Wender PA.
*
Dreyer GB.
Stanford University and Harvard University, Cambridge, USA
Synthetic Studies on Arene–Olefin Cycloadditions. 4. Total Synthesis of (±)-Modhephene.
J. Am. Chem. Soc. 1982;
104: 5805-5807
Key words
(±)-modhephene - sesquiterpene - arene–olefin cycloaddition - semibullvalene rearrangement
- 1,5-addition
Significance
(±)-Modhephene is a sesquiterpene that was first isolated in 1978 from the leaves
of the rayless goldenrod Isocoma Wrightii. It features a unique [3.3.3]propellane core which had not been observed in nature
previously. In 1982, Wender and Dreyer reported the highly efficient seven-step synthesis
of (±)-modhephene relying on a light-mediated arene–olefin cycloaddition. Additionally,
they utilized a semibullvalene rearrangement to install two quaternary carbon centers
in one step.
Comment
The synthesis commenced with the light-mediated cycloaddition of indane (A) and vinyl acetate (B) to give propellane C containing five stereocenters, two of which are quaternary, in a single step. Subsequent
saponification and oxidation afforded ketone E. Treatment of E a with an excess of base and methyl iodide afforded tris-alkylated ketone H. The authors propose that this transformation is enabled through the rapid interconversion
of enolates F and G by a semibullvalene rearrangement. The fourth methyl group required for the synthesis
of (±)-modhephene was introduced using a copper-mediated 1,5-addition followed by
trapping of the transient enolate with phosphoric acid derivative I. Notably, this transformation afforded phosphordiamidate J as a single stereo- and regioisomer. Finally, reductive C–O bond cleavage and subsequent
selective hydrogenation of the sterically less hindered double bond afforded (±)-modhephene
in 93% yield over two steps.
