One-Pot Diastereoselective Synthesis of Pyrrolopiperazine-2,6-diones by a Ugi/Nucleophilic Substitution/N-Acylation Sequence

Abstract

The diastereoselective synthesis of two families of pyrrolopiperazine-2,6-diones is presented. These compounds were prepared by one-pot Ugi/nucleophilic substitution/N-acylation/debenzoylation/(elimination) sequences. This novel route provides straightforward access to a wide variety of pyrrolopiperazine-2,6-diones with high chemical yields and complete diastereoselectivities. The proposed synthetic strategy poses a significant improvement compared to the syntheses of pyrrolopiperazine-2,6-diones previously described, as it allows introduction of different substituents to the C4 position and the diastereoselective generation of a new stereogenic center on the bridgehead carbon (C8a).

Stefano Marcaccini: a pioneer in isocyanide chemistry

“…Following a one-pot two-step methodology, García-Valverde et al described the diastereoselective synthesis of pyrrolopiperazine-2,6-diones ( 502 ). The synthesis is carried out through an Ugi/nucleophilic substitution/ N- acylation/debenzoylation sequence using three doubly functionalised reactants –phenylglyoxal ( 498 ), α-amino esters ( 499 ) and 3-bromopropionic acid ( 468 )- along with the isocyanide ( 31 ; Scheme 103 ) [ 169 ].

Scheme 103 Synthesis of pyrrilopiperazine-2,6-diones

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Concise Synthesis of 2,5-Diketopiperazines via Catalytic Hydroxy-Directed Peptide Bond Formations

“…Although diverse synthetic methodologies have been reported to construct 2,5-diketopiperazines, − including tandem intramolecular N -alkylation of Ugi four-component reaction products, intramolecular C-acylation of peptide enolates, and intramolecular Tsuji–Trost allylation, one of the direct and versatile approaches to synthesize DKPs is the condensation between two amino acids followed by intramolecular cyclization of dipeptide sequences . A significant advantage of this process is the ability to synthesize diversity-oriented DKPs using readily available amino acid components.…”

Stereoselective Synthesis of 12-Tetrazolyl Substituted (E)-5H-Quinazolino[3,2-a]quinazolines via Sequential Ugi-Azide/Staudinger/aza-Wittig/Addition/Ag(I)-Catalyzed Cyclization

“…The isocyanide based multicomponent reactions (I-MCRs), especially Ugi four-component reactions, have played a vital role in organic and medicinal chemistry due to their efficient construction of small-molecule libraries in a mild one-pot fashion. , The Ugi-azide reactions have also provided a powerful method for synthesis of 1,5-disubstituted tetrazoles, as the carboxylic acid component is changed to hydrazoic acid (produced in situ from NaN 3 or TMS-N 3 ). − In recent years, the sequence of Ugi reaction and other organic reactions has been successfully applied in the synthesis of many heterocyclic compounds. − For example, the tandem post-Ugi cyclization and Gold­(I)-catalyzed regioselective annulation were utilized in the preparation of densely functionalized pyrrolo­[1,2- a ]­pyrazine-3,6­(2 H ,4 H )-diones in good to excellent yields . Diverse benzazepinoindoles were assembled in a step-economical, chemo- and regioselective fashion by an Ugi/gold-catalyzed alkyne hydroarylation/Michael addition sequence .…”

“…Diverse benzazepinoindoles were assembled in a step-economical, chemo- and regioselective fashion by an Ugi/gold-catalyzed alkyne hydroarylation/Michael addition sequence . Pyrrolopiperazine-2,6-diones were synthesized by employing a simple Ugi/nucleophilic substitution/N-acylation/debenzoylation sequence with high chemical yields and good diastereoselectivities . Aza-Wittig reaction has become an effective method for preparing nitrogen-containing heterocyclic compounds. − Therefore, we envisage that some heterocyclic compounds would easily be prepared if the Ugi-azide reaction was efficiently combined with the aza-Wittig reaction.…”