Development of novel bifunctional organic superbases for enantioselective synthesis Daniel Rozsar, Darren J. Dixon University of Oxford, Chemistry Research Laboratory, UK This body of work focuses on the development of new bifunctional iminophosphorane (BIMP) superbases, and application thereof, in otherwise out-of-reach enantioselective reactions between cheap and abundant (but poorly reactive) substrates leading to value-added medicinally relevant enantioenriched building blocks. BIMPs possess increased basicity compared to other widely used tertiary amine-based bifunctional catalysts. Increased catalyst activity opens new avenues in enantioselective synthesis, by allowing the usage of unactivated substrates, reducing step counts, and increasing starting material availability. 1 The power of BIMP catalysis is exemplified herein by two recently developed fundamental enantioselective intermolecular conjugate addition reactions. The first transformation represents the first metal-free enantioselective intermolecular conjugate addition to unactivated α,β-unsaturated amides, catalysed by a newly developed squaramide-based iminophosphorane superbase (3 rd generation BIMP). This reaction allows for the enantioselective addition of high pK a alkyl thiols to notoriously unreactive α,β-unsaturated amides, providing previously difficult to obtain β-thioamides in a single step. 2 Since the discovery of 3 rd generation BIMPs, their unique properties have been proven to be useful in other challenging enantioselective addition reactions. 3,4 In a second, related, study the enantioselective intermolecular conjugate addition of nitroalkanes to unactivated α,β-unsaturated esters was developed. This fundamental reaction allows for the use of feedstock substrates and provides pharmaceutically relevant γ-nitroester building blocks in a single step. 5
References 1. Formica, M.; Rozsar, D.; Su, G.; Farley, A. J. M.; Dixon, D. J. Bifunctional Iminophosphorane Superbase Catalysis: Applications in Organic Synthesis. Acc. Chem. Res. 2020 , 53 , 2235–2247. 2. Rozsar, D.; Formica, M.; Yamazaki, K.; Hamlin, T. A.; Dixon, D. J. Bifunctional Iminophosphorane-Catalyzed Enantioselective Sulfa-Michael Addition to Unactivated α,β-Unsaturated Amides. J. Am. Chem. Soc. 2022 , 144 , 1006–1015. 3. Su, G.; Thomson, C. J.; Yamazaki, K.; Rozsar, D.; Chsristensen, K.; Hamlin, T. A.; Dixon, D. J. A Bifunctional Iminophosphorane Squaramide Catalyzed Enantioselective Synthesis of Hydroquinazolines via Intramolecular Aza-Michael Addition to α,β-Unsaturated Esters. Chem. Sci. 2021 , 12 , 6064–6072. 4. Su, G.; Formica, M.; Yamazaki, K.; Hamlin, T. A.; Dixon, D. J. Catalytic Enantioselective Intramolecular Oxa-Michael Reaction to α,β-Unsaturated Esters and Amides. J. Am. Chem. Soc. 2023 , 145 , 12771–12782. 5. Rozsar, D.; Farley, A. J. M.; McLauchlan, I.; Shennan, B. D. A.; Yamazaki, K.; Dixon, D. J. Bifunctional Iminophosphorane ‐ Catalyzed Enantioselective Nitroalkane Addition to Unactivated α,Β‐Unsaturated Esters. Angew. Chem. Int. Ed. 2023 , 62 , e202303391.
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