Organocatalytic Asymmetric Wittig Reactions: Generation of Enantioenriched Axially Chiral Olefins Breaking a Symmetry Plane

Abstract

The first catalytic asymmetric Wittig reaction is presented. Hydrogen-bond donors catalyze the [2+2] cycloaddition reaction between stabilized phosphorus ylides and 4-substituted cyclohexanones, breaking their symmetry plane and furnishing axially chiral olefins with moderate stereoselectivities.Asymmetric organocatalysis has witnessed spectacular advances over the last few years. 1 Transmission of the chiral information from catalyst to substrate has been achieved with high fidelity in an impressive range of chemical transformations. In most cases, the result of these efficient asymmetric protocols is the stereocontrolled formation of a chiral center, typically a tetrahedral carbon atom bearing four different substituents. Also kinetic resolutions, wherein the catalyst distinguishes two enantiomeric substrates and desymmetrization processes, wherein the catalyst recognizes local asymmetry, discriminating two enantiotopic moieties, have been studied in detail. In these latter cases, substrate/product asymmetry is again mostly due to tetrahedral carbon atoms. However, chirality is not restricted to the presence of a chiral center. 2 Compounds featuring a chirality axis or plane are in fact of tremendous importance. Axial/planar chirality is showcased in many natural compounds, 3 ligands or catalysts for asymmetric synthesis, 4 synthetic intermediates, 5 and molecular switches/motors. 6 Use of organocatalysis for the stereocontrolled generation of chiral axes or planes has, however, been largely ignored. 7Herein, we present the first example of a catalytic asymmetric Wittig reaction (Scheme 1). The reaction furnishes enantioenriched axially chiral olefins 3 and is catalyzed by hydrogen-bond donors. The Wittig 8 olefination between carbonyl compounds and phosphorus ylides, together with its related counterparts (Horner 9 involving phosphine oxides and Horner-Wadsworth-Emmons 10 involving phosphonates), is amongst the most venerable transformations of organic chemistry. These powerful methods for C=C bond formation have found ubiquitous applications in organic synthesis, 11 including preparations of axially chiral olefins. 12 Scheme 1 Asymmetric olefination of ketones 1Olefination of a ketone featuring a symmetry plane but lacking a symmetry axis leads in fact to an axially chiral alkene, as exemplified in Scheme 1 for the benchmark reaction for asymmetric Wittig-type processes, with 4-substituted cyclohexanones 1. 13 Stereoselectivity in this class of symmetry-breaking transformations has been achieved in the past using Wittig and related olefinations, exploiting stoichiometric chiral auxiliaries and reagents. 13,14 A single example instead made use of a chiral catalyst. 15,16 Horner-Wadsworth-Emmons olefination of 4-tert-butylcyclohexanone (1a), performed under phase-transfercatalysis conditions, gave the corresponding olefin in only moderate enantioselectivity (<57% ee). We tentatively ascribed this moderate stereocontrol to the reversibility of the first step in Horner-Wadsworth-Emmons reactions. 11a We thus set...

Progress on the Enantioselective Synthesis of Axially Chiral Cycloalkylidenes

“…In 2011, Bernardi and co-workers presented the first catalytic asymmetric Wittig reaction by using a chiral hydrogen-bond donor catalyst (Scheme 17). 30 (R,R)-Taddol was determined as the most effective The use of a highly reactive Wittig reagent is critical to the success of this reaction. The H-bond donor catalyst stabilized the transition-state and controlled the stereochemical outcome.…”

Axial Chirality in Alkylidene‐Cyclic Molecules

“…In addition to HWE reactions, Wittig reaction is another dependable synthetic method for the olefination of carbonyl compounds. In 2011, Bernardi and colleagues reported an organocatalyzed asymmetric Wittig reaction of 4‐substituted cyclohexanones with stabilized phosphorus ylides to synthesize axially chiral olefins (Scheme 1b) [14] . In this reaction, the chiral catalyst 2 or 3 served as hydrogen‐bond donors and played an important role in controlling the stereoselective [2+2] cycloaddition.…”

“…In 2011, Bernardi and colleagues reported an organocatalyzed asymmetric Wittig reaction of 4-substituted cyclohexanones with stabilized phosphorus ylides to synthesize axially chiral olefins (Scheme 1b). [14] In this reaction, the chiral catalyst 2 or 3 served as hydrogen-bond donors and played an important role in controlling the stereoselective [2 + 2] cycloaddition. Upon elimination process, the central chirality transferred to axial chirality with the simultaneous generation of related axially chiral frameworks in moderate enantioselectivity.…”

Stable Axially Chiral Cyclohexylidenes from Catalytic Asymmetric Knoevenagel Condensation

“…In 1998, Arai and Shioiri reported the first catalytic asymmetric HWE reaction of 4‐substituted cyclohexanones with phosphonates using a cinchonine‐derived chiral quaternary ammonium salt as a phase‐transfer catalyst, [12c] however, only moderate enantioselectivity was obtained. Bernardi demonstrated the first catalytic asymmetric Wittig reaction of 4‐substituted cyclohexanones with phosphorus ylides employing a chiral thiourea or TADDOL catalyst, [13c] providing axially chiral olefins with up to 75 % ee. Recently, Jacobsen achieved highly enantioenriched axially chiral alkenes by developing an efficient potassium−isothiourea−boronate catalyst to promote asymmetric Wittig olefinations of 4‐substituted cyclohexanones with non‐stabilized phosphorus ylides [15] .…”