A Structural Revision of Neoveratrenone Prompted by Violation of Bredt's Rule

            In 2003, Crews and Clardy isolated a highly unique steroid derivative, isocyclocitrinol A, from the extract of a saltwater culture of sponge-derived Penicilliun citrinum. The compound exhibited rather uninteresting (weak) antibacterial activity but can be considered quite captivating in terms of its skeletal structure due to the presence of a rarely encountered caged bicyclic motif (highlighted above in blue). The 'citrinane' ring skeleton of isocyclocitrinol A encompasses the first example of a bicyclo[4.4.1] system contained within the A/B substructure of a rearranged steroid. Biosynthetically, this carbon connectivity likely arises via a 1,2-migration of the steroidal C5-C10 bond to generate a new C5-C18 bond. Isocyclocitrinol A is an example of a natural product that violates Bredt’s rule, an empirical observation made by Julius Bredt in the 1920s that states that a double bond cannot be placed at the bridgehead of a bridged bicyclic ring system. Bredt's rule is a consequence of the fact that having a double bond at a bridgehead position is comparable to the incorporation of a trans double bond into a small ring (fewer than eight atoms), which confers a considerable amount of unfavorable ring and angle strain.

            On the basis of Bredt’s rule, a recently reported 'anti-Bredt' natural product, neoveratrenone, was reassigned by the laboratory of Craig Williams at the University of Queensland. Williams and co-workers embarked on a rigorous reinterpretation of the 1D and 2D NMR data presented in the original structure elucidation paper and concluded that, indeed, the putative bicyclo[3.3.1]nonenone-containing neoveratrenone was more accurately characterized by a ‘6-6-5-6’ C-nor-D-homo steroidal skeleton that does not violate Bredt’s rule. The most notable member of the C-nor-D-homo rearranged steroid family is the steroidal alkaloid cyclopamine, which is pharmacologically infamous due its ability to cause fatal birth defects including cyclopia (this link is not for the squeamish). The fascinating chemical synthesis and biochemistry associated with cyclopamine have been the subjects of previous posts at Modern Steroid Science. Williams and co-workers adeptly noticed that a close structural derivative of cyclopamine, verapatuline, was co-isolated with veratrenone, further bolstering the impetus for the structural revision. The contribution by the Williams laboratory provides a great service to the synthetic community in that it will prevent the allocation of resources to synthesize the initially proposed, incorrect, structure.