Solid-Phase Synthesis of 3-Aminopyrrole-2,5-dicarboxylate Analogues Yann Brouillette, Frederik J. R. Rombouts, and William D. Lubell* De ´ partement de Chimie, UniVersite ´ de Montre ´ al, C.P. 6128, Succursale Centre Ville, Montre ´ al, Que ´ bec, Canada H3C 3J7 ReceiVed July 14, 2005 An efficient strategy has been developed for the solid-phase parallel synthesis of 3-aminopyrrole-2,5- dicarboxylate analogues. A library of twenty-nine 2,3,5-trisubstituted pyrroles has been synthesized on Wang resin by a 5-6 step process. The attachment of (2S,4R)-4-hydroxy-N-(PhF)proline cesium salt (PhF ) 9-(9- phenylfluorenyl)) to Wang bromide resin, followed by alcohol oxidation, produced the resin-bound 4-oxo- N-(PhF)prolinate as the pyrrole precursor. Resin-bound 3-aminopyrroles were synthesized by treatment of the oxo-N-(PhF)prolinate resin with different secondary amines and diversified at the 2-position by acylation with trichloroacetyl chloride and haloform reactions with primary amines. 3-Aminopyrrole-2,5-dicarboxylates were isolated in 81-99% purity and 51-99% yields after cleavage from the resin using TFA or sodium methoxide. Introduction Substituted pyrroles are commonly found in natural products, 1,2 drugs, 3,4 conducting materials, 5,6 and insecticides. 7 Amides derived from pyrrole-2-carboxylates are particularly important structural motifs in biologically active molecules likely because of their potential to engage in hydrogen-bond interactions with natural macromolecules. For example, polyamides formed from linking 4-aminopyrrole-2-carboxy- lates serve in the recognition of DNA by natural products, such as distamycin and netropsin (Figure 1) as well as by synthetic analogues that have exhibited antibiotic, antiviral, antimicrobial, and oncolytic properties. 8-16 Amide analogues of pyrrole carboxylates, such as 1 and 2, have similarly served in the recognition of amino acids and peptides in water. 17,18 Moreover, 3-aminopyrrole-2-carboxylates, such as 3, have exhibited anticonvulsant activity by blocking sodium channels in a frequency-dependent manner. 19 Recognizing the importance of 3- and 4-aminopyrrole-2-carboxylates, as well as pyrrole-2,5-dicarboxylates, as motifs for molecular recognition, we have developed a solid-phase strategy for the synthesis of 3-aminopyrrole-2,5-dicarboxylate analogues to provide a novel group of potential ligands and pharma- cophores for the development of drugs and tools for chemical-biology. The pyrrole ring system has been previously synthesized on solid supports by several methods. For example, lamel- larins U and L (Figure 1) have been made by N-alkylation of a supported iodoacetate with 3,4-dihydro-6,7-dimethoxy- isoquinoline followed by [3 + 2] cycloaddition. 20 Few solid- phase methods have, to the best of our knowledge, provided libraries of pyrrole analogues. For example, the cycloaddition of alkynes to solid-supported 1,3-dipoles (method A, Figure 2) 21-23 has been used to provide pyrrole libraries; however, regioisomeric mixtures were obtained using unsymmetrical alkynes. 21 Hantzsch 24 cyclocondensations of resin-bound enaminones with R-bromoketones (method B, Figure 2) 25 has given access to a library of pyrroles; furthermore, related resin-supported Hantzsch methodology has successfully used cyclocondensations of nitroalkenes, 26 aldehydes and nitro- alkanes, 26 and -ketoamides. 27 The Paal-Knorr 28,29 conden- sation of polymer-supported 1,4-diketones with primary amines (method C, Figure 2) has produced tetrasubstituted pyrroles. 30 1,3-Dipolar cycloadditions onto supported vinyl sulfones and the subsequent pyrrole annulation (method D, Figure 2) have delivered isoxazolinopyrrole-2-carboxy- lates. 31,32 Furthermore, pyrrole formation by the homo- coupling of two solid-supported ketones has furnished a * To whom correspondence should be addressed. E-mail: lubell@ chimie.umontreal.ca. Figure 1. Representative examples of bioactive pyrrole 2-car- boxylate analogues. 117 J. Comb. Chem. 2006, 8, 117-126 10.1021/cc0500912 CCC: $33.50 © 2006 American Chemical Society Published on Web 11/23/2005