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Molecules 2010, 15(10), 6773-6794; doi:10.3390/molecules15106773

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

Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
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Received: 21 August 2010 / Revised: 13 September 2010 / Accepted: 20 September 2010 / Published: 28 September 2010
(This article belongs to the Special Issue Diversity Oriented Synthesis)
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Abstract

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.
Keywords: three-component coupling reaction; diversity oriented synthesis; lasofoxifene; nafoxidine; inv-lasofoxifene; inv-nafoxidine three-component coupling reaction; diversity oriented synthesis; lasofoxifene; nafoxidine; inv-lasofoxifene; inv-nafoxidine
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MDPI and ACS Style

Nakata, K.; Sano, Y.; Shiina, I. Synthesis of Lasofoxifene, Nafoxidine and Their Positional Isomers via the Novel Three-Component Coupling Reaction. Molecules 2010, 15, 6773-6794.

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