Ring opening metathesis/cross metathesis and domino metatheses of 8-oxabicyclo[3.2.1]octene derivatives: An approach to pyran-containing natural products.

摘要

The pyran moiety is common to a wide range of natural products, including the marine macrolides Leucascandrolide A and Latrunculin B. It is present in the former as an independent ring and in the latter as part of a bridged-fused system. A notable feature of the pyrans contained in both molecules is the cis-2,6-disubstitution pattern. Traditionally, pyrans have been constructed stereoselectively via aldol-based chemistry. We have developed unique methodology to assemble cis-2,6-disubstituted pyrans by ring-opening metathesis/cross metathesis (ROM/CM) of oxabicyclic octene derivatives using Grubbs' ruthenium-based metathesis catalysts. With judicious choice of donor alkenes, the newly generated pyran contains two highly differentiated olefins for further selective functionalization. We have further extended the methodology to include intramolecular RCM/ROM. This was achieved by tethering the donor olefin to the bicyclic ring system such that the second metathesis process prompts ring closure, generating annulated pyrans. The synthesis of three main classes of compounds was targeted. Placement of the tether at C1 led to spiro-fused bicyclic systems. Linear-fused systems resulted from a tether at C2. Bridged-fused compounds were approached by attachment of the donor olefin at C3. The success of these RCM/ROM processes was highly dependent on the hybridization at C3 of the oxabicyclic octene. Sluggish reactions were accelerated by converting C3 from an sp2 to an sp3 center. In the case of the C2-tethered intermediates, the stereochemistry of the tether further influenced the level of success of the RCM/ROM reaction, with endo-tethers being more favorably aligned for RCM/ROM. Fused pyrans and tetrahydrofurans were achieved in good-to-excellent yield with careful consideration of the effects of the C3, C2, and C1 substituents.