Stereocenter

Organic chemistry

Combinatorial chemistry

Desymmetrization

Stereochemistry

Enantioselective synthesis

Catalysis

Nucleophile

Chemistry

Isatin

Oxindole

Accounts of Chemical Research

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 tandem sequences that allow the facile synthesis of 3,3-disubstituted oxindoles from simple starting materials in a one-pot operation, including a tandem Morita-Baylis-Hillman/bromination/[3 + 2] annulation sequence, a hydrogenation/ketimine formation/asymmetric 6π electrocyclization sequence, a C-H functionalization/Michael addition or amination sequence, and an aza-Wittig/Strecker sequence. We designed oxindole-based diynes to realize a highly enantioselective Cu-catalyzed alkyne-azide cycloaddition (CuAAC), outlining the desymmetrization of prochiral diynes as an effective strategy to exploit asymmetric CuAAC. This Account focuses on the synthetic methodologies developed in our group for the catalytic enantioselective synthesis of 3,3-disubstituted oxindoles and provides an overview of our research on the design, development, and applications of these methods that will provide useful insights for the exploration of new reactions.

Development of Synthetic Methodologies via Catalytic Enantioselective Synthesis of 3,3-Disubstituted Oxindoles