Diastereoselective [3 + 2] vs [4 + 2] Cycloadditions of Nitroprolinates with α,β-Unsaturated Aldehydes and Electrophilic Alkenes: An Example of Total Periselectivity

• Published in: Journal of organic chemistry Vol. 82; no. 12; pp. 6298 - 6312
• Main Authors: Selva, Verónica, Larrañaga, Olatz, Castelló, Luis M, Nájera, Carmen, Sansano, José M, de Cózar, Abel
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.06.2017; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; DENSITY FUNCTIONALS; L-PROLINE; ENANTIOSELECTIVE SYNTHESIS; 1,3-DIPOLAR CYCLOADDITION; AZOMETHINE YLIDES; DIVERSITY; EFFICIENT; CATALYSTS; PYRROLIZIDINE DERIVATIVES; ALKALOIDS
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.7b00903

Diastereoselective multicomponent reactions of enantioenriched 4-nitroprolinates, obtained by enantiocatalyzed 1,3-dipolar cycloaddition (1,3-DC) of imino esters and nitroalkenes, with α,β-unsaturated aldehydes and electrophilic alkenes proceed with total periselectivity depending on the structure of the aldehyde employed. This process evolves through a [3 + 2] 1,3-DC when cinnamaldehyde is used in the presence of an azomethine ylide, giving the corresponding highly substituted pyrrolizidines with endo selectivity. However, in the case of the α,β-unsaturated aldehyde, which contains a hydrogen atom at the γ position, an amine–aldehyde–dienophile (AAD) [4 + 2] cycloaddition takes place by formation of an intermediate 1-amino-1,3-diene, affording highly functionalized cyclohexenes with high endo diastereoselectivity. This AAD process only occurred when a nitro group is bonded to the 4-position of the initial enantiomerically enriched pyrrolidine ring. DFT calculations have been carried out with the aim of explaining this different behavior between pyrrolidines with or without a nitro group, demonstrating the strong nitro-group-dependent periselectivity. The results of these computational studies also support the experimentally obtained absolute configuration of the final adducts.