Synthesis of Isoquinuclidines from Highly Substituted Dihydropyridines via the Diels–Alder Reaction

Abstract

A stereo- and regioselective Diels-Alder reaction for the synthesis of highly substituted isoquinuclidines from dihydropyridines and electron deficient alkenes has been developed. While reactions with activated dienophiles proceed readily under thermal conditions, the use of Lewis acid additives is necessary to facilitate cycloadditions for less reactive alkenes. This procedure affords the target compounds in high yields and diastereoselectivities.

Four‐Component Assembly of Natural‐Product‐Like Ring‐Fused Isoquinuclidines

“…This suggests that the dienamine form is dominant in the methanol/acetonitrile (1:1) mixture with acetic acid present as catalyst. Similarly, as described for dihydropyridines,6 these intermediates are obvious candidates for Diels–Alder reactions, which would result in ring‐fused isoquinuclidines. The isoquinuclidine fragment is pharmaceutically interesting and is present in many biologically active natural products, such as ibogaine,7 dioscorine,8 and lirofoline B9 (Figure 2).…”

Diels–Alder Reactions of 1,2-Dihydropyridines: An Efficient Tool for the Synthesis of Isoquinuclidines

“…Ellman and co-workers developed a stereo-and regioselective Diels-Alder reaction for the synthesis of highly substituted isoquinuclidines (Scheme 7). 11 This work is unprecedented and is shown here due to its requirement to prepare highly substituted 1-alkyl and 1-aryl-1,2-dihydropyridines. Besides the known instability of these compounds, the 1-acyl protecting group also results in an attenuated nucleophilicity of 1,2-DHPs.…”

Diazo Compounds: Versatile Synthons for the Synthesis of Nitrogen Heterocycles via Transition Metal‐Catalyzed Cascade C–H Activation/Carbene Insertion/Annulation Reactions

“…Subsequently, these intermediates can generate heterocycles via various transannulation reactions. In addition, alkynes, alkenes, sulfoxonium ylides, and dioxazolones have been reported as synthons to achieve the synthesis of nitrogen heterocycles catalyzed by transition metals. Because diazo compounds possess the similar characteristic of being electron‐deficient, they have been used as carbene precursors to prepare ortho ‐functionalized arenes bearing various directing groups.…”