Asymmetric intramolecular α-cyclopropanation of aldehydes using a donor/acceptor carbene mimetic

Abstract

Enantioselective α-alkylation of carbonyl is considered as one of the most important processes for asymmetric synthesis. Common alkylation agents, that is, alkyl halides, are notorious substrates for both Lewis acids and organocatalysts. Recently, olefins emerged as a benign alkylating species via photo/radical mechanisms. However, examples of enantioselective alkylation of aldehydes/ketones are scarce and direct asymmetric dialkylation remains elusive. Here we report an intramolecular α-cyclopropanation reaction of olefinic aldehydes to form chiral cyclopropane aldehydes. We demonstrate that an α-iodo aldehyde can function as a donor/acceptor carbene equivalent, which engages in a formal [2+1] annulation with a tethered double bond. Privileged bicyclo[3.1.0]hexane-type scaffolds are prepared in good optical purity using a chiral amine. The synthetic utility of the products is demonstrated by versatile transformations of the bridgehead formyl functionality. We expect the concept of using α-iodo iminium as a donor/acceptor carbene surrogate will find wide applications in chemical reaction development.

Streamlined asymmetric α-difunctionalization of ynones

“…Subsequently, we synthesized ynedienamines, which show unique chemical reactivity toward a broad spectrum of electrophiles and nucleophiles 34 , 35 . In addition, we reported ester-substituted enamines that can be used in an enantioselective Povarov reaction and α-iodoenamine useful in direct α-cyclopropanation of aldehydes 36 , 37 . To access α-difunctionalized ynones, we proposed a fully conjugated diynenamine intermediate that can be functionalized in a streamlined fashion.…”

Radical asymmetric intramolecular α-cyclopropanation of aldehydes towards bicyclo[3.1.0]hexanes containing vicinal all-carbon quaternary stereocenters

“…In particular, such skeletons have also been widely applied as highly useful chiral building blocks in organic synthesis because of unique chemical reactivity for fragmentation and rearrangement 7 – 10 . Various approaches to access these structurally unique scaffolds have been developed 11 – 18 , and most of them are based on the asymmetric intramolecular cyclopropanation of olefins with metallocarbenes as the C1 component 19 – 27 . Despite these significant achievements in the field of metallocarbene chemistry, reactive prefunctionalized reagents, such as diazos, sulfonyl hydrazones, and ylides, have been mostly used as the metallocarbene precursors as the C1 component in this system 11 – 27 .…”

“…Various approaches to access these structurally unique scaffolds have been developed 11 – 18 , and most of them are based on the asymmetric intramolecular cyclopropanation of olefins with metallocarbenes as the C1 component 19 – 27 . Despite these significant achievements in the field of metallocarbene chemistry, reactive prefunctionalized reagents, such as diazos, sulfonyl hydrazones, and ylides, have been mostly used as the metallocarbene precursors as the C1 component in this system 11 – 27 . On the other hand, it is well-known that the efficient construction of chiral all-carbon quaternary stereocenter generally represents a significant and highly important task, but is among the most challenging objectives in organic synthesis due to the inherently unfavorable steric hindrance and relatively small steric differences for efficient enantiocontrol 28 – 31 .…”

“…On the other hand, it is well-known that the efficient construction of chiral all-carbon quaternary stereocenter generally represents a significant and highly important task, but is among the most challenging objectives in organic synthesis due to the inherently unfavorable steric hindrance and relatively small steric differences for efficient enantiocontrol 28 – 31 . Noteworthy is that the efficient formation of bicyclo[3.1.0]hexane scaffolds containing two sterically congested vicinal all-carbon quaternary stereocenters with conventional metallocarbene strategies remains a formidable challenge 19 – 27 . To circumvent the aforementioned challenges, the invention of a catalytic enantioselective intramolecular cyclopropanation method capable of constructing structurally diverse bicyclo[3.1.0]hexane skeletons containing vicinal all-carbon quaternary stereocenters, preferably by using readily available and simple methylene group as C1 source, is highly desirable and will be of great synthetic importance.…”

“…In this scenario, we envisaged that the enamine intermediate, in situ generated from a chiral secondary amine with an aldehyde of the rationally designed alkenyl aldehyde substrate 1 , could undergo a selective single electron transfer (SET) 55 – 59 , followed by 6-endo-trig cyclization and cyclopropanation to afford the optically enriched bicyclo[3.1.0]hexane motif with Cu(I)/chiral amine cooperative catalyst. Noteworthy is that Huang and co-workers have recently reported an asymmetric intramolecular α-cyclopropanation of alkenyl aldehydes with the in situ-generated α-iodoaldehyde as a donor/acceptor carbene mimetic, invoking a stepwise double electrophilic alkylation cascade through 5-exo-trig cyclization 27 . In this reaction, the bis-alkyl substituents at the double bond were essential for implementing the enantioselective reaction, possibly due to indispensable formation of carbocation intermediates, with an exceptionally stoichiometric amount of chiral secondary amine as the promoter.…”