The Organocatalytic α‐Fluorination of Chiral γ‐Nitroaldehydes: the Challenge of Facing the Construction of a Quaternary Fluorinated Stereocenter
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Chiral γ‐nitroaldehydes 1 are easily accessible by the organocatalytic Michael addition of aldehydes to nitroalkenes. In this paper, we report the organocatalytic fluorination of 1 with N ‐fluorobenzenesulfonimide (NFSI) leading to the highly stereoselective construction of a challenging quaternary fluorinated stereocenter at the α position of α,α‐dialkyl aldehydes. The reaction takes place via a chiral trisubstituted enamine, so far rather unexplored in the field of organocatalysis. Fluorinated products 3 are direct precursors of chiral monofluorinated 3,4‐polysubstituted pyrrolidines. Mechanistic details are discussed with the aid of computational results.Keywords:
Stereocenter
Enamine
Michael reaction
A tert-leucine-derived chiral diamine catalyzes the asymmetric Michael addition of nitromethane to five-, six-, and seven-membered β-substituted cyclic enones with excellent enantioselectivity, offering scalable, asymmetric access to all-carbon quaternary stereocenters. The reaction scope can be expanded to include linear acyclic enones, and excellent levels of enantioselectivity are also observed. Furthermore, this organocatalytic, asymmetric nitro-Michael reaction is amenable to multigram scale-up and applications in the construction of an eudesmane sesquiterpenoid skeleton.
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A highly stereoselective one-pot procedure for the synthesis of spiropyrazolone derivatives bearing six contiguous stereogenic centers including two tetrasubstituted carbons has been developed. Under sequential catalysis by two organocatalysts, a cinchona-derived aminosquaramide and DBU, a series of diversely functionalized spiropyrazolones are obtained in good yields (47–62%) and excellent stereoselectivities (up to >25:1 dr and 98–99% ee). The opposite enantiomers of the spiropyrazolones are also accessible by employing a pseudoenantiomeric aminosquaramide catalyst.
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Vicinal
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Chiral γ‐nitroaldehydes 1 are easily accessible by the organocatalytic Michael addition of aldehydes to nitroalkenes. In this paper, we report the organocatalytic fluorination of 1 with N ‐fluorobenzenesulfonimide (NFSI) leading to the highly stereoselective construction of a challenging quaternary fluorinated stereocenter at the α position of α,α‐dialkyl aldehydes. The reaction takes place via a chiral trisubstituted enamine, so far rather unexplored in the field of organocatalysis. Fluorinated products 3 are direct precursors of chiral monofluorinated 3,4‐polysubstituted pyrrolidines. Mechanistic details are discussed with the aid of computational results.
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Enamine
Michael reaction
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An efficient and concise protocol was developed for the synthesis of diverse morphan derivatives 5-7 by the Michael and aza-Michael reaction of different types of quinone monoketals 1 or quinone imine ketals 2 with enaminones or enamine esters 3 promoted by 1,8-diazabicyclo[5.4.0]undec-7-ene in acetone at reflux. Notably, when cyclic enaminone 4 was used as a substrate in the aza-Michael and 1,2-addition reactions with quinone monoketals 1, they gave another novel morphan 8. This method is suitable for parallel synthesis of bridged ring compounds. As a result, highly diverse morphan derivatives were easily and efficiently prepared by the Michael/aza-Michael or aza-Michael/1,2-addition reactions.
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Abstract One of the major challenges of modern asymmetric catalysis is the ability to selectively control the formation of all diastereoisomers of reaction products possessing multiple stereocenters. Pioneers of such diastereodivergent catalytic asymmetric processes have focused on reactions where the newly formed stereogenic centres are proximal to the active carbonyl group. To date, however, diastereodivergent reactions at remote positions remain an unmet challenge. Herein, we describe a catalyst-controlled diastereodivergence in the formation of remote stereocenters in the direct vinylogous Michael reactions of β, γ-unsaturated butenolides to α, β-unsaturated ketones. The reactions are enabled by two complementary, non-enantiomeric multifunctional catalysts, which mutually activate and organise both reactants, affording either the syn- or anti-adduct with high diastereo- and enantioselectivity. These two catalytic systems are also applicable in the Mukaiyama–Michael reactions and tandem Michael–Michael reactions.
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The utility of C(2)-symmetric bipiperidine and bimorpholine derivatives as organocatalysts in the Michael addition of enamine intermediates formed from aldehydes to nitroolefins has been demonstrated. The best results were obtained when the reaction was run in the presence of (2R,2'R)-N-iPr-bipiperidine. The products were formed via an enamine intermediate with high diastereo- and enantioselectivity with relatively short reaction times.
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This chapter contains sections titled: Introduction Terms and Nomenclature Enamines Imines Intramolecular Enamine Michael Additions Sequential Enamine Michael Additions Discussion of Mechanism: Enamine Reactions Lewis-Acid-Mediated Reactions Sequential Michael-Aldol Reactions Lewis-Acid-Catalyzed Intramolecular Michael Additions Discussion of Mechanism: Lewis-Acid-Mediated Reactions Conclusions
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Aldol reaction
Addition reaction
Aldol condensation
Enol ether
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Cascade reaction
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A syn-enantioselective aldol reaction has been developed using Brønsted acid catalysis based on H(8)-BINOL-derived phosphoric acids. This method affords an efficient synthesis of various beta-hydroxy ketones, some of which could not be synthesized using enamine organocatalysis.
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Aldol reaction
Brønsted–Lowry acid–base theory
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