Synergistic Ion-Binding Catalysis Demonstrated via an Enantioselective, Catalytic [2,3]-Wittig Rearrangement

Abstract

Sigmatropic rearrangements number among the most powerful complexity-building transformations in organic synthesis but have remained largely insensitive to enantioselective catalysis due to the diffuse nature of their transition structures. Here, we describe a synergistic ion-binding strategy for asymmetric catalysis of anionic sigmatropic rearrangements. This approach is demonstrated with the enantioselective [2,3]-Wittig rearrangement of α-allyloxy carbonyl compounds to afford highly enantioenriched homoallylic alcohol products. Chiral thiourea catalysts are shown to engage reactive anions and their countercations through a cooperative set of attractive, noncovalent interactions. Catalyst structure–reactivity–selectivity relationship studies and computational analyses provide insight into catalyst–substrate interactions responsible for enantioinduction and allude to the potential generality of this catalytic strategy.

Enantioselective Catalysis of an Anionic Oxy‐Cope Rearrangement Enabled by Synergistic Ion Binding

“…[37,38] An initial survey was conducted in dichloromethane at ambient temperature (~23°C) by varying the Brønsted base promoter employed in conjunction with thiourea catalyst 3 b (Scheme 2; Table 1); the latter had been identified as optimal in the enantioselective [2,3]-Wittig rearrangement reported previously. [28] Very low levels of substrate consumption occurred in the absence of base ( Table 1, entry 1). Strong bases, such as sodium hydride and potassium tert-butoxide, promoted substrate decomposition to numerous, unidentified products (entries 2-4).…”

“…Catalysts 3 a, 3 b, and 4 a were prepared as reported previously. [28] Ureas 7, 8, 10, and 11 were synthesized through the general procedure described below (Scheme 8). Fragments 21 and 22 were prepared as reported previously, [62] and spectral data were in agreement with the published values.…”

“…The importance of electrostatic interactions in modulating reactivity and selectivity in both enzymes [23] and abiological catalyst systems is well appreciated. [24][25][26][27][28] Recently, we reported a synergistic ion-binding strategy for enantioselective catalysis of the [2,3]-Wittig rearrangement. [28] In this system, a polyfunctional chiral thiourea catalyst simultaneously engages both the reactive anion and its cesium countercation to promote stereoselectivity-determining rearrangement.…”

“…[24][25][26][27][28] Recently, we reported a synergistic ion-binding strategy for enantioselective catalysis of the [2,3]-Wittig rearrangement. [28] In this system, a polyfunctional chiral thiourea catalyst simultaneously engages both the reactive anion and its cesium countercation to promote stereoselectivity-determining rearrangement. On the basis of experimental and computational results, enantioinduction was attributed to selective transition-state attraction between Cs + and the migrating allyl anion.…”

Phosphite‐Catalyzed C−H Allylation of Azaarenes via an Enantioselective [2,3]‐Aza‐Wittig Rearrangement

“…Guided by previous reports of the effect of the countercation on stereoselective anionic [2,3]-Wittig rearrangements, [13] we carried out as ystematic screening of countercations of the base.T he use of KHMDS led to as ignificant drop in yield and enantioselectivity (entry 8). Base strength also impacted the efficiency of the reaction, with stronger bases such as LDAand n-BuLi leading to significant drops in both yields and enantioselection (entries 9a nd 10).…”