Periodic Reporting for period 3 - ELDORADO (Electrophilicity-Lifting Directed by Organochalcogen Redox-Auxiliaries and Diversiform Organocatalysis)
Período documentado: 2022-08-01 hasta 2024-01-31
The implementation of viable practices for the ecologically cognizant production and consumption of energy and renewable resources rank among the most pressing societal challenges of the 21st century. Against this background, the design and development of innovative concepts for the sustainable use of energy and energy-rich compounds from regenerative sources becomes a matter of paramount technological and scientific importance. A promising approach that has been put forward in the context of chemical synthesis is the application of visible light as an inexpensive source of energy and air as an abundant and gratuitous oxidant for the derivatization of certain organic molecules. Despite the enormous economic and ecological benefits associated with the use of light and air as integral components of redox reactions, the realization of such processes is strikingly limited to very isolated applications. Consequently, this methodological deficit represents a momentous opportunity for modern chemical sciences to lastingly transform the routine lines of action for the oxidative manipulation of organic molecules. A key issue that needs to be taken into consideration for the design of efficient photo-aerobic oxidation protocols is the identification of proper catalyst systems that allow for the site-, chemo- and (in certain cases) stereoselective activation of individual bonds within polyatomic frameworks. In this regard, the prime objective of the proposed research program is the rational design of non-metallic and in part cooperative catalysis regimes as enabling technologies for the electrophilic activation of non-aromatic carbon–carbon multiple- and carbon-chalcogen single bonds to facilitate a wide and diverse array of heretofore unprecedented oxidative coupling-, addition-, and rearrangement reactions. To demonstrate its utility in a superordinate context, this methodological concept is envisioned to be applied in highly modular enantioselective syntheses of biologically relevant polyketide natural products.
The progress of the project is in line with most of the proposed actions. For instance, we have been successful in designing a photocatalytic cyclocarbonation reaction that provides access to 1,3-dioxygenated carbon scaffolds. Such motifs play a pertinent role in the context of biologically active natural products. The project is still ongoing and its first outcomes will be prepared for publication in due course. We have also focused on the investigation of the reaction parameters that distinguish between classical allylic functionalizations of alkenes performed by selenium-π-acids and the proposed 1,2-difunctionalization. In this context, we found that certain protic solvents dramatically alter the reaction outcome in such a manner that substitution of a C(sp3)-bound selenium entity is strongly preferred over its otherwise prototypical elimination. This change in chemoselectivity is considered to be key in developing 1,2-difunctionalization reaction on alkenes using chalcogen-π-acid catalysts. Currently, we are designing a series of light-driven substitution reactions, in which Se-groups serve as photo-triggered nucleofuges to study the generality of this reaction pathway. Notions gained from this work are envisioned to be implemented in the direct 1,2-difunctionalization of alkenes. Another objective is the design of asymmetric dual & ternary catalytic regimes. In this part of the project we have made significant progress, as we have been successful in synthesizing chiral diselenides that were found to be capable to facilitate high enantioselectivities in the photo-aerobic lactonization of enoic acids as a model reaction. The application of these new catalysts in suitable reactions developed in this project is ongoing. Furthermore, we have been successful in establishing oxidative cross couplings of alkynes with nascent nitrogen nucleophile derived from N-fluorinated reagents to give access to aminoallenes. Results of this endeavor have now been published (Eur. J. Org. Chem. 2021, 1720–1725), which constitute the basis for the design of analogous photo-aerobic reactions. We have also been able to establish a photocatalytic rearrangement reaction to convert simple selenohydrins into α-branched carbonyls. In this context, we have not only been successful in optimizing and scoping the title reaction but have also deciphered its mechanistic details by means of NMR and ultra fast laser spectroscopy as well as computational chemistry.
