Scharinger, F. (2023, July 10). Synthesis of novel heterocycles through unconventional organocatalytic frameworks [Poster Presentation]. 22nd European Symposium on Organic Chemistry (ESOC Ghent 2023), Ghent, Belgium.
Many biologically active molecules and natural products contain nitrogen-containing heterocycles, which are recognized as an important class of compounds with significant biological activity.1,2 Using organocatalysis is a highly effective approach to achieve excellent enantioselectivity in their synthesis.3 We intentionally developed an unconventional organocatalyst derived from amino acids and an achiral phosphoric acid counterpart which resulted in exceptional performance for a range of asymmetric transformations, including epoxidation and aziridination of cyclohexenones. This counteranion enhanced organocatalytic approach was then applied to the synthesis of chiral, N-unprotected octahydroacridines. The tandem mechanism, which involves a Michael addition followed by aldol reaction, proved to be an efficient method for synthesizing these compounds in excellent yields and high enantioselectivity. Due to the sensitive nature of the target structure, we observed that privileged organocatalysts like the cinchona-primary amine with TFA (trifluoracetic acid) or diphenylethylendiamine (DPEN) with TFA exhibited significantly lower performance.4 After discovering the octahydroacridine moiety, we proceeded to develop another aza-Michael aldol tandem reaction to produce novel, highly chiral pyridazine structures. We found that double nitrogen-containing heterocycles can be readily formed from enals and a highly reactive keto-pyridazine amide reagent. Similar to the previous reaction, catalyst screening revealed that privileged catalysts for the asymmetric conversion of enals or ketones were inadequate for this application as well. The only catalyst structure capable of achieving enantioselectivities above 90% with excellent yields was the straightforward one-pot preparation of a mono-substituted DPEN in combination with TFA.
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Project (external):
Union’s Horizon 2020 research
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Project ID:
864991
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Additional information:
Many biologically active molecules and natural products contain nitrogen-containing heterocycles, which are recognized as an important class of compounds with significant biological activity.1,2 Using organocatalysis is a highly effective approach to achieve excellent enantioselectivity in their synthesis.3 We intentionally developed an unconventional organocatalyst derived from amino acids and an achiral phosphoric acid counterpart which resulted in exceptional performance for a range of asymmetric transformations, including epoxidation and aziridination of cyclohexenones. This counteranion enhanced organocatalytic approach was then applied to the synthesis of chiral, N-unprotected octahydroacridines. The tandem mechanism, which involves a Michael addition followed by aldol reaction, proved to be an efficient method for synthesizing these compounds in excellent yields and high enantioselectivity. Due to the sensitive nature of the target structure, we observed that privileged organocatalysts like the cinchona-primary amine with TFA (trifluoracetic acid) or diphenylethylendiamine (DPEN) with TFA exhibited significantly lower performance.4 After discovering the octahydroacridine moiety, we proceeded to develop another aza-Michael aldol tandem reaction to produce novel, highly chiral pyridazine structures. We found that double nitrogen-containing heterocycles can be readily formed from enals and a highly reactive keto-pyridazine amide reagent. Similar to the previous reaction, catalyst screening revealed that privileged catalysts for the asymmetric conversion of enals or ketones were inadequate for this application as well. The only catalyst structure capable of achieving enantioselectivities above 90% with excellent yields was the straightforward one-pot preparation of a mono-substituted DPEN in combination with TFA.
