[2 + 1] Cycloaddition of Catalytic Ruthenium Vinyl Carbenes: A Stereoselective Controlled Access to (Z)- and (E)-Vinyl Epoxypyrrolidines

Abstract

Aza-alkynals undergo a cyclization reaction with diazo compounds in the presence of catalytic amounts of Cp*RuCl(cod) to afford vinyl epoxypyrrolidines, valuable building blocks for the synthesis of biologically active molecules. Ruthenium vinyl carbene intermediates have been invoked to explain the overall [2+1] cycloaddition (epoxy-annulation reaction). The reaction proceeds under mild conditions and in short reaction times (5-80 min) with complete (Z)or (E)-stereoselectivity on the vinyl substituent depending on the nature of the diazo compound used. Theoretical calculations support a mechanistic rationale to explain this controlled process.

Recent Advances in Ruthenium-Catalyzed Carbene/Alkyne Metathesis (CAM) Transformations

“…To explain the observed E stereoselectivity when conjugated diazoalkanes were used, DFT calculations for the transformation from alkyne-carbene complexes A′ to Zand E-ruthenium vinyl carbenes D′ and E′, respectively, were performed (Scheme 29). 29 From the results, trimethylsilyldiazomethane favor the formation of Z-vinyl ruthenium D′ carbenes by 3.1 kcal mol -1 , while conjugated diazoalkanes favor the formation of Evinyl ruthenium carbenes E′ (from 1.9 kcal mol -1 for the…”

“…Scheme 18 Ruthenium-catalyzed heterocyclizations of N-tethered alkynals and alkynones to 2-vinyl oxazine derivatives; Tis = 2,4,6-triisopropylphenyl Remarkably, 2,2-disubstituted aza-alkynals undergo a divergent cyclization reaction leading to vinyl epoxypyrrolidines (n = 0) and epoxypiperidines (n = 1), valuable building blocks for the synthesis of bioactive compounds (Scheme 19). 29 Scheme 19 Cp*Ru(cod)-catalyzed cyclization of ,′-disubstituted aza-alkynals and trimethylsilyldiazomethane to epoxypyrrolidines and epoxypiperidines…”

Synthetic Applications of Vinyl Ruthenium Carbenes Derived from Diazoalkanes and Alkynes

“…Recently, an intramolecular epoxy‐annulation reaction ([2+1] cycloaddition) between the vinyl ruthenium carbene and the π (C=O) bond of aza‐alkynals 62 to furnish vinyl epoxypyrrolidines 63 stereoselectively in good yields was achieved by Saá (Scheme ) …”

Cp*RuCl‐Vinyl Carbenes: Two Faces and the Bifunctional Role in Catalytic Processes

“…Alternatively, our research group and others have been reporting the use of Cp/Cp*RuCl‐based complexes (Cp=cyclopentadiene, Cp*=1,2,3,4,5‐pentamethylcyclopentadiene) for the catalytic generation of ruthenium vinyl carbenes from alkynes and diazo compounds through intermolecular CAM (Figure c) . These intermediates can lead to dienes, cyclopropanes, C−H insertion products, or ylide intermediates, which eventually afford benzoxazines, furans, vinyl dihydropyrans/dihydrooxazines, and vinyl epoxypyrrolidines . Remarkably, Cp*/CpRuCl‐based complexes were the only complexes to give productive tandem CAM processes.…”

“…[11] Thesei ntermediates can lead to dienes, [12] cyclopropanes, [13] CÀHi nsertionp roducts, [14] or ylide intermediates,w hich eventually afford benzoxazines, [15] furans, [16] vinyld ihydropyrans/dihydrooxazines, [17] and vinyl epoxypyrrolidines. [18] Remarkably, Cp*/CpRuCl-based complexesw ere the only complexes to give productivetandem CAM processes.…”