Towards the total synthesis of semi-synthetic opiate species and presilphiperfolan-1-ol.

Abstract

The synthesis of 10-keto opiates is underscored by the urgent need of novel κ-selective opioid agonists that offer comparable analgesic effects to their alkaloid precursors while limiting the risks of physical dependency. While there have been multiple syntheses of oxycodone reported, there has been only one total synthesis of 10-keto-oxycodone to date. Inspired by previous work from the Fukuyama group we investigated a functional group-based approach to oxycodone and 10-keto-oxycodone highlighted by a key oxidative dearomatization step. Efforts made towards this end with be discussed herein. Presilphiperfolanols constitute a family of sesquiterpenes that can undergo further rearrangement to afford a diverse array of terpenoid skeletons due to the ring strain that is inherent to their carbocyclic framework. This structurally complex family of natural products is unique owing to their highly compact tricyclo[5.3.1.04,11]undecane sesquiterpene skeleton that bears five contiguous stereocenters, two all-carbon quaternary centers, and a tertiary hydroxy group. To date, only three natural presilphiperfolanols have been isolated: presilphiperfolan-1β-ol, presilphiperfolan-8α-ol, and presilphiperfolan-9α-ol. In addition to being important biosynthetic precursors, these natural products have also been found to exhibit antimicrobial activity and insecticidal properties. Of particular interest is presilphiperfolan-1β-ol, which has been previously synthesized by Stoltz in the first asymmetric synthesis of a presilphiperfolanol, and subsequently by Tiefenbacher in a semi-synthesis involving supramolecular catalysis. Unlike the approaches by Stoltz and Tiefenbacher, our group has discovered a highly efficient tandem gold (I) catalyzed 5-exo-dig and formal [4+2] cyclization that affords direct access to this tricyclo[5.3.1.04,11]undecane sesquiterpene skeleton. This method has the added benefit of generating 3 of the 5 requisite stereocenters found within the target in a single transformation. Efforts towards the completion of the total synthesis of presilphiperfolan-1-ol will be discussed herein. Experimental and spectral data are provided for all newly synthesized compounds.