Synthesis of the melatonin receptor agonist Ramelteon using a tandem C–H activation–alkylation/Heck reaction and subsequent asymmetric Michael addition

An asymmetric synthesis of the melatonin receptor agonist Ramelteon 1 has been achieved, which involved a tandem C–H activation–alkylation/Heck reaction and subsequent highly diastereoselective asymmetric Michael addition to generate the corresponding chiral intermediate, which was readily converted into Ramelteon 1 in 19% overall yield in 15 linear steps.

Figure optionsDownload as PowerPoint slide

(E)-Ethyl 3-(5-(1-(S)-((tert-butylsulfinyl)imino)ethyl)-2,3-dihydrobenzofuran-4-yl) acrylateC19H25NO4S[α]D25=-4.1 (c 1.0, CHCl3)Absolute configuration: (E,S)

Ethyl 2-((8S)-6-(((S)-tert-butylsulfinyl)imino)-2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)acetateC19H25NO4S[α]D25=+96.9 (c 1.0, CHCl3)Absolute configuration: (8S,S)

(S)-Ethyl 2-(6-oxo-2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)acetate.C15H16O4[α]D25=-73.5 (c 1.0, CHCl3)ee value: 92%Absolute configuration: (S)

(S)-Ethyl 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)acetate.C15H18O3[α]D25=-58.9 (c 1.0, CHCl3)Absolute configuration: (S)

(S)-2-(2,6,7,8-Tetrahydro-1H-indeno[5,4-b]furan-8-yl)ethanol.C13H16O2[α]D25=-81.4 (c 1.0, CHCl3)Absolute configuration: (S)

(S)-2-(2,6,7,8-Tetrahydro-1H-indeno[5,4-b]furan-8-yl)ethanamine.C13H17NO3[α]D25=-69.2 (c 1.0, CHCl3)Absolute configuration: (S)

RamelteonC16H21NO2[α]D25=-54.8 (c 1.0, CHCl3)