The Discovery of Multifunctional Chiral P Ligands for the Catalytic Construction of Quaternary Carbon/Silicon and Multiple Stereogenic Centers

Abstract

Conspectus The development of highly effective chiral ligands is a key topic in enhancing the catalytic activity and selectivity in metal-catalyzed asymmetric synthesis. Traditionally, the difficulty of ligand synthesis, insufficient accuracy in controlling the stereoselectivity, and poor universality of the systems often become obstacles in this field. Using the concept of nonequivalent coordination to the metal, our group has designed and synthesized a series of new chiral catalysts to access various carbon/silicon and/or multiple stereogenic centers containing products with excellent chemo-, diastereo-, and enantioselectivity. In this Account, we summarize a series of new phosphine ligands with multiple stereogenic centers that have been developed in our laboratory. These ligands exhibited good to excellent performance in the transition-metal-catalyzed enantioselective construction of quaternary carbon/silicon and multiple stereogenic centers. In the first section, notable examples of the design and synthesis of new chiral ligands by non-covalent interaction-based multisite activation are described. The integrations of axial chirality, atom-centered chirality, and chiral anions and multifunctional groups into a single scaffold are individually highlighted, as represented by Ar-BINMOLs and their derivative ligands, HZNU-Phos, Fei-Phos, and Xing-Phos. In the second, third, and fourth sections, the enantioselective construction of quaternary carbon stereocenters, multiple stereogenic centers, and silicon stereogenic centers using our newly developed chiral ligands is summarized. These sections refer to detailed reaction information in the chiral-ligand-controlled asymmetric catalysis based on the concept of nonequivalent coordination with multisite activation. Accordingly, a wide array of transition metal and main-group metal catalysts has been applied to the enantioselective synthesis of chiral heterocycles, amino acid derivatives, cyclic ketones, alkenes, and organosilicon compounds bearing one to five stereocenters. This Account shows that this new model of multifunctional ligand-controlled catalysts exhibits excellent stereocontrol and catalytic efficiency, especially in a stereodivergent and atom-economical fashion. Furthermore, a brief mechanistic understanding of the origin of enantioselectivity from our newly developed chiral catalyst systems could inspire further development of new ligands and enhancement of enantioselective synthesis by asymmetric metal catalysis.

Enantioselective palladium-catalyzed C(sp2)–C(sp2) σ bond activation of cyclopropenones by merging desymmetrization and (3 + 2) spiroannulation with cyclic 1,3-diketones

“…Encouraged by the initial results, we carried out preliminary and extensive studies with the aid of chiral TADDOL-derived phosphoramidite ligands that were previously employed for asymmetric palladium catalysis in our group. 69 Unfortunately, these reported P-ligands failed to provide the best level of enantioselectivities and yields (see Tables S1–S7 of the ESI † ). After a judicious modification of the chiral ligands and the choice of reaction parameters, the P-ligand L15 was found to be critical for the palladium-catalyzed (3 + 2) spiro-annulation of 1a and 2a in toluene or chlorobenzene at room temperature (87% yield and 92% ee , see entry 1 of Table 1 ).…”

“…Nevertheless, there is no precedent for the palladium-catalyzed enantioselective variant of the carbon-carbon bond functionalization of cyclopropenones involving a sequential C(sp 2 )-C(sp 2 ) bond activation/(3+2) annulation process. Considered the powerful potential of C-C bond activation and chiral ligands for the enantioselective construction of single quaternary stereocenter, 69 we propose a new strategy for the construction of more quaternary stereocenters that can use cyclopropenones as the active species to achieve desymmetrization of bifunctional compounds (Figure 2C). In this regard, one of the potential problems to control the diastereo-and enantioselectivity lies in the precise recognition function of active intermediate of metal catalyst that formed from the oxidative addition of carboncarbon bond of cyclopropenone to metal species, during desymmetrization of the bifunctional groups before it undergoes (3+2) annulation.…”

“…Considered the powerful potential of C–C bond activation and chiral ligands for the enantioselective construction of a single quaternary stereocenter, 69 we propose a new strategy for the construction of more quaternary stereocenters that can use cyclopropenones as the active species to achieve the desymmetrization of bifunctional compounds ( Fig. 2C ).…”

Nickel(0)-catalyzed divergent reactions of silacyclobutanes with internal alkynes

“…The discovery of general and efficient methodologies to approach silicon-containing organic compounds 1 , including chiral silicons 2 – 10 , has attracted great interest. Because these molecules are fundamentally important with a multitude of applications ranging from organic synthesis, materials science to medicinal chemistry 11 – 16 .…”

Catalytic Enantioselective Construction of Chiroptical Boron-Stereogenic Compounds

“…The chirality of molecules plays a significant role in areas such as life science, biology, medicine, and material science, and the presence of a carbon-stereogenic center is the major feature of chirality in organic compounds. Compared to tremendous and extensive investigations on the generation and utilization of a tetrahedral stereogenic carbon atom, the enantiomerism of tetracoordinate main group heteroelements has also attracted considerable interest, and the chemistry of sulfur-, phosphorus-, and silicon- − stereogenic compounds has been studied in the past decades, which has led to their widespread applications in synthetic chemistry, medicinal chemistry, agrochemistry, and material science (Scheme a). Boron, as another important main group element in organic chemistry, usually adopts a trigonal planar configuration with an empty p-orbital .…”