Asymmetric Synthesis of Enantioenriched 6-Hydroxyl Butyrolactams Promoted by N-Heterocyclic Carbene

Abstract

Herein, an efficient route to synthesize 6-hydroxyl butyrolactams has been successfully developed via an N-heterocyclic carbene-catalyzed formal [3 + 2] annulation of bromoenals with α-amino ketones, followed by reduction. Remarkably, enantioenriched epi-neoclausenamide, which is one of the clausenamide derivatives, could be efficiently prepared by this strategy.

Brønsted Base‐Catalyzed Formal Reductive [3+2] Annulation of 4,4,4‐Trifluorocrotonate and α‐Iminoketones

“…The chemoselective reduction of the keto moiety proceeded with NaBH 4 as the reductant in ethanol to provide 8 in 97 % isolated yield as a 10:1 mixture of diastereomers (Scheme 4 A). [14] Such hydroxy‐substituted γ‐lactams are particularly an important structural motif [7c] . Interestingly, the lactam ring opening occurred by treatment of 5 a with diethylphosphite in the presence of 20 mol % P2‐ t Bu in DMF to provide 9 as a single geometrical stereoisomer (Scheme 4 B).…”

NHC‐Catalyzed Enantioselective Transformations Involving α‐Bromoenals

“…Huang and Fu et al developed stereoselective (3 + 2)annulation of bromoenals 1 with α-amino ketones 44 in the presence of the chiral NHC catalyst N (Scheme 28). [32] A wide range of γ-lactams with excellent enantio-, and diastereoselectivities were obtained using this method. The addition of LiAlH( t OBu) 3 in the reaction mixture can reduce the carbonyl group in compounds 45 to the hydroxyl group towards the synthesis of 6-hydroxyl butyrolactams.…”

One-pot synthesis of γ-lactams from ketoaziridines

“…5 A number of the stereoisomers of clausenamide exhibit different nootropic effects to a greater or lesser degree depending on their discrete stereo-arrangement. 6 These relevant properties have stimulated the search for efficient synthetic methods to achieve the γ-lactam core, 7 such as Lewis acid-catalysed cyclization of carboxylic acid derivatives with amines, 8 [3 + 2] annulation 9 and ring expansion of cyclobutanones. 10 Aziridine is a highly versatile building block, frequently involved in the synthesis of natural compounds and incorporated into the molecular scaffold of numerous bioactive products and pharmaceuticals.…”

“…Moreover, (−)-clausenamide, an anti-dementia drug candidate, isolated from Clausena lansium , 4 has attracted significant synthetic attention. 5 A number of the stereoisomers of clausenamide exhibit different nootropic effects to a greater or lesser degree depending on their discrete stereo-arrangement. 6…”

“…These relevant properties have stimulated the search for efficient synthetic methods to achieve the γ-lactam core, 7 such as Lewis acid-catalysed cyclization of carboxylic acid derivatives with amines, 8 [3 + 2] annulation 9 and ring expansion of cyclobutanones. 10…”