New Spiro-Lactam C-nor-D-homo Steroids

The design and diastereoselective synthesis of new C17 spiro-lactam C-nor-D-homo steroids is described. These constitute structurally simplified analogues of Veratrum alkaloid cyclopamine that may act as Hedgehog (Hh) signaling inhibitors with enhanced chemical and metabolic stability. Two complementary synthetic pathways towards this new class of compounds, that involve the Wagner-Meerwein-type rearrangement to the desired C-nor-D-homo steroid skeleton, the diastereoselective C17 homoallylic amination and the construction of the spiro-lactam ring, have been explored. Notably, the developed approach enables the synthesis of regioisomeric endocyclic [(12(13))] and exocyclic [(13(18))] analogues, thus setting the stage for future structure activity relationship studies. Additionally, the generation of 12-hydroxy C17 homoallylic amino steroidal derivatives as precursors of the new spiro C-nor-D-homo steroids provides access to an unexplored class of compounds with potential bioactivities.