Synthesis of 2,6-dioxatricyclo[3.3.1.03,7]nonanes by intramolecular haloetherification and/or transannular hydroxycyclization of alkenes in [4+3]-cycloadducts

Reference:

Montana, A. M., Barcia, J. A., Kociok-Kohn, G. and Font-Bardia, M., 2009. Synthesis of 2,6-dioxatricyclo[3.3.1.03,7]nonanes by intramolecular haloetherification and/or transannular hydroxycyclization of alkenes in [4+3]-cycloadducts. Tetrahedron, 65 (27), pp. 5308-5321.

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Official URL:

http://dx.doi.org/10.1016/j.tet.2009.04.076

Abstract

The synthesis of new difunctionalized 2,6-dioxatricyclo[3.3.1.03,7]nonanes is described. This type of structure is an interesting synthetic building block for potential bioactive molecules and it was prepared from 8-oxabicyclo[3.2.1]oct-6-en-3-one having a NHBoc function on C-1. This precursor was obtained by a [4+3] cycloaddition reaction of 2-tert-butoxycarbonylaminofuran and the oxyallyl cation generated in situ from 2,4-dibromo-3-pentanone. Reduction of the carbonyl group at C-3 was accomplished in high yield and stereoselective manner to afford the corresponding axial alcohol at C-3 as a major product. Further intramolecular haloetherification of this type of alcohols with NBS and I(py)2BF(4) led to the corresponding bromo and iodo-derivatives at C-8 of the 2,6-dioxatricyclo[3.3.4.0(3,7)]nonane framework, in high yield. Epoxidation of 8-oxabicyclo[3.2.1]oct-6-en-3-ol followed by treatment with NaCN, NaN3, and/or NaOH in MeOH afforded 8-hydroxy-2,6-dioxatricyclo[3.3.1.03,7]nonanes in high yield via a transannular hydroxycyclization mediated by a base and through an alkoxide intermediate. The new 2,6-dioxatricyclo[3.3.1.03,7]nonanes were tested for biological activity against HIV-1 virus and MT-4 lymphoid cell line, showing a low anti-HIV activity and a high degree of cytotoxicity.

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