Asymmetric ion-pair catalysis
Final Report Abstract
Within this project we continued expanding our research in the now established field of metalfree asymmetric Brønsted acid catalysis. In particular, we were interested in identifying new activation modes which are important not only to understand the mechanisms of the reactions but also to broaden the applicability of Brønsted acid catalysis, ion-pair catalysis and metalfree catalysis in general. By developing an acidity scale that besides chiral BINOL-derived phosphoric acid diesters, BINOL-based N-triflyphosphoramides and BINOL-based bis(sulfonyl)imides includes further known acids, we were able to correlate the catalytic properties of the acid catalysts with their pka values, with higher rate constants registered for more acidic Brønsted acid catalysts. Furthermore, we have succeeded in developing a light driven enantioselective hydrogenation of pyrylium ions which takes place through asymmetric ion-pair catalysis and offers access to valuable 4H-chromenes in good yields and excellent enantioselectivities. Based on our experience in asymmetric ion pair and hydrogen bond catalysis, we also aimed at developing a chiral Brønsted acid catalyzed enantioselective intramolecular allylic alkylation for the synthesis of chiral chromanes. However, we did not succeed in developing a metal-free highly enantioselective procedure, and had to alter our approach and take advantage of chiral gold-phosphine complexes for our intramolecular allylic alkylation reaction which offered access to important members of the vitamin E family. Electrocyclic reactions are powerful synthetic tools for the generation of complex molecules in synthetic organic chemistry. For the first time, we were able to develop chiral Brønsted acid catalyzed 6π- and 4π-electrocyclization reactions for the enantioselective synthesis of 1,4- dihydropyridazines and enantio- and diastereoselective synthesis of multisubstituted cyclopentenone derivatives, respectively. Finally we were able to develop several asymmetric transformations based on the in situ generation of ortho-quinone methides (o-QMs) and aza-ortho-quinone methides (aza-o-QMs) analogous. These species are highly reactive, transient intermediates that proved to be important in the synthesis of many complex natural products and bioactive compounds. Despite their usefulness in synthesis, their transient nature led to difficulties for their application in asymmetric synthesis. Nonetheless, we succeeded in finding suitable Brønsted acid catalysts for the generation and activation of these species in situ and control the selectivity of subsequent reactions. With ortho-quinone methides and aza-ortho-quinone methides as key intermediates, we accomplished the synthesis of various classes of compounds (e.g. substituted tetrahydroxanthene derivatives, chromanes, tetrahydroquinolines, triarylmethanes and communesin frameworks) in an asymmetric fashion. Notably, the protocols developed within this project are practical and could be easily scaled-up to mmol/gram scale. Furthermore, they open new avenues in the generation and use of reactive intermediates in the synthesis of optically active bioactive compounds with the aid of metal free Brønsted acid catalysis. We are confident that the described protocols provide a good basis for the development of further Brønsted acid catalyzed reactions.
Publications
- Asymmetric ion pair catalysis of 6π electrocyclizations: Bronsted acid catalyzed enantioselective synthesis of optically active 1,4-dihydropyridazines. Angew. Chem., Int. Ed. 2013, 52, 8008-8011
Das, A.; Volla, C. M. R.; Atodiresei, I.; Bettray, W.; Rueping, M.
(See online at https://doi.org/10.1002/anie.201301638) - On the Acidity and Reactivity of Highly Effective Chiral Bronsted Acid Catalysts: Establishment of an Acidity Scale. Angew. Chem., Int. Ed. 2013, 52, 11569-11572
Kaupmees, K.; Tolstoluzhsky, N.; Raja, S.; Rueping, M.; Leito, I.
(See online at https://doi.org/10.1002/anie.201303605) - Shedding Light on Organocatalysis-Light-Assisted Asymmetric Ion-Pair Catalysis for the Enantioselective Hydrogenation of Pyrylium Ions. Chem. – Eur. J. 2013, 19, 9775-9779
Hsiao, C.-C.; Liao, H.-H.; Sugiono, E.; Atodiresei, I.; Rueping, M.
(See online at https://doi.org/10.1002/chem.201300766) - Complete Field Guide to Asymmetric BINOL-Phosphate Derived Brønsted Acid and Metal Catalysis: History and Classification by Mode of Activation; Brønsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates. Chem. Rev. 2014, 114, 9047-9153
Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M.
(See online at https://doi.org/10.1021/cr5001496) - Enantio- and Diastereoselective Access to Distant Stereocenters Embedded within Tetrahydroxanthenes: Utilizing ortho-Quinone Methides as Reactive Intermediates in Asymmetric Bronsted Acid Catalysis. Angew. Chem., Int. Ed. 2014, 53, 13258-13263
Hsiao, C.-C.; Liao, H.-H.; Rueping, M.
(See online at https://doi.org/10.1002/anie.201406587) - Gold-catalyzed asymmetric allylic substitution of free alcohols. An enantioselective approach to chiral chromans with quaternary stereocenters for the synthesis of vitamin E and analogues. Chem. – Eur. J. 2014, 20, 13913-13917
Uria, U.; Vila, C.; Lin, M.-Y.; Rueping, M.,
(See online at https://doi.org/10.1002/chem.201403768) - Asymmetric Bronsted Acid Catalyzed Synthesis of Triarylmethanes-Construction of Communesin and Spiroindoline Scaffolds. Angew. Chem., Int. Ed. 2015, 54, 15540-15544
Liao, H.-H.; Chatupheeraphat, A.; Hsiao, C.-C.; Atodiresei, I.; Rueping, M.
(See online at https://doi.org/10.1002/anie.201505981) - Ortho-Quinone Methides as Reactive Intermediates in Asymmetric Bronsted Acid Catalyzed Cycloadditions with Unactivated Alkenes by Exclusive Activation of the Electrophile. Angew. Chem., Int. Ed. 2015, 54, 5762-5765
Hsiao, C.-C.; Raja, S.; Liao, H.-H.; Atodiresei, I.; Rueping, M.
(See online at https://doi.org/10.1002/anie.201409850) - Catalytic Asymmetric Piancatelli Rearrangement: Bronsted Acid Catalyzed 4π Electrocyclization for the Synthesis of Multisubstituted Cyclopentenones. Angew. Chem., Int. Ed. 2016, 55, 14126-14130
Cai, Y.; Tang, Y.; Atodiresei, I.; Rueping, M.
(See online at https://doi.org/10.1002/anie.201608023) - Multiple Hydrogen-Bond Activation in Asymmetric Bronsted Acid Catalysis. Chem. – Eur. J. 2018, 24, 7718-7723
Liao, H.-H.; Hsiao, C.-C.; Atodiresei, I.; Rueping, M.
(See online at https://doi.org/10.1002/chem.201800677)
