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

Abstract

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.

Diastereoselective multicomponent Amine-Aldehyde-Dienophile (AAD) process for the synthesis of polysubstituted cyclohex-2-enylamines

“…More recently, our group introduced an AAD reaction with chiral nitroprolinate 3c obtaining the enantiopure endo-diastereoisomers 4c as exclusive product in the crude mixture with excellent yields after purification (Scheme 2c). 8 In this multicomponent reaction, it was possible to induce the absolute configuration of three new stereogenic centers in a single reaction step. In fact, this mechanism is the basic interaction of similar organocatalytic Diels-Alder reactions.…”

Nitroprolinates as Nucleophiles in Michael‐type Additions and Acylations. Synthesis of Enantiomerically Enriched Fused Amino‐pyrrolidino‐[1,2‐a]pyrazinones and ‐diketopiperazines

“…A family of enantiomerically enriched spironitroprolinates 5 were obtained by our group from iminolactones and nitroalkenes which are currently tested as anticancer agents . The presence of the nitro group in this skeleton induced special conformations of the five membered ring causing spectacular effects in its biological activity and its chemical reactivity …”

“…[7] The presence of the nitro group in this skeleton induced special conformations of the five membered ring causing spectacular effects in its biological activity and its chemical reactivity. [8] Diastereomeric exo-6 and endo-6 4-nitroprolinates have been used as chiral organocatalysts in aldol reactions. [9] endo-6 Preferentially promoted the polymerization of D-lactide, whereas exo-6 preferentially polymerized L-lactide from a racemic mixture.…”

“…[9,14,15] exo-6 a Series were employed as amino component in the multicomponent aminoÀ aldehydeÀ dienophile (AAD) [8] reaction affording chiral cyclohex-2-enyl amines and in two different multicomponent 1,3-cycloadditions furnishing pyrrolizidines. [8,16] According to the experience of our group in the synthesis [7] of the enantiomerically enriched nitroprolinates 6, [17,18] and the reactivity exhibited by the amino moiety of these structures 6-7, we focused our interest in the Michael type addition of the chiral pyrrolidines 6. So, in this work we studied the scope and the stereochemical course of the one pot process starting from imino ester 9 a and 8 a to yield compound 10 a (Scheme 1), avoiding the isolation of intermediate exo-6 a.…”

“…In addition, the NH−D−EhuPhos ligand 7 has been efficiently employed in the 1,3‐dipolar cycloadditions (1,3‐DC) to yield nitroprolinates and structurally rigid spirocompounds from chiral γ‐lactams . exo ‐ 6 a Series were employed as amino component in the multicomponent amino−aldehyde−dienophile (AAD) reaction affording chiral cyclohex‐2‐enyl amines and in two different multicomponent 1,3‐cycloadditions furnishing pyrrolizidines …”