Organocatalytic Synthesis of Triflones Bearing Two Non‐Adjacent Stereogenic Centers

Abstract

Trifluoromethylsulfones (triflones) are useful compounds for synthesis and beyond. Yet, methods to access chiral triflones are scarce. Here, we present a mild and efficient organocatalytic method for the stereoselective synthesis of chiral triflones using α‐aryl vinyl triflones, building blocks previously unexplored in asymmetric synthesis. The peptide‐catalyzed reaction gives rise to a broad range of γ‐triflylaldehydes with two non‐adjacent stereogenic centers in high yields and stereoselectivities. A catalyst‐controlled stereoselective protonation following a C−C bond formation is key to control over the absolute and relative configuration. Straightforward derivatization of the products into, e.g., disubstituted δ‐sultones, γ‐lactones, and pyrrolidine heterocycles highlights the synthetic versatility of the products.

Machine Learning to Develop Peptide Catalysts─Successes, Limitations, and Opportunities

“…18 Examples include aldol 19 and conjugate addition reactions with a diverse range of electrophiles, including nitroolefins, 18,20−25 maleimides, 26,27 dicyanoolefins, 28 allenamides, 29 and vinyl triflones. 30 These conventional catalyst development studies were guided by detailed conformational and mechanistic studies that revealed, for example, the importance of a balance between flexibility and rigidity, 7 the trans/cis ratio of the tertiary amide, 18,31 endo-N-pyramidalization of the enamine intermediate, 32,33 and the role of an internal proton donor for the performance of the tripeptide catalysts. 34 Among the many Pro-Pro-Xaa catalysts identified for different reactions, H-DPro-Pro-Glu-NH 2 features a rigid ground state, 7 but all others (e.g., H-Pro-Pro-Asp-NH 2 , H-DPro-Pro-Gln-OH, H-DPro-Pro-Gln-OH) are more flexible.…”

“…These catalysts feature a single well-defined conformation. This excellent match between the mechanism-guided and modeling-guided results is striking. In prior catalyst optimization campaigns that used mechanism-based considerations, distinctly different Pro-Pro-Xaa catalysts emerged. ,− , These reactions include aldol and conjugate additions to vinyl triflones, maleimides, , or disubstituted nitroolefins. , These “manually” optimized catalysts afford the addition products with high stereoselectivities (typically 90–99% ee) and feature a residue other than Glu in the Xaa position, varied absolute configurations at the α-carbons of the amino acids, alternative coordinating moieties to COOH, substituted Pro residues, or a combination of those features. These expert-knowledge-guided catalyst optimizations built on the common Pro-Pro-Xaa scaffold.…”

Pseudo-Diastereodivergent Synthesis of Chiral Fluorenes Bearing Bis-1,3-Nonadjacent Stereogenic Centers via Organocatalytic Desymmetrization of meso-Epoxides

“…Taking inspiration from these elegant studies, − we designed a series of 9-fluorenyl-based meso -epoxides as a platform to investigate the feasibility of chiral Brønsted acid catalyzed desymmetrization reactions of both stereoisomers of epoxides (Scheme B, right). Compared to previous studies, , our design offers unique features.…”

“…More recently, He and Zhang, along with their co-workers, have independently reported on the efficient protocol for enantio- and diastereodivergent synthesis of 1,3-nonadjacent stereocenters bearing both a stereogenic center and a stereogenic axis via the synergistic Cu/Pd dual catalysis (Scheme A, B) . However, all of the aforementioned accomplishments have resulted in chiral molecules bearing stereogenic elements in a mono-1,3-nonadjacent relationship . To our knowledge, the catalytic asymmetric stereodivergent construction of bis-1,3-nonadjacent stereocenters has yet to be realized (Scheme A, C) .…”

Quantitative and Nondestructive Colorimetric Amine Detection Method for the Solid-Phase Peptide Synthesis as an Alternative to the Kaiser Test

“…Solid-phase peptide synthesis (SPPS) is a widely used method for chemical peptide synthesis. , To monitor the completion of peptide coupling reactions, the Kaiser test based on the ninhydrin reaction has been utilized to visualize unreacted free amino groups on the resin (Figure a) . However, the Kaiser test has several disadvantages: (1) some amino acids, such as proline , and N -alkylated , and α,α-disubstituted , α-amino acids, are not detectable; (2) a small amount of resin must be aliquoted from a peptide synthesis vessel for the test; (3) toxic KCN is necessary as a reductant; (4) quantitative analysis is impractical; etc. Aliquoting resin is a common drawback for reaction-based amine detection methods. , To address these issues, nondestructive one-pot amine detection methods have been developed .…”