Sulfoxide-Directed Enantioselective Synthesis of Functionalized Tetrahydropyridines

Abstract

The highly selective base-promoted cyclization of enantiopure sulfinyl dienamines provides stereodefined sulfinyl 1,2,3,6-tetrahydropyridines (dr up to 99:1). Subsequent sigmatropic rearrangement affords tetrahydropyridin-3-ols in good yields and selectivities.Piperidines and 3-hydroxypiperidines are prevalent motifs within nature 1 as well as in conformationally restricted peptidomimetics 2 and synthetic drugs. 3 Their presence in numerous bioactive compounds and their pronounced pharmacological properties have attracted considerable attention to the asymmetric syntheses of these targets. 4 One of the most versatile routes to these nitrogen-containing frameworks is the aza-DielsÀAlder reaction involving either aza-dienophiles or aza-dienes. 5 Alternatively, additionÀ cyclization to imines, 6 ring expansion of furan derivatives, 7 reduction of pyridine scaffolds, 8 ring closing metathesis 9 (RCM) on dialkyl substituted nitrogen substrates, or several approaches via nucleophilic attack of nitrogen onto different acceptors have been extensively employed to furnish the piperidine skeleton. 10 Many of these strategies require the use of amino acids or substrates bearing chiral auxiliaries to

Recent Advances in the Application of Ring-Closing Metathesis for the Synthesis of Unsaturated Nitrogen Heterocycles

“…17 Tetrahydropyridines present a greater challenge, however many versatile methods have been developed including 6πcyclization strategies 18 such as the aza-Diels-Alder reaction 19 (Scheme 1). Alternative strategies take advantage of traditional amine reactivity including nucleophilic additions to substituted olefins 20 and phosphine catalysis 4a,21 to promote the cyclization to generate the desired tetrahydropyridines. Finally, similar mechanistic strategies for accessing 3-pyrrolines and tetrahydropyridines have been reported, including allene annulation 22 and the reduction of the aromatic pyrroles and pyridines.…”

Remote Stereocontrol in the Synthesis of Acyclic 1,4-Diols and 1,4-Aminoalcohols from 2-Sulfinyl Dienes

“…This alternative approach would install both stereocenters in a single synthetic operation with overall remote stereocontrol of one center into the other. Our previous reports on the synthesis of dihydropyrans and tetrahydropyridines through an intramolecular conjugate addition to ( Z , Z )-2-sulfinyl dienes supported the viability of the approach . Some years ago we reported an efficient Stille coupling protocol to prepare 2- sulfinyl dienes ( III ) from iodo vinyl sulfoxides 1 and vinyl stannanes as a general methodology .…”

Chiral Tetrahydropyridines via FeCl3-Catalyzed Carbonyl-Olefin Metathesis

“…1A). Additional strategies include the cyclization of sulfinyl dienamines, 7 ring expansion of furan derivatives, 8 the reduction of pyridine scaffolds, 9 and transition metal-catalyzed cyclizations. 10 While these strategies provide differentially substituted tetrahydropyridines, they often require precious metal catalysts, expensive chiral ligands, extended reaction times, or have a limited substrate scope.…”