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

Authors
Journal
Tetrahedron
0040-4020
Publisher
Elsevier
Publication Date
Volume
65
Issue
27
Identifiers
DOI: 10.1016/j.tet.2009.04.076
Keywords
  • [4+3] Cycloaddition
  • 8-Oxabicyclo[3.2.1]Oct-6-En-3-One
  • 2
  • 6-Dioxatricyclo[3.3.1.03.7]Nonanes
  • Haloetherification
  • Transannular Hydroxycyclization
Disciplines
  • Biology

Abstract

Abstract The synthesis of new difunctionalized 2,6-dioxatricyclo[3.3.1.0 3,7]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[3.3.1.0 3,7]nonane framework, in high yield. Epoxidation of 8-oxabicyclo[3.2.1]oct-6-en-3-ol followed by treatment with NaCN, NaN 3, and/or NaOH in MeOH afforded 8-hydroxy-2,6-dioxatricyclo[3.3.1.0 3,7]nonanes in high yield via a transannular hydroxycyclization mediated by a base and through an alkoxide intermediate. The new 2,6-dioxatricyclo[3.3.1.0 3,7]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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