Synthesis of Enantioenriched Indolines by a Conjugate Addition/Asymmetric Protonation/Aza-Prins Cascade Reaction.

A conjugate addition/asymmetric protonation/aza-Prins cascade reaction has been developed for the enantioselective synthesis of fused polycyclic indolines. A catalyst system generated from ZrCl4 and 3,3'-dibromo-BINOL enables the synthesis of a range of polycyclic indolines in good yields and with high enantioselectivity. A key finding is the use of TMSCl and 2,6-dibromophenol as a stoichiometric source of HCl to facilitate catalyst turnover. This transformation is the first in which a ZrCl4 ⋅BINOL complex serves as a chiral Lewis-acid-assisted Brønsted acid.

Direct, Enantioselective Synthesis of Pyrroloindolines and Indolines From Simple Indole Derivatives.

The (R)-BINOL•SnCl4-catalyzed formal (3 + 2) cycloaddition between 3-substituted indoles and benzyl 2-trifluoroacetamidoacrylate is a direct, enantioselective method to prepare pyrroloindolines from simple starting materials. However, under the originally disclosed conditions, the pyrroloindolines are formed as mixtures of diastereomers, typically in the range of 3:1 to 5:1 favoring the exo-product. The poor diastereoselectivity detracts from the synthetic utility of the reaction. We report here that use of methyl 2-trifluoroacetamidoacrylate in conjunction with (R)-3,3'-dichloro-BINOL•SnCl4 provides the corresponding pyrroloindolines with improved diastereoselectivity (typically ≥10:1). Guided by mechanistic studies, a one-flask synthesis of enantioenriched indolines by in situ reduction of a persistent iminium ion is also described.

Enantioselective synthesis of pyrroloindolines by a formal [3 + 2] cycloaddition reaction.

(R)-BINOL·SnCl(4) was found to catalyze a formal [3 + 2] cycloaddition reaction between C(3)-substituted indoles and 2-amidoacrylates to provide pyrroloindolines. A variety of pyrroloindolines were prepared with high enantioselectivity in one step from simple precursors. This methodology is expected to facilitate the total synthesis of pyrroloindoline alkaloids, an important class of biologically active natural products.