Gold(I)-Catalyzed Transformations with Bifunctional Ligands and the Synthesis of Daucane Natural Products

Abstract

Homogenous gold(I) catalysis has become a powerful tool for the rapid buildup of molecular complexity from relatively simple starting materials. In the last two decades, the potential of gold(I) catalysis has been evidenced by its application in the synthesis of numerous natural products due to its high chemoselectivity towards the activation of alkynes. Usually, gold(I) is prepared as a stable gold(I)-chloride precatalyst, which requires activation to be catalytically active. This is usually performed by adding exogenous chloride scavengers, such as silver salts, which can also exhibit catalytic activity and give rise to side reactions, a phenomenon generally known as the “silver effect”. To eliminate the need for such additives, new designs for silver-free gold(I) catalysis have been developed over the past decade. Despite the exponential development observed in gold(I) catalysis, the enantioselective versions of this class of transformations remain underdeveloped, mainly due to the linear dicoordination of gold(I) complexes, which places the chiral information on the direct opposite site of the reactive center.

The activation of alkynes, which are not prochiral, and the outer-sphere mechanism of gold(I)-mediated reactions further complicate the development of effective catalytic enantioselective processes.

In this Doctoral Thesis we have addressed these problems by strategically introducing hydrogen bond donors into the ligand scaffold to allow the removal of labile ligands from the coordination sphere of the metal center.

First, we designed a library of triphenylphosphine-based self-activating gold(I)-catalysts bearing (thio)urea/squaramide motifs on the ligand, and we tested them in the cycloisomerization of N-propargylbenzamides. Experimental mechanistic studies, as well as DFT calculations, pointed out the role of the dual hydrogen bond donors in the activation of the gold(I)-chloride bond, allowing substrate coordination and catalytic turnover.

Second, we developed the Hydrogen Bonded Counterion-Directed Catalysis (HCDC), a novel approach for asymmetric gold(I) catalysis. HCDC relies on the use of (a)chiral gold(I)-catalysts embedded with hydrogen bond donors in combination with chiral counterions. The role of the hydrogen bond donor is to abstract the counterion from the coordination sphere of the metal center, while maintaining it close enough to allow for the transfer of the chiral information. This novel methodology allowed the transformation of 1,n-enynes with and without the addition of external nucleophiles in very high yields and enantioselectivities.

Finally, we completed the total synthesis of two members of the daucane family natural products, aspterric acid and shisanwilsonene A. Additionally, we synthesized the structure proposed for penigrisacid A by its isolation team and confirmed that it had been misassigned. A new structure has been proposed based on the experimental spectroscopic data as well as DFT-predicted NMR calculations.