Heterocyclic compounds containing a chiral pyrrolidine motif commonly appear in natural alkaloids and pharmaceutically active substances, and serve as building blocks commonly used for total syntheses; therefore there has been great demand for highly efficient asymmetric synthetic methods to access these compounds. [1,2] Optically active 2,3-dihydropyrroles are important unsaturated heterocyclic compounds that can not only be transformed into multisubstituted pyrrolidines for the synthesis of chiral building blocks, but can also be applied to the total synthesis of natural products.[3] The synthetic approaches to access enantioenriched pyrrolidines include chiral-auxiliary-assisted asymmetric synthesis and a number of transition-metal-catalyzed asymmetric dipolar addition reactions.[2] However, organocatalytic approaches to access chiral pyrrolidines are scarce [4] despite the growth in asymmetric organocatalysis in modern organic synthesis. [5] Moreover, the asymmetric catalytic synthesis of chiral 2,3-dihydropyrroles remains elusive and the discovery of catalytic asymmetric reactions that yield optically active 2,3-dihydropyrroles is an important challenge. Over 30 years ago, cycloaddition reactions of metalated isocyanides to a,b-unsaturated carbonyl and nitrile compounds were reported to generate racemic 2,3-dihydropyrroles.[6] An enantioselective version of this transformation may provide a method for direct access to chiral dihydropyrroles and would therefore be valuable in the synthesis of chiral building blocks and related alkaloids.[2] In contrast to the long history of nonasymmetric variants, [6] enantioselective, catalytic cycloaddition reactions of isocyanoesters with electron-deficient olefins are not yet available. Herein, we report the first catalytic asymmetric cycloaddition reaction of isocyanoesters [7] to nitroolefins by using alkaloid-derived bases to form highly functionalized 2,3-dihydropyrroles with excellent enantioselectivities (up to > 99 % ee).Our mechanistic proposal for the formal cycloaddition reaction catalyzed by a chiral base is shown in Scheme 1. The chiral base could promote an asymmetric Michael addition of isocyanoesters 1 to electron-deficient olefins, such as nitroolefins 2, by activating the acidic a-carbon atom of 1 to generate intermediates I. Subsequent intramolecular cyclization reactions of intermediates I afforded precursor 1,2-dihydropyrroles II, which may be converted into dihydropyrrole 3 after protonation. [6] Cinchona alkaloids and their derivatives have been revealed as efficient organocatalysts for many asymmetric reactions, [8] particularly for a variety of asymmetric Cnucleophilic addition reactions in which the basic functionalities of the alkaloid activates acidic a-carbon pronucleophiles (Figure 1). [9][10][11][12] Surprisingly, to the best of our knowledge, isocyanoesters have not yet been used as nucleophiles in these reactions, or in other organic base-catalyzed nucleophilic addition reactions. Despite this, we still believed that cinchona alkaloids...

Heterocyclic compounds containing a chiral pyrrolidine motif commonly appear in natural alkaloids and pharmaceutically active substances, and serve as building blocks commonly used for total syntheses; therefore there has been great demand for highly efficient asymmetric synthetic methods to access these compounds. [1,2] Optically active 2,3-dihydropyrroles are important unsaturated heterocyclic compounds that can not only be transformed into multisubstituted pyrrolidines for the synthesis of chiral building blocks, but can also be applied to the total synthesis of natural products.[3] The synthetic approaches to access enantioenriched pyrrolidines include chiral-auxiliary-assisted asymmetric synthesis and a number of transition-metal-catalyzed asymmetric dipolar addition reactions.[2] However, organocatalytic approaches to access chiral pyrrolidines are scarce [4] despite the growth in asymmetric organocatalysis in modern organic synthesis. [5] Moreover, the asymmetric catalytic synthesis of chiral 2,3-dihydropyrroles remains elusive and the discovery of catalytic asymmetric reactions that yield optically active 2,3-dihydropyrroles is an important challenge. Over 30 years ago, cycloaddition reactions of metalated isocyanides to a,b-unsaturated carbonyl and nitrile compounds were reported to generate racemic 2,3-dihydropyrroles.[6] An enantioselective version of this transformation may provide a method for direct access to chiral dihydropyrroles and would therefore be valuable in the synthesis of chiral building blocks and related alkaloids.[2] In contrast to the long history of nonasymmetric variants, [6] enantioselective, catalytic cycloaddition reactions of isocyanoesters with electron-deficient olefins are not yet available. Herein, we report the first catalytic asymmetric cycloaddition reaction of isocyanoesters [7] to nitroolefins by using alkaloid-derived bases to form highly functionalized 2,3-dihydropyrroles with excellent enantioselectivities (up to > 99 % ee).Our mechanistic proposal for the formal cycloaddition reaction catalyzed by a chiral base is shown in Scheme 1. The chiral base could promote an asymmetric Michael addition of isocyanoesters 1 to electron-deficient olefins, such as nitroolefins 2, by activating the acidic a-carbon atom of 1 to generate intermediates I. Subsequent intramolecular cyclization reactions of intermediates I afforded precursor 1,2-dihydropyrroles II, which may be converted into dihydropyrrole 3 after protonation. [6] Cinchona alkaloids and their derivatives have been revealed as efficient organocatalysts for many asymmetric reactions, [8] particularly for a variety of asymmetric Cnucleophilic addition reactions in which the basic functionalities of the alkaloid activates acidic a-carbon pronucleophiles (Figure 1). [9][10][11][12] Surprisingly, to the best of our knowledge, isocyanoesters have not yet been used as nucleophiles in these reactions, or in other organic base-catalyzed nucleophilic addition reactions. Despite this, we still believed that cinchona alkaloids...

No abstract

The first chiral thiourea-catalyzed stereoselective 1,3-dipolar cycloaddition of azomethine ylides with nitroalkenes afforded highly substituted pyrrolidines with high diastereoselectivities of up to >99:1 dr and moderate enantioselectivities.