Catalyst Control over Twofold and Higher-Order Stereogenicity by Atroposelective Arene Formation

Schmidt, Tanno A. and Sparr, Christof. (2021) Catalyst Control over Twofold and Higher-Order Stereogenicity by Atroposelective Arene Formation. Accounts of Chemical Research, 54 (12). pp. 2764-2774.

[img] PDF - Accepted Version

Official URL: https://edoc.unibas.ch/84337/

Downloads: Statistics Overview


Contradictory to the first intuitive impression that forging putatively flat aromatic rings evades stereoisomerism, a striking variety of atropisomeric compounds are conceivable by the formation of arenes, offering captivating avenues for catalyst-controlled stereoselective strategies. Since the assembled atropisomeric products that contain one or several rotationally restricted single bonds are characterized by especially well defined molecular architectures, they are distinctly suitable for numerous pertinent applications. In view of the fascinating areneforming aldol condensation pathways taking place in polyketide biosynthesis (cydases/aromatases (CYC/ARO)), the versatile small-molecule-catalyzed aldol reaction appeared as an exceptionally appealing synthetic means to prepare various unexplored atropisomeric compounds in our efforts presented herein. In our initial studies, the use of secondary amine organocatalysts provided excellent selectivities in stereoselective arene-forming aldol condensations for a broad range of atropisomeric products, such as biaryls and rotationally restricted aromatic amides. In further analogy to polyketide biosynthesis, it was also conceivable that several aromatic rings are formed in catalytic cascade reactions. The use of small-molecule catalysts thereby enabled us to transfer this concept to the conversion of unnatural and noncanonical polyketide substrates, thus giving access to atropisomers with particular value for synthetic applications. The versatility of the stereoselective aldol reactions with numerous catalytic activation modes further provided a strategy to individually control several stereogenic axes, similar to the various methodologies developed for controlling stereocenter configurations. By the use of iterative building block additions combined with catalyst-controlled aldol reactions to form the aromatic rings, stereodivergent pathways for catalyst-substrate-matched and -mismatched products were obtained. Besides secondary amines, cinchona-alkaloid-based quaternary ammonium salts also proved to be highly efficient in overcoming severe substrate bias. The obtained atropisomeric multiaxis systems, with all of the biaryl bonds suitably restricted in rotation even at high temperatures, are spatially distinctly defined. The helical secondary structure is therefore excellently suited for several captivating applications. While previous catalyst-controlled stereoselective methods distinguish two stereoisomers for each stereogenic unit, catalyst control beyond the realms of this dualistic stereoisomerism remained unexplored. By the selective preparation of Oki atropisomers characterized by their sixfold stereogenicity in Rh-catalyzed [2 + 2 + 2] cyclotrimerizations, one out of the six possible stereoisomers resulting from the restricted rotation of a single bond was shown to be catalytically addressable. Catalyst control over higher-order stereogenicity therefore further interconnects conformational analysis and stereoselective catalysis and offers captivating avenues to explore uncharted stereochemical space for creating a broad range of unprecedented molecular motifs.
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Organische Chemie (Sparr)
UniBasel Contributors:Schmidt, Tanno Alexander and Sparr, Christof
Item Type:Article, refereed
Article Subtype:Further Journal Contribution
Publisher:American Chemical Society
Note:Publication type according to Uni Basel Research Database: Journal item
Identification Number:
edoc DOI:
Last Modified:15 Jun 2022 01:30
Deposited On:30 Aug 2021 11:16

Repository Staff Only: item control page