Enantioselektive Synthese des Morphingerüstes durch eine photochemische Cyclisierungsreaktion
Zusammenfassung der Projektergebnisse
In this project an expedient 9-step total synthesis of (±)-morphine as well as a convenient visible-light mediated photocyclization have been developed. The short total synthesis of (±)-morphine was achieved by employing two key strategic cyclizations: 1) a diastereoselective light‐mediated cyclization of an O‐arylated butyrolactone to form a tricyclic cis‐fused benzofuran and 2) a cascade ene–yne–ene ring closing metathesis to forge the tetracyclic morphine core. This approach offers a novel, stereoselective access to the morphine core, which is characterized by the installation of key functional groups at an appropriate oxidation level to minimize late stage transformations and protecting group manipulations. Despite the total synthesis being one of the shortest to date, the low yielding UV-mediated photocyclization reduces the sustainability and efficiency of the synthesis. Inspired by this, the investigation was shifted to the development of a 6 pi heterocyclization under visible light photocatalysis. We discovered that irradiation of cyclic 2-aryloxyenones with blue LED light in the presence of catalytic amounts of an IrIII complex led to efficient arylation to obtain cis-fused dihydrobenzofurans in high yields. 2-Arylthioenones and 2-arylaminoenones also cyclized effectively under these conditions to give the corresponding dihydrothiophenes or dihydroindoles, respectively. In general, the reaction had high tolerance of substitution on both the enone and the aryl moieties, and consistently high diastereoselectivity. In comparison to the previously reported UV-mediated cyclization, our method offered the advantage of milder conditions, a substantially wider substrate scope (54 substrates were made in total), higher yields, and a more convenient reaction set-up. Quantum calculations demonstrated that the reaction proceeded via a conrotatory ring closure in the triplet excited state of the enones. In addition, it was possible to demonstrate some enantioselection in the photocyclization and, for specific substrates, moderate enantioselectivities could be achieved. The transformations developed and synthetic solutions disclosed in this project offer new methods to access rigid structural motifs which may be of interest to drug development.
Projektbezogene Publikationen (Auswahl)
- “A Cascade Strategy Enables a Total Synthesis of (±)-Morphine”, Angew. Chem. 2016, 128, 14518–14521; Angew. Chem. Int. Ed. 2016, 55, 14306–14309
S. Chu, N. Münster, T. Balan, M. D. Smith
(Siehe online unter https://doi.org/10.1002/anie.201608526) - “Visible Light Photocatalysis of 6π Heterocyclization”, Angew. Chem. 2017,129, 9596–9600; Angew. Chem. Int. Ed. 2017, 56, 9468–9472
N. Münster, N. A. Parker, L. van Dijk, R. S. Paton, M. D. Smith
(Siehe online unter https://doi.org/10.1002/anie.201705333)
