Arylation of [6,6]-spiroacetal enol ethers: reactivity and rearrangement Kylee M. Aumann, Peter C. Healy, Mark J. Coster ⇑ Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan 4111, Queensland, Australia article info Article history: Received 22 October 2010 Revised 9 December 2010 Accepted 17 December 2010 Available online 23 December 2010 Keywords: Spiroacetal Enol ether Tetrahydrochroman Rearrangement Hexahydrochroman abstract Attempts to selectively arylate [6,6]-spiroacetal enol ethers at the 2-position delivered unexpected results. Palladium-mediated arylation conditions afforded the double-Heck product, whereas reaction with benzenesulfinic acid resulted in a facile rearrangement into the corresponding 5-phenylsulfonyl- 3,4,5,6-tetrahydrochromans, providing access to 5-aryl-3,4,5,6-tetrahydrochroman and hexahydrochro- man derivatives. Ó 2011 Elsevier Ltd. All rights reserved. Spiroacetals 1 are a common structural motif found in many nat- ural products derived from marine organisms, insects, plants, and fungi. 2 These natural products vary greatly in structural complex- ity and biological activity, acting as insect pheromones, and dis- playing antibacterial, antifungal, and anti-proliferative properties, among others. 3 Interestingly, of the more than 2500 spiroacetal- containing natural products identified to date, only one, integra- mycin (1, Fig. 1), incorporates a 2-aryl substituent. 4 Integramycin was first isolated from the fermentation extracts of Actinoplanes sp. in 2002, and has been shown to inhibit strand transfer reactions mediated by the viral enzyme HIV-1 integrase, with an IC 50 value of 4 lM. 3b Additionally, integramycin exhibits no activity in DNA- ase assays at 100 lM, implying that it selectively inhibits HIV-1 integrase over other DNA interactive enzymes. Integramycin poses a challenging synthetic target, comprising thirteen stereocenters and three chemically disparate regions: the aryl spiroacetal, cis-decalin, and tetramic acid subunits. To date, there have been no reported total syntheses of integramycin, although the aryl spiroacetal subunit and the cis-decalin fragments have been synthesized by the groups of Floreancig 5 and Roush, 6 respectively. Floreancig and coworkers employed a ruthenium- mediated hydroesterification and a C,O-dianionic addition to a lac- tone to afford the spiroacetal in their stereoselective synthesis of the aryl spiroacetal subunit. 5 We sought to develop an alternative methodology to access 2-arylspiroacetals, initially focusing on a model system. We now report our investigation of two strategies for the synthesis of the desired 2-arylspiroacetal motif 2, via a common spiroacetal enol ether 3: (i) a Heck reaction 7 and subsequent hydrogenation, and (ii) the addition of benzenesulfinic acid across the enol ether double bond, followed by displacement of phenyl- sulfinate using an appropriate arylzinc reagent. 8 Spiroacetal enol ether 3 could, in turn, be derived from appropriately substituted exo-methylene tetrahydropyran 4 and an acrolein derivative 5, O O OH O NH O OH OH HO OH H H H 1 Figure 1. Integramycin. O O Ar X O O X O O X Arylation/ Reduction or Addition/ Substitution HDA Reaction 3 2 4 5 R R R Scheme 1. Strategies for 2-arylspiroacetal synthesis. 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2010.12.076 ⇑ Corresponding author. Tel.: +61 7 3735 6037; fax: +61 7 3735 6001. E-mail address: m.coster@griffith.edu.au (M.J. Coster). Tetrahedron Letters 52 (2011) 1070–1073 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet