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Procedure

A 1-L single-necked, round-bottomed flask was charged with Wang resin (50.0 g, 36.5 mmol), DMF (500 mL), triphenylphosphine (47.9 g, 5 equiv.), and carbon tetrabromide

(60.5 g, 5 equiv.). The flask was shaken for 2.5 h at rt, and the resin was then filtered, washed sequentially (300 mL volumes) with DMF (twice), DCM (twice), DMF (twice), DCM (twice), and /'-PrOH (twice), and dried by bubbling air through the resin.The resin was suspended in DMF and reacted with 4-fluoro-3-nitrobenzoic acid (13.5 g, 2 equiv.), cesium iodide (18.96 g, 2 equiv.), and DIEA (9.43 g, 2 equiv.) at rt overnight. The final yellow resin was filtered, washed thoroughly (300 mL volumes) with water (twice), DMF (twice), DCM (twice), /'-PrOH (twice), water (twice), DMF (twice), DCM (twice), /'-PrOH (twice), and dried, first by bubbling air through it and then in an oven (70° C) under reduced pressure overnight to afford a 3-nitro-4-aniline benzoate resin 100 with the theoretical loading of 0.698 mmol g_1.

A 50-mL single necked, round-bottomed flask was charged with the 4-fluoro-3-nitroben-zoic acid loaded resin 100, the amino acid ester hydrochloride salts (2 equiv.), and 5 % DIEA/DMFThe mixture was agitated at rt for 24 h, filtered, washed with DMF (three times), DCM (three times), /'-PrOH (three times) in that order twice, and dried to afford enan-tiomerically pure aniline intermediate 101.

The intermediate resin 101 (150 mg) was treated with oxygen-free 2 M SnCI2 (20 equiv.), and oxygen-free DMF (1.5 mL). The reaction vessel was purged with argon for 1 min , sealed, and agitated overnight in a pre-heated heating block (80° C).The resin was then filtered and washed thoroughly (1.5-2.0 mL volumes) with water (three times), /'-PrOH (three times), DCM (three times), /'-PrOH (three times), and CHCI3 (three times) and dried to afford the benzopiperazinone resin 102.

Introduction of N4 acyl groups was achieved by treatment of the N4-unsubstituted benzopiperazinone resin 102 (150 mg) with NaHC03 (10 equiv.), and chloro- or thiochlorofor-mate (10 equiv.) in anhydrousTHF (1.5 mL).The reaction vessel was purged with argon for 1 min , sealed, and agitated overnight in a pre-heated heating block (80° C).The resin was then filtered and washed thoroughly (1.5-2.0 mL volumes) with water (three times), /-PrOH (three times), DCM (three times), /-PrOH (three times), and CHCI3 (three times) and dried to provide the resin-bound N4-substituted benzopiperazinone resin 103.

3.4.18 Tctrahydro-P-carbolines

The combinatorial chemist's considerable interest in the tetrahydro-3-carboline scaffold (1,2,3,4-tetrahydropyrido [3,4-b]indoles) is already reflected by various published reports on the efforts to derivatize this compound class efficiently on solid phase. Tetrahydro-P-car-bolines are a key structural motif common to a large class of tryptophan-derived natural product alkaloids, and have been shown to have the potential to interact with biological targets. The spectrum of pharmacological properties is broad within this compound class, and includes the modulation of central nervous system targets [136], For instance, compounds inhibiting monoamine oxidase A or binding with serotonin receptors are known [137]. Binding with the GABAA receptor ion channel and the modulation of anxiety control mechanisms, convulsion and sleep have also been reported [138,139]. In principle, P-carbolines possess sufficient sites for functionalization in order to allow the production of diverse combinatorial libraries. Mostly, it is the chemistry of the Pictet-Spengler [140] reaction that was used in developing solid-phase synthesis protocols. This reaction, based on the intramolecular inter-

action between an iminium ion and an aromatic C-nucleophile, utilizes tryptophan analogs and aldehydes (or ketones) to afford P-carboline derivatives that can be further functional-ized with acid halides, isocyanates, and sulfonyl chlorides. On the other hand, the reported low reactivity of the position-2 nitrogen seems to preclude broad systematic derivatization [141]. Nonetheless, with the availability of a wide variety of aldehydes and ketones, as well as a number of substituted tryptophan derivatives, a reasonably large number of P-carbolines may be aimed for. For the solid phase, a linker which will withstand the acid Pictet-Spengler conditions is required. The Wang linker [142] used by Mayer et al. [141] (Scheme 29), although acid-cleavable, is sufficiently stable, and the Kaiser linker employed in Scheme 28 [143] is also entirely unaffected at higher acid concentrations. A 4-hydroxythiophenol linker proposed in [144] (Scheme 30) is useful for the incorporation of additional diversity during the cleavage from the solid support by aminolysis of the ester linkage with a primary amine. Alternatively, acylation at the carboline 2-position with Boc-protected a- or P-amino acid derivatives, followed by deprotection and neutralization, results in an intramolecular cycliza-tion and cleavage to afford six- and seven-membered bis-lactams.

2. R2CHO In DCM. 6 h time linker time linker

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