N‐Heterocyclic Carbene Control over Multiple Stereogenicities: Atroposelective Synthesis of Axially Chiral Phthalimides

Abstract

The design of a NHC‐catalyzed methodology for the straightforward access to hitherto unknown axially chiral N‐aryl phthalimides has provided a breakthrough in the field of multichirality control. Anticipating a formal (4+2) oxidative annulation, the use of NHC‐derived chiral dienolate as ambident partner toward N‐aryl maleimides unexpectedly yields original bis‐succinimide‐type compounds featuring a multichiral architecture with up to four stereogenic centers and two remote chiral axes. The overall pseudo‐three components reaction between an enal and two equivalents of a N‐aryl maleimide proceeds with excellent enantioselectivity and complete diastereoselectivity. This study illustrates the high synthetic potential of chiral NHC‐activated dienolates for the rapid and highly diastereo‐ and enantioselective preparation of underexplored atropisomers in the pentatomic series, featuring multiple stereogenic elements including challenging Csp2−N chiral axes. The practicality of this reaction is highlighted by a broad substrate scope and a scaled‐up synthesis. Moreover, the easy base‐induced transformation of the chiral bis‐succinimide precursors allows to prepare the initially planned N‐aryl phthalimide atropisomers with excellent retention of enantiopurity.

Nonsilyl Bicyclic Secondary Amine Catalysts for the Asymmetric Transfer Hydrogenation of α,β-Unsaturated Aldehydes

“…Following the experimental procedure, (E)-3-(3-methoxyphenyl)but-2-enal 6g (35 mg, 0.20 mmol, 1.0 equiv) and Hantzsch ester 7a (76 mg, 0.30 mmol, 1.5 equiv) in the presence of the catalyst 5a (3 mg, 0.01 mmol, 5 mol %), and benzoic acid (2 mg, 0.02 mmol, 0.1 equiv) were converted to product 8g was purified as a clear liquid (25 mg, 68% yield) from the crude reaction mixture using flash column chromatography [Silica gel, hexane/EtOAc (70: 30)]. R f = 0.5 [hexane/EtOAc (70: 30)]. HPLC analysis Daicel Chiralcel IC, 4.6 mm × 250 mm (hexane/IPA = 97:03, 1.0 mL/min, 210 nm), t R (major) = 20.4 min, t R (minor) = 19.2 min, 96% ee.…”

“…After completion of the reaction (monitored by TLC), the reaction mass was cooled to 0 °C, quenched with aqueous saturated NH 4 Cl solution (20 mL), and extracted with EtOAc (3 × 20 mL). The organic phases were combined, washed with ice-cold water (2 × 50 mL), dried over Na 2 SO 4 , concentrated under reduced pressure to get the crude product 4c, which was purified as a viscous liquid (0.16 g, 78% yield) from the crude reaction mixture using flash column chromatography [Silica gel, hexane/EtOAc (70: 30)]. R f = 0.5 [hexane/EtOAc (50:50)].…”

“…30)]. R f = 0.2 [hexane/EtOAc (70:30)]. HPLC analysis Daicel Chiralcel AS-H, 4.6 mm × 250 mm (hexane/IPA = 90:10, 0.5 mL/min, 210 nm), t R (major) = 28.3 min, t R (minor) = 32.3 min, 90% ee.…”

Catalytic Asymmetric Synthesis of Atropisomers Bearing Multiple Chiral Elements: An Emerging Field

“…Very recently, a representative example on the catalytic asymmetric synthesis of axially chiral phthalimides with up to four stereogenic centers and two remote chiral axes was reported by Amatore, Constantieux, and co-workers (Scheme 11a). [37] Initially, they designed a chiral NHC-catalyzed desymmetrizative formal (4 + 2) oxidative annulation of N-aryl maleimides 23 with enals 57. Unexpectedly, enals 57 reacted with two equivalents of N-aryl maleimide 23 to afford bissuccinimides 58 bearing six stereogenic elements including four carbon stereocenters and two remote Csp 2 À N stereogenic axes with excellent diastereo-and enantioselectivities.…”

“…This is particularly true for the construction of chiral frameworks bearing multiple non‐adjacent chiral elements. Very recently, a representative example on the catalytic asymmetric synthesis of axially chiral phthalimides with up to four stereogenic centers and two remote chiral axes was reported by Amatore, Constantieux, and co‐workers (Scheme 11a) [37] . Initially, they designed a chiral NHC‐catalyzed desymmetrizative formal (4+2) oxidative annulation of N ‐aryl maleimides 23 with enals 57 .…”