Synthetic Approaches to the Axane Family of Sesquiterpenoids. Total Synthesis of dl-Axamide-4, dl-Axisonitrile-4, and (dl)-Axisothiocyanate-4

Two methods for the preparation of perhydroindan 7 are described. One involves an intramolecular free radical cyclization in a key step and proceeds in 13 steps and 9% yield from anisole (9). The other involves an intramolecular conjugate addition mediated by pyrrolidine (28 → 7) and proceeds in five steps and 30% overall yield from vinylogous ester 29. Two unsuccessful attempts to convert 7 into axane sesquiterpenoids 1–6 are described. The synthesis of axanes 4–6 was achieved using a potassium tert-butoxide catalyzed cyclization of a dienoic keto ester as a key step (47 + 48 → 49). Conversion of α,β-unsaturated ester 49 to vinyl isocyanate 57 was accomplished using a Curtius rearrangement and reduction of 57 with lithium triethylborohydride completed the synthesis of axamide-4 (4). The preparation of axisonitrile-4 (5) and axisothiocyanate-4 (6) from 4 is also described.