DOI: 10.1002/adsc.201300018 Double Gold-Catalysed Annulation of Indoles by Enynones Stephen J. Heffernan, a James P. Tellam, a Marine E. Queru, a Andrew C. Silvanus, a David Benito, a Mary F. Mahon, a Alan J. Hennessy, b Benjamin I. Andrews, b and David R. Carbery a, * a Department of Chemistry, University of Bath, Claverton Down, Bath, BA27AY, U.K. Fax: (+ 44)-1225-386-231; phone: (+ 44)-1225-386-144; e-mail: d.carbery@bath.ac.uk b GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG12NY, U.K. Received: January 3, 2013; Published online: April 9, 2013 Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300018. Abstract: The gold-catalysed double functionalisa- tion of indoles is presented. Enynones are used to annulate indoles via a double sodium tetrachloroau- rate-catalysed process involving a mixture of C À H activation and alkyne activation modes of promo- tion. Good yields for the formation of medicinally relevant [6,5,7]-tricyclic indoles are realised. Keywords: cascade reactions; catalysis; diversity; gold; indoles Introduction Indoles are an extensive and important family of bio- logically active molecules. [1] The indole nucleus plays a key role in mammalian neurochemistry in the form of the neurotransmitter serotonin and is therefore piv- otal to a large number of physiological functions. Ad- ditionally, indoles and indole-derived compounds are found in an extraordinary range of secondary natural product metabolites with wide-ranging associated bio- logical activities. [2,3] Thirdly, the indole skeleton has been incorporated into a large number of medicinal chemistry designs and clinical products and as such has been viewed as a privileged structure. [4,5] When considered together, it is therefore understandable why indoles remain an area of intense synthetic ex- ploration, [6] both in terms of de novo syntheses [7] but also in the elaboration of pre-existing indole frame- works. [8] Three structurally related indoles (1–3, Figure 1), recently reported in the medicinal chemistry literature with potent biological activity, have attracted our in- terest due to the presence of a shared [6,5,7]-fused tri- cyclic indole core. Indole 1 displays high potency and excellent oral bioavailability in mouse model tumour xenografts, acting as an aurora kinase inhibitor. [9] Carboxamide 2 acts as a potent and selective inhibi- tor of the deacetylase, SIRT1 2. [10] This amide repre- sents the most active SIRT1 inhibitor reported to date and with a favourable ADME profile, has been sug- gested as a lead towards therapeutics. Additionally, indole 3 has been reported as a potent and selective fatty-acid binding protein (FABP) inhibitor. [11] In each instance, the specified [6,5,7]-core offered maxi- mum biological activity in their respective assays in comparison with the [6,5,6]- and [6,5,5]-fused tricyclic homologues. Accordingly, it is reasonable to suggest that this [6,5,7] indole core displays significant promise in me- dicinal drug-discovery contexts and would benefit from future exploration. It is noteworthy that the [6,5,7]-indole core in 1–3 was constructed through a classical Fischer indole synthesis and therefore ac- cessed from restricted chemical space. With a clear medicinal rationale, we reasoned that novel and flexi- ble approaches to such [6,5,7]-tricyclic indoles might open new areas of chemical space for exploration in a small-molecule discovery context. In addition, a number of natural products with impressive biologi- cal activity exist which feature this [6,5,7]-tricyclic core. For example, actinophyllic acid, [12] the ambi- guines [13] and the ervatamine-silicine alkaloids [14] all feature this key indole structural unit. Results and Discussion Building on our Brønsted acid-catalysed annulation of indoles [15] by divinyl ketones we have sought to expand the scope of such indole-focussed annulations. With this in mind, we chose to consider structurally related ketonic double electrophiles, such as enyn- Adv. Synth. Catal. 2013, 355, 1149 – 1159  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1149 FULL PAPERS