Stereodivergent Nucleophilic Additions to Racemic β-Oxo Acid Derivatives: Fast Addition Outcompetes Stereoconvergence in the Archetypal Configurationally Unstable Electrophile

Abstract

Additions of carbon nucleophiles to racemic α-stereogenic β-oxo acid derivatives that deliver enantiomerically enriched tertiary alcohols are valuable, but uncommon. This article describes stereodivergent Cu-catalyzed borylative cyclizations of racemic β-oxo acid derivatives bearing tethered pro-nucleophilic olefins to deliver highly functionalized cyclopentanols containing four contiguous stereogenic centers. The reported protocol is applicable to a range of β-oxo acid derivatives, and the diastereomeric products are readily isolable by typical chromatographic techniques. α-Stereogenic-β-keto esters are typically thought to have extreme or spontaneous configurational fragility, but mechanistic studies for this system reveal an unusual scenario wherein productive catalysis occurs on the same time scale as background substrate racemization and completely outcompetes on-cycle epimerization, even under the basic conditions of the reaction.

Mechanism of a Dually Catalyzed Enantioselective Oxa-Pictet–Spengler Reaction and the Development of a Stereodivergent Variant

“…This scenario is distinct from a classic kinetic resolution in which one enantiomer reacts significantly faster than the other . While examples of such processes have been reported, they remain relatively rare despite their significant potential utility. , The possibility of developing a stereodivergent oxa-Pictet–Spengler reaction with racemic tryptophols was evaluated with (±)- 7a , a material that can be readily prepared in one step from indole and the appropriate epoxide (Table ). Catalyst 1b provided a promising result, with both diastereomers of product 8a being obtained with significant ee (entry 1).…”

Enantioconvergent iso-Pictet-Spengler Reactions: Organocatalytic Synthesis of Chiral Tetrahydro-γ-carbolines

“…We envisioned that a stereoconvergent iso -Pictet-Spengler reaction could be a valuable platform for the synthesis of versatile THγCs from readily accessible ß-dicarbonyls. Stereoconvergent additions to chiral racemic ß-keto and ß-imino acid derivatives via dynamic kinetic resolution have previously proven to be effective in synthesizing valuable alcohols and amines under a wide range of conditions. − Nonhydrogenative stereoconvergent additions − to ß-imino acid derivatives, such as the projected iso -Pictet-Spengler reaction, are typically accomplished by treating the ß-dicarbonyl (or ß-dicarbonyl surrogate) with a primary amine tethered to a nucleophile under Brønsted acid catalysis (Scheme a). − Following condensation, intramolecular cyclization or addition provides the chiral secondary or tertiary amine. Reactions of ß-imino acid derivatives are underexplored compared to their ß-keto counterparts; we hypothesize that they hold promise for future reaction development.…”

Desymmetrization of Cyclohexadienones Containing a Quaternary γ-Carbon Atom by Conjugate Addition of Boron Nucleophiles

“…α-Chiral boron compounds are key intermediates in synthetic organic chemistry, largely because carbon–boron bonds can be readily converted into carbon–oxygen and carbon–nitrogen as well as carbon–carbon bonds without loss of the stereochemical information . Their synthesis can be achieved by various strategies, , and among these, the copper-catalyzed enantioselective conjugate addition of boron nucleophiles to α,β -unsaturated carbonyl compounds has emerged as particularly effective in recent years. , Following the pioneering work of Lee and Yun in 2008, this method was expanded to a variety of Michael acceptors, including enones, esters, aldehydes, and amides, as well as other electron-deficient alkenes, such as alkenyl-substituted sulfones and phosphine oxides (Scheme A). However, nucleophilic borylation of sterically hindered π systems, particularly in a neopentylic position, is still rare, except for a few isolated examples (Scheme B). In 2009, Feng and Yun found that a γ,γ -disubstituted cyclohexenone was too unreactive .…”