Selective acceleration of disfavored enolate addition reactions by anion-π interactions

Abstract

In chemistry and biology, cation-π interactions contribute significantly to many important transformations. In sharp contrast, reactions accomplished with support from the complementary anion-π interactions are essentially unknown. In this report, we show that anion-π interactions can determine the selectivity of the enolate chemistry of malonate half thioesters. Their addition to enolate acceptors is central in natural product biosynthesis but fails without enzymes because non-productive decarboxylation dominates. The newly designed and synthesized anion-π tweezers invert this selectivity by accelerating the disfavored and decelerating the favored process. The discrimination of anionic tautomers of different planarization and charge delocalization on π-acidic surfaces is expected to account for this intriguing "tortoise-and-hare catalysis." Almost exponentially increasing selectivity with increasing π acidity of the catalyst supports that contributions from anion-π interactions are decisive.

Fig. 1. In nature, carbocation chemistry in the biosynthesis of terpenes and steroids is accomplished with cation–π interactions (red circles indicate the position of π-basic amino-acid residues in the cation–π enzyme for substrate 1). The complementary enolate chemistry in polyketide biosynthesis and the beginning of both pathways fails in solution because decarboxylation of 2 (solid arrows) dominates over enolate addition (dashed arrows). In this report, selective acceleration of this disfavored but relevant process is achieved with anion–π interactions (blue background) and explained with the discrimination between non-planar tautomers (2) and planar tautomers (4/5; BH⁺: protonated base, E = electrophilic carbon).

Fig. 2. Structure of substrates (6–9), favored product f (3), disfavored product d (10), the minimalist bifunctional catalyst 12, anion–π tweezer 13 and control bases 11 and 17.

Fig. 3. (a) Dependence of η^d/f, i.e. the yield η^d of the intrinsically disfavored product (10) divided by η^f of the favored product (3), on the energy of the LUMO of tweezers 13–16 at RT (red, [black circle], □) and 5 °C (blue, ♦) for substrates 6 ([black circle], ♦) and 7 (□) with 8; with exponential curve fit. Controls 11 (△) and 17 (▽) select below E_LUMO = –3.7 eV of π-neutral NDIs. (b) Stepwise oxidation of the core substituents of anion–π tweezers 14 gradually increases the π acidity of the catalyst without global structural changes. All tweezers used are mixtures of stereoisomers (axial chirality, sulfoxides).

Fig. 4. (a) Dependence of the changes in activation energy ΔE_a for substrate 6 for the favored decarboxylation (ΔEfa, ○) and the disfavored addition (to 8, ΔEda, [black circle]) on the π acidity of anion–π tweezers 13–16 (E_LUMO), relative to control 17, at 5 °C, with exponential curve fit (Table 1, entries 10–13). (b) Selective acceleration of a disfavoured reaction: dependence of ΔΔEd–fa, i.e., ΔEda – ΔEfa, for 6 on the π acidity of 13–16 (E_LUMO) compared to control 11 ([black circle], ♦, □) or 17 (X) at RT ([black circle], X, □) and 5 °C (♦) for 6 ([black circle], X, ♦) and 7 (□) with 8, with exponential curve fit (compare Table 1).