Solid-Phase Synthesis of 3-Aminopyrrole-2,5-dicarboxylate Analogues

Abstract

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.

De Novo Conception of Small Molecule Modulators Based on Endogenous Peptide Ligands: Pyrrolodiazepin-2-one γ-Turn Mimics That Differentially Modulate Urotensin II Receptor-Mediated Vasoconstriction ex Vivo

“…(2 S ,4 R )-4-Hydroxy- N -1-(PhF)­proline was prepared as previously described , and converted to its cesium salt (2.1 g, 5.6 mmol, 2.5 equiv) as described in ref for attachment onto Wang bromide resin , (2.5 g, 0.9 mmol/g, 2.25 mmol) swollen in 100 mL of dry DMF in the presence of 2,3,11,12-dibenzo-1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene (1.4 g, 3.90 mmol, 1.75 equiv) in a 500 mL Morton flask. The reaction mixture was heated at 70 °C and agitated gently with a mechanical stirrer for 108 h. The beige brown resin was filtered, washed, and dried under vacuum before storage, usually under argon, in the refrigerator.…”

“…SynPhase spindles and cogs (Mimotopes Pty Ltd., Clayton, Victoria, Australia) were used to identify resins in Kans by color-coding. (2 S ,4 R )-4-Hydroxy- N -1-(PhF)­proline was prepared from (2 S ,4 R )-4-hydroxy- N -1-(PhF)­proline methyl ester according to refs and . Protected amino acids [Fmoc-Leu and Fmoc-Orn] were purchased from GL Biochem Ltd. (Shanghai, China).…”

“…The organic phase was dried with sodium sulfate and evaporated to a residue, which was purified by column chromatography (2% Et 2 O/hexanes). Evaporation of the collected fractions gave PhFH (0.129 g, 0.5 mmol, mp 146 °C, lit . mp 148 °C) corresponding to a loading of 0.89 mmol/g (81% conversion).…”

The 9-Phenyl-9-fluorenyl Group for Nitrogen Protection in Enantiospecific Synthesis

“…Pf as a protecting group for α-amino carbonyls has proven its utility in liquid phase synthesis. Its possibilities in solid phase synthesis have been examined [ 53 , 54 , 55 ] and it can act as a linker in the syntheses of alkaloids, heterocycles and amino acids. Structurally stable Pf-protected amino compounds on solid support are a valuable source in the building of chiral amino compounds libraries.…”

Solid-Phase Synthesis of Pyrrole Derivatives through a Multicomponent Reaction Involving Lys-Containing Peptides

“…Herein we report an efficient method based on that MCR for the solid-phase synthesis of peptide–pyrrole chimeras in which the pyrrole is built on the ε-amino function of a lysine (Lys) residue (Scheme ). MCRs are ideal for diversity-oriented synthesis and easy to implement, and they can be considered under the umbrella of green chemistry because they show a high atom efficiency…”