Asymmetric syntheses of 8-oxabicyclo[3,2,1]octanes: a cationic cascade cyclization.

tropane alkaloids, and consequently there is an increasing interest in their potential pharmaceutical use, particularly against cocaine abuse. Compelled by the interesting biological activities of 8oxatropanes, many groups have embarked on the search for new methodologies to construct this bicyclic structure. For example, Molander and co-workers have reported a Lewis acid promoted double allylation of 1, 4-dicarbonyl compounds to construct 8-oxatropanes. The same group later reported the syntheses of 8-oxatropanes using a TiCl4-promoted cycloaddition of a bis(trimethylsilyl enol ether) and 1,4-dicarbonyl compounds. Chiu and co-workers found that the cycloaddition reaction also worked well using epoxy enol silanes as the dienophile. Another cycloaddition component, allenamide, which was proposed by Hsung and coworkers has also been applied in this reaction successfully. Recently, Wang and co-workers developed a Lewis acid catalyzed intramolecular cycloaddition of alkynylcyclopropyl ketones with carbonyls to build this skeleton. In addition, many metals such as rhodium(II), platinum(II), gold(I), and tungsten catalyze the 1,3-dipolar cycloaddition of carbonyl ylides and have been shown to be effective in constructing the 8-oxatropane scaffold. Despite the excellent progress made thus far for the synthesis of 8-oxatropanes, practical and asymmetric selective methods are still lacking. Herein, we report an efficient diastereoselective and enantioselective synthesis of 8-oxabicyclo-[3.2.1]octane through a cationic cascade reaction mediated by TiCl4. Previously, we have reported the syntheses of fiveand six-membered ring compounds using the Mukaiyama aldol/ Prins cascade reaction (Scheme 1a). We hypothesized that the same cascade reaction design could be also applied for the assembly of seven-membered rings (Scheme 1b). With this notion in mind, we treated a solution of the 1,4-cyclic acetal 1a and silyl enol ether 2a with 1.2 equivalents of TiCl4 in the hope of getting either the seven-membered ring compoundA or B. Surprisingly, this reaction afforded the 8-oxatropane 3a in 91% yield as a single isomer. No trace of side products, such as those produced from a chlorine trapping of tert-butyl cation (A) or a Friedel–Crafts reaction with the phenyl group (B), were observed. The structure of 3a was ascertained by Figure 1. Selected examples of natural products containing the 8-oxatropane core.