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

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

,  and *
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
* Author to whom correspondence should be addressed.
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
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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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