Our results strongly indicate that weakly polar C–Se bonds can be readily activated in such a way that the Se-entity starts to act like a strong nucleofuge, but only upon a photo(cata)lytic stimulus. This opportunity has pertinent implications, since synthetic methods the rely on this concept are anticipated to display chemoselectivities that are unparalleled by current synthetic techniques. This prospect is further valorized by the possibility to obtain high control over the stereochemical outcome of a given reaction by using our chiral Se-catalysts. Considering that most of the reactions investigated in this project solely require air as a terminal oxidant, it is also expected that our future synthetic protocols will be able outperform many cognate catalytic procedures in terms of carbon efficiency.
The formation of C(sp2)–heteroatom bonds by catalytic means arguably belongs to the group of most heavily investigated and sought-after reactions in the area of modern chemical synthesis. Among the most common protocols used to forge such bond motifs rank transition metal-catalyzed cross couplings. Even today, many of such protocols still suffer from suboptimal redox-economy, since often at least one of the reaction partners has to be used in a non-optimal oxidation states in simply to exhibit the desired reactivity. The dependence on redox-suboptimal coupling partners can bear significant disadvantages, such as cost-inefficiency and co-production of environmentally critical waste. One of the key-goals in this project is to overcome such disadvantages by using photo-aerobically driven chalcogen-π-acid catalysts for the redox-economic formation of C(sp2)–heteroatom as well as C(sp2)–C(sp2) bonds. Our findings already indicate that particularly alkenes can serve as non-activated coupling partners for a broad series of non-preactivated heteroatomic nucleophiles. In combination with our studies on chiral chalcogen-π-acid catalysts the future outcomes of this project are anticipated to pave a complementary entryway toward axially chiral target molecules.
Iterative reaction manifolds arguably represent one of the most versatile and reliable approaches toward structural complexity in chemistry. Looking at how nature assembles complex molecules, such as proteins, polysaccharides or polyketides, iterativity remains a common feature in the biosynthesis of all of these compound classes. A major leap toward mimicking this profound assembly logic has been taken by the use of Se-residues as redox auxiliaries within selenohydrins to photocatalytically initiate 1,2-migrations to furnish α-branched carbonyls. These latter species are easily converted into selenohydrins that are extended by one C-atom compared to the parent selenohydrin. This unprecedented assembly concept is expected to be very suitable for the generalized synthesis of complex natural products, such as polyketides, with important pharmaceutical activities.
The formation of C(sp2)–heteroatom bonds by catalytic means arguably belongs to the group of most heavily investigated and sought-after reactions in the area of modern chemical synthesis. Among the most common protocols used to forge such bond motifs rank transition metal-catalyzed cross couplings. Even today, many of such protocols still suffer from suboptimal redox-economy, since often at least one of the reaction partners has to be used in a non-optimal oxidation states in simply to exhibit the desired reactivity. The dependence on redox-suboptimal coupling partners can bear significant disadvantages, such as cost-inefficiency and co-production of environmentally critical waste. One of the key-goals in this project is to overcome such disadvantages by using photo-aerobically driven chalcogen-π-acid catalysts for the redox-economic formation of C(sp2)–heteroatom as well as C(sp2)–C(sp2) bonds. Our findings already indicate that particularly alkenes can serve as non-activated coupling partners for a broad series of non-preactivated heteroatomic nucleophiles. In combination with our studies on chiral chalcogen-π-acid catalysts the future outcomes of this project are anticipated to pave a complementary entryway toward axially chiral target molecules.
Iterative reaction manifolds arguably represent one of the most versatile and reliable approaches toward structural complexity in chemistry. Looking at how nature assembles complex molecules, such as proteins, polysaccharides or polyketides, iterativity remains a common feature in the biosynthesis of all of these compound classes. A major leap toward mimicking this profound assembly logic has been taken by the use of Se-residues as redox auxiliaries within selenohydrins to photocatalytically initiate 1,2-migrations to furnish α-branched carbonyls. These latter species are easily converted into selenohydrins that are extended by one C-atom compared to the parent selenohydrin. This unprecedented assembly concept is expected to be very suitable for the generalized synthesis of complex natural products, such as polyketides, with important pharmaceutical activities.