Synthesis of pyrrolizidine diols via azide-diene cycloadditions

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Virginia Polytechnic Institute and State University


The generality of the [4+1] annulation methodology in the context of natural product synthesis was demonstrated by extending its applicability to the heteroatom (nitrogen) case thus allowing access to the alkaloid field. This novel methodology involved the intramolecular union of a hypovalent nitrogen atom equivalent and a conjugated diene to afford a pyrroline ring. The flexibility of this strategy was exemplified by the formal synthesis of ring-A oxygenated pyrrolizidine alkaloids platynecine 8, turneforcidine 9, hastanecine 10, and dihydroxyheliotridane 11.

The key features of this technology involved preparation of azidodiene ill, its cyclization, via the intermediate triazoline which was not isolated, to vinylaziridines 234, and the vinylaziridine-pyrroline rearrangement of several derivatives of 234 to pyrrolizidines 239, 241, and 242. A study of the thermal decomposition of oxygenated azidodienes such as 196 and 233 was carried out. Conclusive results regarding the stereochemical control of the C-7 substituent were attained and used for the formal stereospecific syntheses of pyrrolizidinediols 8, 9, 10, and 11.

The possibility of asymmetric induction was also investigated, and was realized in the microbial reduction of only one of the enantiomers of alcohol ill protected as ester 248, providing potential access to either enantiomeric series of pyrrolizidine diols.

[see document for diagram of chemical reaction]