Resin capturing

Such a strategy follows the philosophy of resin capture, as introduced by Armstrong and Keating Keating TA, Armstrong RW. Postcondensation modifications of Ugi four-component condensation products 1-isocyano-cyclohexane as a convertible isocyanide. Mechanism of conversion, synthesis of diverse structures, and demonstration of resin capture. J Am Chem Soc 1996 118 2574-2583. See also Brown SD, Armstrong RW. Synthesis of tetrasubstituted ethylenes on solid support via resin capture. J Am Chem Soc 1996 118 6331-6332. 

This novel resin-bound CHD derivative was then utilized in the preparation of an amide library under microwave irradiation. Reaction of the starting resin-bound CHD with an acyl or aroyl chloride yields an enol ester, which, upon treatment with amines, leads to the corresponding amide, thus regenerating the CHD. This demonstrates the feasibility of using the CHD resin as a capture and release reagent for the synthesis of amides. The resin capture/release methodology [126] aids in the removal of impurities and facilitates product purification. 

Scheme 7.105 Generation of an amide library utilizing resin capture-release methodology.

A parallel solution-phase asymmetric synthesis of a-branched amines has been reported by Ellman and coworkers based on stereoselective addition of organomag-nesium reagents to enantiomerically pure tert-butanesulfinyl imines [156]. Micro-wave heating was utilized in two of the steps of this synthesis of asymmetric amines, both for the imine formation and for the resin capture (Scheme 7.128). 

Solution-phase library Resin scavenging Resin capture Split and mix... 

In a soluble polymer strategy comparable to resin-capture [145], Janda reported a MeO-PEGsooo-supported dialkyl borane reagent (31) that was used in the purification of a solution-phase library of y9-amino alcohols [146]. Purification was achieved by simply adding (31) to the crude reaction mixture followed by subsequent precipitation of the polymer with diethyl ether to give polymer-supported 1,3,2-oxazaboroU-dine (32) (Scheme 5.2). The /9-amino alcohol product could then be released from the soluble support by treatment with acid. In a two-step synthetic strategy that is readily amendable to automation, the isolation of a small library of /9-amino alcohols was accomplished with all compounds obtained in >80% purity. 

Scheme 7. Resin captured synthesis of polystyrene-bound chiral Co(salen) complex 36.

Scheme 2. The indole core structure is present in natural products and drugs, like for example Indomethacine and can therefore be considered as a privileged structure. A resin-capture-release strategy to synthesize an indole based compound library has been developed by Waldmann and co-workers.

A solid phase library synthesis method based on the Fischer indole synthesis was developed (Scheme A resin-capture-release method... 

X., Schultz, P. G. (2002) Resin-capture and release strategy toward combinatorial libraries of 2,6,9-substituted purines. J Comb Chem 4, 183-186. (b) Ding, S., Gray, N. 

A carbodiimide-grafted polystyrene resin was reacted with tetramethyl-guanidine to give an interesting biguanide structure (Scheme 13). This was assayed as a catalyst for a transesterification reaction.33 Incidentally, resin-bound guanidines are useful bases for processes involving resin capture.34... 

The work by Armstrong was extended to include the room temperature resin capture of trisubstituted ethenes with a pendant boronate group.80 Modification of the amide linker above to a novel silyl-based one allowed for the traceless cleavage of superior analogues. 

Keating, T. A. Armstrong, R. W. Postcondensation Modifications of Ugi 4-Component Condensation Products—1-Isocyanocyclohexane as a Convertible lsocyanide—Mechanism of Conversion, Synthesis of Diverse Structures, and Demonstration of Resin Capture, J. Am. Chem. Soc. 1996, 118, 2574-2583. 

Brown, S. D. Armstrong, R. W. Parallel Synthesis of Tamoxifen and Derivatives on Solid Support via Resin Capture, J. Org. Chem. 1997, 62, 7076-7077. 

Resin capture can be faster and more efficient than classical methods of purification (e.g., chromatography). Chemoselective sequestration requires minimal amounts of solvent for separating reactants from solution-phase products. Gradient elution techniques, common in chromatographic separations, are avoided, saving time and solvent. Additionally, concurrent use... 

Resin Capture of Products from Solution-Phase Syntheses... 

The first report of resin capture in solution-phase chemical library synthesis involved the covalent capture of solution-phase Ugi reaction products onto a functionalized polystyrene resin.73 Excess reactants, reagents, and reagent byproducts were washed away from the resin-captured intermediates. Further manipulation and release afforded purified solution-phase products for screening. More recently the same group reported on resin capture as a technique for the preparation of tetrasubstituted olefin libraries.74 75 As illustrated in Scheme 5, m-vinyl di-boryl esters were reacted with aryl halides (R3ArX) in parallel Suzuki reactions, leading to solution-phase intermediates. Another Suzuki reaction, this time with the... 

An interesting variant of cationic-resin capture has recently been reported wherein a strongly acidic cation exchange resin mediated sequential amine deprotection and resin capture (Scheme 6).78 Protected aminoalco-hols were reacted with an excess of isocyanates to form /V-BOC-amine carbamates in solution phase. Methanol was subsequently added to quench excess isocyanates as the neutral methyl carbamate byproducts. Sulfonic acid resin 51 was then used to affect amine-BOC group deprotection and resin capture of the deprotected amines. Washing of the resin bed and release (ammonia/methanol) afforded purified amine carbamate products. 

Anionic resin capture of solution-phase library products has also been reported. The anion exchange resin A-26 hydroxide 6 was used in a dual capacity to mediate Dieckmann condensations of solution-phase library intermediates and also to affect resin capture of the formed tetramic acids as polymer-bound intermediates (Scheme 7).79 Rinsing, followed by tri-... 

A four-step synthesis of a series of 4-hydroxyquinolinones starting from anthranilates is shown in Scheme 13.86 Resin capture of the Dieckmann cyclization intermediates was used as the main purification technique for this synthesis. Rinsing of the resin-captured adducts removed neutral and... 

Devraj, R. V. Naing, W. Parlow, J. J. Yang, S. Flynn, D. L. Resin-Capture of Solution Phase Thioureas and Thioamides by Polymer-Supported a-Bromo Ketones, Tetrahedron Lett., submitted. 

The second stage is the proof of principle In this phase, we take the initial theoretical library idea and begin to apply chemistry experiments to validate experimental designs and potential library schemes at this stage, one also evaluates the method of library production (solid/solution/hybrid phases). In this phase, which is usually the longest phase in any library production process, we will perform the initial experiments, optimize the chemical yields and purities, modify the experiments to generate easily removable by-products, which can be removed by traditional parallel purification methods (i.e. SPE, Resin capture), and determine the most feasible route to the final product. 

Grafting a scaffold to a polymeric support sometimes involves heterocycles having more than one atom susceptible to SNAr reactions. Characteristic examples for syntheses involving SNAr resin capture reactions are derivatizations of pyrazines,11 pyrimidines,12 and triazines.13,14... 

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