldor SW, Siegel M: Combinatorial chemistry using polymer-supported reagents. Curr Opin Chem Bio/ (1997) 1:101-106. This review highlights advances in the use of polymer-supported quench reagents and polymer-supported reagents/catalysts through early 1997.
14. Creswell MW, Bolton GL, Hodges JC, Meppen M: Combinatorial synthesis of dihydropyridone libraries and their derivatives. Tetrahedron (1998) 54:3983-3998. This paper highlights the feasibility of mult/step solution-phase chemical library synthesis, using polymer quenching techniques and liquid phase extractions as the only purification methods for the five step synthesis of a series of substituted 4-aminopiperidines. The use of polymer-supported quench techniques to purify incomplete reactions is also highlighted.
15. Parlow JJ, Flynn DL: Solution-phase parallel synthesis of a benzoxazinone library using complementary molecular reactivity and molecular recognition (CMR/R) purification technology. Tetrahedron (1998) 54:4013-4031. This paper highlights the feasibility of multistep solution-phase library synthesis using polymer-supported quenching techniques, polymeric reagents, and sequestration-enabling reagents as the purification methods in a five step benzoxazinone synthesis. The purification of incomplete reactions is also highlighted as a strength of this method compared to solid phase synthesis techniques.
16. Ault-Justus SE, Hodges JC, Wilson MW: Generation of a library of 4-thlazolidinones utilizing polymer supported quench (PSQ) reagent methodology. Biotechnol Bioeng (1998)61:17-22.
17. Parlow JJ, Vazquez ML, Flynn DL: A mixed resin bed for the quenching and purification of tetrabirrylammonium fluoride mediated desilylating reactions. Bioorg Med Chem Lett (1998) in press.
18. Parlow JJ: The use of anion exchange resins for the synthesis of combinatorial libraries containing aryl and heteroaryl ethers. Tetrahedron Z.e//(1996) 37:5257- 5260.
19. Xu W, Mohan R, Morrissey MM: Polymer-supported bases in combinatorial chemistry: synthesis of aryl ethers from phenols and alky I halides and aryl halides. Tetrahedron Lett (1997) 38:7337-7340.
20. Gayo LM, Suto MJ: Ion-exchange resins for solution-phase parallel synthesis of chemical libraries. Tetrahedron Lett (1997)38:513-516.
21. Suto MJ, Gayo-Fung LM, Palanki MSS, Sullivan R: Solution-phase parallel synthesis using ion-exchange resins. Tetrahedron (1998) 54:4141-4150. This paper highlights the use of ion exchange resins in the purification of solution-phase chemical libraries. The paper also highlights the use of ion exchange resins in the purification of 'resin release steps' wherein diversity elements are introduced into a chemical library upon release from a solid support.
22. Rynn DL, Devraj RV, Naing W, Parlow JJ, Weidner JJ, Yang S: High-throughput solution-phase chemical library synthesis/purification using molecular recognition-based sequestration strategies. Med Chem Res (1998) submitted for publication. This review summarizes the growing number of techniques that have been developed over the last two years in complementarymolecular reactivity and molecular recognition based purification strategies.
23. Sim MM, Ganesan A: Solution-phase synthesis of a combinatorial thiohydantoin library. J Org Chem (1997) 62:3230-3235.
24. Nikam SS, Kornberg BE, AulKlustus SF, Rafferty MF: Novel quenchers for solution-phase parallel synthesis. Tetrahedron Lett (1998) 39:1121-1124.
25. Chucholowski A, Masquelin T, Obrecht D, Stadlwieser J, Villalgordo JM: Novel solution- and solid-phase strategies for the parallel and combinatorial synthesis of low-molecularweight compound libraries. C/Mroa(1996) 50:525-530. This review highlights methods used for both solution-phase and solid phase synthesis. Of particular interest is their development of bifunctional solution-phase linking reagents (sequestration enabling reagents) that enable the sequestration of in situ tagged species from solution-phase.
26. Siegel MG, Hahn PJ, Dressman BA, Fritz JE, Grunweil JR, Kaldor SVV: Rapid purification of small molecule libraries by ion exchange chromatography. Tetrahedron Lett (1997) 38:3357-3360.
27. Parlow JJ, Naing W, South MS, Flynn DL In situ chemical tagging: tetrafluorophthalic anhydride as a "Sequestration Enabling Reagent" (SER) in the purification of solutionphase combinatorial libraries. Tetrahedron Lett (1997) 38:7959-7962. This paper highlights the use of tetrafluorophthalic anhydride as a sequestration-enabling reagent for the in situ chemical tagging of weak nucteophlles. The carboxy-tagged derivatives are then sequestered from solution-phase.
28. Parlow JJ, Mischke DA, Woodard SS: Utility of complementary molecular reactivity and molecular recognition (CMR/R) technology and polymer-supported reagents in the solution-phase synthesis of heterocyclic carboxamides. J Org Chem (I3S7) 62:5908-5919.
29. Starkey GW, Parlow JJ, Flynn DL: Chemically-tagged Mitsunobu reagents for use in solution-phase chemical library synthesis. BloorgMedChem £e//{1998) in press. Soluble, bifunctional chemically-tagged reagents are reported for use in the Mitsunobu reaction. Purification of chemical library reactions is accomplished by sequestration of the tagged reagent and reagent by-products from solution-phase.
30. Brown SD, Armstrong RW: Parallel synthesis of tamoxifen and derivatives on solid support via resin capture. J Org Chem (1997) 62:7076-7077. This paper describes the covalent capture of vinyl boronic ester intermediates by covalent bond formation to a polymer-tethered aryl iodide. Release of the tethered, purified products from the resin support is accomplished by TFA-mediated release from a silyltraceless linker. See reference [12].
31. Shuker AJ, Siegel MG, Matthews DP, Weigel LO: The application of high-throughput synthesis and purification to the preparation of ethanolamines. Tetrahedron Lett (1997)38:6149-6152.
32. Kulkami BA, Ganesan A: Ion-exchange resins for combinatorial synthesis: 2,4-pyrrolidinediones by Dieckmann condensation. Angew Chem Int Ed Engl (1997) 36:24542455.
33. Liu YS, Zhao C, Bergbreiter DE, Romo D: Simultaneous deprotection and purification of BOC-amines based on ionic resin capture. JOrg C/;e/n(1998) 63:3471-3473.
34. Virgilio M, Schurer SC, Ellman JA: Expedient solid-phase synthesis of putative β-turn mimetics incorporating the i + 1, i + 2, and i + 3 side chains. Tetrahedron Lett (1996) 37:6961-6964. This paper describes the use of ionic resin capture/release as a method for purifying a solution-phase tetramic acid library. This seminal report describes the use of a soluble, bifunctional carboxytagged phosphine reagent to mediate the release of polymer-bound intermediates into solution-phase. A polymer-bound guanidine is then utilized to remove the carboxy-tagged reagent and reagent byproduct.
35. Deegan TL, Gooding OW, Baudart S, Porco Jr JA: Nonacidic cleavage of Wang-derived ethers from solid support: utilization of a mixed-bed scavenger for DDQ. Tetrahedron Lett (1997) 38:4973-4976. This paper describes the use of DDQ to mediate the release of polymer-bound products into solution-phase. A mixed resin bed, containing polymer-bound ascorbate and a polymer-bound base, is employed to quench excess DDQ and sequester the phenolic DDQ by-product.
36. Rueter JK, Nortey SO, Baxter EW, Leo GC, Reitz AB: ArylsuKonate esters solid phase organic synthesis. I. Cleavage with amines, thiolate, and imidazole. Tetrahedron Lett (1998) 39:975-978.