Conformational Control of Chiral Amido-Thiourea Catalysts Enables Improved Activity and Enantioselectivity

Abstract

While aryl pyrrolidinoamido thioureas derived from α-amino acids are effective catalysts in a number of asymmetric transformations, they exist as mixtures of slowly interconverting amide rotamers. Herein, the compromising role of amide bond isomerism is analyzed experimentally and computationally. A modified catalyst structure that exists almost exclusively as a single amide rotamer is introduced. This modification is shown to result in improved reactivity and enantioselectivity by minimizing competing reaction pathways.

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

“…Accordingly, the 2-arylpyrrolidine was alkylated to constrain the amide in exclusively the ( Z )-rotameric form, thereby positioning the aryl group proximal to the H-bond donor active site (see Supporting Information for NMR and crystallographic characterization). 36 Catalysts bearing this constrained amide ( 4 , 5 , and 6 ) proved reactive and displayed improved enantioselectivity (entries 3–7). Complementary tuning of the arylpyrrole moiety revealed that catalysts 5b and 6b enable access to product 2a in high enantiomeric excess (entries 5 and 7), even with reduced catalyst loading (entry 8).…”

Non-Covalent Interactions in Enantioselective Organocatalysis: Theoretical and Mechanistic Studies of Reactions Mediated by Dual H-Bond Donors, Bifunctional Squaramides, Thioureas and Related Catalysts

“…Although preliminary DFT analysis did not distinguish whether catalyst activation proceeds by a 4H-or a 2H-Cl − -binding geometry, i.e., via I or II (Figure 48), in the solid-state, a 4H-geometry was observed, a fact, which guided the choices of structural changes [90,91]. A methyl substituent, shown previously to minimize competing reaction pathways and improve reactivity and the ees, was introduced [94]. The bisthioureas were also linked in a way that disfavored aggregation while still resembling the structures of the untethered monomers.…”

Halides as versatile anions in asymmetric anion-binding organocatalysis

“…These findings proved to be decisive in the development of new and more efficient anion-binding catalysts. By introducing a methyl group (R = Me) into the pyrrolidine moiety of the initial catalyst design, the amide is conformationally constricted to the ( Z )-rotamer [ 75 ]. Consequently, improved enantioselectivity and catalytic efficiency could be observed (>95% conv., 97% ee).…”