Resin-Supported Maleimide

Maleimide is a well-known Michael acceptor, dienophile and dipolarophile and hence is another versatile functional moiety that has found multiple uses in combinatorial chemistry as both a scavenger as well as a template in library synthesis [15]. Barrett [16] and Porco [17] have both reported the synthesis of a polystyrene resin-supported maleimide but did not report its use in the scavenging of nucleophiles. Hall and coworkers have described the synthesis of a supported-maleimide 

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A special case is the binding of maleimides onto Tr resins (151) [260]. The latter were used efficiently in Diels-Alder and [2 -1- 3]-heterodipolar additions [261]. By anchoring maleimide to a trityl chloride resin through its silver salt [260], Barrett and co-workers [261] were able, after performing a one-pot synthesis by combining the preformed free base of the amino ester, the aldehyde, the dehydrating agent, the Lewis acid and the base in the presence of the solid-supported maleimide, to obtain the desired cycloadduct product (157). In this way, they were able to produce a 120-member library (Scheme 32). 

Hoveyda et al. [262] prepared different N-aryhnaleimidobenzoic acids linked to SASRIN resin, whose double bond present in the maleimido moiety could act as a convenient dipolarophile in cycloaddition reactions. Thus, solution-generated a-iminoesters (from different aromatic aldehydes and aminoesters) were reacted vdth the supported maleimides (158) under Tsuge [263] conditions. Formation of the expected syn-endo cycloadduct (160) was observed after only 1 h at room temperature (Scheme 33). From structure-reactivity analysis, the authors concluded that the cycloaddition reaction is more sensitive to steric then to electronic factors on the azomethine yhde counterpart. The advantage of this procedure stems essentially from the fact that the iminoesters (159) are formed in situ. Aldehydes containing a-hydrogens could also be employed. Moreover, the resin in this case also plays the role of a protective group, because, in contrast with N-alkyl and N-aryl (see above) maleimides, N-unsubstituted maleimide is not suitable for 1,3 dipolar cycloadditions. 

Five-membered heterocycles with one nitrogen atom can be prepared from azomethine ylide-type dipoles and alkynes or alkenes. Several solid-supported cycloadditions with maleimide as a dipolarophile have been reported. Trityl resin-bound maleimide captured azomethine ylides that were generated in situ from amino acid methyl esters and aldehydes, and substituted resin-bound pyrrolidines were obtained (Scheme 11.1). Traceless cleavage of the C—N bond between acid-sensitive trityl resin and the IV-unsubstimted cycloadduct was achieved with 50% trifluoroacetic acid. 

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. 

Uncatalyzed Diels-Alder reactions and [2 + 3]-heterodipolar cycloadditions can be performed on a variety of acrylic or maleimide-based resins. One simple method is to link an acrylic residue to a polymeric support via an ester or an amide linkage. 

Alanine methyl ester (92 mg, 0.66 mmol) in toluene (2 mb) was added to a slurry of maleimide supported on trityl resin (200 mg, ca. 0.22 mmol),... 

Diels-Alder reaction with support-bound 4-[3-(tert-butyldimethylsilyloocy)buta-l,3-die-nyl] groups (Scheme 65) [310] N-[(Fluoren-9-ylmethoxycarbonyl)ethyl]maleimide (304) (135 mg, 0.375 mmol) was weighed into a screw-cap vial (Reacti-Vial) and toluene (800 pL) was added. The vial was sealed and heated until the dienophile dissolved, and resin bearing a diene (302 or 306) was added and allowed to swell in reagent and solution. The vial was sealed and kept at 110 °C overnight The reaction solution was drained and the resin washed as follows ... 

As shown in Scheme 4.3.4, several substituted hydroxybenzaldehydes 226 were attached to Wang resin 84 via an alkylaryl ether linkage through a Mitsunobu reaction to give 227. These polymer-supported aldehydes were allowed to react with an a-amino ester 228 and maleimide 229 in DMF to give immobilised proline analogues 230 that were liberated from the resin by treatment with 50% TFA to afford 231. The dipolar cycloaddition provided mixtures of diastereoisomers, which could be separated by HPLC. 

A simple, efficient multicomponent sequence was recently developed to synthesize a-hydroxyalkylpiperidine derivatives from a 4-boronohydrazonodiene, maleimides and aldehydes (Scheme 9.36) [78]. The high diastereoselectivity of these tandem reactions can be explained by a complete endo-selectivity in the first step and a cyclic chair-like transition state in the allylboration reaction. The absolute stereochemistry of the final products can be controlled by using an optically pure l-aza-4-borono-l,3 butadiene. This multi-component reaction can also be realized on a solid support, using an N-arylmaleidobenzoic acid functionalized resin. Very recently, this process... 

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