UC Berkeley

The addition of nitrogen, oxygen, and carbon nucleophiles to carbon-carbon unsaturated bonds is an atom economical method of generating structural complexity from simple starting materials. As soft Lewis acids with high oxidation potentials, gold(I)-complexes are attractive catalysts for these types of transformations. Although many reactions catalyzed by gold(I) have now been reported, we identified two conspicuous deficiencies: few of enantioselective methods and a lack of nucleophilic additions to alkenes. This dissertation will describe advances on both fronts. First, we will discuss the discovery and characterization of chiral phosphinegold(I)-bis-p-nitrobenzoate complexes which catalyze the asymmetric hydroamination of allenes. Second, the isolation of proposed alkene hydroamination intermediates will be reported.

Chapter 1. A brief perspective on the current resurgence of homogeneous gold(I)-catalysis will be presented, with an emphasis on the development of enantioselective reactions.

Chapter 2. The metal catalyzed asymmetric hydroamination of allenes has been an unsolved problem in syntheic chemistry for many years. In this chapter, we describe our efforts to apply chiral biarylposphinegold(I) complexes to this transformation. Over the course of this work, we characterized a polymeric mono-cationic complex (R)-[BINAP(Au₂Cl)]BF₄, and uncovered a dramatic counterion effect. This discovery led to the utilization of phosphinegold(I)-bis-p-nitrobenzoate complexes for the asymmetric hydroamination of allenes. The catalysts were applied to the enantioselective formation of vinyl pyrrolidines and piperidines in 70-99% enantiomeric excess. The structure of a bis-p-nitrobenzoategold(I) complex, (R)-ClMeOBiPHEP(AuOPNB)₂, was verified by X-ray crystallography.

Chapter 3. Chiral ligands and counterions were employed in the gold(I)-catalyzed enantioselective intramolecular additions of hydrazines and hydroxylamines to allenes. Chiral phosphinegold(I)-bis-p-nitrobenzoate complexes are versatile catalysts for the enantioselective hydroamination of allenes. The addition of oxygen nucleophiles, however, required the use of chiral anions. These complementary methods allow access to chiral vinyl isoxolidines, tetrahydrooxazines, and differentially protected pyrazolidines.

Chapter 4. This chapter will describe the first direct experimental evidence for the elementary step of gold-promoted nucleophilic addition to an alkene. Alkylgold(I) complexes were formed from the gold(I)-promoted intramolecular addition of various amine nucleophiles to alkenes. Deuterium-labeling studies and X-ray crystal structures provided support for a mechanism involving anti-addition of the nucleophile to a gold-activated alkene. This mechanism was verified by DFT analysis. Ligand studies indicated that the rate of aminoauration was drastically increased by use of electron-poor arylphosphines, which were also shown to be favored in ligand exchange experiments. Attempts at protodeauration led only to recovery of the starting olefins, though the gold could be removed under reducing conditions to provide the purported hydroamination products. The reactivity of alkylgold complexes with zinc and palladium are described. An unexpected oxidation to gold(III) was also uncovered.

Chapter 5. Investigations into the gold(I)-catalyzed addition of carbon nucleophiles to allenes will be discussed. One such reaction, a gold(I)-catalyzed 5-endo-trig reaction, worked with a variety of carbon nucleophiles, incuding silyl enol ethers, β-ketoesters and dinitriles. This transformation opens access to a variety of substituted cyclopentenes. These carbocycles are complementary to the products available through the Conia-ene and 5-endo-dig methodology. In addition, we demonstrate the transfer of chirality from an allene precursor, producing a quaternary stereocenter with a vicinal tertiary center. We also report a gold(I)-catalyzed 5-endo/exo-trig cyclization of substrates which contain two-carbon linkers between the pendant nucleophile and allene. Investigations into the mechanism of this cyclization are included, as well as attempts to isolate a proposed allylgold(I) intermediate.

Chapter 6. A synopsis of our results will be presented, with a perspective on the evolving field of gold(I)-catalysis.