Stereoselective Organocatalyzed Synthesis of α‐Fluorinated β‐Amino Thioesters and Their Application in Peptide Synthesis

Abstract

a-Fluorinated b-amino thioesters were obtained in high yields and stereoselectivities by organocatalyzed addition reactions of a-fluorinated monothiomalonates (F-MTMs) to N-Cbz-and N-Boc-protected imines. The transformation requires catalyst loadings of only 1 mol % and proceeds under mild reaction conditions. The obtained addition products were readily used for coupling-reagent-free peptide synthesis in solution and on solid phase. The a-fluoro-b-(carb)amido moiety showed distinct conformational preferences, as determined by crystal structure and NMR spectroscopic analysis.

Modern Approaches for Asymmetric Construction of Carbon–Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and Pharmaceutical Needs

“…In 2016, Wennemers and co-authors reported an asymmetric organocatalyzed Mannich addition reaction of imines 267 with α -fluorinated monothiomalonates 266 as nucleophiles (Scheme 107). 292 The re action used only 1 mol % of bifunctional cinchona alkaloid–thiourea C60 as a chiral organocatalyst, which catalyzed the reaction very well, affording the corresponding α -fluorinated β -amino thioesters 268 in excellent yields (80−99%), high diastereo (4:1 → 20:1 dr) and enantioselectivities (91−99.9% ee). The protecting group on the amino group showed obvious effect on the chemical yields, and usually the Cbz-protect imines affords obviously higher yields.…”

Synthesis of Monothiomalonates – Versatile Thioester Enolate Equivalents for C–C Bond Formations

“…Among the most straightforward methods are C–C bond formations that utilize thioester enolates . [ ][ ] The formation of thioester enolates under mild conditions is not trivial due to the comparatively low acidity of the H‐atom at the α ‐carbon (C( α )) combined with the reactivity of thioesters towards nucleophilic bases . Organocatalytic methods that use surrogates of thioester enolates have therefore become popular for the stereoselective incorporation of thioester moieties into organic molecules.…”

“…Organocatalytic methods that use surrogates of thioester enolates have therefore become popular for the stereoselective incorporation of thioester moieties into organic molecules. [ ][ ][ ]…”

“…Moreover, MTMs bearing a removable protecting group on the oxoester moiety allow for a controlled addition reaction and subsequent decarboxylation upon removal of the protecting group. Organocatalytic addition reactions between MTMs and electrophiles proceed therefore in the presence of low catalyst loadings (1 – 5 mol‐%) and provide the corresponding addition products in enhanced yields and stereoselectivities compared to reactions with MAHTs . The addition products, among which γ ‐nitrothioesters, β ‐amino thioesters, indoles, dihydrocoumarins and dihydroquinolinones, and oxindoles, [ ][ ] contain aside from the thioester orthogonally addressable functional groups and are therefore valuable synthetic building blocks.…”