Generality-oriented optimization of enantioselective aminoxyl radical catalysis

Abstract

Catalytic enantioselective methods that are generally applicable to a broad range of substrates are rare. We report a strategy for the oxidative desymmetrization of meso-diols predicated on a nontraditional catalyst optimization protocol by using a panel of screening substrates rather than a singular model substrate. Critical to this approach was rational modulation of a peptide sequence in the catalyst incorporating a distinct aminoxyl-based active residue. A general catalyst emerged, providing high selectivity in the delivery of enantioenriched lactones across a broad range of diols, while also achieving up to ~100,000 turnovers.

Figure 1.

A generality-oriented optimization strategy for enantioselective catalysis with peptidyl aminoxyl radicals. (A) Optimization paradigms in asymmetric catalysis: traditional vs generality-oriented strategies. (B) Precedents for chiral aminoxyl and oxoammonium catalysts (12, 19, 20, 23). (C) This work: A modular, small-peptide-based platform for aminoxyl asymmetric catalysis. Azc-OMe was accessed in 7 steps with a single chromatographic separation.

Figure 2.

Generality-oriented optimization through combinatorial screening of catalysts with a substrate library and iterative modification of catalyst structure. (A) Chiral lactone formation via meso-diol desymmetrization. (B) Chemical space of meso-1,4-diols defined using Mordred descriptors and a uniform manifold approximation and projection (UMAP) with molecular fingerprints of commercial meso-1,4-diols from a Reaxys^® search. (C) Meso-diol substrates: optimization set. (D) catalyst structure optimization. (E) optimization data and box and whisker chart for the calculated ΔΔG^‡ for the optimization data (F) Crystal structures of peptides P3b and P7.

Figure 3.

Substrate scope. Absolute stereochemistry was assigned by analogy to L1, L4, and L6. *0.001 mol% P7, 96 h, –50 °C, then 2 mol% ACT, 0.3 equiv TCCA, r.t., 6 h. ^†Isolated as the methyl ester after SiO₂ catalyzed methanolysis. ^‡After trituration with pentane. ^§10 mol% P7.

Figure 4.

Mechanistic analysis. (A) Basis for mechanistic model. (B) Intermolecular competition studies. (C) Featurization of products (1,3-diols S23 and S24 were omitted from the analysis as they do not form lactones upon oxidation). For discussion of L14 as a false positive, see Supplementary Materials.