Gold(I)-catalyzed intramolecular enantioselective hydroalkoxylation reaction for the total synthesis of metabolites containing the tetrahydrofuran core

Several natural products and biologically active compounds present oxygenated five- membered rings as structural motif. In particular, substituted tetrahydrofurans are commonly occurring building blocks found both within terrestrial and marine metabolites. These substances exhibit a wide range of biological activities such as anti-microbial, anti- tumoral, anthelmintic, anti-malarial and anti-protozoal. As such, over the last decades, considerable efforts have been devoted towards the development of efficient and completely stereoselective strategies for the construction of substituted THF rings. Many efforts indeed in this thesis have been devoted to the development of a new synthetic methodology to access such building block, exploiting a versatile and efficient gold(I) catalysis. In particular, this thesis reports the first example of accelerative asymmetric gold(I) catalysis via chiral ligand metal cooperation. An asymmetrically positioned remote amide group in the 3’ position of the designed gold(I) chiral binaphtyl ligand enables a selective acceleration of the cyclization reaction of allenyl substrates into one prochiral allene face through general base catalysis, achieved by H-bonding with the incoming nucleophlic hydroxyl group. Owing to the accelerative nature of the catalysis, a high level of efficiency and selectivity can be accessed, which is proved thanks to exceptional ee values and extremely low catalyst loading, as low as 100 ppm. This type of catalytic scenario demonstrates to be of wide applicability. Firstly, attention has been drawn towards 4-allen-1-ols, which can undergo the gold(I) cyclization reaction smoothly in feasible conditions with almost quantitative yields and very high ee values, both with achiral and chiral substrates; in the latter case the reaction remains highly efficient and most importantly maintains excellent allene facial selectivities regardless of the substrate stereochemistry. Moreover, many functional groups are well tolerated. Secondly, the attention has been driven towards Medius, which undergoes cyclization reaction affording disubstituted THF systems in high yields and exceptionally high ee values exploiting the same type of approach above described. The employment of classical approaches such as Toste’s or Widenhoefer’s or Mikami’s does not afford high ee or dr values, despite excellent yields. On the other hand, moderate dr values are obtained as a consequence of poor control of the catalyst over the prochiral center present in the substrate, as can be expected. Nevertheless, extremely high ee values are ensured by the great allene facial selectivity attack by the nucleophile. Moreover, the absolute as well as the relative configurations of the stereogenic centers present in the product of the cyclization of Medius have been determined, proving that the cis product is preferred over the trans one. In the third place, a complete methodological work on the gold(I) cyclization reaction of Remotus has been also carried out. Even in this case, like in Medius’ one, quantitative yields and very high ee values can be obtained through Zhang’s catalyst. However, as expected, very poor dr values can be accessed as a consequence of the nature of the substrate. To sum up, this thesis proves that gold(I) catalysis, in particular in the case of gold(I) ligand accelerative catalysis, represents a powerful tool in organic synthesis to enantioselectively build variably substituted THF systems in almost quantitative yields, exceptionally high ee values, and good dr values, using an extremely low catalyst loading thanks to the efficiency of the catalysis.