Abstract
Tricyclic furan derivatives with multiple chiral centers are ubiquitous in natural products. Construction of such tricyclic scaffolds in a stereocontrolled, step-economic, and atom-economic manner is a key challenge. Here we show a nickel-catalyzed highly enantioselective synthesis of hydronaphtho[1,8-bc]furans with five contiguous chiral centers via desymmetrization of alkynyl-cyclohexadienone by oxidative cyclization and following formal [4 + 2] cycloaddition processes. Alkynyl-cyclohexadienone was synthesized in one step from easily accessible phenols. This reaction represents excellent chemo-selectivity, regio-selectivity, diastereo-selectivity, and enantio-selectivity (single diastereomer, up to 99% ee). An extraordinary regioselectivity in the formal [4 + 2] cycloaddition step with enones revealed the diverse reactivity of the nickelacycle intermediate. Desymmetrization of alkynyl-cyclohexadienones via oxidative cyclization on nickel was supported by the isolation of a nickelacycle from a stoichiometric reaction. Enantioenriched tricyclic products contain various functional groups such as C=O and C=C. The synthetic utility of these products was demonstrated by derivatization of these functional groups.
Highlights
Tricyclic furan derivatives with multiple chiral centers are ubiquitous in natural products
Alkynylcyclohexadienone were synthesized in one step from accessible phenols
The oxidative cyclization of an enantiotropic enone with a tethered alkyne unit would form a tricyclic fused nickelacycle[20,21,22,23,24] with three chiral centers, which could react with another olefin to yield a tricyclic product with the concomitant generation of two more chiral centers
Summary
The reaction of 1a with 1-aryl-2-buten-1-ones (2e–2i) gave 3ae–3ai in slightly lower yields (62–70%), albeit enantioselectivities remained excellent (94–97% ee) In these cases, about 5% of fullyintermolecular [2 + 2 + 2] cycloaddition products (3′) of an alkyne unit of dienone-yne (1a) with two enones (2e–2i) were observed (See Supplementary Fig. 10 for 3ae′). Ethyl as well as 2-methoxyethyl-substituted alkynyl-cyclohexadienone (1b and 1c) gave 3bb, 3bj, 3ca, and 3ck with 2b, 2j, 2a, and 2k, respectively in good yields (60–73%) with excellent enantioselectivities (96–99%). An ethyl-group and a triethylsilyloxy-methyl-substituted alkynyl-cyclohexadienone (1h and 1i, respectively) gave corresponding tricyclic fused rings 3he, 3ic, and 3ik with 2e, 2c, and 2k, respectively, in good yields and enantioselectivities (69–77% yields, 95–98% ee). It supports all the stereo selective and regioselective outcomes in 3
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