Assembly of Spirooxindole Derivatives Containing Four Consecutive Stereocenters via Organocatalytic Michael–Henry Cascade Reactions

Abstract

A novel organocatalytic strategy for the synthesis of highly substituted spirocyclopentaneoxindoles was developed employing simple nitrostyrenes and 3-substituted oxindoles as starting materials. Michael-Henry cascade reactions, enabled through cinchona alkaloid organocatalysis, provided products in high yield and excellent enantioselectivity in a single step.

Molecular diversity of spirooxindoles. Synthesis and biological activity

“…have developed a convergent synthetic strategy that employs enone 352, which was serving as the dipolarophile in the stereoselective intermolecular nitrone 353 cyloaddition reactions as a key step (Scheme 102)[202].…”

Asymmetric Domino Double Michael Addition of Nitroolefins and Aldehyde Esters with trans-Perhydroindolic Acid as an Organocatalyst

“…3 However, the majority of methods concern the synthesis of six-membered cycloalkanes possessing multiple stereocenters in their backbone. 4 Few examples relate to the construction of five-membered systems, [5][6][7][8][9] including those employing multistep reactions. 5,9 In 2007, Wang reported an asymmetric organocatalytic cascade double Michael addition reaction in which a cyclopentane backbone could be constructed with three stereogenic centers.…”

“…4 Few examples relate to the construction of five-membered systems, [5][6][7][8][9] including those employing multistep reactions. 5,9 In 2007, Wang reported an asymmetric organocatalytic cascade double Michael addition reaction in which a cyclopentane backbone could be constructed with three stereogenic centers. 6 The following year, the Córdova group developed a series of amino-, formyl-, and ester-functionalized cyclopentanes with four stereocenters (97-99% ee) via a one-pot transformation.…”

“…8 Recently, Barbas developed a highly selective organocatalytic Michael-Henry cascade reaction that provides spirooxindole core structures with four consecutive stereogenic centers in excellent chemical and optical yield. 9 The above examples either utilized substrates not easily accessible or provided somewhat low diastereoselectivities and reaction activities. Thus, the search for an efficient protocol for the construction of the less researched polysubstituted cyclopentane with contiguous multiple stereocenters from readily accessible substrates is worthy of investigation.…”

Core‐Structure‐Motivated Design of Iminium–Enolate Organocascade Reactions: Enantioselective Syntheses of 5,6‐Dihydroindolizines

“…[2] The 5,6,7,8-tetra-and 5,6-dihydroindolizine frameworks ( Figure 1) have recently drawn tremendous interest from both synthetic and medicinal chemists because of their properties as anti-tumor, [3a,g] antileukemia, [3b] anti-cholinergic agents, [2a] and other important biological activities. Recently, there has been considerable progress in the field of organocatalytic asymmetric synthesis of other important nitrogen-containing heterocycles based on the (ox)indole skeleton, [6,7] but the enantioselective synthesis of pyrrole derivatives has been less studied because of the difficulties in stereocontrol and mode of activation. [4] Thus, the design of new synthetic methods to provide molecules in this class of compounds is of interest, and intramolecular cyclization of intermediates using metal-catalyzed, [5c-g] radical, [5h-i] and base-induced processes have been reported.…”