The objective of our work is to present a new synthetic application of beta-nitroacrylates, substrates that are gaining increasing importance as precursors of highly functionalized intermediates.1 Different 3-alkyl substituted nitro ethylacrylates may be easily synthesized through nitro aldol condensation between the proper nitroalkane and ethyl glyoxylate, followed by reaction with mesyl chloride and treatment with a base to afford the desired product isolated with a single chromatographic purification.2 We exploited chiral primary amine catalysis to obtain highly functionalized cyclohexanone derivatives starting from alfa,beta-unsaturated ketones and beta-nitroacrylates; the use of 9-deoxy-epicinchona alkaloids, that have already proved to be very effective catalysts in lots of different transformations3, in the presence of an acidic co-catalyst allowed to obtain cyclohexanone rings endowed with three stereogenic centers with complete regionselectivity and high enantiomeric excess. In particular, the reaction between (E)-4-phenyl-3-buten-2-one and (E)-ethyl-3-nitropent- 2-enoate, catalyzed by 9-amino-9-deoxy-epi-quinine and salicylic acid, gave product 1 in 70% yield, with an endo/exo ratio of 1:3 and 96.5% and 95% enantiomeric excess for the two diastereoisomers, respectively. The reaction promoted by the quasi-enantiomer catalyst 9-amino-9-deoxy-epi-quinidine afforded the desired product in comparable yields and stereoselectivity, showing an opposite sense of enantioselection.The reaction proceeds through a dienamine catalyzed pathway4; this kind of activation has already been used to perform Diels-Alder reactions between cyclohexenone and nitrostirene.5 The mechanism through which the dienamine intermediate reacts with beta-nitroacrylates is still uncertain, as there are no conclusive evidence to support a [4+2] cycloaddition pathway rather than a double-Michael addition cascade sequence.references:1 H. Ishikawa, T. Suzuki, H. Orita, T. Uchimaru, Y. Hayashi, Chem. Eur. J., 2010, 16, 12616-12626. 2 R. Ballini, D. Fiorini, A. Palmieri, Tetrahedron Lett., 2004, 45, 7027-7029. 3 Melchiorre, Angew. Chem. Int. Ed., 2012, 51, 9748-9770. 4 L.-Y Wu, G. Bencivenni, M. Mancinelli, A. Mazzanti, G. Bartoli, P. Melchiorre, Angew. Chem. Int. Ed., 2009, 48, 7196-7199. 5 G. N. Stowe, K. D. Janda, Tetrahedron Lett., 2001, 52, 2085-2087.

Organocatalytic stereoselective one-pot synthesis of highly functionalized cyclohexanones / E. Massolo, M. Benaglia, A. Palmieri. ((Intervento presentato al 18. convegno European Symposium on Organic Chemistry tenutosi a Marseille nel 2013.

Organocatalytic stereoselective one-pot synthesis of highly functionalized cyclohexanones

E. Massolo;M. Benaglia;
2013

Abstract

The objective of our work is to present a new synthetic application of beta-nitroacrylates, substrates that are gaining increasing importance as precursors of highly functionalized intermediates.1 Different 3-alkyl substituted nitro ethylacrylates may be easily synthesized through nitro aldol condensation between the proper nitroalkane and ethyl glyoxylate, followed by reaction with mesyl chloride and treatment with a base to afford the desired product isolated with a single chromatographic purification.2 We exploited chiral primary amine catalysis to obtain highly functionalized cyclohexanone derivatives starting from alfa,beta-unsaturated ketones and beta-nitroacrylates; the use of 9-deoxy-epicinchona alkaloids, that have already proved to be very effective catalysts in lots of different transformations3, in the presence of an acidic co-catalyst allowed to obtain cyclohexanone rings endowed with three stereogenic centers with complete regionselectivity and high enantiomeric excess. In particular, the reaction between (E)-4-phenyl-3-buten-2-one and (E)-ethyl-3-nitropent- 2-enoate, catalyzed by 9-amino-9-deoxy-epi-quinine and salicylic acid, gave product 1 in 70% yield, with an endo/exo ratio of 1:3 and 96.5% and 95% enantiomeric excess for the two diastereoisomers, respectively. The reaction promoted by the quasi-enantiomer catalyst 9-amino-9-deoxy-epi-quinidine afforded the desired product in comparable yields and stereoselectivity, showing an opposite sense of enantioselection.The reaction proceeds through a dienamine catalyzed pathway4; this kind of activation has already been used to perform Diels-Alder reactions between cyclohexenone and nitrostirene.5 The mechanism through which the dienamine intermediate reacts with beta-nitroacrylates is still uncertain, as there are no conclusive evidence to support a [4+2] cycloaddition pathway rather than a double-Michael addition cascade sequence.references:1 H. Ishikawa, T. Suzuki, H. Orita, T. Uchimaru, Y. Hayashi, Chem. Eur. J., 2010, 16, 12616-12626. 2 R. Ballini, D. Fiorini, A. Palmieri, Tetrahedron Lett., 2004, 45, 7027-7029. 3 Melchiorre, Angew. Chem. Int. Ed., 2012, 51, 9748-9770. 4 L.-Y Wu, G. Bencivenni, M. Mancinelli, A. Mazzanti, G. Bartoli, P. Melchiorre, Angew. Chem. Int. Ed., 2009, 48, 7196-7199. 5 G. N. Stowe, K. D. Janda, Tetrahedron Lett., 2001, 52, 2085-2087.
Settore CHIM/06 - Chimica Organica
Organocatalytic stereoselective one-pot synthesis of highly functionalized cyclohexanones / E. Massolo, M. Benaglia, A. Palmieri. ((Intervento presentato al 18. convegno European Symposium on Organic Chemistry tenutosi a Marseille nel 2013.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/235284
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