A Telescoped Route to 2,6‐Disubstituted 2,3,4,5‐Tetrahydropyridines and 2,6‐<i>syn</i>‐Disubstituted Piperidines: Total Synthesis of (−)‐Grandisine G

The first catalytic asymmetric five‐component tandem reactions of β‐keto esters, aromatic aldehydes and anilines have been established in the presence of a chiral phosphoric acid, affording densely functionalized tetrahydropyridines with concomitant generation of five σ bonds and two stereogenic centers in high diastereo‐ and enantioselectivities (up to >99:1 dr, 95:5 er). In addition, the first isolation and preparation of a diene species as the key intermediate of the reaction has been successfully realized, leading to the formation of the desired tetrahydropyridine via further condensation with in situ generated imine, which supported the proposed tandem [4+2] reaction pathway to some extent. This protocol not only represents the first enantioselective example of this five‐component tandem reaction, but also provides an unprecedented access to enantioenriched tetrahydropyridines with structural diversity, which holds great potential in medicinal chemistry.

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Catalytic Asymmetric Five‐Component Tandem Reaction: Diastereo‐ and Enantioselective Synthesis of Densely Functionalized Tetrahydropyridines with Biological Importance

Shi

Tan

Zhu

et al. 2013

Adv Synth Catal

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Enantioselective Organocatalyzed Formal [4+2] Cycloaddition of Ketimines with Allenoates: Easy Access to a Tetrahydropyridine Framework with a Chiral Tetrasubstituted Stereogenic Carbon Center

et al. 2014

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Enantioselective organocatalytic synthesis of tetrahydropyridines bearing a chiral tetrasubstituted carbon stereogenic center has been achieved. The spiro-type monoaryl phosphine catalyst, (R)-SITCP, was found to promote the formal [4 + 2] cycloaddition of saccharin-derived ketimines and a-methyl allenoate to afford the corresponding six-membered N-heterocycles in high yields and excellent regioselectivities with up to 93% ee.[a] Dr. Scheme 1. Formal [4+2] cycloaddition of cyclic ketimine 1 with a-methyl allenoate 2.

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1,2‐Asymmetric Induction in Diastereoselective Zwitterionic Aza‐Claisen Rearrangements: Key Steps in Optically Active Alkaloid Synthesis

2013

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The zwitterionic aza‐Claisen rearrangement of optically active N‐allylpyrrolidines and α‐phenoxyacetyl fluorides proceeds with complete simple diastereoselectivity (internal asymmetric induction) and complete 1,2‐asymmetric induction to generate a new C–C bond adjacent to a chiral C‐N‐Boc functionality. The resulting γ,δ‐unsaturated amides were cyclised to give the corresponding pyrrolizidinones, which enabled the determination of the relative configuration of the stereotriads. Vinyl group degradation and a final lactam reduction gave an optically active analogue of (+)‐petasinine (a pyrrolizidine alkaloid). Furthermore, the stereotriad‐containing amides should be useful key intermediates for the total synthesis of optically active elaeocarpin (an indolizidine alkaloid).

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A Telescoped Route to 2,6‐Disubstituted 2,3,4,5‐Tetrahydropyridines and 2,6‐syn‐Disubstituted Piperidines: Total Synthesis of (−)‐Grandisine G

Cited by 4 publications

References 16 publications

Catalytic Asymmetric Five‐Component Tandem Reaction: Diastereo‐ and Enantioselective Synthesis of Densely Functionalized Tetrahydropyridines with Biological Importance

Catalytic Asymmetric Five‐Component Tandem Reaction: Diastereo‐ and Enantioselective Synthesis of Densely Functionalized Tetrahydropyridines with Biological Importance

Enantioselective Organocatalyzed Formal [4+2] Cycloaddition of Ketimines with Allenoates: Easy Access to a Tetrahydropyridine Framework with a Chiral Tetrasubstituted Stereogenic Carbon Center

1,2‐Asymmetric Induction in Diastereoselective Zwitterionic Aza‐Claisen Rearrangements: Key Steps in Optically Active Alkaloid Synthesis

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A Telescoped Route to 2,6‐Disubstituted 2,3,4,5‐Tetrahydropyridines and 2,6‐syn‐Disubstituted Piperidines: Total Synthesis of (−)‐Grandisine G

Cited by 4 publications

References 16 publications

Catalytic Asymmetric Five‐Component Tandem Reaction: Diastereo‐ and Enantioselective Synthesis of Densely Functionalized Tetrahydropyridines with Biological Importance

Catalytic Asymmetric Five‐Component Tandem Reaction: Diastereo‐ and Enantioselective Synthesis of Densely Functionalized Tetrahydropyridines with Biological Importance

Enantioselective Organocatalyzed Formal [4+2] Cycloaddition of Ketimines with Allenoates: Easy Access to a Tetrahydropyridine Framework with a Chiral Tetrasubstituted Stereogenic Carbon Center

1,2‐Asymmetric Induction in Diastereo­selective Zwitterionic Aza‐Claisen Rearrangements: Key Steps in Optically Active Alkaloid Synthesis

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Product

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1,2‐Asymmetric Induction in Diastereoselective Zwitterionic Aza‐Claisen Rearrangements: Key Steps in Optically Active Alkaloid Synthesis