Himandrine

Entries 5 to 8 are synthetic applications in more complex molecules. Entries 5 and 6 illustrate the diphenylphosphoroyl azide method. Entry 7 was used in the late stages of the synthesis of an antitumor macrolide, zampanolide, to introduce the amino group. The ultimate target molecule in Entry 8 is himandrine, one of several polycyclic alkaloids isolated from an ancient plant species. 

The first synthesis of the hexacyclic himandrine skeleton was achieved by L.N. Mander and co-workers. The last six-membered heterocycle was formed via an intramolecular Wacker-type oxidation in which the terminal alkene side-chain reacted with the secondary amine functionality. The oxidation was conducted in anhydrous acetonitrile to insure that the Pd-alkene complex was substituted exclusively by the internal nucleophile. The resulting six-membered enamine was then hydrogenated and the MOM protecting groups removed to give the desired final product. 

Himbacine, himandridine, himbadine, himgaline, himbosine, himandrine, himgravine, himandreline, himbeline, himandravine, himgrine, alkaloid G.B. 13... 

Finally, in Wander s synthesis of the hexacyclic himandrin skeleton, amino-alkene 100 was oxidized to its corresponding methyl ketone, which was trapped by nucleophilic addition of the amine.7 Dehydration of the adduct then delivered enamine 100, which possessed all six rings of the himandrine skeleton. 

In his approach toward the synthesis of the alkaloid himandrine [101, 102], Ciufolini applied his oxidative phenol (spiro)amidation reaction, using DIB in TFA, to the chiral dienyl sulfonamide 156 to generate the aza-spirocycle 157, which was then heated in added toluene (reflux) to furnish the entfo-Diels-Alder cycloadduct 158 as the major regioisomer. An epimerization occurred in situ to deliver the himandrine-like trani-decaline system 159 in a combined yield of 32%, together with the epimerized minor Diels-Alder regioisomer [101] (Fig. 39). 

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