Unexpected diastereoinversion in the Tsuj-Trost reaction: from experimental observation to computational mechanistic explanation Emanuele Casali,* Alessio Porta, Lucio Toma, Giuseppe Zanoni Department of Chemistry, University of Pavia, Italy Heterocyclic compounds play an important role in biological functions, and hydrogenated furans are one of the earliest examples of these compounds that are relevant to organisms. Ribose units, for example, are fundamental in the lateral structure of the DNA double helix. Neurofurans have been found to play an even greater role as they are the principal products of the oxidative stress in human brain cells. In oder to study the synthesis of two diastereomeric tetrahydrofurans, our group developed a strategy using the Tsuji-Trost palladium catalyzed allylic alkylation as the cyclization reaction of the meso -diol 1 (Figure 1). [1],[2],[3]
Figure 1. Cyclization of1and Trost modular-ligands. During the experimentation, an unexpected behavior was observed: changing the absolute configuration of the palladium ligand, the reaction became diastereo- and enantioselective, passing through a diastereoinversion process. [4] This result, without affecting diastereo- and enantio-selectivity, had never been observed before using this reaction. [2],[3] The underlying assumption for this observation could be the presence of two different mechanisms, each of which is active with a specific ligand. Computational studies were undertaken in order to explain this surprising stereochemical output. By using DFT calculations we found that ( R , R )-anden ligand afforded a perfect match between the experimental and the calculated results. We concluded that the enantioselective step is the chiral recognition of one of the two enantiotopic faces followed by acetate ion departures. The Re -face of the S -portion of 1 is the most favored one. The cyclisation step is the diastereoselective event, since it is responsible for the distribution of the final four isomers. We nextcomputationallyinvestigated the ( S , S )-dach ligand, but the results did not match with the experimental ones. In particular, the Si -face of the R -portion of 1 resulted to be the most favored one, while experimentally the complexation and loss of the acetate group are preferred on to the Si -face of the same S -portion, like with the ( R , R )-andenligand. For the first time, we envisioned the role of the amide group of the dachligand in assisting the oxidative addition step, favoring the removal of the acetate group through a complex H-bond network. We thus explained the counterintuitive selectivity experimentally observed in this first step. This is a completely different behaviour of the ligand in regulating the H-bond interactions: the ( R , R )-anden cannot structurally provide the H-bond between one of its amide NH groups and the acetate leaving specie, thus not being able to provide the network of interactions occurring between the substate and the ( S , S )-dach ligand.This research provides new insights into the synthesis of furans with specific stereochemistry, a great potential for various biological and medicinal applications as well as natural product synthesis. References
1. Tsuji, J. et al. , Tetrahedron Lett ., 1965 , 6 , 4387-4388. 2. Trost, B.M. et al ., J . Am. Chem. Soc ., 1973 , 95 , 292-294. 3. Trost, B.M. et al. , J. Am. Chem. Soc ., 1999 , 121 , 4545-4554. 4. Zanoni, G. et al. , J. Org. Chem ., 2013 , 78 , 5556−5567.
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