Periodic Reporting for period 1 - RadCrossSyn (Radical and Radical-Polar Crossover Logic in Terpenoid Synthesis)
Okres sprawozdawczy: 2022-05-01 do 2024-10-31
As the largest class of natural products, terpenoids play a variety of roles in mediating antagonistic and beneficial interactions macroscopically, i.e. among organisms, and microscopically, i.e. on a (sub)cellular level. They defend many species of plants, animals, and microorganisms against predators, pathogens, and competitors, and they are involved in conveying messages within these organisms.
Facilitating and streamlining the access to the most complex terpenoids, heavily rearranged and highly oxidized triterpenoids, requires an understanding of Nature’s ways to biosynthesize these structures, i.e. of their biogenesis. So far, biogenesis proposals have, in lieu of validated intermediates and enzymes, followed the paradigm of polar mechanisms and evoked standard textbook reactions involving ionic intermediates to account for skeletal rearrangements.
The main goal of the project is to establish a new paradigm in the chemical synthesis of rearranged triterpenoids with implications for the biogenesis of this class of natural products, by providing synthetic evidence for radical and radical-polar crossover rearrangements as viable and robust means to access triterpenoid natural product with high selectivity and yield.
Application of radical-polar crossover logic will then lead to robust and selective routes to access “drugable” triterpenoid natural products modulating the immune system, targeting cancer, and combating pathogens.
Facilitating and streamlining the access to the most complex terpenoids, heavily rearranged and highly oxidized triterpenoids, requires an understanding of Nature’s ways to biosynthesize these structures, i.e. of their biogenesis. So far, biogenesis proposals have, in lieu of validated intermediates and enzymes, followed the paradigm of polar mechanisms and evoked standard textbook reactions involving ionic intermediates to account for skeletal rearrangements.
The main goal of the project is to establish a new paradigm in the chemical synthesis of rearranged triterpenoids with implications for the biogenesis of this class of natural products, by providing synthetic evidence for radical and radical-polar crossover rearrangements as viable and robust means to access triterpenoid natural product with high selectivity and yield.
Application of radical-polar crossover logic will then lead to robust and selective routes to access “drugable” triterpenoid natural products modulating the immune system, targeting cancer, and combating pathogens.
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.
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.
Our publication on the first successfully performed radical-polar crossover rearrangement in a complex setting of the spirochensilides is a major breakthrough.
It clearly shows the underlying rationale of the project is both viable and, more importantly, leads to a streamlined synthesis of a highly complex natural products (only 10 steps in case of spirochensilide A, while a previous total synthesis by the group of Chen required 27 steps). This can be attributed to the fact, that without the need for a sacrificial functionality to be introduced beforehand (i.e. a leaving group at the steroid scaffold) the methyl shifts could be directly affected by a radical-initiated radical polar-crossover process. Earlier strategies had to achieve comparable reactivity toward a rearrangement by lengthy functional group interconversion/redox operations to eventually install a leaving group and accessing the reactive ionic (polar) intermediate under harsh (i.e. strongly Lewis-acidic) conditions.]
It clearly shows the underlying rationale of the project is both viable and, more importantly, leads to a streamlined synthesis of a highly complex natural products (only 10 steps in case of spirochensilide A, while a previous total synthesis by the group of Chen required 27 steps). This can be attributed to the fact, that without the need for a sacrificial functionality to be introduced beforehand (i.e. a leaving group at the steroid scaffold) the methyl shifts could be directly affected by a radical-initiated radical polar-crossover process. Earlier strategies had to achieve comparable reactivity toward a rearrangement by lengthy functional group interconversion/redox operations to eventually install a leaving group and accessing the reactive ionic (polar) intermediate under harsh (i.e. strongly Lewis-acidic) conditions.]