From Amino Acids to Enantiopure Bicyclic Isoxazolidinylpyridin‐4(1<i>H</i>)‐ones through Intramolecular Nitrone Cycloadditions

Romeo, Roberto; Iannazzo, Daniela; Piperno, Anna; Chiacchio, Maria Assunta; Corsaro, Antonino; Rescifina, Antonio

doi:10.1002/ejoc.200400847

Eur J Org Chem

2005

DOI: 10.1002/ejoc.200400847

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From Amino Acids to Enantiopure Bicyclic Isoxazolidinylpyridin‐4(1H)‐ones through Intramolecular Nitrone Cycloadditions

Roberto Romeo

Daniela Iannazzo

Anna Piperno

et al.

Abstract: Homochiral bicyclic isoxazolidinylpyridin‐4(1H)‐ones have been synthesised by an intramolecular nitrone cycloaddition process, starting from homochiral β‐amino acids. Stereoselection at C2 or C3 of the acyclic substrate appears to give the best results in the control of the stereochemistry of the new formed chiral centres. The synthetic approach has been further directed towards functionalised piperidones. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

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Cited by 7 publications

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“…To study the ring size effect on the diastereo-and enantioselectivity, 5-and 6-alkenylaldehydes (1 b and 1 c) were applied in this organocatalytic one-pot asymmetric tandem reaction to afford bicyclic [3,3,0]-and [4,3,0]-isoxazolidine derivatives 3 r and 3 s, respectively, with similar results (Scheme 3). Notably, only the exo product was observed when 1 c was used.…”

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“…Such a phenomenon could be attributed to the unfavored steric hindrance between the ortho-substituted group and the aldehyde in the presence of catalyst I. The electronic nature of the substitutents in the aromatic ring has little effect on the yield, diastereo-and enantioselectivity ( Table 2, entries [4][5][6][7][8][9]. Nitroalkenes bearing furanyl and naphthyl groups were also successfully used in this reaction with 95:5 d.r.…”

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Highly Stereoselective One‐Pot Synthesis of Bicyclic Isoxazolidines with Five Stereogenic Centers by an Organocatalytic Process

et al. 2009

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Highly Stereoselective One‐Pot Synthesis of Bicyclic Isoxazolidines with Five Stereogenic Centers by an Organocatalytic Process

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“…Most importantly, the introduction of a stereogenic center at the a position of the nitrone can result in asymmetric induction, leading to the generation of new stereocenters having defined configurations. [4] However, multistep synthetic routes were required to synthesize molecules bearing stereocenters at the a position of the nitrone and the olefin moiety from optical sources, such as amino acids and sugars. Although several organocatalytic asymmetric nitrone [3+2] cycloadditions have been documented, [5] the enantioselective intramolecular version remains a challenge.…”

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Highly Stereoselective One‐Pot Synthesis of Bicyclic Isoxazolidines with Five Stereogenic Centers by an Organocatalytic Process

et al. 2009

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Dedicated to Professor Pierre Vogel on the occasion of his 65th birthday Intramolecular nitrone/alkene cycloadditions have received a great deal of attention as a useful methodology for the formation of the intriguing frameworks found in natural products and biologically interesting compounds.[1] The key feature of this approach is the suitable elaboration of the primary cycloadducts, which has proven to be a practical strategy for making different heterocyclic systems.[2] Owing to the labile nature of the NÀO bond under mild reducing conditions, the isoxazolidines provide easy access to a variety of 1,3-difunctional amino alcohols.[3] Particularly, if the intramolecular cycloaddition of nitrone is linked to olefin moiety by a tether of appropriate length, the regio-and diastereoselectivities can be dramatically improved. Most importantly, the introduction of a stereogenic center at the a position of the nitrone can result in asymmetric induction, leading to the generation of new stereocenters having defined configurations.[4] However, multistep synthetic routes were required to synthesize molecules bearing stereocenters at the a position of the nitrone and the olefin moiety from optical sources, such as amino acids and sugars. Although several organocatalytic asymmetric nitrone [3+2] cycloadditions have been documented, [5] the enantioselective intramolecular version remains a challenge. Herein, we disclose an organocatalytic one-pot asymmetric synthesis of bicyclic isoxazolidines through a domino process involving a Michael addition/ in situ condensation/intramolecular nitrone [3+2] cycloaddition sequence.In 2003, our group first described the a-aminoxylation of aldehydes with excellent enantioselectivity. [6a,b] Recently, we also reported highly stereoselective syntheses of tetrahydro-1,2-oxazines by tandem a-aminoxylation and aza-Michael addition.[6] Surprisingly, when we changed the electron-withdrawing group in an aldehyde from a nitro or a malonate group to an ester group, an unexpected bicyclic isoxazolidine product was obtained in 11 % yield with high regioselectivity, endo/exo selectivity, and diastereoselectivity (Scheme 1), by an intramolecular nitrone [3+2] cycloaddition. This finding led us to investigate whether enantiopure bicyclicisoxazolidine products could be obtained if we introduced a stereogenic center at the a position of the aldehyde by asymmetric organocatalysis, which would then undergo subsequent in situ condensation and intramolecular nitrone [3+2] cycloaddition.Recently, asymmetric organocatalytic domino reactions have provided efficient ways to construct complex molecules, and have become a powerful tool in organic chemistry. [7] Among the organocatalytic reactions explored, extensive efforts have been devoted to the Michael addition of aldehydes to nitroolefins. [8] We rationalized that by introducing a stereocenter at the a position of the aldehyde through an asymmetric Michael addition and then subsequent in situ condensation and intramolecular cycloaddition, a novel approach to ...

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Competitive Formation of β‐Enaminones and 3‐Amino‐2(5H)‐furanones from the Isoxazolidine System: A Combined Synthetic and Quantum Chemical Study

et al. 2010

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Treatment of 3‐alkoxycarbonyl‐4‐acyl‐ or 3,4‐dialkoxycarbonyl‐substituted isoxazolidines with a mild base, such as tetrabutylammonium fluoride, affords β‐enaminones and/or 3‐methylamino‐2(5H)‐furanones according to the nature of the substituents at C4 and C5. Two alternative mechanisms (lactonization and retro‐aldolization) have been rationalized by DFT quantum chemical methods. Any realistic theoretical modeling requires the explicit inclusion of countercation and solvent effects.

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From Amino Acids to Enantiopure Bicyclic Isoxazolidinylpyridin‐4(1H)‐ones through Intramolecular Nitrone Cycloadditions

Cited by 7 publications

References 16 publications

Highly Stereoselective One‐Pot Synthesis of Bicyclic Isoxazolidines with Five Stereogenic Centers by an Organocatalytic Process

Highly Stereoselective One‐Pot Synthesis of Bicyclic Isoxazolidines with Five Stereogenic Centers by an Organocatalytic Process

Highly Stereoselective One‐Pot Synthesis of Bicyclic Isoxazolidines with Five Stereogenic Centers by an Organocatalytic Process

Competitive Formation of β‐Enaminones and 3‐Amino‐2(5H)‐furanones from the Isoxazolidine System: A Combined Synthetic and Quantum Chemical Study

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