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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Pyrrolo[3,2-e][1,4]diazepin-2-one γ-Turn Mimic Synthesis onTAP Soluble SupportNicolas Boutard, Julien Dufour-Gallant, and William D. LubellDépartement de Chimie, Université de Montréal, C.P. 6128 Succursale Centre-Ville,Montréal, Québec, H3C 3J7, CanadaIntroduction1,4-Aryldiazepin-2-ones are privileged structures, which display a wide range of biologicalactivities, including antagonism at G-protein coupled receptors, enzyme inhibition andantibiotic activity. Moreover, the diazepin-2-one ring can mimic an inverse γ-turn peptideconformation (Figure 1) [1,2]. We have developed a modular solution-phase method foraccessing pyrrolo[3,2-e][1,4]diazepin-2-one scaffold 1 from N-(PhF)-4-hydroxyproline 3(Scheme 1) employing a diastereoselective Pictet-Spengler reaction [1]. Tetraarylphosphonium(TAP) salts have emerged as solubility control groups (SCGs) forapplications as soluble supports of reagents and for the preparation of small molecules andpeptides [3-5]. These SCGs are soluble in polar solvent systems and precipitated in lowpolarity solvents. In the context of a study directed towards the development of a supportedsynthesis of γ-turn mimics, we now present our results concerning the preparation ofheterocyclic scaffold 1 on TAP soluble support.Fig. 1. γ-Turn, pyrrolo[3,2-e][1,4]diazepin-2-one scaffold (1) and “Merrifield TAP” (2).Results and DiscussionSoluble supports offer practical advantages for organic synthesis such as the oppourtunityto perform reactions under homogenous conditions. Protocols used for the synthesis of 1 insolution [1] were adopted using “Merrifield resin-like” (4'-(bromomethyl)-[1,1'-biphenyl]-4-yl)triphenylphosphonium support 2 as its perchlorate salt [5] (Figure 1), because of itsstability to acidic conditions used in the TFA-catalyzed Pictet-Spengler reaction and itsease of precipitation in Et 2 O. All reactions were monitored by TLC (MeOH/CH 2 Cl 2eluents) and RP-HPLC-MS. Work-ups were followed by a saturated aqueous LiClO 4 wash,-to ensure the presence of the ClO 4 counteranion, a dionized water wash, drying oversodium sulfate and concentration. The resulting residue was disolved in a minimum volumeof CH 2 Cl 2 and precipitated upon addition of a 5-fold volume of Et 2 O.(2S,4R)-4-Hydroxy-N-(PhF)proline 3 was prepared according to the previouslydescribed procedure [6] and converted to the corresponding cesium salt, 4, by treatmentwith 20% Cs 2 CO 3 until pH 7, and dried under vacuum. “Merrifield-TAP”-bound4-hydroxy-N-(PhF)proline 5 was obtained by reacting cesium salt 4 (10 mol% excess) and2 with a catalytic amount of potassium iodide in DMF at 60°C for 3 h as indicated by TLC(Scheme 1) [7]. The alcohol was oxidized with oxalyl chloride, DMSO and DIEA in DCMat low temperature to give 4-oxoproline 6 in high conversion, albeit as an unstableintermiediate which was immediately used in the following step. Ketone 6 wasquantitatively converted to pyrrole 7 by reaction with N-benzylamine and a catalyticamount of p-TsOH at room temperature in CH 3 CN, because TAP salts have limitedsolubility in THF [8]. Amine acylation of 7 was accomplished using Fmoc-Phe activatedwith bis(trichloromethyl)carbonate (BTC) and 2,4,6-collidine in a DCM/THF 8:2 mixtureto allow solubility of all species [9]. The Fmoc group of the aminoacylpyrrole 8 wasremoved by treatment with a piperidine/DCM 1:1 mixture for 10 min. The key268