Direct Noncovalent Activation of α,β‐Unsaturated Aldehydes for the Stereodivergent Synthesis of Substituted Cyclohexenes

Abstract

HOMO-raising noncovalent activation of α-aryl α,β-unsaturated aldehydes using a bifunctional Brønsted base catalyst is achieved. The catalytically generated dienolate intermediate undergoes all-carbon [4+2] cyclizations with nitroolefins, leading to chiral cyclohexenes with four contiguous stereocenters in high yields and with excellent enantioseletivity. Furthermore, the diastereodivergent synthesis of the products is realized by introducing a second steric control to the bifunctional catalyst; 4 isomers out of 16 possible stereoisomers of the products were selectively produced by simple use of two catalysts and their (pseudo)enantiomers. The results presented here provide new insights into the remote activation of the carbonyl functionality as well as the stereodivergent synthesis of complex chiral molecules with multiple stereocenters.

Extended Enolates: Versatile Intermediates for Asymmetric C‐H Functionalization via Noncovalent Catalysis

“…Relying on a cinchona alkaloid/indanolamine‐derived bifunctional thiourea catalyst C21 they developed a tandem Michael/Henry reaction sequence between α‐aryl α,β‐unsaturated aldehydes 116 and aromatic nitroolefins for the construction of pentasubstituted cyclohexenes 117 (Scheme 32 ). [80] Although the reactions required from 4 to 8 days for completion and a 20 mol% catalyst loading, highly enantioenriched products with diastereoselectivities ranging from 3 : 1 to >20 : 1 were obtained. Interestingly, epimeric cycloadduct 118 could be obtained with similar efficiency by shifting to squaramide catalyst C22 .…”

Asymmetric Construction of Halogenated Cyclic Quaternary Carbon Center through Enolate Activation of Aldehydes

“…16 Another inspiring work was recently reported by Xu and co-workers, in which the dienolate intermediates generated in situ from enals could undergo a highly enantioselective all-carbon [4+2] cyclization with nitroolefins, although the enal substrates were limited to 2,4diaryl-2-enal (Scheme 5, b). 17 We envisioned that the strategy of non-covalent catalysis might be a potential solution to address the reactivity problem of the less reactive branched aldehydes, particularly those with -halo substituents.…”

Organocatalytic Asymmetric Vinylogous Michael Reactions

“…The Xu group described a stereodivergent [4+2] cyclization (AVM/cyclization cascade) of α,β‐unsaturated aldehydes 130 and nitroolefins 92 for the asymmetric synthesis of cyclohexenes 132 and 134 featuring four contiguous all‐carbon stereocenters (Scheme ) . Through a noncovalent activation mode using bifunctional Brønsted base catalysts 131 and 133 individually, the chiral dienolate complexes were formed in situ from 130 .…”