Gold(I)-catalyzed transformations have been widely used for constructing complex molecular structures under mild reaction conditions. In this context, our group has been focused on finding new ways of activating triple bonds towards both intramolecular and intermolecular reactions with alkenes. In this Doctoral Thesis, we focused on the use of polarized heteroatom-substituted alkynes for both racemic and asymmetric reactions.

We developed two distinct strategies for stereoselective gold(I)-catalyzed cyclizations of 1,n-enynes utilizing, for the first time, a chiral auxiliary approach. Firstly, a stereoselective cascade cyclization of 1,5-enynamides was achieved through the use of commercially available [JohnPhosAu(MeCN)SbF₆] catalyst using the Oppolzer camphorsultam as a chiral auxiliary. This approach involved a one-pot cyclization-hydrolysis sequence, resulting in the direct formation of enantioenriched spirocyclic ketones. Secondly, the stereoselective alkoxycyclization of 1,6-enynamides was directed by an Evans-type oxazolidinone. A reduction-hydrolysis sequence was employed to remove the auxiliary, yielding enantioenriched β-tetralones. DFT studies gave insights over the experimentally observed diastereoselectivity showing that the cyclization occurs preferentially through the Si face of the alkene, due to the steric clash of the Re face with the chiral auxiliary.

Cyclobutenes and cyclobutanone derivatives are scaffolds of great interest since they constitute common motifs within natural products and they are useful intermediates in organic synthesis. We developed a new synthetic method that allows the direct access to cyclobutenyl ethers, with good yields and excellent regioselectivities, via a gold(I)-catalyzed [2+2] cycloaddition of alkenes with terminal ynol ethers. These functionalized alkynes can be considered as stable equivalents of ketenes, which are usually difficult to handle. Hydrolysis or bromination of the [2+2] products led to cyclobutanones.

The development of the first enantioselective gold(I)-catalyzed alkoxycyclization of 1-bromo-1,6-enynes was accomplished through the use of a modified JohnPhos ligand featuring a distal C₂-2,5-diarylpyrrolidine moiety affording enantioenriched 5-membered-ring vinyl bromides, which can be easily further functionalized through Pd-catalysis. Interestingly, both experimental and theoretical investigations of the reaction mechanism revealed the occurrence of an in-cycle racemization process, which was demonstrated to occur through a reversible 1,2-H shift. These findings contribute to a new general understanding of gold(I)-catalyzed alkoxycyclizations, for which a detail model has been herein described for the first time.

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