Polymer-assisted solution-phase (PASP) library synthesis of α-ketoamides

Abstract

A parallel solution‐phase library synthesis of α‐ketoamides is described. The two‐step library synthesis is accomplished using polymer‐assisted solution‐phase (PASP) synthesis techniques. This high‐yielding, multi‐step sequence utilizes sequestering resins for the removal of reactants, reactant by‐products, and tagged reagents. The first step of the library synthesis utilizes PASP resins to mediate the amide coupling of an α‐hydroxy acid with an amine. The second step uses PASP resins for the periodinane oxidation of the α‐hydroxy acid to an α‐ketoamide leaving highly pure products after simple filtration and evaporation. © 2000 John Wiley & Sons, Inc. Biotechnol Bioeng (Comb Chem) 71:51–57, 2000.

Immobilized Carbodiimide Assisted Flow Combinatorial Protocol to Facilitate Amide Coupling and Lactamization

“…However, for solvent, the necessity for benzotriazole additives, and reaction tolerance to non-nucleophilic bases, a significant level of contradiction is observed. For solvent dichloromethane (DCM) and chloroform (CHCl 3 ) have been traditionally favored because of superior resin swelling capabilities. ,,,,,,,,,− Furthermore, it has been proposed that solvent polarity endows significant impacts . For example, polar aprotic solvents, including acetonitrile, dimethyl sulfoxide, 1,2-dichloroethane, and tetrahydrofuran (THF), have been reported to impart deleterious effects .…”

“…However, upon employing identical reaction conditions, along with one-equivalent of HOBt under microwave irradiation, reaction conversion increased to >95% . Conversely, numerous examples of near quantitative conversion have been reported in the absence of a benzotriazole additive, although perhaps of significance, these protocols were performed within DCM ,,,,, or CHCl 3 , ,, whereas the Sauer protocol employed DMA as a solvent.…”

“…For these, ring-opening metathesis (ROMP)-based and polyethylene glycol-based (PEG)-based polymers were employed as immobilization matrices (i.e., 2 and 3, Figure 1, respectively); however, these have received minimal attention 11−15 At present, a handful of PS-carbodiimide resins are commercially available, and of these, the most commonly utilized are resin-4 16−22 and resin-5, 23−30 and the ethylcarbodiimide functionalized resin-6 31−37 (Figure 2). These resins have been successfully employed in a myriad of synthetic programs ranging from combinatorial synthesis, 22,23,26,28,38 diversity orientated synthesis, 16,27,33,36 peptide macrocyclization, 39,40 and within the synthesis of an approved pharmaceutical agent. 19 While there exists some anecdotal evidence that immobilization can enhance the reactivity of a carbodiimide reagent through a "site-isolation" or a "pseudodilution-effect", 41,42 the primary advantages of utilizing solid-supported carbodiimide reagents are realized during reaction workup and purification.…”

“…Further, it is becoming increasingly evident that the advantages provided by immobilized species have only been partially realized through their application in batch-based chemistries. Indeed, it is becoming apparent that additional gains are attainable when these agents are integrated into flow-based synthetic protocols. − …”

“…At present, a handful of PS-carbodiimide resins are commercially available, and of these, the most commonly utilized are resin- 4 − and resin- 5 , − and the ethylcarbodiimide functionalized resin- 6 − (Figure ). These resins have been successfully employed in a myriad of synthetic programs ranging from combinatorial synthesis, ,,,, diversity orientated synthesis, ,,, peptide macrocyclization, , and within the synthesis of an approved pharmaceutical agent …”