Catalytic Asymmetric Hydrogenation of 2,3,5-Trisubstituted Pyrroles

Abstract

Catalytic asymmetric hydrogenation of N-Boc-protected pyrroles proceeded with high enantioselectivity by using a ruthenium catalyst modified with a trans-chelating chiral bisphosphine PhTRAP. The ruthenium catalyst prepared from Ru(eta3-methallyl)2(cod) and (S,S)-(R,R)-PhTRAP in the presence of triethylamine was the most enantioselective for the asymmetric hydrogenation of methyl pyrrole-2-carboxylate, giving the desired (S)-proline derivative with 79% ee in 92% yield. Moreover, 2,3,5-trisubstituted pyrroles bearing a large substituent at the 5-position were hydrogenated with 93-99.7% ee. The asymmetric reduction of 4,5-dimethylpyrrole-2-carboxylate gave only all-cis isomer and created three chiral centers with high degree of stereocontrol in a single process. This is the first highly enantioselective reduction of pyrroles.

Adventure in Asymmetric Hydrogenation: Synthesis of Chiral Phosphorus Ligands and Asymmetric Hydrogenation of Heteroaromatics

“…In 2008, Kuwano and coworkers extended their catalytic system to the asymmetric hydrogenation of N-Boc-pyrroles using Ru(h 3 -methylallyl) 2 (cod)/(S,S)-(R,R)-PhTRAP as catalyst (Scheme 27) [105]. The selectivity can be improved by adding a catalytic amount of triethylamine with 99% ee.…”

Ferrocenyl‐Aryl Based trans‐Chelating Diphosphine Ligands: Synthesis, Molecular Structure and Application in Enantioselective Hydrogenation

“…Of all trans-spanning chiral ligands known to date, the TRAP ligand family shows by far the broadest range of applicability. The use of TRAP ligands leads to high conversion as well as moderate to high product enantiomeric excess, not only in the hydrogenation of alkenes and heterocycles [12,13] but also in hydrosilylations, [14] Michael reactions, [15] aldol reactions [16] and other transformations. [17] Over the years, our own efforts in ligand design have resulted in the development of a number of ciscoordinating diphosphine ligand families including the so-called Walphos ligands (Figure 1).…”

Intermolecular Dearomatization Reaction of Pyrroles Promoted by Silica Gel

“…[2] Among the substrates, pyrrole and its derivatives can undergo the dearomatization reaction to deliver complex molecules. For instance, in 2007, an elegant [4+3] cyclization of pyrrole with 2-(siloxy)vinyldiazoacetate catalyzed by adamantyl glycine-derived Rh 2 (S-PTAD) 4 was reported by Davies and co-workers, offering a promising access to optically active tropanes. [3] Later, the groups of Kuwano and Zhou and Fan reported asymmetric hydrogenative dearomatizations of pyrrole derivatives by chiral Ru and Pd catalysts, respectively.…”

“…[3] Later, the groups of Kuwano and Zhou and Fan reported asymmetric hydrogenative dearomatizations of pyrrole derivatives by chiral Ru and Pd catalysts, respectively. [4,5] Recently, we described a Pd-catalyzed intermolecular allylic dearomatization reaction of pyrroles, providing various chiral polysubstituted 2H-pyrroles in excellent enantioselectivity and regioselectivity (Scheme 1, top).…”