Journal Name ARTICLE J. Name ., 2018, 00, 1-3 | 1 Received 00th January 20xx, Accepted 00th January 20xx DOI: 10.1039/x0xx00000x This document is the accepted manuscript version of a published work that appeared in final form in Cat. Sci. Technol. 2018, 5251-5258. DOI: 10.1039/c8cy00684a. Ni-Catalysed Intramolecular [4+4]-Cycloadditions of Bis-dienes towards Eight-membered Fused Bicyclic Systems: A Combined Experimental and Computational Study Nuria Llorente, aǂ Héctor Fernández-Pérez, aǂ Antonio Bauzá, c Antonio Frontera* c and Anton Vidal- Ferran* a,b Detailed investigations on the use of nickel(0)-based catalysts for intramolecular [4+4]-cycloadditions are presented. Nickel(0) complexes derived from electron-rich triarylphosphines proved to be efficient catalysts for intramolecular [4+4]- cycloadditions of an array of structurally diverse bis-dienes (10 examples, up to 78% isolated yield). The reported synthetic methodology leads to cis-eight-membered fused [6.3.0] bicyclic compounds as well as trans- or cis- eight-membered fused [6.4.0] bicyclic systems. Computational studies on the stereo-determining step of the reaction in combination with experimental results demonstrated that the stereochemical outcome is dictated by the length of the chain linking the two diene units and the geometry of the C=C double bonds of the substrates. Introduction Medium-sized cyclic compounds, and in particular eight- membered fused polycyclic systems, are key structural motifs in a significant number of natural products. 1 Among the different strategies for the preparation of such compounds, 2 metal- mediated intramolecular [4+4]-cycloadditions are an elegant, efficient, and atom-economical synthetic methodology. Although metal-mediated [4+4]-cycloadditions of two diene units have been known for some time, 3 it was Wender’s research group 4 who pioneered the use of intramolecular nickel-catalysed [4+4]-cycloadditions for the highly diastereoselective synthesis of complex natural products (or advanced synthetic intermediates thereof). In Wender’s studies, the configurations of the substituted carbons in the tether linking the two diene units were responsible for the high diastereoselectivities observed. 4 The practicality of this approach was demonstrated by preparing (+)-asteriscanolide and (±)-salsolene oxide using this chemistry as the key step. 5 More recently, Cheung and co-workers have used rhodium(I) complexes as catalysts in this type of cycloaddition for the efficient preparation of the corresponding cyclooctadiene derivatives, 6 though harsher reaction conditions than those reported by Wender are required. Whilst diastereoselective nickel-catalysed intramolecular [4+4]-cycloadditions of bis-dienes have been reported, the study of this nickel chemistry on prochiral bis-dienes containing heteroatoms in the tether between the two diene units remained scarcely explored. 4 Herein, we wish to report our findings on the development of nickel(0)-based achiral catalysts for intramolecular [4+4]-cycloadditions of structurally diverse prochiral bis-diene substrates (Scheme 1). We also aim to disclose the effects of substituents and C=C double bond geometries on the outcome of the [4+4]-cycloadditions. Computational studies have been performed to identify the relevant transition states of the stereo-determining step and their relative stabilities and consequently provide a rationalisation of the stereochemical outcome of the reaction. Results and Discussion Study of the [4+4]-cycloadditions At the onset of our studies, we used oxygen-containing bis- diene 1a as the model substrate, as its preparation was already reported. 7 The intramolecular [4+4]-cycloaddition of 1a was a. Institute of Chemical Research of Catalonia (ICIQ) & The Barcelona Institute of Science and Technology (BIST), Av. Països Catalans 16, 43007 Tarragona, Spain. E- mail: avidal@iciq.cat b. ICREA, Passeig Lluís Companys 23, 08010 Barcelona, Spain. c. Departament de Química, Universitat de les Illes Balears (UIB), Ctra. de Valldemossa km 7.5, 07122 Palma de Mallorca, Spain. † Electronic Supplementary Information (ESI) available: Experimental procedures, spectral data for known and new compounds, selected crystallographic information and cartesian coordinates of the calculated structures. CCDC 1834976 and 1834977 contains the supplementary crystallographic data for this paper. See DOI: 10.1039/x0xx00000x. ǂ These authors contributed equally to this work.