N-Heterocyclic carbene-catalyzed enantioselective hetero-[10 + 2] annulation

Abstract

Higher-order cycloadditions are a powerful strategy for the construction of polycycles in one step. However, an efficient and concise version for the induction of asymmetry is lacking. N-heterocyclic carbenes are widely used organocatalysts for asymmetric synthesis and could be an ideal choice for enantioselective higher-order cycloadditions. Here, we report an enantioselective [10 + 2] annulation between catalytically formed aza-benzofulvene intermediates and trifluoromethyl ketone derivatives. This protocol exhibits a wide scope, high yields, and good ee values, reflecting a robust and efficient higher-order cycloaddition. Density functional theory calculations provide an accurate prediction of the reaction enantioselectivity, and in-depth insight to the origins of stereocontrol.

On the Number of π‐Electrons Involved in Stepwise Cycloaddition Reactions

“…Pyrrole-2-carbaldehydes and their benzofused analogs may, upon condensation with an organocatalyst, be converted into to azafulvenes, a motif which has been reported to participate in several higher-order cycloadditions. [21,31,32] The cycloaddition of the non-benzofused 6π-component 5 a, the enamine of pyrrole-2-carbaldehyde and pyrrolidine, with 2 a, the iminium-ion of cinnamaldehyde and pyrrolidine (Scheme 4), was investigated computationally. The obtained results were compared to those obtained using benzofused Figure 5 presents the TS energies of TS-Aza-1 and TS-Aza-2 for the Aza-[X + 2] cycloaddition series which are all exergonic.…”

“…We subsequently investigated the behavior of a system, which is isoelectronic to the cyclopentadienyl‐based substrates. Pyrrole‐2‐carbaldehydes and their benzofused analogs may, upon condensation with an organocatalyst, be converted into to azafulvenes, a motif which has been reported to participate in several higher‐order cycloadditions [21,31,32] …”

Catalyst-controlled stereoselective carbon–heteroatom bond formations by N-heterocyclic carbene (NHC) organocatalysis

“…83 (3) The development of aza-fulvene intermediate III from indole/ pyrrole aldehydes 48 has enabled rapid access to multiple spiroheterocycles, which was initiated by nucleophilic C-N bond formations with activated carbonyl electrophiles 49 (Scheme 18c). [84][85][86][87] (4) Furthermore, activation of nitrogen atoms at the remote site is also feasible by NHC catalysis, involving a triaza-diene intermediate IV from the oxidation of aza-Breslow intermediates. Highly stereoselective C-N forming reactions were readily achieved by harnessing the generated triaza-diene intermediates IV with electrophilic components 49 (Scheme 18d).…”

Biomimetic enantioselective synthesis of β,β-difluoro-α-amino acid derivatives

“…Then, Jørgensen 47 , Deng 48 – 50 , Shi 51 , 52 , and others 53 – 55 further extended this strategy to construct chiral amino acids and chiral trifluoromethylamines. Building upon our continued interests in organic fluorides 56 – 61 and the limitations for the rapid synthesis of chiral fluoro amino acids, we report here an approach to achieve dFAAS via biomimetic enantioselective [1,3]-proton-shift reactions. Notably, the yielded chiral dFAAs are useful synthons for producing various valuable molecules, such as difluoro peptides, difluoro amino alcohols, and difluoro alkaloid 62 .…”