Polymer-supported reagents ester synthesis

From a medicinal chemist s point of view, oxadiazoles are among the most important heterocycles as they are one of the most commonly used bioisosters for amide and ester groups [67]. As such it is hardly surprising that the two regioisomeric oxadiazole scaffolds received the most interest in the field of microwave-assisted synthesis using polymer-supported reagents. 

Another field of application for active esters is solid-phase synthesis. Some polymer-supported reagents are available commercially (see Fig. 9). The acid is first immobilized on a polymer support as an active ester and the excess reagents are washed away conveniently. Finally, the amide is released by amine treatment. During the cleavage, a limited amount of amine can be used to avoid the presence of excess amine in the final mixture. The acid is loaded onto the resin using classic ester condensation methods for TFP resin 35 (66), HOBt resin 36 (67), and oxime resin 37 (68). In the case of the triazine resin 38, the acid is loaded via an aromatic nucleophilic substitution in the presence of a base (69). 

A convergent synthesis of the potent selective inhibitor of the enzyme phosphodiesterase sildenafil (Viagra) has been based on polymer supported reagents [134], In this synthesis, the HOBt-supported resin 126 has been used for the isolation and preparation of the resin-bound active ester 128, performed by coupling polymer 126 with the benzoic acid sulfonamide derivative 127 by means of PyBrop (Scheme 7.40). Subsequent reaction of active ester 128 with aminopyrazole 129 gave rise to the clean synthesis of amide 130, which has been transformed into sildenafil (131) after a base-promoted pyrimidinone formation. 

Wang resin served as the polymer support. Reagent 16 is a very effective coupling reagent for the synthesis of esters (17) and amides (18). 

The synthesis of some multiblock copolymers was attempted by successive polymerization using this iniferter technique. However, pure tri- or tetrablock copolymers free from homopolymers were not isolated by solvent extraction because no suitable solvent was found for the separation. In 1963, Merrifield reported a brilliant solid-phase peptide synthesis using a reagent attached to the polymer support. If a similar idea can be applied to the iniferter technique, pure block copolymer could be synthesized by radical polymerization. The DC group attached to a polystyrene gel (PSG) through a hydrolyzable ester spacer was prepared and used as a PSG photoiniferter (Eq. 53) [186] ... 

Kumari, K. A. Sreekumar, K. Polymeric Acyl Transfer Reagents Synthesis of Amides Using Polystyrene Supported Oximino Esters, Polymer 1996,37, 171. 

The majority of reported solid-phase combinatorial syntheses of the lactam core utilize a [2-i-2] cycloaddition reaction of ketenes with resin-bound imines [33-41]. A further development of the Staudinger reaction was reported by Mata and coworkers using Mukaiyama s reagent [42]. In addition, a stereoselective synthesis of chi-rally pure P-lactams has been performed as a first utilization of polymer-supported oxazolidine aldehydes [43]. Other strategies include an ester enolate-imine condensation [44], an Hg(OCOCF3)2-mediated intramolecular cydization [45], and Miller hydroxamate synthesis [46]. Because of the variability derived from the scaffold synthesis, not many attempts have been made to derivatize the resin-bound lactam template [47]. One of the most detailed descriptions of a versatile (3-lactam synthesis on a resin employed amino acids tethered as esters on Sasrin resin [48]. 

In the Merrifield method, the C-terminal amino acid is joined as a benzyl ester to the solid polymer support and then the polypeptide chain is extended one amino acid at a time from the N-terminal end. The advantage of polypeptide synthesis on a solid support is that the polymer beads with the peptide chains anchored on them are completely insoluble in the solvents used in the synthesis. Furthermore, excess reagents (e.g., DCC) and by-products (e.g., DCU) are removed after each step simply by washing the polymer beads. When synthesis is completed, the polypeptide is released from the polymer beads by cleavage of the benzyl ester. The steps in solid-phase synthesis of a polypeptide are summarized in Figure 27.11. 

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