One-Pot Cannizzaro Cascade Synthesis of ortho-Fused Cycloocta-2,5-dien-1-ones from 2-Bromo(hetero)aryl Aldehydes

Significance Statement

Exploration of 8-membered ring chemistry and the exploitation of such molecules as drug candidates by the pharmaceutical industry is significantly underrepresented. This is partly due to the considerable transannular and conformational strain associated with the formation of such medium-sized-rings. The importance of cyclooctanoid products in the pharmaceutical industry can be highlighted by the drug Taxol, famous for its anti-cancer activity.

We have developed a easily carried out scalable method of synthesising ortho-fused cycloocta-2,5-dien-1-one cores in a simple and very efficient process. We can deliver analytically pure 8-ring molecules from cascading chemical reactions involving 3-4 simple (often commercially available) compounds on gram scales. We propose a mechanism that includes a striking Cannizzaro-like 1,5-hydride transfer, uniquely unmasking an electrophilic ynone (COC≡C) and nucleophilic carbanion (C-) which react to give highly effective 8-ring formation.

This novel and exciting chemistry is aimed at making the discovery of new pharmaceutical targets based on medium rings easier using methodology that has wide and highly tuneable 

One-Pot Cannizzaro Cascade Synthesis of ortho-Fused Cycloocta-2,5-dien-1-ones from 2-Bromo(hetero)aryl Aldehydes

Journal Reference

Angew Chem Int Ed Engl. 2015;54(36):10648-51.

Burroughs L1, Eccleshare L1, Ritchie J1, Kulkarni O1, Lygo B1, Woodward S2, Lewis W1.

[expand title=”Show Affiliations”]
  1. School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD (UK).
  2. School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD (UK). [email protected].
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Abstract

An intramolecular Cannizzaro-type hydride transfer to an in situ prepared allene enables the synthesis of ortho-fused 4-substituted cycloocta-2,5-dien-1-ones with unprecedented technical ease for an eight-ring carboannulation. Various derivatives could be obtained from commercially available (hetero)aryl aldehydes, trimethylsilylacetylene, and simple propargyl chlorides in good yields.

© 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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