Carbene cascades for the formation of bridged polycyclic rings Santa Jansone-Popova, Phong Q. Le, Jeremy A. May * Department of Chemistry, University of Houston, 112 Fleming Building, Houston, TX 77204-5003, United States article info Article history: Received 20 January 2014 Received in revised form 6 March 2014 Accepted 7 March 2014 Available online 22 March 2014 Keywords: Bridged rings Cascade reactions Carbene chemistry CeH bond insertion Alkynes Caged rings abstract A general strategy to synthesize bridged polycyclic molecules is presented. The synthesis is accomplished via a cascade reaction initiated by rhodium carbene formation. Subsequent intramolecular reaction with an alkyne is then followed by a transannular CeH bond insertion. A rationale for prediction of the major structural isomer that is formed is described and applied to a wide variety of substrates. This rationale is based on conformational and stereoelectronic considerations for the ring system in the substrate. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction and background Examples abound of polycyclic natural products where a bridged bicyclic core is fused with additional rings (Fig. 1). These compounds routinely possess important biological activities that are applicable to the study of biochemical pathways and the de- velopment of new disease treatments. Many of these natural products are isolable in only scarce quantities from natural sources. Thus, a practical synthetic approach is needed to furnish the ma- terial to investigate the properties of these compounds. There has been a significant effort to develop methods for the synthesis of bridged bicycles. The variety of strategies developed to synthesize different bridged rings includes ring formation via radical in- termediates, 1 enolate additions, 2 pericyclic cycloadditions, 3 and Michael reaction cascades. 4 However, each of these methods typi- cally targets only one unique size and connectivity for the bridged ring system. For example, the bicyclo[2.2.2]octane cores of tashir- onin A (1) and maoecrystal V have been targeted with an intra- molecular DielseAlder reaction. 5 However, adenanthin (5) would require a completely different strategy. A rapid, generalized ap- proach to generate different bridged polycycles from common starting points would increase synthetic utility, flexibility, and efficiency. We recently disclosed a generalized strategy to synthesize bridged polycycles like 9 (Scheme 1). 6 By altering the ring in 6, a variety of bridged ring sizes may be formed with differing points of connection. This cascade reaction approach to bridged polycycles is initiated through catalytic diazo decomposition 7 of an a-diazo carbonyl 8 like 6 and terminates in a CeH bond insertion. 9 Impor- tantly, the CeH bond insertion allows for new CeC bond formation without prefunctionalization of the carbocycle, allowing for greater synthetic efficiency. 10 The carbene cascade reaction proposed herein forms multiple CeC bonds in a single reaction to further increase efficiency. While bridged ring systems contain 17e23 kcal/ mol of ring strain relative to cyclohexane, 11 the high reactivity of the carbene intermediates allow the reaction to proceed. Fig. 1. Bridged polycyclic natural products. * Corresponding author. Tel.: þ1 832 842 8808; fax: þ1 713 743 2709; e-mail address: jmay@uh.edu (J.A. May). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2014.03.060 Tetrahedron 70 (2014) 4118e4127