Sasrin aldehyde

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. 

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]. 

Chloromethyl resin Wang resin 2-Chlorotrityl resin Rink amide resin Hydroxymethyl resin Sasrin resin Sieber resin Aldehyde resin PAL amide resin TentaGel S NH2... 

In a similar fashion, resin-bound imines 109 were employed to prepare a library of structurally diverse P-lactams by [2+2] cycloaddition reactions with different ketenes. Thus, as shown in Scheme 4.1.22, amino acids tethered to the acid labile Sasrin resin (103) were condensed quantitatively to imines 109 by using a large excess of alkyl, aryl, or a,P-unsaturated aldehydes in a mixture of trimethylorthoformate and dichloromethane. Optimisation studies of the [2+2] cycloaddition step, showed that conversion to P-lactams 110 could only take place by slow addition of acid chlorides to a suspension of the imine resin at 0°C in the presence of triethylamine. By using a large excess of ketene at high concentration, the cycloaddition of imines derived from even sterically hindered amino acids [e.g. valine) could be carried out with full conversion. After mild TFA cleavage from the resin and preparative HPLC purification, the p-lactams 111, 112 were isolated in yields of 55-97%. 

Resin-bound maleimide has been used as a dipolarophile in the synthesis of N-substituted pyrrolidines as well (Scheme 11.2). " Cycloaddition with a-imino esters, which were generated from aryl aldehydes and amino acid esters, yielded resin-bound pyrrolidines. The compounds were bound to the acid-cleavable SASRIN resin with an ester linkage and then cleaved from the resin as carboxylic acids with highly diluted trifluoroacetic acid. 

A library of highly functionalized pyrrolidines was prepared from resin-bound azomethine ylides and electron-deficient olefins (Scheme 11.7). Four amino acids, four aldehydes, five olefins, and three acyl chlorides were used as building blocks to produce a library of diverse cycloadducts for various enzymatic assays. Ester-linked products were cleaved from TentaGel or SASRIN resins as carboxylic acids with diluted trifluoroacetic acid. Structural diversity of the proline derivatives was enhanced with iV-acylation of the pyrrolidines. 

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