Bioinspired total syntheses of (±)-dictazole B and (±)-tubastrindole B: "The aplysinopsins' cascade"

When trying to figure out the natural origin of the aplysinopsin family of alkaloids, one essential feature emerges from the isolation reports. All the congeners of this series are indeed coming from sponges or stony corals collected in shallow waters, which means within reach of sunlight. Three dinstinct scaffolds are represented in the family and, on a structural basis, a dimerization step is obviously needed at some point to form the more challenging dictazole-type and tubastrindole-type alkaloids. Guided by these biosynthetic considerations, we have carried-out the first total synthesis of (±)-dictazole B [1] through a diastereoselective [2+2] photocycloaddition between two aplysinopsin-type monomers. Beyond this surprisingly simple and efficient synthesis, we then considered dictazole-type compounds as possible intermediates toward their tubastrindole-type relatives. This fruitful ring expansion approach led to the first total synthesis of (±)-tubastrindole B [2] with full retention of configuration during the cascade. Given these results, one could imagine that the chosen centrosymmetric dictazole-type precursors might exist in nature even if they have not been isolated to date. Our work has also resulted in the synthesis of a transient intermediate explaining the formation of other natural products of the series. Moreover, the extended study uncovered a synthetic network around these marine alkaloids [3].

Keywords: Total synthesis, Biomimetic synthesis, Alkaloids, Self-assembly.

References:

[1] Skiredj A, Beniddir MA, Joseph D, Leblanc K, Bernadat G, Evanno L, Poupon E. Spontaneous biomimetic formation of (±)-dictazole B under irradiation with artificial sunlight. Angew Chem Int Ed 2014; 53: 6419 – 6424

[2] Skiredj A, Beniddir MA, Joseph D, Leblanc K, Bernadat G, Evanno L, Poupon E. A unified bioinspired “Aplysinopsin cascade”: total synthesis of (±)-tubastrindole B and related biosynthetic congeners. Org Lett 2014; 16: 4980 – 4983

[3] Skiredj A, Beniddir MA, Joseph D, Bernadat G, Evanno L, Poupon E. Harnessing the intrinsic reactivity within the aplysinopsin series for the synthesis of intricate dimers: natural from start to finish. Synthesis 2015; 47: 2367 – 2376

No conflict of interest has been declared by the author(s).