Three‐Step Total Synthesis of Ramelteon via a Catellani Strategy

Abstract

Ramelteon is the first medicine in human history that treat insomnia as a melatonin receptor agonist. Herein, we report an efficient three-step synthetic route to access it from commercially available 2,3-dihydrobenzofuran-4-amine, which represents as the shortest racemic synthesis to date with a 26 % overall yield. Key to the success is the application of the intermolecular Catellani-type alkylation and intramolecular redox-relay Heck cyclization cascade for preparation of the key indane-containing aldehyde. The unique primary amide-involved reductive amination of aldehyde is another feature of this route. New process of ramelteon can be developed based on this chemistry.[a] S.

Benzo-Fused-Ring Toolbox Based on Palladium/Norbornene Cooperative Catalysis: Methodology Development and Applications in Natural Product Synthesis

“…Ramelteon possesses a distinct tricyclic core scaffold including a dihydrobenzofuran and an indane motif. Our retrosynthetic proposal for ramelteon is shown in Scheme A . We thought that ramelteon could be obtained from aldehyde 36 via a reductive amination.…”

Concise Six-Step Asymmetric Approach to Ramelteon from an Acetophenone Derivative Using Ir, Rh, Cu, and Ni Catalysis

“…Purification by flash chromatography (Biotage SNAP Cartridge KP-Sil using a EtOAc/n-heptane 2−40% gradient) furnished 1-(2,3-dihydrobenzofuran-4-yl)ethanone 4 (3.47 g, 35% recovered material) and pure 6,7-dihydro-1H-indeno [5,4b]furan-8(2H)-one 5 (2.85 g, 27% yield and 41% yield based on consumed 4) as an off white solid: mp 132.5 °C (DSC onset) and 133.5 °C (DSC peak); 1 H NMR (500 MHz, CDCl 3 ) δ 7.21 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 4.66 (t, J = 8.9 Hz, 2H), 3.48 (t, J = 8.9 Hz, 2H), 3.11−3.05 (m, 2H), 2.72−2.66 (m, 2H); 13 C{ 1 H} NMR (125 MHz, CDCl 3 ) δ 207. 4, 160.2, 147.1, 133.6, 125.6, 123.9, 115.6, 72.3, 37.1, 28.4, 25.4 Preparation of (E)-2-(1,2,6,7-Tetrahydro-8H-indeno [5,4-b]furan-8-ylidene)acetonitrile (7). Compound 7 (1.56 g, yield 77%) as a white crystalline solid was prepared according to literature procedures: 3a−c mp 140.5 °C (DSC onset) and 147.5 °C (DSC peak) (lit.…”

“…However, ramelteon’s molecular structure consisting of a tricyclic 1,6,7,8-tetrahydro-2 H -indeno­[5,4- b ]­furan core containing a chiral substituent suggests that its concise and efficient asymmetric synthesis might be challenging. Although several synthetic approaches to ramelteon − or its key intermediates − have been devised, they have been either very long, starting from advanced bicyclic or tricyclic intermediates, or produced racemic ramelteon (Scheme , see Supporting Information document for expanded discussion). In our work, we present a concise six-step asymmetric synthesis of ramelteon from a monocyclic 3-hydroxyacetophenone starting material by using iridium, rhodium, copper, and nickel catalysis to construct the tricyclic core and assemble the chiral side chain .…”

Stereoselective Remote Functionalization via Palladium‐Catalyzed Redox‐Relay Heck Methodologies

“…This strategy has subsequently been applied in the four‐step total synthesis of (±)‐eptazocine (previously ≥7 steps), showcasing that more complex quaternary benzylic stereocenters, prevalent in a number of bioactive molecules, can be generated efficiently. Later, a modified set of conditions were employed in the three‐step total synthesis of (±)‐ramelteon (previously ≥4 steps) [67] . Attempts to establish an asymmetric variant of this methodology have been initiated, so far with only limited success and moderate enantiocontrol (Scheme 33).…”

“…4steps). [67] Attempts to establish an asymmetric variant of this methodology have been initiated, sof ar with only limited success andm oderate enantiocontrol (Scheme 33).…”