Document Type

Article

Rights

Available under a Creative Commons Attribution Non-Commercial Share Alike 4.0 International Licence

Disciplines

1.4 CHEMICAL SCIENCES, 1.6 BIOLOGICAL SCIENCES

Publication Details

Journal of Organic Research & Development

Abstract

PH46A, belonging to a class of 1,2-Indane dimers, has been developed by our research group as a potential therapeutic agent for the treatment of inflammatory and autoimmune diseases. The initial synthetic route to PH46A gave a low overall yield, due in large part to the generation of undesired diastereoisomer 5 and the unwanted enantiomer (R,R)-8 during the synthesis. The aim of this work was to carry out a comprehensive investigation into the stereoselective synthesis of PH46A. Significant progress was made on the ketone reduction step, where the use of triisobutylaluminum [TiBA, Al(iBu)3] afforded high selectivity for the target diastereoisomer (rac)-6, compared to the unfavorable ratio obtained using a previous process. This enabled a multikilo scale synthesis of PH46A in a GMP environment. Further, a brief proof-of-principle investigation was carried out using an achiral phase transfer catalyst (PTC) for alkylation at the methine carbon of the parent indanone.

DOI

https://doi.org/10.1021/acs.oprd.7b00258

Funder

The Wellcome Trust UK, Enterprise Ireland

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