FULL PAPER DOI: 10.1002/ejoc.200700986 Synthesis of Angularly Fused Carbocycles via Tandem Radical Cyclization of α-Carbonyl Radicals Chandran Prakash [a] and Arasambattu K. Mohanakrishnan* [a] Keywords: Radicals / Cyclization / Polycycles An α-carbonyl radical cyclization approach towards the syn- thesis of angularly fused tricyclic systems is described. On reduction with tributyltin hydride, bromo ketones yield a α- carbonyl radical that undergoes successive 5-exo-dig/trig cy- clizations, resulting in two or four contiguous stereocenters. Introduction Tandem-cyclization strategies for the synthesis of angu- larly fused carbocycles [1,2] have gained considerable promi- nence since these frameworks exist in many natural prod- ucts. The tandem construction of the rings can provide an inherently efficient approach to the synthesis of an angu- larly fused tricyclic system if the stereochemistry is con- trolled. Thus, tandem radical cyclization [3] ranks among the most powerful methods to construct a tricyclic ring system in a single step from a monocyclic precursor. During the last fifteen years, Sha and co-workers exploited the α-car- bonyl radical cyclization strategy to synthesize several natu- ral products, including ()-modhephene, [4a] (–)-dendrobi- ne, [4b] (–)-5-oxosilphiperfol-6-ene, [4c] dimethyl gloiosphone A [4d] and (+)-paniculatine. [4e] The syntheses of these natural products were achieved by homolytic Bu 3 SnH-mediated cleavage of the corresponding α-iodo cycloalkanones fol- lowed by intramolecular cyclization. Results and Discussion The angular tricyclic framework has received prominent attention among synthetic chemists. Several elegant strate- gies reported [5] for such ring systems are based on a tandem radical cyclization. Hence, a systematic study was under- taken to synthesize the angular tricyclic skeletons 1–3 of the natural products agariblazeispirol C, [6] dankasterone [7] and laurenene [8] following the α-carbonyl radical cyclization approach established by Sha and co-workers. [4] Towards the realization of this objective, all our attempts to prepare the required α-iodo cycloalkanones were found [a] Department of Organic Chemistry, University of Madras, Guindy, Campus, Chennai 600025, Tamil Nadu, India Fax: +91-44-22352494 E-mail: mohan_67@hotmail.com Eur. J. Org. Chem. 2008, 1535–1543 © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1535 (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) to be cumbersome. Additionally, we found it difficult to re- produce the iodination of silyl enol ether when using the existing NaI/mCPBA protocol. [9] On the other hand, even though, in some cases the α-iodo cycloalkanones were pre- pared using Sha’s procedure in reasonable yields, they are highly unstable and photo-labile. In particular, tertiary α- iodo ketone undergoes extensive decomposition even at room temperature (Figure 1). Figure 1. Natural products containing angular tricyclic units. We believe that the labile nature of α-iodo cycloalk- anones is a bottleneck for applying the α-carbonyl radical cyclization strategy to the synthesis of core skeleton of the above-mentioned natural products. In this regard, we have recently reported a facile preparation of α-bromo and α- iodo cycloalkanones using NaX/FeCl 3 . [10] As expected, rel- atively, the α-bromo cycloalkanones were found to be more stable. Initially, we tested the tandem radical cyclization ap- proach with the synthesis of 6–5–5 angular tricyclic sys- tems [4e] 7a and 7b (Scheme 1). A CuI-promoted 1,4-ad-