Our efforts began by targeting the construction of thallusin, relying on the connection of selector (terpenoid part) and chelator (pyridine carboxylic acid) through implementing an unprecedented 6-endo-dig arylative cyclization. The effect of different transition metal catalysts, ligands, bases, solvents, and substrate designs were studied on specifically designed model systems; however, only 5-exo-dig arylative cyclization was observed. On the other hand, thallusin was thought to be accessible from transition metal-catalyzed diastereoselective 6-endo-trig cyclization of stereochemically defined allenol. Toward this end, we have developed a novel method for the Au(I) catalyzed 6-endo trig cyclization of β-hydroxy allenols and sequential iododeauration of a σ-gold intermediate to generate 3-iodo-3,4-dihydropyrans.
Two different approaches were developed for the synthesis of the selector (terpene framework) of thallusin in enantiopure form 1) diastereoisomer separation by using chiral auxiliary 2) asymmetric polyene cyclization. In the 1st approach, an enantiomerically pure selector (terpenoid part) was obtained from dihydro--inone by using a chiral auxiliary in good yield. In the 2nd approach, an enantioselective polyene cyclization was established by using a substrate for a chiral iridium-based catalyst, inducing an enantioselective cyclization cascade. Finally, an excellent ee of >98 % was achieved and enabled a highly efficient synthesis of the terpene framework of (‒)-thallusin. Both approaches could lead to a common intermediate (-hydroxy aldehyde) for the synthesis of (‒)-thallusin. For the 6-endo-trig-cyclization, a method was developed for an efficient installation of an allenol on the -hydroxy aldehyde scaffold. The developed Au(I) catalyzed 6-endo trig cyclization of the β-hydroxy allenol furnished the tricyclic vinyl-iodo-alcohol in excellent yield. A Negishi coupling of zincated pyridine dicarboxylates was then developed for the completion of the total synthesis. In summary, we have developed an efficient and modular synthetic route for the enantiopure synthesis for (‒)- thallusin and its derivative. (+)-Thallusin and its derivatives were also synthesized by following the same sequence. Synthesized thallusin and its derivatives were tested for the morphogenesis activity of Ulva mutabilis in collaboration, generating key SAR data for exploring thallusin, and allowing to determine the potency of (-)-thallusin in Ulva mutabilis (EC50 = 5 pM).
The results of the project were presented in a different conference by Dr. Seema Rani. [a) GDCh Wissenschaftsforum Chemie held at RWTH Aachen, Germany, during September 2019; title of the poster: Synthetic studies towards Thallusin. b) Early Career Investigators (ECIs) meeting held at Brussels, Belgium, during February 2019. Title of the presentation: Total synthesis and SAR studies of thallusin derivatives in green macroalgae]. Dr. Rani has also presented these results in The Long Night of Science Festival. The results will be published in three publications, one on the first stereoselective total synthesis of (-)-thallusin and initial profiling of analogs (in preparation for Angew. Chem.), a second one on methodological details of the 6-endo cyclization (in preparation for Eur. J. Org. Chem.), and a third one on the polyene cyclization methodology (in preparation for Org. Lett.). Further contributions to forthcoming publications of the host lab are anticipated, especially to biological testing initiatives that are currently intensified. These results will also be published on the IOMC website of the FSU and on the host group’s website (www.arndtgroup.uni-jena.de).
