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Keywords:
acetaldehyde; acetaldehyde dimethyl acetal; cascade reaction; multicomponent reaction; organocatalysis
Abstract
Asymmetric organocatalyzed multicomponent reactions represent an important toolbox in the field of organic synthesis to build complex scaffolds starting from simple starting materials. The Enders three-component cascade reaction was a cornerstone in the field and a plethora of organocatalyzed cascade reactions followed. However, acetaldehyde was not shown as a successful reaction partner, probably because of its high reactivity. Herein, we report the Enders-type cascade reaction using acetaldehyde dimethyl acetal, as a masked form of acetaldehyde. This strategy directly converts acetaldehyde, nitroalkenes and enals into stereochemically dense cyclohexenals in good yield and excellent enantioselectivity.
Introduction
Multicomponent reactions (MCRs) are chemical processes that involve three or more compounds, in which the product contains all the atoms of the reagents, except for condensation coproducts, such as water, hydrogen chloride or other small molecules [1-3]. MCRs have a great advantage over the classical two-component reactions; they allow the construction of complex molecular motifs in only one synthetic operational step starting from simpler building blocks. For this reason, the use of MCRs is appealing in the construction of natural or synthetic products [2-5] or libraries of compounds [2], and is generally considered an advantage in organic synthesis for atom economy, waste reduction and time saving. Cascade reactions are defined as chemical processes in which two or more bondforming steps happen under identical reaction conditions, and where a subsequent transformation takes place at the functionality obtained in the former bond-forming event. Cascade reactions are valuable tools for streamlining the synthesis of structurally complex molecules in a single operation and from readily available substrates. Their combination with asymmetric aminocatalysis [4.6-8] has recently led to innovative approaches for the one-step enantioselective preparation of stereochemically dense molecules. Nowadays, organocatalytic cascade processes provide a powerful tool for achieving molecular complexity. Their synthetic potential has been demonstrated by their application in the total synthesis of complex natural compounds [2.4.9-12].
A remarkable example of an amino-catalyzed cascade process was reported by Enders [11], a three-component cascade reaction for the synthesis of polyfunctionalized cyclohexenes bearing multiple stereocenters. The reaction is promoted by a chiral secondary amine, which is capable of catalyzing each step of the process activating the substrates through enamine and iminium ion catalysis towards...