Organocatalytic Asymmetric Mannich Cyclization of Hydroxylactams with Acetals: Total Syntheses of (−)‐Epilupinine, (−)‐Tashiromine, and (−)‐Trachelanthamidine

Abstract

An asymmetric, organocatalytic, one-pot Mannich cyclization between a hydroxylactam and acetal is described to provide fused, bicyclic alkaloids bearing a bridgehead N atom. Both aliphatic and aromatic substrates were used in this transformation to furnish chiral pyrrolizidinone, indolizidinone, and quinolizidinone derivatives in up to 89% yield and 97% ee. The total syntheses of (-)-epilupinine, (-)-tashiromine, and (-)-trachelanthamidine also achieved to demonstrate the generality of the process.

New syntheses of (±)-tashiromine and (±)-epitashiromine via enaminone intermediates

“…Pure samples for characterisation could be obtained by flash column chromatography on silica gel using a 95:4.75:0.25 mixture of methanol/dichloromethane/ammonium hydroxide. The spectroscopic data compared well with previously published results [7]. In particular, 13 C chemical shifts for both tashiromine and epitashiromine were within ±1.0 ppm of those reported by Dieter et al [32] and Kim et al [33].…”

Eantiospecific Synthesis of Chiral Pyrrolidine‐fused Piperazine Derivatives via Diaza‐Cope Rearrangement

“…Despite the potential importance of this type of compounds in pharmaceutical industry, the lack of a general asymmetric protocol to access enantiomerically pure molecules possessing the bicyclic structure has largely prevented their exploitation in the studies of physiologically active compounds. To the best of our knowledge, reports on the asymmetric synthesis of the bicyclic piperidinopyrrolidine structure have been scarce . In 2014, Koley et al .…”

“…To the best of our knowledge, reports on the asymmetric synthesis of the bicyclic piperidinopyrrolidine structure have been scarce. 10,11 In 2014, Koley et al reported an asymmetric synthesis of piperazinopyrrolidinones via organocatalytic Mannich-type cyclization from a hydroxylactam and an acetal using MacMillan's catalyst. 10 However, the scope of this protocol is somewhat limited: asymmetric synthesis of only three examples having a common hydroxymethyl substitution on the piperazine ring was reported.…”

“…10 However, the scope of this protocol is somewhat limited: asymmetric synthesis of only three examples having a common hydroxymethyl substitution on the piperazine ring was reported. 10,11 Therefore, development of a general synthetic method to access both stereoisomers of enantiomerically pure piperazinopyrrolidine core structure would be highly desirable. Herein, we report a new asymmetric synthesis of enantiomerically pure chiral piperazinopyrrolidinone derivatives 1 via diaza-Cope rearrangement (DCR) (Scheme 1).…”

Cinchona Alkaloid Catalyzed Sulfa-Michael Addition Reactions Leading to Enantiopure β-Functionalized Cysteines

“…1 This is manifested in the increasing number of successful studies that have been reported for a large variety of organic reactions, such as the Henry reaction, 2 Michael additions, 3 Mannich reactions, 4 Morita-Baylis-Hillman reactions, 5 cycloadditions 6 and multi-component cascade reactions. 7 In most of the reported studies, the reactions are performed with organocatalysts derived from a limited number of privileged structures e.g.…”