Kinetic resolution of substituted amido[2.2]paracyclophanes via asymmetric electrophilic amination

Abstract

Planar chiral [2.2]paracyclophane derivatives are a type of structurally intriguing and practically useful chiral molecules, which have found a range of important applications in the field of asymmetric catalysis and material science. However, access to enantioenriched [2.2]paracyclophanes represents a longstanding challenge in organic synthesis due to their unique structures, which are still highly dependent on the chiral chromatography separation technique and classical chemical resolution strategy to date. In this work, we report on an efficient and versatile kinetic resolution protocol for various substituted amido[2.2]paracyclophanes, including those with pseudo-geminal, pseudo-ortho, pseudo-meta and pseudo-para disubstitutions, using chiral phosphoric acid (CPA)-catalyzed asymmetric amination reaction, which was also applicable to the enantioselective desymmetrization of an achiral diamido[2.2]paracyclophane. Detailed experimental studies shed light on a new reaction mechanism for the electrophilic aromatic C-H amination, which proceeded through sequential triazane formation and N[1,5]-rearrangement. The facile large-scale kinetic resolution reaction and diverse derivatizations of both the recovered chiral starting materials and the C-H amination products showcased the potential of this method.

Rhodium(II)-Catalyzed Asymmetric Cyclopropanation and Desymmetrization of [2.2]Paracyclophanes

“…By measuring the enantioselectivity of recovered starting material 1c (47% ee) and the overall conversion based on 1c (35%), a selectivity ( s ) factor for the reaction was estimated to be 20. Optical rotation comparison showed that the recovered [2.2]paracyclophane 1c was enriched in the ( R p ) enantiomer . Hence, product 3ca is drawn as the product derived from the ( S f ) enantiomer of 1c .…”

“…Even so, the asymmetric synthesis of functionalized paracyclophanes remains a significant challenge. Typically, enantiomerically pure [2.2]­paracyclophanes are produced either by resolution of diastereomeric derivatives , or by kinetic resolution. − In recent years, new approaches using desymmetrization or dynamic kinetic resolution have been developed (Scheme B). These include desymmetrization of meso -diformyl­[2.2]­paracyclophanes by oxidation or reduction and of diamido[2.2]­paracyclophanes by asymmetric electrophilic substitution …”

“…These include desymmetrization of meso -diformyl[2.2]paracyclophanes by oxidation 13 or reduction 14 and of diamido[2.2]paracyclophanes by asymmetric electrophilic substitution. 9 …”

“…These include desymmetrization of meso-diformyl [2.2]paracyclophanes by oxidation 13 or reduction 14 and of diamido [2.2]paracyclophanes by asymmetric electrophilic substitution. 9 In this study, we examined whether the enantioselective reaction of donor/acceptor carbenes with paracyclophanes would result in the ready generation of novel paracyclophane derivatives. Previous studies on the reaction of [2.2]paracyclophane with diazomethane resulted in the formation of a mixture of mono-, di-, tri-, and polysubstituted derivatives, including two regioisomeric monosubstituted products in undefined yields (Scheme 1C).…”

Synthesis of [2.2]Paracyclophane-Fused Heterocycles via Palladium-Catalyzed C–H Activation/Annulation of [2.2]Paracyclophanecarboxamides with Arynes

“…In the past two decades, transition-metal-catalyzed C–H functionalization has witnessed a booming development, and been successfully employed to access [2.2]­paracyclophane derivatives . Meanwhile, palladium-catalyzed intramolecular C–H activation offers an efficient pathway to afford [2.2]­paracyclophane-fused heterocycles by introducing appropriate coupling partners tethered to the [2.2]­paracyclophane backbone (Scheme b). , Nevertheless, the lower catalytic efficiency due to the constraint by the sterically hindered configuration of the [2.2]­paracyclophane skeleton and the limited types of the tethering coupling partners restrict their further applications. Therefore, the development of intermolecular C–H activation with highly reactive coupling reagents to access [2.2]­paracyclophane-fused heterocycles is highly desirable.…”