Synthesis of Lasofoxifene, Nafoxidine and Their Positional Isomers via the Novel Three-Component Coupling Reaction

• Main Authors: Isamu Shiina, Kenya Nakata, Yoshiyuki Sano
• Format: Article
• Language: English
• Published: MDPI AG 2010-09-01
• Series: Molecules
• Subjects: three-component coupling reaction; diversity oriented synthesis; lasofoxifene; nafoxidine; inv-lasofoxifene; inv-nafoxidine
• Online Access: http://www.mdpi.com/1420-3049/15/10/6773/

A Lewis acid-mediated three-component coupling reaction was successfully applied for the synthesis of lasofoxifene (1), nafoxidine (2), and their positional isomers, inv-lasofoxifene (3) and inv-nafoxidine (4). In the presence of HfCl4, the desired one-pot coupling reaction among 4-pivaloyloxybenzaldehyde (5), cinnamyltrimethylsilane (6), and anisole proceeded to afford the corresponding 3,4,4-triaryl-1-butene 7 in high yield. The iodocarbocyclization of the coupling product and the successive elimination of hydrogen iodide forming the olefin part, followed by the migration of the double-bond afforded the common synthetic intermediate of lasofoxifene (1) and nafoxidine (2) via a very concise procedure. Additionally, the syntheses of their positional isomers inv-lasofoxifene (3) and inv-nafoxidine (4) were also achieved through very convenient protocols.