Chemical synthesis of (S)-spiro(estradiol-17,2′-[1,4]oxazinan)- 6′-one derivatives bearing two levels of molecular diversity

Article abstract of DOI:10.1002/ejoc.200701077

The present study shows the development of a strategy that can afford different estradiol derivatives bearing a 17-spiro-δ-lactone moiety with a nitrogen atom inserted in the lactone ring. Such [1,4]oxazinan-6′-one derivatives contain two levels of molecular diversity introduced to modulate biological activity. The strategy employed to prepare these compounds includes the stereoselective formation of a 17β-oxirane from the carbonyl group of estrone, the regioselective opening of the resulting oxirane with various hydrophobic amino acids (giving the first level of diversity), the spirolactonization, the alkylation of nitrogen by different functional groups (producing the second level of diversity), and final deprotection, when necessary. A series of (S)-spiro-(estradiol-17,2′-[1,4]oxazinan)-6′- one derivatives was generated to illustrate the usefulness of this diversification strategy, which could easily be extended to other steroidal and nonsteroidal ketone scaffolds for interacting with additional biological targets. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.