A temporary-bridge strategy for enantioselective organocatalyzed synthesis of aza-seven-membered rings

Abstract

We report the first enantioselective organocatalyzed domino synthesis of azepane moieties. This temporary-bridge strategy is based on a conceptually original annulation of ambident electrophilic and 1,4-bis-nucleophilic α-ketoamides with 1,3-bis-electrophilic enals. The obtained oxygen-bridged azepanes can be selectively transformed into optically active azepanone, azepanol or azepanedione derivatives of high synthetic value.

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…[95] Bonne,R odriguez, and co-workers utilized an asymmetric domino Michael/hemiaminalization reaction to synthesize the oxygen-bridged azepanes 220, which have multiple stereogenic centers and are also useful for further diversifications. [96] As shown in Scheme 56, 1,4-bis-nucleophilic a-keto amides 218 and b-aryl-substituted enals 42 reacted together under the catalysiso f( S)-45 via an asymmetric domino Michael/hemiaminalization/acetalization reactiont o afford 220 with concomitantf ormation of three covalent bonds and the creationo ff our stereogenic centers. [96] In contrast, under the same reactionc onditions, a-keto amides 41,w hich lack the g-nucleophilic carbon, react with 42 to produce 1,3,5-triarylpyrrolidin-2-ones 43 via an asymmetric domino aza-Michael/ aldol reaction (Scheme 11).…”

Expeditious Synthesis of Enantioenriched Tetrahydropyrans via Chemoselective C−N bond Cleavage of Aza‐Oxa‐Bicyclo[3.2.1]Octanes

“…Recently, our group studied the chiral amine‐catalyzed synthesis of optically active aza‐oxa‐bicyclo[3.2.1]octane 3 from simple achiral α‐ketoamides 1 and enals 2 . These valuable synthetic platforms allowed us to further access functionalized azepanes 4 exploiting the lability of the C−O bond (Scheme ) . In this context, we disclose a new temporary‐bridge strategy based on a chemoselective C−N bond cleavage leading to the formation of highly diastereo‐ and enantioselective construction of new functionalized tetrahydropyrans 5 , bearing three consecutive stereogenic centers.…”

Enantioenriched Methylene‐Bridged Benzazocanes Synthesis by Organocatalytic and Superacid Activations

“…[30,31] Recently,w es tudied the organocatalyzed enantioselective synthesis of aza-oxa-bicyclo-[3.2.1]octanes. [32] Based on this work, we envisioned that starting from simple achiral a-ketoamides 1 and enals 2, enantioenriched oxabridged azepanes 3 could be temporarily generated and subsequently exploited to access stereoselectively the targeted methanobenzazocanes 4.T his strategy relies on the superacid-promoted formation of ah ighly reactive N-acyl iminium ion A,w hich could counterbalance the unfavorable eight-membered ring formation ( Figure 1C). Overall, this synthetic sequence can be formally seen as arare case of enantioselective Pictet-Spengler reaction to achieve chiral medium-size nitrogen-containing polycyclicd erivatives.…”