Asymmetric Total Synthesis of Meptazinol

Abstract

The first enantioselective synthesis of (S)-meptazinol in 14 steps from commercially available ethyl 4-oxo-3,4-dihydropyridine-1­(2H)-carboxylate, being widely used in racemic form for pain treatment, and, en route, the formal synthesis of two anti-Alzheimer’s agents are reported. A novel ring expansion of 2-azabicyclo[4.1.0]­heptanes, readily available via the stereoselective cyclopropanation of 1,2,3,4-tetrahydropyridine-4-ols, provides an effective entry to 3,3-disubstituted azepanes that represent the core for a variety of approved drugs.

Highly Enantioselective Catalytic Lactonization at Nonactivated Primary and Secondary γ-C–H Bonds

“…Importantly, the products thus formed, P11 and P12, provide the opportunity to access important structural motifs present in a variety of approved drugs, such as C3-quaternary azepanes. 29 With the identification of 2 CF3 and 2 iPr as preferential catalysts for highly enantioselective primary C−H oxidation, γlactonization at secondary sites was investigated (Figure 4). The oxidation of cyclohexanecarboxylic acid (S13), which contains two enantiotopic γ-methylenic units, results in full substrate conversion with formation of only a small amount of γ-lactone P13.…”

“…In this scenario, the present methodology also enables γ -C–H bond lactonization at primary sites in carboxylic acids bearing aryl bromides ( S11 ), which are usually incompatible in C–H activation reactions catalyzed by noble metals due to hydrodehalogenation, as well as electron-poor aromatic moieties ( S12 ). Importantly, the products thus formed, P11 and P12 , provide the opportunity to access important structural motifs present in a variety of approved drugs, such as C3-quaternary azepanes …”

“…Importantly, the products thus formed, P11 and P12 , provide the opportunity to access important structural motifs present in a variety of approved drugs, such as C3-quaternary azepanes. 29 …”