[5+3] Cycloaddition of 3-Oxidopyrylium: A Novel Route to Functionalized Cyclooctanoids from Furans

We report a facile and efficient synthesis of highly func- tionalized cyclooctanoid derivatives by employing a dimerization reaction of 3-oxidopyrylium ylides. Different substituents are intro- duced on the dimer and the stereochemical outcome of the resultant cyclooctanoids is unambiguously established by single-crystal X- ray analysis. The synthesis of cyclooctanoid systems from acyclic pre- cursors remains a challenging problem, mainly because of the unfavorable entropic and enthalpic factors that pre- clude ring closure. The difficulty associated with the con- struction of cyclooctanoids and their ubiquity in numerous diverse natural products have prompted the search for novel methods for their construction. 1-3 3-Oxi- dopyrylium ylide (1) (Scheme 1), generated by base treat- ment of acetoxypyranones, readily undergoes cycloadditions with various dienophiles to produce the corresponding cycloadducts. This approach has been proved to be a highly useful method for the synthesis of seven-membered carbocycles and natural products. 4 However, in the absence of suitable dienophiles, the reac- tive 3-oxidopyrylium ylide readily undergoes self-dimer- ization and generates the polycyclic structures with excellent regio- and stereoselectivity (Scheme 1). This re- action was first reported by Hendrickson and Farina in 1980, but, surprisingly, no further studies have been re- ported until we disclosed our investigations on exploring the use of dimer 2 towards the synthesis of functionally rich cyclooctanoid derivatives. 5-7 In this paper, we wish to present a detailed account of our investigations into the stereocontrolled transformation of cycloadduct 2 into highly functionalized cyclooctanoid 8-13 systems. We demonstrate that different substituents can be introduced onto the cycloadduct 2 in a stereoselective manner by virtue of conformational rigidity imparted by the oxa bridge to the flexible systems. We believe that the results reported herein may be useful for the application of dimerization reactions of oxidopyrylium ions in the total synthesis of cyclooctanoid natural products.