Toward this aim, we engaged immediately at the start of the project in the syntheses of three terpenoid natural products: asperfloketal A, penicillitone, and spirochensilide A. In all three cases, we could achieve the set goal and show for spirochensilide A, that a radical-polar crossover process is highly selective and key to a superior strategy for its time- and cost-efficient synthesis.
With the first successful application of our pivotal radical-polar crossover strategy without the need for a sacrificial functionality to be introduced beforehand, we could also contribute a chemically sensible hypothesis of concerted rearrangements to the controversial biogenesis of the spirochensilides. Points of divergence after each rearrangement step eventually allowed to access the abifarine family of natural products, with abifarine B as an achieved target.
At the example of penicillitone, on the other hand, and making use of our previous work on the synthesis of 14,15-seco-steroids, we could show an intramolecular vinylogous aldol pathway (i.e. polar reactivity) to be competent in establishing its 15(14→11)-abeo-ergostane system. Since a similar intermediate has been employed in this route as has been used to access the strophasterol class of natural products in an earlier publication of our group, this work also points at a possible biosynthetic connection between penicillitone and the strophasterols.
Furthermore, we elaborated on our synthetic rationale toward the asperfloketals, members of the growing class of anthrasteroids. The anthrasteroid rearrangement has been discussed for the formation of the eponymous substance class since its discovery. We were able to chemically emulate it from a plausible biogenetic precursor and showed how it accounts for the formation of asperfloketals A and B through a mechanistic bifurcation event. As a result, these natural products arise from double Wagner–Meerwein rearrangements, making them 1(10→5),1(5→6)- and 1(10→5),4(5→6)diabeo-14,15-secosteroids, respectively. To establish an efficient route to a bioinspired precursor, we devised a sequence of orchestrated oxidative activation and rearrangement from ergosterol.
We combined these insights and carved out our idea of biogenetic space-guided synthetic planning. This novel and powerful tool has already helped us to design short, economically and ecologically preferable routes to complex rearranged triterpenoids and abeo-steroids.
