Highly diastereoselective synthesis of 3-hydroxy-2,2,3-trisubstituted indolines via intramolecular trapping of ammonium ylides with ketones

Carbon-heteroatom bonds (C-X) are ubiquitous and are among the most reactive components of organic compounds. Therefore investigations of the construction of C-X bonds are fundamental and vibrant fields in organic chemistry. Transition-metal-catalyzed heteroatom-hydrogen bond (X-H) insertions via a metal carbene or carbenoid intermediate represent one of the most efficient approaches to form C-X bonds. Because of the availability of substrates, neutral and mild reaction conditions, and high reactivity of these transformations, researchers have widely applied transition-metal-catalyzed X-H insertions in organic synthesis. Researchers have developed a variety of rhodium-catalyzed asymmetric C-H insertion reactions with high to excellent enantioselectivities for a wide range of substrates. However, at the time that we launched our research, very few highly enantioselective X-H insertions had been documented primarily because of a lack of efficient chiral catalysts and indistinct insertion mechanisms. In this Account, we describe our recent studies of copper- and iron-catalyzed asymmetric X-H insertion reactions by using chiral spiro-bisoxazoline and diimine ligands. The copper complexes of chiral spiro-bisoxazoline ligands proved to be highly enantioselective catalysts for N-H insertions of α-diazoesters into anilines, O-H insertions of α-diazoesters into phenols and water, O-H insertions of α-diazophosphonates into alcohols, and S-H insertions of α-diazoesters into mercaptans. The iron complexes of chiral spiro-bisoxazoline ligands afforded the O-H insertion of α-diazoesters into alcohols and water with unprecedented enantioselectivities. The copper complexes of chiral spiro-diimine ligands exhibited excellent reactivity and enantioselectivity in the Si-H insertion of α-diazoacetates into a wide range of silanes. These transition-metal-catalyzed X-H insertions have many potential applications in organic synthesis because the insertion products, including chiral α-aminoesters, α-hydroxyesters, α-hydroxyphosphonates, α-mercaptoesters, and α-silyl esters, are important building blocks for the synthesis of biologically active compounds. The electronic properties of α-diazoesters and anilines markedly affected the enantioselectivity of N-H insertion reaction, which supports a stepwise ylide insertion mechanism. A novel binuclear spiro copper complex was isolated and fully characterized using X-ray diffraction analysis and ESI-MS analysis. The positive nonlinear effect indicated that binuclear copper complexes were the catalytically active species. The 14-electron copper centers, trans coordination model, perfect C(2)-symmetric chiral pocket, and Cu-Cu interaction facilitate the performance of the chiral spiro catalysts in X-H insertion reactions.

Multicomponent reactions (MCRs) are one-pot processes in which three or more starting materials form a product that incorporates the structural features of each reagent. These reactions date back to the mid-19th century, when Strecker first prepared α-aminonitriles through the condensation of aldehydes with ammonia and hydrogen cyanide. In addition to affording products with structural complexity and diversity, MCRs offer the advantages of simplicity, synthetic efficiency, synthetic convergence, and atom economy. Therefore, they have played an important role in modern synthetic organic chemistry and drug-discovery research. The irreversible trapping of an active intermediate generated from two components by a third one offers an effective way to discover novel MCRs. In cases where the intermediate from the first two components is reactive enough to generate a two-component byproduct, it becomes challenging to control of the chemoselectivity of these MCRs over the side reaction. For example, researchers had expected that ammonium/oxonium ylides, high energy intermediates that have acidic protons and basic carbanions attached to adjacent carbons, would be too reactive to be intercepted by external electrophiles. Instead, a very fast 1,2-proton transfer would neutralize the charge separation, resulting in a stable N-H/O-H insertion product. In this Account, we present our efforts toward the development of novel MCRs via trapping of the active ammonium/oxonium ylide intermediates with a number of electrophiles. In these reactions, a "delayed proton transfer" that occurs after the trapping process produces novel multicomponent coupling products. Thus, transition-metal-catalyzed MCRs of diazocarbonyl compounds, anilines/alcohols, and electrophiles efficiently afford polyfunctional molecules such as α-amino-β-hydroxy acids, α-hydroxy-β-amino acids, α,β-diamino acids, and α,β-dihydroxy acid derivatives. We have also applied a cooperative catalysis strategy to some of these MCRs leading to reactions with high chemo-, diastereo-, and enantioselectivity. These MCRs also provide solid experimental evidence for the existence of the active protic onium ylides.