Polymer-supported ester

Polymer-supported esters are widely used in solid-phase peptide synthesis, and extensive information for this specialized protection is reported annually. Some activated esters that have been used as macrolide precursors and some that have been used in peptide synthesis are also described in this chapter the many activated esters that are used in peptide synthesis are discussed elsewhere. A useful... 

The first, and still widely used, polymer-supported ester is formed from an amino acid and a chloromethylated copolymer of styrene-divinylbenzene. Originally it was cleaved by basic hydrolysis (2 N NaOH, FtOH, 25°, 1 h). Subsequently, it has been cleaved by hydrogenolysis (H2/Pd-C, DMF, 40°, 60 psi, 24 h, 71% yield), and by HF, which concurrently removes many amine protective groups. Monoesterification of a symmetrical dicarboxylic acid chloride can be effected by reaction with a hydroxymethyl copolymer of styrene-divinylbenzene to give an ester a mono salt of a diacid was converted into a dibenzyl polymer. ... 

Polymer-supported esters are widely used in solid-phase peptide synthesis, and extensive information on this specialized protection is reported annually. Some activated esters that have been used as macrolide precursors and some that have been used in peptide synthesis are also described in this chapter the many activated esters that are used in peptide synthesis are discussed elsewhere. A useful list, with references, of many protected amino acids (e.g., -NH2, COOH, and side-chain-protected compounds) has been compiled/ Some general methods for the preparation of esters are provided at the beginning of this chapter conditions that are unique to a protective group are described with that group/ Some esters that have been used as protective groups are included in Reactivity Chart 6. 

Mendez L, Testero SA, Mata EG (2007) For hydrolysis of polymer-supported esters by TMTOH. Tetrahedron Lett 48 1757... 

Enholm [26] has reported the first examples of asymmetric radical cy-clizations on soluble polymer supports. The stereocontrol element employed consists of a (+)-isosorbide group attached by a 4-carbon chain to each subunit of a soluble succinimide-derived ROMP backbone. Treatment of the radical cychzation substrate 162 with tributyltin hydride in the presence of zinc chloride followed by hydrolysis of the resulting polymer-supported ester 163 gave the desired product 164 in 80% yield and > 90% ee (Scheme 38). The use of alternative Lewis acids, such as magnesium bromide etherate and ytterbiiun (III) triflate, resulted in lower enantioselectivities, 84% and 72% respectively. No such decrease in selectivity was observed in analogous reactions carried out off-support [27], suggesting that the polymer backbone is somehow responsible for this phenomenon. 

Walters, M. A. Chameleon catches in combinatorial chemistry Tebbe olefination of polymer supported esters and the synthesis of amines, cyclohexanones, enones, methyl ketones and thiazoles. Chemtracts 1999,12, 679-683. 

The substitution of chlorine by PhCHjCO and CH2=CHC02 in a soluble chloromethylated polystyrene leads to polymer-supported esters that may be used for the preparation of cyclopropyl derivatives. This is the first report of a reaction between two functionalized polymers. ... 

One widely used method of formation of protected compounds involves polymer-supported reagents, with the advantage of simple workup by filtration and automated syntheses, especially of polypeptides. Polymer-supported reagents are used to protect a terminal — COOH group as a polymer-bound ester (RCOOR —( ) during peptide syntheses, to protect primary alcohols as... 

A polymer-supported sulfonamide, prepared from an amino acid activated ester and a polystyrene-sulfonamide, is stable to acidic hydrolysis (CF3COOH HBr/ HOAc). It is cleaved by the safety-catch method shown below. ... 

Desyl bromide, DBU, benzene, reflux, 57-95% yield. A polymer-supported version of this ester has been prepared. ... 

A polymer-supported sulfonamide, prepared from an amino acid activated ester... 

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. 

The N-substituted aminoacids required could be prepared by microwave-assisted reductive amination of aminoacid methyl esters with aldehydes, and although in the Westman report soluble NaBH(OAc)3 was used to perform this step, other reports have shown how this transformation can be performed in using polymer-supported borohydrides (such as polymer-supported cyanoborohydride) under microwave irradiation [90]. An additional point of diversity could be inserted by use of a palladium-catalyzed reaction if suitably substituted aldehydes had been used. Again, these transformations might eventually be accomplished using supported palladium catalysts under microwave irradiation, as reported by several groups [91-93]. 

In 2004, Weberskirch and co-workers tried a new approach by synthesising [RhBr(COD)(NHC)] 23 (NHC = l-(2 -hydroxyethyl)-3-methylimidazolidine-2-ylidene) [28]. Subsequently, attaching the unsymmetrical, monohydroxy-functionalised NHC by ester groups to an amphiphilic, water-soluble polymer support (ps)... 

Preparation of Esters by Use of a Polymer-Supported Carboxylic Acid Imidazolide... 

In 2001, Sarko and coworkers disclosed the synthesis of an 800-membered solution-phase library of substituted prolines based on multicomponent chemistry (Scheme 6.187) [349]. The process involved microwave irradiation of an a-amino ester with 1.1 equivalents of an aldehyde in 1,2-dichloroethane or N,N-dimethyl-formamide at 180 °C for 2 min. After cooling, 0.8 equivalents of a maleimide dipo-larophile was added to the solution of the imine, and the mixture was subjected to microwave irradiation at 180 °C for a further 5 min. This produced the desired products in good yields and purities, as determined by HPLC, after scavenging excess aldehyde with polymer-supported sulfonylhydrazide resin. Analysis of each compound by LC-MS verified its purity and identity, thus indicating that a high quality library had been produced. 

As a suitable model reaction, the coupling of various substituted carboxylic acids to polymer resins has been investigated by Stadler and Kappe (Scheme 7.8) [28]. The resulting polymer-bound esters served as useful building blocks in a variety of further solid-phase transformations. In a preliminary experiment, benzoic acid was attached to Merrifield resin under microwave conditions within 5 min (Scheme 7.8 a). This functionalization was additionally used to determine the effect of micro-wave irradiation on the cleavage of substrates from polymer supports (see Section 7.1.10). The benzoic acid was quantitatively coupled within 5 min via its cesium salt utilizing standard glassware under atmospheric reflux conditions at 200 °C. 

Varma and Kappe have developed a method that enables the rapid and parallel synthesis of DHPM 58 (Scheme 8.22) but does not rely on polymer-supported building blocks and therefore does not require the development of solid-phase linkingcleaving chemistry. They showed that polyphosphate ester (PPE) serves as an excel-... 

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