Axially chiral amides are a class of non-biaryl and C₂-unsymmetric atropisomers which are promising chiral reagents, auxiliaries, and ligands in asymmetric reactions and catalysis. Encouraging results on preparation and synthetic application of enantiomerically pure non-biaryl atropisomers have emerged during the last five years. Their full potential still waits for further exploration. 2-Substituted N,N-diisopropyl-1-naphthamides possess sufficient large rotational energy barrier along the C-C(O)N single bond. When a suitable substituent such as a methyl group is attached to the C2 position of the naphthyl ring, the atropisomers are configurationally stable at ambient temperature so that they can be resolved and handled by conventional methods. A C8 heteroatom substituent such as a met...[ Read more ]

Axially chiral amides are a class of non-biaryl and C₂-unsymmetric atropisomers which are promising chiral reagents, auxiliaries, and ligands in asymmetric reactions and catalysis. Encouraging results on preparation and synthetic application of enantiomerically pure non-biaryl atropisomers have emerged during the last five years. Their full potential still waits for further exploration. 2-Substituted N,N-diisopropyl-1-naphthamides possess sufficient large rotational energy barrier along the C-C(O)N single bond. When a suitable substituent such as a methyl group is attached to the C2 position of the naphthyl ring, the atropisomers are configurationally stable at ambient temperature so that they can be resolved and handled by conventional methods. A C8 heteroatom substituent such as a methoxy group can further strengthen thermal stability of N,N-diisopropyl-1-naphthamides toward rotation along the C-C(O)N single bond. Therefore, C8,C2-disubstituted N,N-diisopropyl-1-naphthamides are an excellent scaffold for investigation.

We developed a "chiral wall" template approach for design, synthesis, and application of non-biaryl and C₂-unsymmetric atropisomeric P,O-ligands in catalytic enantioselective carbon-carbon bond formation. Following a brief overview on axially chiral amides in Chapter 1, enantiomerically pure N,N-diisopropyl-1-naphthamides possessing a hydroxyl-containing substituent at C2 were resolved by HPLC over a chiral stationary phase as described in Chapter 2. The absolute stereochemistry of the resolved alcohols were established, for the first time, by X-ray crystallographic analysis of the corresponding camphanates. Desymmetrization of cyclic meso anhydrides was performed using the atropisomeric naphthamide-derived alcohol, giving complete diastereoselectivity. This study consolidates our "chiral wall" concept based on the C8,C2-disubstituted N,N-diisopropyl-1-naphthamide scaffold.

Taking the advantage of the amide-directed ortho lithiation, we introduced a dialkyl- or diphenyl-phosphino group at C2 of N,N-diisopropyl-1-naphthamide bearing an additional oxygen substituent at C8. Described in Chapter 3 are the synthesis of a novel class of atropisomeric naphthamide-derived P,O-ligands via a chemical resolution approach and their application in the Pd-catalyzed asymmetric allylic alkylation (AAA). For the first time, we prepared these atropisomeric P,O-ligands which are devoid of central chirality and demonstrated that the axial chirality alone is capable of inducing high enantioselectivity in AAA up to 94.7% ee. Through X-ray crystallographic analysis of the allyl-Pd complexes of the atropisomeric P,O-ligands, we obtained detailed structural insight on the active catalytic species and successfully formulated the mechanistic models for AAA according to the "chiral wall" template.

In Chapter 4, we applied the atropisomeric P,O-ligands to the Pd-catalyzed intermolecular asymmetric Heck reaction (AHR) of 2,3-dihydrofuran. Optimization on reaction conditions including ligand structure, ligand:Pd ratio, solvent, base, and aryl triflates were carried out. For the AHRs of 1-naphthyl triflates, 2-aryl-2,5-dihydrofurans were formed as the sole products and enantioselectivity up to 84.2% ee was achieved for the AHR of 4-methoxy-1-naphthyl triflate. In contrast, the AHRs of 2-naphthyl and C4-substituted phenyl triflates afforded both regioisomers and low enantioselectivity. Mechanistic models according to the established "cationic pathway" were proposed to account for the results of AHR albeit further validation is still needed.

The final Chapter 5 presents some preliminary results on the Pd-catalyzed AAA using P-chiral secondary phosphine oxides (s-POs) as the monodentate monophosphorus chiral ligands. Enantioselectivity up to 79.9% ee was induced. This study serves as the first example that P-chiral s-POs are the promising chiral ligands for catalytic enantioselective carbon-carbon bond formation which parallels to the recent application of this class of chiral ligands in the Ir-catalyzed asymmetric hydrogenation of imines. We confirmed that P-chiral s-POs are configurationally stable in the presence of transition metals both in solid state and in solution. A remarkable solvent effect was observed on the AAA and it suggests that P-chiral s-POs are relatively weak ligands compared to other common phosphorus ligands.

The successful results on the Pd-catalyzed AAA and AHR using atropisomeric P,O-ligands lay down a firm foundation for further evolution of the "chiral wall" template based on C8,C2-disubstituted N,N-diisopropyl-1-naphthamide scaffold. On the other hand, our preliminary results of asymmetric catalysis by the air-stable P-chiral s-POs suggest further exploration on this class of monodentate monophosphorus ligands in order to explore their full potential in asymmetric catalysis.