Amine‐Promoted Asymmetric (4+2) Annulations for the Enantioselective Synthesis of Tetrahydropyridines: A Traceless and Recoverable Auxiliary Strategy

Abstract

Substituted tetrahydropyridines and piperidines are common six-membered heterocycles found in biologically active natural products and synthetic pharmaceuticals. [1] One of the most versatile and reliable methods to prepare this class of six-membered heterocycles is the aza-Diels-Alder reaction. [2] Particularly, the recent development of dienamine catalysis [3] has added a powerful dimension to the aza-Diels-Alder reaction, which strongly relies on the formation of the dienamines developed by the groups of Barbas, [4] Jørgensen, [5] and Chen [5] by 1,2-addition of the amine catalyst to enone or enal (Scheme 1). Despite extensive studies and noteworthy

Phosphine-catalyzed [4+2] annulations of α-aminonitriles with allenoates: Synthesis of functionalized tetrahydropyridines

“…(2)] [29] . However, the construction of highly substituted tetrahydropyridine derivatives via a phosphine or amine-catalyzed [4+2] annulation of 2-(acetoxymethyl)buta-2,3-dienoates with C,N-bisnucleophiles is unexploited [30] .…”

Amine-promoted asymmetric [4+2] cycloadditions of α-acetoxymethyl allenoate and dual activated alkenes: stereoselective synthesis of poly-substituted cyclohexenes

“…3). 9 The resulted dienamine A exhibits excellent diene reactivity toward the aza-Diels-Alder reaction with imine. As our ongoing interest in the transformations of allenoate, 10 we herein report the amine-promoted asymmetric [4+2] cycloadditions of 2-acetoxymethyl allenoate 1 with dual activated alkenes, which provide a facile access to the poly-substituted cyclohexenes with good stereoselectivity.…”

Dehydrogenative Aza-[4 + 2] Cycloaddition of Amines with 1,3-Dienes via Dual Catalysis

“…Tetrahydropyridine (THP) derivatives are basic structural motifs embedded in numerous natural products, bioactive compounds, and pharmaceuticals (Scheme a) . For example, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, I ), well known as a prodrug to the neurotoxin MPP + , has been proven to cause permanent symptoms of Parkinson’s disease by destroying dopaminergic neurons in the substantia nigra of the brain. , (+)-Cannabisativine ( II ) was isolated in 1975 from the roots and leaves of the common marijuana plant, Cannabis sativa L. and contains a trans -2,6-disubstituted-1,2,3,6-tetrahydropyridine ring with an unusual macrocyclic spermidine alkaloid. , The bioactive compound III was synthesized by Prachayasittikul et al, and its 1,2,3,6-tetrahydropyridine skeleton with multiple substituents presented antibacterial activity against S. pyogenes and M. catarrhalis . , Whereas the approaches that rely on olefin metathesis, nucleophilic additions, the reduction of pyridine derivatives, and transition-metal-catalyzed cyclization have been well developed to access these nitrogen-containing heterocycles, the aza-Diels–Alder reaction , of imines with dienes is still a powerful and atom-economical tool to construct 1,2,3,6-tetrahydropyridine rings.…”