PerspectiveOrganic Chemistry

Lewis acids turn unreactive substrates into pure enantiomers

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Science  26 Feb 2016:
Vol. 351, Issue 6276, pp. 918-919
DOI: 10.1126/science.aaf2577

Asymmetric synthesis, reactions that produce a high proportion of one enantiomer of a chiral compound relatively to the other, are of ever-growing importance, particularly for creating pure pharmaceuticals. Asymmetric catalysis (1) uses a recyclable or regenerated chiral molecule to perform these reactions, but achieving high yields can be challenging if the substrate is relatively unreactive. On page 949 of this issue, Gatzenmeier et al. (2) report a highly efficient method that relies on an in situ–generated catalyst to produce complex structures in excellent yields of almost pure enantiomers from low-reactivity starting materials.

Chiral catalysts interact with substrates to create an asymmetric environment around a newly formed chiral center. Among strategies used by organic chemists to organize this interaction, Lewis acid organocatalysis, which uses chiral electron-deficient organic molecules (neutral or cationic) to address specific functional groups in substrates, has gained considerable attention because of their environmental advantages over traditional metal-centered catalysts. Nevertheless, the benefits of these organic catalysts have been tempered by the lack of sufficiently strong Lewis acids to activate unreactive substrates and by the need for large catalyst loadings. Silicon-based catalysts, whose Lewis acidity can be easily enhanced by the introduction of less Lewis basic counteranions, have been routinely used as organic Lewis acids (3, 4). However, despite their high catalytic activity, few chiral silyl cationic catalysts (combining one or more chiral groups and a strong activation capacity in a single entity) have been developed. The emerging concept of asymmetric counteranion-directed catalysis (ACDC), a type of catalytic system that uses an enantiopure anion to induce enantioselectivity in a reaction arising from a cationic intermediate (57), allows both functions of asymmetric catalysis to be performed with separate partners, so the reactivity of each is easier to tune.

ACDC applied to the Diels–Alder reaction.

Based on their previous work (A), Gatzenmeier et al. activated cinnamates via silylium-ACDC (B) using an in situ–generated catalyst (C).


In 2009, List and co-workers (8) disclosed a highly enantioselective, silyl cation–catalyzed Mukaiyama aldol reaction that relies solely on the chirality of an anionic counterion (a disulfonimide anion) (see the figure, panel A) to induce asymmetry. Interestingly, extremely low catalyst loadings sufficed, thus demonstrating high catalytic performance of these new Lewis acids. However, in the Mukaiyama aldol reaction, preactivation of one substrate under the form of an O-silylated oxonium is required (see the figure, panel A), adding an extra step to the overall process.

Gatzenmeier et al. considered whether this new mode of chiral anion–directed asymmetric silyloxonium activation could be expanded to a more challenging reaction in which the silylated reagents would not be required. In this context, the Diels–Alder reaction—a [4π + 2π] cycloaddition between a diene and a dienophile for the construction of six-membered carbocycles—was selected. Despite numerous advances in enantioselective Diels–Alder reactions, some dienophiles remain poorly reactive toward this transformation, such as α,β-unsaturated esters called cinnamates (9).

The only previous example using cinnamates, reported by Ryu and Corey (10), required very high catalyst loadings. Based on their work, Gatzenmeier et al. performed the silylation of this unreactive α,β-unsaturated ester in situ to provide a cationic, more reactive dienophile. An enantiopure anion could then ion-pair with this cationic dienophile and create an asymmetric environment for the Diels–Alder reaction to take place (see the figure, panels B and C). The silyl-transfer reagent needs to be regenerated at the end of the process in order for it to be part of the catalytic system.

Chiral disulfonimides were first examined as chiral counterion precursors in this reaction but had mediocre activity. Considering that the nature of counteranions strongly influences Lewis acidities of the cationic partners, Gatzenmeier et al. decided to investigate the Diels–Alder reaction with carbanions, which would be expected to form a combination of greater overall Lewis acidity. To evaluate those carbon-centered anions, they designed a range of enantiopure C–H acid precatalysts that would react in situ with the silyl-transfer reagent to generate an ion pair as a catalyst (see the figure, panels B and C). With respect to the substrate scope, Gatzenmeier et al. achieved impressive stereoinductions (up to 97:3 enantiomer ratio) and excellent yields in such a transformation. The protocol can be applied to a variety of cinnamates, including hetero-aromatic substrates, showing its wide applicability. Furthermore, this strategy cleverly combines the benefits of silylated compounds (nontoxic and air and water stable) with exceptionally low catalyst loadings (only 1 mole percent).

The work of Gatzenmeier et al. allows normally unreactive cinnamates to undergo Diels–Alder cyclization. This method of activation based on the tunability of Lewis acids could give rise to extensive applications in any challenging Lewis-acid–catalyzed reaction. More broadly, through its C–H acidic function, this new catalyst could turn into an effective alternative in reactions catalyzed by Brønsted acids.


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