The genus Daphniphyllum have been long used in traditional Chinese medicine. Investigations of various Daphniphyllum alkaloids revealed diverse and promising biological profiles. There are about 330 Daphniphyllum alkaloids have been isolated to date, making up a structurally fascinating natural product family. The challenging caged architectures and promising bioactivities, making these alkaloids intriguing synthetic targets. Encouraged by numerous pioneering efforts, our group at SUSTech focused on the total synthesis of Daphniphyllum alkaloids with highly diversified structures (Angew. Chem. Int. Ed. 2019, 58, 7390; J. Am. Chem. Soc. 2019, 141, 11713; J. Am. Chem. Soc. 2019, 141, 13043; Org. Lett. 2019, 21, 4309; Chin. J. Org. Chem. 2019, 39, 1079 ).

Since the isolation of yuzurimine in 1966, nearly fifty yuzurimine-type alkaloids were isolated, which account for almost one-sixth of all known Daphniphyllum alkaloids to date. Despite extensive synthetic studies, total synthesis of yuzurimine-type alkaloids — the largest subfamily of the Daphniphyllum alkaloids — has not been achieved. Therefore, we decide to take this challenge and, set caldaphnidine J as our first target. As shown in Figure 1, our approach features 1) a facile ring expansion strategy; 2) a Pd-catalyzed regioselective hydroformylation; 3) a Sm(II)-mediated pinacol coupling that produced the critical 7/5 bicyclic system; and 4) a novel, one-pot Swern oxidation/ketene dithioacetal Prins reaction. What this work achieves is the first synthesis of a member of the largest yet unexplored subfamily of the Daphniphyllum alkaloids.

Figure 1. Total synthesis of (+)-caldaphnidine J

Here, we would like to share a little story behind the Swern oxidation/ketene dithioacetal Prins reaction (Figure 2): While the oxidation of the secondary hydroxyl group in compound 5 gave decomposition or messy results under various conditions, the TFAA/DMSO condition produced a major, unknown product. LC-MS analysis indicated the “desired” MS peak ([M+H]⁺=560.2) of ketone 8 and an unknown, major MS peak: 608.2. The following NMR analysis, however, indicated that both the ketone carbonyl and the ketene dithioacetal motifs are missing. This unexpected result prompted us to thoroughly characterize this unknown product, which finally was structurally assigned as compound 6. It well fits the MS peak [M+H]⁺ (608.2) and, the MS peak of 560.2 can also be perfectly explained as a result of [M-MeS]⁺. An unexpected, novel one-pot Swern oxidation/ketene dithioacetal Prins reaction was so discovered.

Figure 2. Discovery of a one-pot Swern oxidation/ketene dithioacetal Prins reaction

More details of this work can be found here: “Asymmetric total synthesis of yuzurimine-type Daphniphyllum alkaloid (+)-caldaphnidine J” in Nature Communications: https://doi.org/10.1038/s41467-020-17350-x