Organocatalytic Enantioselective Synthesis of Tetrahydropyridines

Abstract

Tetrahydropyridines are important heterocycles present in many molecules of natural and non‐natural origins that exhibit a wide array of biological activities. With several sp3‐hybridized carbon atoms in their structure, they often include one or several stereogenic centers, whose control represents a great synthetic challenge. For the past two decades, enantioselective organocatalysis has developed as a very powerful strategy to perform the synthesis of enantioenriched compounds, including heterocycles. In this Microreview, we wish to provide the readers with a general overview about the organocatalytic strategies that have been used to achieve the preparation of diversified families of tetrahydropyridines, thereby providing elements of reflection for further developments.

Diastereoselective Synthesis of 2,6‐Disubstituted‐1,2,3,6‐Tetrahydropyridines through a Palladium‐Catalyzed Intramolecular Allylic Amination

“…According to the literature reporting catalyzed allylic amination to form the six‐membered ring of piperidines,[3c], dihydroquinolines or substituted amines, the alcohol function can be free or activated as a carbonate or an acetate. In order to optimize the reaction conditions for our TP synthesis, we decided to start from either alcohol 3a or methyl carbonate 4a (Table ).…”

“…With precursor 4a‐ syn in hand, the cyclization reaction was investigated. First, and based on Unenishi transformation,[3c] 30 mol‐% of PdCl 2 (CH 3 CN) 2 was used to validate the feasibility of the cyclization to 5a and determine the best solvent (Table , entries 1–4). At room temperature, DCE gave faster total conversion in favor of a diastereoisomer with a 82:18 ratio.…”

“…[1b], [1c], Among these approaches, the synthesis of 2,6‐disubstituted‐TP/piperidines have attracted much attention because these heterocycles are found in many interesting products with a wide range of pharmacological activities. [1a], [1b], [3a] Various methods have been described for the preparation of cis ‐ or trans ‐2,6‐disubstituted‐TP including cationic cyclization,[3a] nucleophilic substitution, ring‐closing metathesis, aza‐Diels–Alder[1b] and Mitsunobu[1c] reactions, allyl nitrone cyclization, aza‐[2,3]‐Wittig rearragements of vinylaziridines or diastereoselective C–H functionalization . However, methods leading to trans ‐2,6‐disubstituted‐TP/piperidines are less reported, because the trans relative configuration is thermodynamically disfavored .…”

“…During our previous studies, we developed a methodology to prepare stereoselectively either 2,6‐ cis or 2,6‐ trans ‐disubstituted‐piperidines via a Michael‐type cyclization . This methodology used β′‐carbamate‐α,β‐unsaturated ketone[3a] as a key precursor. We further envisioned that 2,6‐disubstituted‐TP could be formed via a palladium‐catalyzed intramolecular allylic amination.…”

Organocatalytic Synthesis of Highly Functionalized Heterocycles by Enantioselective aza-Morita–Baylis–Hillman-Type Domino Reactions

“…Tetrahydropyridines 64) are also known to exhibit interesting bioactivities, such as their antioxidant, antibiofilm, anti-inflammatory, and pluripotent inhibitory properties against human cancer cell lines. 65) In 2011, we reported another aza-MBH-type domino reaction (Chart 6).…”