This Review summarizes the advances in the construction of all-carbon quaternary stereocenters via catalytic enantioselective desymmetrization of prochiral and meso-compounds, highlights the power and potential of this strategy in the total synthesis of natural products and biologically active compounds, and outlines the synthetic opportunities still available.

3,3-Disubstituted oxindoles are widely distributed in natural products, drugs, and pharmaceutically active compounds. The absolute configuration and the substituents on the fully substituted C3 stereocenter of the oxindole often significantly influence the biological activity. Therefore, tremendous efforts have made to develop catalytic enantioselective syntheses of this prominent structural motif. Research in this area is further fueled by the ever-increasing demand for modern probe- and drug-discovery programs for synthetic libraries of chiral compounds that are derived from privileged scaffolds with high structural diversity. Notably, the efficient construction of fully substituted C3 stereocenters of oxindole, tetrasubstituted or all-carbon quaternary, spirocyclic or not, also becomes a test ground for new synthetic methodologies. We have been engaged in developing efficient methods for diversity-oriented synthesis of chiral 3,3-disubstituted oxindoles from readily available starting materials. We have systematically developed catalytic enantioselective methods to prepare 3-substituted 3-hydroxyoxindoles, 3-aminooxindoles, and 3-thiooxindoles, quaternary oxindoles, and spirocyclic oxindoles. These protocols can be classified into six approaches: (1) enantioselective addition of nucleophiles to isatins or isatin ketimines; (2) unprotected 3-substituted oxindoles as nucleophiles; (3) functionalization of oxindole-derived tetrasubstituted alkenes; (4) desymmetrization of oxindole-based diynes; (5) spirocyclopropyl oxindoles as donor-acceptor (D-A) cyclopropanes; and (6) elaboration of diazooxindoles. By the use of these methods, chiral oxindoles with rich structural diversity are readily accessed with high to excellent enantioselectivity. Some methods have been used for the enantioselective formal or total synthesis of natural products, bioactive compounds, or their analogues. On the basis of these studies, we developed synthetic methodologies that have potential application. We designed phosphoramide-based bifunctional catalysts for the efficient construction of quaternary oxindoles: a cinchona-alkaloid-derived phosphoramide for the Michael addition of unprotected 3-substituted oxindoles to nitroolefins with broad substrate scope and a chiral 1,2-cyclohexanediamine-derived bifunctional phosphoramide for the activation of fluorinated enol silyl ethers for the addition to isatylidene malononitrile. The phosphoramide-based catalysts achieved better enantiofacial control than the analogous H-bond-donor-derived catalysts in these reactions, suggesting the potential of the former in new chiral catalyst development. We identified chiral Au(I) and Hg(II) catalysts for olefin cyclopropanation of diazooxindoles. We further disclosed the effective activation of spirocyclopropyl oxindoles by using electron-withdrawing N-protecting groups for enantioselective [3 + 3] cycloaddition, offering the promise of constructing a diverse range of spirocyclic oxindoles by the use of such monoactivated D-A cyclopropanes. We developed t...

The catalytic enantioselective assembly of spirocyclic molecules featuring a spiro quaternary carbon stereocenter is currently of great interest because such privileged 3D structures are widely present in natural products that exhibit a broad spectrum of biological and pharmacological activities. This review summarizes the advances based on six major synthetic strategies and showcases the reaction mechanisms in detail. The advantages and limitations of each synthetic strategy are presented, and the remaining synthetic opportunities are outlined.

A spiroketal bisphosphine (SKP) derived chiral digold complex is identified as a powerful catalyst for the highly diastereo- and enantioselective synthesis of spirocyclopropyloxindoles from diazooxindoles and a broad range of alkenes, including both cis and trans 1,2-disubstituted alkenes.

We report a highly stereoselective synthesis of all-carbon or fluorinated tetrasubstituted alkenes from diazo reagents and fluorinated enol silyl ethers, using C-F bond as a synthetic handle. Cationic Au catalysis plays a key role in this reaction. Remarkable fluorine effects on the reactivity and selectivity was also observed.

It is reported for the first time that Hg(II) can catalyze the cyclopropanation of diazo reagents and alkenes, which contributes to the unprecedented highly diastereo- and enantioselective synthesis of spirocyclopropyloxindoles.

Phosphoranes 2 are identified as a class of effective Lewis bases to activate chiral (salen)AlCl complex 1 to enhance its electrophilicity. Accordingly, a three-component catalyst system consisting of complex 1, phosphorane 2e, and Ph3PO is developed as a powerful tool for asymmetric ketone cyanosilylation. In particular, an unprecedented highly enantioselective cyanosilylation of linear aliphatic ketones is achieved. A tandem Wittig-cyanosilylation sequence starting from phosphorane 2a and enals 10 is further achieved, which internally utilizes the Ph3PO byproduct and remaining phosphorane 2a as cocatalysts for cyanosilylation of α,β,γ,δ-unsaturated enones, providing atom-efficient access to valuable chiral conjugated dienes and enynes. The high efficiency of the cyanosilylation originates from orthogonal activation of both (salen)AlCl complex 1 and cyanotrimethylsilane by the phosphorane and Ph3PO, respectively. This mechanistic insight is supported by NMR, MS, and ReactIR analyses and DFT calculations. Furthermore, the formation of charged complexes through the activation of chiral complex 1 by phosphorane 2a is confirmed by electrical conductivity experiments.

Recent progress in asymmetric catalysis using chiral only-at-metal complexes is reviewed, with emphasis on Ir(iii) and Rh(iii) systems.