Total Synthesis Highlights

Sordaricin (2) is the aglycone of sordarin (3), the parent of a family of clinically-effective
antifungal agents. Lewis N. Mander of the Australian National University has published (J. Org.
Chem. 2005, 70, 1654.) a full account of their enantioconvergent synthesis of 2 (see below), based
on the intramolecular Diels-Alder cyclization of the triene 1. For a complementary total synthesis
by Narasaka of sordaricin (2), see Org. Chem. Highlights 2005, April 4.
To prepare 1, two enantiomerically-pure pieces were needed, 10 and 11. As it developed, 10 was
prepared from one enantiomer of 4, and 11 was prepared from the other enantiomer of 4. In both
the synthesis of 10 and the synthesis of 11, the folded nature of the tricyclic ring system was used
to control relative (and absolute) configuration around the cyclopentane ring. Conjugate addition
to (+)-4 followed by alkylation led to the cis dialkyl 5. The retro Diels-Alder unmasking of the
enone was effected by heating to reflux in 1,2-dichlorobenzene while a stream of nitrogen was
bubbled through the solution. Conjugate addition to 6 proceeded to the more open face of the
enone, to give 7. Removal of the carbonyl under conditions that did not epimerize the adjacent
methyl group followed by oxidation of the isopropenyl group then led to 10.
With the iodide 10 in hand, the preparation of the triene 15 could proceed. The single quaternary
center of 15 was constructed by deprotonation of the nitrile 11, followed by alkylation with 10.
Again, bond formation proceeded on the outside face of the tricyclic ketone, to give 12. Because it
was thought (correctly, as it developed) that the Diels-Alder cyclization would proceed with
higher selectivity at lower temperature, 13 was cracked to give the enone 14.
Methoxycarbonylation with the Mander reagent followed by enol triflate formation and
Cu-mediated coupling then delivered the triene 15.